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WO2025117682A1 - Cyclin-dependent kinase 2 degraders - Google Patents

Cyclin-dependent kinase 2 degraders Download PDF

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Publication number
WO2025117682A1
WO2025117682A1 PCT/US2024/057671 US2024057671W WO2025117682A1 WO 2025117682 A1 WO2025117682 A1 WO 2025117682A1 US 2024057671 W US2024057671 W US 2024057671W WO 2025117682 A1 WO2025117682 A1 WO 2025117682A1
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Prior art keywords
compound
optionally substituted
pharmaceutically acceptable
acceptable salt
membered
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French (fr)
Inventor
Philip D. RAMSDEN
Kiran BOPPANA
Xiang Liu
Thomas A. Dineen
Jagadeesh MALINENI
Kumaragurubaran NAGASWAMY
Srinivasan Thangathirupathy
Luis Torres
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Blueprint Medicines Corp
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Blueprint Medicines Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

Definitions

  • CDK cyclin-dependent kinase
  • BACKGROUND CDKs are serine/threonine protein kinases that have a central role in cell cycle progression. CDK levels remain relatively constant throughout the cell cycle, and it is the selective activation of specific CDKs allows tor the proper ordering of the steps in cell cycle progression.
  • Cyclins and their binding partner CDKs are key regulatory enzymes driving the cell cycle and cell proliferation.
  • the catalytic activities of CDKs are regulated by their interactions with cyclins (including cyclin A, cyclin B, D-type cyclins, and cyclins E), and with CDK inhibitors (Ding, L. et al., Int. J. Mol. Sci. (2020) 21(6): 1960).
  • cyclins including cyclin A, cyclin B, D-type cyclins, and cyclins E
  • CDK inhibitors Ding, L. et al., Int. J. Mol. Sci. (2020) 21(6): 1960.
  • CDK1 mitotic CDK
  • multiple interphase CDKs including CDK2, CDK4, and CDK6.
  • Cyclin E is part of the core cell cycle machinery as it complexes with CDK2 to move cells through the first gap phase (G1)/synthetic (S) boundary via inactivation of the retinoblastoma tumor suppressor protein (Rb) and release of the transcription factor E2F1.
  • Cyclin E protein levels peak at the G1/S progression, followed by an increase in cyclin A levels in the S phase. Both cyclin E and A interact with and activate CDK2, whereas cyclin A can also bind CDK1.
  • Cyclin D1 is an important cell cycle regulator that activates CDK4/6.
  • CDK4/6 phosphorylate the Rb protein, leading to the release of its repression on the transcription factor E2F1, which is then free to induce the expression of proteins involved in G1 to S phase transition.
  • This fluctuation in cyclin expression results in the oscillation in CDK activity and the tightly regulated cell cycle.
  • the cell cycle is often dysregulated, and such cells then develop dependencies on individual cyclins or CDKs, such as CDK2, providing opportunities for therapeutic targeting (Suski, J.M. et al., Cancer Cell (2021) 39(6): 759-778).
  • CDK2, CDK4, and CDK6 inhibitors Given their key roles in the cell cycle, CDK2, CDK4, and CDK6 inhibitors have been developed for therapeutic cancer targeting.
  • CDK4/6 inhibitors have been approved for the treatment of stage IV or recurrent hormone receptor positive (HR+)/human epidermal growth factor receptor-2 negative (HER2-) breast cancers (Goel, S. et al., Nat. Rev. Cancer (2022) 22(6): 356-372; Sherr, C.J. et al., Cancer Discov. (2016) Cancer Disc.6(4): 353-367).
  • HR+ recurrent hormone receptor positive
  • HER2- human epidermal growth factor receptor-2 negative
  • anti-CDK2 therapies may impact a broad number of cancers that have acquired dependency on CDK2 or harbor gene alterations that require intact CDK2 function for oncogenesis.
  • TPD Targeted protein degradation
  • the warheads bind to the target protein of interest with high affinity.
  • the E3 ubiquitin ligase-binding moieties recruit E3 ligases that ubiquitinate the target protein and prompt the target protein to be recognized and subsequently degraded by 26S proteasome.
  • the two ligands are connected by linkers of various flavors.
  • No CDK2degrader has been approved by FDA so far.
  • a few CDK2 degraders have been reported. For example, Teng and Gray et. al. have reported a CDK2/5 dual degrader TMX-2172 (Teng, M. et al., Angew. Chem. In. Ed.
  • Some of the compounds of the disclosure are orally bioavailable and selectively and catalytically degrade their target protein (e.g., CDK2) over other CDKs and other proteins.
  • CDK2 target protein
  • a compound represented by Formula (I): or a pharmaceutically acceptable salt thereof wherein the definition of each variable is provided below.
  • a compound represented by Formula (Ia): or a pharmaceutically acceptable salt thereof wherein the definition of each variable is provided below.
  • a pharmaceutical composition comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • a method of degrading CDK2 comprising contacting CDK2 with a compound of the disclosure, or a pharmaceutically acceptable salt thereof.
  • a method of treating a cancer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure.
  • a compound of the disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure in the manufacture of a medicament for the treatment of cancers.
  • a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure for use in the treatment of cancers are compounds and compositions that modulate (e.g., by protein degradation) the activity of CDK2.
  • R 1 is selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and 3 to 6-membered heterocyclyl, wherein the C1-C6alkyl is optionally substituted with 1 to 3 R a1 , wherein C3-C6cycloalkyl is optionally substituted with 1 to 4 R b1 , wherein the 3 to 6-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NR c1 and then is optionally substituted on a ring carbon with 1 to 4 R b1 ;
  • R 2 is selected from H, D, C1-C4alkyl, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 3 R a2 ;
  • R 3 is selected from H, D, halo, CN, C1-C4alkyl, and C3-C6cyclco
  • R 1 is selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and 3 to 6-membered heterocyclyl, wherein the C 1 -C 6 alkyl is optionally substituted with 1 to 3 R a1 , wherein C 3 -C 6 cycloalkyl is optionally substituted with 1 to 4 R b1 , wherein the 3 to 6-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NR c1 and then is optionally substituted on a ring carbon with 1 to 4 R b1 ;
  • R 2 is selected from H, D, C 1 -C 4 alkyl, and C 3 -C 6 cyclcoalkyl, wherein the C 1 -C 4 alkyl is optionally substituted with 1 to 3 R a2 ;
  • R 3 is selected from H, D,
  • R 2 is selected from H, D, C1-C4alkyl, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 3 R a2 ;
  • R 3 is selected from H, D, halo, CN, C1-
  • R 1 is selected from C1-C6alkyl, C3-C6cycloalkyl, and 3 to 6-membered heterocyclyl, wherein the C1-C6alkyl is optionally substituted with 1 to 3 R a1 , wherein C3-C6cycloalkyl is optionally substituted with 1 to 3 R b1 , and wherein the 3 to 6-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NR c1 and then is optionally substituted on a ring carbon with 1 to 3 R b1 ;
  • R 2 is selected from H, D, C1-C4alkyl, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 3 R a2 ;
  • R 3 is selected from H, D, halo, CN
  • the compound described herein is represented by Formula (IV): or a pharmaceutically acceptable salt thereof, wherein t is an integer from 0 to 4, and wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , ring A, L 1 , X 1 , L 2 , X 2 , L 3 , X 3 , L 4 , W, and R b8 are as defined herein.
  • the compound described herein is represented by Formula (IVa): or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , ring A, L 1 , X 1 , L 2 , X 2 , L 3 , X 3 , L 4 , t, and R b8 are as defined herein.
  • the compound described herein is represented by Formula (IVb): or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , ring A, L 1 , X 1 , L 2 , X 2 , L 3 , X 3 , L 4 , t, and R b8 are as defined herein.
  • the compound described herein is represented by Formula ( or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , ring A, L 1 , X 1 , L 2 , X 2 , L 3 , X 3 , L 4 , t, and R b8 are as defined herein.
  • the compound described herein is represented by Formula (IVd): or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , ring A, L 1 , X 1 , L 2 , X 2 , L 3 , X 3 , L 4 , t, and R b8 are as defined herein.
  • the compound described herein is represented by Formula (V):
  • the compound described herein is represented by Formula (Va): (Va), or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , ring A, L 1 , X 1 , L 2 , X 2 , L 3 , X 3 , L 4 , t, and R b8 are as defined herein.
  • the compound described herein is represented by Formula (Vb): (Vb), or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , ring A, L 1 , X 1 , L 2 , X 2 , L 3 , X 3 , L 4 , t, and R b8 are as defined herein.
  • the compound described herein is represented by Formula (Vc):
  • the compound described herein is represented by Formula (Vd): or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , ring A, L 1 , X 1 , L 2 , X 2 , L 3 , X 3 , L 4 , t, and R b8 are as defined herein.
  • the compound described herein is represented by Formula (Ve): (Ve), or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , ring A, L 1 , X 1 , L 2 , X 2 , L 3 , X 3 , L 4 , t, and R b8 are as defined herein.
  • the compound described herein is represented by Formula (Vf):
  • R 1 is selected from C1-C6alkyl, C3-C6cycloalkyl, and 3 to 6-membered heterocyclyl, wherein the C 1 -C 6 alkyl is optionally substituted with 1 or 2 R a1 , and wherein the 3 to 6- membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NR c1 ;
  • R 2 is selected from H, D, C 1 -C 4 alkyl, and C 3 -C 6 cyclcoalkyl, wherein the C 1 -C 6 alkyl is optionally substituted with 1 or 2 R a2 ;
  • R 3 is selected from H, D, C1-C4alkyl, and C3-C6cyclcoalkyl;
  • R 4 is selected from H, D, halo, OH, CN, C1-C4alkyl,
  • R 1 is C1-C6alkyl, wherein the C1-C6alkyl is optionally substituted with 1 or 2 R a1 ;
  • R 2 is selected from H, D, and C1-C4alkyl, wherein the C1-C6alkyl is optionally substituted with 1 or 2 R a2 ;
  • R 3 is selected from H, D, and C 1 -C 4 alkyl;
  • R 4 is selected from H, D, halo, OH, CN, and C 1 -C 4 alkyl, wherein the C 1 -C 4 alkyl is optionally substituted with 1 to 3 groups each independently selected from D, halo, OH, and CN;
  • R 5 is selected from H, D, halo, OH, CN, and C1-C4alkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 3 groups each independently selected from D, halo, OH, and CN;
  • R 5 is selected from
  • R 1 is C1-C6alkyl, wherein the C1-C6alkyl is optionally substituted with 1 or 2 R a1 ;
  • R 2 is selected from H, D, and C1-C4alkyl;
  • R 3 is selected from H, D, and C1-C4alkyl;
  • R 4 is selected from H, D, halo, CN, and C1-C4alkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 3 groups each independently selected from D, halo, OH, and CN;
  • R 5 is selected from H, D, and C 1 -C 4 alkyl;
  • R 6 is H or D;
  • R 7 is selected from H, D, and C1-C4alkyl;
  • Ring A is selected from 6-membered heterocyclyl, 6-membered aryl, and 6-membered heteroaryl, wherein the 6-membere
  • the compound described herein is represented by Formula (VI): or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , ring A, L 1 , X 1 , L 2 , X 2 , L 4 , ring B, Y 1 , and m are as defined herein.
  • the compound described herein is represented by Formula (VII):
  • the compound described herein is represented by Formula (VIIa): (VIIa), or a pharmaceutically acceptable salt thereof, and wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , ring A, L 1 , X 1 , L 2 , X 2 , L 4 , R b8 , and t are as defined herein.
  • the compound described herein is represented by Formula (VIIb): or a pharmac L 1 , X 1 , L 2 , X 2 , L 4 , R b8 , and t are as defined herein.
  • the compound described herein is represented by Formula (VIII):
  • t is an integer from 0 to 3
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , ring A, L 1 , X 1 , L 2 , X 2 , L 4 , Y 2 , R b8 , and t are as defined herein.
  • the compound described herein is represented by Formula (VIIIa): (VIIIa), or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , ring A, L 1 , X 1 , L 2 , X 2 , L 4 , R b8 , and t are as defined herein.
  • the compound described herein is represented by Formula (VIIIb): (VIIIb), or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , ring A, L 1 , X 1 , L 2 , X 2 , L 4 , R b8 , and t are as defined herein.
  • the compound described herein is represented by Formula (VIIIc):
  • the compound described herein is represented by Formula (VIIId): or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , ring A, L 1 , X 1 , L 2 , X 2 , L 4 , R b8 , and t are as defined herein.
  • the compound described herein is represented by Formula (VIIId): or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , ring A, L 1 , X 1 , L 2 , X 2 , L 4 , R b8 , and t are as defined herein.
  • the compound described herein is represented by Formula (VIIIe): or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , ring A, L 1 , X 1 , L 2 , X 2 , L 4 , R b8 , and t are as defined herein.
  • the compound described herein is represented by Formula (VIIIf): (VIIIf), or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , ring A, L 1 , X 1 , L 2 , X 2 , L 4 , R b8 , and t are as defined herein.
  • the compound described herein is represented by Formula (IX): or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , ring A, L 1 , X 1 , L 2 , X 2 , L 4 , R b8 , and t are as defined herein.
  • R 1 is selected from C1-C6alkyl, C3-C6cycloalkyl, and 3 to 6-membered heterocyclyl, wherein the C 1 -C 6 alkyl is optionally substituted with 1 or 2 R a1 , and wherein the 3 to 6- membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NR c1 ;
  • R 2 is selected from H, D, C 1 -C 4 alkyl, and C 3 -C 6 cyclcoalkyl, wherein the C 1 -C 6 alkyl is optionally substituted with 1 or 2 R a2 ;
  • R 3 is selected from H, D, C 1 -C 4 alkyl, and C 3 -C 6 cyclcoalkyl;
  • R 4 is selected from H, D, halo, OH, CN, C1-C4alkyl,
  • R 1 is C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted with 1 or 2 R a1 ;
  • R 2 is selected from H, D, and C1-C4alkyl, wherein the C1-C6alkyl is optionally substituted with 1 or 2 R a2 ;
  • R 3 is selected from H, D, and C1-C4alkyl;
  • R 4 is selected from H, D, halo, OH, CN, and C 1 -C 4 alkyl, wherein the C 1 -C 4 alkyl is optionally substituted with 1 to 3 groups each independently selected from D, halo, OH, and CN;
  • R 5 is selected from H, D, halo, OH, CN, and C1-C4alkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 3 groups each independently selected
  • R 1 is selected from C1-C6alkyl, C3-C6cycloalkyl, and 3 to 6- membered heterocyclyl, wherein the C 1 -C 6 alkyl is optionally substituted with 1 or 2 R a1 , and wherein the 3 to 6-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NR c1 .
  • R 1 is C1-C6alkyl optionally substituted with 1 to 3 R a1 .
  • R 1 is C1-C6alkyl optionally substituted with 1 or 2 R a1 .
  • R 1 is C1-C6alkyl optionally substituted with OH. In some embodiments, R 1 is C1-C6alkyl. In some embodiments, R 1 is CH3 or CH2C(CH3)2OH. In some embodiments, R 1 is CH3. In some embodiments, R 1 is CH2C(CH3)2OH. In some embodiments, R 2 is selected from H, D, and C1-C4alkyl, wherein the C1- C4alkyl is optionally substituted with 1 to 3 R a2 . In some embodiments, R 2 is H or C1-C4alkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 3 R a2 .
  • R 2 is H, D, or C 1 -C 4 alkyl. In some embodiments, R 2 is H or D. In some embodiments, R 2 is H. In some embodiments, R 3 is selected from H, D, halo, CN, and C1-C4alkyl. In some embodiments, R 3 is H. In some embodiments, R 3 is H or D. In some embodiments, R 4 is selected from H, D, halo, OH, CN, C1-C4alkyl, and C1- C 4 alkoxy, wherein the C 1 -C 4 alkyl and C 1 -C 4 alkoxy are each optionally substituted with 1 to 4 groups each independently selected from D, halo, OH and CN.
  • R 4 is C 1 -C 4 alkyl, CN, or halo, wherein said C 1 -C 4 alkyl is optionally substituted with 1 to 3 groups each independently selected from halo.
  • R 4 is CH3, CHF2, CF3, CN, or Cl.
  • R 4 is CH 3 .
  • R 4 is CHF 2 .
  • R 4 is CF3.
  • R 4 is CN.
  • R 4 is Cl.
  • R 4 is H, D, CH3, CHF2, CF3, CN, or Cl.
  • R 4 is H, CH 3 , CHF 2 , CF 3 , CN, or Cl.
  • R 4 is H or D. In some embodiments, R 4 is H. In some embodiments, R 5 is selected from H, D, halo, OH, CN, C 1 -C 4 alkyl, and C 1 - C 4 alkoxy, wherein the C 1 -C 4 alkyl and C 1 -C 4 alkoxy are each optionally substituted with 1 to 4 groups each independently selected from D, halo, OH and CN. In some embodiments, R 5 is selected from H, D, halo, OH, and CN. In some embodiments, R 5 is H or D. In some embodiments, R 5 is H. In some embodiments, R 6 is H. In some embodiments, R 6 is D.
  • R 7 is selected from H, D, and C1-C4alkyl. In some embodiments, R 7 is H or C 1- C 4 alkyl. In some embodiments, R 7 is methyl. In some embodiments, R 7 is H. In some embodiments, R 7 is H, D, or C1-C4alkyl. In some embodiments, R 7 is H, D, or methyl. In some embodiments, R 7 is H or methyl.
  • Ring A is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, C5-C12spirocycloalkyl, 5 to 12-membered spiroheterocyclyl, 6 to 12-membered aryl, and 5 or 6-membered heteroaryl, wherein the C3-C6cycloalkyl, C5-C12spirocycloalkyl, and 6 to 12-membered aryl are each optionally substituted with 1 to 4 R b2 , and wherein the 3 to 6-membered heterocyclyl, 5 to 12-membered spiroheterocyclyl, and 5 or 6-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NR c2 and then are optionally substituted on a ring carbon with 1 to 4 R b2 .
  • Ring A is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, C 5 -C 12 spirocycloalkyl, 5 to 12-membered spiroheterocyclyl, 6 to 12-membered aryl, and 5 or 6-membered heteroaryl, wherein the C3-C6cycloalkyl, C5-C12spirocycloalkyl, and 6 to 12-membered aryl are each optionally substituted with 1 or 2 R b2 , and wherein the 3 to 6-membered heterocyclyl, 5 to 12-membered spiroheterocyclyl, and 5 or 6-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NR c2 and then are optionally substituted on a ring carbon with 1 or 2 R b2 .
  • Ring A is selected from C 3 -C 6 cycloalkyl, 3 to 6-membered heterocyclyl, C5-C12spirocycloalkyl, 5 to 12-membered spiroheterocyclyl, phenyl, and 5 or 6- membered heteroaryl, wherein the C3-C6cycloalkyl, C5-C12spirocycloalkyl, and phenyl are each optionally substituted with 1 to 4 R b2 , and wherein the 3 to 6-membered heterocyclyl, 5 to 12-membered spiroheterocyclyl, and 5 or 6-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NR c2 and then are optionally substituted on a ring carbon with 1 to 4 R b2 .
  • Ring A is selected from C 3 -C 6 cycloalkyl, 3 to 6-membered heterocyclyl, C5-C12spirocycloalkyl, 5 to 12-membered spiroheterocyclyl, phenyl, and 5 or 6- membered heteroaryl, wherein the C 3 -C 6 cycloalkyl, C 5 -C 12 spirocycloalkyl, and phenyl are each optionally substituted with 1 or 2 R b2 , and wherein the 3 to 6-membered heterocyclyl, 5 to 12-membered spiroheterocyclyl, and 5 or 6-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NR c2 and then are optionally substituted on a ring carbon with 1 or 2 R b2 .
  • Ring A is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, C 5 -C 12 spirocycloalkyl, 5 to 12-membered spiroheterocyclyl, phenyl, and 5 or 6- membered heteroaryl, wherein the C3-C6cycloalkyl, C5-C12spirocycloalkyl, and phenyl are each optionally substituted with R b2 , and wherein the 3 to 6-membered heterocyclyl, 5 to 12- membered spiroheterocyclyl, and 5 or 6-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NR c2 and then are optionally substituted on a ring carbon with R b2 .
  • Ring A is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, C9-C12spirocycloalkyl, 9 to 12-membered spiroheterocyclyl, phenyl, and 5 or 6- membered heteroaryl, wherein the C3-C6cycloalkyl, C9-C12spirocycloalkyl, and phenyl are each optionally substituted with 1 to 4 R b2 , and wherein the 3 to 6-membered heterocyclyl, 9 to 12-membered spiroheterocyclyl, and 5 or 6-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NR c2 and then are optionally substituted on a ring carbon with 1 to 4 R b2 .
  • Ring A is selected from C 3 -C 6 cycloalkyl, 3 to 6-membered heterocyclyl, C 9 -C 12 spirocycloalkyl, 9 to 12-membered spiroheterocyclyl, phenyl, and 5 or 6-membered heteroaryl, wherein the C3-C6cycloalkyl, C9- C 12 spirocycloalkyl, and phenyl are each optionally substituted with 1 or 2 R b2 , and wherein the 3 to 6-membered heterocyclyl, 9 to 12-membered spiroheterocyclyl, and 5 or 6-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NR c2 and then are optionally substituted on a ring carbon with 1 or 2 R b2 .
  • Ring A is selected from C 3 -C 6 cycloalkyl, 3 to 6-membered heterocyclyl, C 9 - C12spirocycloalkyl, 9 to 12-membered spiroheterocyclyl, phenyl, and 5 or 6-membered heteroaryl, wherein the C3-C6cycloalkyl, C9-C12spirocycloalkyl, and phenyl are each optionally substituted with R b2 , and wherein the 3 to 6-membered heterocyclyl, 9 to 12- membered spiroheterocyclyl, and 5 or 6-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NR c2 and then are optionally substituted on a ring carbon with R b2 .
  • Ring A is selected from C 3 -C 6 cycloalkyl optionally substituted with 1 to 4 R b2 . In some embodiments, Ring A is selected from C3-C6cycloalkyl optionally substituted with 1 or 2 R b2 . In some embodiments, Ring A is selected from C 3 -C 6 cycloalkyl optionally substituted with R b2 . In some embodiments, Ring A is C 3 -C 6 cycloalkyl. In some embodiments, Ring A is cyclohexyl optionally substituted with 1 to 4 R b2 . In some embodiments, Ring A is cyclohexyl optionally substituted with 1 or 2 R b2 .
  • Ring A is cyclohexyl optionally substituted with R b2 . In some embodiments, Ring A is cyclohexyl. In some embodiments, Ring A is 6 to 12-membered aryl optionally substituted with 1 to 4 R b2 . In some embodiments, Ring A is 6 to 12-membered aryl optionally substituted with 1 or 2 R b2 . In some embodiments, Ring A is 6 to 12-membered aryl optionally substituted with R b2 . In some embodiments, Ring A is 6 to 12-membered aryl. In some embodiments, Ring A is phenyl optionally substituted with 1 to 4 R b2 .
  • Ring A is phenyl optionally substituted with 1 or 2 R b2 . In some embodiments, Ring A is phenyl optionally substituted with R b2 . In some embodiments, Ring A is phenyl. In some embodiments, Ring A is selected from 3 to 12-membered heterocyclyl optionally substituted with 1 to 4 R b2 . In some embodiments, Ring A is selected from 3 to 12- membered heterocyclyl optionally substituted with 1 or 2 R b2 . In some embodiments, Ring A is selected from 3 to 12-membered heterocyclyl optionally substituted with R b2 . In some embodiments, Ring A is selected from 3 to 12-membered heterocyclyl. In some embodiments, Ring A is selected from 3 to 12-membered heterocyclyl.
  • Ring A is selected from 3 to 6-membered heterocyclyl optionally substituted with 1 to 4 R b2 . In some embodiments, Ring A is selected from 3 to 6- membered heterocyclyl optionally substituted with 1 or 2 R b2 . In some embodiments, Ring A is selected from 3 to 6-membered heterocyclyl optionally substituted with R b2 . In some embodiments, Ring A is selected from 3 to 6-membered heterocyclyl. In some embodiments, Ring A is piperidinyl optionally substituted with 1 to 4 R b2 . In some embodiments, Ring A is piperidinyl optionally substituted with 1 or 2 R b2 .
  • Ring A is piperidinyl optionally substituted with R b2 . In some embodiments, Ring A is piperidinyl. In some embodiments, Ring A is selected from 5 to 12-membered spiroheterocyclyl optionally substituted with 1 to 4 R b2 . In some embodiments, Ring A is selected from 5 to 12- membered spiroheterocyclyl optionally substituted with 1 or 2 R b2 . In some embodiments, Ring A is selected from 5 to 12-membered spiroheterocyclyl optionally substituted with R b2 . In some embodiments, Ring A is selected from 5 to 12-membered spiroheterocyclyl.
  • Ring A is 9 to 12-membered spiroheterocyclyl optionally substituted with 1 to 4 R b2 . In some embodiments, Ring A is 9 to 12-membered spiroheterocyclyl optionally substituted with 1 or 2 R b2 . In some embodiments, Ring A is 9 to 12-membered spiroheterocyclyl optionally substituted with R b2 . In some embodiments, Ring A is 9 to 12-membered spiroheterocyclyl. In some embodiments, Ring A is 6 to 11-membered spiroheterocyclyl optionally substituted with 1 to 4 R b2 .
  • Ring A is 6 to 11-membered spiroheterocyclyl optionally substituted with 1 or 2 R b2 . In some embodiments, Ring A is 6 to 11-membered spiroheterocyclyl optionally substituted with R b2 . In some embodiments, Ring A is 6 to 11-membered spiroheterocyclyl. In some embodiments, Ring A is 2-azaspiro[3.3]heptanyl optionally substituted with 1 to 4 R b2 . In some embodiments, Ring A is 2-azaspiro[3.3]heptanyl optionally substituted with 1 or 2 R b2 .
  • Ring A is 2-azaspiro[3.3]heptanyl optionally substituted with R b2 . In some embodiments, Ring A is 2-azaspiro[3.3]heptanyl. In some embodiments, Ring A is selected from 5 to 12-membered heteroaryl optionally substituted with 1 to 4 R b2 . In some embodiments, Ring A is selected from 5 to 12- membered heteroaryl optionally substituted with 1 or 2 R b2 . In some embodiments, Ring A is selected from 5 to 12-membered heteroaryl optionally substituted with R b2 . In some embodiments, Ring A is selected from 5 to 12-membered heteroaryl.
  • Ring A is selected from 5 or 6-membered heteroaryl optionally substituted with 1 to 4 R b2 . In some embodiments, Ring A is selected from 5 or 6-membered heteroaryl optionally substituted with 1 or 2 R b2 . In some embodiments, Ring A is selected from 5 or 6-membered heteroaryl optionally substituted with R b2 . In some embodiments, Ring A is selected from 5 or 6-membered heteroaryl. In some embodiments, Ring A is pyridinyl optionally substituted with 1 to 4 R b2 . In some embodiments, Ring A is pyridinyl optionally substituted with 1 or 2 R b2 .
  • Ring A is pyridinyl optionally substituted with R b2 . In some embodiments, Ring A is pyridinyl. In some embodiments, Ring A is cyclohexyl, phenyl, piperidinyl, 2- azaspiro[3.3]heptanyl, or pyridinyl, each of which is optionally substituted with 1 to 4 R b2 . In some embodiments, Ring A is cyclohexyl, phenyl, piperidinyl, 2-azaspiro[3.3]heptanyl, or pyridinyl, each of which is optionally substituted with 1 or 2 R b2 .
  • Ring A is cyclohexyl, phenyl, piperidinyl, 2-azaspiro[3.3]heptanyl, or pyridinyl, each of which is optionally substituted with R b2 .
  • Ring A is cyclohexyl, phenyl, piperidinyl, 2-azaspiro[3.3]heptanyl, or pyridinyl.
  • R b2 is selected from C 1- C 4 alkyl and halo.
  • R b2 is C 1- C 4 alkyl.
  • R b2 is halo.
  • R b2 is selected from F and methyl.
  • X 1 is selected from C3-C10cycloalkyl, 3 to 12-membered heterocyclyl, 6 to 12-membered aryl, and 5 to 12- membered heteroaryl, wherein the C3-C10cycloalkyl and 6 to 12-membered aryl are each optionally substituted with 1 to 4 R b3 , and wherein the 3 to 12-membered heterocyclyl and 5 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NR c4 and then are optionally substituted on a ring carbon with 1 to 4 R b3 .
  • X 1 is selected from covalent bond, C3-C6cycloalkyl, 3 to 6- membered heterocyclyl, phenyl, and 5 or 6-membered heteroaryl, wherein the C 3 - C6cycloalkyl and phenyl are each optionally substituted with 1 to 3 R b3 , and wherein the 3 to 6-membered heterocyclyl and 5 or 6-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NR c4 and then are optionally substituted on a ring carbon with 1 to 3 R b3 .
  • X 1 is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, phenyl, and 5 or 6-membered heteroaryl, wherein the C 3 -C 6 cycloalkyl and phenyl are each optionally substituted with 1 to 3 R b3 , and wherein the 3 to 6-membered heterocyclyl and 5 or 6-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NR c4 and then are optionally substituted on a ring carbon with 1 to 3 R b3 .
  • X 1 is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, and 5 or 6-membered heteroaryl, wherein the C 3 -C 6 cycloalkyl is optionally substituted with 1 to 3 R b3 , wherein the 3 to 6-membered heterocyclyl and 5 or 6-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NR c4 and then are optionally substituted on a ring carbon with 1 to 3 R b3 .
  • X 1 is selected from C3-C10cycloalkyl optionally substituted with 1 to 3 R b3 .
  • X 1 is selected from C3-C10cycloalkyl optionally substituted with 1 or 2 R b3 . In some embodiments, X 1 is selected from C3-C10cycloalkyl optionally substituted with R b3 . In some embodiments, X 1 is selected from C 3 -C 10 cycloalkyl. In some embodiments, X 1 is selected from C3-C6cycloalkyl optionally substituted with 1 to 3 R b3 . In some embodiments, X 1 is selected from C 3 -C 6 cycloalkyl optionally substituted with 1 or 2 R b3 .
  • X 1 is selected from C3-C6cycloalkyl optionally substituted with R b3 . In some embodiments, X 1 is selected from C 3 -C 6 cycloalkyl. In some embodiments, X 1 is cyclobutyl or cyclohexyl, each optionally substituted with 1 to 3 R b3 . In some embodiments, X 1 is cyclobutyl or cyclohexyl, each optionally substituted with 1 or 2 R b3 . In some embodiments, X 1 is cyclobutyl or cyclohexyl, each optionally substituted with R b3 .
  • X 1 is cyclobutyl or cyclohexyl. In some embodiments, X 1 is cyclobutyl. In some embodiments, X 1 is cyclohexyl. In some embodiments, X 1 is selected from 3 to 12-membered heterocyclyl optionally substituted with 1 to 3 R b3 . In some embodiments, X 1 is selected from 3 to 12-membered heterocyclyl optionally substituted with 1 or 2 R b3 . In some embodiments, X 1 is selected from 3 to 12-membered heterocyclyl optionally substituted with R b3 . In some embodiments, X 1 is selected from 3 to 12-membered heterocyclyl.
  • X 1 is selected from 3 to 6-membered heterocyclyl optionally substituted with 1 to 3 R b3 . In some embodiments, X 1 is selected from 3 to 6-membered heterocyclyl optionally substituted with 1 or 2 R b3 . In some embodiments, X 1 is selected from 3 to 6-membered heterocyclyl optionally substituted with R b3 . In some embodiments, X 1 is selected from 3 to 6-membered heterocyclyl. In some embodiments, X 1 is pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with 1 to 3 R b3 .
  • X 1 is pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with 1 or 2 R b3 . In some embodiments, X 1 is pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with R b3 . In some embodiments, X 1 is pyrrolidinyl, piperidinyl, or piperazinyl. In some embodiments, X 1 is selected from 5 to 12-membered heteroaryl optionally substituted with 1 to 3 R b3 . In some embodiments, X 1 is selected from 5 to 12-membered heteroaryl optionally substituted with 1 or 2 R b3 .
  • X 1 is selected from 5 to 12-membered heteroaryl optionally substituted with R b3 . In some embodiments, X 1 is selected from 5 to 12-membered heteroaryl. In some embodiments, X 1 is selected from 5 or 6-membered heteroaryl optionally substituted with 1 to 3 R b3 . In some embodiments, X 1 is selected from 5 or 6-membered heteroaryl optionally substituted with 1 or 2 R b3 . In some embodiments, X 1 is selected from 5 or 6-membered heteroaryl optionally substituted with R b3 . In some embodiments, X 1 is selected from 5 or 6-membered heteroaryl.
  • X 1 is 1,2,3-triazolyl optionally substituted with 1 or 2 R b3 . In some embodiments, X 1 is 1,2,3-triazolyl optionally substituted with R b3 . In some embodiments, X 1 is 1,2,3-triazolyl.
  • L 2 is - *(CH2CH2O)r-(CH2)n-.
  • L 2 is -(CH2)n-.
  • L 2 is - CH 2 -.
  • L 2 is -CH 2 CH 2 -.
  • L 2 is -*(CH 2 ) n -O- (CH2)n-.
  • X 2 is a covalent bond.
  • X 2 is selected from C 3 -C 10 cycloalkyl, 3 to 12-membered heterocyclyl, 6 to 12-membered aryl, and 5 to 12- membered heteroaryl, wherein the C3-C10cycloalkyl and 6 to 12-membered aryl are each optionally substituted with 1 to 4 R b4 , and wherein the 3 to 12-membered heterocyclyl and 5 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NR c6 and then are optionally substituted on a ring carbon with 1 to 4 R b4 .
  • X 2 is selected from C3-C10cycloalkyl, 3 to 12-membered heterocyclyl, and 5 to 12-membered heteroaryl, wherein the C 3 -C 10 cycloalkyl is optionally substituted with 1 to 4 R b4 , and wherein the 3 to 12-membered heterocyclyl and 5 to 12- membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NR c6 and then are optionally substituted on a ring carbon with 1 to 4 R b4 .
  • X 2 is selected from C3-C10cycloalkyl, 3 to 12-membered heterocyclyl, and 5 to 12-membered heteroaryl, wherein the C3-C10cycloalkyl is optionally substituted with 1 or 2 R b4 , and wherein the 3 to 12-membered heterocyclyl and 5 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NR c6 and then are optionally substituted on a ring carbon with 1 or 2 R b4 .
  • X 2 is selected from C 3 -C 10 cycloalkyl, 3 to 12-membered heterocyclyl, and 5 to 12-membered heteroaryl, wherein the C3-C10cycloalkyl is optionally substituted with R b4 , and wherein the 3 to 12- membered heterocyclyl and 5 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NR c6 and then are optionally substituted on a ring carbon with R b4 .
  • X 2 is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, and 5 to 6-membered heteroaryl, wherein the C 3 -C 6 cycloalkyl is optionally substituted with 1 to 4 R b4 , and wherein the 3 to 6-membered heterocyclyl and 5 to 6- membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NR c6 and then are optionally substituted on a ring carbon with 1 to 4 R b4 .
  • X 2 is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, and 5 to 6- membered heteroaryl, wherein the C 3 -C 6 cycloalkyl is optionally substituted with 1 or 2 R b4 , and wherein the 3 to 6-membered heterocyclyl and 5 to 6-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NR c6 and then are optionally substituted on a ring carbon with 1 or 2 R b4 .
  • X 2 is selected from C3- C 6 cycloalkyl, 3 to 6-membered heterocyclyl, and 5 to 6-membered heteroaryl, wherein the C3-C6cycloalkyl is optionally substituted with R b4 , and wherein the 3 to 6-membered heterocyclyl and 5 to 6-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NR c6 and then are optionally substituted on a ring carbon with R b4 .
  • X 2 is selected from C 3 -C 6 cycloalkyl, 3 to 6- membered heterocyclyl, and 5 to 6-membered heteroaryl, wherein the 3 to 6-membered heterocyclyl and 5 to 6-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NR c6 .
  • X 2 is selected from C 3 -C 10 cycloalkyl optionally substituted with 1 to 3 R b4 .
  • X 2 is selected from C3-C10cycloalkyl optionally substituted with 1 or 2 R b4 .
  • X 2 is selected from C 3 -C 10 cycloalkyl optionally substituted with R b4 . In some embodiments, X 2 is selected from C3-C10cycloalkyl. In some embodiments, X 2 is selected from C 3 -C 6 cycloalkyl optionally substituted with 1 to 3 R b4 . In some embodiments, X 2 is selected from C3-C6cycloalkyl optionally substituted with 1 or 2 R b4 . In some embodiments, X 2 is selected from C3-C6cycloalkyl optionally substituted with R b4 . In some embodiments, X 2 is selected from C3-C6cycloalkyl.
  • X 2 is cyclohexyl optionally substituted with 1 to 3 R b4 . In some embodiments, X 2 is cyclohexyl optionally substituted with R b4 . In some embodiments, X 2 is cyclohexyl. In some embodiments, X 2 is selected from 3 to 12-membered heterocyclyl optionally substituted with 1 to 3 R b4 . In some embodiments, X 2 is selected from 3 to 12-membered heterocyclyl optionally substituted with R b4 . In some embodiments, X 2 is selected from 3 to 12-membered heterocyclyl.
  • X 2 is selected from 3 to 6-membered heterocyclyl optionally substituted with 1 to 3 R b4 . In some embodiments, X 2 is selected from 3 to 6-membered heterocyclyl optionally substituted with R b4 . In some embodiments, X 2 is selected from 3 to 6-membered heterocyclyl. In some embodiments, X 2 is azetidinyl, piperidinyl, or piperazinyl, each optionally substituted with 1 to 3 R b4 . In some embodiments, X 2 is azetidinyl, piperidinyl, or piperazinyl, each optionally substituted with R b4 .
  • X 2 is azetidinyl, piperidinyl, or piperazinyl. In some embodiments, X 2 is azetidinyl. In some embodiments, X 2 is piperidinyl. In some embodiments, X 2 is piperazinyl. In some embodiments, X 2 is selected from 5 to 12-membered heteroaryl optionally substituted with 1 to 3 R b4 . In some embodiments, X 2 is selected from 5 to 12-membered heteroaryl optionally substituted with 1 or 2 R b4 . In some embodiments, X 2 is selected from 5 to 12-membered heteroaryl optionally substituted with R b4 .
  • X 2 is selected from 5 to 12-membered heteroaryl. In some embodiments, X 2 is selected from 5 or 6-membered heteroaryl optionally substituted with 1 to 3 R b4 . In some embodiments, X 2 is selected from 5 or 6-membered heteroaryl optionally substituted with 1 or 2 R b4 . In some embodiments, X 2 is selected from 5 or 6-membered heteroaryl optionally substituted with R b4 . In some embodiments, X 2 is selected from 5 or 6-membered heteroaryl. In some embodiments, X 2 is 1,2,3-triazolyl optionally substituted with 1 or 2 R b4 .
  • X 3 is selected from 3 to 12-membered heterocyclyl having 1 to 3 ring heteroatoms each independently selected from O, S, N, and NR c9 and then is optionally substituted on a ring carbon with 1 to 3 R b6 . In some embodiments, X 3 is selected from 3 to 12-membered heterocyclyl having 1 to 3 ring heteroatoms each independently selected from O, S, N, and NR c9 and then is optionally substituted on a ring carbon with 1 or 2 R b6 .
  • X 3 is selected from 3 to 12-membered heterocyclyl having 1 to 3 ring heteroatoms each independently selected from O, S, N, and NR c9 and then is optionally substituted on a ring carbon with R b6 .
  • X 3 is selected from 3 to 12- membered heterocyclyl having 1 to 3 ring heteroatoms each independently selected from O, S, N, and NR c9 .
  • X 3 is selected from 3 to 6-membered heterocyclyl having 1 to 3 ring heteroatoms each independently selected from O, S, N, and NR c9 and then is optionally substituted on a ring carbon with 1 to 3 R b6 .
  • X 3 is selected from 3 to 6- membered heterocyclyl having 1 to 3 ring heteroatoms each independently selected from O, S, N, and NR c9 and then is optionally substituted on a ring carbon with 1 or 2 R b6 . In some embodiments, X 3 is selected from 3 to 6-membered heterocyclyl having 1 to 3 ring heteroatoms each independently selected from O, S, N, and NR c9 and then is optionally substituted on a ring carbon with R b6 . In some embodiments, X 3 is selected from 3 to 6- membered heterocyclyl having 1 to 3 ring heteroatoms each independently selected from O, S, N, and NR c9 .
  • X 3 is selected from piperazinyl and piperidinyl, each optionally substituted on a ring carbon with 1 to 3 R b6 . In some embodiments, X 3 is selected from piperazinyl and piperidinyl, each optionally substituted on a ring carbon with 1 or 2 R b6 . In some embodiments, X 3 is selected from piperazinyl and piperidinyl, each optionally substituted on a ring carbon with R b6 . In some embodiments, X 3 is selected from piperazinyl and piperidinyl. In some embodiments, X 3 is piperazinyl. In some embodiments, X 3 is piperidinyl. In some embodiments, X 3 is piperidinyl.
  • X 2 – L 3 – X 3 form a C 5 -C 12 spirocycloalkyl or 5 to 12-membered spiroheterocyclyl, wherein the C5-C12spirocycloalkyl is optionally substituted with 1 to 4 R b7 , and wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NR c10 and then are optionally substituted on a ring carbon with 1 to 4 R b7 .
  • X 2 – L 3 – X 3 form a C5-C12spirocycloalkyl or 5 to 12-membered spiroheterocyclyl, wherein the C5-C12spirocycloalkyl is optionally substituted with 1 or 2 R b7 , and wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NR c10 and then are optionally substituted on a ring carbon with 1 or 2 R b7 .
  • X 2 – L 3 – X 3 form a C 5 -C 12 spirocycloalkyl or 5 to 12-membered spiroheterocyclyl, wherein the C 5 - C12spirocycloalkyl is optionally substituted with R b7 , and wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NR c10 and then are optionally substituted on a ring carbon with R b7 .
  • X 2 – L 3 – X 3 form a C 5 -C 12 spirocycloalkyl or 5 to 12-membered spiroheterocyclyl, wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NR c10 .
  • X 2 – L 3 – X 3 form a 5 to 12-membered spiroheterocyclyl, wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NR c10 and then are optionally substituted on a ring carbon with 1 to 4 R b7 .
  • X 2 – L 3 – X 3 form a 5 to 12-membered spiroheterocyclyl, wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NR c10 and then are optionally substituted on a ring carbon with 1 or 2 R b7 .
  • X 2 – L 3 – X 3 form a 5 to 12-membered spiroheterocyclyl, wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NR c10 and then are optionally substituted on a ring carbon with R b7 .
  • X 2 – L 3 – X 3 form a 5 to 12-membered spiroheterocyclyl, wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NR c10 .
  • X 2 – L 3 – X 3 form a 10 or 11-membered spiroheterocyclyl, wherein the 10 or 11-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NR c10 and then are optionally substituted on a ring carbon with 1 to 4 R b7 .
  • X 2 – L 3 – X 3 form a 10 or 11-membered spiroheterocyclyl, wherein the 10 or 11-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NR c10 and then are optionally substituted on a ring carbon with 1 or 2 R b7 .
  • X 2 – L 3 – X 3 form a 10 or 11-membered spiroheterocyclyl, wherein the 10 or 11-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NR c10 and then are optionally substituted on a ring carbon with R b7 .
  • X 2 – L 3 – X 3 form a 10 or 11-membered spiroheterocyclyl, wherein the 10 or 11-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NR c10 .
  • two X 3 form a C5-C12spirocycloalkyl or 5 to 12-membered spiroheterocyclyl, wherein the C 5 -C 12 spirocycloalkyl is optionally substituted with 1 to 4 R b7 , and wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NR c10 and then are optionally substituted on a ring carbon with 1 to 4 R b7 .
  • two X 3 form a C5-C12spirocycloalkyl or 5 to 12-membered spiroheterocyclyl, wherein the C 5 -C 12 spirocycloalkyl is optionally substituted with 1 or 2 R b7 , and wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NR c10 and then are optionally substituted on a ring carbon with 1 or 2 R b7 .
  • two X 3 form a C5- C 12 spirocycloalkyl or 5 to 12-membered spiroheterocyclyl, wherein the C 5 - C12spirocycloalkyl is optionally substituted with R b7 , and wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NR c10 and then are optionally substituted on a ring carbon with R b7 .
  • two X 3 form a C5-C12spirocycloalkyl or 5 to 12-membered spiroheterocyclyl, wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NR c10 .
  • two X 3 form a 5 to 12-membered spiroheterocyclyl, wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NR c10 and then are optionally substituted on a ring carbon with 1 to 4 R b7 .
  • two X 3 form 3,9-diazaspiro[5.5]undecane optionally substituted on a ring carbon with 1 to 4 R b7 . In some embodiments, two X 3 form 3,9- diazaspiro[5.5]undecane optionally substituted on a ring carbon with 1 or 2 R b7 . In some embodiments, two X 3 form 3,9-diazaspiro[5.5]undecane optionally substituted on a ring carbon with R b7 . In some embodiments, two X 3 form 3,9-diazaspiro[5.5]undecane. In some embodiments, L 4 is a covalent bond.
  • L 4 is selected from -O- and -NR c11 -.
  • Ring B is .
  • m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, n is 0. In some embodiments, n is an integer from 1 to 8. In some embodiments, n is an integer from 0 to 4. In some embodiments, n is an integer from 0 to 3. In some embodiments, n is an integer from 0 to 2. In some embodiments, n is 0 or 1. In some embodiments, n is an integer from 1 to 4. In some embodiments, n is an integer from 1 to 3. In some embodiments, n is 1 or 2. In some embodiments, n is an integer from 2 to 8. In some embodiments, n is an integer from 2 to 4.
  • n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, q is 0. In some embodiments, q is 1 or 2. In some embodiments, q is 0 or 1. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, r is an integer from 1 to 5. In some embodiments, r is an integer from 1 to 4. In some embodiments, r is an integer from 1 to 3.
  • r is 1 or 2. In some embodiments, r is 1. In some embodiments, r is an integer from 2 to 6. In some embodiments, r is an integer from 2 to 4. In some embodiments, r is 2 or 3. In some embodiments, r is an integer from 3 to 6. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, r is 4. In some embodiments, r is 5. In some embodiments, r is 6. In some embodiments, s is 0. In some embodiments, s is 1. In some embodiments, t is 0. In some embodiments, t is an integer from 0 to 3. In some embodiments, t is 0 or 2. In some embodiments, t is an integer from 1 to 4.
  • t is an integer from 1 to 3. In some embodiments, t is an integer from 2 to 3. In some embodiments, t is 1. In some embodiments, t is 2. In some embodiments, t is 3. In some embodiments, t is 4. In some embodiments, the compound is selected from Table 1. Table 1. Selected bifunctional degrader compounds.
  • alkyl used alone or as part of a larger moiety, such as “alkoxy” and the like, means a saturated aliphatic straight-chain or branched monovalent hydrocarbon radical. Unless otherwise specified, an alkyl group typically has 1 to 8 carbon atoms (C 1 -C 8 alkyl) (i.e., 1, 2, 3, 4, 5, 6, 7, or 8), alternatively, 1 to 6 carbon atoms (C1-C6alkyl) (i.e., 1, 2, 3, 4, 5, or 6), alternatively, 1 to 4 carbon atoms (C 1 -C 4 alkyl) (i.e., 1, 2, 3, or 4).
  • a “(C1-C4)alkyl” group means a radical having from 1 to 4 carbon atoms in a linear or branched arrangement. Examples include methyl, ethyl, n-propyl, iso-propyl, butyl, tert-butyl, and the like.
  • alkenylene used alone or as part of a larger moiety, means an alkyl group that is a bivalent hydrocarbon radical in which one or more carbon-carbon single bonds is replaced by a double bond.
  • alkynylene used alone or as part of a larger moiety, means an alkyl group that is a bivalent hydrocarbon radical in which one or more carbon-carbon single bonds is replaced by a triple bond.
  • alkoxy means a monovalent radical composed of an alkyl group attached through an oxygen linking atom, represented by -O-alkyl. Examples include methoxy, ethoxy, propoxy, butoxy, and the like.
  • aryl refers to a radical of a 6 to 12-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 ⁇ electrons shared in a cyclic array) having ring carbon atoms provided in an aromatic ring system. Examples of aryl groups include phenyl, naphthyl, and the like. The number of ring members designates the number of ring members in the fused ring system.
  • aryl group may be described as, e.g., a 6 to 12- membered aryl, alternatively, a 6 to 10-membered aryl, wherein the term “membered” refers to the non-hydrogen ring atoms within the moiety.
  • cycloalkyl refers to non-aromatic cyclic hydrocarbons including cyclized alkyl and alkenyl groups. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3, or 4 fused, bridged, or spiro rings) ring systems.
  • a cycloalkyl has 3 to 10 carbon atoms (C3-C10cycloalkyl), alternatively, 3 to 8 carbon atoms (C3- C 8 cycloalkyl), alternatively, 3 to 6 carbon atoms (C 3 -C 6 cycloalkyl).
  • Cycloalkyl also includes ring systems comprising two cycloalkyl groups, as defined above, sharing 2, 3, or 4 adjacent ring atoms to form a fused or bridged bicycloalkyl.
  • Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[4.2.0]octanyl, octahydro-1H-indenyl, decahydronaphthalenyl, bicyclo[2.2.1]hepantyl, bicyclo[2.2.2]octantyl, bicyclo[3.2.1]octanyl, bicyclo[3.2.2]nonanyl, and the like.
  • the term “spirocycloalkyl” refers to a group comprising two cycloalkyls which share one common ring atom.
  • a spirocycloalkyl has 5 to 12 carbon atoms (C5-C12spirocycloalkyl), alternatively, 5 to 10 carbon atoms (C5-C10cycloalkyl).
  • Examples include spiro[2.2]pentanyl, spiro[3.3]heptanyl, spiro[3.5]nonanyl, spiro[5.5]undecanyl, and the like.
  • the term “E3 ubiquitin ligase-binding moiety” refers to a chemical group that binds to an E3 ubiquiting ligase.
  • E3 ubiquitin ligase binding moieties are known and well-described in the art, for example: Bondeson, D. P., et al. Nat Chem Biol.201511(8):611-617; An S, et al. EBioMedicine 201836:553-562; Paiva S-L. et al, Curr. Op. in Chem. Bio.2010, 50:111- 119, each of which is incorporated by reference in its entirety.
  • halo means halogen and includes chloro (Cl), fluoro (F), bromo (Br), and iodo (I).
  • heterocyclyl refers to a monocyclic or bicyclic non- aromatic ring radical. Unless otherwise specified, a heterocyclyl has 3 to 12 ring atoms (i.e., 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12-membered), alternatively, 3 to 10 ring atoms (i.e., 3, 4, 5, 6, 7, 8, 9, or 10-membered), alternatively, 3 to 6 ring atoms (i.e., 3, 4, 5, or 6-membered), selected from carbon atoms and and 1 to 4 heteroatoms, wherein each heteroatom is independently selected from oxygen (O), sulfur (S), including sulfoxide and sulfone, and nitrogen (N or NR c1 , including quaternary nitrogen, oxidized nitrogen (e.g., NO)).
  • O oxygen
  • S sulfur
  • N or NR c1 including quaternary nitrogen, oxidized nitrogen (e.g., NO)
  • Heterocyclyl also includes ring systems comprising a heterocycle which shares 2, 3, or 4 adjacent ring atoms with a cycloalkyl or a second heterocycle, as defined herein.
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • heterocyclyl groups include azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, azepanyl, oxepanyl, thiepanyl, tetrahydropyridinyl, 1,2-thiazinanyl-1,1-dioxide, 3-azabicyclo[4.2.0]-octanyl, octahydro-1H-indolyl, decahydroquinolinyl, decahydro-1,5- naphthyridinyl, 5-oxabicyclo[2.1.1]-hexanyl, 3-oxabicyclo[3.1.0]hexanyl, 6- oxabicyclo[3.1.1]heptanyl, 2-oxabicyclo[2.2.2]octanyl, 7-oxabi
  • spiroheterocyclyl refers to bicyclic non-aromatic ring radical comprising a heterocycle which shares one common ring atom with a cycloalkyl or a second heterocycle.
  • a spiroheterocyclyl has 5 to 12 ring atoms (i.e., 5, 6, 7, 8, 9, 10, 11, or 12-membered), alternatively, 5 to 10 ring atoms (i.e., 5, 6, 7, 8, 9, or 10-membered), selected from carbon atoms and 1 to 4 heteroatoms, wherein each heteroatom is independently selected from oxygen (O), sulfur (S), including sulfoxide and sulfone, and nitrogen (N or NR c1 , including quaternary nitrogen, oxidized nitrogen (e.g., NO)).
  • O oxygen
  • S sulfur
  • N or NR c1 including quaternary nitrogen, oxidized nitrogen (e.g., NO)
  • heteroaryl refers to a radical of a 5-12 membered monocyclic or bicyclic aromatic ring system (e.g., having 6 or 10 ⁇ electrons shared in a cyclic array) 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 (“5–12 membered heteroaryl”).
  • Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system.
  • 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 group may be described as, e.g., a 6- 10-membered heteroaryl, wherein the term “membered” refers to the non-hydrogen ring atoms within the moiety.
  • linker moiety and “linker” refer to a bivalent chemical moiety that binds (e.g., bridges) two separate entities to one another.
  • linker moiety and linker can refer to a bivalent chemical moiety that is covalently bonded to both ring A of the compounds of the disclosure and group Z or Z’ of the compounds of the disclosure.
  • linker moiety and linker can further refer to a bivalent chemical moiety that is covalently bonded to both ring A of the compounds of the disclosure and ring B of the compounds of the disclosure.
  • pharmaceutically acceptable salt refers to a pharmaceutical salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, and is commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. describes pharmacologically acceptable salts in J. Pharm. Sci., 1977, 66, 1–19. Included in the present teachings are pharmaceutically acceptable salts of the compounds disclosed herein. Compounds having basic groups can form pharmaceutically acceptable salts with pharmaceutically acceptable acid(s).
  • Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include salts of inorganic acids (such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, and sulfuric acids) and of organic acids (such as acetic, benzenesulfonic, benzoic, ethanesulfonic, methanesulfonic, and succinic acids).
  • Compounds of the present teachings with acidic groups such as carboxylic acids can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s).
  • Suitable pharmaceutically acceptable basic salts include ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts).
  • Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomeric and enantiomeric forms of a compound. Enantiomers are stereoisomers that are mirror images of each other. Diastereomers are stereoisomers having two or more chiral centers that are not identical and are not mirror images of each other.
  • the enrichment of the indicated configuration relative to the opposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99% or 99.9% (except when the designation “rac” or “racemate” accompanies the structure or name, as explained in the following two paragraphs).
  • “Enrichment of the indicated configuration relative to the opposite configuration” is a mole percent and is determined by dividing the number of compounds with the indicated stereochemical configuration at the chiral center(s) by the total number of all of the compounds with the same or opposite stereochemical configuration in a mixture.
  • the stereochemical configuration at a chiral center in a compound is depicted by chemical name (e.g., where the configuration is indicated in the name by “R” or “S”) or structure (e.g., the configuration is indicated by “wedge” bonds) and the designation “rac” or “racemate” accompanies the structure or is designated in the chemical name, a racemic mixture is intended.
  • a disclosed compound having a chiral center is depicted by its chemical name without indicating a configuration at that chiral center with “S” or “R”, the name is meant to encompass the compound with the S configuration at that chiral center, the compound with the R configuration at that chiral center or the compound with a mixture of the R and S configuration at that chiral center.
  • a racemic mixture means a mixture of 50% of one enantiomer and 50% of its corresponding enantiomer.
  • the present teachings encompass all enantiomerically-pure, enantiomerically-enriched, diastereomerically pure, diastereomerically enriched, and racemic mixtures, and diastereomeric mixtures of the compounds disclosed herein.
  • Enantiomeric and diastereomeric mixtures can be resolved into their component enantiomers or stereoisomers by well known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent.
  • Enantiomers and diastereomers can also be obtained from diastereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well known asymmetric synthetic methods.
  • “Peak 1” in the Experimental section refers to an intended reaction product compound obtained from a chromatography separation/purification that elutes earlier than a second intended reaction product compound from the same preceding reaction.
  • the second intended product compound is referred to as “peak 2”.
  • peak 2 When a disclosed compound is designated by a name or structure that indicates a single enantiomer, unless indicated otherwise, the compound is at least 60%, 70%, 80%, 90%, 99% or 99.9% optically pure (also referred to as “enantiomerically pure”).
  • Optical purity is the weight in the mixture of the named or depicted enantiomer divided by the total weight in the mixture of both enantiomers.
  • stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in a diastereomeric pair), it is to be understood that, unless otherwise indicated, one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers are included. It is to be further understood that the stereoisomeric purity of the named or depicted stereoisomers at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight. The stereoisomeric purity in this case is determined by dividing the total weight in the mixture of the stereoisomers encompassed by the name or structure by the total weight in the mixture of all of the stereoisomers.
  • any position specifically designated as “D” or “deuterium” is understood to have deuterium enrichment at 50, 80, 90, 95, 98 or 99%.
  • “Deuterium enrichment” is a mole percent and is determined by dividing the number of compounds with deuterium at the indicated position by the total number of all of the compounds. When a position is designated as “H” or “hydrogen”, the position has hydrogen at its natural abundance. When a position is silent as to whether hydrogen or deuterium is present, the position has hydrogen at its natural abundance.
  • One specific alternative embodiment is directed to a compound of the disclosure having deuterium enrichment of at least 5, 10, 25, 50, 80, 90, 95, 98 or 99% at one or more positions not specifically designated as “D” or “deuterium”.
  • moieties e.g., alkyl, alkoxy, cycloalkyl or heterocyclyl
  • substituents e.g., alkyl, alkoxy, cycloalkyl or heterocyclyl
  • many moieties are referred to as being either “substituted” or “optionally substituted”.
  • a moiety is modified by one of these terms, unless otherwise noted, it denotes that any portion of the moiety that is known to one skilled in the art as being available for substitution can be substituted, which includes one or more substituents. Where if more than one substituent is present, then each substituent may be independently selected. Such means for substitution are well-known in the art and/or taught by the instant disclosure.
  • the optional substituents can be any substituents that are suitable to attach to the moiety.
  • compositions in another aspect, provided herein is a pharmaceutical composition comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient and (a “pharmaceutical composition of the disclosure”).
  • “Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the formulation and/or administration of an active agent to and/or absorption by a subject and can be included in the pharmaceutical compositions of the disclosure without causing a significant adverse toxicological effect on the subject.
  • Non- limiting examples of pharmaceutically acceptable carriers/excipients include: (1) sugars, such as, e.g., lactose, glucose, and sucrose; (2) starches, such as, e.g., corn starch and potato starch; (3) cellulose and its derivatives, such as, e.g., sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as, e.g., cocoa butter and suppository waxes; (9) oils, such as, e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as, e.g., propylene glycol; (11) polyols, such as, e.g., glycerin, sorbitol, mannitol,
  • the disclosure provides methods of modulating (e.g., degrading) CDK2 activity and therefore are useful for treating diseases for which CDK2 are dysregulated, such as cancer.
  • the method of modulating is a method of degrading CDK2 comprising contacting CDK2 with a compound of the disclosure, or a pharmaceutically acceptable salt thereof.
  • the method of modulating is a method of degrading CDK2 in a subject in need thereof, comprising contacting CDK2 with an effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure.
  • Compounds of the disclosure are CDK2 degraders.
  • degrader means that a compound, or a pharmaceutically acceptable salt thereof, degrades CDK2 protein.
  • degrade means the partial or full breakdown of CDK2 proteins, which reduces or eliminates the biological activity of CDK2, as compared to the amount of those proteins in the absence of the degrader (e.g., before administration of the degrader).
  • the term “degrade” means a decrease in the levels of CDK2 protein of at least 5%, at least 10%, at least 20%, at least 50%, at least 60%, at least 79%, at least 80%, at least 90% or at least 95% (e.g., before administration of the degrader or at two different timepoints during treatment with the degrader).
  • inhibit means a decrease in the levels of CDK2 of 5% to 25%, 25% to 50%, 50 to 70%, 75 to 100%.
  • degrade means a decrease in the levels of CDK2 of about 95% to 100%, e.g., a decrease in activity of 95%, 96%, 97%, 98%, 99%, or 100%.
  • a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure for use in the treatment of cancers is provided herein.
  • a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure for use in the prevention of cancers is provided herein.
  • treating refers to 1) inhibiting the disease in an individual who is experiencing or displaying the pathology or symptomatology of the disease (i.e., arresting further development of the pathology and/or symptomatology), or 2) ameliorating the disease in an individual who is experiencing or displaying the pathology or symptomatology of the disease (i.e., reversing the pathology and/or symptomatology).
  • preventing or “prevention” refers to preventing the disease in an individual who may be predisposed to the disease but does not yet experience or display the pathology or symptomatology of the disease.
  • the disclosure is directed to a method of preventing a disease in a patient, by administering to the patient a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof.
  • contacting refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
  • contacting CDK2, or “contacting” a cell with a compound of the disclosure, includes the administration of a compound of the present disclosure to a subject or patient, such as a human, having CDK2, as well as, for example, introducing a compound of the disclosure into a sample containing a cellular or purified preparation containing CDK2.
  • an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal.
  • an in vitro cell can be a cell in a cell culture.
  • an in vivo cell is a cell living in an organism such as a mammal.
  • Compounds of the disclosure, or pharmaceutically acceptable salts thereof, are CDK2 degraders with warheads that target CDK2 with high affinity and selectivity compared to traditional small-molecule inhibitors.
  • CDK2 degrader means a compound which selectively and catalytically degrades CDK2 over other CDKs and other proteins. Said another way, a CDK2 degrader shows no or low degradation of other CDKs and other proteins.
  • a CDK2 degrader degrades CDK2 to a greater extent in terms of DC 50 value (i.e., the DC50 value is nanomolar) when compared with the degradation of other CDKs and other proteins. Degradation can be measured using known biochemical assays.
  • the DC 50 value refers to the concentration at which 50% maximal degradation was observed.
  • a CDK2 degrader may show degradation that is at least 2-fold relative to another target protein (e.g., at least 10-fold; at least 15-fold; at least 20-fold; at least 30-fold; at least 40-fold selectivity; at least 50-fold; at least 60-fold; at least 70-fold; at least 80-fold; at least 90-fold; at least 100-fold; at least 125-fold; at least 150-fold; at least 175-fold; or at least 200- fold.
  • another target protein e.g., at least 10-fold; at least 15-fold; at least 20-fold; at least 30-fold; at least 40-fold selectivity; at least 50-fold; at least 60-fold; at least 70-fold; at least 80-fold; at least 90-fold; at least 100-fold; at least 125-fold; at least 150-fold; at least 175-fold; or at least 200- fold.
  • a CDK2 degrader exhibits at least 15-fold selectivity over another CDK, e.g., CDK1, CDK4, and CDK6.
  • the compounds of the disclosure are selective against CDK2 versus CDK1.
  • compounds show at least 10-fold selectivity for CDK2 versus CDK1.
  • compounds show at least 20-fold selectivity for CDK2 versus CDK1.
  • compounds show at least 30-fold selectivity for CDK2 versus CDK1.
  • compounds show at least 40-fold selectivity for CDK2 versus CDK1.
  • compounds show at least 50-fold selectivity for CDK2 versus CDK1.
  • the compounds of the disclosure are selective against CDK2 versus CDK4 and/or CDK6.
  • compounds show at least 10-fold selectivity for CDK2 versus CDK4 and/or CDK6.
  • compounds show at least 20-fold selectivity for CDK2 versus CDK4 and/or CDK6.
  • compounds show at least 30-fold selectivity for CDK2 versus CDK4 and/or CDK6.
  • compounds show at least 40-fold selectivity for CDK2 versus CDK4 and/or CDK6.
  • compounds show at least 50-fold selectivity for CDK2 versus CDK4 and/or CDK6.
  • compounds show at least 100-fold selectivity for CDK2 versus CDK4 and/or CDK6.
  • the compounds of the disclosure are selective against CDK2 versus CDK1.
  • compounds show at least 10-fold selectivity for CDK2 versus CDK1.
  • compounds show at least 20-fold selectivity for CDK2 versus CDK1.
  • compounds show at least 30-fold selectivity for CDK2 versus CDK1.
  • compounds show at least 40-fold selectivity for CDK2 versus CDK1.
  • compounds show at least 50-fold selectivity for CDK2 versus CDK1.
  • the compounds of the disclosure are selective against CDK2 versus CDK6.
  • compounds show at least 10-fold selectivity for CDK2 versus CDK6. In some embodiments, compounds show at least 20-fold selectivity for CDK2 versus CDK6. In some embodiments, compounds show at least 30-fold selectivity for CDK2 versus CDK6. In some embodiments, compounds show at least 40-fold selectivity for CDK2 versus CDK6. In some embodiments, compounds show at least 50-fold selectivity for CDK2 versus CDK6. Some compounds of the disclosure have the advantage of oral bioavailability. In some embodiments, a compound of the disclosure selectively degrades its target protein compared to other CDKs and other proteins.
  • a compound of the disclosure catalytically degrades its target protein, which may require a lower dose compared to traditional small molecule inhibitor.
  • CDK4/6 inhibitors including ribociclib, palbociclib, and abemaciclib, bind the adenosine triphosphate (ATP) cleft, which contains the catalytic residues, and compete with ATP to inhibit activity.
  • ATP adenosine triphosphate
  • a compound of the disclosure is a bifunctional degrader with a warhead that binds to the target protein (e.g., CDK2) linked to an E3 ubiquitin ligase-binding moiety that recruit E3 ligases to ubiquitinate the target protein and prompt the target protein to be recognized and subsequently degraded by 26S proteasome.
  • the compounds of the disclosure can be used repeatedly to trigger this targeted protein degradation.
  • a compound of the disclosure may eliminate certain side effects, for example, drug-drug interactions and off-target effects, such as CDK6 mediated heme toxicity.
  • a method of treating a cancer in a patient in need thereof comprising administering to a patient a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure.
  • a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure in the manufacture of a medicament for the treatment of cancers.
  • a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure in the preparation of a medicament for the treatment of cancers.
  • a compound of the disclosure, or a pharmaceutically acceptable salt thereof is administered as first line therapy.
  • a compound of the disclosure, or a pharmaceutically acceptable salt thereof is administered as second (or later) line therapy.
  • cancer refers to any malignant and/or invasive growth or tumor caused by abnormal cell growth. Cancer encompasses all forms of cancer including, but not limited to, all forms of solid tumors, carcinomas, melanomas, blastomas, sarcomas, lymphomas, and leukemias.
  • Cancer also includes primary cancer that originates at a specific site in the body, a metastatic cancer that has spread from the place in which it started to other parts of the body, a recurrence from the original primary cancer after remission, and a second primary cancer that is a new primary cancer in a person with a history of previous cancer of a different type from the latter one.
  • the cancer is a solid tumor cancer.
  • the solid tumor cancer is a carcinoma or a sarcoma (e.g., CIC- DUX4 sarcoma).
  • the solid tumor cancer is an adenocarcinoma, a carcinoma, or a cystadenocarcinoma.
  • cancers that are treatable using compounds of the disclosure, or pharmaceutically acceptable salts thereof include, but are not limited to, bone cancers, breast cancers.
  • Exemplary bone cancers include, but are not limited to, benign chondroma, chondroblastoma, chondromyxofibroma, chondrosarcoma, Ewing’s sarcoma, fibrosarcoma, giant cell tumors, malignant fibrous histiocytoma, malignant lymphoma (e.g., reticulum cell sarcoma), malignant giant cell tumor chordoma, multiple myeloma, osteochronfroma (e.g., osteocartilaginous exostoses), osteogenic sarcoma (e.g., osteosarcoma, e.g.,), and osteoid osteoma.
  • benign chondroma chondroblastoma
  • chondromyxofibroma chondrosarcoma
  • Ewing’s sarcoma fibrosarcoma
  • giant cell tumors malignant fibrous histiocytoma
  • malignant lymphoma e
  • Exemplary breast cancers include, but are not limited to, ductal carcinoma in situ, ER+ breast cancer (estrogen receptor positive breast cancer); ER+/HER2- breast cancer (estrogen receptor positive, human epidermal growth factor 2 negative breast cancer); HR+ breast cancer (hormone receptor positive breast cancer); HR+/HER2- breast cancer (hormone receptor positive, human epidermal growth factor 2 negative breast cancer); HER2- breast cancer (human epidermal growth factor 2 negative breast cancer); HER2+ breast cancer (human epidermal growth factor 2 positive breast cancer); HER2-low breast cancer (human epidermal growth factor 2 low breast cancer); invasive ductal carcinoma (IDC); invasive lobular carcinoma, lobular carcinoma in situ, PR+/HER2- breast cancer (progesterone receptor positive, human epidermal growth factor 2 negative breast cancer); triple negative breast cancer (TNBC); and tubular breast carcinoma.
  • IDC invasive ductal carcinoma
  • IDC invasive lobular carcinoma, lobular carcinoma in situ
  • PR+/HER2- breast cancer progesterone receptor
  • Exemplary gastrointestinal cancers include, but are not limited to, cancers of the anus (e.g., anal cancer, e.g., anal neuroendocrine carcinoma), colon (e.g., colon adenocarcinoma (COAD)); colorectal cancer (e.g., hereditary non-polyposis colorectal cancer); esophagus (e.g., adenocarcinoma, leiomyosarcoma, lymphoma, and squamous cell carcinoma); familiar adenomatous polyposis carcinoma; gall bladder (e.g., adenocarcinoma and cholangiocarcinoma); intestinal type and diffuse type gastric adenocarcinoma (e.g., gastrointestinal stromal tumor); large bowel (e.g., adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); large intestine (
  • Exemplary genitourinary tract cancers include, but are not limited to, cancers of the adrenal gland (e.g., adrenocortical carcinoma); bladder (e.g., adenocarcinoma, sarcoma, small cell carcinoma, squamous cell carcinoma, and transitional cell carcinoma); kidney (e.g., adenocarcinoma, renal cell carcinoma (RCC), urothelial carcinoma, juxtaglomerular cell tumor (reninoma), angiomyolipoma, Bellinio duct carcinoma, clear-cell sarcoma of the kidney, and mesoblastic nephroma, renal oncocytoma, and Wilm’s tumor [nephroblastoma]); renal pelvis; pancreas; penis; prostate (e.g., adenocarcinoma (PRAD), androgen receptor positive (AR+) or AR-dependent prostate cancer, AR-independent prostate cancer, carcinoma, castration-resistant prostate cancer (CRPC),
  • Exemplary gynecological cancers include, but are not limited to, cancers of the cervix (e.g., adenocarcinoma, adenosquamous carcinoma, cervical carcinoma, cervical squamous cell carcinoma (CESC), glassy cell carcinoma, neuroendocrine tumor, pre-tumor cervical dysplasia, small cell carcinoma, squamous cell carcinoma, and villoglandular adenocarcinoma); fallopian tubes (e.g., carcinoma); labia; ovaries (e.g., dysgerminoma, granulosa-thecal cell tumors, malignant teratoma, ovarian carcinoma (e.g., endometroid tumor, high-grade serous ovarian cancer (HGSOC), high-grade serous carcinoma (HGSC), mucinous cystadenocarcinoma, serous cystadenocarcinoma, and unclassified carcinoma), and Sertoli-Leydig cell tumors); uterus (
  • Exemplary head and neck cancers include, but are not limited to, acoustic neuroma, adenocarcinoma, eye cancer (e.g., intraocular malignant melanoma, ocular melanoma, and retinoblastoma), glioblastoma, lymphosarcoma, melanoma, nasal and paranasal cancer, nasal cavity cancer, oral cancer or mouth cancer (e.g., lip cancer, salivary gland cancer, and tongue cancer), osteosarcoma, pituitary adenoma, rhabdosarcoma, sinus cancer, squamous cell carcinoma, throat cancer (e.g., hypopharngx, oropharyngeal cancer, laryngeal cancer, nasopharyngeal cancer), parathyroid cancer, and thyroid cancer (e.g., medullary and papillary).
  • eye cancer e.g., intraocular malignant melanoma, ocular mel
  • Exemplary hematological cancers include, but are not limited to, lymphomas and leukemias such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), Burkitt's lymphoma, chronic lymphocytic leukemia (CLL), chronic myelogenic lymphoma, chronic myelogenous leukemia (CML), cutaneous T-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), hairy cell lymphoma, Hodgkin lymphoma, mantle cell lymphoma, Non-Hodgkin lymphoma (e.g., follicular lymphoma, relapsed or refractory NHL, and recurrent follicular), multiple myeloma (MM), myelodysplasia syndrome (MDS), myelofibrosis (PMF), myeloproliferative diseases (e.g., primary
  • liver cancers include, but are not limited to, hepatoma e.g., angiosarcoma, cholangiocarcinoma (also referred to as bile duct cancer), hemangioma, hepatoblastoma, hepatocellular adenoma, and hepatocellular carcinoma (HCC).
  • hepatoma e.g., angiosarcoma, cholangiocarcinoma (also referred to as bile duct cancer), hemangioma, hepatoblastoma, hepatocellular adenoma, and hepatocellular carcinoma (HCC).
  • Exemplary nervous system cancers include, but are not limited to, cancers of the brain (e.g., astrocytoma, brain lower grade glioma (LGG), brain stem glioma,d congenital tumors, ependymoma, germinoma (pinealoma), glioma, glioblastoma, glioblastoma multiforme (GBM), medulloblastoma, and oligodendroglioma); central nervous system lymphoma; Lhermitte-Duclos disease; meninges (e.g., gliomatosis, meningioma, and meningiosarcoma); neuroblastoma; schwannoma; spinal cord (e.g., glioma, meningioma, neurofibroma, sarcoma, and spinal axis tumor); and skull (e.g., granuloma, hemangioma,
  • Exemplary respiratory tract cancers include, but are not limited to, epidermoid carcinoma; lung cancer including, but not limited to, alveolar (bronchiolar) carcinoma; bronchial adenoma; bronchogenic carcinoma (e.g., adenocarcinoma, squamous cell, undifferentiated small cell, and undifferentiated large cell); chondromatous hamartoma; epidermal growth factor receptor mutant positive (EGFRm+) non-small cell lung cancer; non-small cell lung cancer (NSCLC); small cell lung cancer (SCLC); and pleuropulmonary blastoma; and mesothelioma.
  • lung cancer including, but not limited to, alveolar (bronchiolar) carcinoma; bronchial adenoma; bronchogenic carcinoma (e.g., adenocarcinoma, squamous cell, undifferentiated small cell, and undifferentiated large cell); chondromatous hamartoma; epidermal growth factor receptor mutant positive
  • Exemplary sarcomas include, but are not limited to, angiosarcoma, chondrosarcoma, epithelioid sarcoma, Ewing’s sarcoma, fibroma, fibrosarcoma, harmatoma, Kaposi’s sarcoma, lipoma, liposarcoma, myxoma, osteosarcoma (e.g., chondroblastic osteosarcoma), rhabdomyoma, rhabdomyosarcoma, and teratoma.
  • angiosarcoma e.g., chondroblastic osteosarcoma
  • chondroblastic osteosarcoma e.g., chondroblastic osteosarcoma
  • rhabdomyoma rhabdomyosarcoma
  • teratoma teratoma
  • Exemplary skin cancers include, but are not limited to, angioma, basal cell carcinoma, BRAF and HSP90 inhibition-resistant melanoma, cutaneous melanoma, dermatofibroma, lipoma, Kaposi’s sarcoma, keloids, melanoma, Merkel cell carcinoma, metastatic malignant melanoma, moles dysplastic nevi, sebaceous gland carcinoma, and squamous cell carcinoma.
  • the cancer is anal cancer, bladder cancer, brain cancer, breast cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, skin cancer, thyroid cancer, urothelial cancer, or uterine cancer.
  • the cancer is anal cancer, breast cancer, colorectal cancer, endometrial cancer, gastric cancer, liver cancer, lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, or uterine cancer.
  • the cancer is characterized by an elevation or an amplification of the cyclin E1 (CCNE1) gene and/or cyclin E2 (CCNE2) gene (e.g., based on copy number) and/or a level of CCNE1 and/or CCNE2 higher than a control level of CCNE1 (referred to herein as a “change in the levels of CCNE1 and/or CCNE2”).
  • the cancer is characterized by high microsatellite instability (MSIhigh).
  • MSIhigh microsatellite instability
  • the cancer is characterized by Genomic Identification of Significant Targets in Cancer (GISTIC).
  • the cancer is pheochromocytoma and paraganglioma (PCPG).
  • the cancer is a refractory cancer, which is also referred to as a treatment-resistant cancer.
  • the cancer is platinum-resistant and/or platinum-refractory.
  • the cancer has progressed despite treatment with a platinum agent.
  • the cancer is breast cancer (BC).
  • the breast cancer is advanced or metastatic breast cancer.
  • the breast cancer is HR+/HER2- BC.
  • the breast cancer is ER+/HER2- BC.
  • the breast cancer is PR+/HER2- BC.
  • the breast cancer is TNBC. In some embodiments, the breast cancer is refractory. In some embodiments, the breast cancer is chemotherapy resistant breast cancer, endocrine resistant breast cancer, radiotherapy resistant breast cancer, trastuzumab resistant breast cancer, or breast cancer demonstrating primary or acquired resistance to CDK4/CDK6 inhibition. In some embodiments, the breast cancer is responsive to treatment with a CDK4/6 inhibitor. In some embodiments, the breast cancer is resistant to treatment with a CDK4/6 inhibitor. In some embodiments, the breast cancer has progressed despite treatment with a CDK4/6 inhibitor.
  • the breast cancer has progressed despite a first treatment with palbociclib, ribociclib, and/or fulvestrant and a second treatment with abemaciclib and/or fulvestrant.
  • the method further comprises administering to the patient a therapeutically acceptable amount of a CDK4/6 inhibitor.
  • the CDK4/6 inhibitor is abemaciclib.
  • the CDK4/6 inhibitor is palbociclib.
  • the CDK4/6 inhibitor is ribociclib.
  • the cancer is (a) ovarian cancer; (b) characterized by a change in the levels of CCNE1 and/or CCNE2; or (c) both (a) and (b).
  • the ovarian cancer is selected from dysgerminoma, a granulosa-thecal cell tumor, malignant teratoma, endometroid tumor, HGSOC, HGSC, mucinous cystadenocarcinoma, serous cystadenocarcinoma, and unclassified carcinoma.
  • the ovarian cancer is HGSOC.
  • the cancer is (a) endometrial cancer; (b) characterized by a change in the levels of CCNE1 and/or CCNE2; or (c) both (a) and (b).
  • the endometrial cancer is selected from carcinosarcoma, clear cell endometrial carcinoma, endometrial carcinoma, grade 3 endometriod endometrial cancer, and SEC.
  • the endometrial cancer is SEC.
  • the cancer is (a) lung cancer; (b) characterized by a change in the levels of CCNE1 and/or CCNE2; or (c) both (a) and (b).
  • the lung cancer is NSCLC.
  • the lung cancer is SCLC.
  • cancers treatable with a compound of the disclosure, or a pharmaceutically acceptable salt thereof include advanced/relapsed tumors; platinum- resistant or platinum-refractory ovarian cancer; endometrial cancer (with prior platinum therapy) that has progressed following 2 or more lines of therapies; gastric cancer (with prior platinum therapy) that has progressed following 2 or more lines of therapies; and HR+/HER2- BC (including both ER+/HER2- BC and PR+/HER2- BC) that has progressed despite treatment with one or more CDK4/6 inhibitors.
  • cancers treatable with a compound of the disclosure, or a pharmaceutically acceptable salt thereof include platinum-resistant or platinum-refractory CCNE1 amplified ovarian cancer; CCNE1 amplified endometrial cancer that has failed 2 or more lines of therapies; CCNE1 amplified advanced/relapsed tumors that do not belong to the other groups; HR+/HER2- BC that has progressed despite CDK4/6i; and platinum-resistant or platinum-refractory CCNE1 amplified ovarian cancer.
  • the subject has CCNE1 amplified advanced/relapsed tumors.
  • the subject has CCNE1 amplified platinum-resistant or platinum-refractory ovarian cancer.
  • the subject has endometrial cancer (with prior platinum therapy, e.g., wherein the patient has been previously treated with a platinum therapy) that has progressed following 2 or more lines of therapies (including the platinum therapy).
  • the subject has CCNE1 amplified endometrial cancer that has failed 2 or more lines of therapies (which may include a prior platinum therapy).
  • the subject has gastric cancer (with prior platinum therapy e.g., wherein the patient has been previously treated with a platinum therapy) that has progressed following 2 or more lines of therapies (including the platinum therapy).
  • the subject has HR+/HER- breast cancer that has progressed despite treatment with one or more CDK4/6 inhibitors.
  • the subject has TNBC that has progressed despite one or more lines of therapies.
  • the subject has AR+ prostate cancer that has progressed despite one or more lines of therapies.
  • the subject has pancreatic cancer that has progressed despite one or more lines of therapies.
  • the subject has PDAC that has progressed despite one or more lines of therapies.
  • the subject has CCNE1 elevated lung cancer.
  • the subject has NSCLC that has progressed despite treatment with one or more EGFR inhibitors (e.g., osimertinib).
  • the subject has CCNE1 elevated NSCLC that has progressed despite treatment with one or more EGFR inhibitors (e.g., osimertinib).
  • EGFR inhibitors e.g., osimertinib.
  • Compounds of the disclosure or pharmaceutically acceptable salts thereof can be administered as the sole pharmaceutical agent or in combination with one or more other anti- cancer agents for the treatment of cancer, where the combination causes no unacceptable adverse effects.
  • the other anti-cancer agents are standard of care agents appropriate for the particular cancer.
  • additional anticancer therapeutic agent means any one or more therapeutic agent, other than a compound described herein (e.g., Formulae (I), (Ia), (II), (III), or subformulas thereof), or a pharmaceutically acceptable salt thereof, that is or can be used in the treatment of cancer.
  • the additional anticancer agent is a protein kinase B (PKB) or AKT inhibitor including, but not limited to, afuresertib, capivasertib, ipatasertib, miransertib, and temsirolimus.
  • the AKT inhibitor is capivasertib.
  • the additional anticancer agent is an agent that inhibits the androgen receptor (AR) signaling pathway including, but not limited to, abiraterone, bicalutamide, enzalutamide, flutamide, ketoconazole, and niltamide.
  • AR androgen receptor
  • the agent that inhibits the androgen receptor signaling pathway is enzalutamide.
  • the additional anticancer agent is an antibody including, but not limited to, atezolizumab, bevacizumab, margetuximab (e.g., margetuximab-cmkb), pembrolizumab, pertuzumab, ramucirumab, sacituzumab, and trastuzumab.
  • the antibody is trastuzumab.
  • the additional anticancer agent is an antibody-drug conjugate (ADC) including, but not limited to, anetumab ravtasine, belantamab mafodotin, brentuximab vedotin, datopotamab deruxtecan, disitamab vedotin, farletuzumab ecteribulin, gemtuzumab ozogamicin, inotuzumab ozogamicin, ladiratuzumab vedotin, enfortumab vedotin, loncastuximab tesirine, luveltamab tazevibulin, moxetumomab pasudotox, mirvetuximab soravtansine (e.g., mirvetuximab soravtansine-gynx), patritumab deruxtecan, polatuzumab ved
  • ADC
  • the ADC is sacituzumab govitecan, trastuzumab deruxtecan, or trastuzumab emtansine. In some embodiments, the ADC is trastuzumab deruxtecan.
  • the additional anticancer agent is a CDK4/6 inhibitor including, but not limited to, abemacicilb, BPI-16350, CS3002, dalpiciclib, ETH-155008, FCN-437c, HS-10342, lerociclib, palbociclib, P276-00, PF-07224826, PRT3645, ribociclib, SHR6390, SPH4336, trilaciclib, TQB3616, and XZP-3287.
  • the CDK4/6 inhibitor is abemacicilb, lerociclib, palbociclib, or ribociclib.
  • the CDK4/6 inhibitor is abemaciclib.
  • the CDK4/6 inhibitor is lerociclib. In some embodiments, the CDK4/6 inhibitor is palbociclib. In some embodiments, the CDK4/6 inhibitor is ribociclib.
  • the additional anticancer agent is a chemotherapeutic agent including, but not limited to, cyclophosphamide, doxorubicin, epirubicin, eribulin, ixabepilone, liposomal doxorubicin, methotrexate, platinum agents (e.g., carboplatin, cisplatin, and oxaliplatin), pyrimidine antagonists (e.g., 5-fluorouracil (5-FU), capecitabine, cytarabine, and gemcitabine), taxanes (e.g., cabazitaxel, docetaxel, and paclitaxel), sabizabulin, thiotepa, vinblastine, and vinorelbine.
  • chemotherapeutic agent including
  • the chemotherapeutic agent is carboplatin.
  • the additional anticancer agent is an endocrine agent, such as an aromatase inhibitor (e.g., anastrozole, exemestane, fadrozole, formestane, and letrozole), a luteinizing hormone-releasing hormone (LHRH) receptor agonist (e.g., leuprolide, and leuprorelin), a Selective Estrogen-Receptor Downregulator (SERD) (e.g., amcenestrant, camizestrant, elacestrant, fulvestrant, giredestrant, imlunestrant, rintodestrant, taragarestrant, and ZB716), or a Selective Estrogen Receptor Modulator (SERM) (e.g., afimoxifene, arzoxifene, chili fod, clomiphene, fispemif
  • SERM Selective Estrogen Re
  • the endocrine agent is anastrozole, elacestrant, exemestane, fulvestrant, letrozole, raloxifene, tamoxifen, toremifene, or a combination thereof.
  • the additional anticancer agent is an aromatase inhibitor.
  • the aromatase inhibitor is anastrozole, exemestane, or letrozole.
  • the additional anticancer agent is a SERD.
  • the SERD is elacestrant or fulvestrant.
  • the SERD is elacestrant.
  • the SERD is fulvestrant.
  • the additional anticancer agent is an epidermal growth factor receptor (EGFR) inhibitor including, but not limited to, afatinib, dacomitinib, erlotinib, gefitinib, neratinib, osimertinib, poziotinib, pyrotinib, regorafenib, or vandetanib, or an EGFR antibody such as cetuximab, panitumumab, or necitumumab.
  • the EGFR inhibitor is neratinib or osimertinib.
  • the EGFR inhibitor is neratinib.
  • the EGFR inhibitor is osimertinib.
  • the additional anticancer agent is a human epidermal growth factor receptor 2 (HER2) inhibitor including, but not limited to, lapatinib, neratinib, pyrotinib, and tucatinib.
  • the HER2 inhibitor is lapatinib.
  • the HER2 inhibitor is neratinib.
  • the HER2 inhibitor is tucatinib.
  • the additional anticancer agent is a hormone therapy including, but not limited to, goserelin, and megestrol. In some embodiments, the additional anticancer agent is goserelin.
  • the additional anticancer agent is megestrol.
  • the additional anticancer agent is a polyadenosine 5’- diphosphoribose polymerase (PARP) inhibitor including, but not limited to, fluzoparib, niraparib, olaparib, rucaparib, and talazoparib.
  • PARP polyadenosine 5’- diphosphoribose polymerase
  • the PARP inhibitor is olaparib.
  • the PARP inhibitor is talazoparib.
  • the additional anticancer agent is a phosphatidylinositol-4,5- bisphosphate 3-kinase (PI3K) inhibitor including, but not limited to, alpelisib, BPI-21668, buparlisib, copanlisib, CYH33, duvelisib, gedatolisib, GSK2636771, HS-10352, idelalisib, inavolisib, LOXO-783, MEN-1611, RLY-2608, temsirolimus, taselisib, TQB-3525, and umbralisib.
  • PI3K phosphatidylinositol-4,5- bisphosphate 3-kinase
  • the PI3K inhibitor is alpelisib, copanlisib, duvelisib, idelalisib, or umbralisib. In some embodiments, the PI3K inhibitor is alpelisib.
  • the additional anticancer agent is a vascular endothelial growth factor receptor (VEGFR) inhibitor including, but not limited to, anlotinib, apatinib, axitinib, famitinib, lenvatinib, pazopanib, and sunitinib. In some embodiments, the VEGFR inhibitor is apatinib.
  • a compound of the disclosure, or a pharmaceutically acceptable salt thereof is administered in combination with an AKT inhibitor or a PI3K inhibitor, an endocrine agent, and, optionally, a CDK4/6 inhibitor.
  • a compound of the disclosure, or a pharmaceutically acceptable salt thereof is administered in combination with alpelisib or capivasertib, fulvestrant, and, optionally, abemacicilb, palbociclib, or ribociclib.
  • a compound of the disclosure, or a pharmaceutically acceptable salt thereof is administered as second (or later) line therapy following treatment with an antibody, e.g., trastuzumab.
  • a compound of the disclosure, or a pharmaceutically acceptable salt thereof is administered in combination with an antibody and, optionally, a chemotherapeutic agent.
  • a compound of the disclosure, or a pharmaceutically acceptable salt thereof is administered in combination with bevacizumab, pertuzumab, or trastuzumab and, optionally, capecitabine, carboplatin, docetaxel, doxorubicin, paclitaxel, or a combination thereof.
  • a compound of the disclosure, or a pharmaceutically acceptable salt thereof is administered as second (or later) line therapy following treatment with one or more chemotherapeutic agent.
  • a compound of the disclosure, or a pharmaceutically acceptable salt thereof is administered as second (or later) line therapy following treatment with a pyrimidine antagonist and/or gemcitabine, and/or a platinum agent.
  • a compound of the disclosure, or a pharmaceutically acceptable salt thereof is administered in combination with a chemotherapeutic agent.
  • a compound of the disclosure, or a pharmaceutically acceptable salt thereof is administered in combination with 5-FU.
  • a compound of the disclosure, or a pharmaceutically acceptable salt thereof is administered in combination with gemcitabine.
  • a compound of the disclosure, or a pharmaceutically acceptable salt thereof is administered in combination with carboplatin, cisplatin, or oxaliplatin. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with carboplatin. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with cisplatin. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with one or more of a pyrimidine antagonist, gemcitabine, a CDK4/6 inhibitor, and a platinum agent.
  • a compound of the disclosure, or a pharmaceutically acceptable salt thereof is administered in combination with 5-FU, gembcitabine, ribociclib, and, optionally, cisplatin.
  • a compound of the disclosure, or a pharmaceutically acceptable salt thereof is administered as second (or later) line therapy following treatment with an endocrine therapeutic agent and/or a CDK4/CDK6 inhibitor.
  • a compound of the disclosure, or a pharmaceutically acceptable salt thereof is administered as second (or later) line therapy following treatment with an endocrine therapeutic agent, e.g., an aromatase inhibitor, a SERM or a SERD.
  • a compound of the disclosure, or a pharmaceutically acceptable salt thereof is administered as second (or later) line therapy following treatment with a CDK4/CDK6 inhibitor. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with an endocrine agent and, optionally, a CDK4/6 inhibitor.
  • a compound of the disclosure, or a pharmaceutically acceptable salt thereof is administered in combination with anastrozole, elacestrant, exemestane, fulvestrant, letrozole, raloxifene, tamoxifen, or toremifene, and, optionally, abemacicilb, palbociclib, or ribociclib, or a combination thereof.
  • a compound of the disclosure, or a pharmaceutically acceptable salt thereof is administered in combination with anastrozole, exemestane, or letrozole and abemacicilb, palbociclib, or ribociclib.
  • a compound of the disclosure, or a pharmaceutically acceptable salt thereof is administered in combination with letrozole. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with fulvestrant. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with fulvestrant and ribociclib. In some embodiments, the combination further comprises a chemotherapeutic agent. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with fulvestrant, ribociclib, carboplatin, or a combination thereof.
  • a compound of the disclosure, or a pharmaceutically acceptable salt thereof is administered in combination with a CDK4/6 inhibitor.
  • the CDK4/6 inhibitor is abemaciclib.
  • the CDK4/6 inhibitor is palbociclib.
  • the CDK4/6 inhibitor is ribociclib.
  • a compound of the disclosure, or a pharmaceutically acceptable salt thereof is administered as second (or later) line therapy following treatment with an EGFR inhibitor, e.g., osimertinib.
  • a compound of the disclosure, or a pharmaceutically acceptable salt thereof is administered in combination with an EGFR inhibitor and, optionally, a chemotherapeutic agent.
  • a compound of the disclosure, or a pharmaceutically acceptable salt thereof is administered in combination with neratinib or osimertinib and, optionally, capecitabine, gemcitabine, paclitaxel, or a combination thereof.
  • a compound of the disclosure, or a pharmaceutically acceptable salt thereof is administered in combination with osimertinib.
  • a compound of the disclosure, or a pharmaceutically acceptable salt thereof is administered in combination with a HER2 inhibitor, a chemotherapeutic agent, and, optionally, an antibody.
  • a compound of the disclosure, or a pharmaceutically acceptable salt thereof is administered in combination with neratinib or tucatinib, capecitabine, and, optionally, trastuzumab.
  • Methods of Administration and Dosage Forms means an amount when administered to the subject or patient which results in beneficial or desired results, including clinical results, e.g., inhibits, suppresses or reduces the symptoms of the condition being treated in the subject as compared to a control.
  • an effective amount can be given in unit dosage form (e.g., 0.1 mg to about 50 g per day, alternatively from 1 mg to about 5 grams per day.
  • an “effective amount” of compound or pharmaceutically acceptable salt thereof administered to provide an “effective amount” to the subject will depend on the mode of administration, the type, and severity of the disease or condition, and on the characteristics of the subject, such as general the route of administration, the time of administration, the rate of excretion of the particular active ingredient being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular active ingredient employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. When administered in combination with other therapeutic agents, an “effective amount” of any additional therapeutic agent(s) will depend on the type of drug used.
  • Suitable dosages are known for approved therapeutic agents and can be adjusted by the skilled artisan according to the condition of the subject, the type of condition(s) being treated and the amount of a compound of the disclosure or a pharmaceutically acceptable salt thereof being used by following, for example, dosages reported in the literature and recommended in the Physician’s Desk Reference (57th ed., 2003).
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the compounds of the disclosure employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • a suitable daily dose of a compound of the disclosure will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
  • the terms “administer”, “administering”, “administration”, and the like, as used herein, refer to methods that may be used to enable delivery of compositions to the desired site of biological action. These methods include, but are not limited to, intraarticular (in the joints), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, orally, topically, intrathecally, inhalationally, transdermally, rectally, and the like.
  • Administration techniques that can be employed with the agents and methods described herein are found in e.g., Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, PA.
  • the particular mode of administration and the dosage regimen will be selected by the attending clinician, taking into account the particulars of the case (e.g. the subject, the disease, the disease state involved, the particular treatment, and whether the treatment is prophylactic).
  • Treatment can involve daily or multi-daily or less than daily (such as weekly or monthly, etc.) doses over a period of a few days to months, or even years.
  • Biomarkers and Pharmacodynamics Markers The disclosure further provides predictive markers including, but not limited to, biomarkers and pharmacodynamic markers, which can be monitored based on levels including, but not limited to, DNA (e.g., cDNA); RNA (e.g., messenger ribonucleic acid (mRNA) and micro ribonucleic acid (miRNA)); gene copy number; gene expression; gene sequence; protein expression (e.g., protein overexpression); expression levels, enzyme activity, phosphorylation levels, or mutations, to identify those human subjects having, suspected of having, or at risk of developing a cancer for whom administering a CDK2 degrader is likely to be effective.
  • DNA e.g., cDNA
  • RNA e.g., messenger ribonucleic acid (mRNA) and micro ribonucleic acid (miRNA)
  • gene copy number gene expression
  • gene sequence gene sequence
  • protein expression e.g., protein overexpression
  • the biomarker is selected from cancer antigen 125 (CA-125); carcinoembryonic antigen (CEA); checkpoint kinase 1 (CHK1); cyclin A1 (CCNA1); cyclin A2 (CCNA2); cyclin D1 (CCND1); cyclin D2 (CCND2); cyclin D3 (CCND3); cyclin E1 (CCNE1); cyclin E2 (CCNE2); cyclin-dependent kinase 1 (CDK1); CDK2; cyclin-dependent kinase 3 (CDK3); CDK4; cyclin-dependent kinase 5 (CDK5); CDK6; cyclin-dependent kinase 18 (CDK18); cyclin-dependent kinase inhibitor 1A (CDKN1A); cyclin-dependent kinase inhibitor 1B (CDKN1B); cyclin-dependent kinase inhibitor 2A (CDKN2A, also cyclin-dependent
  • the biomarker is selected from CA-125, CCNE1, CCNE2, CEA, KRAS, Ki-67 (or MKI67), p16 (or CDKN2A), RB, PSA, TK1, and the corresponding proteins encoded by these genes.
  • the levels of a biomarker are modulated in response to administration of an effective dose of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, to a subject.
  • a biomarker is absent.
  • the modulation results in the loss of expression of the corresponding protein, a decrease in gene copy numbers, a decrease in phosphorylated protein, or a decrease in protein activity.
  • the biomarker has a mutation (e.g., a loss of function mutation). In some embodiments, a biomarker or a biomarker mutant is functional. In some embodiments, a change in the levels of a biomarker before and after administration of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or at two different timepoints during treatment with a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is indicative/predictive that a subject having or at risk of developing a cancer has responded to treatment with a compound of the disclosure, or a pharmaceutically acceptable salt thereof. In some embodiments, the levels of a biomarker before and after administration of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, are changed by at least 10%.
  • the levels of the biomarker before and after administration of a compound of the disclosure, or a pharmaceutically acceptable salt thereof are changed by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the levels of the biomarker before and after administration of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, are changed by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.
  • the levels of the biomarker before and after administration of a compound of the disclosure, or a pharmaceutically acceptable salt thereof are increased. In some embodiments, the levels of the biomarker before and after administration of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, are reduced. In some embodiments, the levels of the biomarker at two different timepoints during treatment with a compound of the disclosure, or a pharmaceutically acceptable salt thereof, are changed by at least 10%. In some embodiments, the levels of the biomarker at two different timepoints during treatment are changed by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.
  • the levels of the biomarker at two different timepoints during treatment are changed by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.
  • the levels of the biomarker at two different timepoints during administration of a compound of the disclosure, or a pharmaceutically acceptable salt thereof are increased.
  • the levels of the biomarker at two different timepoints during administration of a compound of the disclosure, or a pharmaceutically acceptable salt thereof are reduced.
  • a method of treating cancer in a patient in need thereof comprising: i.
  • a method of monitoring a response in a patient having or at risk of developing cancer comprising: i.
  • a compound of the disclosure or a pharmaceutically acceptable salt thereof
  • additional biological samples are obtained from the subject and compared to the levels of the biomarkers measured in a patient with a normally functioning pathway (a “control level”) to continue monitoring.
  • additional biological samples are obtained from the patient and compared to the levels of the biomarkers measured in the first biological sample to continue monitoring.
  • the biomarker is CA-125.
  • CA-125 is a large transmembrane glycoprotein encoded by the MUC16 gene.
  • the cancer is ovarian cancer characterized by overexpression of CA-125.
  • the biomarker is CCNE1 or CCNE2.
  • CCNE1 is encoded by the cyclin E1 (“CCNE1”) gene (GenBank Accession No. NM_001238).
  • CCNE1 acts as a regulatory subunit of CDK2, and CCNE1 is a cell cycle factor essential for the control of the cell cycle at the G1/S transition (Ohtsubo et al., 1995, Mol. Cell. Biol.15:2612-2624).
  • a method of treating a cancer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure, wherein the patient has an amplification of the CCNE1 gene (e.g., based on copy number) and/or has a higher level of CCNE1 than a control level of CCNE1.
  • the cancer is a solid tumor cancer.
  • the level of CCNE1 in a patient is higher before administration of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, than after said administration.
  • the expression level of CCNE1 may be the level of CCNE1 mRNA.
  • the expression level of CCNE1 may be the level of CCNE1 protein.
  • the expression level of CCNE1 may be an indirect measure of the level of CCNE1 mRNA or protein.
  • the biomarker is CEA.
  • CEA is a heavily glycosylated protein encoded by carcinoembryonic antigen cell adhesion molecule 5 (CEACAM5).
  • the cancer is selected from breast cancer, colorectal cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, and prostate cancer
  • the biomarker is KRAS.
  • the cancer is colon cancer, lung cancer, or pancreatic cancer.
  • the cancer is colon cancer, lung cancer, or pancreatic cancer characterized by a higher level of KRAS than a control level of KRAS.
  • the biomarker is the marker of proliferation Ki-67.
  • the biomarker is p16.
  • the gene CDKN2A encodes p16, which acts as a negative regulator of the proliferation of normal cells by interacting with CDK4 and CDK6.
  • the biomarker is RB1.
  • Retinoblastoma protein (Rb or RB) is a tumor suppressor protein encoded by the gene RB transcriptional corepressor 1 (RB1).
  • the RB1 gene has a mutation (e.g., a loss of function mutation).
  • Rb is activated upon phosphorylation by cyclin D-CDK4/6 at Ser780 and Ser795 and/or at Ser807 and/or Ser811 and by cyclin E/CDK2 at Ser807 and Ser811 and Thr821.
  • the contemplated biomarker is phosphorylation of Rb at any phosphorylation site. In some embodiments, the biomarker is phosphorylation at the serine corresponding to amino acid position 780 (Ser780 or S780) and/or the serine corresponding to amino acid position 795 (Ser795 or S795). In some embodiments, the contemplated biomarker is phosphorylation of Rb at the serine corresponding to amino acid position 807 (Ser807 or S807) and/or the serine corresponding to amino acid position 811 (Ser811 or S811).
  • the contemplated biomarker is phosphorylation of Rb at the threonine corresponding to amino acid position 821 (Thr821 or T821). In some embodiments, the contemplated biomarker is phosphorylation of Rb at the threonine corresponding to amino acid position 826 (Thr826 or T826). In some embodiments, the levels of phosphorylated Rb are reduced compared to a control level of phosphorylated Rb. In some embodiments, the biomarker is PSA. In some embodiments, the cancer is prostate cancer characterized by higher levels of PSA than a control level of PSA. In some embodiments, the biomarker is TK1. TK1 is a direct downstream target of Rb-E2F pathway.
  • TK1 is important for DNA repair following DNA damage because TK1 is necessary for the formation of nucleotides outside of the S phase.
  • a TK1 mutant has a resistance mutation.
  • TK1 is differentially methylated.
  • TK1 is serum TK1.
  • the levels of TK1 enzyme activity are reduced compared to a control level of TK1 enzyme activity.
  • the reactions for preparing compounds of the disclosure can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis.
  • suitable solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected by the skilled artisan.
  • Preparation of compounds of the disclosure can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art.
  • chemistry of protecting groups can be found, for example, in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.
  • Reactions can be monitored according to any suitable method known in the art.
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.
  • HPLC high performance liquid chromatography
  • Hal is a halogen, typically I, Br, Cl or F
  • the compound (X) may be alkylated by halide (XI) in the presence of an organic or inorganic base, such as DIPEA, TEA, Na 2 CO 3 or K 2 CO 3 in DMF, DCM, MeCN, DMSO or NMP, optionally in the presence of a catalyst such as KI, to give the compound (II).
  • an organic or inorganic base such as DIPEA, TEA, Na 2 CO 3 or K 2 CO 3 in DMF, DCM, MeCN, DMSO or NMP
  • a catalyst such as KI
  • this alkylation reaction may occur under mild acid catalysis such as p-TsOH in a solvent such as IPA at elevated temperature.
  • compound (II) may be obtained from halide (XI) and amine (X) by a palladium catalysed coupling reaction, such as a Buchwald-Hartwig type reaction, using a suitable palladium catalyst in the presence of phosphine ligands, in the presence of a suitable inorganic base, in a solvent at elevated temperature and optionally under microwave irradiation.
  • a palladium catalysed coupling reaction such as a Buchwald-Hartwig type reaction
  • a suitable palladium catalyst in the presence of phosphine ligands
  • a suitable inorganic base in a solvent at elevated temperature and optionally under microwave irradiation.
  • Scheme 2 The compound (II) may be obtained by reaction of the amine (XIII) and halide (XII) by a palladium catalysed coupling reaction, such as a Buchwald-Hartwig type reaction, as previously described in Scheme 1.
  • ring A is linked to L through a N atom.
  • L is -L 1 -X 1 -L 2 -(L 3 )p-(X 3 )q-L 4 -, or -X 1 -L 2 -(L 3 )p-(X 3 )q-L 4 -, or -L 2 -(L 3 )p-(X 3 )q-L 4 -, or -(L 3 )p- (X 3 )q-L 4 -, or -(X 3 )q-L 4 -, or -L 4 -, its analogues or pre-cursors.
  • L is a pre-cursor of L, such that reaction between compounds (XIV) and (XV) forms L, wherein L is connected to ring A through an amide bond, L’’ contains a terminal carboxylic acid.
  • the carboxylic acid (XV) may be coupled with amine (XIV) using an amide coupling agent, such as PyBop or HATU, in the presence of an organic base, typically DIPEA, to give compound (II).
  • L’ is -L 1 -X 1 -L 2 -(L 3 )p-(X 3 )q-L 4 -, or -L 1 -X 1 -L 2 -(L 3 )p-(X 3 )q-, or -L 1 -X 1 -L 2 -(L 3 )p-, or - L 1 -X 1 -L 2 -, or -L 1 -X 1 -, or -L 1 -, its analogues or pre-cursors.
  • L’ is a pre-cursor of L, such that reaction between (X) and (XI) forms L.
  • compound (II) may be obtained from halide (XVII) and amine (XVI) by a Buchwald type palladium catalysed coupling reaction as previously described in Scheme 1.
  • compound (II) may be obtained by an alklyation reaction of amine (XVI) with halide (XVII) as previously described in Scheme 1.
  • Compound (II) may be obtained by a reductive amination reaction between the aldehyde (XVI) and amine (XV), or amine (XVI) and aldehyde (XV) in the presence of a suitable reducing agent such as STAB or MP-cycanoborohydride.
  • a suitable reducing agent such as STAB or MP-cycanoborohydride.
  • compound (II) may be obtained by an alkylation reaction between compound (XVI) that contains a suitable leaving group, such as a Br, Cl, I, F, mesylate or tosylate and amine (XV), or amine (XVI) and compound (XV) that contains a suitable leaving group, such as Br, Cl, I, F mesylate or tosylate, in the presence of a suitable organic or inorganic base, as previously described in Scheme 1.
  • L ’ and L ’’ form L through an -SO 2 -N- bond.
  • Compound (II) may be obtained by an alkylation reaction between sulfonyl chloride (XVI) and amine (XV) in the presence of a suitable organic or inorganic base, optionally at elevated temperature.
  • L ’ and L ’’ form L through an -CO 2 -NH- bond.
  • Compound (II) may be obtained by an amide bond forming reaction between amine (XVI) and carboxylic acid (XV), or carboxylic acid (XVI) and amine (XVI), as previously described in Scheme 3.
  • L ’ and L ’’ form L by formation of a 5 to 12-membered arylheterocycle.
  • Compound (II) may be obtained by a cycloaddition reaction between compounds (XV) and (XVI).
  • compound (II) may be obtained by reaction of azide (XVI) and acetylene (XV), or acetylene (XVI) and azide (XV) by a copper catalysed cycloaddition reaction.
  • Compounds (XVI) may be converted to alternative compounds (XVI) by reaction with -X 1 -L 2 -(L 3 )p-(X 3 )q-L 4 -, or -L 2 -(L 3 )p-(X 3 )q-L 4 -, or -(L 3 )p-(X 3 )q-L 4 -, or -(X 3 )q-L 4 -, or - L 4 -, its analogues or pre-cursors, so that L ’ and L ’’ form L following the reactions described in Scheme 6.
  • Compounds (XV) may be converted to alternative compounds (XV) by reaction with - its a nalogues or pre-cursors, so that L and L form L following the reactions described in Scheme 6.
  • Scheme 7 R 6 is H
  • Compound (XXI) may be obtained from the nitro compound (XX) by a reduction reaction under catalytic hydrogenation conditions, typically Pd/C in H 2 , or by reaction with a reducing metal, such as Fe or Zn in the presence of a suitable acid in a solvent such as EtOH.
  • Compound (XVI) may be obtained from the amine (XXI) and halide (XI) by an alkylation reaction or reaction under Buchwald-Hartwig coupling conditions, as previously described in Scheme 1.
  • Scheme 8 Compound (XXIV) may be obtained by reaction of the halide (XXII) and boronate ester (XXIII) under Suzuki-type palladium catalysed cross coupling reaction conditions.
  • Compound (XV) may be obtained from compound (XXIV) by a reduction reaction under catalytic hydrogenations conditions, as previously described in Scheme 7.
  • transformations include, but are not limited to, reduction of a C 1 -C 4 carboxylic ester to provide an alcohol, oxidation of a primary alcohol to provide an aldehyde, hydrolysis of a C1-C4 carboxylic ester to provide a carboxylic acid, hydrolysis of an acetal to provide an aldehyde, alkylation of a primary or secondary N or O atom to provide a secondary or tertiary amine or ether, and conversion of an alcohol to an azide via a leaving group, such as a tosylate, by reaction with NaN 3 .
  • a leaving group such as a tosylate
  • Typical protecting groups may comprise, a carbamate, preferably a Boc or CBz group for the protection of primary or secondary aliphatic amines, tert-butyl for the protection of carboxylic acids and tosylate for the protection of primary aliphatic alcohols. It will be appreciated that it may be necessary and/or desirable to carry out the transformations in a different order from that described in the schemes, or to modify one or more of the transformations, to provide the desired compound of the invention. Compounds that contain one or more stereocenters may be separated into their separate stereoisomers by typical methods such as chiral SFC or chiral HPLC techniques as indicated in the Intermediates and Examples below.
  • HPLC-A (X-BRIDGE-C18 (150 x 19 mm), 5 ⁇ m; 0-100% MeCN/H2O (0.1% HCO2H)); HPLC-B (X-SELECT-C18 (250 x 19 mm), 5 ⁇ m; 0-100% MeCN/H 2 O (0.1% HCO 2 H)); HPLC-C (X-BRIDGE-C18 (250 x 19 mm), 5 ⁇ m; 0-100% MeCN/H 2 O (0.1% HCO 2 H)); HPLC-D (SUNFIRE-C18 (250 x 10 mm), 5 ⁇ m; 0-100% MeCN/ H2O (0.1% HCO2H)); HPLC-E (KROMOSIL-C18 (150 x 25 mm), 10 ⁇ m 0-100% MeCN/H2O (0.1% HCO2H)); HPLC-F 9YMC TRIART (50 x 2.1 mm) 1.7 ⁇ m; 0-100% MeCN (0.05%
  • 2,5-dichloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidine A mixture of 2,4,5-trichloropyrimidine (1 g, 5.45 mmol), 1-methyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.69 g, 8.17 mmol), Pd(dppf)Cl 2 (100 mg, 122 ⁇ mol), Cs2CO3 (3.55 g, 10.9 mmol) in dioxane (50 mL) and H2O (10 mL) was stirred at 50°C for 2 h.
  • Step-1 Synthesis of tert-butyl 4-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)prop- 2-yn-1-yl)oxy)piperidine-1-carboxylate
  • Cesium carbonate (2.52 g, 7.74 mmol) was added to a stirred solution of 3-(5-bromo-1- oxoisoindolin-2-yl)piperidine-2,6-dione (1.0 g, 3.10 mmol) and tert-butyl 4-(prop-2-yn-1- yloxy)piperidine-1-carboxylate (1.11 g, 4.64 mmol) in DMF (10 mL) and the mixture purged with nitrogen for 15 min.
  • Step-2 Synthesis of 3-(1-oxo-5-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)isoindolin-2- yl)piperidine-2,6-dione
  • tert-butyl 4-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)prop-2-yn-1-yl)oxy)piperidine-1-carboxylate (Step 1, 1.3 g, 2.70 mmol) in DCM (13 mL) was added 4.0 M HCl in dioxane (6.5 mL) at 0 °C and allowed to stir at rt for 3 h.
  • Step 2 Synthesis of 2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetic acid
  • tert-butyl 2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oxy)acetate (Step 1, 0.30 g, 0.82 mmol) in DCM (5 mL) was added TFA (3 mL) at 0 °C and the mixture stirred at rt for 2 h.
  • the reaction mixture was concentrated under reduced pressure to afford the title compound as a white solid (0.20g, 80%).
  • Step 1 Synthesis of tert-butyl 9-(3-bromophenyl)-3,9-diazaspiro[5.5]undecane-3- carboxylate
  • tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate 5 g, 19.7 mmol
  • DCM 100 mL
  • 3-bromophenyl)boronic acid 7.90 g, 39.3 mmol
  • triethylamine 8.19 mL, 59 mmol
  • Step 1 Synthesis of tert-butyl 4-((3-(3-(2,6-dioxopiperidin-3-yl)phenyl)prop-2-yn-1- yl)oxy)piperidine-1-carboxylate
  • 3-(3-iodophenyl)piperidine-2,6-dione 1.0 g, 3.17 mmol
  • tert- butyl 4-(prop-2-yn-1-yloxy)piperidine-1-carboxylate (1.37 g, 5.71 mmol) in DMF (10 mL) was added cesium carbonate (2.59 g, 7.93 mmol) and purged with nitrogen gas for 15 min.
  • Step 1 Synthesis of tert-butyl 4-(4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2- methylphenyl)prop-2-yn-1-yl)oxy)piperidine-1-carbonyl)piperidine-1-carboxylate
  • 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (262 mg, 1.142 mmol)
  • HATU 434 mg, 1.142 mmol
  • DMF 15 mL
  • 1-(2-methyl-3-(3- (piperidin-4-yloxy)prop-1-yn-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione Intermediate 11, 325 mg, 0.952 mmol
  • DIPEA 0.97 mL, 2.856 mmol
  • Step 2 Synthesis of 1-(2-methyl-3-(3-((1-(piperidine-4-carbonyl)piperidin-4-yl)oxy)prop-1- yn-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione
  • Step 1 Synthesis of methyl (1r,4r)-4-((3-fluoro-4-nitrophenyl)sulfonamido)cyclohexane-1- carboxylate
  • methyl (1r,4r)-4-aminocyclohexane-1-carboxylate 10 g, 63.61 mmol
  • DCM DCM
  • 3-fluoro-4-nitrobenzenesulfonyl chloride 22.86 g, 95.41 mmol
  • TEA (19.31 g, 191 mmol
  • Step 1 Synthesis of tert-butyl 4-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)prop- 2-yn-1-yl)oxy)piperidine-1-carboxylate
  • 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione 1.0 g, 3.10 mmol
  • tert-butyl 4-(prop-2-yn-1-yloxy)piperidine-1-carboxylate (1.111 g, 4.64 mmol) in DMF (10 mL) was added cesium carbonate (2.521 g, 7.74 mmol) and the resulting solution purged with nitrogen gas for 15 min.
  • Step 1 Synthesis of 3-fluoro-4-nitro-N-(2-(prop-2-yn-1-yloxy)ethyl)benzenesulfonamide.
  • 2-(prop-2-yn-1-yloxy)ethan-1-amine hydrochloride (1.50 g, 11.06 mmol)
  • 3-fluoro-4-nitrobenzenesulfonyl chloride (3.98 g, 16.59 mmol)
  • DCM 7.5 mL
  • triethylamine 4 mL, 27.66 mmol
  • Step 2 Synthesis of 4-amino-3-fluoro-N-(2-(prop-2-yn-1-yloxy)ethyl)benzenesulfonamide Iron powder (16.3 g, 291 mmol) and ammonium chloride (15.6 g, 291 mmol) were added to a stirred solution of 3-fluoro-4-nitro-N-(2-(prop-2-yn-1-yloxy)ethyl)benzenesulfonamide (Step 1, 4.40 g, 14.6 mmol) in ethanol (22 mL) and water (22 mL) and stirred at 80 °C for 2 h.
  • reaction mixture was filtered through a pad of celite and washed with methanol (2x 30 mL). The filtrate was concentrated under reduced pressure and the remaining aqueous solution extracted with DCM (50 mL). The combined organics were dried (Na 2 SO 4 ) and concentrated under reduced pressure to afford the title compound as a brown gum (3.80 g, 96%).
  • Step 1 Synthesis of tert-butyl ((3-fluoro-4-nitrophenyl)sulfonyl)glycinate.
  • a solution of tert-butyl glycinate (2.00 g, 15.3 mmol) and triethylamine (3.86 g, 38.2 mmol) in DCM (20 mL) was stirred for 15 min at rt and cooled to 0 °C before 3-fluoro-4- nitrobenzenesulfonyl chloride (5.48 g, 22.9 mmol) was added and stirring continued at 0 °C for 2 h.
  • the reaction mixture was quenched with ice-cold water (20 mL) and extracted with DCM (3x 25 mL).
  • Step 3 Synthesis of tert-butyl ((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4- yl)-5-(trifluoromethyl)pyrimidin-2-yl) amino) phenyl) sulfonyl) glycinate.
  • Step 4 Synthesis of ((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)glycine.
  • Step 8 Synthesis of 3-(1-oxo-5-(4-(piperazin-1-ylmethyl)piperidin-1-yl)isoindolin-2- yl)piperidine-2,6-dione trifluoroacetate.
  • Step 1 Synthesis of tert-butyl 2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2,7- diazaspiro[3.5]nonane-7-carboxylate
  • 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1 g, 3.09 mmol)
  • tert- butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (488 mg, 2.16 mmol)
  • Pd-PEPPSI-IHeptCl 3- chloropyridine 120 mg, 123 ⁇ mol
  • Cs 2 CO 3 (3 g, 9.26 mmol) in dioxane (40 mL) was stirred at 100 °C for 3 h.
  • Step 1 Synthesis of ethyl 1-((1r,4r)-4-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonamido)cyclohexane-1- carbonyl)piperidine-4-carboxylate.
  • HATU 80.17 mg, 0.21 mmol
  • (1r,4r)-4-((3-fluoro-4-((4-(1- (2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)phenyl)sulfonamido)cyclohexane-1-carboxylic acid (Intermediate 15, 150 mg, 0.250 mmol), DIPEA (0.13 mL, 0.75 mmol) and ethyl piperidine-4-carboxylate (39.3 mg, 0.250 mmol) in dry DMF (3 mL) 0 °C and the reaction mixture warmed to rt and stirred for 16 h.
  • Step 1 Synthesis of tert-butyl 4-((2-(1-methyl-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oxy)piperidine-1-carboxylate.
  • Step 2 Synthesis of 1-methyl-3-(1-oxo-4-(piperidin-4-yloxy)isoindolin-2-yl)piperidine-2,6- dione.
  • the title compound was prepared (100 mg, 58%) from tert-butyl 4-((2-(1-methyl-2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)piperidine-1-carboxylate (Step 1) using an analogous method to that described for Intermediate 54, Step 2.
  • LCMS m/z 358 [M+H] + .
  • Intermediate 43 Synthesis of 1-methyl-3-(1-oxo-4-(piperidin-4-yloxy)isoindolin-2-yl)piperidine-2,6- dione.
  • the title compound was prepared (100 mg, 58%) from tert-butyl 4-((2-(1-methyl-2,6- dioxopiperidin-3-yl)-1-oxo
  • Step 1 Synthesis of tert-butyl (1-((4-((4-((4-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl) prop-2-yn-1-yl) oxy) piperidin-1-yl) methyl) piperidin-1-yl) sulfonyl) piperidin-4-yl) carbamate
  • 3-(1-oxo-4-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)isoindolin-2- yl)piperidine-2,6-dione (Intermediate 16, 0.16 g, 0.28 mmol) in DCM (5 mL) and tert-butyl (1-(chlorosulfonyl) piperidin-4-yl) carbamate (0.12 g, 0.42 mmol) was added triethylamine (0.19 mL,
  • Step 2 Synthesis 3-(4-(3-((1-((1-((4-aminopiperidin-1-yl)sulfonyl)piperidin-4- yl)methyl)piperidin-4-yl)oxy)prop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione
  • tert-butyl (1-((4-((4-((4-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin- 4-yl) prop-2-yn-1-yl) oxy) piperidin-1-yl) methyl) piperidin-1-yl) sulfonyl) piperidin-4-yl) carbamate (0.17 g, 0.23 mmol) in DCM (3 mL) was added TFA (0.42 mL, 5.52 mmol) at 0 °C and the
  • Step 1 Synthesis of tert-butyl 4-((4-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)piperidine-1-carboxylate
  • 3-(1-oxo-4-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)isoindolin-2- yl)piperidine-2,6-dione (Intermediate 16, 0.30 g, 0.79 mmol) and tert-butyl 4- formylpiperidine-1-carboxylate (0.21 g, 1.02 mmol) in MeOH (3 mL) were added acetic acid (0.004 mL, 0.079 mmol) followed by MP-cynoborohydride (0.30 g) was added at rt and the resulting reaction mixture was stir
  • Step 2 Synthesis of 3-(1-oxo-4-(3-((1-(piperidin-4-ylmethyl)piperidin-4-yl)oxy)prop-1-yn-1- yl)isoindolin-2-yl)piperidine-2,6-dione
  • a solution of tert-butyl 4-((4-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)prop-2- yn-1-yl)oxy)piperidin-1-yl)methyl)piperidine-1-carboxylate (0.19 g, 0.33 mmol) in formic acid (2.5 mL) was stirred at rt for 4 h.
  • Step 1 Synthesis of tert-butyl 4-((3-(3-(2,6-dioxopiperidin-3-yl)phenyl)prop-2-yn-1- yl)oxy)piperidine-1-carboxylate
  • 3-(3-iodophenyl)piperidine-2,6-dione (1.00 g, 3.17 mmol)
  • tert- butyl 4-(prop-2-yn-1-yloxy)piperidine-1-carboxylate (1.37 g, 5.71 mmol) in DMF (10 mL) was added caesium carbonate (2.59 g, 7.93 mmol) at rt and purged with nitrogen gas for 15 min.
  • Step 2 Synthesis of 3-(3-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)phenyl)piperidine-2,6-dione
  • tert-butyl 4-((3-(3-(2,6-dioxopiperidin-3-yl)phenyl)prop-2-yn-1- yl)oxy)piperidine-1-carboxylate (Step 1, 1.20 g, 2.81 mmol) in DCM (12 mL) was added 4 M hydrochloric acid in dioxane (6 mL) dropwise at 0 °C and the resulting reaction mixture was allowed to stir at rt for 3 h.
  • Step 1 Synthesis of tert-butyl 4-((3-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)prop- 2-yn-1-yl)oxy)piperidine-1-carboxylate
  • 1-(4-bromophenyl)dihydropyrimidine-2,4(1H,3H)-dione (2 g, 7.43 mmol)
  • tert-butyl 4-(prop-2-yn-1-yloxy)piperidine-1-carboxylate (2.67 g, 11.1 mmol) in MeCN (30 mL) was added caesium carbonate (6.05 g, 18.6 mmol) at rt and purged with argon gas for 15 min before BrettPhos Pd G4 (0.68 g, 0.74 mmol) and copper(I) iodide (0.28 g, 1.49 mmol) added at rt and
  • Step 2 Synthesis of 1-(4-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)phenyl)dihydropyrimidine- 2,4(1H,3H)-dione
  • tert-butyl 4-((3-(4-(2,4-dioxotetrahydropyrimidin-1(2H)- yl)phenyl)prop-2-yn-1-yl)oxy)piperidine-1-carboxylate (1.2 g, 4.46 mmol) in DCM (6 mL) was added 4M hydrochloric acid in dioxane (6 mL) at 0 °C and the reaction mixture stirred at rt for 2 h.
  • Step 1 Synthesis of tert-butyl 2-(4-bromophenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate
  • tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate 5.0 g, 22.1 mmol
  • (4-bromophenyl)boronic acid 8.87 g, 44.2 mmol
  • triethylamine 9.2 mL, 66.3 mmol
  • Step 2 Synthesis of tert-butyl 2-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-2,7- diazaspiro[3.5]nonane-7-carboxylate
  • tert-butyl 2-(4-bromophenyl)-2,7-diazaspiro[3.5]nonane-7- carboxylate 6.0 g, 15.7 mmol
  • 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine 13.13 g, 31.5 mmol
  • dioxane 120 mL
  • water (12 mL) was added potassium phosphate (8.35 g, 39.3 mmol) at rt.
  • Step 3 Synthesis of tert-butyl 2-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,7- diazaspiro[3.5]nonane-7-carboxylate
  • tert-butyl 2-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-2,7- diazaspiro[3.5]nonane-7-carboxylate (4.50 g, 7.61 mmol) in ethanol (20 mL) was added Pd/C (4.50 g) and stirred at rt under H 2 (120 psi) atmosphere for 48 h.
  • Step 4 Synthesis of 3-(4-(2,7-diazaspiro[3.5]nonan-2-yl)phenyl)piperidine-2,6-dione
  • tert-butyl 2-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,7- diazaspiro[3.5]nonane-7-carboxylate (1.90 g, 4.60 mmol) in DCM (10 mL) was added, 4M hydrochloric acid in dioxane (5 mL) at 0 °C and the resulting reaction mixture stirred at rt for 2 h.
  • Step 2 Synthesis of 3-(4-(3-((1-(piperidin-4-ylmethyl)piperidin-4-yl)oxy)prop-1-yn-1- yl)phenyl)piperidine-2,6-dione
  • tert-butyl 4-((4-((3-(4-(2,6-dioxopiperidin-3-yl)phenyl)prop-2-yn-1- yl)oxy)piperidin-1-yl)methyl)piperidine-1-carboxylate (0.35 g, 0.67 mmol) in DCM (3.5 mL) was added 4 M hydrochloric acid in dioxane (1.75 mL) at 0 °C and the reaction mixture was stirred at rt for 3 h.
  • Step 1 Synthesis of tert-butyl 4-(1'-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[4,4'-bipiperidine]-1- carbonyl)piperidine-1-carboxylate
  • 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (0.07 g, 0.31 mmol) and HATU (0.17 g, 0.46 mmol)
  • DMF 1 mL
  • Step 2 Synthesis of 3-(4-(1'-(piperidine-4-carbonyl)-[4,4'-bipiperidin]-1- yl)phenyl)piperidine-2,6-dione 4 M hydrochloric acid in dioxane (2.96 mL) was added at 0 °C to a stirred solution of tert- butyl 4-(1'-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[4,4'-bipiperidine]-1-carbonyl)piperidine-1- carboxylate (0.11 g, 0.20 mmol) in DCM (2 mL) and the resulting reaction mixture stirred at rt for 3 h.
  • Step 1 Synthesis of N-(2-bromoethyl)-3-fluoro-4-nitrobenzenesulfonamide
  • 2-bromoethan-1-amine 2.0 g, 16.1 mmol
  • triethylamine 4.89 g, 48.4 mmol
  • 3-fluoro-4-nitrobenzenesulfonyl chloride 5.79 g, 24.19 mmol
  • the reaction mixture was diluted with water (500 mL) and extracted with DCM (3x 50 mL). The combined organics were dried (Na 2 SO 4 ) and concentrated under reduced pressure.
  • Step 2 Synthesis of 4-amino-N-(2-chloroethyl)-3-fluorobenzenesulfonamide To a stirred solution of N-(2-bromoethyl)-3-fluoro-4-nitrobenzenesulfonamide (1.0 g, 3.05 mmol) in ethanol and water (20 mL, 1:1) at rt was added iron powder (3.30 g, 61.13 mmol) and NH4Cl (3.42 g, 61.13 mmol) and the resulting reaction mixture stirred at 60 °C for 2 h.
  • Step 3 Synthesis of N-(2-chloroethyl)-3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide (48)
  • 4-amino-N-(2-chloroethyl)-3-fluorobenzenesulfonamide (0.50 g, 1.97 mmol)
  • TsOH 0.07 g, 0.39 mmol
  • Step 2 Synthesis of benzyl 4-(2-(1-(2-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonamido)ethyl)piperidin- 4-yl)acetyl)piperazine-1-carboxylate To a stirred solution of benzyl 4-(2-(piperidin-4-yl)acetyl)piperazine-1-carboxylate (0.2 g, 0.57 mmol) and N-(2-chloroethyl)-3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide (Intermediate 61, 0.24 g, 0.
  • Step 1 Synthesis of tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)piperazin-1-yl)methyl)piperidine-1-carboxylate DIPEA (1.37 g, 10.59 mmol) was added to a stirred solution of tert-butyl 4-(piperazin-1- ylmethyl)piperidine-1-carboxylate (1.00 g, 3.53 mmol) and 2-(2,6-dioxopiperidin-3-yl)-4- fluoroisoindoline-1,3-dione (1.17 g, 4.23 mmol) in DMSO (10 mL) at rt and the resulting reaction mixture stirred at 90 °C for 16 h.
  • Step 2 Synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-(4-(piperidin-4-ylmethyl)piperazin-1- yl)isoindoline-1,3-dione hydrochloride: 4.0 M hydrochloric acid in dioxane (4.8 mL) dropwise at 0 °C to a stirred solution tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)methyl)piperidine- 1-carboxylate (1.20 g, 2.22 mmol) in DCM (12 mL) and the resulting reaction mixture stirred at rt for 2 h.
  • Step 1 Synthesis of tert-butyl (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycinate DIPEA (9.46 mL, 54.30 mmol) was added at rt to a stirred solution of 2-(2,6-dioxopiperidin- 3-yl)-4-fluoroisoindoline-1,3-dione (5 g,18.1 mmol) and tert-butyl glycinate (4.75 g, 36.20 mmol) in DMSO (50 mL) and the resulting reaction mixture stirred at 90 °C for 16 h.
  • Step 2 Synthesis of (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycine: TFA (25 mL) was added dropwise at 0 °C to a stirred solution tert-butyl (2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycinate (5 g, 12.9 mmol) in DCM (25 mL) and the resulting reaction mixture stirred at rt for 2 h.
  • Step 1 Synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-((2-hydroxyethyl)amino)isoindoline-1,3- dione DIPEA (12.7 g, 98.2 mmol) was added at rt to a stirred solution of 2-(2,6-dioxopiperidin-3- yl)-4-fluoroisoindoline-1,3-dione (5.43 g, 19.65 mmol) and 2-aminoethan-1-ol (1.00 g, 16.37 mmol) in DMSO (20 mL) and the resulting reaction mixture stirred at 90 °C for 16 h.
  • Step 2 Synthesis of 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl 4- methylbenzenesulfonate TEA (0.39 mL, 2.76 mmol) was added dropwise at 0 °C to a stirred solution of 2-(2,6- dioxopiperidin-3-yl)-4-((2-hydroxyethyl)amino)isoindoline-1,3-dione (0.35 g, 1.10 mmol) and 4-toluenesulfonyl chloride (0.31 mg, 1.66 mmol) in DCM (5 mL) and the resulting reaction mixture stirred at rt for 16 h.
  • Step 1 Synthesis of tert-butyl 9-(2-((3-fluoro-4-nitrophenyl)sulfonamido)ethyl)-3,9- diazaspiro[5.5]undecane-3-carboxylate
  • a solution of 3-fluoro-4-nitrobenzenesulfonyl chloride (3.86 g, 16.13 mmol) in DCM (20 mL) was added dropwise to a stirred solution of tert-butyl 9-(2-aminoethyl)-3,9- diazaspiro[5.5]undecane-3-carboxylate (2.40 g, 8.06 mmol) and TEA (3.3 mL, 24.2 mmol) in DCM (20 mL) at -10 °C and stirred for 2 h at the same temperature.
  • Step 2 Synthesis of tert-butyl 9-(2-((4-amino-3-fluorophenyl)sulfonamido)ethyl)-3,9- diazaspiro[5.5]undecane-3-carboxylate
  • tert-butyl 9-(2-((3-fluoro-4-nitrophenyl)sulfonamido)ethyl)-3,9- diazaspiro[5.5]undecane-3-carboxylate (1.40 g, 2.79 mmol) in EtOH (25 mL) was added Fe (3.07 g, 55.9 mmol) and NH 4 Cl (2.96 g, 55.9 mmol) solution in water (25 mL) at rt and the resulting reaction mixture stirred at 80 oC for 2 h.
  • Step 3 Synthesis of tert-butyl 9-(2-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonamido)ethyl)-3,9- diazaspiro[5.5]undecane-3-carboxylate
  • tert-butyl 9-(2-((4-amino-3-fluorophenyl)sulfonamido)ethyl)-3,9- diazaspiro[5.5]undecane-3-carboxylate (0.86 g, 1.83 mmol) and 1-(4-(2-chloro-5- (trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 1, 0.58 g, 1.83
  • Step 1 Synthesis of 5-(tert-butoxycarbonyl)-2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan- 13-yl 4-methylbenzenesulfonate 4-methylbenzenesulfonyl chloride (8.18 g, 42.9 mmol) was added portion wise to a stirred solution of tert-butyl (tert-butoxycarbonyl)(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)carbamate (10 g, 28.6 mmol) and TEA (12 mL, 85.9 mmol) in DCM (100.00 mL) under an inert atmosphere at 0 °C and the reaction mixture was allowed to warm to rt and stirred for 18 h.
  • Step 2 Synthesis of tert-butyl (2-(2-(2-azidoethoxy)ethoxy)ethyl)(tert- butoxycarbonyl)carbamate NaN3 (3.87 g, 59.6 mmol) was added to a stirred solution of 5-(tert-butoxycarbonyl)-2,2- dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl 4-methylbenzenesulfonate (10 g, 19.9 mmoL) in DMF (60 mL) at rt and the reaction mixture heated at 60 °C for 16h. The reaction mixture was diluted with water (60 mL) and extracted with EtOAc (3x 60 mL).
  • Step 3 Synthesis of tert-butyl (2-(2-(2-aminoethoxy)ethoxy)ethyl)(tert- butoxycarbonyl)carbamate
  • tert-butyl (2-(2-(2-azidoethoxy)ethoxy)ethyl)(tert-butoxycarbonyl)carbamate 4.0 g, 10.7 mmoL
  • acetic acid 0.61 mL, 10.7 mmoL
  • EtOH 180 mL
  • 10% palladium on carbon (0.45 g, 4.27 mmoL) under an inert atmosphere at rt and hydrogenated under H 2 gas at 50 psi pressure at rt for 5 h.
  • Step 4 Synthesis of tert-butyl (tert-butoxycarbonyl)(2-(2-(2-((3-fluoro-4- nitrophenyl)sulfonamido)ethoxy)ethoxy)ethyl)carbamate TEA (3.5 mL, 9.75 mmoL) was added to a stirred solution tert-butyl (2-(2-(2- aminoethoxy)ethoxy)ethyl)(tert-butoxycarbonyl)carbamate (3.5 g, 10.0 mmoL) in DCM (35 mL) at 0 °C and stirred for 15 min.
  • TEA 3.5 mL, 9.75 mmoL
  • Step 5 Synthesis of tert-butyl (tert-butoxycarbonyl)(5-((3-fluoro-4-nitrophenyl)sulfonyl)-2,2- dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl)carbamate
  • tert-butyl (tert-butoxycarbonyl)(2-(2-(2-((3-fluoro-4- nitrophenyl)sulfonamido)ethoxy)ethoxy)ethyl)carbamate (3.30 g, 5.98 mmoL) in THF (66 mL) was added sodium hydride (598 mg, 60 % NaH, 14.95 mmoL) at 0 °C and stirred for 5 min.
  • Step 1 Synthesis of tert-butyl (17-azido-3,6,9,12,15-pentaoxaheptadecyl) (tert- butoxycarbonyl) carbamate
  • tert-butoxycarbonyl tert-butoxycarbonyl
  • Step 2 Synthesis of tert-butyl (17-amino-3,6,9,12,15-pentaoxaheptadecyl) (tert- butoxycarbonyl) carbamate
  • Step 3 Synthesis of tert-butyl (tert-butoxycarbonyl) (17-((3-fluoro-4-nitrophenyl) sulfonamido)-3,6,9,12,15-pentaoxaheptadecyl)carbamate
  • tert-butyl (17-amino-3,6,9,12,15-pentaoxaheptadecyl) (tert- butoxycarbonyl) carbamate (Step 2, 1.4 g, 2.91 mmol) in DCM (14 mL) was added triethylamine (1.01 mL, 7.28 mmol) dropwise at 0 °C and stirred for 15 min.
  • Step 4 Synthesis of tert-butyl (17-((4-amino-3-fluorophenyl) sulfonamido)-3,6,9,12,15- pentaoxaheptadecyl)(tert-butoxycarbonyl)carbamate
  • tert-butyl (tert-butoxycarbonyl) (17-((3-fluoro-4-nitrophenyl) sulfonamido)-3,6,9,12,15-pentaoxaheptadecyl)carbamate (Step 3, 1.50 g, 2.19 mmol) in EtOH (15 mL) and water (15 mL) was added ammonium chloride (2.34 g, 43.9 mmol) and Fe powder (2.45 g, 43.9mmoL) at 0 °C and the resulting reaction mixture stirred at 55 °C for 3h.
  • Step 5 Synthesis of tert-butyl (tert-butoxycarbonyl) (17-((3-fluoro-4-((4-(1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl) sulfonamido)-3,6,9,12,15-pentaoxaheptadecyl) carbamate To a stirred solution of 1-(4-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)- 2-methylpropan-2-ol Intermediate 1 (0.35 g, 1.10 mmol) and tert-butyl (17-((4-amino-3- fluorophenyl) sulfonamido)-3,6,9,12,15-pentaoxaheptadecyl)(tert-butoxycarbon
  • Step 6 Synthesis of N-(17-amino-3,6,9,12,15-pentaoxaheptadecyl)-3-fluoro-4-((4-(1-(2- hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl) pyrimidin-2-yl)amino) benzenesulfonamide hydrochloride
  • tert-butyl (tert-butoxycarbonyl) 17.((3-fluoro-4-((4-(1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl) sulfonamido)-3,6,9,12,15-pentaoxaheptadecyl) carbamate (Step 5, 0.24 g, 0.25 mmol) in DCM (2.4 mL)
  • Step 1 Synthesis of 2-(2-(2-(3-bromophenoxy)ethoxy)ethan-1-ol
  • 2-(2-(2-hydroxyethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (RSC Adv., 2020, 10, 21464-21472, 1.00 g, 3.29 mmol) and 3-bromophenol (0.85 g, 4.93 mmol) in MeCN (10 mL) was added potassium carbonate (1.36 g, 9.86 mmol) at rt and the resulting reaction mixture stirred at 80 °C for 16 h.
  • Step 2 Synthesis of 2-(2-(2-(3-(2,6-bis(benzyloxy)pyridin-3- yl)phenoxy)ethoxy)ethoxy)ethan-1-ol
  • 2-(2-(2-(3-bromophenoxy)ethoxy)ethoxy)ethan-1-ol (Step 1, 1.00 g, 3.28 mmol) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.37 g, 3.28 mmol) in dioxane (10 mL) and water (1 mL) was added solution of potassium phosphate (2.09 g, 9.83 mmol) under argon at rt.
  • reaction mixture was degassed with argon and PdCl2(dppf).DCM (0.27 g, 0.33 mmol) added and the resulting reaction mixture stirred at 110 °C for 3 h.
  • the reaction mixture was filtered through celite and the celite bed was washed with EtOAc (3x 30 mL). The filtrate was washed with water (50 mL) and brine (30 mL). The organics were dried (Na2SO4), concentrated under reduced pressure and the residue purified by combi-flash (SiO2, 10-20% EtOAc/PE) to afford the title compound as white semi-solid (1.10 g, 65%).
  • LCMS m/z 516 [M+H] + .
  • Step 3 Synthesis of 3-(3-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)phenyl)piperidine-2,6-dione
  • 2-(2-(2-(3-(2,6-bis(benzyloxy)pyridin-3- yl)phenoxy)ethoxy)ethan-1-ol (Step 2, 1.00 g, 3.28 mmol) in ethanol (10 mL) was added Palladium on carbon (0.30 g) at rt under nitrogen atmosphere and the reaction vessel filled with H 2 (50 psi) and stirred at rt for 16 h under H 2 .
  • Step 4 Synthesis of 2-(2-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)ethoxy)ethoxy)ethyl 4- methylbenzenesulfonate
  • 3-(3-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)phenyl)piperidine-2,6- dione (Step 3, 0.35 g, 1.04 mmol) and p-toluenesulfonyl chloride (0.40 g, 2.08 mmol) in DCM (7 mL) was added DMAP (0.01 g, 0.10 mmol) followed by dropwise addition of TEA (0.43 mL, 3.11 mmol) at 0 °C and the resulting reaction mixture stirred at rt for 16 h.
  • Step 5 Synthesis of 3-(3-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)phenyl)piperidine-2,6-dione
  • 2-(2-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)ethoxy)ethoxy)ethyl 4- methylbenzenesulfonate (Step 4, 0.37 g, 0.75 mmol) in DMF (7.4 mL) was added sodium azide (0.07 mg, 1.13 mmol) at rt and the resulting reaction mixture stirred at 60 °C for 3 h.
  • the reaction mixture was diluted with water (50 mL) and extracted using EtOAc (2x 30 mL).
  • Step 4 Synthesis of benzyl 9-((1-((3-fluoro-4-nitrophenyl)sulfonyl)piperidin-4-yl)methyl)- 3,9-diazaspiro[5.5]undecane-3-carboxylate
  • benzyl 9-(piperidin-4-ylmethyl)-3,9-diazaspiro[5.5]undecane-3- carboxylate hydrochloride (Step 3, 0.85 g, 2.01 mmol) and 3-fluoro-4-nitrobenzenesulfonyl chloride (1.45 g, 6.04 mmol) in DCM (25 mL) was added TEA (0.61 g, 6.04 mmol) dropwise at 0 °C and the resulting reaction mixture stirred at 0 °C
  • Step 5 Synthesis of benzyl 9-((1-((4-amino-3-fluorophenyl)sulfonyl)piperidin-4-yl)methyl)- 3,9-diazaspiro[5.5]undecane-3-carboxylate
  • benzyl 9-((1-((3-fluoro-4-nitrophenyl)sulfonyl)piperidin-4- yl)methyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (Step 4, 1.10 g,1.87 mmol) in EtOH (40 mL) and water (40 mL), iron powder (2.09 g, 37.4 mmol) and ammonium chloride (2.0 g, 37.4 mmol) were added and stirred at 70 °C for 2 h.
  • Step 6 Synthesis of benzyl 9-((1-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)piperidin-4- yl)methyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate 1-(4-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol Intermediate 1 (0.34 g, 1.07 mmol) was added at rt to a stirred solution of benzyl 9-((1-((4- amino-3-fluorophenyl)sulfonyl)piperidin-4-yl)methyl)-3,9-diazaspiro[5.5]undecane-3- carboxy
  • Step 7 Synthesis of 1-(4-(2-((4-((4-((4-((3,9-diazaspiro[5.5]undecan-3-yl)methyl)piperidin-1- yl)sulfonyl)-2-fluorophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2- methylpropan-2-ol.
  • Step 1 Synthesis of 3-(3-(4-hydroxybut-1-yn-1-yl)phenyl)piperidine-2,6-dione
  • 3-(3-bromophenyl)piperidine-2,6-dione 3 g, 11.19 mmol
  • but-3- yn-1-ol 2.35 g, 33.6 mmol
  • DIPEA.trihydrofluoride 2.35 g, 55.9 mmol
  • Step-2 Synthesis of 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)but-3-yn-1-yl 4- methylbenzenesulfonate
  • 3-(3-(4-hydroxybut-1-yn-1-yl)phenyl)piperidine-2,6-dione (Step 1, 2 g, 7.77 mmol) in DCM (30 mL) was added TEA (3.23 mL, 23.3 mmol) at 0 o C followed by the addition of 4-toluenesulfonyl chloride (2.22 g, 11.7 mmol) in DCM (10 mL) and the reaction mixture warmed to rt and stirred for 16 h.
  • Step-3 Synthesis of 3-(3-(4-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)but-1-yn-1- yl)phenyl)piperidine-2,6-dione
  • 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)but-3-yn-1-yl 4- methylbenzenesulfonate (Step 2, 350 mg, 0.88 mmol) and 4-(1,3-dioxolan-2-yl)piperidine (138.5 mg, 0.88 mmol) in DMF (3.5 mL) were added sodium bicarbonate (222 mg, 2.64 mmol) and KBr (21 mg, 0.18 mmol) at rt and the reaction mixture heated 90 °C for 16 h.
  • Step 4 Synthesis of 1-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)but-3-yn-1-yl)piperidine-4- carbaldehyde TFA (1 mL) was added to a stirred solution of 3-(3-(4-(4-(1,3-dioxolan-2-yl)piperidin-1- yl)but-1-yn-1-yl)phenyl)piperidine-2,6-dione (Step 3, 110 mg, 0.28 mmol) in DCM (1 mL) and water (0.2 mL) and the reaction mixture stirred at rt for 16h.
  • Step 1 Synthesis of tert-butyl (6-((3-fluoro-4-nitrophenyl)sulfonamido)hexyl)carbamate
  • tert-butyl (6-aminohexyl)carbamate 5.0 g, 23.1 mmol
  • 3-fluoro- 4-nitrobenzenesulfonyl chloride 8.30 g, 34.7 mmol
  • TEA 4.60 g, 46.2 mmol
  • Step 2 Synthesis of tert-butyl (6-((4-amino-3-fluorophenyl)sulfonamido)hexyl)carbamate
  • tert-butyl (6-((3-fluoro-4-nitrophenyl)sulfonamido)hexyl)carbamate (Step 1, 0.50 g, 1.19 mmol) in MeOH (5 mL) was added Pd/C (0.10 g) at rt under nitrogen and the reaction vessel was filled with H2 (50 psi) and stirred at rt for 2 h under H2.
  • the reaction mixture was filtered through a pad of celite and washed with MeOH (3x 50 mL).
  • Step 3 and 4 Synthesis of 3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-N-(6-((2,2,2-trifluoroacetyl)-l4- azaneyl)hexyl)benzenesulfonamide
  • the title compound was prepared from tert-butyl (6-((4-amino-3- fluorophenyl)sulfonamido)hexyl)carbamate (Step 2, 0.30 g, 0.94 mmol) and 1-(4-(2-chloro-5- (trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol Intermediate 1 (0.36 g, 0.94 mmol) using an analogous 2 -Step method to that described for Intermediate 71, Step 5 and 6.
  • Step 1 Synthesis of tert-butyl (5-((3-fluoro-4-nitrophenyl)sulfonamido)pentyl)carbamate
  • the title compound was prepared as a brown liquid (6.0g, 60%) from tert-butyl (5- aminohexyl)carbamate (5 g, 24.71 mmol) and 3-fluoro-4-nitrobenzenesulfonyl chloride (11.84 g, 7.32 mmol) using an analogous method to that described for Intermediate 71, Step 1.
  • Step 2, 3, 4, 5 Synthesis of N-(5-aminopentyl)-3-fluoro-4-((4-(1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide hydrochloride
  • the title compound was prepared from tert-butyl (5-((3-fluoro-4- nitrophenyl)sulfonamido)pentyl)carbamate (Step 1) using an analogous 4-Step procedure as described for Intermediate 70, 55 Steps 5, 6, 7, 8.
  • LCMS m/z 560 [M+H] + .
  • Intermediate 93 Synthesis of N-(5-aminopentyl)-3-fluoro-4-((4-(1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- y
  • Step 1 and 2 Synthesis of tert-butyl (7-((4-amino-3- fluorophenyl)sulfonamido)heptyl)carbamate
  • the title compound was prepared from tert-butyl (7-aminoheptyl)carbamate and 3-fluoro-4- nitrobenzenesulfonyl chloride using an analogous 2-Step procedure as described for Intermediate 91, Step 5 and 6.
  • LCMS m/z 404 [M+H] + . Step 3, 4.
  • Step 1, 2, 3. Synthesis of 11-((4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)piperidin-4-one.
  • the title compound was prepared as a white solid (0.60 g) from piperidin-4-one using an analogous 3-Step procedure as described for Intermediate 71, Step 3, 4, 5.
  • LCMS m/z 539 [M+H] + . Step 4.
  • Step 1 Synthesis of methyl (1r,4r)-4-((3-fluoro-N-methyl-4- nitrophenyl)sulfonamido)cyclohexane-1-carboxylate
  • the title compound was prepared as a brown solid (1.1 g, 53%) from methyl (1r,4r)-4-((3- fluoro-4-nitrophenyl)sulfonamido)cyclohexane-1-carboxylate (Intermediate 14, Step 1; 2.00 g, 5.55 mmol) using an analogous method to that described for Intermediate 97, Step 1.
  • LCMS m/z 375 [M+H] + .
  • Step 2 Synthesis of methyl (1r,4r)-4-((4-amino-3-fluoro-N- methylphenyl)sulfonamido)cyclohexane-1-carboxylate
  • the title compound was prepared as a black solid (900 mg, 98%) from methyl (1r,4r)-4-((3- fluoro-N-methyl-4-nitrophenyl)sulfonamido)cyclohexane-1-carboxylate (Step 1, 1 g) using an analogous method to that described for Intermediate 71, Step 4.
  • LCMS m/z 345 [M+H] + .
  • Step 3 Synthesis of methyl (1r,4r)-4-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N- methylphenyl)sulfonamido)cyclohexane-1-carboxylate
  • Step 2 0.90 g, 2.61 mmol
  • Intermediate 1 (1.01 g, 3.14 mmol) in dioxane (20 mL) was added caesium
  • Step 4 Synthesis of 3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-N-((1r,4r)-4-(hydroxymethyl)cyclohexyl)-N- methylbenzenesulfonamide
  • methyl (1r,4r)-4-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N- methylphenyl)sulfonamido)cyclohexane-1-carboxylate (Step 3, 0.215 g, 0.350 mmol) in THF (50 mL) was added LiAlH4 (0.64 mL, 1.27 mmol) at 0 °C and
  • Step 1 Synthesis of N-(2-chloroethyl)-3-fluoro-N-methyl-4-nitrobenzenesulfonamide.
  • 2-chloro-N-methylethan-1-amine 2.0 g, 21.4 mmol
  • DCM DCM
  • TEA 9.28 mL, 64.2 mmol
  • 3-fluoro-4- nitrobenzenesulfonyl chloride (6.15 g, 25.7 mmol) and the resulting mixture stirred at 0 °C for 1 h.
  • the reaction mixture was diluted with water (80 mL) and extracted with DCM (3x 60 mL).
  • Step 1 Synthesis of tert-butyl 4-((1-(2-(2- (((benzyloxy)carbonyl)amino)ethoxy)ethyl)piperidin-4-yl)methyl)piperazine-1-carboxylate
  • 2-(2-(((benzyloxy)carbonyl)amino)ethoxy)ethyl 4- methylbenzenesulfonate (0.75 g, 1.91 mmol)
  • tert-butyl 4-(piperidin-4- ylmethyl)piperazine-1-carboxylate (0.54 g, 1.91 mmol) in MeCN (15 mL) was added potassium carbonate (0.79 g, 5.72 mmol) at rt and the resulting reaction mixture stirred at 80 °C for 16 h.
  • Step 2 Synthesis of tert-butyl 4-((1-(2-(2-aminoethoxy)ethyl)piperidin-4- yl)methyl)piperazine-1-carboxylate
  • tert-butyl 4-((1-(2-(2- (((benzyloxy)carbonyl)amino)ethoxy)ethyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (Step 1, 0.60 g, 1.19 mmol) in MeOH (12 mL) were added Pd/C (0.10 g) and stirred at rt for 4 h.
  • Step 3 and 4 Synthesis of tert-butyl 4-((1-(2-(2-((4-amino-3- fluorophenyl)sulfonamido)ethoxy)ethyl)piperidin-4-yl)methyl)piperazine-1-carboxylate
  • the title compound was prepared as a colourless solid (0.20 g, 66%) from tert-butyl 4-((1-(2- (2-aminoethoxy)ethyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (Step 2) using an analogous 2-Step procedure as described for Intermediate 91, Step 1 and 2.
  • LCMS m/z 544 [M+H] + .
  • Step 5 and 6 Synthesis of 3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-N-(2-(2-(4-(piperazin-1-ylmethyl)piperidin-1- yl)ethoxy)ethyl)benzenesulfonamide
  • the title compound was prepared as a brown semi-solid from tert-butyl 4-((1-(2-(2-((4- amino-3-fluorophenyl)sulfonamido)ethoxy)ethyl)piperidin-4-yl)methyl)piperazine-1- carboxylate (Step 4) using an analogous 2-Step procedure as described for Intermediate 71, Step 5 and 6.
  • Step 1 Synthesis of tert-butyl (14-azido-3,6,9,12-tetraoxatetradecyl)(tert- butoxycarbonyl)carbamate
  • tert-butyl 14-azido-3,6,9,12-tetraoxatetradecyl 4-methylbenzenesulfonate (6.0 g, 14.4 mmol) in DMF (7.4 mL) was added di-tert-butyl iminodicarbonate (3.45 g, 15.8 mmol) at rt and the resulting reaction mixture stirred at 60 °C for 3 h.
  • the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2x 60 mL).
  • Step 2 Synthesis of tert-butyl (14-amino-3,6,9,12-tetraoxatetradecyl)(tert- butoxycarbonyl)carbamate
  • tert-butyl (14-azido-3,6,9,12-tetraoxatetradecyl)(tert- butoxycarbonyl)carbamate (Step 1, 2.30 g, 4.97 mmol) in MeOH (25 mL) was added Pd/C (0.53 g) at rt under nitrogen atmosphere.
  • reaction vessel was filled with H2 (50 psi) gas and the resulting reaction mixture was stirred at rt for 3 h under H2 gas atmosphere.
  • the reaction mixture was filtered through a pad of celite and washed with MeOH (3x 25 mL). The filtrate was evaporated under reduced pressure and the residue purified by combi-flash (SiO2, 4% MeOH/DCM) to afford the title compound as colourless liquid (2.0g, 92%).
  • LCMS m/z 437 [M+H] + .
  • Step 3 Synthesis of tert-butyl (14-((4-bromo-3-fluorophenyl)sulfonamido)-3,6,9,12- tetraoxatetradecyl)(tert-butoxycarbonyl)carbamate
  • tert-butyl (14-amino-3,6,9,12-tetraoxatetradecyl)(tert- butoxycarbonyl)carbamate Step 2, 0.50 g, 1.15 mmol
  • 4-bromo-3-fluorobenzenesulfonyl chloride (0.63 g, 2.29 mmol)
  • DCM 15 mL
  • Step 4 Synthesis of tert-butyl (tert-butoxycarbonyl)(14-((4-((5-cyano-4-(1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)methyl)-3-fluorophenyl)sulfonamido)- 3,6,9,12-tetraoxatetradecyl)carbamate
  • tert-butyl (14-((4-bromo-3-fluorophenyl)sulfonamido)-3,6,9,12- tetraoxatetradecyl)(tert-butoxycarbonyl)carbamate (Step 3, 0.30 g, 0.45 mmol) and 2-amino- 4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile Intermediate 107 (0.92 g, 0.36 mmol) in di
  • reaction mixture was purged with argon and Pd2(dba)3 (0.41 g, 0.05 mmol) and XantPhos (0.51 g, 0.09 mmol) added at rt and the resulting reaction mixture heated in a microwave oven at 160 °C for 20 min.
  • the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3x 30 mL). The combined organics were dried (Na2SO4), concentrated under reduced pressure and the residue purified by combi-flash (SiO2, 50% EtOAc/PE) to afford the title compound as a light brown solid (0.22 g, 58%).
  • LCMS m/z 851 [M+H] + .
  • Step 5 Synthesis of N-(14-amino-3,6,9,12-tetraoxatetradecyl)-4-((5-cyano-4-(1-(2-hydroxy- 2-methylpropyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)methyl)-3-fluorobenzenesulfonamide hydrochloride 4 M hydrochloric acid in dioxane (5 mL) was added at 0 °C to a stirred solution of tert-butyl (tert-butoxycarbonyl)(14-((4-((5-cyano-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4- yl)pyrimidin-2-yl)methyl)-3-fluorophenyl)sulfonamido)-3,6,9,12- tetraoxatetradecyl)carbamate (Step 4, 0.22 mg, 0.26 mmol) in DCM (5 mL) and
  • Step 1 Synthesis of tert-butyl 3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oxy)azetidine-1-carboxylate
  • 3-(4-hydroxy-1-oxoisoindolin-2-yl) piperidine-2,6-dione (0.50 g, 1.92 mmol)
  • NaHCO3 (0.48 g, 5.76 mmol
  • KBr 0.27 g, 2.30 mmol
  • tert-butyl 3-(tosyloxy)azetidine-1-carboxylate (1.88 g, 5.76 mmol) at rt and the resulting reaction mixture stirred at 80 °C for 16 h.
  • Step 2 Synthesis of 3-(4-(azetidin-3-yloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydroacid
  • tert-butyl 3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oxy)azetidine-1-carboxylate (Step 1, 0.30 g, 0.72 mmol) in DCM (0.6 mL) was added 4 M HCl in dioxane(0.60 mL) at 0 °C and the reaction mixture was stirred at rt for 2h.
  • Step 3 Synthesis of tert-butyl (1-((4-((3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oxy)azetidin-1-yl)methyl)piperidin-1-yl)sulfonyl)piperidin-4-yl)carbamate
  • 3-(4-(azetidin-3-yloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride Step 2, 0.35 g, 1.11 mmol
  • tert-butyl (1-((4-(iodomethyl)piperidin-1- yl)sulfonyl)piperidin-4-yl)carbamate Intermediate 34, Step 1; 0.70 g, 1.43 mmol) in dioxane (7 mL) was added DIPEA (0.6 mL,
  • Step 4 Synthesis of 3-(4-((1-((1-((4-aminopiperidin-1-yl)sulfonyl)piperidin-4- yl)methyl)azetidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride
  • tert-butyl (1-((4-((3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oxy)azetidin-1-yl)methyl)piperidin-1-yl)sulfonyl)piperidin-4-yl)carbamate (Step 3, 0.40 g, 0.59 mmol) in DCM (8 mL) was added 4 M HCl in dioxane(0.80 mL) at 0 °C and the reaction mixture stirred for 2h at rt.
  • Step 1 Synthesis of tert-butyl (1-((4-(prop-2-yn-1-yloxy)piperidin-1-yl)sulfonyl)piperidin-4- yl)carbamate
  • TEA (1.45 mL, 6.81 mmol) was added dropwise at 0 °C to a stirred solution of tert-butyl (1- (chlorosulfonyl)piperidin-4-yl)carbamate (Intermediate 39, 1.00 g, 3.35 mmol) and 4-(prop- 2-yn-1-yloxy)piperidine (0.56 g, 4.02 mmol) in DCM (10 mL) and the reaction mixture stirred at rt for 4 h.
  • Step 2 Synthesis of 1-((4-(prop-2-yn-1-yloxy)piperidin-1-yl)sulfonyl)piperidin-4-amine hydrochloride 4 M hydrochloric acid in dioxane (5 mL) was added dropwise at 0 °C to a stirred solution of tert-butyl (1-((4-(prop-2-yn-1-yloxy)piperidin-1-yl)sulfonyl)piperidin-4-yl)carbamate (Step 1, 700 mg, 1.743 mmol) in DCM (5 mL) and the reaction mixture stirred at rt for 2 h.
  • Step 3 Synthesis of 2-methyl-1-(4-(2-((1-((4-(prop-2-yn-1-yloxy)piperidin-1- yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1- yl)propan-2-ol: To a stirred solution of 1-((4-(prop-2-yn-1-yloxy)piperidin-1-yl)sulfonyl)piperidin-4-amine hydrochloride (0.30 g, 0.89 mmol) and 1-(4-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H- pyrazol-1-yl)-2-methylpropan-2-ol Intermediate 1
  • Step 1 Synthesis of tert-butyl (1-((4-((4-(prop-2-yn-1-yloxy)piperidin-1-yl)methyl)piperidin- 1-yl)sulfonyl)piperidin-4-yl)carbamate
  • 4-(prop-2-yn-1-yloxy)piperidine hydrochloride (0.80 g, 4.56 mmol)
  • tert-butyl 4-formylpiperidine-1-carboxylate (0.97 g , 4.56 mmol) in 1,2-dichloroethane (8 mL) was added acetic acid (0.026 mL) at rt and the resulting reaction mixture stirred at rt for 2 h.
  • Step 2 Synthesis of 1-(piperidin-4-ylmethyl)-4-(prop-2-yn-1-yloxy)piperidine hydrochloride
  • tert-butyl (1-((4-((4-(prop-2-yn-1-yloxy)piperidin-1- yl)methyl)piperidin-1-yl)sulfonyl)piperidin-4-yl)carbamate (0.5 g, 1.49 mmol) in DCM (2 mL) was added 4 M hydrochloric acid in dioxane (2 mL) dropwise at 0 °C and the reaction mixture stirred at rt for 2 h.
  • Step 3 Synthesis of 2-methyl-1-(4-(2-((1-((4-((4-((4-(prop-2-yn-1-yloxy)piperidin-1- yl)methyl)piperidin-1-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)- 1H-pyrazol-1-yl)propan-2-ol
  • the title compound was prepared as an off-white solid (0.35 g,) from 1-(piperidin-4- ylmethyl)-4-(prop-2-yn-1-yloxy)piperidine hydrochloride (Step 2) and tert-butyl (1- (chlorosulfonyl)piperidin-4-yl)carbamate (Intermediate 39) using an analogous 3-Step procedure as described for Intermediate 115.
  • Step 1 Synthesis of benzyl 3,3-difluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4- yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate
  • benzyl 4-amino-3,3-difluoropiperidine-1-carboxylate 0.2 g, 0.740 mmol
  • DIPEA 0.44 mL, 3.70 mmol
  • Step-2 Synthesis of 1-(4-(2-((3,3-difluoropiperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol
  • benzyl 3,3-difluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol- 4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate (Step 1, 0.3 g, 0.54 mmol) in EtOH (6 mL) was added 10% Pd/C (0.058 g, 0.54 mmol) at rt and the reaction mixture stirred at rt for 3h under hydrogen pressure (14 psi).
  • Step-3 Synthesis of 1-(4-(2-((1-((4-(1,3-dioxolan-2-yl)piperidin-1-yl)sulfonyl)-3,3- difluoropiperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2- methylpropan-2-ol
  • Step 2 To the stirred solution of 1-(4-(2-((3,3-difluoropiperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Step 2, 0.24 g, 0.57 mmol) in DCM (5 mL) were added sequentially TEA (0.24 mL, 1.71 mmol) and 4-(1,3- dioxolan-2-yl)piperidine-1-sulfonyl chloride (Inter
  • Step 1 Synthesis of 2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)oxy)ethoxy)ethyl 4-methylbenzenesulfonate Tosyl chloride (0.70 g, 3.69 mmol) was added portion wise at 0 °C to a stirred solution of 2- (2,6-dioxopiperidin-3-yl)-4-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)isoindoline-1,3-dione (Bioorg.
  • Step 2 Synthesis of 4-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione
  • Acetic acid (2.2 mg, 0.37 mmol) was added to a solution of 3-(1-oxo-5-(3-(piperidin-4- yloxy)prop-1-yn-1-yl)isoindolin-2-yl)piperidine-2,6-dione (Intermediate 6, 70 mg, 0.184 mmol) and 1-((4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)piperidine-4-carbaldehyde (Intermediate 4, 113 mg, 0.202 mmol) in DCM (5 mL) and stirred at rt under N216 h.
  • HATU (57.0 mg, 0.150 mmol) was added to a mixture of (1r,4r)-4-((3-fluoro-4-((4-(1-(2- hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)phenyl)sulfonamido)cyclohexane-1-carboxylic acid (Intermediate 15, 75 mg, 0.125 mmol), 3-(1-oxo-5-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)isoindolin-2-yl)piperidine-2,6-dione (Intermediate 6, 42.9 mg, 0.112 mmol) and DIPEA (0.065 mL, 0.375 mmol) in DMF (2 mL) at 0 oC under N 2 and warmed to rt and stirred for 18h.
  • DIPEA 0.065 mL
  • HATU 0.055 g, 0.14 mmol
  • 1-(((1r,4r)-4-((3-fluoro-4-((4-(1-(2- hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)phenyl)sulfonamido)cyclohexyl)methyl)piperidine-4-carboxylic acid (Intermediate 29, 0.1g, 0.143 mmol), 3-(4-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)phenyl)piperidine-2,6- dione hydrochloride (Intermediate 28, 52 mg, 0.143 mmol) and DIPEA (55.6 mg, 0.43 mmol) in DMF (2 mL) at 0 °C under N2.
  • Acetic acid (0.001 mL, 0.018 mmol) was added to a solution of 1-((4-((4-(1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1- yl)sulfonyl)piperidine-4-carbaldehyde (Intermediate 4, 100 mg, 0.179 mmol) and 3-(4-(3,9- diazaspiro[5.5]undecan-3-yl)phenyl)piperidine-2,6-dione (Intermediate 9, 61 mg, 0.179 mmol) in DCE (2 mL) at rt and the mixture stirred at rt for 16 h.
  • Acetic Acid (0.001 mL, 0.018 mmol) was added to a solution of 1-((4-((4-(1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1- yl)sulfonyl)piperidine-4-carbaldehyde (Intermediate 4, 100 mg, 0.179 mmol) and 3-(3-(3,9- diazaspiro[5.5]undecan-3-yl)phenyl)piperidine-2,6-dione (Intermediate 10, 61 mg, 0.179 mmol) in DCE (2 mL) and stirred at rt for 16 h.
  • Acetic acid (2.11 mg, 0.035 mmol) was added to solution of 3-(4-(3,9- diazaspiro[5.5]undecan-3-yl)phenyl)piperidine-2,6-dione (Intermediate 9, 60 mg, 0.176 mmol) and N-((1r,4r)-4-formylcyclohexyl)-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-sulfonamide (Intermediate 5, 111 mg, 0.193 mmol) in 1,2-Dichloroethane (5 mL).
  • Step 1 Synthesis of tert-butyl (1-((4-oxopiperidin-1-yl)sulfonyl)piperidin-4-yl)carbamate.
  • Tert-butyl (1-(chlorosulfonyl) piperidine-4-yl) carbamate (3.014 g, 10.0 mmol) was added to a solution of piperidin-4-one (1 g, 10.0 mmol) in DCM (10 mL) at 0 °C and TEA (4.230 mL, 30.2 mmol) and the reaction mixture stirred at rt for 3 h.
  • the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3x 50 mL).
  • Step 3 Synthesis of 1-((4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)piperidin-4-one p-Toluene sulfonic acid monohydrate (0.320 g, 1.69 mmol) was added to a solution of 1-((4- aminophenyl)sulfonyl) piperidine-4-one hydrochloride (Step 2, 0.5 g, 1.69 mmol), and 1-(4- (2-chloro-5-(trifluoromethyl) pyrimidine-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate XX, 0.54 g, 1.69 mmol) in IPA (5 mL) at room temperature under nitrogen atmosphere and the reaction mixture heated at 90 °C for 16 h.
  • reaction mixture was cooled to 0 oC and STAB (60.6 mg, 0.286 mmol) was added and the reaction mixture warmed to rt and stirred for 3h.
  • the reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3x 15 mL). The combined organics were washed with brine (15 mL), dried (Na2SO4) and concentrated under reduced pressure.
  • reaction mixture was filtered through pad of celite, washed with EtOAc (2x 30 mL). The filtrate was concentrated under reduced pressure and the residue purified by reverse phase column chromatography (25-35% H2O (0.1% HCO2H)/MeCN) to afford the title compound as a pale brown solid (0.19 g, 100%).
  • Example 10 was separated by chiral-SFC (Column/dimensions : Kinetex C-18 (21*250 mm *5 ⁇ m), Mobile phase A : ABC, Mobile phase B: 100% Acetonitrile, Gradient (Time/%B): 0/10, 2/10, 10/35.
  • reaction mixture was evaporated to dryness and the residue purified by prep-HPLC (Xselect CSH C18 OBD 30 x 150 mm, 5 ⁇ m; 18-28% MeCN/H2O (0.1% HCO2H)) to afford the title compound as a white solid 28.6 mg, 21%).
  • reaction mixture was evaporated to dryness under reduced pressure and the residue purified on prep-TLC 20:1 DCM/MeOH) followed by prep-HPLC (Xcelect CSH F-pheny OBD, 30 x150 mm, 5 ⁇ m; 20-31% MeCN/H2O (0.1% HCO 2 H)) to afford title compound as a white solid (13.4 mg, 7.4%).
  • Step 1 Synthesis of tert-butyl 2-methyl-4-((4-(1-methyl-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate
  • 2-chloro-4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine (Intermediate 43, Step 1; 500 mg, 1.90 mmol)
  • tert-butyl 4-amino-2-methylpiperidine-1- carboxylate (488 mg, 2.28 mmol)
  • DIPEA 491 mg, 3.80 mmol
  • reaction mixture was purified on C18 column with 40% MeCN/H 2 O followed by prep-HPLC (Xselect CSH C18 OBD, 30 x 150 mm, 5 ⁇ m; 28-42% MeCN/H2O (0.1% HCO2H)) to afford the title compound as a white solid (24.2 mg, 17%).
  • Example 18 and 19. N-((1s,4s)-4-((4-(4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)- yl)phenyl)prop-2-yn-1-yl)oxy)piperidine-1-carbonyl)piperidin-1-yl)methyl)cyclohexyl)-3- fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin- 2-yl)amino)benzenesulfonamide and N-((1r,4r)-4-((4-(4-((3-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)phenyl)prop-2-yn-1-yl)oxy)piperidine-1- carbonyl)piperidin-1-yl)methyl)cyclohex
  • Acetic acid (0.05 mL) was added to a stirred solution of a 2:1 mixture of 3-fluoro-N-((1r,4r)- 4-formylcyclohexyl)-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide and a 2:1 mixture of 3-fluoro-N- ((1r,4r)-4-formylcyclohexyl)-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide and 3-fluoro-N-((1s,4s)-4- formylcyclohexyl)-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol
  • Example 21 N-((1r,4r)-4-((4-(4-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)prop- 2-yn-1-yl)oxy)piperidine-1-carbonyl)piperidin-1-yl)methyl)cyclohexyl)-3-fluoro-4-((4-(1-(2- hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide
  • the title compound was prepared from 3-(1-oxo-4-(3-(piperidin-4-yloxy)prop-1-yn-1- yl)isoindolin-2-yl)piperidine-2,6-dione (Intermediate 16) using an analogous method to that described for Example 19.
  • Example 24 N-(2-((1-(2-(9-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-3,9- diazaspiro[5.5]undecan-3-yl)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)ethyl)-3-fluoro-4-((4-(1- (2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide To a stirred solution of 3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-N-(2-(prop-2-yn-1-yloxy)ethyl)benzenes
  • reaction mixture was quenched with cold water (20 mL) and extracted with ethyl acetate (3x 15 mL). The combined organics were washed with water (2x 15 mL), brine (15 mL) and dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by prep-HPLC-B to afford the title compound as a yellow solid (80 mg, 43%).
  • Example 25 N-(2-((1-(2-(1'-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-[4,4'- bipiperidin]-1-yl)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)ethyl)-3-fluoro-4-((4-(1-(2-hydroxy- 2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide
  • reaction mixture was quenched with cold water (20 mL) and extracted with ethyl acetate (3x 15 mL). The combined organics were washed with water (2x 15 mL), brine (15 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by prep-HPLC-C to afford the title compound as a yellow solid (40 m g, 28%).
  • Example 26 N-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1- yl)methyl)piperidin-1-yl)-2-oxoethyl)-3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide
  • the reaction mixture was allowed to warm to rt and stirred for 16 h.
  • the reaction mixture was diluted with ice-cold water (10 mL) and extracted with ethyl acetate (3x 15 mL).
  • the combined organics were washed with water (2x 15 mL), brine (15 mL), dried (Na 2 SO 4 ) and concentrated under reduced pressure.
  • the residue was purified by Prep-HPLC-C to afford the title compound as a yellow solid (53 mg, 3%).
  • Example 27 2-(2,6-dioxopiperidin-3-yl)-5-(1'-(2-(4-((3-((4-((4-((4-(1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1- yl)sulfonyl)propoxy)methyl)-1H-1,2,3-triazol-1-yl)ethyl)-[4,4'-bipiperidin]-1-yl)isoindoline- 1,3-dione
  • Example 29 N-(1-(((1r,4r)-4-(9-(4-(2,6-dioxopiperidin-3-yl)phenyl)-3,9- diazaspiro[5.5]undecane-3-carbonyl)cyclohexyl)methyl)piperidin-4-yl)-3-fluoro-4-((4-(1-(2- hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide

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Abstract

The present disclosure provides a compound represented by structural Formula (I): Formula (I), or a pharmaceutically acceptable salt thereof. Compounds of the disclosure are useful for degrading cyclin-dependent kinases (CDKs) and for treating diseases and disorders mediated by CDKs.

Description

CYCLIN-DEPENDENT KINASE 2 DEGRADERS RELATED APPLICATIONS This application claims priority to U.S. Provisional Application Serial Number 63/605,062, filed on December 1, 2023, the entire contents of which are hereby incorporated by reference herein. FIELD The disclosure relates to novel compounds and their use as degraders of cyclin- dependent kinase (CDK) 2, which have a central role in cell cycle progression. BACKGROUND CDKs are serine/threonine protein kinases that have a central role in cell cycle progression. CDK levels remain relatively constant throughout the cell cycle, and it is the selective activation of specific CDKs allows tor the proper ordering of the steps in cell cycle progression. Cyclins and their binding partner CDKs are key regulatory enzymes driving the cell cycle and cell proliferation. The catalytic activities of CDKs are regulated by their interactions with cyclins (including cyclin A, cyclin B, D-type cyclins, and cyclins E), and with CDK inhibitors (Ding, L. et al., Int. J. Mol. Sci. (2020) 21(6): 1960). In mammals there is one mitotic CDK (CDK1) and multiple interphase CDKs, including CDK2, CDK4, and CDK6. Cyclin E is part of the core cell cycle machinery as it complexes with CDK2 to move cells through the first gap phase (G1)/synthetic (S) boundary via inactivation of the retinoblastoma tumor suppressor protein (Rb) and release of the transcription factor E2F1. Cyclin E protein levels peak at the G1/S progression, followed by an increase in cyclin A levels in the S phase. Both cyclin E and A interact with and activate CDK2, whereas cyclin A can also bind CDK1. At the G2/M boundary, cyclin B levels increase, resulting in activation of CDK1. Cyclin D1 is an important cell cycle regulator that activates CDK4/6. Upon activation, CDK4/6 phosphorylate the Rb protein, leading to the release of its repression on the transcription factor E2F1, which is then free to induce the expression of proteins involved in G1 to S phase transition. This fluctuation in cyclin expression results in the oscillation in CDK activity and the tightly regulated cell cycle. In cancer cells, the cell cycle is often dysregulated, and such cells then develop dependencies on individual cyclins or CDKs, such as CDK2, providing opportunities for therapeutic targeting (Suski, J.M. et al., Cancer Cell (2021) 39(6): 759-778). Given their key roles in the cell cycle, CDK2, CDK4, and CDK6 inhibitors have been developed for therapeutic cancer targeting. Several CDK4/6 inhibitors have been approved for the treatment of stage IV or recurrent hormone receptor positive (HR+)/human epidermal growth factor receptor-2 negative (HER2-) breast cancers (Goel, S. et al., Nat. Rev. Cancer (2022) 22(6): 356-372; Sherr, C.J. et al., Cancer Discov. (2016) Cancer Disc.6(4): 353-367). However, their effects are limited by intrinsic or acquired resistance to CDK4/6 inhibitors, and almost all patients progress after treatment (Yuan, K. et al., Acta Pharm. Sin. B (2021) 11(1): 30-54, Epub 2000). Multiple mechanisms of resistance to CDK4/6 inhibitors have been previously identified, including loss of Rb and amplification and/or overexpression of p16, CDK6, cyclin D1, and cyclin E, where activation of the cyclin E-CDK2 pathway compensates for CDK4/6 inhibition via a bypass mechanism. Recent research has identified the aberrant activation of cyclin E/CDK2 as key mechanism by which tumors can evade CDK4/6 blockade (Freeman-Cook, K. et al., Cancer Cell (2021) 39: 1404-1421; Wang, B. et al., Front. Oncol. (2021) 11: 405), indicating that CDK4/6 inhibitor resistance might be overcome by CDK2 inhibitor treatment. Independent of prior exposure to CDK4/6 inhibitors, a variety of tumor types have also been demonstrated to have dysregulation and dependence of cell proliferation on the cyclin E/CDK2 axis, by harboring amplification or overexpression of the cyclin E1 gene CCNE1 (Ooi, A. et al., Hum. Pathol. (2017) 61: 58-67, Epub 2016; Nakayama, K. et al., Int. J. Oncol. (2016) 48(2): 506-516). Thus, anti-CDK2 therapies may impact a broad number of cancers that have acquired dependency on CDK2 or harbor gene alterations that require intact CDK2 function for oncogenesis. Targeted protein degradation (TPD) has emerged recently as an attractive novel therapeutic approach, due to the potential benefits including improved selectivity and catalytic nature hence less stringent requirement on exposure compared to traditional small- molecule inhibitors (Békés, M. et al., Nat. Rev. Drug Discov. (2022) 21(3): 181-200). Heterobifunctional degraders, or proteolysis-targeting chimeras (PROTAC), are a commonly used therapeutic modality to achieve targeted protein degradation (Lai, A.C. and Crews, C.M., Nat. Rev. Drug Discov. (2017) 16(2): 101-114). PROTACs are bifunctional degraders that include 2 binding moieties, i.e. the warheads and the E3 ubiquitin ligase-binding moieties. The warheads bind to the target protein of interest with high affinity. The E3 ubiquitin ligase-binding moieties recruit E3 ligases that ubiquitinate the target protein and prompt the target protein to be recognized and subsequently degraded by 26S proteasome. The two ligands are connected by linkers of various flavors. No CDK2degrader has been approved by FDA so far. A few CDK2 degraders have been reported. For example, Teng and Gray et. al. have reported a CDK2/5 dual degrader TMX-2172 (Teng, M. et al., Angew. Chem. In. Ed. (2020) 59(33): 13865-13870), Wang and Rao have reported a selective CDK2 degrader (Wang, L. et al., Nat. Chem. Biol. (2021) 17(5): 567-575). But they either lack the necessary selectivity or drug-like properties to become anit-CDK2 therapies for human patients. There remains a need for the development of potent and targeted CDK2 degraders which can be used to treat CDK2 dependent cancers. SUMMARY Provided herein are compounds, or pharmaceutically acceptable salts thereof, and compositions that are useful for degrading CDK2, and for treating various cancers. The compounds of the disclosure are potent degraders of CDK2 (see Biological Example 1). Some of the compounds of the disclosure are orally bioavailable and selectively and catalytically degrade their target protein (e.g., CDK2) over other CDKs and other proteins. In one aspect, provided herein is a compound represented by Formula (I):
Figure imgf000004_0001
or a pharmaceutically acceptable salt thereof, wherein the definition of each variable is provided below. In another aspect, provided herein is a compound represented by Formula (Ia):
Figure imgf000004_0002
or a pharmaceutically acceptable salt thereof, wherein the definition of each variable is provided below. In another aspect, provided herein is a compound represented by Formula (II):
Figure imgf000005_0001
or a pharmaceutically acceptable salt thereof, wherein the definition of each variable is provided below. In another aspect, provided herein is a pharmaceutical composition comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In another aspect, provided herein is a method of degrading CDK2, comprising contacting CDK2 with a compound of the disclosure, or a pharmaceutically acceptable salt thereof. In another aspect, provided herein is a method of treating a cancer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure. In another aspect, provided herein is the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure in the manufacture of a medicament for the treatment of cancers. In another aspect, provided herein is a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure for use in the treatment of cancers. DETAILED DESCRIPTION Compounds of the Disclosure Provided herein, among other things, are compounds and compositions that modulate (e.g., by protein degradation) the activity of CDK2. In one aspect, provided herein is a compound of Formula (I):
Figure imgf000006_0001
or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from C1-C6alkyl, C3-C6cycloalkyl, and 3 to 6-membered heterocyclyl, wherein the C1-C6alkyl is optionally substituted with 1 to 3 Ra1, wherein C3-C6cycloalkyl is optionally substituted with 1 to 4 Rb1, wherein the 3 to 6-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc1 and then is optionally substituted on a ring carbon with 1 to 4 Rb1; R2 is selected from H, D, C1-C4alkyl, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 3 Ra2; R3 is selected from H, D, halo, CN, C1-C4alkyl, and C3-C6cyclcoalkyl; R4 is selected from H, D, halo, OH, CN, C1-C4alkyl, C1-C4alkoxy, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 4 groups each independently selected from D, halo, OH and CN; R5 is selected from H, D, halo, OH, CN, C1-C4alkyl, C1-C4alkoxy, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 4 groups each independently selected from D, halo, OH and CN; R6 is H or D; Ring A is selected from C3-C10cycloalkyl, 3 to 12-membered heterocyclyl, C5- C12spirocycloalkyl, 5 to 12-membered spiroheterocyclyl, 6 to 12-membered aryl, and 5 to 12-membered heteroaryl, wherein the C3-C10cycloalkyl, C5-C12spirocycloalkyl, and 6 to 12-membered aryl are each optionally substituted with 1 to 4 Rb2, and wherein the 3 to 12-membered heterocyclyl, 5 to 12-membered spiroheterocyclyl, and 5 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc2 and then are optionally substituted on a ring carbon with 1 to 4 Rb2; Each Ra1 and Ra2 is independently selected from D, halo, OH, C3-C6cycloalkyl, and 3 to 6- membered heterocyclyl, wherein the C3-C6cycloalkyl is optionally substituted with D, OH, or -CH2OH, wherein the 3 to 6-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc13 and then is optionally substituted on a ring carbon with D, OH, or -CH2OH; Each Rb1 and Rb2 is independently selected from D, halo, OH, CN, N(Rc14)2, C1-C4alkyl, and C1-C4alkoxy, or two Rb attached to the same atom, form a =O, wherein the C1-C4alkyl and C1-C4alkoxy each optionally substituted with 1 to 4 groups each independently selected from D, halo, OH and CN; Each Rc1, Rc2, Rc13, and Rc14 is independently selected from H, D, C1-C4alkyl, and C(=O)-C1- 4alkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 4 groups each independently selected from D and OH; L is a linker moiety; and Z is an E3 ubiquitin ligase-binding moiety. In some embodiments, provided herein is a compound of Formula (Ia):
Figure imgf000007_0001
or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, and Ring A are defined as defined herein; L is a linker moiety; and Z’ is a means for binding an E3 ubiquitin ligase. In another aspect, provided herein is a compound of Formula (II),
Figure imgf000007_0002
or a pharmaceutically acceptable salt thereof, wherein R1 is selected from C1-C6alkyl, C3-C6cycloalkyl, and 3 to 6-membered heterocyclyl, wherein the C1-C6alkyl is optionally substituted with 1 to 3 Ra1, wherein C3-C6cycloalkyl is optionally substituted with 1 to 4 Rb1, wherein the 3 to 6-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc1 and then is optionally substituted on a ring carbon with 1 to 4 Rb1; R2 is selected from H, D, C1-C4alkyl, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 3 Ra2; R3 is selected from H, D, halo, CN, C1-C4alkyl, and C3-C6cyclcoalkyl; R4 is selected from H, D, halo, OH, CN, C1-C4alkyl, C1-C4alkoxy, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 4 groups each independently selected from D, halo, OH and CN; R5 is selected from H, D, halo, OH, CN, C1-C4alkyl, C1-C4alkoxy, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 4 groups each independently selected from D, halo, OH and CN; R6 is H or D; R7 is selected from H, D, C1-C4alkyl, and C(=O)-C1-4alkyl; Ring A is selected from C3-C10cycloalkyl, 3 to 12-membered heterocyclyl, C5- C12spirocycloalkyl, 5 to 12-membered spiroheterocyclyl, 6 to 12-membered aryl, and 5 to 12-membered heteroaryl, wherein the C3-C10cycloalkyl, C5-C12spirocycloalkyl, and 6 to 12-membered aryl are each optionally substituted with 1 to 4 Rb2, and wherein the 3 to 12-membered heterocyclyl, 5 to 12-membered spiroheterocyclyl, and 5 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc2 and then are optionally substituted on a ring carbon with 1 to 4 Rb2; L is a linker moiety; Ring B is:
Figure imgf000008_0001
Each Y1 is independently selected from C(Rd5)2 and NRc12; Y2 is C(Re3)2 or C(=O); W is CH or N; Each Ra1 and Ra2 is independently selected from D, halo, OH, C3-C6cycloalkyl, and 3 to 6- membered heterocyclyl, wherein the C3-C6cycloalkyl is optionally substituted with D, OH, or -CH2OH, wherein the 3 to 6-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc13 and then is optionally substituted on a ring carbon with D, OH, or -CH2OH; Each Rb1, Rb2, and Rb8 is independently selected from D, halo, OH, CN, N(Rc14)2, C1-C4alkyl, and C1-C4alkoxy, or two Rb1 or Rb2 attached to the same atom, form a =O, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 4 groups each independently selected from D, halo, OH and CN; Each Rc1, Rc2, Rc12, Rc13, and Rc14 is independently selected from H, D, C1-C4alkyl, and C(=O)-C1-4alkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 4 groups each independently selected from D and OH; Each Rd5 is independently selected from H, D, halo, OH, C1-C4alkyl, and C3-C6cycloalkyl; Each Re3 is independently selected from H, D, and C1-C4alkyl; m is 0, 1, or 2; and t is an integer from 0 to 4. In some embodiments, provided herein is a compound of Formula (III):
Figure imgf000009_0001
or a pharmaceutically acceptable salt thereof, wherein R1 is selected from C1-C6alkyl, C3-C6cycloalkyl, and 3 to 6-membered heterocyclyl, wherein the C1-C6alkyl is optionally substituted with 1 to 3 Ra1, wherein C3-C6cycloalkyl is optionally substituted with 1 to 4 Rb1, wherein the 3 to 6-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc1 and then is optionally substituted on a ring carbon with 1 to 4 Rb1; R2 is selected from H, D, C1-C4alkyl, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 3 Ra2; R3 is selected from H, D, halo, CN, C1-C4alkyl, and C3-C6cyclcoalkyl; R4 is selected from H, D, halo, OH, CN, C1-C4alkyl, C1-C4alkoxy, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 4 groups each independently selected from D, halo, OH and CN; R5 is selected from H, D, halo, OH, CN, C1-C4alkyl, C1-C4alkoxy, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 4 groups each independently selected from D, halo, OH and CN; R6 is H or D; R7 is selected from H, D, C1-C4alkyl, and C(=O)-C1-4alkyl; Ring A is selected from C3-C10cycloalkyl, 3 to 12-membered heterocyclyl, C5- C12spirocycloalkyl, 5 to 12-membered spiroheterocyclyl, 6 to 12-membered aryl, and 5 to 12-membered heteroaryl, wherein the C3-C10cycloalkyl, C5-C12spirocycloalkyl, and 6 to 12-membered aryl are each optionally substituted with 1 to 4 Rb2, and wherein the 3 to 12-membered heterocyclyl, 5 to 12-membered spiroheterocyclyl, and 5 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc2 and then are optionally substituted on a ring carbon with 1 to 4 Rb2; L1 is selected from a covalent bond, -S(=O)2-, -*NRc3-S(=O)2-, -*S(=O)2-NRc3-, -*S(=O)2- NRc3-(C(Rd1)2)n-, -*S(=O)2-(C(Rd1)2)n-O-(C(Rd1)2)n-, -*NRc3-S(=O)2-(C(Rd1)2)n-O- (C(Rd1)2)n-, and -*S(=O)2-NRc3-(C(Rd1)2)n-O-(C(Rd1)2)n-, wherein * denotes the point of attachment of L1 to Ring A; X1 is selected from a covalent bond, C3-C10cycloalkyl, 3 to 12-membered heterocyclyl, 6 to 12-membered aryl, and 5 to 12-membered heteroaryl, wherein the C3-C10cycloalkyl and 6 to 12-membered aryl are each optionally substituted with 1 to 4 Rb3, and wherein the 3 to 12-membered heterocyclyl and 5 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc4 and then are optionally substituted on a ring carbon with 1 to 4 Rb3; L2 is selected from a covalent bond, -(C(Rd2)2)n-, -*NRc5-(C(Rd2)2)n-, -*(C(Rd2)2)n-C(=O)-, - *(C(Rd2)2)n-O-(C(Rd2)2)n-, and -*(C(Re1)2C(Re1)2O)r-(C(Rd2)2)n-, wherein * denotes the point of attachment of L2 to X1; X2 is selected from a covalent bond, C3-C10cycloalkyl, 3 to 12-membered heterocyclyl, 6 to 12-membered aryl, and 5 to 12-membered heteroaryl, wherein the C3-C10cycloalkyl and 6 to 12-membered aryl are each optionally substituted with 1 to 4 Rb4, and wherein the 3 to 12-membered heterocyclyl and 5 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc6 and then are optionally substituted on a ring carbon with 1 to 4 Rb4; or X1– L2– X2 form a C5-C12spirocycloalkyl or 5 to 12-membered spiroheterocyclyl, wherein the C5-C12spirocycloalkyl is optionally substituted with 1 to 4 Rb5, and wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc7 and then are optionally substituted on a ring carbon with 1 to 4 Rb5; L3 is selected from -O-, -(C(Rd3)2)n-, -*NRc8-(C(Rd3)2)n-, -*C(=O)-(C(Rd3)2)n-, and - *(C(Re2)2C(Re2)2O)r-(C(Rd3)2)n-, wherein * denotes the point of attachment of L3 to X2; Each X3 is selected from C3-C10cycloalkyl, 3 to 12-membered heterocyclyl, 6 to 12- membered aryl, and 5 to 12-membered heteroaryl, wherein the C3-C10cycloalkyl and 6 to 12-membered aryl are each optionally substituted with 1 to 4 Rb6, and wherein the 3 to 12-membered heterocyclyl and 5 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc9 and then are optionally substituted on a ring carbon with 1 to 4 Rb6; or X2– L3– X3 form a C5-C12spirocycloalkyl or 5 to 12-membered spiroheterocyclyl, wherein the C5-C12spirocycloalkyl is optionally substituted with 1 to 4 Rb7, and wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc10 and then are optionally substituted on a ring carbon with 1 to 4 Rb7; or Two X3 form a C5-C12spirocycloalkyl or 5 to 12-membered spiroheterocyclyl, wherein the C5-C12spirocycloalkyl is optionally substituted with 1 to 4 Rb7, and wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc10 and then are optionally substituted on a ring carbon with 1 to 4 Rb7; L4 is selected from a covalent bond, -O-, -C(=O)-, -(C(Rd4)2)n-, -NRc11-, -*NRc11-(C(Rd4)2)n-, -*(C(Rd4)2)n-NRc11-, -*O-(C(Rd4)2)n-, -*(C(Rd4)2)n-O-, -*C(=O)-(C(Rd4)2)n-, - *(C(Rd4)2)n-C(=O)-, -*C2-C6alkenylene-(O)s-, -*C2-C6alkynylene-(O)s-, -*O- (C(Rd4)2)n-C(=O)-, -*O-(C(Rd4)2)n-C(=O)-NRc11-, -*O-(C(Rd4)2)n-NRc11-C(=O)-, - *NRc11-(C(Rd4)2)n-C(=O)-NRc11-, -*NRc11-(C(Rd4)2)n-C(=O)-, and -*NRc11-(C(Rd4)2)n- NRc11-C(=O)- wherein * denotes the point of attachment of L4 to Ring B; wherein no more than three of L1, X1, L2, X2, and L4 can simultaneously be a covalent bond; Ring B is 10
Figure imgf000012_0001
Each Y1 is independently selected from C(Rd5)2 and NRc12; Y2 is C(Re3)2 or C(=O); W is CH or N; Each Ra1 and Ra2 is independently selected from D, halo, OH, C3-C6cycloalkyl, and 3 to 6- membered heterocyclyl, wherein the C3-C6cycloalkyl is optionally substituted with D, OH, or -CH2OH, and wherein the 3 to 6-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc13 and then is optionally substituted on a ring carbon with D, OH, or -CH2OH; Each Rb1, Rb2, Rb3, Rb4, Rb5, Rb6, Rb7, and Rb8 is independently selected from D, halo, OH, CN, N(Rc14)2, C1-C4alkyl, and C1-C4alkoxy, or two Rb1, Rb2 Rb3, Rb4, Rb5, Rb6, or Rb7 attached to the same atom, form a =O, wherein the C1-C4alkyl and C1-C4alkoxy each optionally substituted with 1 to 4 groups each independently selected from D, halo, OH and CN; Each Rc1, Rc2, Rc3, Rc4, Rc5, Rc6, Rc7, Rc8, Rc9, Rc10, Rc11, Rc12, Rc13, and Rc14 is independently selected from H, D, C1-C4alkyl, and C(=O)-C1-4alkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 4 groups each independently selected from D and OH; Each Rd1, Rd2, Rd3, Rd4, and Rd5 is independently selected from H, D, halo, OH, C1-C4alkyl, and C3-C6cycloalkyl; Each Re1, Re2, and Re3 is independently selected from H, D, and C1-C4alkyl; m is 0, 1, or 2; n is an integer from 0 to 8; p is 0 or 1; q is 0, 1, or 2; r is an integer from 1 to 6; s is 0 or 1; and t is an integer from 0 to 4. In some embodiments, provided herein is a compound of a formula described herein, or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from C1-C6alkyl, C3-C6cycloalkyl, and 3 to 6-membered heterocyclyl, wherein the C1-C6alkyl is optionally substituted with 1 to 3 Ra1, wherein C3-C6cycloalkyl is optionally substituted with 1 to 3 Rb1, and wherein the 3 to 6-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc1 and then is optionally substituted on a ring carbon with 1 to 3 Rb1; R2 is selected from H, D, C1-C4alkyl, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 3 Ra2; R3 is selected from H, D, halo, CN, C1-C4alkyl, and C3-C6cyclcoalkyl; R4 is selected from H, D, halo, OH, CN, C1-C4alkyl, C1-C4alkoxy, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 3 groups each independently selected from D, halo, OH and CN; R5 is selected from H, D, halo, OH, CN, C1-C4alkyl, C1-C4alkoxy, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 3 groups each independently selected from D, halo, OH and CN; R6 is H or D; R7 is selected from H, D, C1-C4alkyl, and C(=O)-C1-4alkyl; Ring A is selected from C3-C8cycloalkyl, 3 to 10-membered heterocyclyl, C5- C10spirocycloalkyl, 5 to 10-membered spiroheterocyclyl, 6 to 10-membered aryl, and 5 to 10-membered heteroaryl, wherein the C3-C8cycloalkyl, C5-C10spirocycloalkyl, and 6 to 10-membered aryl are each optionally substituted with 1 to 3 Rb2, and wherein the 3 to 10-membered heterocyclyl, 5 to 10-membered spiroheterocyclyl, and 5 to 10-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc2 and then are optionally substituted on a ring carbon with 1 to 3 Rb2; L1 is selected from a covalent bond, -S(=O)2-, -*S(=O)2-NRc3-, -*S(=O)2-NRc3-(C(Rd1)2)n-, - *S(=O)2-(C(Rd1)2)n-O-(C(Rd1)2)n-, and -*S(=O)2-NRc3-(C(Rd1)2)n-O-(C(Rd1)2)n-, wherein * denotes the point of attachment of L1 to Ring A; X1 is selected from a covalent bond, C3-C8cycloalkyl, 3 to 10-membered heterocyclyl, 6 to 10-membered aryl, and 5 to 10-membered heteroaryl, wherein the C3-C8cycloalkyl and 6 to 10-membered aryl are each optionally substituted with 1 to 3 Rb3, and wherein the 3 to 10-membered heterocyclyl and 5 to 10-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc4 and then are optionally substituted on a ring carbon with 1 to 3 Rb3; L2 is selected from a covalent bond, -(C(Rd2)2)n-, -*NRc5-(C(Rd2)2)n-, -*(C(Rd2)2)n-C(=O)-, - *(C(Rd2)2)n-O-(C(Rd2)2)n-, and -*(C(Re1)2C(Re1)2O)r-(C(Rd2)2)n-, wherein * denotes the point of attachment of L2 to X1; X2 is selected from a covalent bond, C3-C8cycloalkyl, 3 to 10-membered heterocyclyl, 6 to 10-membered aryl, and 5 to 10-membered heteroaryl, wherein the C3-C8cycloalkyl and 6 to 10-membered aryl are each optionally substituted with 1 to 3 Rb4, and wherein the 3 to 10-membered heterocyclyl and 5 to 10-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc6 and then are optionally substituted on a ring carbon with 1 to 3 Rb4; or X1– L2– X2 form a C5-C10spirocycloalkyl or 5 to 10-membered spiroheterocyclyl, wherein the C5-C10spirocycloalkyl is optionally substituted with 1 to 3 Rb5, and wherein the 5 to 10-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc7 and then are optionally substituted on a ring carbon with 1 to 3 Rb5; L3 is selected from -O-, -(C(Rd3)2)n-, -*NRc8-(C(Rd3)2)n-, -*C(=O)-(C(Rd3)2)n-, and - *(C(Re2)2C(Re2)2O)r-(C(Rd3)2)n-, wherein * denotes the point of attachment of L3 to X2; Each X3 is selected from C3-C8cycloalkyl, 3 to 10-membered heterocyclyl, 6 to 10- membered aryl, and 5 to 10-membered heteroaryl, wherein the C3-C8cycloalkyl and 6 to 10-membered aryl are each optionally substituted with 1 to 3 Rb6, and wherein the 3 to 10-membered heterocyclyl and 5 to 10-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc9 and then are optionally substituted on a ring carbon with 1 to 3 Rb6; or X2– L3– X3 form a C5-C10spirocycloalkyl or 5 to 10-membered spiroheterocyclyl, wherein the C5-C10spirocycloalkyl is optionally substituted with 1 to 3 Rb7, and wherein the 5 to 10-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc10 and then are optionally substituted on a ring carbon with 1 to 3 Rb7; or Two X3 form a C5-C10spirocycloalkyl or 5 to 10-membered spiroheterocyclyl, wherein the C5-C10spirocycloalkyl is optionally substituted with 1 to 3 Rb7, wherein the 5 to 10- membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc10 and then are optionally substituted on a ring carbon with 1 to 4 Rb7; L4 is selected from a covalent bond, -O-, -C(=O)-, -(C(Rd4)2)n-, -NRc11-, -*NRc11-(C(Rd4)2)n-, -*(C(Rd4)2)n-NRc11-, -*O-(C(Rd4)2)n-, -*(C(Rd4)2)n-O-, -*C(=O)-(C(Rd4)2)n-, - *(C(Rd4)2)n-C(=O)-, -*C2-C6alkenylene-(O)s-, -*C2-C6 alkynylene-(O)s-, -*O- (C(Rd4)2)n-C(=O)-, -*O-(C(Rd4)2)n-C(=O)-NRc11-, -*O-(C(Rd4)2)n-NRc11-C(=O)-, - *NRc11-(C(Rd4)2)n-C(=O)-NRc11-, -*NRc11-(C(Rd4)2)n-C(=O)-, and -*NRc11- (C(Rd4)2)n-NRc11-C(=O)- wherein * denotes the point of attachment of L4 to Ring B; wherein no more than two of L1, X1, L2, X2, and L4 can simultaneously be a covalent bond; Ring B is
Figure imgf000015_0001
Each Y1 is independently selected from C(Rd5)2 and NRc12; Y2 is C(Re3)2 or C(=O); W is CH or N; Each Ra1 and Ra2 is independently selected from D, halo, OH, C3-C6cycloalkyl, and 3 to 6- membered heterocyclyl, wherein the C3-C6cycloalkyl is optionally substituted with D, OH, or -CH2OH, and wherein the 3 to 6-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc13 and then is optionally substituted on a ring carbon with D, OH, or -CH2OH; Each Rb1, Rb2, Rb3, Rb4, Rb5, Rb6, Rb7, and Rb8 is independently selected from D, halo, OH, CN, N(Rc14)2, C1-C4alkyl, and C1-C4alkoxy, or two Rb1, Rb2 Rb3, Rb4, Rb5, Rb6, or Rb7 attached to the same atom, form a =O, wherein the C1-C4alkyl and C1-C4alkoxy each optionally substituted with 1 to 4 groups each independently selected from D, halo, OH and CN; Each Rc1, Rc2, Rc3, Rc4, Rc5, Rc6, Rc7, Rc8, Rc9, Rc10, Rc11, Rc12, Rc13, and Rc14 is independently selected from H, D, C1-C4alkyl, and C(=O)-C1-4alkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 3 groups each independently selected from D and OH; Each Rd1, Rd2, Rd3, Rd4, and Rd5 is independently selected from H, D, halo, OH, C1-C4alkyl, and C3-C6cycloalkyl; Each Re1, Re2, and Re3 is independently selected from H, D, and C1-C4alkyl; m is 0 or 1; n is an integer from 0 to 6; p is 0 or 1; q is 0, 1, or 2; r is an integer from 1 to 6; s is 0 or 1; and t is an integer from 0 to 3. In some embodiments, the compound described herein is represented by Formula (IV):
Figure imgf000016_0001
or a pharmaceutically acceptable salt thereof, wherein t is an integer from 0 to 4, and wherein R1, R2, R3, R4, R5, R6, R7, ring A, L1, X1, L2, X2, L3, X3, L4, W, and Rb8 are as defined herein. In some embodiments, the compound described herein is represented by Formula (IVa):
Figure imgf000016_0002
or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, ring A, L1, X1, L2, X2, L3, X3, L4, t, and Rb8 are as defined herein. In some embodiments, the compound described herein is represented by Formula (IVb):
Figure imgf000017_0001
or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, ring A, L1, X1, L2, X2, L3, X3, L4, t, and Rb8 are as defined herein. In some embodiments, the compound described herein is represented by Formula (
Figure imgf000017_0002
or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, ring A, L1, X1, L2, X2, L3, X3, L4, t, and Rb8 are as defined herein. In some embodiments, the compound described herein is represented by Formula (IVd):
Figure imgf000017_0003
or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, ring A, L1, X1, L2, X2, L3, X3, L4, t, and Rb8 are as defined herein. In some embodiments, the compound described herein is represented by Formula (V):
Figure imgf000018_0001
or a pharmaceutically acceptable salt thereof, wherein t is an integer from 0 to 3, and wherein R1, R2, R3, R4, R5, R6, R7, ring A, L1, X1, L2, X2, L3, X3, L4, Y2, and Rb8 are as defined herein. In some embodiments, the compound described herein is represented by Formula (Va):
Figure imgf000018_0002
(Va), or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, ring A, L1, X1, L2, X2, L3, X3, L4, t, and Rb8 are as defined herein. In some embodiments, the compound described herein is represented by Formula (Vb):
Figure imgf000018_0003
(Vb), or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, ring A, L1, X1, L2, X2, L3, X3, L4, t, and Rb8 are as defined herein. In some embodiments, the compound described herein is represented by Formula (Vc):
Figure imgf000019_0001
or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, ring A, L1, X1, L2, X2, L3, X3, L4, t, and Rb8 are as defined herein. In some embodiments, the compound described herein is represented by Formula (Vd):
Figure imgf000019_0002
or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, ring A, L1, X1, L2, X2, L3, X3, L4, t, and Rb8 are as defined herein. In some embodiments, the compound described herein is represented by Formula (Ve):
Figure imgf000019_0003
(Ve), or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, ring A, L1, X1, L2, X2, L3, X3, L4, t, and Rb8 are as defined herein. In some embodiments, the compound described herein is represented by Formula (Vf):
Figure imgf000020_0001
or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, ring A, L1, X1, L2, X2, L3, X3, L4, t, and Rb8 are as defined herein. In some embodiments, described herein is a compound of a formula described herein, or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from C1-C6alkyl, C3-C6cycloalkyl, and 3 to 6-membered heterocyclyl, wherein the C1-C6alkyl is optionally substituted with 1 or 2 Ra1, and wherein the 3 to 6- membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc1; R2 is selected from H, D, C1-C4alkyl, and C3-C6cyclcoalkyl, wherein the C1-C6alkyl is optionally substituted with 1 or 2 Ra2; R3 is selected from H, D, C1-C4alkyl, and C3-C6cyclcoalkyl; R4 is selected from H, D, halo, OH, CN, C1-C4alkyl, C1-C4alkoxy, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 3 groups each independently selected from D, halo, OH and CN; R5 is selected from H, D, halo, OH, CN, C1-C4alkyl, C1-C4alkoxy, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 3 groups each independently selected from D, halo, OH and CN; R6 is H or D; R7 is selected from H, D, C1-C4alkyl, and C(=O)-C1-4alkyl; Ring A is selected from C3-C8cycloalkyl, 3 to 10-membered heterocyclyl, 5 to 10-membered spiroheterocyclyl, 6 to 10-membered aryl, and 5 to 10-membered heteroaryl, wherein the C3-C8cycloalkyl and 6 to 10-membered aryl are each optionally substituted with 1 to 3 Rb2, and wherein the 3 to 10-membered heterocyclyl, 5 to 10-membered spiroheterocyclyl, and 5 to 10-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc2 and then are optionally substituted on a ring carbon with 1 to 3 Rb2; L1 is selected from -S(=O)2-, -*S(=O)2-NRc3-, -*S(=O)2-NRc3-(C(Rd1)2)n-, -*S(=O)2- (C(Rd1)2)n-O-(C(Rd1)2)n-, and -*S(=O)2-NRc3-(C(Rd1)2)n-O-(C(Rd1)2)n-, wherein * denotes the point of attachment of L1 to Ring A; X1 is selected from a covalent bond, C3-C8cycloalkyl, 3 to 10-membered heterocyclyl, 6 to 10-membered aryl, and 5 to 10-membered heteroaryl, wherein the C3-C8cycloalkyl and 6 to 10-membered aryl are each optionally substituted with 1 to 3 Rb3, and wherein the 3 to 10-membered heterocyclyl and 5 to 10-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc4 and then are optionally substituted on a ring carbon with 1 to 3 Rb3; L2 is selected from a covalent bond, -(C(Rd2)2)n-, -*NRc5-(C(Rd2)2)n-, -*(C(Rd2)2)n-C(=O)-, - *(C(Rd2)2)n-O-(C(Rd2)2)n-, and -*(C(Re1)2C(Re1)2O)r-(C(Rd2)2)n-, wherein * denotes the point of attachment of L2 to X1; X2 is selected from a covalent bond, C3-C8cycloalkyl, 3 to 10-membered heterocyclyl, 6 to 10-membered aryl, and 5 to 10-membered heteroaryl, wherein the C3-C8cycloalkyl and 6 to 10-membered aryl are each optionally substituted with 1 to 3 Rb4, and wherein the 3 to 10-membered heterocyclyl and 5 to 10-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc6 and then are optionally substituted on a ring carbon with 1 to 3 Rb4; or X1– L2– X2 form a 5 to 10-membered spiroheterocyclyl, wherein the 5 to 10-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc7 and then are optionally substituted on a ring carbon with 1 to 3 Rb5; L3 is selected from -O-, -(C(Rd3)2)n-, -*NRc8-(C(Rd3)2)n-, -*C(=O)-(C(Rd3)2)n-, and - *(C(Re2)2C(Re2)2O)r-(C(Rd3)2)n-, wherein * denotes the point of attachment of L3 to X2; X3 is selected from C3-C8cycloalkyl, 3 to 10-membered heterocyclyl, 6 to 10-membered aryl, and 5 to 10-membered heteroaryl, wherein the C3-C8cycloalkyl and 6 to 10-membered aryl are each optionally substituted with 1 to 3 Rb6, and wherein the 3 to 10-membered heterocyclyl and 5 to 10-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc9 and then are optionally substituted on a ring carbon with 1 to 3 Rb6; or X2– L3– X3 form a 5 to 10-membered spiroheterocyclyl, wherein the 5 to 10-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc10 and then are optionally substituted on a ring carbon with 1 to 3 Rb7; or L4 is selected from a covalent bond, -O-, -C(=O)-, -(C(Rd4)2)n-, -NRc11-, -*NRc11-(C(Rd4)2)n-, -*O-(C(Rd4)2)n-, -*(C(Rd4)2)n-O-, -*C(=O)-(C(Rd4)2)n-, -*C2-C6alkenylene-(O)s-, -*C2- C6alkynylene-(O)s-, -*O-(C(Rd4)2)n-C(=O)-, -*O-(C(Rd4)2)n-C(=O)-NRc11-, -* NRc11- (C(Rd4)2)n-C(=O)-NRc11-, and -*NRc11-(C(Rd4)2)n-C(=O)- wherein * denotes the point of attachment of L4 to Ring B; wherein at least one of X1 and X2 is not a covalent bond; Y2 is C(Re3)2 or C(=O); Each Ra1 and Ra2 is independently selected from D, halo, OH, C3-C6cycloalkyl, and 3 to 6- membered heterocyclyl, wherein the 3 to 6-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc13; Each Rb1, Rb2, Rb3, Rb4, Rb5, Rb6, Rb7, and Rb8 is independently selected from D, halo, OH, CN, N(Rc14)2, C1-C4alkyl, and C1-C4alkoxy, or two Rb1, Rb2 Rb3, Rb4, Rb5, Rb6, or Rb7 attached to the same atom, form a =O, wherein the C1-C4alkyl and C1-C4alkoxy each optionally substituted with 1 to 3 groups each independently selected from D, halo, OH and CN; Each Rc1, Rc2, Rc3, Rc4, Rc5, Rc6, Rc7, Rc8, Rc9, Rc10, Rc11, Rc13, and Rc14 is independently selected from H, D, C1-C4alkyl, and C(=O)-C1-4alkyl; Each Rd1, Rd2, Rd3, and Rd4 is independently selected from H, D, halo, OH, C1-C4alkyl, and C3-C6cycloalkyl; Each Re1, Re2, and Re3 is independently selected from H, D, and C1-C4 alkyl; n is an integer from 0 to 4; p is 0 or 1; q is 0, 1, or 2; r is an integer from 1 to 6; s is 0 or 1; and t is an integer from 0 to 3. In some embodiments, described herein is a compound of a formula described herein, or a pharmaceutically acceptable salt thereof, wherein: R1 is C1-C6alkyl, wherein the C1-C6alkyl is optionally substituted with 1 or 2 Ra1; R2 is selected from H, D, and C1-C4alkyl, wherein the C1-C6alkyl is optionally substituted with 1 or 2 Ra2; R3 is selected from H, D, and C1-C4alkyl; R4 is selected from H, D, halo, OH, CN, and C1-C4alkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 3 groups each independently selected from D, halo, OH, and CN; R5 is selected from H, D, halo, OH, CN, and C1-C4alkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 3 groups each independently selected from D, halo, OH, and CN; R6 is H or D; R7 is selected from H, D, and C1-C4alkyl; Ring A is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, 6-membered aryl, and 5 or 6-membered heteroaryl, wherein the C3-C6cycloalkyl and 6-membered aryl are each optionally substituted with 1 to 3 Rb2, and wherein the 3 to 6-membered heterocyclyl and 5 or 6-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc2 and then are optionally substituted on a ring carbon with 1 to 3 Rb2; L1 is selected from -S(=O)2-, -*S(=O)2-NRc3-, -*S(=O)2-NRc3-(C(Rd1)2)n-, -*S(=O)2- (C(Rd1)2)n-O-(C(Rd1)2)n-, and -*S(=O)2-NRc3-(C(Rd1)2)n-O-(C(Rd1)2)n-, wherein * denotes the point of attachment of L1 to Ring A; X1 is selected from a covalent bond, C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, 6- membered aryl, and 5 or 6-membered heteroaryl, wherein the C3-C6cycloalkyl and 6- membered aryl are each optionally substituted with 1 to 3 Rb3, and wherein the 3 to 6- membered heterocyclyl and 5 or 6-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc4 and then are optionally substituted on a ring carbon with 1 to 3 Rb3; L2 is selected from a covalent bond, -(C(Rd2)2)n-, -*NRc5-(C(Rd2)2)n-, -*(C(R2d)2)n-C(=O)-, - *(C(Rd2)2)n-O-(C(Rd2)2)n-, and -*(C(Re1)2C(Re1)2O)r-(C(Rd2)2)n-, wherein * denotes the point of attachment of L2 to X1; X2 is selected from a covalent bond, C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, 6- membered aryl, and 5 or 6-membered heteroaryl, wherein the C3-C6cycloalkyl and 6- membered aryl are each optionally substituted with 1 to 3 Rb4, and wherein the 3 to 6- membered heterocyclyl and 5 or 6-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc6 and then are optionally substituted on a ring carbon with 1 to 3 Rb4; or X1– L2– X2 form a 5 to 10-membered spiroheterocyclyl, wherein the 5 to 10-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc7 and then are optionally substituted on a ring carbon with 1 to 3 Rb5; L3 is selected from -O-, -(C(Rd3)2)n-, -*NRc8-(C(Rd3)2)n-, -*C(=O)-(C(Rd3)2)n-, and - *(C(Re2)2C(Re2)2O)r-(C(Rd3)2)n-, wherein * denotes the point of attachment of L3 to X2; X3 is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, 6-membered aryl, and 5 or 6-membered heteroaryl, wherein the C3-C6cycloalkyl and 6-membered aryl are each optionally substituted with 1 to 3 Rb6, and wherein the 3 to 6-membered heterocyclyl and 5 or 6-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc9 and then are optionally substituted on a ring carbon with 1 to 3 Rb6; or X2– L3– X3 form a 5 to 10-membered spiroheterocyclyl, wherein the 5 to 10-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc10 and then are optionally substituted on a ring carbon with 1 to 3 Rb7; or L4 is selected from a covalent bond, -O-, -C(=O)-, -(C(Rd4)2)n-, -NRc11-, -*NRc11-(C(Rd4)2)n-, -*O-(C(Rd4)2)n-, -*(C(Rd4)2)n-O-, -*C(=O)-(C(Rd4)2)n-, -*C2-C6alkenylene-(O)s-, -*C2- C6 alkynylene-(O)s-, -*O-(C(Rd4)2)n-C(=O)-, -*O-(C(Rd4)2)n-C(=O)-NRc11-, -* NRc11- (C(Rd4)2)n-C(=O)-NRc11-, wherein * denotes the point of attachment of L4 to Ring B; wherein at least one of X1 and X2 is not a covalent bond; Y2 is C(Re3)2 or C(=O); Each Ra1 and Ra2 is independently selected from H, D, OH, and C1-C4alkyl; Each Rb2, Rb3, Rb4, Rb5, Rb6, Rb7, and Rb8 is independently selected from D, halo, OH, CN, C1-C4alkyl, and C1-C4alkoxy, or two Rb2 Rb3, Rb4, Rb5, Rb6, or Rb7 attached to the same atom, form a =O, wherein the C1-C4alkyl and C1-C4alkoxy each optionally substituted with 1 to 3 groups each independently selected from D, halo, OH and CN; Each Rc2, Rc3, Rc4, Rc5, Rc6, Rc7, Rc8, Rc9, Rc10, and Rc11 is independently selected from H, D, and C1-C4alkyl; Each Rd1, Rd2, Rd3, and Rd4 is independently selected from H, D, and C1-C4alkyl; Each Re1, Re2, and Re3 is independently H or D; n is an integer from 0 to 4; p is 0 or 1; q is 0, 1, or 2; r is an integer from 1 to 6; s is 1; and t is an integer from 0 to 3. In some embodiments, described herein is a compound of a formula described herein, or a pharmaceutically acceptable salt thereof, wherein: R1 is C1-C6alkyl, wherein the C1-C6alkyl is optionally substituted with 1 or 2 Ra1; R2 is selected from H, D, and C1-C4alkyl; R3 is selected from H, D, and C1-C4alkyl; R4 is selected from H, D, halo, CN, and C1-C4alkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 3 groups each independently selected from D, halo, OH, and CN; R5 is selected from H, D, and C1-C4alkyl; R6 is H or D; R7 is selected from H, D, and C1-C4alkyl; Ring A is selected from 6-membered heterocyclyl, 6-membered aryl, and 6-membered heteroaryl, wherein the 6-membered aryl is optionally substituted with 1 or 2 Rb2, and wherein the 6-membered heterocyclyl and 6-membered heteroaryl have 1 or 2 ring heteroatoms each independently selected from O, S, N, and NRc2 and then are optionally substituted on a ring carbon with 1 or 2 Rb2; L1 is -S(=O)2- or -*S(=O)2-NRc3-wherein * denotes the point of attachment of L1 to Ring A; X1 is C6cycloalkyl or 6-membered heterocyclyl, wherein the C6cycloalkyl is optionally substituted with 1 or 2 Rb3, and wherein the 6-membered heterocyclyl has 1 or 2 ring heteroatoms each independently selected from O, S, N, and NRc4 and then is optionally substituted on a ring carbon with 1 or 2 Rb3; L2 is selected from a covalent bond, -(C(Rd2)2)n-, -*NRc5-, and -C(=O)-, wherein * denotes the point of attachment of L2 to X1; X2 is a covalent bond or 3 to 6-membered heterocyclyl, wherein the 3 to 6-membered heterocyclyl has 1 or 2 ring heteroatoms each independently selected from O, S, N, and NRc6 and then is optionally substituted on a ring carbon with 1 or 2 Rb4; or X1– L2– X2 form a 7 to 10-membered spiroheterocyclyl, wherein the 7 to 10-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc7 and then are optionally substituted on a ring carbon with 1 or 2 Rb5; L3 is -O- or -(C(Rd3)2)n-, wherein * denotes the point of attachment of L3 to X2; X3 is 6-membered heterocyclyl, wherein the 6-membered heterocyclyl has 1 or 2 ring heteroatoms each independently selected from O, S, N, and NRc9 and then is optionally substituted on a ring carbon with 1 or 2 Rb6; or X2– L3– X3 form a 7 to 10-membered spiroheterocyclyl, wherein the 7 to 10-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc10 and then are optionally substituted on a ring carbon with 1 or 2 Rb7; or L4 is selected from a covalent bond, -O-, -*C2-C6 alkynylene-(O)s-, -*O-(C(Rd4)2)n-C(=O)-, and -*O-(C(Rd4)2)n-C(=O)-NRc11-, wherein * denotes the point of attachment of L4 to Ring B; wherein no more than two of L1, X1, L2, X2, and L4 can simultaneously be a covalent bond; Ring B is
Figure imgf000026_0001
Y2 is C(Re3)2 or C(=O); W is CH or N; Ra1 is independently selected from H, D, OH, and C1-C4alkyl; Each Rb2, Rb3, Rb4, Rb5, Rb6, and Rb7 is independently selected from D, halo, OH, and CN; Each Rc2, Rc3, Rc4, Rc5, Rc6, Rc7, Rc9, Rc10, and Rc11 is independently selected from H, D, and C1-C4alkyl; Each Rd1, Rd2, Rd3, and Rd4 is independently selected from H, D, and C1-C4alkyl; Re3 is independently H or D; m is 0; n is 1; p is 0 or 1; q is 0, 1, or 2; fs is 1; and t is an integer from 0 to 2. In some embodiments, the compound described herein is represented by Formula (VI):
Figure imgf000027_0001
or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, ring A, L1, X1, L2, X2, L4, ring B, Y1, and m are as defined herein. In some embodiments, the compound described herein is represented by Formula (VII):
Figure imgf000028_0001
or a pharmaceutically acceptable salt thereof, wherein t is an integer from 0 to 4, and wherein R1, R2, R3, R4, R5, R6, R7, ring A, L1, X1, L2, X2, L4, and Rb8 are as defined herein. In some embodiments, the compound described herein is represented by Formula (VIIa):
Figure imgf000028_0002
(VIIa), or a pharmaceutically acceptable salt thereof, and wherein R1, R2, R3, R4, R5, R6, R7, ring A, L1, X1, L2, X2, L4, Rb8, and t are as defined herein. In some embodiments, the compound described herein is represented by Formula (VIIb): or a pharmac
Figure imgf000028_0003
L1, X1, L2, X2, L4, Rb8, and t are as defined herein. In some embodiments, the compound described herein is represented by Formula (VIII):
Figure imgf000029_0001
or a pharmaceutically acceptable salt thereof, wherein t is an integer from 0 to 3, and wherein R1, R2, R3, R4, R5, R6, R7, ring A, L1, X1, L2, X2, L4, Y2, Rb8, and t are as defined herein. In some embodiments, the compound described herein is represented by Formula (VIIIa):
Figure imgf000029_0002
(VIIIa), or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, ring A, L1, X1, L2, X2, L4, Rb8, and t are as defined herein. In some embodiments, the compound described herein is represented by Formula (VIIIb):
Figure imgf000029_0003
(VIIIb), or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, ring A, L1, X1, L2, X2, L4, Rb8, and t are as defined herein. In some embodiments, the compound described herein is represented by Formula (VIIIc):
Figure imgf000030_0001
or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, ring A, L1, X1, L2, X2, L4, Rb8, and t are as defined herein. In some embodiments, the compound described herein is represented by Formula (VIIId):
Figure imgf000030_0002
or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, ring A, L1, X1, L2, X2, L4, Rb8, and t are as defined herein. In some embodiments, the compound described herein is represented by Formula (VIIIe):
Figure imgf000030_0003
or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, ring A, L1, X1, L2, X2, L4, Rb8, and t are as defined herein. In some embodiments, the compound described herein is represented by Formula (VIIIf):
Figure imgf000031_0001
(VIIIf), or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, ring A, L1, X1, L2, X2, L4, Rb8, and t are as defined herein. In some embodiments, the compound described herein is represented by Formula (IX):
Figure imgf000031_0002
or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, ring A, L1, X1, L2, X2, L4, Rb8, and t are as defined herein. In some embodiments, the compounds described herein of a formula described herein, or a pharmaceutically acceptable thereof, wherein: R1 is selected from C1-C6alkyl, C3-C6cycloalkyl, and 3 to 6-membered heterocyclyl, wherein the C1-C6alkyl is optionally substituted with 1 or 2 Ra1, and wherein the 3 to 6- membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc1; R2 is selected from H, D, C1-C4alkyl, and C3-C6cyclcoalkyl, wherein the C1-C6alkyl is optionally substituted with 1 or 2 Ra2; R3 is selected from H, D, C1-C4alkyl, and C3-C6cyclcoalkyl; R4 is selected from H, D, halo, OH, CN, C1-C4alkyl, C1-C4alkoxy, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 3 groups each independently selected from D, halo, OH and CN; R5 is selected from H, D, halo, OH, CN, C1-C4alkyl, C1-C4alkoxy, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 3 groups each independently selected from D, halo, OH and CN; R6 is H or D; R7 is selected from H, D, C1-C4alkyl, and C(=O)-C1-4alkyl; Ring A is selected from C3-C8cycloalkyl, 3 to 10-membered heterocyclyl, 5 to 10-membered spiroheterocyclyl, 6 to 10-membered aryl, and 5 to 10-membered heteroaryl, wherein the C3-C8cycloalkyl and 6 to 10-membered aryl are each optionally substituted with 1 to 3 Rb2, and wherein the 3 to 10-membered heterocyclyl, 5 to 10-membered spiroheterocyclyl, and 5 to 10-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc2 and then are optionally substituted on a ring carbon with 1 to 3 Rb2; L1 is selected from -S(=O)2-, -*S(=O)2-NRc3-, -*S(=O)2-NRc3-(C(Rd1)2)n-, -*S(=O)2- (C(Rd1)2)n-O-(C(Rd1)2)n-, and -*S(=O)2-NRc3-(C(Rd1)2)n-O-(C(Rd1)2)n-, wherein * denotes the point of attachment of L1 to Ring A; X1 is selected from a covalent bond, C3-C8cycloalkyl, 3 to 10-membered heterocyclyl, 6 to 10-membered aryl, and 5 to 10-membered heteroaryl, wherein the C3-C8cycloalkyl and 6 to 10-membered aryl are each optionally substituted with 1 to 3 Rb3, and wherein the 3 to 10-membered heterocyclyl and 5 to 10-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc4 and then are optionally substituted on a ring carbon with 1 to 3 Rb3; L2 is selected from a covalent bond, -(C(Rd2)2)n-, -*NRc5-(C(Rd2)2)n-, -*(C(Rd2)2)n-C(=O)-, - *(C(Rd2)2)n-O-(C(Rd2)2)n-, and -*(C(Re1)2C(Re1)2O)r-(C(Rd2)2)n-, wherein * denotes the point of attachment of L2 to X1; X2 is selected from a covalent bond, C3-C8cycloalkyl, 3 to 10-membered heterocyclyl, 6 to 10-membered aryl, and 5 to 10-membered heteroaryl, wherein the C3-C8cycloalkyl and 6 to 10-membered aryl are each optionally substituted with 1 to 3 Rb4, and wherein the 3 to 10-membered heterocyclyl and 5 to 10-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc6 and then are optionally substituted on a ring carbon with 1 to 3 Rb4; or X1– L2– X2 form a 5 to 10-membered spiroheterocyclyl, wherein the 5 to 10-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc7 and then are optionally substituted on a ring carbon with 1 to 3 Rb5; L4 is selected from a covalent bond, -O-, -C(=O)-, -(C(Rd4)2)n-, -NRc11-, -*NRc11-(C(Rd4)2)n-, -*O-(C(Rd4)2)n-, -*(C(Rd4)2)n-O-, -*C(=O)-(C(Rd4)2)n-, -*C2-C6alkenylene-(O)s-, -*C2- C6 alkynylene-(O)s-, -*O-(C(Rd4)2)n-C(=O)-, -*O-(C(Rd4)2)n-C(=O)-NRc11-, -* NRc11- (C(Rd4)2)n-C(=O)-NRc11-, wherein * denotes the point of attachment of L4 to Ring B; wherein at least one of X1 and X2 is not a covalent bond; Y2 is C(Re3)2 or C(=O); Each Ra1 and Ra2 is independently selected from D, halo, OH, C3-C6cycloalkyl, and 3 to 6- membered heterocyclyl, wherein the 3 to 6-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc13; Each Rb2, Rb3, Rb4, Rb5, and Rb8 is independently selected from D, halo, OH, CN, N(Rc14)2, C1-C4alkyl, and C1-C4alkoxy, or two Rb2 Rb3, Rb4, or Rb5 attached to the same atom, form a =O, wherein the C1-C4alkyl and C1-C4alkoxy each optionally substituted with 1 to 3 groups each independently selected from D, halo, OH and CN; Each Rc1, Rc2, Rc3, Rc4, Rc5, Rc6, Rc7, Rc11, Rc13, and Rc14 is independently selected from H, D, C1-C4alkyl, and C(=O)C1-4alkyl; Each Rd1, Rd2, and Rd4 is independently selected from H, D, halo, OH, C1-C4alkyl, and C3- C6cycloalkyl; Each Re1 and Re3 is independently selected from H, D, and C1-C4 alkyl; n is an integer from 0 to 4; r is an integer from 1 to 6; s is 0 or 1; and t is an integer from 0 to 3. In some embodiments, the compounds described herein of a formula described herein, or a pharmaceutically acceptable thereof, wherein: R1 is C1-C6alkyl, wherein the C1-C6alkyl is optionally substituted with 1 or 2 Ra1; R2 is selected from H, D, and C1-C4alkyl, wherein the C1-C6alkyl is optionally substituted with 1 or 2 Ra2; R3 is selected from H, D, and C1-C4alkyl; R4 is selected from H, D, halo, OH, CN, and C1-C4alkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 3 groups each independently selected from D, halo, OH, and CN; R5 is selected from H, D, halo, OH, CN, and C1-C4alkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 3 groups each independently selected from D, halo, OH, and CN; R6 is H or D; R7 is selected from H, D, and C1-C4alkyl; Ring A is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, 6-membered aryl, and 5 or 6-membered heteroaryl, wherein the C3-C6cycloalkyl and 6-membered aryl are each optionally substituted with 1 to 3 Rb2, wherein the 3 to 6-membered heterocyclyl and 5 or or 6-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc2 and then are optionally substituted on a ring carbon with 1 to 3 Rb2; L1 is selected from -S(=O)2-, -*S(=O)2-NRc3-, -*S(=O)2-NRc3-(C(Rd1)2)n-,-*S(=O)2- (C(Rd1)2)n-O-(C(Rd1)2)n-, and -*S(=O)2-NRc3-(C(Rd1)2)n-O-(C(Rd1)2)n-, wherein * denotes the point of attachment of L1 to Ring A; X1 is selected from a covalent bond, C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, 6- membered aryl, and 5 or 6-membered heteroaryl, wherein the C3-C6cycloalkyl and 6- membered aryl are each optionally substituted with 1 to 3 Rb3, and wherein the 3 to 6- membered heterocyclyl and 5 or 6-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc4 and then are optionally substituted on a ring carbon with 1 to 3 Rb3; L2 is selected from a covalent bond, -(C(Rd2)2)n-, -*NRc5-(C(Rd2)2)n-, -*(C(Rd2)2)n-C(=O)-, - *(C(Rd2)2)n-O-(C(Rd2)2)n-, and -*(C(Re1)2C(Re1)2O)r-(C(Rd2)2)n-, wherein * denotes the point of attachment of L2 to X1; X2 is selected from a covalent bond, C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, 6- membered aryl, and 5 or 6-membered heteroaryl, wherein the C3-C6cycloalkyl and 6- membered aryl are each optionally substituted with 1 to 3 Rb4, and wherein the 3 to 6- membered heterocyclyl and 5 or 6-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc6 and then are optionally substituted on a ring carbon with 1 to 3 Rb4; or X1– L2– X2 form a 5 to 10-membered spiroheterocyclyl, wherein the 5 to 10-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc7 and then are optionally substituted on a ring carbon with 1 to 3 Rb5; L4 is selected from a covalent bond, -O-, -C(=O)-, -(C(Rd4)2)n-, -NRc11-, -*NRc11-(C(Rd4)2)n-, -*O-(C(Rd4)2)n-, -*(C(Rd4)2)n-O-, -*C(=O)-(C(Rd4)2)n-, -*C2-C6alkenylene-(O)s-, -*C2- C6 alkynylene-(O)s-, -*O-(C(Rd4)2)n-C(=O)-, -*O-(C(Rd4)2)n-C(=O)-NRc11-, -*NRc11- (C(Rd4)2)n-C(=O)-NRc11-, wherein * denotes the point of attachment of L4 to Ring B; wherein at least one of X1 and X2 is not a covalent bond; Y2 is C(Re3)2 or C(=O); Each Ra1 and Ra2 is independently selected from H, D, and C1-C4alkyl; Each Rb2, Rb3, Rb4, Rb5, and Rb8 is independently selected from D, halo, OH, CN, C1-C4alkyl, and C1-C4alkoxy, or two Rb2, Rb3, Rb4, or Rb5 attached to the same atom, form a =O, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 3 groups each independently selected from D, halo, OH and CN; Each Rc2, Rc3, Rc4, Rc5, Rc6, Rc7, Rc11, Rc13, and Rc14 is independently selected from H, D, and C1-C4alkyl; Each Rd1, Rd2, Rd3, and Rd4 is independently selected from H, D, and C1-C4alkyl; Each Re1 and Re3 is independently H or D; n is an integer from 0 to 4; r is an integer from 1 to 6; s is 1; and t is an integer from 0 to 3. In some embodiments, R1 is selected from C1-C6alkyl, C3-C6cycloalkyl, and 3 to 6- membered heterocyclyl, wherein the C1-C6alkyl is optionally substituted with 1 or 2 Ra1, and wherein the 3 to 6-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc1. In some embodiments, R1 is C1-C6alkyl optionally substituted with 1 to 3 Ra1. In some embodiments, R1 is C1-C6alkyl optionally substituted with 1 or 2 Ra1. In some embodiments, R1 is C1-C6alkyl optionally substituted with OH. In some embodiments, R1 is C1-C6alkyl. In some embodiments, R1 is CH3 or CH2C(CH3)2OH. In some embodiments, R1 is CH3. In some embodiments, R1 is CH2C(CH3)2OH. In some embodiments, R2 is selected from H, D, and C1-C4alkyl, wherein the C1- C4alkyl is optionally substituted with 1 to 3 Ra2. In some embodiments, R2 is H or C1-C4alkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 3 Ra2. In some embodiments, R2 is H, D, or C1-C4alkyl. In some embodiments, R2 is H or D. In some embodiments, R2 is H. In some embodiments, R3 is selected from H, D, halo, CN, and C1-C4alkyl. In some embodiments, R3 is H. In some embodiments, R3 is H or D. In some embodiments, R4 is selected from H, D, halo, OH, CN, C1-C4alkyl, and C1- C4alkoxy, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 4 groups each independently selected from D, halo, OH and CN. In some embodiments, R4 is C1-C4alkyl, CN, or halo, wherein said C1-C4alkyl is optionally substituted with 1 to 3 groups each independently selected from halo. In some embodiments, R4 is CH3, CHF2, CF3, CN, or Cl. In some embodiments, R4 is CH3. In some embodiments, R4 is CHF2. In some embodiments, R4 is CF3. In some embodiments, R4 is CN. In some embodiments, R4 is Cl. In some embodiments, R4 is H, D, CH3, CHF2, CF3, CN, or Cl. In some embodiments, R4 is H, CH3, CHF2, CF3, CN, or Cl. In some embodiments, R4 is H or D. In some embodiments, R4 is H. In some embodiments, R5 is selected from H, D, halo, OH, CN, C1-C4alkyl, and C1- C4alkoxy, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 4 groups each independently selected from D, halo, OH and CN. In some embodiments, R5 is selected from H, D, halo, OH, and CN. In some embodiments, R5 is H or D. In some embodiments, R5 is H. In some embodiments, R6 is H. In some embodiments, R6 is D. In some embodiments, R7 is selected from H, D, and C1-C4alkyl. In some embodiments, R7 is H or C1-C4alkyl. In some embodiments, R7 is methyl. In some embodiments, R7 is H. In some embodiments, R7 is H, D, or C1-C4alkyl. In some embodiments, R7 is H, D, or methyl. In some embodiments, R7 is H or methyl. In some embodiments, Ring A is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, C5-C12spirocycloalkyl, 5 to 12-membered spiroheterocyclyl, 6 to 12-membered aryl, and 5 or 6-membered heteroaryl, wherein the C3-C6cycloalkyl, C5-C12spirocycloalkyl, and 6 to 12-membered aryl are each optionally substituted with 1 to 4 Rb2, and wherein the 3 to 6-membered heterocyclyl, 5 to 12-membered spiroheterocyclyl, and 5 or 6-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc2 and then are optionally substituted on a ring carbon with 1 to 4 Rb2. In some embodiments, Ring A is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, C5-C12spirocycloalkyl, 5 to 12-membered spiroheterocyclyl, 6 to 12-membered aryl, and 5 or 6-membered heteroaryl, wherein the C3-C6cycloalkyl, C5-C12spirocycloalkyl, and 6 to 12-membered aryl are each optionally substituted with 1 or 2 Rb2, and wherein the 3 to 6-membered heterocyclyl, 5 to 12-membered spiroheterocyclyl, and 5 or 6-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc2 and then are optionally substituted on a ring carbon with 1 or 2 Rb2. In some embodiments, Ring A is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, C5-C12spirocycloalkyl, 5 to 12-membered spiroheterocyclyl, phenyl, and 5 or 6- membered heteroaryl, wherein the C3-C6cycloalkyl, C5-C12spirocycloalkyl, and phenyl are each optionally substituted with 1 to 4 Rb2, and wherein the 3 to 6-membered heterocyclyl, 5 to 12-membered spiroheterocyclyl, and 5 or 6-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc2 and then are optionally substituted on a ring carbon with 1 to 4 Rb2. In some embodiments, Ring A is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, C5-C12spirocycloalkyl, 5 to 12-membered spiroheterocyclyl, phenyl, and 5 or 6- membered heteroaryl, wherein the C3-C6cycloalkyl, C5-C12spirocycloalkyl, and phenyl are each optionally substituted with 1 or 2 Rb2, and wherein the 3 to 6-membered heterocyclyl, 5 to 12-membered spiroheterocyclyl, and 5 or 6-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc2 and then are optionally substituted on a ring carbon with 1 or 2 Rb2. In some embodiments, Ring A is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, C5-C12spirocycloalkyl, 5 to 12-membered spiroheterocyclyl, phenyl, and 5 or 6- membered heteroaryl, wherein the C3-C6cycloalkyl, C5-C12spirocycloalkyl, and phenyl are each optionally substituted with Rb2, and wherein the 3 to 6-membered heterocyclyl, 5 to 12- membered spiroheterocyclyl, and 5 or 6-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc2 and then are optionally substituted on a ring carbon with Rb2. In some embodiments, Ring A is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, C9-C12spirocycloalkyl, 9 to 12-membered spiroheterocyclyl, phenyl, and 5 or 6- membered heteroaryl, wherein the C3-C6cycloalkyl, C9-C12spirocycloalkyl, and phenyl are each optionally substituted with 1 to 4 Rb2, and wherein the 3 to 6-membered heterocyclyl, 9 to 12-membered spiroheterocyclyl, and 5 or 6-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc2 and then are optionally substituted on a ring carbon with 1 to 4 Rb2. In some embodiments, Ring A is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, C9-C12spirocycloalkyl, 9 to 12-membered spiroheterocyclyl, phenyl, and 5 or 6-membered heteroaryl, wherein the C3-C6cycloalkyl, C9- C12spirocycloalkyl, and phenyl are each optionally substituted with 1 or 2 Rb2, and wherein the 3 to 6-membered heterocyclyl, 9 to 12-membered spiroheterocyclyl, and 5 or 6-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc2 and then are optionally substituted on a ring carbon with 1 or 2 Rb2. In some embodiments, Ring A is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, C9- C12spirocycloalkyl, 9 to 12-membered spiroheterocyclyl, phenyl, and 5 or 6-membered heteroaryl, wherein the C3-C6cycloalkyl, C9-C12spirocycloalkyl, and phenyl are each optionally substituted with Rb2, and wherein the 3 to 6-membered heterocyclyl, 9 to 12- membered spiroheterocyclyl, and 5 or 6-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc2 and then are optionally substituted on a ring carbon with Rb2. In some embodiments, Ring A is selected from C3-C6cycloalkyl optionally substituted with 1 to 4 Rb2. In some embodiments, Ring A is selected from C3-C6cycloalkyl optionally substituted with 1 or 2 Rb2. In some embodiments, Ring A is selected from C3-C6cycloalkyl optionally substituted with Rb2. In some embodiments, Ring A is C3-C6cycloalkyl. In some embodiments, Ring A is cyclohexyl optionally substituted with 1 to 4 Rb2. In some embodiments, Ring A is cyclohexyl optionally substituted with 1 or 2 Rb2. In some embodiments, Ring A is cyclohexyl optionally substituted with Rb2. In some embodiments, Ring A is cyclohexyl. In some embodiments, Ring A is 6 to 12-membered aryl optionally substituted with 1 to 4 Rb2. In some embodiments, Ring A is 6 to 12-membered aryl optionally substituted with 1 or 2 Rb2. In some embodiments, Ring A is 6 to 12-membered aryl optionally substituted with Rb2. In some embodiments, Ring A is 6 to 12-membered aryl. In some embodiments, Ring A is phenyl optionally substituted with 1 to 4 Rb2. In some embodiments, Ring A is phenyl optionally substituted with 1 or 2 Rb2. In some embodiments, Ring A is phenyl optionally substituted with Rb2. In some embodiments, Ring A is phenyl. In some embodiments, Ring A is selected from 3 to 12-membered heterocyclyl optionally substituted with 1 to 4 Rb2. In some embodiments, Ring A is selected from 3 to 12- membered heterocyclyl optionally substituted with 1 or 2 Rb2. In some embodiments, Ring A is selected from 3 to 12-membered heterocyclyl optionally substituted with Rb2. In some embodiments, Ring A is selected from 3 to 12-membered heterocyclyl. In some embodiments, Ring A is selected from 3 to 6-membered heterocyclyl optionally substituted with 1 to 4 Rb2. In some embodiments, Ring A is selected from 3 to 6- membered heterocyclyl optionally substituted with 1 or 2 Rb2. In some embodiments, Ring A is selected from 3 to 6-membered heterocyclyl optionally substituted with Rb2. In some embodiments, Ring A is selected from 3 to 6-membered heterocyclyl. In some embodiments, Ring A is piperidinyl optionally substituted with 1 to 4 Rb2. In some embodiments, Ring A is piperidinyl optionally substituted with 1 or 2 Rb2. In some embodiments, Ring A is piperidinyl optionally substituted with Rb2. In some embodiments, Ring A is piperidinyl. In some embodiments, Ring A is selected from 5 to 12-membered spiroheterocyclyl optionally substituted with 1 to 4 Rb2. In some embodiments, Ring A is selected from 5 to 12- membered spiroheterocyclyl optionally substituted with 1 or 2 Rb2. In some embodiments, Ring A is selected from 5 to 12-membered spiroheterocyclyl optionally substituted with Rb2. In some embodiments, Ring A is selected from 5 to 12-membered spiroheterocyclyl. In some embodiments, Ring A is 9 to 12-membered spiroheterocyclyl optionally substituted with 1 to 4 Rb2. In some embodiments, Ring A is 9 to 12-membered spiroheterocyclyl optionally substituted with 1 or 2 Rb2. In some embodiments, Ring A is 9 to 12-membered spiroheterocyclyl optionally substituted with Rb2. In some embodiments, Ring A is 9 to 12-membered spiroheterocyclyl. In some embodiments, Ring A is 6 to 11-membered spiroheterocyclyl optionally substituted with 1 to 4 Rb2. In some embodiments, Ring A is 6 to 11-membered spiroheterocyclyl optionally substituted with 1 or 2 Rb2. In some embodiments, Ring A is 6 to 11-membered spiroheterocyclyl optionally substituted with Rb2. In some embodiments, Ring A is 6 to 11-membered spiroheterocyclyl. In some embodiments, Ring A is 2-azaspiro[3.3]heptanyl optionally substituted with 1 to 4 Rb2. In some embodiments, Ring A is 2-azaspiro[3.3]heptanyl optionally substituted with 1 or 2 Rb2. In some embodiments, Ring A is 2-azaspiro[3.3]heptanyl optionally substituted with Rb2. In some embodiments, Ring A is 2-azaspiro[3.3]heptanyl. In some embodiments, Ring A is selected from 5 to 12-membered heteroaryl optionally substituted with 1 to 4 Rb2. In some embodiments, Ring A is selected from 5 to 12- membered heteroaryl optionally substituted with 1 or 2 Rb2. In some embodiments, Ring A is selected from 5 to 12-membered heteroaryl optionally substituted with Rb2. In some embodiments, Ring A is selected from 5 to 12-membered heteroaryl. In some embodiments, Ring A is selected from 5 or 6-membered heteroaryl optionally substituted with 1 to 4 Rb2. In some embodiments, Ring A is selected from 5 or 6-membered heteroaryl optionally substituted with 1 or 2 Rb2. In some embodiments, Ring A is selected from 5 or 6-membered heteroaryl optionally substituted with Rb2. In some embodiments, Ring A is selected from 5 or 6-membered heteroaryl. In some embodiments, Ring A is pyridinyl optionally substituted with 1 to 4 Rb2. In some embodiments, Ring A is pyridinyl optionally substituted with 1 or 2 Rb2. In some embodiments, Ring A is pyridinyl optionally substituted with Rb2. In some embodiments, Ring A is pyridinyl. In some embodiments, Ring A is cyclohexyl, phenyl, piperidinyl, 2- azaspiro[3.3]heptanyl, or pyridinyl, each of which is optionally substituted with 1 to 4 Rb2. In some embodiments, Ring A is cyclohexyl, phenyl, piperidinyl, 2-azaspiro[3.3]heptanyl, or pyridinyl, each of which is optionally substituted with 1 or 2 Rb2. In some embodiments, Ring A is cyclohexyl, phenyl, piperidinyl, 2-azaspiro[3.3]heptanyl, or pyridinyl, each of which is optionally substituted with Rb2. In some embodiments, Ring A is cyclohexyl, phenyl, piperidinyl, 2-azaspiro[3.3]heptanyl, or pyridinyl. In some embodiments, Rb2 is selected from C1-C4alkyl and halo. In some embodiments, Rb2 is C1-C4alkyl. In some embodiments, Rb2 is halo. In some embodiments, Rb2 is selected from F and methyl. In some embodiments, Rb2 is F. In some embodiments, Rb2 is methyl. In some embodiments, L1 is selected from covalent bond, -S(=O)2-, -*NRc3-S(=O)2-, - *S(=O)2-NRc3-, -*S(=O)2-NRc3-(C(Rd1)2)n-, -*S(=O)2-(C(Rd1)2)n-O-(C(Rd1)2)n-, -*NRc3- S(=O)2-(C(Rd1)2)n-O-(C(Rd1)2)n-, and -*S(=O)2-NRc3-(C(Rd1)2)n-O-(C(Rd1)2)n-. In some embodiments, L1 is selected from -S(=O)2-, -*NRc3-S(=O)2-, -*S(=O)2-NRc3-, -*S(=O)2- NRc3-(C(Rd1)2)n-, -*S(=O)2-(C(Rd1)2)n-O-(C(Rd1)2)n-, -*NRc3-S(=O)2-(C(Rd1)2)n-O-(C(Rd1)2)n- , and -*S(=O)2-NRc3-(C(Rd1)2)n-O-(C(Rd1)2)n-. In some embodiments, L1 is selected from covalent bond, -S(=O)2-, -*S(=O)2-NRc3-, -*S(=O)2-(C(Rd1)2)n-O-(C(Rd1)2)n-, and -*S(=O)2- NRc3-(C(Rd1)2)n-O-(C(Rd1)2)n-. In some embodiments, L1 is selected from -S(=O)2-, - *S(=O)2-NRc3-, -*S(=O)2-(C(Rd1)2)n-O-(C(Rd1)2)n-, and -*S(=O)2-NRc3-(C(Rd1)2)n-O- (C(Rd1)2)n-. In some embodiments, L1 is selected from -S(=O)2-, -*S(=O)2-NRc3-, -*S(=O)2- (C(Rd1)2)n-O-(C(Rd1)2)n-, and -*S(=O)2-NRc3-(C(Rd1)2)n-O-(C(Rd1)2)n-. In some embodiments, L1 is selected from -S(=O)2- and -*S(=O)2-NRc3-. In some embodiments, L1 is -S(=O)2-. In some embodiments, L1 is -*S(=O)2-NRc3-. In some embodiments, L1 is -*S(=O)2-(C(Rd1)2)n- O-(C(Rd1)2)n-. In some embodiments, L1 is -*S(=O)2-NRc3-(C(Rd1)2)n-O-(C(Rd1)2)n-. In some embodiments, L1 is covalent bond. In some embodiments, L1 is selected from -S(=O)2-, -*S(=O)2-NRc3-, -*S(=O)2- (C(Rd1)2)n-O-(C(Rd1)2)n-, and -*S(=O)2-NRc3-(C(Rd1)2)n-O-(C(Rd1)2)n-. In some embodiments, L1 is selected from -S(=O)2- and -*S(=O)2-NH-. In some embodiments, L1 is -*S(=O)2- (CH2)3-O-CH2-. In some embodiments, L1 is -*S(=O)2-N(CH2CH2OH)-CH2-. In some embodiments, L1 is -*S(=O)2-NH-(CH2)2-O-CH2-. In some embodiments, X1 is a covalent bond. In some embodiments, X1 is selected from C3-C10cycloalkyl, 3 to 12-membered heterocyclyl, 6 to 12-membered aryl, and 5 to 12- membered heteroaryl, wherein the C3-C10cycloalkyl and 6 to 12-membered aryl are each optionally substituted with 1 to 4 Rb3, and wherein the 3 to 12-membered heterocyclyl and 5 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc4 and then are optionally substituted on a ring carbon with 1 to 4 Rb3. In some embodiments, X1 is selected from covalent bond, C3-C6cycloalkyl, 3 to 6- membered heterocyclyl, phenyl, and 5 or 6-membered heteroaryl, wherein the C3- C6cycloalkyl and phenyl are each optionally substituted with 1 to 3 Rb3, and wherein the 3 to 6-membered heterocyclyl and 5 or 6-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc4 and then are optionally substituted on a ring carbon with 1 to 3 Rb3. In some embodiments, X1 is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, phenyl, and 5 or 6-membered heteroaryl, wherein the C3-C6cycloalkyl and phenyl are each optionally substituted with 1 to 3 Rb3, and wherein the 3 to 6-membered heterocyclyl and 5 or 6-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc4 and then are optionally substituted on a ring carbon with 1 to 3 Rb3. In some embodiments, X1 is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, and 5 or 6-membered heteroaryl, wherein the C3-C6cycloalkyl is optionally substituted with 1 to 3 Rb3, wherein the 3 to 6-membered heterocyclyl and 5 or 6-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc4 and then are optionally substituted on a ring carbon with 1 to 3 Rb3. In some embodiments, X1 is selected from C3-C10cycloalkyl optionally substituted with 1 to 3 Rb3. In some embodiments, X1 is selected from C3-C10cycloalkyl optionally substituted with 1 or 2 Rb3. In some embodiments, X1 is selected from C3-C10cycloalkyl optionally substituted with Rb3. In some embodiments, X1 is selected from C3-C10cycloalkyl. In some embodiments, X1 is selected from C3-C6cycloalkyl optionally substituted with 1 to 3 Rb3. In some embodiments, X1 is selected from C3-C6cycloalkyl optionally substituted with 1 or 2 Rb3. In some embodiments, X1 is selected from C3-C6cycloalkyl optionally substituted with Rb3. In some embodiments, X1 is selected from C3-C6cycloalkyl. In some embodiments, X1 is cyclobutyl or cyclohexyl, each optionally substituted with 1 to 3 Rb3. In some embodiments, X1 is cyclobutyl or cyclohexyl, each optionally substituted with 1 or 2 Rb3. In some embodiments, X1 is cyclobutyl or cyclohexyl, each optionally substituted with Rb3. In some embodiments, X1 is cyclobutyl or cyclohexyl. In some embodiments, X1 is cyclobutyl. In some embodiments, X1 is cyclohexyl. In some embodiments, X1 is selected from 3 to 12-membered heterocyclyl optionally substituted with 1 to 3 Rb3. In some embodiments, X1 is selected from 3 to 12-membered heterocyclyl optionally substituted with 1 or 2 Rb3. In some embodiments, X1 is selected from 3 to 12-membered heterocyclyl optionally substituted with Rb3. In some embodiments, X1 is selected from 3 to 12-membered heterocyclyl. In some embodiments, X1 is selected from 3 to 6-membered heterocyclyl optionally substituted with 1 to 3 Rb3. In some embodiments, X1 is selected from 3 to 6-membered heterocyclyl optionally substituted with 1 or 2 Rb3. In some embodiments, X1 is selected from 3 to 6-membered heterocyclyl optionally substituted with Rb3. In some embodiments, X1 is selected from 3 to 6-membered heterocyclyl. In some embodiments, X1 is pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with 1 to 3 Rb3. In some embodiments, X1 is pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with 1 or 2 Rb3. In some embodiments, X1 is pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with Rb3. In some embodiments, X1 is pyrrolidinyl, piperidinyl, or piperazinyl. In some embodiments, X1 is selected from 5 to 12-membered heteroaryl optionally substituted with 1 to 3 Rb3. In some embodiments, X1 is selected from 5 to 12-membered heteroaryl optionally substituted with 1 or 2 Rb3. In some embodiments, X1 is selected from 5 to 12-membered heteroaryl optionally substituted with Rb3. In some embodiments, X1 is selected from 5 to 12-membered heteroaryl. In some embodiments, X1 is selected from 5 or 6-membered heteroaryl optionally substituted with 1 to 3 Rb3. In some embodiments, X1 is selected from 5 or 6-membered heteroaryl optionally substituted with 1 or 2 Rb3. In some embodiments, X1 is selected from 5 or 6-membered heteroaryl optionally substituted with Rb3. In some embodiments, X1 is selected from 5 or 6-membered heteroaryl. In some embodiments, X1 is 1,2,3-triazolyl optionally substituted with 1 or 2 Rb3. In some embodiments, X1 is 1,2,3-triazolyl optionally substituted with Rb3. In some embodiments, X1 is 1,2,3-triazolyl. In some embodiments, L2 is selected from covalent bond, -*(C(Re1)2C(Re1)2O)r- (C(Rd2)2)n-, -(C(Rd2)2)n-, -*(C(Rd2)2)n-C(=O)-, -*NRc5-(C(Rd2)2)n-, and -*(C(Rd2)2)n-O- (C(Rd2)2)n-. In some embodiments, L2 is selected from -*(C(Re1)2C(Re1)2O)r-(C(Rd2)2)n-, - (C(Rd2)2)n-, -*(C(Rd2)2)n-C(=O)-, -*NRc5-(C(Rd2)2)n-, and -*(C(Rd2)2)n-O-(C(Rd2)2)n-. In some embodiments, L2 is -*(C(Re1)2C(Re1)2O)r-(C(Rd2)2)n-. In some embodiments, L2 is - (C(Rd2)2)n-. In some embodiments, L2 is -*(C(Rd2)2)n-C(=O)-. In some embodiments, L2 is - *NRc5-(C(Rd2)2)n-. In some embodiments, L2 is -*(C(Rd2)2)n-O-(C(Rd2)2)n-. In some embodiments, L2 is covalent bond. In some embodiments, L2 is selected from -*(CH2CH2O)r-(CH2)n-, -(CH2)n-, - *(CH2)n-C(=O)-, -*NRc5-(CH2)n-, and -*(CH2)n-O-(CH2)n-. In some embodiments, L2 is - *(CH2CH2O)r-(CH2)n-. In some embodiments, L2 is -(CH2)n-. In some embodiments, L2 is - CH2-. In some embodiments, L2 is -CH2CH2-. In some embodiments, L2 is -*(CH2)n-O- (CH2)n-. In some embodiments, X2 is a covalent bond. In some embodiments, X2 is selected from C3-C10cycloalkyl, 3 to 12-membered heterocyclyl, 6 to 12-membered aryl, and 5 to 12- membered heteroaryl, wherein the C3-C10cycloalkyl and 6 to 12-membered aryl are each optionally substituted with 1 to 4 Rb4, and wherein the 3 to 12-membered heterocyclyl and 5 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc6 and then are optionally substituted on a ring carbon with 1 to 4 Rb4. In some embodiments, X2 is selected from C3-C10cycloalkyl, 3 to 12-membered heterocyclyl, and 5 to 12-membered heteroaryl, wherein the C3-C10cycloalkyl is optionally substituted with 1 to 4 Rb4, and wherein the 3 to 12-membered heterocyclyl and 5 to 12- membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc6 and then are optionally substituted on a ring carbon with 1 to 4 Rb4. In some embodiments, X2 is selected from C3-C10cycloalkyl, 3 to 12-membered heterocyclyl, and 5 to 12-membered heteroaryl, wherein the C3-C10cycloalkyl is optionally substituted with 1 or 2 Rb4, and wherein the 3 to 12-membered heterocyclyl and 5 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc6 and then are optionally substituted on a ring carbon with 1 or 2 Rb4. In some embodiments, X2 is selected from C3-C10cycloalkyl, 3 to 12-membered heterocyclyl, and 5 to 12-membered heteroaryl, wherein the C3-C10cycloalkyl is optionally substituted with Rb4, and wherein the 3 to 12- membered heterocyclyl and 5 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc6 and then are optionally substituted on a ring carbon with Rb4. In some embodiments, X2 is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, and 5 to 6-membered heteroaryl, wherein the C3-C6cycloalkyl is optionally substituted with 1 to 4 Rb4, and wherein the 3 to 6-membered heterocyclyl and 5 to 6- membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc6 and then are optionally substituted on a ring carbon with 1 to 4 Rb4. In some embodiments, X2 is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, and 5 to 6- membered heteroaryl, wherein the C3-C6cycloalkyl is optionally substituted with 1 or 2 Rb4, and wherein the 3 to 6-membered heterocyclyl and 5 to 6-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc6 and then are optionally substituted on a ring carbon with 1 or 2 Rb4. In some embodiments, X2 is selected from C3- C6cycloalkyl, 3 to 6-membered heterocyclyl, and 5 to 6-membered heteroaryl, wherein the C3-C6cycloalkyl is optionally substituted with Rb4, and wherein the 3 to 6-membered heterocyclyl and 5 to 6-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc6 and then are optionally substituted on a ring carbon with Rb4. In some embodiments, X2 is selected from C3-C6cycloalkyl, 3 to 6- membered heterocyclyl, and 5 to 6-membered heteroaryl, wherein the 3 to 6-membered heterocyclyl and 5 to 6-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc6. In some embodiments, X2 is selected from C3-C10cycloalkyl optionally substituted with 1 to 3 Rb4. In some embodiments, X2 is selected from C3-C10cycloalkyl optionally substituted with 1 or 2 Rb4. In some embodiments, X2 is selected from C3-C10cycloalkyl optionally substituted with Rb4. In some embodiments, X2 is selected from C3-C10cycloalkyl. In some embodiments, X2 is selected from C3-C6cycloalkyl optionally substituted with 1 to 3 Rb4. In some embodiments, X2 is selected from C3-C6cycloalkyl optionally substituted with 1 or 2 Rb4. In some embodiments, X2 is selected from C3-C6cycloalkyl optionally substituted with Rb4. In some embodiments, X2 is selected from C3-C6cycloalkyl. In some embodiments, X2 is cyclohexyl optionally substituted with 1 to 3 Rb4. In some embodiments, X2 is cyclohexyl optionally substituted with Rb4. In some embodiments, X2 is cyclohexyl. In some embodiments, X2 is selected from 3 to 12-membered heterocyclyl optionally substituted with 1 to 3 Rb4. In some embodiments, X2 is selected from 3 to 12-membered heterocyclyl optionally substituted with Rb4. In some embodiments, X2 is selected from 3 to 12-membered heterocyclyl. In some embodiments, X2 is selected from 3 to 6-membered heterocyclyl optionally substituted with 1 to 3 Rb4. In some embodiments, X2 is selected from 3 to 6-membered heterocyclyl optionally substituted with Rb4. In some embodiments, X2 is selected from 3 to 6-membered heterocyclyl. In some embodiments, X2 is azetidinyl, piperidinyl, or piperazinyl, each optionally substituted with 1 to 3 Rb4. In some embodiments, X2 is azetidinyl, piperidinyl, or piperazinyl, each optionally substituted with Rb4. In some embodiments, X2 is azetidinyl, piperidinyl, or piperazinyl. In some embodiments, X2 is azetidinyl. In some embodiments, X2 is piperidinyl. In some embodiments, X2 is piperazinyl. In some embodiments, X2 is selected from 5 to 12-membered heteroaryl optionally substituted with 1 to 3 Rb4. In some embodiments, X2 is selected from 5 to 12-membered heteroaryl optionally substituted with 1 or 2 Rb4. In some embodiments, X2 is selected from 5 to 12-membered heteroaryl optionally substituted with Rb4. In some embodiments, X2 is selected from 5 to 12-membered heteroaryl. In some embodiments, X2 is selected from 5 or 6-membered heteroaryl optionally substituted with 1 to 3 Rb4. In some embodiments, X2 is selected from 5 or 6-membered heteroaryl optionally substituted with 1 or 2 Rb4. In some embodiments, X2 is selected from 5 or 6-membered heteroaryl optionally substituted with Rb4. In some embodiments, X2 is selected from 5 or 6-membered heteroaryl. In some embodiments, X2 is 1,2,3-triazolyl optionally substituted with 1 or 2 Rb4. In some embodiments, X2 is 1,2,3-triazolyl optionally substituted with Rb4. In some embodiments, X2 is 1,2,3-triazolyl. In some embodiments, L3 is selected from -O-, -*C(=O)-(C(Rd3)2)n-, -(C(Rd3)2)n-, and -*(C(Re2)2C(Re2)2O)r-(C(Rd3)2)n-. In some embodiments, L3 is -O-. In some embodiments, L3 is -*C(=O)-(C(Rd3)2)n-. In some embodiments, L3 is -(C(Rd3)2)n-. In some embodiments, L3 is -*(C(Re2)2C(Re2)2O)r-(C(Rd3)2)n-. In some embodiments, L3 is selected from -O-, -*C(=O)-(CH2)n-, -(CH2)n-, and - *(CH2CH2O)r-(CH2)n-. In some embodiments, L3 is -*C(=O)-(CH2)n-. In some embodiments, L3 is -(CH2)n-. In some embodiments, L3 is -*(CH2CH2O)r-(CH2)n-. In some embodiments, X3 is selected from 3 to 12-membered heterocyclyl having 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc9 and then is optionally substituted on a ring carbon with 1 to 3 Rb6. In some embodiments, X3 is selected from 3 to 12-membered heterocyclyl having 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc9 and then is optionally substituted on a ring carbon with 1 or 2 Rb6. In some embodiments, X3 is selected from 3 to 12-membered heterocyclyl having 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc9 and then is optionally substituted on a ring carbon with Rb6. In some embodiments, X3 is selected from 3 to 12- membered heterocyclyl having 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc9. In some embodiments, X3 is selected from 3 to 6-membered heterocyclyl having 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc9 and then is optionally substituted on a ring carbon with 1 to 3 Rb6. In some embodiments, X3 is selected from 3 to 6- membered heterocyclyl having 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc9 and then is optionally substituted on a ring carbon with 1 or 2 Rb6. In some embodiments, X3 is selected from 3 to 6-membered heterocyclyl having 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc9 and then is optionally substituted on a ring carbon with Rb6. In some embodiments, X3 is selected from 3 to 6- membered heterocyclyl having 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc9. In some embodiments, X3 is selected from piperazinyl and piperidinyl, each optionally substituted on a ring carbon with 1 to 3 Rb6. In some embodiments, X3 is selected from piperazinyl and piperidinyl, each optionally substituted on a ring carbon with 1 or 2 Rb6. In some embodiments, X3 is selected from piperazinyl and piperidinyl, each optionally substituted on a ring carbon with Rb6. In some embodiments, X3 is selected from piperazinyl and piperidinyl. In some embodiments, X3 is piperazinyl. In some embodiments, X3 is piperidinyl. In some embodiments, X2– L3– X3 form a C5-C12spirocycloalkyl or 5 to 12-membered spiroheterocyclyl, wherein the C5-C12spirocycloalkyl is optionally substituted with 1 to 4 Rb7, and wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc10 and then are optionally substituted on a ring carbon with 1 to 4 Rb7. In some embodiments, X2– L3– X3 form a C5-C12spirocycloalkyl or 5 to 12-membered spiroheterocyclyl, wherein the C5-C12spirocycloalkyl is optionally substituted with 1 or 2 Rb7, and wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc10 and then are optionally substituted on a ring carbon with 1 or 2 Rb7. In some embodiments, X2– L3– X3 form a C5-C12spirocycloalkyl or 5 to 12-membered spiroheterocyclyl, wherein the C5- C12spirocycloalkyl is optionally substituted with Rb7, and wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc10 and then are optionally substituted on a ring carbon with Rb7. In some embodiments, X2– L3– X3 form a C5-C12spirocycloalkyl or 5 to 12-membered spiroheterocyclyl, wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc10. In some embodiments, X2– L3– X3 form a 5 to 12-membered spiroheterocyclyl, wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc10 and then are optionally substituted on a ring carbon with 1 to 4 Rb7. In some embodiments, X2– L3– X3 form a 5 to 12-membered spiroheterocyclyl, wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc10 and then are optionally substituted on a ring carbon with 1 or 2 Rb7. In some embodiments, X2– L3– X3 form a 5 to 12-membered spiroheterocyclyl, wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc10 and then are optionally substituted on a ring carbon with Rb7. In some embodiments, X2– L3– X3 form a 5 to 12-membered spiroheterocyclyl, wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc10. In some embodiments, X2– L3– X3 form a 10 or 11-membered spiroheterocyclyl, wherein the 10 or 11-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc10 and then are optionally substituted on a ring carbon with 1 to 4 Rb7. In some embodiments, X2– L3– X3 form a 10 or 11-membered spiroheterocyclyl, wherein the 10 or 11-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc10 and then are optionally substituted on a ring carbon with 1 or 2 Rb7. In some embodiments, X2– L3– X3 form a 10 or 11-membered spiroheterocyclyl, wherein the 10 or 11-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc10 and then are optionally substituted on a ring carbon with Rb7. In some embodiments, X2– L3– X3 form a 10 or 11-membered spiroheterocyclyl, wherein the 10 or 11-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc10. In some embodiments, two X3 form a C5-C12spirocycloalkyl or 5 to 12-membered spiroheterocyclyl, wherein the C5-C12spirocycloalkyl is optionally substituted with 1 to 4 Rb7, and wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc10 and then are optionally substituted on a ring carbon with 1 to 4 Rb7. In some embodiments, two X3 form a C5-C12spirocycloalkyl or 5 to 12-membered spiroheterocyclyl, wherein the C5-C12spirocycloalkyl is optionally substituted with 1 or 2 Rb7, and wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc10 and then are optionally substituted on a ring carbon with 1 or 2 Rb7. In some embodiments, two X3 form a C5- C12spirocycloalkyl or 5 to 12-membered spiroheterocyclyl, wherein the C5- C12spirocycloalkyl is optionally substituted with Rb7, and wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc10 and then are optionally substituted on a ring carbon with Rb7. In some embodiments, two X3 form a C5-C12spirocycloalkyl or 5 to 12-membered spiroheterocyclyl, wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc10. In some embodiments, two X3 form a 5 to 12-membered spiroheterocyclyl, wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc10 and then are optionally substituted on a ring carbon with 1 to 4 Rb7. In some embodiments, two X3 form 3,9-diazaspiro[5.5]undecane optionally substituted on a ring carbon with 1 to 4 Rb7. In some embodiments, two X3 form 3,9- diazaspiro[5.5]undecane optionally substituted on a ring carbon with 1 or 2 Rb7. In some embodiments, two X3 form 3,9-diazaspiro[5.5]undecane optionally substituted on a ring carbon with Rb7. In some embodiments, two X3 form 3,9-diazaspiro[5.5]undecane. In some embodiments, L4 is a covalent bond. In some embodiments, L4 is selected from -O-, -C(=O)-, -(C(Rd4)2)n-, -NRc11-, - *NRc11-(C(Rd4)2)n-, -*(C(Rd4)2)n-NRc11-, -*O-(C(Rd4)2)n-, -*(C(Rd4)2)n-O-, -*C(=O)- (C(Rd4)2)n-, -*(C(Rd4)2)n-C(=O)-, -*C2-C6alkenylene-(O)s-, -*C2-C6alkynylene-(O)s-, -*O- (C(Rd4)2)n-C(=O)-, -*O-(C(Rd4)2)n-C(=O)-NRc11-, -*O-(C(Rd4)2)n-NRc11-C(=O)-, -*NRc11- (C(Rd4)2)n-C(=O)-NRc11-, -*NRc11-(C(Rd4)2)n-C(=O)-, and -*NRc11-(C(Rd4)2)n-NRc11-C(=O)-. In some embodiments, L4 is selected from covalent bond, -O-, -NRc11-, -*NRc11- (C(Rd4)2)n-C(=O)-NRc11-, -*C2-C6alkenylene-(O)s-, -*C2-C6alkynylene-(O)s-, -*NRc11- (C(Rd4)2)n-, -*O-(C(Rd4)2)n-C(=O)-, -*NRc11-(C(Rd4)2)n-C(=O)-, and -*O-(C(Rd4)2)n-C(=O)- NRc11-. In some embodiments, L4 is selected from -O-, -NRc11-, -*NRc11-(C(Rd4)2)n-C(=O)- NRc11-, -*C2-C6alkenylene-(O)s-, -*C2-C6alkynylene-(O)s-, -*NRc11-(C(Rd4)2)n-, -*O- (C(Rd4)2)n-C(=O)-, -*NRc11-(C(Rd4)2)n-C(=O)-, and -*O-(C(Rd4)2)n-C(=O)-NRc11-. In some embodiments, L4 is selected from covalent bond, -O-, -NH-, -*NH-(CH2)n- C(=O)-NH-, -*C2-C6alkynylene-(O)s-, -*NH-(CH2)n-, -*O-(CH2)n-C(=O)-, -*NH-(CH2)n- C(=O)-, and -*O-(CH2)n-C(=O)-NH-. In some embodiments, L4 is selected from -O-, -NH-, - *NH-(CH2)n-C(=O)-NH-, -*C2-C6alkynylene-(O)s-, -*NH-(CH2)n-, -*O-(CH2)n-C(=O)-, - *NH-(CH2)n-C(=O)-, and -*O-(CH2)n-C(=O)-NH-. In some embodiments, L4 is selected from -O- and -NRc11-. In some embodiments, L4 is -*NRc11-(C(Rd4)2)n-C(=O)-NRc11-. In some embodiments, L4 is -*O-(C(Rd4)2)n-C(=O)-NRc11-. In some embodiments, L4 is -*C2- C6alkynylene-O-. In some embodiments, L4 is -*C2-C6alkynylene-. In some embodiments, L4 is -*C3alkynylene-. In some embodiments, Ring A is phenyl optionally substituted with 1 to 4 Rb2 and L1 is -*S(=O)2-NRc3-. In some embodiments, Ring A is phenyl optionally substituted with 1 to 4 Rb2, L1 is - *S(=O)2-NRc3-, and X1 is C3-C8cycloalkyl. In some embodiments, Ring A is piperidinyl optionally substituted with 1 to 4 Rb2 and L1 is -S(=O)2-. In some embodiments, Ring A is piperidinyl optionally substituted with 1 to 4 Rb2, L1 is -S(=O)2-, and X1 is 3 to 10-membered heterocyclyl. In some embodiments, Ring B is
Figure imgf000049_0001
. In some embodiments, Ring
Figure imgf000049_0002
In some embodiments, Rb8 is halo or C1-C4alkyl. In some embodiments, Rb8 is F or methyl. In some embodiments, Rb8 is methyl. In some embodiments, W is CH. In some embodiments, W is N. In some embodiments, Y1 is C(Rd5)2. In some embodiments, Y1 is CH2. In some embodiments, Y1 is NRc12. In some embodiments, Y1 is NH. In some embodiments, Y2 is C(Re3)2. In some embodiments, Y2 is CH2. In some embodiments, Y2 is C(=O). In some embodiments, m is 0. In some embodiments, m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, n is 0. In some embodiments, n is an integer from 1 to 8. In some embodiments, n is an integer from 0 to 4. In some embodiments, n is an integer from 0 to 3. In some embodiments, n is an integer from 0 to 2. In some embodiments, n is 0 or 1. In some embodiments, n is an integer from 1 to 4. In some embodiments, n is an integer from 1 to 3. In some embodiments, n is 1 or 2. In some embodiments, n is an integer from 2 to 8. In some embodiments, n is an integer from 2 to 4. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, q is 0. In some embodiments, q is 1 or 2. In some embodiments, q is 0 or 1. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, r is an integer from 1 to 5. In some embodiments, r is an integer from 1 to 4. In some embodiments, r is an integer from 1 to 3. In some embodiments, r is 1 or 2. In some embodiments, r is 1. In some embodiments, r is an integer from 2 to 6. In some embodiments, r is an integer from 2 to 4. In some embodiments, r is 2 or 3. In some embodiments, r is an integer from 3 to 6. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, r is 4. In some embodiments, r is 5. In some embodiments, r is 6. In some embodiments, s is 0. In some embodiments, s is 1. In some embodiments, t is 0. In some embodiments, t is an integer from 0 to 3. In some embodiments, t is 0 or 2. In some embodiments, t is an integer from 1 to 4. In some embodiments, t is an integer from 1 to 3. In some embodiments, t is an integer from 2 to 3. In some embodiments, t is 1. In some embodiments, t is 2. In some embodiments, t is 3. In some embodiments, t is 4. In some embodiments, the compound is selected from Table 1. Table 1. Selected bifunctional degrader compounds.
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
The term “alkyl” used alone or as part of a larger moiety, such as “alkoxy” and the like, means a saturated aliphatic straight-chain or branched monovalent hydrocarbon radical. Unless otherwise specified, an alkyl group typically has 1 to 8 carbon atoms (C1-C8alkyl) (i.e., 1, 2, 3, 4, 5, 6, 7, or 8), alternatively, 1 to 6 carbon atoms (C1-C6alkyl) (i.e., 1, 2, 3, 4, 5, or 6), alternatively, 1 to 4 carbon atoms (C1-C4alkyl) (i.e., 1, 2, 3, or 4). As used herein, a “(C1-C4)alkyl” group means a radical having from 1 to 4 carbon atoms in a linear or branched arrangement. Examples include methyl, ethyl, n-propyl, iso-propyl, butyl, tert-butyl, and the like. The term “alkenylene”, used alone or as part of a larger moiety, means an alkyl group that is a bivalent hydrocarbon radical in which one or more carbon-carbon single bonds is replaced by a double bond. The term “alkynylene”, used alone or as part of a larger moiety, means an alkyl group that is a bivalent hydrocarbon radical in which one or more carbon-carbon single bonds is replaced by a triple bond. The term “alkoxy” means a monovalent radical composed of an alkyl group attached through an oxygen linking atom, represented by -O-alkyl. Examples include methoxy, ethoxy, propoxy, butoxy, and the like. The term “aryl” refers to a radical of a 6 to 12-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic array) having ring carbon atoms provided in an aromatic ring system. Examples of aryl groups include phenyl, naphthyl, and the like. The number of ring members designates the number of ring members in the fused ring system. An aryl group may be described as, e.g., a 6 to 12- membered aryl, alternatively, a 6 to 10-membered aryl, wherein the term “membered” refers to the non-hydrogen ring atoms within the moiety. The term “cycloalkyl” refers to non-aromatic cyclic hydrocarbons including cyclized alkyl and alkenyl groups. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3, or 4 fused, bridged, or spiro rings) ring systems. Unless otherwise specified, a cycloalkyl has 3 to 10 carbon atoms (C3-C10cycloalkyl), alternatively, 3 to 8 carbon atoms (C3- C8cycloalkyl), alternatively, 3 to 6 carbon atoms (C3-C6cycloalkyl). “Cycloalkyl” also includes ring systems comprising two cycloalkyl groups, as defined above, sharing 2, 3, or 4 adjacent ring atoms to form a fused or bridged bicycloalkyl. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[4.2.0]octanyl, octahydro-1H-indenyl, decahydronaphthalenyl, bicyclo[2.2.1]hepantyl, bicyclo[2.2.2]octantyl, bicyclo[3.2.1]octanyl, bicyclo[3.2.2]nonanyl, and the like. The term “spirocycloalkyl” refers to a group comprising two cycloalkyls which share one common ring atom. Unless otherwise specified, a spirocycloalkyl has 5 to 12 carbon atoms (C5-C12spirocycloalkyl), alternatively, 5 to 10 carbon atoms (C5-C10cycloalkyl). Examples include spiro[2.2]pentanyl, spiro[3.3]heptanyl, spiro[3.5]nonanyl, spiro[5.5]undecanyl, and the like. The term “E3 ubiquitin ligase-binding moiety” refers to a chemical group that binds to an E3 ubiquiting ligase. E3 ubiquitin ligase binding moieties are known and well-described in the art, for example: Bondeson, D. P., et al. Nat Chem Biol.201511(8):611-617; An S, et al. EBioMedicine 201836:553-562; Paiva S-L. et al, Curr. Op. in Chem. Bio.2010, 50:111- 119, each of which is incorporated by reference in its entirety. The term “halo” means halogen and includes chloro (Cl), fluoro (F), bromo (Br), and iodo (I). The term “heterocyclyl” or “heterocycle” refers to a monocyclic or bicyclic non- aromatic ring radical. Unless otherwise specified, a heterocyclyl has 3 to 12 ring atoms (i.e., 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12-membered), alternatively, 3 to 10 ring atoms (i.e., 3, 4, 5, 6, 7, 8, 9, or 10-membered), alternatively, 3 to 6 ring atoms (i.e., 3, 4, 5, or 6-membered), selected from carbon atoms and and 1 to 4 heteroatoms, wherein each heteroatom is independently selected from oxygen (O), sulfur (S), including sulfoxide and sulfone, and nitrogen (N or NRc1, including quaternary nitrogen, oxidized nitrogen (e.g., NO)). “Heterocyclyl” also includes ring systems comprising a heterocycle which shares 2, 3, or 4 adjacent ring atoms with a cycloalkyl or a second heterocycle, as defined herein. In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Examples of heterocyclyl groups include azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, azepanyl, oxepanyl, thiepanyl, tetrahydropyridinyl, 1,2-thiazinanyl-1,1-dioxide, 3-azabicyclo[4.2.0]-octanyl, octahydro-1H-indolyl, decahydroquinolinyl, decahydro-1,5- naphthyridinyl, 5-oxabicyclo[2.1.1]-hexanyl, 3-oxabicyclo[3.1.0]hexanyl, 6- oxabicyclo[3.1.1]heptanyl, 2-oxabicyclo[2.2.2]octanyl, 7-oxabicyclo[4.1.1]octanyl, 8- oxabicyclo[3.2.1]octanyl, and the like. The term “spiroheterocyclyl” refers to bicyclic non-aromatic ring radical comprising a heterocycle which shares one common ring atom with a cycloalkyl or a second heterocycle. Unless otherwise specified, a spiroheterocyclyl has 5 to 12 ring atoms (i.e., 5, 6, 7, 8, 9, 10, 11, or 12-membered), alternatively, 5 to 10 ring atoms (i.e., 5, 6, 7, 8, 9, or 10-membered), selected from carbon atoms and 1 to 4 heteroatoms, wherein each heteroatom is independently selected from oxygen (O), sulfur (S), including sulfoxide and sulfone, and nitrogen (N or NRc1, including quaternary nitrogen, oxidized nitrogen (e.g., NO)). Examples include 2-azaspiro[3.3]heptanyl, 2,5-diazaspiro[3.3]heptanyl, 2,7-diazaspiro[3.5]nonanyl, 3- azaspiro[5.5]undecanyl, diazaspiro[5.5]undecanyl, and the like. The term “heteroaryl” refers to a radical of a 5-12 membered monocyclic or bicyclic aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic array) 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 (“5–12 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. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system. 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 group may be described as, e.g., a 6- 10-membered heteroaryl, wherein the term “membered” refers to the non-hydrogen ring atoms within the moiety. The terms “linker moiety” and “linker” refer to a bivalent chemical moiety that binds (e.g., bridges) two separate entities to one another. As used herein, the terms “linker moiety” and “linker” can refer to a bivalent chemical moiety that is covalently bonded to both ring A of the compounds of the disclosure and group Z or Z’ of the compounds of the disclosure. The terms “linker moiety” and “linker” can further refer to a bivalent chemical moiety that is covalently bonded to both ring A of the compounds of the disclosure and ring B of the compounds of the disclosure. The term “pharmaceutically acceptable salt” refers to a pharmaceutical salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, and is commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. describes pharmacologically acceptable salts in J. Pharm. Sci., 1977, 66, 1–19. Included in the present teachings are pharmaceutically acceptable salts of the compounds disclosed herein. Compounds having basic groups can form pharmaceutically acceptable salts with pharmaceutically acceptable acid(s). Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include salts of inorganic acids (such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, and sulfuric acids) and of organic acids (such as acetic, benzenesulfonic, benzoic, ethanesulfonic, methanesulfonic, and succinic acids). Compounds of the present teachings with acidic groups such as carboxylic acids can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s). Suitable pharmaceutically acceptable basic salts include ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts). Compounds having one or more chiral centers can exist in various stereoisomeric forms, i.e., each chiral center can have an R or S configuration or can be a mixture of both. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomeric and enantiomeric forms of a compound. Enantiomers are stereoisomers that are mirror images of each other. Diastereomers are stereoisomers having two or more chiral centers that are not identical and are not mirror images of each other. When the stereochemical configuration at a chiral center in a compound having one or more chiral centers is depicted by its chemical name (e.g., where the configuration is indicated in the chemical name by “R” or “S”) or structure (e.g., the configuration is indicated by “wedge” bonds), the enrichment of the indicated configuration relative to the opposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99% or 99.9% (except when the designation “rac” or “racemate” accompanies the structure or name, as explained in the following two paragraphs). “Enrichment of the indicated configuration relative to the opposite configuration” is a mole percent and is determined by dividing the number of compounds with the indicated stereochemical configuration at the chiral center(s) by the total number of all of the compounds with the same or opposite stereochemical configuration in a mixture. When the stereochemical configuration at a chiral center in a compound is depicted by chemical name (e.g., where the configuration is indicated in the name by “R” or “S”) or structure (e.g., the configuration is indicated by “wedge” bonds) and the designation “rac” or “racemate” accompanies the structure or is designated in the chemical name, a racemic mixture is intended. When two stereoisomers are depicted by their chemical names or structures, and the names or structures are connected by an “or”, one or the other of the two stereoisomers is intended, but not both. When a disclosed compound having a chiral center is depicted by a structure without showing a configuration at that chiral center, the structure is meant to encompass the compound with the S configuration at that chiral center, the compound with the R configuration at that chiral center, or the compound with a mixture of the R and S configuration at that chiral center. When a disclosed compound having a chiral center is depicted by its chemical name without indicating a configuration at that chiral center with “S” or “R”, the name is meant to encompass the compound with the S configuration at that chiral center, the compound with the R configuration at that chiral center or the compound with a mixture of the R and S configuration at that chiral center. A racemic mixture means a mixture of 50% of one enantiomer and 50% of its corresponding enantiomer. The present teachings encompass all enantiomerically-pure, enantiomerically-enriched, diastereomerically pure, diastereomerically enriched, and racemic mixtures, and diastereomeric mixtures of the compounds disclosed herein. Enantiomeric and diastereomeric mixtures can be resolved into their component enantiomers or stereoisomers by well known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Enantiomers and diastereomers can also be obtained from diastereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well known asymmetric synthetic methods. “Peak 1” in the Experimental section refers to an intended reaction product compound obtained from a chromatography separation/purification that elutes earlier than a second intended reaction product compound from the same preceding reaction. The second intended product compound is referred to as “peak 2”. When a disclosed compound is designated by a name or structure that indicates a single enantiomer, unless indicated otherwise, the compound is at least 60%, 70%, 80%, 90%, 99% or 99.9% optically pure (also referred to as “enantiomerically pure”). Optical purity is the weight in the mixture of the named or depicted enantiomer divided by the total weight in the mixture of both enantiomers. When the stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in a diastereomeric pair), it is to be understood that, unless otherwise indicated, one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers are included. It is to be further understood that the stereoisomeric purity of the named or depicted stereoisomers at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight. The stereoisomeric purity in this case is determined by dividing the total weight in the mixture of the stereoisomers encompassed by the name or structure by the total weight in the mixture of all of the stereoisomers. In the compounds of the disclosure, any position specifically designated as “D” or “deuterium” is understood to have deuterium enrichment at 50, 80, 90, 95, 98 or 99%. “Deuterium enrichment” is a mole percent and is determined by dividing the number of compounds with deuterium at the indicated position by the total number of all of the compounds. When a position is designated as “H” or “hydrogen”, the position has hydrogen at its natural abundance. When a position is silent as to whether hydrogen or deuterium is present, the position has hydrogen at its natural abundance. One specific alternative embodiment is directed to a compound of the disclosure having deuterium enrichment of at least 5, 10, 25, 50, 80, 90, 95, 98 or 99% at one or more positions not specifically designated as “D” or “deuterium”. As used herein, many moieties (e.g., alkyl, alkoxy, cycloalkyl or heterocyclyl) are referred to as being either “substituted” or “optionally substituted”. When a moiety is modified by one of these terms, unless otherwise noted, it denotes that any portion of the moiety that is known to one skilled in the art as being available for substitution can be substituted, which includes one or more substituents. Where if more than one substituent is present, then each substituent may be independently selected. Such means for substitution are well-known in the art and/or taught by the instant disclosure. The optional substituents can be any substituents that are suitable to attach to the moiety. Pharmaceutical Compositions In another aspect, provided herein is a pharmaceutical composition comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient and (a “pharmaceutical composition of the disclosure”). “Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the formulation and/or administration of an active agent to and/or absorption by a subject and can be included in the pharmaceutical compositions of the disclosure without causing a significant adverse toxicological effect on the subject. Non- limiting examples of pharmaceutically acceptable carriers/excipients include: (1) sugars, such as, e.g., lactose, glucose, and sucrose; (2) starches, such as, e.g., corn starch and potato starch; (3) cellulose and its derivatives, such as, e.g., sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as, e.g., cocoa butter and suppository waxes; (9) oils, such as, e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as, e.g., propylene glycol; (11) polyols, such as, e.g., glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as, e.g., ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as, e.g., magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) lactate buffer solutions; (21) cyclodextrins, such as, e.g., CAPTISOL®; and (22) other non-toxic compatible substances employed in pharmaceutical formulations. Methods of Treatment In one aspect, the disclosure provides methods of modulating (e.g., degrading) CDK2 activity and therefore are useful for treating diseases for which CDK2 are dysregulated, such as cancer. In some embodiments, the method of modulating is a method of degrading CDK2 comprising contacting CDK2 with a compound of the disclosure, or a pharmaceutically acceptable salt thereof. In some embodiments, the method of modulating is a method of degrading CDK2 in a subject in need thereof, comprising contacting CDK2 with an effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure. Compounds of the disclosure are CDK2 degraders. The use of the word “degrader” means that a compound, or a pharmaceutically acceptable salt thereof, degrades CDK2 protein. The terms “degrade”, “degrading”, or “degradation” mean the partial or full breakdown of CDK2 proteins, which reduces or eliminates the biological activity of CDK2, as compared to the amount of those proteins in the absence of the degrader (e.g., before administration of the degrader). In some alternatives, the term “degrade” means a decrease in the levels of CDK2 protein of at least 5%, at least 10%, at least 20%, at least 50%, at least 60%, at least 79%, at least 80%, at least 90% or at least 95% (e.g., before administration of the degrader or at two different timepoints during treatment with the degrader). In other alternatives, inhibit means a decrease in the levels of CDK2 of 5% to 25%, 25% to 50%, 50 to 70%, 75 to 100%. In some embodiments, degrade means a decrease in the levels of CDK2 of about 95% to 100%, e.g., a decrease in activity of 95%, 96%, 97%, 98%, 99%, or 100%. Such decreases can be measured using a variety of techniques that would be recognizable by one of skill in the art, including in vitro degradation assays. In another aspect, provided herein is a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure for use in the treatment of cancers. In another aspect, provided herein is a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure for use in the prevention of cancers. As used herein the term “treating” or “treatment” refers to 1) inhibiting the disease in an individual who is experiencing or displaying the pathology or symptomatology of the disease (i.e., arresting further development of the pathology and/or symptomatology), or 2) ameliorating the disease in an individual who is experiencing or displaying the pathology or symptomatology of the disease (i.e., reversing the pathology and/or symptomatology). As used herein the term “preventing” or “prevention” refers to preventing the disease in an individual who may be predisposed to the disease but does not yet experience or display the pathology or symptomatology of the disease. In some embodiments, the disclosure is directed to a method of preventing a disease in a patient, by administering to the patient a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof. As used herein, the term “contacting” refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, “contacting” CDK2, or “contacting” a cell with a compound of the disclosure, includes the administration of a compound of the present disclosure to a subject or patient, such as a human, having CDK2, as well as, for example, introducing a compound of the disclosure into a sample containing a cellular or purified preparation containing CDK2. As used herein, the term “cell” is meant to refer to a cell that is in vitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal. In some embodiments, an in vitro cell can be a cell in a cell culture. In some embodiments, an in vivo cell is a cell living in an organism such as a mammal. Compounds of the disclosure, or pharmaceutically acceptable salts thereof, are CDK2 degraders with warheads that target CDK2 with high affinity and selectivity compared to traditional small-molecule inhibitors. As used herein, the term “CDK2 degrader” means a compound which selectively and catalytically degrades CDK2 over other CDKs and other proteins. Said another way, a CDK2 degrader shows no or low degradation of other CDKs and other proteins. A CDK2 degrader degrades CDK2 to a greater extent in terms of DC50 value (i.e., the DC50 value is nanomolar) when compared with the degradation of other CDKs and other proteins. Degradation can be measured using known biochemical assays. The DC50 value refers to the concentration at which 50% maximal degradation was observed. The ability to selectively target CDK2 with a compound of the disclosure provides advantages in terms of targeted degradation of CDK2, little to no off-target activity, and an increased probability of clinical success in comparison with traditional small-molecule inhibitors. A CDK2 degrader may show degradation that is at least 2-fold relative to another target protein (e.g., at least 10-fold; at least 15-fold; at least 20-fold; at least 30-fold; at least 40-fold selectivity; at least 50-fold; at least 60-fold; at least 70-fold; at least 80-fold; at least 90-fold; at least 100-fold; at least 125-fold; at least 150-fold; at least 175-fold; or at least 200- fold. In some alternatives, a CDK2 degrader exhibits at least 15-fold selectivity over another CDK, e.g., CDK1, CDK4, and CDK6. In some embodiments, the compounds of the disclosure are selective against CDK2 versus CDK1. In some embodiments, compounds show at least 10-fold selectivity for CDK2 versus CDK1. In some embodiments, compounds show at least 20-fold selectivity for CDK2 versus CDK1. In some embodiments, compounds show at least 30-fold selectivity for CDK2 versus CDK1. In some embodiments, compounds show at least 40-fold selectivity for CDK2 versus CDK1. In some embodiments, compounds show at least 50-fold selectivity for CDK2 versus CDK1. In some embodiments, the compounds of the disclosure are selective against CDK2 versus CDK4 and/or CDK6. In some embodiments, compounds show at least 10-fold selectivity for CDK2 versus CDK4 and/or CDK6. In some embodiments, compounds show at least 20-fold selectivity for CDK2 versus CDK4 and/or CDK6. In some embodiments, compounds show at least 30-fold selectivity for CDK2 versus CDK4 and/or CDK6. In some embodiments, compounds show at least 40-fold selectivity for CDK2 versus CDK4 and/or CDK6. In some embodiments, compounds show at least 50-fold selectivity for CDK2 versus CDK4 and/or CDK6. For example, compounds show at least 100-fold selectivity for CDK2 versus CDK4 and/or CDK6. In some embodiments, the compounds of the disclosure are selective against CDK2 versus CDK1. In some embodiments, compounds show at least 10-fold selectivity for CDK2 versus CDK1. In some embodiments, compounds show at least 20-fold selectivity for CDK2 versus CDK1. In some embodiments, compounds show at least 30-fold selectivity for CDK2 versus CDK1. In some embodiments, compounds show at least 40-fold selectivity for CDK2 versus CDK1. In some embodiments, compounds show at least 50-fold selectivity for CDK2 versus CDK1. In some embodiments, the compounds of the disclosure are selective against CDK2 versus CDK6. In some embodiments, compounds show at least 10-fold selectivity for CDK2 versus CDK6. In some embodiments, compounds show at least 20-fold selectivity for CDK2 versus CDK6. In some embodiments, compounds show at least 30-fold selectivity for CDK2 versus CDK6. In some embodiments, compounds show at least 40-fold selectivity for CDK2 versus CDK6. In some embodiments, compounds show at least 50-fold selectivity for CDK2 versus CDK6. Some compounds of the disclosure have the advantage of oral bioavailability. In some embodiments, a compound of the disclosure selectively degrades its target protein compared to other CDKs and other proteins. In some embodiments, a compound of the disclosure catalytically degrades its target protein, which may require a lower dose compared to traditional small molecule inhibitor. For example, many CDK4/6 inhibitors, including ribociclib, palbociclib, and abemaciclib, bind the adenosine triphosphate (ATP) cleft, which contains the catalytic residues, and compete with ATP to inhibit activity. In some embodiments, a compound of the disclosure is a bifunctional degrader with a warhead that binds to the target protein (e.g., CDK2) linked to an E3 ubiquitin ligase-binding moiety that recruit E3 ligases to ubiquitinate the target protein and prompt the target protein to be recognized and subsequently degraded by 26S proteasome. The compounds of the disclosure can be used repeatedly to trigger this targeted protein degradation. In some embodiments, a compound of the disclosure may eliminate certain side effects, for example, drug-drug interactions and off-target effects, such as CDK6 mediated heme toxicity. In another aspect, provided herein is a method of treating a cancer in a patient in need thereof comprising administering to a patient a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure. In another aspect, provided herein is the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure in the manufacture of a medicament for the treatment of cancers. In another aspect, provided herein is the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure in the preparation of a medicament for the treatment of cancers. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered as first line therapy. In other embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered as second (or later) line therapy. As used herein “cancer” refers to any malignant and/or invasive growth or tumor caused by abnormal cell growth. Cancer encompasses all forms of cancer including, but not limited to, all forms of solid tumors, carcinomas, melanomas, blastomas, sarcomas, lymphomas, and leukemias. Cancer also includes primary cancer that originates at a specific site in the body, a metastatic cancer that has spread from the place in which it started to other parts of the body, a recurrence from the original primary cancer after remission, and a second primary cancer that is a new primary cancer in a person with a history of previous cancer of a different type from the latter one. In embodiments of the cancers and the methods provided herein, the cancer is a solid tumor cancer. In embodiments, the solid tumor cancer is a carcinoma or a sarcoma (e.g., CIC- DUX4 sarcoma). In embodiments, the solid tumor cancer is an adenocarcinoma, a carcinoma, or a cystadenocarcinoma. In some embodiments, the subject has an advanced and/or relapsed solid tumor. In some embodiments, cancers that are treatable using compounds of the disclosure, or pharmaceutically acceptable salts thereof, include, but are not limited to, bone cancers, breast cancers. gastrointestinal cancers, genitourinary tract cancers, gynecological cancers, head and neck cancers, hematological cancers, liver cancers, nervous system cancers, respiratory tract cancers, sarcomas, and skin cancers. Exemplary bone cancers include, but are not limited to, benign chondroma, chondroblastoma, chondromyxofibroma, chondrosarcoma, Ewing’s sarcoma, fibrosarcoma, giant cell tumors, malignant fibrous histiocytoma, malignant lymphoma (e.g., reticulum cell sarcoma), malignant giant cell tumor chordoma, multiple myeloma, osteochronfroma (e.g., osteocartilaginous exostoses), osteogenic sarcoma (e.g., osteosarcoma, e.g.,), and osteoid osteoma. Exemplary breast cancers include, but are not limited to, ductal carcinoma in situ, ER+ breast cancer (estrogen receptor positive breast cancer); ER+/HER2- breast cancer (estrogen receptor positive, human epidermal growth factor 2 negative breast cancer); HR+ breast cancer (hormone receptor positive breast cancer); HR+/HER2- breast cancer (hormone receptor positive, human epidermal growth factor 2 negative breast cancer); HER2- breast cancer (human epidermal growth factor 2 negative breast cancer); HER2+ breast cancer (human epidermal growth factor 2 positive breast cancer); HER2-low breast cancer (human epidermal growth factor 2 low breast cancer); invasive ductal carcinoma (IDC); invasive lobular carcinoma, lobular carcinoma in situ, PR+/HER2- breast cancer (progesterone receptor positive, human epidermal growth factor 2 negative breast cancer); triple negative breast cancer (TNBC); and tubular breast carcinoma. Exemplary gastrointestinal cancers include, but are not limited to, cancers of the anus (e.g., anal cancer, e.g., anal neuroendocrine carcinoma), colon (e.g., colon adenocarcinoma (COAD)); colorectal cancer (e.g., hereditary non-polyposis colorectal cancer); esophagus (e.g., adenocarcinoma, leiomyosarcoma, lymphoma, and squamous cell carcinoma); familiar adenomatous polyposis carcinoma; gall bladder (e.g., adenocarcinoma and cholangiocarcinoma); intestinal type and diffuse type gastric adenocarcinoma (e.g., gastrointestinal stromal tumor); large bowel (e.g., adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); large intestine (e.g., adenocarcinoma, hamartoma, leiomyoma, tubular adenoma, and villous adenoma,); pancreas (e.g., adenocarcinoma (PAAD), carcinoid tumors, ductal adenocarcinoma, glucagonoma, gastrinoma, insulinoma, islet cell cancer, and vipoma); small intestine (e.g., adenocarcinoma (PDAC), carcinoid tumors, fibroma, hemangioma, leiomyoma, lipoma, lymphoma, Kaposi’s sarcoma, and neurofibroma); stomach (or gastric cancer, e.g., adenocarcinoma, carcinoma, leiomyosarcoma, and lymphoma); and rectum carcinoma (e.g., rectum adenocarcinoma (READ)). Exemplary genitourinary tract cancers include, but are not limited to, cancers of the adrenal gland (e.g., adrenocortical carcinoma); bladder (e.g., adenocarcinoma, sarcoma, small cell carcinoma, squamous cell carcinoma, and transitional cell carcinoma); kidney (e.g., adenocarcinoma, renal cell carcinoma (RCC), urothelial carcinoma, juxtaglomerular cell tumor (reninoma), angiomyolipoma, Bellinio duct carcinoma, clear-cell sarcoma of the kidney, and mesoblastic nephroma, renal oncocytoma, and Wilm’s tumor [nephroblastoma]); renal pelvis; pancreas; penis; prostate (e.g., adenocarcinoma (PRAD), androgen receptor positive (AR+) or AR-dependent prostate cancer, AR-independent prostate cancer, carcinoma, castration-resistant prostate cancer (CRPC), hormone refractory prostate adenocarcinoma, and sarcoma); testis (e.g., adenomatoid tumors, choriocarcinoma, embryonal carcinoma, fibroadenoma, fibroma, interstitial cell carcinoma, lipoma, sarcoma, seminoma, teratoma, and teratocarcinoma); ureteral cancer, and urethra (e.g., adenocarcinoma, squamous cell carcinoma, and transitional cell carcinoma). Exemplary gynecological cancers include, but are not limited to, cancers of the cervix (e.g., adenocarcinoma, adenosquamous carcinoma, cervical carcinoma, cervical squamous cell carcinoma (CESC), glassy cell carcinoma, neuroendocrine tumor, pre-tumor cervical dysplasia, small cell carcinoma, squamous cell carcinoma, and villoglandular adenocarcinoma); fallopian tubes (e.g., carcinoma); labia; ovaries (e.g., dysgerminoma, granulosa-thecal cell tumors, malignant teratoma, ovarian carcinoma (e.g., endometroid tumor, high-grade serous ovarian cancer (HGSOC), high-grade serous carcinoma (HGSC), mucinous cystadenocarcinoma, serous cystadenocarcinoma, and unclassified carcinoma), and Sertoli-Leydig cell tumors); uterus (e.g., carcinosarcoma, clear cell endometrial carcinoma, endometrial carcinoma, grade 3 endometriod endometrial cancer, serous endometrial cancer (SEC), uterine carcinosarcoma (UCS), and uterine corpus endometrial carcinoma (UCEC)); vagina (e.g., botryoid sarcoma (embryonal rhabdomyosarcoma), clear cell carcinoma, and squamous cell carcinoma); and vulva (e.g., adenocarcinoma, fibrosarcoma, intraepithelial carcinoma, melanoma, and squamous cell carcinoma). Exemplary head and neck cancers include, but are not limited to, acoustic neuroma, adenocarcinoma, eye cancer (e.g., intraocular malignant melanoma, ocular melanoma, and retinoblastoma), glioblastoma, lymphosarcoma, melanoma, nasal and paranasal cancer, nasal cavity cancer, oral cancer or mouth cancer (e.g., lip cancer, salivary gland cancer, and tongue cancer), osteosarcoma, pituitary adenoma, rhabdosarcoma, sinus cancer, squamous cell carcinoma, throat cancer (e.g., hypopharngx, oropharyngeal cancer, laryngeal cancer, nasopharyngeal cancer), parathyroid cancer, and thyroid cancer (e.g., medullary and papillary). Exemplary hematological cancers include, but are not limited to, lymphomas and leukemias such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), Burkitt's lymphoma, chronic lymphocytic leukemia (CLL), chronic myelogenic lymphoma, chronic myelogenous leukemia (CML), cutaneous T-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), hairy cell lymphoma, Hodgkin lymphoma, mantle cell lymphoma, Non-Hodgkin lymphoma (e.g., follicular lymphoma, relapsed or refractory NHL, and recurrent follicular), multiple myeloma (MM), myelodysplasia syndrome (MDS), myelofibrosis (PMF), myeloproliferative diseases (e.g., primary polycythemia vera (PV), and essential thrombocytosis (ET)), T-cell acute lymphoblastic lymphoma (T-ALL), and Waldenstrom's Macroglubulinemia. Exemplary liver cancers include, but are not limited to, hepatoma e.g., angiosarcoma, cholangiocarcinoma (also referred to as bile duct cancer), hemangioma, hepatoblastoma, hepatocellular adenoma, and hepatocellular carcinoma (HCC). Exemplary nervous system cancers include, but are not limited to, cancers of the brain (e.g., astrocytoma, brain lower grade glioma (LGG), brain stem glioma,d congenital tumors, ependymoma, germinoma (pinealoma), glioma, glioblastoma, glioblastoma multiforme (GBM), medulloblastoma, and oligodendroglioma); central nervous system lymphoma; Lhermitte-Duclos disease; meninges (e.g., gliomatosis, meningioma, and meningiosarcoma); neuroblastoma; schwannoma; spinal cord (e.g., glioma, meningioma, neurofibroma, sarcoma, and spinal axis tumor); and skull (e.g., granuloma, hemangioma, osteitis deformans, osteoma, and xanthoma). Exemplary respiratory tract cancers include, but are not limited to, epidermoid carcinoma; lung cancer including, but not limited to, alveolar (bronchiolar) carcinoma; bronchial adenoma; bronchogenic carcinoma (e.g., adenocarcinoma, squamous cell, undifferentiated small cell, and undifferentiated large cell); chondromatous hamartoma; epidermal growth factor receptor mutant positive (EGFRm+) non-small cell lung cancer; non-small cell lung cancer (NSCLC); small cell lung cancer (SCLC); and pleuropulmonary blastoma; and mesothelioma. Exemplary sarcomas include, but are not limited to, angiosarcoma, chondrosarcoma, epithelioid sarcoma, Ewing’s sarcoma, fibroma, fibrosarcoma, harmatoma, Kaposi’s sarcoma, lipoma, liposarcoma, myxoma, osteosarcoma (e.g., chondroblastic osteosarcoma), rhabdomyoma, rhabdomyosarcoma, and teratoma. Exemplary skin cancers include, but are not limited to, angioma, basal cell carcinoma, BRAF and HSP90 inhibition-resistant melanoma, cutaneous melanoma, dermatofibroma, lipoma, Kaposi’s sarcoma, keloids, melanoma, Merkel cell carcinoma, metastatic malignant melanoma, moles dysplastic nevi, sebaceous gland carcinoma, and squamous cell carcinoma. In embodiments of the methods provided herein, the cancer is anal cancer, bladder cancer, brain cancer, breast cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, skin cancer, thyroid cancer, urothelial cancer, or uterine cancer. In embodiments of the methods provided herein, the cancer is anal cancer, breast cancer, colorectal cancer, endometrial cancer, gastric cancer, liver cancer, lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, or uterine cancer. In some embodiments of the cancers and methods disclosed herein, the cancer is characterized by an elevation or an amplification of the cyclin E1 (CCNE1) gene and/or cyclin E2 (CCNE2) gene (e.g., based on copy number) and/or a level of CCNE1 and/or CCNE2 higher than a control level of CCNE1 (referred to herein as a “change in the levels of CCNE1 and/or CCNE2”). In some embodiments of the cancers and methods disclosed herein, the cancer is characterized by high microsatellite instability (MSIhigh). In some embodiments of the cancers and methods disclosed herein, the cancer is characterized by Genomic Identification of Significant Targets in Cancer (GISTIC). In some embodiments, the cancer is pheochromocytoma and paraganglioma (PCPG). In some embodiments, the cancer is a refractory cancer, which is also referred to as a treatment-resistant cancer. In some embodiments, the cancer is platinum-resistant and/or platinum-refractory. In some embodiments, the cancer has progressed despite treatment with a platinum agent. In some embodiments of the cancers and methods disclosed herein, the cancer is breast cancer (BC). In some embodiments, the breast cancer is advanced or metastatic breast cancer. In some embodiments, the breast cancer is HR+/HER2- BC. In some embodiments, the breast cancer is ER+/HER2- BC. In some embodiments, the breast cancer is PR+/HER2- BC. In some embodiments, the breast cancer is TNBC. In some embodiments, the breast cancer is refractory. In some embodiments, the breast cancer is chemotherapy resistant breast cancer, endocrine resistant breast cancer, radiotherapy resistant breast cancer, trastuzumab resistant breast cancer, or breast cancer demonstrating primary or acquired resistance to CDK4/CDK6 inhibition. In some embodiments, the breast cancer is responsive to treatment with a CDK4/6 inhibitor. In some embodiments, the breast cancer is resistant to treatment with a CDK4/6 inhibitor. In some embodiments, the breast cancer has progressed despite treatment with a CDK4/6 inhibitor. In some embodiments, the breast cancer has progressed despite a first treatment with palbociclib, ribociclib, and/or fulvestrant and a second treatment with abemaciclib and/or fulvestrant. In some embodiments of the methods disclosed herein, the method further comprises administering to the patient a therapeutically acceptable amount of a CDK4/6 inhibitor. In some embodiments, the CDK4/6 inhibitor is abemaciclib. In some embodiments, the CDK4/6 inhibitor is palbociclib. In some embodiments, the CDK4/6 inhibitor is ribociclib. In some embodiments, the cancer is (a) ovarian cancer; (b) characterized by a change in the levels of CCNE1 and/or CCNE2; or (c) both (a) and (b). In some embodiments, the ovarian cancer is selected from dysgerminoma, a granulosa-thecal cell tumor, malignant teratoma, endometroid tumor, HGSOC, HGSC, mucinous cystadenocarcinoma, serous cystadenocarcinoma, and unclassified carcinoma. In some embodiments, the ovarian cancer is HGSOC. In some embodiments, the cancer is (a) endometrial cancer; (b) characterized by a change in the levels of CCNE1 and/or CCNE2; or (c) both (a) and (b). In some embodiments, the endometrial cancer is selected from carcinosarcoma, clear cell endometrial carcinoma, endometrial carcinoma, grade 3 endometriod endometrial cancer, and SEC. In some embodiments, the endometrial cancer is SEC. In some embodiments, the cancer is (a) lung cancer; (b) characterized by a change in the levels of CCNE1 and/or CCNE2; or (c) both (a) and (b). In some embodiments, the lung cancer is NSCLC. In some embodiments, the lung cancer is SCLC. In some embodiments, cancers treatable with a compound of the disclosure, or a pharmaceutically acceptable salt thereof, include advanced/relapsed tumors; platinum- resistant or platinum-refractory ovarian cancer; endometrial cancer (with prior platinum therapy) that has progressed following 2 or more lines of therapies; gastric cancer (with prior platinum therapy) that has progressed following 2 or more lines of therapies; and HR+/HER2- BC (including both ER+/HER2- BC and PR+/HER2- BC) that has progressed despite treatment with one or more CDK4/6 inhibitors. In some embodiments, cancers treatable with a compound of the disclosure, or a pharmaceutically acceptable salt thereof, include platinum-resistant or platinum-refractory CCNE1 amplified ovarian cancer; CCNE1 amplified endometrial cancer that has failed 2 or more lines of therapies; CCNE1 amplified advanced/relapsed tumors that do not belong to the other groups; HR+/HER2- BC that has progressed despite CDK4/6i; and platinum-resistant or platinum-refractory CCNE1 amplified ovarian cancer. In one embodiment, the subject has CCNE1 amplified advanced/relapsed tumors. In one embodiment, the subject has CCNE1 amplified platinum-resistant or platinum-refractory ovarian cancer. In one embodiment, the subject has endometrial cancer (with prior platinum therapy, e.g., wherein the patient has been previously treated with a platinum therapy) that has progressed following 2 or more lines of therapies (including the platinum therapy). In one embodiment, the subject has CCNE1 amplified endometrial cancer that has failed 2 or more lines of therapies (which may include a prior platinum therapy). In one embodiment, the subject has gastric cancer (with prior platinum therapy e.g., wherein the patient has been previously treated with a platinum therapy) that has progressed following 2 or more lines of therapies (including the platinum therapy). In one embodiment, the subject has HR+/HER- breast cancer that has progressed despite treatment with one or more CDK4/6 inhibitors. In one embodiment, the subject has TNBC that has progressed despite one or more lines of therapies. In one embodiment, the subject has AR+ prostate cancer that has progressed despite one or more lines of therapies. In one embodiment, the subject has pancreatic cancer that has progressed despite one or more lines of therapies. In one embodiment, the subject has PDAC that has progressed despite one or more lines of therapies. In one embodiment, the subject has CCNE1 elevated lung cancer. In one embodiment, the subject has NSCLC that has progressed despite treatment with one or more EGFR inhibitors (e.g., osimertinib). In one embodiment, the subject has CCNE1 elevated NSCLC that has progressed despite treatment with one or more EGFR inhibitors (e.g., osimertinib). Combination Therapies Compounds of the disclosure or pharmaceutically acceptable salts thereof can be administered as the sole pharmaceutical agent or in combination with one or more other anti- cancer agents for the treatment of cancer, where the combination causes no unacceptable adverse effects. In some embodiments, the other anti-cancer agents are standard of care agents appropriate for the particular cancer. The term “additional anticancer therapeutic agent” as used herein means any one or more therapeutic agent, other than a compound described herein (e.g., Formulae (I), (Ia), (II), (III), or subformulas thereof), or a pharmaceutically acceptable salt thereof, that is or can be used in the treatment of cancer. In some embodiments, the additional anticancer agent is a protein kinase B (PKB) or AKT inhibitor including, but not limited to, afuresertib, capivasertib, ipatasertib, miransertib, and temsirolimus. In some embodiments, the AKT inhibitor is capivasertib. In some embodiments, the additional anticancer agent is an agent that inhibits the androgen receptor (AR) signaling pathway including, but not limited to, abiraterone, bicalutamide, enzalutamide, flutamide, ketoconazole, and niltamide. In some embodiments, the agent that inhibits the androgen receptor signaling pathway is enzalutamide. In some embodiments, the additional anticancer agent is an antibody including, but not limited to, atezolizumab, bevacizumab, margetuximab (e.g., margetuximab-cmkb), pembrolizumab, pertuzumab, ramucirumab, sacituzumab, and trastuzumab. In some embodiments, the antibody is trastuzumab. In some embodiments, the additional anticancer agent is an antibody-drug conjugate (ADC) including, but not limited to, anetumab ravtasine, belantamab mafodotin, brentuximab vedotin, datopotamab deruxtecan, disitamab vedotin, farletuzumab ecteribulin, gemtuzumab ozogamicin, inotuzumab ozogamicin, ladiratuzumab vedotin, enfortumab vedotin, loncastuximab tesirine, luveltamab tazevibulin, moxetumomab pasudotox, mirvetuximab soravtansine (e.g., mirvetuximab soravtansine-gynx), patritumab deruxtecan, polatuzumab vedotin, praluzatamab ravtansine, raludotatug deruxtecan, sacituzumab govitecan (e.g., sacituzumab govitecan-hziy), tisotumab vedotin (e.g., tisotumab vedotin-tftv), trastuzumab deruxtecan (e.g., fam-trastuzumab deruxtecan-nxki), trastuzumab duocarmazine, trastuzumab emtansine (e.g., ado-trastuzumab emtansine), tusamitamab ravtasine, upifitamab rilsodotin, and XMT-2056. In some embodiments, the ADC is sacituzumab govitecan, trastuzumab deruxtecan, or trastuzumab emtansine. In some embodiments, the ADC is trastuzumab deruxtecan. In some embodiments, the additional anticancer agent is a CDK4/6 inhibitor including, but not limited to, abemacicilb, BPI-16350, CS3002, dalpiciclib, ETH-155008, FCN-437c, HS-10342, lerociclib, palbociclib, P276-00, PF-07224826, PRT3645, ribociclib, SHR6390, SPH4336, trilaciclib, TQB3616, and XZP-3287. In some embodiments, the CDK4/6 inhibitor is abemacicilb, lerociclib, palbociclib, or ribociclib. In some embodiments, the CDK4/6 inhibitor is abemaciclib. In some embodiments, the CDK4/6 inhibitor is lerociclib. In some embodiments, the CDK4/6 inhibitor is palbociclib. In some embodiments, the CDK4/6 inhibitor is ribociclib. In some embodiments, the additional anticancer agent is a chemotherapeutic agent including, but not limited to, cyclophosphamide, doxorubicin, epirubicin, eribulin, ixabepilone, liposomal doxorubicin, methotrexate, platinum agents (e.g., carboplatin, cisplatin, and oxaliplatin), pyrimidine antagonists (e.g., 5-fluorouracil (5-FU), capecitabine, cytarabine, and gemcitabine), taxanes (e.g., cabazitaxel, docetaxel, and paclitaxel), sabizabulin, thiotepa, vinblastine, and vinorelbine. In some embodiments, the chemotherapeutic agent is carboplatin. In some embodiments, the additional anticancer agent is an endocrine agent, such as an aromatase inhibitor (e.g., anastrozole, exemestane, fadrozole, formestane, and letrozole), a luteinizing hormone-releasing hormone (LHRH) receptor agonist (e.g., leuprolide, and leuprorelin), a Selective Estrogen-Receptor Downregulator (SERD) (e.g., amcenestrant, camizestrant, elacestrant, fulvestrant, giredestrant, imlunestrant, rintodestrant, taragarestrant, and ZB716), or a Selective Estrogen Receptor Modulator (SERM) (e.g., afimoxifene, arzoxifene, bazedoxifene, clomiphene, fispemifene, lasofoxifene, raloxifene, ormeloxifene, ospemifene, tamoxifen, tesmilifene, toremifene, and trilostane). In some embodiments, the endocrine agent is anastrozole, elacestrant, exemestane, fulvestrant, letrozole, raloxifene, tamoxifen, toremifene, or a combination thereof. In some embodiments, the additional anticancer agent is an aromatase inhibitor. In some embodiments, the aromatase inhibitor is anastrozole, exemestane, or letrozole. In some embodiments, the additional anticancer agent is a SERD. In some embodiments, the SERD is elacestrant or fulvestrant. In some embodiments, the SERD is elacestrant. In some embodiments, the SERD is fulvestrant. In some embodiments, the S
Figure imgf000094_0001
In some embodiments, the additional anticancer agent is an epidermal growth factor receptor (EGFR) inhibitor including, but not limited to, afatinib, dacomitinib, erlotinib, gefitinib, neratinib, osimertinib, poziotinib, pyrotinib, regorafenib, or vandetanib, or an EGFR antibody such as cetuximab, panitumumab, or necitumumab. In some embodiments, the EGFR inhibitor is neratinib or osimertinib. In some embodiments, the EGFR inhibitor is neratinib. In some embodiments, the EGFR inhibitor is osimertinib. In some embodiments, the additional anticancer agent is a human epidermal growth factor receptor 2 (HER2) inhibitor including, but not limited to, lapatinib, neratinib, pyrotinib, and tucatinib. In some embodiments, the HER2 inhibitor is lapatinib. In some embodiments, the HER2 inhibitor is neratinib. In some embodiments, the HER2 inhibitor is tucatinib. In some embodiments, the additional anticancer agent is a hormone therapy including, but not limited to, goserelin, and megestrol. In some embodiments, the additional anticancer agent is goserelin. In some embodiments, the additional anticancer agent is megestrol. In some embodiments, the additional anticancer agent is a polyadenosine 5’- diphosphoribose polymerase (PARP) inhibitor including, but not limited to, fluzoparib, niraparib, olaparib, rucaparib, and talazoparib. In some embodiments, the PARP inhibitor is olaparib. In some embodiments, the PARP inhibitor is talazoparib. In some embodiments, the additional anticancer agent is a phosphatidylinositol-4,5- bisphosphate 3-kinase (PI3K) inhibitor including, but not limited to, alpelisib, BPI-21668, buparlisib, copanlisib, CYH33, duvelisib, gedatolisib, GSK2636771, HS-10352, idelalisib, inavolisib, LOXO-783, MEN-1611, RLY-2608, temsirolimus, taselisib, TQB-3525, and umbralisib. In some embodiments, the PI3K inhibitor is alpelisib, copanlisib, duvelisib, idelalisib, or umbralisib. In some embodiments, the PI3K inhibitor is alpelisib. In some embodiments, the additional anticancer agent is a vascular endothelial growth factor receptor (VEGFR) inhibitor including, but not limited to, anlotinib, apatinib, axitinib, famitinib, lenvatinib, pazopanib, and sunitinib. In some embodiments, the VEGFR inhibitor is apatinib. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with an AKT inhibitor or a PI3K inhibitor, an endocrine agent, and, optionally, a CDK4/6 inhibitor. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with alpelisib or capivasertib, fulvestrant, and, optionally, abemacicilb, palbociclib, or ribociclib. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered as second (or later) line therapy following treatment with an antibody, e.g., trastuzumab. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with an antibody and, optionally, a chemotherapeutic agent. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with bevacizumab, pertuzumab, or trastuzumab and, optionally, capecitabine, carboplatin, docetaxel, doxorubicin, paclitaxel, or a combination thereof. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered as second (or later) line therapy following treatment with one or more chemotherapeutic agent. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered as second (or later) line therapy following treatment with a pyrimidine antagonist and/or gemcitabine, and/or a platinum agent. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with a chemotherapeutic agent. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with 5-FU. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with gemcitabine. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with carboplatin, cisplatin, or oxaliplatin. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with carboplatin. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with cisplatin. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with one or more of a pyrimidine antagonist, gemcitabine, a CDK4/6 inhibitor, and a platinum agent. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with 5-FU, gembcitabine, ribociclib, and, optionally, cisplatin. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered as second (or later) line therapy following treatment with an endocrine therapeutic agent and/or a CDK4/CDK6 inhibitor. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered as second (or later) line therapy following treatment with an endocrine therapeutic agent, e.g., an aromatase inhibitor, a SERM or a SERD. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered as second (or later) line therapy following treatment with a CDK4/CDK6 inhibitor. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with an endocrine agent and, optionally, a CDK4/6 inhibitor. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with anastrozole, elacestrant, exemestane, fulvestrant, letrozole, raloxifene, tamoxifen, or toremifene, and, optionally, abemacicilb, palbociclib, or ribociclib, or a combination thereof. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with anastrozole, exemestane, or letrozole and abemacicilb, palbociclib, or ribociclib. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with letrozole. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with fulvestrant. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with fulvestrant and ribociclib. In some embodiments, the combination further comprises a chemotherapeutic agent. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with fulvestrant, ribociclib, carboplatin, or a combination thereof. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with a CDK4/6 inhibitor. In some embodiments, the CDK4/6 inhibitor is abemaciclib. In some embodiments, the CDK4/6 inhibitor is palbociclib. In some embodiments, the CDK4/6 inhibitor is ribociclib. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered as second (or later) line therapy following treatment with an EGFR inhibitor, e.g., osimertinib. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with an EGFR inhibitor and, optionally, a chemotherapeutic agent. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with neratinib or osimertinib and, optionally, capecitabine, gemcitabine, paclitaxel, or a combination thereof. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with osimertinib. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with a HER2 inhibitor, a chemotherapeutic agent, and, optionally, an antibody. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with neratinib or tucatinib, capecitabine, and, optionally, trastuzumab. Methods of Administration and Dosage Forms The term “effective amount” or “therapeutically effective amount” means an amount when administered to the subject or patient which results in beneficial or desired results, including clinical results, e.g., inhibits, suppresses or reduces the symptoms of the condition being treated in the subject as compared to a control. For example, an effective amount can be given in unit dosage form (e.g., 0.1 mg to about 50 g per day, alternatively from 1 mg to about 5 grams per day. The precise amount of compound or pharmaceutically acceptable salt thereof administered to provide an “effective amount” to the subject will depend on the mode of administration, the type, and severity of the disease or condition, and on the characteristics of the subject, such as general the route of administration, the time of administration, the rate of excretion of the particular active ingredient being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular active ingredient employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. When administered in combination with other therapeutic agents, an “effective amount” of any additional therapeutic agent(s) will depend on the type of drug used. Suitable dosages are known for approved therapeutic agents and can be adjusted by the skilled artisan according to the condition of the subject, the type of condition(s) being treated and the amount of a compound of the disclosure or a pharmaceutically acceptable salt thereof being used by following, for example, dosages reported in the literature and recommended in the Physician’s Desk Reference (57th ed., 2003). A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the disclosure employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. In general, a suitable daily dose of a compound of the disclosure will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. The terms “administer”, “administering”, “administration”, and the like, as used herein, refer to methods that may be used to enable delivery of compositions to the desired site of biological action. These methods include, but are not limited to, intraarticular (in the joints), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, orally, topically, intrathecally, inhalationally, transdermally, rectally, and the like. Administration techniques that can be employed with the agents and methods described herein are found in e.g., Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, PA. The particular mode of administration and the dosage regimen will be selected by the attending clinician, taking into account the particulars of the case (e.g. the subject, the disease, the disease state involved, the particular treatment, and whether the treatment is prophylactic). Treatment can involve daily or multi-daily or less than daily (such as weekly or monthly, etc.) doses over a period of a few days to months, or even years. A “subject” or “patient” is a mammal in need of medical treatment, preferably a human, but can also be an animal in need of veterinary treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like). In one aspect, the patient is a human. In some embodiments, the patient is an adult human. Biomarkers and Pharmacodynamics Markers The disclosure further provides predictive markers including, but not limited to, biomarkers and pharmacodynamic markers, which can be monitored based on levels including, but not limited to, DNA (e.g., cDNA); RNA (e.g., messenger ribonucleic acid (mRNA) and micro ribonucleic acid (miRNA)); gene copy number; gene expression; gene sequence; protein expression (e.g., protein overexpression); expression levels, enzyme activity, phosphorylation levels, or mutations, to identify those human subjects having, suspected of having, or at risk of developing a cancer for whom administering a CDK2 degrader is likely to be effective. In some embodiments, the biomarker is selected from cancer antigen 125 (CA-125); carcinoembryonic antigen (CEA); checkpoint kinase 1 (CHK1); cyclin A1 (CCNA1); cyclin A2 (CCNA2); cyclin D1 (CCND1); cyclin D2 (CCND2); cyclin D3 (CCND3); cyclin E1 (CCNE1); cyclin E2 (CCNE2); cyclin-dependent kinase 1 (CDK1); CDK2; cyclin-dependent kinase 3 (CDK3); CDK4; cyclin-dependent kinase 5 (CDK5); CDK6; cyclin-dependent kinase 18 (CDK18); cyclin-dependent kinase inhibitor 1A (CDKN1A); cyclin-dependent kinase inhibitor 1B (CDKN1B); cyclin-dependent kinase inhibitor 2A (CDKN2A, also referred to as “p16” and “p16-INK4a”); E2F transcription factor 1 (E2F1); E2F transcription factor 2 (E2F2); E2F transcription factor 3 (E2F3); EGFR; enhancer of zeste 2 polycomb repressive complex 2 (EZH2); ER; F-box and WD repeat domain containing 7 (FBXW7); Harvey rat sarcoma virus proto-oncogene, GTPase (HRAS); Kirsten rat sarcoma virus oncogene homolog (KRAS); marker of proliferation Ki-67 (MKI67 or Ki-67); myelocytomatosis (MYC) proto-oncogene; v-myc avian myelocytomatosis viral oncogene lung carcinoma derived (MYCL); v-myc avian myelocytomatosis viral related oncogene, neuroblastoma derived (MYCN); neuroblastoma rat sarcoma virus oncogene homolog (NRAS); HER2; human epidermal growth factor receptor-3 (HER3); prostate-specific antigen (PSA); retinoblastoma transcriptional corepressor 1 (RB1); retinoblastoma transcriptional corepressor like 1 (RBL1); retinoblastoma transcriptional corepressor like 2 (RBL2); thymidine kinase 1 (TK1), and the corresponding proteins encoded by these genes. In some embodiments, the biomarker is selected from CA-125, CCNE1, CCNE2, CEA, KRAS, Ki-67 (or MKI67), p16 (or CDKN2A), RB, PSA, TK1, and the corresponding proteins encoded by these genes. In some embodiments, the levels of a biomarker are modulated in response to administration of an effective dose of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, to a subject. In some embodiments, a biomarker is absent. In some embodiments, the modulation results in the loss of expression of the corresponding protein, a decrease in gene copy numbers, a decrease in phosphorylated protein, or a decrease in protein activity. In some embodiments, the biomarker has a mutation (e.g., a loss of function mutation). In some embodiments, a biomarker or a biomarker mutant is functional. In some embodiments, a change in the levels of a biomarker before and after administration of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or at two different timepoints during treatment with a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is indicative/predictive that a subject having or at risk of developing a cancer has responded to treatment with a compound of the disclosure, or a pharmaceutically acceptable salt thereof. In some embodiments, the levels of a biomarker before and after administration of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, are changed by at least 10%. In some embodiments, the levels of the biomarker before and after administration of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, are changed by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the levels of the biomarker before and after administration of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, are changed by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the levels of the biomarker before and after administration of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, are increased. In some embodiments, the levels of the biomarker before and after administration of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, are reduced. In some embodiments, the levels of the biomarker at two different timepoints during treatment with a compound of the disclosure, or a pharmaceutically acceptable salt thereof, are changed by at least 10%. In some embodiments, the levels of the biomarker at two different timepoints during treatment are changed by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the levels of the biomarker at two different timepoints during treatment are changed by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the levels of the biomarker at two different timepoints during administration of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, are increased. In some embodiments, the levels of the biomarker at two different timepoints during administration of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, are reduced. In another aspect, provided herein is a method of treating cancer in a patient in need thereof comprising: i. testing, or having tested, a first biological sample obtained from the patient with cancer, thereby measuring levels of one or more biomarkers in the patient’s cancer; ii. comparing the levels of the one or more biomarkers in step i. to levels of one or more biomarkers measured in a patient with a normally functioning pathway; iii. in response to determining that the patient’s cancer will be sensitive to a compound of the disclosure, or a pharmaceutically acceptable salt thereof, treating the subject with a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof. In another aspect, provided herein is a method of monitoring a response in a patient having or at risk of developing cancer comprising: i. administering to the patient in need thereof a therapeutically effective amount a compound of the disclosure, or a pharmaceutically acceptable salt thereof; ii. testing, or having tested, a first biological sample obtained from the patient, thereby measuring levels of one or more biomarkers in the biological sample; iii. comparing the levels of the one or more biomarkers in step ii. to levels of one or more biomarkers measured in a patient with a normally functioning pathway; and iv. determining whether the patient having or at risk of developing cancer has responded to treatment with a compound of the disclosure, or a pharmaceutically acceptable salt thereof, if the comparison in step iii shows a change in the levels of one or more biomarkers. In some embodiments, additional biological samples are obtained from the subject and compared to the levels of the biomarkers measured in a patient with a normally functioning pathway (a “control level”) to continue monitoring. In some embodiments, additional biological samples are obtained from the patient and compared to the levels of the biomarkers measured in the first biological sample to continue monitoring. In some embodiments, the biomarker is CA-125. CA-125 is a large transmembrane glycoprotein encoded by the MUC16 gene. In some embodiments, the cancer is ovarian cancer characterized by overexpression of CA-125. In some embodiments, the biomarker is CCNE1 or CCNE2. CCNE1 is encoded by the cyclin E1 (“CCNE1”) gene (GenBank Accession No. NM_001238). CCNE1 acts as a regulatory subunit of CDK2, and CCNE1 is a cell cycle factor essential for the control of the cell cycle at the G1/S transition (Ohtsubo et al., 1995, Mol. Cell. Biol.15:2612-2624). In another aspect, provided herein is a method of treating a cancer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure, wherein the patient has an amplification of the CCNE1 gene (e.g., based on copy number) and/or has a higher level of CCNE1 than a control level of CCNE1. In some embodiments, the cancer is a solid tumor cancer. In some embodiments, the level of CCNE1 in a patient is higher before administration of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, than after said administration. In some embodiments, the expression level of CCNE1 may be the level of CCNE1 mRNA. In other embodiments, the expression level of CCNE1 may be the level of CCNE1 protein. In other embodiments, the expression level of CCNE1 may be an indirect measure of the level of CCNE1 mRNA or protein. In some embodiments, the biomarker is CEA. CEA is a heavily glycosylated protein encoded by carcinoembryonic antigen cell adhesion molecule 5 (CEACAM5). In some embodiments, the cancer is selected from breast cancer, colorectal cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, and prostate cancer, In some embodiments, the biomarker is KRAS. In some embodiments, the cancer is colon cancer, lung cancer, or pancreatic cancer. In some embodiments, the cancer is colon cancer, lung cancer, or pancreatic cancer characterized by a higher level of KRAS than a control level of KRAS. In some embodiments, the biomarker is the marker of proliferation Ki-67. In some embodiments, the cancer characterized by a higher level of Ki-67 than a control level of Ki- 67. In some embodiments, the biomarker is p16. The gene CDKN2A encodes p16, which acts as a negative regulator of the proliferation of normal cells by interacting with CDK4 and CDK6. In some embodiments, the biomarker is RB1. Retinoblastoma protein (Rb or RB) is a tumor suppressor protein encoded by the gene RB transcriptional corepressor 1 (RB1). In some embodiments, the RB1 gene has a mutation (e.g., a loss of function mutation). Rb is activated upon phosphorylation by cyclin D-CDK4/6 at Ser780 and Ser795 and/or at Ser807 and/or Ser811 and by cyclin E/CDK2 at Ser807 and Ser811 and Thr821. In some embodiments, the contemplated biomarker is phosphorylation of Rb at any phosphorylation site. In some embodiments, the biomarker is phosphorylation at the serine corresponding to amino acid position 780 (Ser780 or S780) and/or the serine corresponding to amino acid position 795 (Ser795 or S795). In some embodiments, the contemplated biomarker is phosphorylation of Rb at the serine corresponding to amino acid position 807 (Ser807 or S807) and/or the serine corresponding to amino acid position 811 (Ser811 or S811). In some embodiments, the contemplated biomarker is phosphorylation of Rb at the threonine corresponding to amino acid position 821 (Thr821 or T821). In some embodiments, the contemplated biomarker is phosphorylation of Rb at the threonine corresponding to amino acid position 826 (Thr826 or T826). In some embodiments, the levels of phosphorylated Rb are reduced compared to a control level of phosphorylated Rb. In some embodiments, the biomarker is PSA. In some embodiments, the cancer is prostate cancer characterized by higher levels of PSA than a control level of PSA. In some embodiments, the biomarker is TK1. TK1 is a direct downstream target of Rb-E2F pathway. It is involved in cellular proliferation through the recovery of the nucleotide thymidine in the DNA salvage pathway. TK1 is important for DNA repair following DNA damage because TK1 is necessary for the formation of nucleotides outside of the S phase. In some embodiments, a TK1 mutant has a resistance mutation. In some embodiments, TK1 is differentially methylated. In some embodiments, TK1 is serum TK1. In some embodiments, the levels of TK1 enzyme activity are reduced compared to a control level of TK1 enzyme activity. Synthesis Compounds of the disclosure, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes. The reactions for preparing compounds of the disclosure can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by the skilled artisan. Preparation of compounds of the disclosure can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety. Reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1H or 13C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.
Figure imgf000105_0001
Scheme 1 Hal is a halogen, typically I, Br, Cl or F The compound (X) may be alkylated by halide (XI) in the presence of an organic or inorganic base, such as DIPEA, TEA, Na2CO3 or K2CO3 in DMF, DCM, MeCN, DMSO or NMP, optionally in the presence of a catalyst such as KI, to give the compound (II). Alternatively, this alkylation reaction may occur under mild acid catalysis such as p-TsOH in a solvent such as IPA at elevated temperature. Alternatively, compound (II) may be obtained from halide (XI) and amine (X) by a palladium catalysed coupling reaction, such as a Buchwald-Hartwig type reaction, using a suitable palladium catalyst in the presence of phosphine ligands, in the presence of a suitable inorganic base, in a solvent at elevated temperature and optionally under microwave irradiation.
Figure imgf000105_0002
Scheme 2 The compound (II) may be obtained by reaction of the amine (XIII) and halide (XII) by a palladium catalysed coupling reaction, such as a Buchwald-Hartwig type reaction, as previously described in Scheme 1.
Figure imgf000106_0001
Scheme 3 In Scheme 3, ring A is linked to L through a N atom. L” is -L1-X1-L2-(L3)p-(X3)q-L4-, or -X1-L2-(L3)p-(X3)q-L4-, or -L2-(L3)p-(X3)q-L4-, or -(L3)p- (X3)q-L4-, or -(X3)q-L4-, or -L4-, its analogues or pre-cursors. L” is a pre-cursor of L, such that reaction between compounds (XIV) and (XV) forms L, wherein L is connected to ring A through an amide bond, L’’ contains a terminal carboxylic acid. The carboxylic acid (XV) may be coupled with amine (XIV) using an amide coupling agent, such as PyBop or HATU, in the presence of an organic base, typically DIPEA, to give compound (II).
Figure imgf000106_0002
Scheme 4 L’ is -L1-X1-L2-(L3)p-(X3)q-L4-, or -L1-X1-L2-(L3)p-(X3)q-, or -L1-X1-L2-(L3)p-, or - L1-X1-L2-, or -L1-X1-, or -L1-, its analogues or pre-cursors. In Scheme 4, L’ is a pre-cursor of L, such that reaction between (X) and (XI) forms L. In Scheme 4, wherein L’ is attached to ring B through a N atom, compound (II) may be obtained from halide (XVII) and amine (XVI) by a Buchwald type palladium catalysed coupling reaction as previously described in Scheme 1. Alternatively, compound (II) may be obtained by an alklyation reaction of amine (XVI) with halide (XVII) as previously described in Scheme 1. In Scheme 4, wherein L’ is attached to ring B through a *C2-C6alkynylene-(O)(s)- group, compound (II) may be obtained from the alkyne (XVI) and halide (XVII) by a Sonagashira type palladium and copper catalysed cross coupling reaction.
Figure imgf000107_0001
Scheme 5 In Scheme 5, Y1 is NH and W is CH. Compound (II) may be obtained from the amine (XVIII) and halide (XIX) by an alkylation reaction as previously described in Scheme 1.
Figure imgf000107_0002
In scheme 6, L' and L’’ react to form L. In Scheme 6, L’ and L’’ form L through a CH2-N bond. Compound (II) may be obtained by a reductive amination reaction between the aldehyde (XVI) and amine (XV), or amine (XVI) and aldehyde (XV) in the presence of a suitable reducing agent such as STAB or MP-cycanoborohydride. Alternatively, compound (II) may be obtained by an alkylation reaction between compound (XVI) that contains a suitable leaving group, such as a Br, Cl, I, F, mesylate or tosylate and amine (XV), or amine (XVI) and compound (XV) that contains a suitable leaving group, such as Br, Cl, I, F mesylate or tosylate, in the presence of a suitable organic or inorganic base, as previously described in Scheme 1. L’ and L’’ form L through an -SO2-N- bond. Compound (II) may be obtained by an alkylation reaction between sulfonyl chloride (XVI) and amine (XV) in the presence of a suitable organic or inorganic base, optionally at elevated temperature. L’ and L’’ form L through an -CO2-NH- bond. Compound (II) may be obtained by an amide bond forming reaction between amine (XVI) and carboxylic acid (XV), or carboxylic acid (XVI) and amine (XVI), as previously described in Scheme 3. L’ and L’’ form L by formation of a 5 to 12-membered arylheterocycle. Compound (II) may be obtained by a cycloaddition reaction between compounds (XV) and (XVI). For example, wherein the aylheterocycle is a 1,2,3-triazole, compound (II) may be obtained by reaction of azide (XVI) and acetylene (XV), or acetylene (XVI) and azide (XV) by a copper catalysed cycloaddition reaction. Compounds (XVI) may be converted to alternative compounds (XVI) by reaction with -X1-L2-(L3)p-(X3)q-L4-, or -L2-(L3)p-(X3)q-L4-, or -(L3)p-(X3)q-L4-, or -(X3)q-L4-, or - L4-, its analogues or pre-cursors, so that L’ and L’’ form L following the reactions described in Scheme 6. Compounds (XV) may be converted to alternative compounds (XV) by reaction with - its a
Figure imgf000108_0001
nalogues or pre-cursors, so that L and L form L following the reactions described in Scheme 6.
Figure imgf000108_0002
Scheme 7 In scheme 7, R6 is H Compound (XXI) may be obtained from the nitro compound (XX) by a reduction reaction under catalytic hydrogenation conditions, typically Pd/C in H2, or by reaction with a reducing metal, such as Fe or Zn in the presence of a suitable acid in a solvent such as EtOH. Compound (XVI) may be obtained from the amine (XXI) and halide (XI) by an alkylation reaction or reaction under Buchwald-Hartwig coupling conditions, as previously described in Scheme 1.
Figure imgf000109_0001
Scheme 8 Compound (XXIV) may be obtained by reaction of the halide (XXII) and boronate ester (XXIII) under Suzuki-type palladium catalysed cross coupling reaction conditions. Compound (XV) may be obtained from compound (XXIV) by a reduction reaction under catalytic hydrogenations conditions, as previously described in Scheme 7. Compounds (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), and (XV) are commercially available or may be prepared by the methods described in the Intermediates and Examples below. Compounds (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), and (XV) may undergo further reaction to provide alternative compounds (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), and (XV) by chemical transformations known to those skilled in the art. These transformations include, but are not limited to, reduction of a C1-C4 carboxylic ester to provide an alcohol, oxidation of a primary alcohol to provide an aldehyde, hydrolysis of a C1-C4 carboxylic ester to provide a carboxylic acid, hydrolysis of an acetal to provide an aldehyde, alkylation of a primary or secondary N or O atom to provide a secondary or tertiary amine or ether, and conversion of an alcohol to an azide via a leaving group, such as a tosylate, by reaction with NaN3. It will be appreciated by those skilled in the art that it may be necessary to utilise a suitable protecting group strategy for the preparation of compounds of Formula (II). Typical protecting groups may comprise, a carbamate, preferably a Boc or CBz group for the protection of primary or secondary aliphatic amines, tert-butyl for the protection of carboxylic acids and tosylate for the protection of primary aliphatic alcohols. It will be appreciated that it may be necessary and/or desirable to carry out the transformations in a different order from that described in the schemes, or to modify one or more of the transformations, to provide the desired compound of the invention. Compounds that contain one or more stereocenters may be separated into their separate stereoisomers by typical methods such as chiral SFC or chiral HPLC techniques as indicated in the Intermediates and Examples below. EXAMPLES The following examples are intended to be illustrative and are not intended to be limiting in any way to the scope of the disclosure. Abbreviations ACN acetonitrile AcOH acetic acid aq. aqueous ATP adenosine-5’-triphosphate BEH ethylene bridged hybrid particle BINAP 2,2’-bis(diphenylphosphino)-1,1’-binaphthalene Boc tert-butoxy carbonyl br broad BrettPhos Pd G3 [(2-Di-cyclohexylphosphino-3,6-dimethoxy-2′,4′,6′- triisopropyl-1,1′- biphenyl)-2-(2′-amino-1,1′ -biphenyl)]palladium(II) methanesulfonate BrettPhos Pd G4 bs broad singlet BSA bovine serum albumin °C degrees Celsius d doublet DCE dichloroethane DCM dichloromethane dd doublet of doublets DIBAL-H diisobutylaluminium hydride DIPEA N-ethyldiisopropylamine or N,N-diisopropylethylamine DMA N,N-dimethylacetamide DMAP 4-dimethylaminopyridine DMF dimethylformamide DMSO dimethylsulfoxide dq doublet of quartets DTT dithiothreitol EGTA ethylene glycol-bis(β-aminoethyl ether)-N,N,N’,N’-tetraacetic acid Et3N or TEA triethylamine Et2O diethyl ether EtOAc ethyl acetate EtOH ethanol equiv. equivalent(s) FBS fetal bovine serum g gram(s) GST glutathione S-transferase h hour(s) HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid Hex hexane 1H-NMR proton nuclear magnetic resonance HPLC high performance liquid chromatography HTRF homogeneous time resolved fluorescence IPA isopropanol LAH lithium aluminium hydride LCMS liquid chromatography mass spectrometry µL microliter(s) µm micrometer(s) µmol micromole(s) m multiplet M molar mAb monoclonal antibody MeCN acetonitrile MeOH methanol mg milligram(s) MHz megahertz min minute(s) mL milliliter(s) mM millimolar mmol millimole(s) MTBE methyl tert-butyl ether m/z mass to charge ratio nL nanoliter(s) nm nanometer(s) NMP N-methyl pyrrolidine PBS phosphate buffered saline Pd/C palladium on charcoal Pd2(dba)3  tris(dibenzylideneacetone)dipalladium (0) Pd(dppf)Cl2 [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(OAc)2 palladium acetate Pd(PPh3)2Cl2 palladium(II)bis(triphenylphosphine) dichloride PE petroleum ether prep-TLC preparative thin layer chromatography psi pounds per square inch PTSA p-toluenesulfonic acid PyBOP benzotriazol-1-yloxytripyrrolindinophosphonium hexafluorophosphate q quartet RPMI Roswell Park Memorial Institute rt room temperature s singlet sat. saturated SFC supercritical fluid chromatography STAB sodium triacetoxyborohydride t triplet tBuOH tert butanol t-BuOK potassium tert-butoxide TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TsOH p-toluenesulfonic acid U unit(s) UPLC ultra performance liquid chromatography Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene XPhos 2-dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl HPLC Codes. Organic gradient 0-100%, optimised for each sample. HPLC-A (X-BRIDGE-C18 (150 x 19 mm), 5 ^m; 0-100% MeCN/H2O (0.1% HCO2H)); HPLC-B (X-SELECT-C18 (250 x 19 mm), 5 ^m; 0-100% MeCN/H2O (0.1% HCO2H)); HPLC-C (X-BRIDGE-C18 (250 x 19 mm), 5 ^m; 0-100% MeCN/H2O (0.1% HCO2H)); HPLC-D (SUNFIRE-C18 (250 x 10 mm), 5 ^m; 0-100% MeCN/ H2O (0.1% HCO2H)); HPLC-E (KROMOSIL-C18 (150 x 25 mm), 10 ^m 0-100% MeCN/H2O (0.1% HCO2H)); HPLC-F 9YMC TRIART (50 x 2.1 mm) 1.7 ^m; 0-100% MeCN (0.05% TFA)/H2O (0.05% TFA)); HPLC-H (KROMOSIL-C18 (150 x 25 mm), 10 ^m; 0-100% MeCN/H2O (10 mM NH4HCO3)); HPLC-I (SUNFIRE-C18 (150 x 19 mm), 5 ^m 0-100% MeCN/H2O (0.1% HCO2H)); HPLC-J (X-BRIDGE-C18 (250 x 10 mm), 5 ^m; 0-100% MeCN/H2O (0.1% HCO2H)); HPLC-K (X-BRIDGE C18 (150 x 4.6 mm), 3.5 µm 0-100% MeCN/H2O (10 mM NH4OAc)); HPLC-L (INERTSIL ODS-3 (250 x 20 mm), 5 ^m; 0-100% MeOH/H2O (0.1% TFA)); HPLC-M (X-BRIDGE C18 (150 x 30 mm), 5 ^m 0-100% MeCN/H2O (0.1% HCO2H)); HPLC-N (Atlantis-T3 (250 x 19 mm) 5 ^m; 0-100% MeCN/H2O (0.1% HCO2H)); HPLC-O (YMC Diol (250 x 10 mm), 5 ^m; 0-100% MeCN/H2O (0.1% HCO2H)); HPLC-P (X-BRIDGE Prep C18 (150 x 30 mm), 5 ^m; 0-100% MeCN/H2O (0.1% HCO2H)); HPLC-Q (Acquity UPLC BEH C18 (100 x 2.1 mm) 1.7 ^m) 0-100% MeCN/H2O (0.05% HCO2H)); HPLC-R (Atlantis-T3- (250 x 21.2), 5 ^m; 0-100% MeCN/H2O (0.1% HCO2H)); HPLC-S (YMC HYDROSPARE C18 (150 x 25 mm) 10 µm 0-100% MeCN/H2O (0.1% HCO2H)); HPLC-T (GEMINI NX C18 (250 x 21 mm) 7 ^m, 0-100% MeCN/H2O (0.1 % HCO2H)). Intermediate 1. Synthesis of 1-(4-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol- 1-yl)-2-methylpropan-2-ol
Figure imgf000114_0001
To a stirred solution of 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazol-1-yl)propan-2-ol (5.0 g, 18.79 mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine (8.99 g, 41.33 mmol) in dioxane (45 mL ) was added solution of sodium carbonate (5.97 g, 56.36 mmol) in water (25 mL) at rt. The reaction mixture was purged with N2 for 15 min and Pd(dppf)Cl2.DCM (860 mg, 0.939 mmol) added at rt and the resulting reaction mixture stirred under N2 at 80 °C for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3x 50 mL). The combined organics were washed with brine (50 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 20-30% EtOAc/Hex) to afford the title compound as a brown solid (1.50 g, 25%). LCMS m/z = 321 [M+H]+. Intermediate 2. 2-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile
Figure imgf000114_0002
A mixture of 2,4-dichloropyrimidine-5-carbonitrile (1 g, 5.74 mmol), 1-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.20 g, 5.74 mmol), Pd(dppf)Cl2 (168 mg, 230 µmol), K2CO3 (1.18 g, 8.61 mmol) in dioxane (30 mL) and water (6 mL) was stirred at 50℃ for 3 h. The reaction mixture was evaporated to dryness and the residue purified by silica gel chromatography (1% MeOH/DCM) to afford the title compound as a yellow solid (450 mg, 36%). LCMS m/z = 220 [M+H]+. Intermediate 3. 2,5-dichloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidine
Figure imgf000114_0003
A mixture of 2,4,5-trichloropyrimidine (1 g, 5.45 mmol), 1-methyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.69 g, 8.17 mmol), Pd(dppf)Cl2 (100 mg, 122 µmol), Cs2CO3 (3.55 g, 10.9 mmol) in dioxane (50 mL) and H2O (10 mL) was stirred at 50℃ for 2 h. The reaction mixture was evaporated to dryness and the residue purified by silica gel chromatography to afford the title compound as an off-white solid (450 mg, 36%). LCMS m/z = 229 [M+H]+. Intermediate 4. 1-((4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)piperidine-4-carbaldehyde
Figure imgf000115_0001
Step 1. Synthesis of ethyl 1-((4-((tert-butoxycarbonyl)amino)piperidin-1- yl)sulfonyl)piperidine-4-carboxylate To a stirred solution of ethyl piperidine-4-carboxylate (4.0 g, 25.44 mmol) and tert-butyl piperidin-4-ylcarbamate (5.09 g, 25.44 mmol) in DCM (125 mL) and THF (125 mL) were added triethylamine (14.30 mL, 101.7 mmol) followed by sulfuryl chloride (2.05 mL, 25.44 mmol) in dropwise manner over 30 min at 0 °C and the resulting mixture stirred for 2h at same temperature. The reaction was quenched with water (300 mL) and extracted with DCM (2x 150 mL). The combined organics was washed with brine solution (200 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 30-40% EtOAc/PE) to afford the title compound as a white solid (4.9 g, 46%). LCMS m/z = 420 [M+H]+. Step 2. Synthesis of ethyl 1-((4-aminopiperidin-1-yl)sulfonyl)piperidine-4-carboxylate hydrochloride To a stirred solution of ethyl 1-((4-((tert-butoxycarbonyl)amino)piperidin-1- yl)sulfonyl)piperidine-4-carboxylate (Step 1, 2.0 g 4.77 mmol) in DCM (20 mL) was added dropwise over 5 min 4.0 M HCl in dioxane (15 mL) at 0 °C. The reaction mixture was allowed to stir at rt for 2 h and concentrated and co-distilled with DCM (2x 50mL) under reduced pressure to obtain the title compound as a white solid (2.0 g) which was used without purification. LCMS m/z = 320 [M+H]+. Step 3. Synthesis of ethyl 1-((4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)piperidine-4-carboxylate A 48 mL sealed tube was charged with ethyl 1-((4-aminopiperidin-1-yl)sulfonyl)piperidine- 4-carboxylate hydrochloride (Step 2, 2.0 g, 5.62 mmol), 1-(4-(2-chloro-5- (trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 1, 1.26 g, 3.93 mmol) in dioxane (15 mL) and DIPEA (2.95 mL 16.86 mmol) at rt and the resulting reaction mixture stirred at 100 °C for 16 h. The reaction mixture was diluted with water (250 mL) and extracted with DCM (2x 100 mL). The combined organics were washed with brine solution (150 mL), dried (Na2SO4), concentrated under reduced and the residue purified by column chromatography (SiO2, 40-50% EtOAc/PE) to afford the title compound as a brown, sticky liquid (1.72 g, 50 %). LCMS m/z = 604 [M+H]+. Step 4. Synthesis of 1-(4-(2-((1-((4-(hydroxymethyl)piperidin-1-yl)sulfonyl)piperidin-4- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol To a stirred solution of ethyl 1-((4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)piperidine-4-carboxylate (Step 3, 1.71 g, 2.83 mmol) in THF (60 mL) was added LAH (2.0M in THF, 4.18 mL, 99 mmol) dropwise over 10 min at 0° C and stirred for 1h. The reaction was quenched with saturated NH4Cl solution (250 mL) and extracted with EtOAc (2x 80 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure to obtain the title compound (1.27 g, 80%) which was used without purification. LCMS m/z = 562 [M+H]+. Step 5. Synthesis of 1-((4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)piperidine-4-carbaldehyde To a stirred solution of 1-(4-(2-((1-((4-(hydroxymethyl)piperidin-1-yl)sulfonyl)piperidin-4- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Step 4, 1.27 g, 2.26 mmol) in DCM (40 mL) was added portion wise Dess-Martin periodinane (1.92 g, 4.52 mmol) at 0° C and the reaction stirred at rt for 2h. The reaction mixture was filtered through celite bed and washed with DCM (100 mL). The filtrate was washed with water (150 mL) and saturated NaHCO3 solution (150 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 50%- 60% EtOAc/PE) to afford the title compound as a sticky off-white solid (0.72 g, 57%). LCMS m/z = 560 [M+H]+. Intermediate 5. N-((1r,4r)-4-formylcyclohexyl)-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-sulfonamide.
Figure imgf000117_0001
Step 1. Synthesis of methyl (1r,4r)-4-((4-((tert-butoxycarbonyl)amino)piperidine)-1- sulfonamido)cyclohexane-1-carboxylate To the stirred solution of methyl (1r,4r)-4-aminocyclohexane-1-carboxylate (1 g, 6.36 mmol), tert-butyl piperidin-4-ylcarbamate (1.274 g, 6.36 mmol) in DCM (20 mL) was added Et3N (644 mg, 6.36 mmol) and the resulted mixture cooled to -15 °C and sulfuryl chloride (858 mg, 6.36 mmol) and stirred for 2 h at -15 °C. The reaction mixture was diluted with water (30 mL) and extracted with DCM (3x 45 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure and the residue purified by flash chromatography (SiO2, 30% EtOAc/PE) to afford the title compound as a white solid (250 mg, 9.4%). LCMS m/z = 420 [M+H]+. Step 2. Synthesis of methyl (1r,4r)-4-((4-aminopiperidine)-1-sulfonamido)cyclohexane-1- carboxylate hydrochloride To a stirred solution of methyl (1r,4r)-4-((4-((tert-butoxycarbonyl)amino)piperidine)-1- sulfonamido)cyclohexane-1-carboxylate (Step 1, 1 g, 2.38 mmol) in DCM (30 mL) was added, 4M HCl in dioxane (20 mL) at 0 °C and the resulting mixture stirred at rt for 3 h. The reaction mixture was concentrated under reduced pressure to afford the title compound as white solid (600 mg, 71%) which was used without further purification. LCMS m/z = 320 [M+H]+. Step 3. Synthesis of methyl (1r,4r)-4-((4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4- yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine)-1-sulfonamido)cyclohexane-1- carboxylate To a solution of methyl (1r,4r)-4-((4-aminopiperidine)-1-sulfonamido)cyclohexane-1- carboxylate hydrochloride (Step 2, 1.8 g, 5.64 mmol), 1-(4-(2-chloro-5- (trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 1, 813 mg, 2.54 mmol) in dioxane (20 mL) was added DIPEA (3 mL, 16.9 mmol) and the resulting mixture heated to 90 °C for 16 h. The reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (3x 40 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 2% MeOH/DCM) to afford the title compound as a gummy solid (1.36 g, 40%). LCMS m/z = 604 [M+H]+. Step 4. Synthesis of 4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-N-((1r,4r)-4-(hydroxymethyl)cyclohexyl)piperidine- 1-sulfonamide Lithium aluminium hydride (2M in THF, 2.80 mL, 4.307 mmol) was added dropwise to a stirred solution of methyl (1r,4r)-4-((4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)- 5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine)-1-sulfonamido)cyclohexane-1- carboxylate (Step 3, 1.3 g, 2.15 mmol) in THF (20 mL) at -5 °C. The reaction mixture was allowed to stir at rt for 2 h. The reaction was quenched with sat. NH4Cl solution (20 mL) and extracted with EtOAc (3x 30 mL). The combined organics were dried (Na2SO4) and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (SiO2, 3% MeOH/DCM to afford the title compound as a gummy solid (1.1 g, 89%). LCMS m/z = 576 [M+H]+. Step 5. Synthesis of N-((1r,4r)-4-formylcyclohexyl)-4-((4-(1-(2-hydroxy-2-methylpropyl)- 1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-sulfonamide To the stirred solution of 4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-N-((1r,4r)-4-(hydroxymethyl)cyclohexyl)piperidine- 1-sulfonamide (Step 4, 1.1 g, 1.91 mmol) in DCM (30 mL) was added Dess-Martin periodinane (1.62 g, 3.82 mmol) at 0 °C and then allowed to warm to rt for 1h. The reaction mixture was filtered through a pad of celite and the filtrate diluted with water (30 mL) and extracted into DCM (3x 40 mL). The combined organics were dried (Na2SO4) and concentrated under reduced. The residue was purified by column chromatography on neutral alumina (4% MeOH/DCM) to afford the title compound as a light brown gummy solid (630 mg, 57%). LCMS m/z = 574 [M+H]+. Intermediate 6. 3-(1-oxo-5-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)isoindolin-2-yl)piperidine- 2,6-dione.
Figure imgf000119_0001
Step-1: Synthesis of tert-butyl 4-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)prop- 2-yn-1-yl)oxy)piperidine-1-carboxylate Cesium carbonate (2.52 g, 7.74 mmol) was added to a stirred solution of 3-(5-bromo-1- oxoisoindolin-2-yl)piperidine-2,6-dione (1.0 g, 3.10 mmol) and tert-butyl 4-(prop-2-yn-1- yloxy)piperidine-1-carboxylate (1.11 g, 4.64 mmol) in DMF (10 mL) and the mixture purged with nitrogen for 15 min. To this were added dichlorobis (triphenylphosphine)palladium (217 mg, 0.31 mmol) and copper(I) iodide (118 mg, 0.62 mmmol) under nitrogen and the mixture stirred at 70 °C for 16 h. The reaction mixture was quenched with cold water (30 mL) and extracted with EtOAc (3x 30 mL). The combined organics were washed with ice cold water (3x 30 mL), saturated ammonium chloride solution (2x 30 mL), dried over (Na2SO4) and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (SiO2, EtOAc/PE) to afford the title compound as a brown solid (1.3 g, 87 % yield). 1H-NMR (400 MHz, DMSO-d6): 11.00 (s, 1H), 7.72 (d, 2H), 7.58 (d, 1H), 5.14-5.09 (dd, 1H), 4.49-4.44 (m, 3H), 4.36-4.32 (m, 1H), 3.73-3.71 (m, 1H), 3.68-3.61 (m, 2H), 3.18-3.16 (m, 2H), 3.06 (m, 1H), 2.62 (m, 1H), 2.49-2.38 (m, 1H), 2.16-1.99 (m, 1H), 1.87-1.73 (m, 2H), 1.42 (br s, 9H), 1.39-1.34 (m, 2H). Step-2: Synthesis of 3-(1-oxo-5-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)isoindolin-2- yl)piperidine-2,6-dione To a stirred solution of tert-butyl 4-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)prop-2-yn-1-yl)oxy)piperidine-1-carboxylate (Step 1, 1.3 g, 2.70 mmol) in DCM (13 mL) was added 4.0 M HCl in dioxane (6.5 mL) at 0 °C and allowed to stir at rt for 3 h. The reaction mixture was concentrated under reduced pressure and the residue quenched with saturated sodium bicarbonate (30 mL) and extracted with 20% IPA/CHCl3 (3x 30 mL). The combined organics was dried (Na2SO4) and evaporated to dryness under reduced pressure to afford the title compound as a brown solid (900 mg, 87%). LCMS m/z = 382 [M+H]+. Intermediate 7. (1r,4r)-4-(bromomethyl)cyclohexan-1-amine hydrochloride.
Figure imgf000120_0001
To a stirred solution of tert-butyl ((1r,4r)-4-(bromomethyl)cyclohexyl)carbamate [ACS Medicinal Chemistry Letters (2012), 3(2), 129-134)] (10 g, 34.22 mmol) in DCM (30.0 mL) was added 4 M HCl in dioxane (20 mL) at 0 °C and the reaction mixture stirred at rt for 3 h. The reaction mixture was concentrated and co-distilled with DCM (2x 50 mL) under reduced pressure. The residue was washed with diethyl ether and dried under vacuum to afford the title compound as a tan solid (9.0 g, 75%) as a light brown semi solid. 1
Figure imgf000120_0002
(400 MHz, DMSO-d6): 7.93 (s, 1H), 3.43-342 (d, 2H), 2.92-2.89 (m, 1H), 1.91-1.89 (m, 2H), 1.86-1.84 (m, 2H), 1.56-1.54 (m, 1H), 1.31-1.28 (m, 2H), 1.12-1.02 (m, 2H). Intermediate 8. 2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetic acid.
Figure imgf000120_0003
Step 1. Synthesis of tert-butyl 2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oxy)acetate To a stirred solution of 3-(4-hydroxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.50 g, 1.8 mmol) in DMF (5 mL) was added tert-butyl 2-bromoacetate (0.48 g, 2.40 mmol) at rt and the reaction mixture stirred at 100 °C for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3x 50 mL). The combined organics were washed with brine (50 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by RP column chromatography using C18 column (7-80% MeCN/H2O (0.1% HCO2H) to afford the title compound as a brown solid (1.50 g, 25%). LCMS m/z = 375 [M+H]+. Step 2: Synthesis of 2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetic acid To a stirred solution of tert-butyl 2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oxy)acetate (Step 1, 0.30 g, 0.82 mmol) in DCM (5 mL) was added TFA (3 mL) at 0 °C and the mixture stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure to afford the title compound as a white solid (0.20g, 80%). LCMS m/z = 319 [M+H]+. Intermediate 9. 3-(4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)piperidine-2,6-dione.
Figure imgf000121_0001
Step 1. Synthesis of tert-butyl 9-(4-bromophenyl)-3,9-diazaspiro[5.5]undecane-3- carboxylate To a stirred solution of tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (5 g, 19.7 mmol) in DCM (100 mL) was added (4-bromophenyl)boronic acid (7.90 g, 39.3 mmol) and triethylamine (8.20 mL, 59.0 mmol). The solution was purged with O2 gas for 15 min. Copper (II) acetate (1.43 g, 7.86 mmol) was added to the reaction mixture and the reaction stirred at rt for 16 h. Water (150 mL) was added and the reaction mixture filtered through a pad of celite and washed with DCM (2x 200 mL). The combined organics were dried (Na2SO4) and concentrated under the reduced pressure and the residue purified by silica gel chromatography (SiO2, 10-50% EtOAc/PE) to afford the title compound as a semi-solid (8 g; 75%). LCMS m/z = 409 [M+H]+. Step 2. Synthesis of tert-butyl 9-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-3,9- diazaspiro[5.5]undecane-3-carboxylate Potassium phosphate (10.37 g, 48.9 mmol) was added to a stirred solution of tert-butyl 9-(4- bromophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (Step 1, 8 g, 19.5 mmol), 2,6- bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (12.2 g, 29.3 mmol) in dioxane/water (176 mL, 10/1) and the mixture degassed with argon for 20 min. PdCl2(dppf).DCM (798 mg, 0.98 mmol) was added to the reaction mixture and the solution again purged with argon and heated for 3h at 110°C. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The residue was dissolved in EtOAc (100 mL), washed with water (4x 100 mL) and brine (2x 100 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure and the residue purified by silica gel chromatography (SiO2, 0-6% EtOAc/PE) to afford the title compound as a colourless semi-solid (7g, 79%). LCMS m/z = 620 [M+H]+. Step 3. Synthesis of tert-butyl 9-(4-(2,6-dioxopiperidin-3-yl)phenyl)-3,9- diazaspiro[5.5]undecane-3-carboxylate To a suspension of tert-butyl 9-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-3,9- diazaspiro[5.5]undecane-3-carboxylate (Step 2, 4.5 g, 7.26 mmol) in EtOH (200 mL) was added Palladium on activated carbon, 10% Pd, (50% wet with water), unreduced (4 g). The reaction mixture was stirred at room temperature under H2 (120 psi) for 48 h. The reaction mixture was filtered through a pad of celite, washed with MeOH (2x 20 mL). The filtrate was concentrated under the reduced pressure and the residue was purified by Combi-flash chromatography (SiO2, 20-60% EtOAc/PE) to afford the title compound as an off-white solid (1.9 g, 59%). LCMS m/z = 442 [M+H]+. Step 4. Synthesis of 3-(4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)piperidine-2,6-dione 4N HCl in Dioxane (10 mL) was added to a stirred solution of tert-butyl 9-(4-(2,6- dioxopiperidin-3-yl)phenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (Step 3, 3.4 g, 4.60 mmol) in DCM (60 mL), at 0 ºC and the reaction was stirred at rt for 3 h. The reaction mixture was concentrated and co-distilled with dichloromethane (2x 50mL) under reduced pressure and the residue diluted with sat aq NaHCO3 (25 mL) and extracted with 10% IPA/CHCl3 (5x 100 mL). The combined organics were dried (Na2SO4) and evaporated to dryness under reduced pressure to afford the title compound as an off-white solid (2.4g, 91%). LCMS m/z = 342 [M+H]+. Intermediate 10. 3-(3-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)piperidine-2,6-dione.
Figure imgf000123_0001
Step 1. Synthesis of tert-butyl 9-(3-bromophenyl)-3,9-diazaspiro[5.5]undecane-3- carboxylate To a stirred solution of tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (5 g, 19.7 mmol) in DCM (100 mL) were added (3-bromophenyl)boronic acid (7.90 g, 39.3 mmol) and triethylamine (8.19 mL, 59 mmol) and O2 gas was purged through the solution for 15 min. Copper (II) acetate (1.43 g, 7.86 mmol) was added to the reaction mixture and the reaction was stirred at rt for 16 h. The reaction was quenched with water (150 mL), filtered through a pad of celite and washed with DCM (2x 200 mL). The combined organics were dried (Na2SO4) and concentrated under the reduced pressure. The residue was purified by Combflash chromatography (SiO2, 10-50% EtOAc/PE) to afford the title compound as an off-white solid (6.4 g; 80%). LCMS m/z = 409 [M+H]+. Step 2. Synthesis of tert-butyl 9-(3-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-3,9- diazaspiro[5.5]undecane-3-carboxylate To a stirred solution of tert-butyl 9-(4-bromophenyl)-3,9-diazaspiro[5.5]undecane-3- carboxylate (Step 1, 8 g, 19.5 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine (12.23 g, 29.3 mmol) and potassium phosphate (10.37 g, 48.86 mmol) in dioxane/water (176 mL, 10:1) and the mixture degassed with argon for 20 min. PdCl2(dppf).DCM (798 mg, 0.98 mmol) was added and the solution purged with argon and heated for 3 h at 110°C. The reaction mixture was diluted with water (150 mL) and filtered through a pad of celite. The celite pad was washed with DCM (2x 200 mL) and the combined organics dried (Na2SO4) and concentrated under the reduced pressure to afford the title compound as an off-white solid (6.5 g, 67%). LCMS m/z = 620 [M+H]+. Step 3. Synthesis of tert-butyl 9-(3-(2,6-dioxopiperidin-3-yl)phenyl)-3,9- diazaspiro[5.5]undecane-3-carboxylate To a suspension of tert-butyl 9-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-3,9- diazaspiro[5.5]undecane-3-carboxylate (Step 2, 6 g, 9.68 mmol) in Ethanol (100 mL) was added Palladium on activated carbon, 10% Pd, (50% wet with water, 6 g) and the reaction mixture stirred at room temperature under H2 (120 psi) atmosphere for 48 h. The reaction mixture was filtered through a pad of celite and washed with methanol (4x 100 mL). The filtrate was concentrated under reduced pressure and the residue purified by silica gel chromatography (SiO2, 10-50% EtOAc/PE) followed by silica gel chromatography (SiO2, 20- 60% EtOAc/PE) to afford the title compound as an off-white solid (2.6 g, 61%). LCMS m/z = 442 [M+H]+. Step 4. Synthesis of 3-(3-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)piperidine-2,6-dione 4N HCl in dioxane (5 mL) was added to a stirred solution of tert-butyl 9-(3-(2,6- dioxopiperidin-3-yl)phenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (Step 3, 2.6 g, 5.89 mmol) in DCM (40 mL), at 0 ºC. After completion of reaction the reaction mixture was concentrated under reduced pressure and the residue diluted with sat aq NaHCO3 (25 mL) and extracted with 10% IPA/CHCl3. The combined organics were dried (Na2SO4) and evaporated to dryness under reduced pressure to afford the title compound as an off-white solid (1.9 g, 94%). Intermediate 11. 1-(2-methyl-3-(3-(piperidin-4-yloxy)prop-1-yn-1- yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione.
Figure imgf000124_0001
Step 1. Synthesis of tert-butyl 4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2- methylphenyl)prop-2-yn-1-yl)oxy)piperidine-1-carboxylate A mixture of 1-(3-bromo-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione (WO2015197028 A1, 1.5 g, 5.30 mmol.), tert-butyl 4-(prop-2-yn-1-yloxy)piperidine-1- carboxylate (1.90 g, 7.95 mmol.) and Cs2CO3 (4.32 g, 13.25 mmol.) in MeCN (15 mL) at rt was purged with nitrogen gas for 15 min and BrettPhos Pd G4 (488 mg, 0.53 mmol.) and copper(I) iodide (202 mg, 1.06 mmol.) were added under N2 and the resulting reaction mixture stirred at 80 °C for 16 h. The reaction mixture was evaporat4ed to dryness under reduced and the residue was purified by silica gel chromatography (SiO2, 50-60% EtOAc/PE) to afford the title compound as a brown solid (1.2 g, 51%). LCMS m/z = 442 [M+H]+. Step 2. Synthesis of 1-(2-Methyl-3-(3-(piperidin-4-yloxy)prop-1-yn-1- yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione Formic acid (12 mL) was added to tert-butyl 4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)- yl)-2-methylphenyl)prop-2-yn-1-yl)oxy)piperidine-1-carboxylate (Step 1, 1.2 g, 2.49 mmol) at rt room temperature and stirred at rt for 2 h. The reaction mixture was evaporated to dryness and the residue diluted with water (50 mL) and extracted with 10% MeOH/CHCl3 (3x 50 mL). The combined organics were washed with brine (50 mL), dried (Na2SO4) and evaporated to dryness under reduced pressure to afford the title compound was a brown gum (780 mg, 84%). LCMS m/z = 342 [M+H]+. Intermediate 12. 3-(3-(3-((1-(piperidine-4-carbonyl)piperidin-4-yl)oxy)prop-1-yn-1- yl)phenyl)piperidine-2,6-dione.
Figure imgf000126_0001
Step 1. Synthesis of tert-butyl 4-((3-(3-(2,6-dioxopiperidin-3-yl)phenyl)prop-2-yn-1- yl)oxy)piperidine-1-carboxylate To a stirred solution of 3-(3-iodophenyl)piperidine-2,6-dione (1.0 g, 3.17 mmol) and tert- butyl 4-(prop-2-yn-1-yloxy)piperidine-1-carboxylate (1.37 g, 5.71 mmol) in DMF (10 mL) was added cesium carbonate (2.59 g, 7.93 mmol) and purged with nitrogen gas for 15 min. To this was added dichlorobis(triphenylphosphine)palladium (0.223 g, 0.32 mmol) and copper (I) Iodide (121 mg, 0.64 mmol) and stirred at 70 °C for 4h. The reaction was quenched with cold water (50 mL) and extracted with EtOAc (3x 50 mL). The combined organics were washed with ice cold water (3x 50 mL), saturated ammonium chloride solution (2x 50 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 50-60% EtOAc/PE) to afford the title compound as a brown solid (1.2 g, 88%). LCMS m/z = 427 [M+H]+. Step 2. Synthesis of 3-(3-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)phenyl)piperidine-2,6-dione To a stirred solution tert-butyl 4-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)prop- 2-yn-1-yl)oxy)piperidine-1-carboxylate (Step 1, 1.2 g, 2.81 mmol) in DCM (12 mL) was added 4.0 M HCl in dioxane (6 mL) drop-wise at 0° C and then stirred at rt for 3 h. The reaction mixture was concentrated under reduced pressure and the residue quenched with saturated sodium bicarbonate (30 mL) and extracted with 20% IPA/CHCl3 (3x 30 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as a brown solid (700 mg, 76%). LCMS m/z = 327 [M+H]+. Step 3. Synthesis of tert-butyl 4-(4-((3-(3-(2,6-dioxopiperidin-3-yl)phenyl)prop-2-yn-1- yl)oxy)piperidine-1-carbonyl)piperidine-1-carboxylate DIPEA (1.2 mL, 1.92 mmol) was added to a stirred solution of 3-(3-(3-(piperidin-4- yloxy)prop-1-yn-1-yl)phenyl)piperidine-2,6-dione (Step 2, 250 mg, 0.77 mmol) and 1-(tert- butoxycarbonyl)piperidine-4-carboxylic acid (211 mg, 0.92 mmol) in DMF (5 mL) at 0 °C and stirred for 5 min before HATU (524 mg, 1.38 mmol) was added and the reaction mixture stirred at rt for 16 h. The reaction was quenched with cold water (20 mL) and extracted with 10 % MeOH/DCM (3x 25 mL). The combined organics were washed with water (2x 25 mL), brine (25 mL), dried (Na2SO4) and evaporated to dryness. The residue was purified by column chromatography (SiO2, 60-70% EtOAc/PE) to afford the title compound as a brown solid (300 mg, 73%). LCMS m/z = 538 [M+H]+. Step 4. Synthesis of 3-(3-(3-((1-(piperidine-4-carbonyl)piperidin-4-yl)oxy)prop-1-yn-1- yl)phenyl)piperidine-2,6-dione To a stirred solution of tert-butyl 4-(4-((3-(3-(2,6-dioxopiperidin-3-yl)phenyl)prop-2-yn-1- yl)oxy)piperidine-1-carbonyl)piperidine-1-carboxylate (Step 3, 300 mg, 0.56 mmol) in DCM (3 mL), was added 4.0 M HCl in dioxane (1.5 mL) drop-wise at 0° C and the reaction mixture stirred at rt for 4h. The reaction was concentrated under reduced pressure and the residue quenched with cold water (50 mL) and extracted with Et2O (3x 50 mL). The aqueous layer was basified with saturated sodium bicarbonate (50 mL) and extracted with 20% IPA/CHCl3 (3x 50 mL), dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as a brown solid (180 mg, 74%). LCMS m/z = 438 [M+H]+. Intermediate 13. 1-(2-methyl-3-(3-((1-(piperidine-4-carbonyl)piperidin-4-yl)oxy)prop-1-yn- 1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione.
Figure imgf000127_0001
Step 1: Synthesis of tert-butyl 4-(4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2- methylphenyl)prop-2-yn-1-yl)oxy)piperidine-1-carbonyl)piperidine-1-carboxylate To a stirred solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (262 mg, 1.142 mmol) and HATU (434 mg, 1.142 mmol) in DMF (15 mL) was added 1-(2-methyl-3-(3- (piperidin-4-yloxy)prop-1-yn-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (Intermediate 11, 325 mg, 0.952 mmol) followed by DIPEA (0.497 mL, 2.856 mmol) at rt and the resulting reaction mixture was stirred for 16 h at rt. The reaction mixture was diluted with ice-cold water (20 mL) and extracted with EtOAc (3x 20 mL). The combined organics were dried (Na2SO4) and evaporated under reduced pressure and the residue purified by combi-flash (SiO2, 50% EtOAc/PE) to afford the title compound as a red solid (0.10 g, 19%). LCMS m/z = 556 [M+H]+. Step 2: Synthesis of 1-(2-methyl-3-(3-((1-(piperidine-4-carbonyl)piperidin-4-yl)oxy)prop-1- yn-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione A solution of tert-butyl 4-(4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2- methylphenyl)prop-2-yn-1-yl)oxy)piperidine-1-carbonyl)piperidine-1-carboxylate (0.1 g, 0.18 mmol) in formic acid (3 mL) was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure to afford the title compound as a red solid (0.08 g, 98%). LCMS m/z = 453 [M+H]+. Intermediate 14. Mixture of 3-fluoro-N-((1r,4r)-4-formylcyclohexyl)-4-((4-(1-(2-hydroxy- 2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide and 3-fluoro-N-((1s,4s)-4-formylcyclohexyl)-4-((4-(1-(2- hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide.
Figure imgf000129_0001
Step 1. Synthesis of methyl (1r,4r)-4-((3-fluoro-4-nitrophenyl)sulfonamido)cyclohexane-1- carboxylate To a solution of methyl (1r,4r)-4-aminocyclohexane-1-carboxylate (10 g, 63.61 mmol) in DCM (80 mL) was added 3-fluoro-4-nitrobenzenesulfonyl chloride (22.86 g, 95.41 mmol) and TEA (19.31 g, 191 mmol) at -10 ºC and stirred for 2h. The reaction was quenched with cold water (100 mL) and extracted with DCM (3x 150 mL). The combined organics were dried (Na2SO4) and evaporated to dryness under reduced pressure and the residue was purified by column chromatography (SiO2, 25-30% EtOAc/PE) to afford the title compound as a yellow solid (7 g). LCMS m/z = 361 [M+H]+. Step 2. Synthesis of methyl (1r,4r)-4-((4-amino-3-fluorophenyl)sulfonamido)cyclohexane-1- carboxylate Fe powder (26.35 g, 472 mmol) and NH4Cl (25.23 g, 472 mmol) were added to a stirred solution of methyl 4-((3-fluoro-4-nitrophenyl)sulfonamido)cyclohexane-1-carboxylate (Step 1, 8.5 g, 23.6 mmol) in EtOH (60 mL) and H2O (60 mL) and the reaction mixture stirred at 80 ºC for 4 h. The reaction mixture was filtered through a pad of celite bed the filtrate extracted with 10% MeOH/DCM. The combined organics were dried (Na2SO4) and concentrated under reduced pressure to afford methyl (1s,4s)-4-((4-amino-3- fluorophenyl)sulfonamido)cyclohexane-1-carboxylatethe title compound (6 g, 77%). LCMS m/z = 331 [M+H]+. Step 3. Synthesis of methyl (1r,4r)-4-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonamido)cyclohexane-1- carboxylate To a stirred solution of methyl (1r,4r)-4-((4-amino-3-fluorophenyl)sulfonamido)cyclohexane- 1-carboxylate (Step 2, 0.9 g, 2.72 mmol) and 1-(4-(2-chloro-5-(trifluoromethyl)pyrimidin-4- yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 1, 1.05 g, 3.27 mmol) in dioxane (10 mL) was added Cs2CO3 (2.66 g, 8.17 mmol) at rt . The reaction mixture was purged with N2 for 10 min and Pd(OAc)2 (183 mg, 0.82 mmol) and BINAP (509 mg, 0.82 mmol) were added at rt. The resulting mixture was stirred under Ar at 100 °C for 2 h in the microwave. After 2h the reaction mixture was quenched with cold water (150 mL) and extracted with EtOAc (3x 80 mL). The combined organics were washed with brine (50 mL), dried (Na2SO4) and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (SiO2, 35% EtOAc/PE) to afford the title compound as a brown solid (0.75 g, 45%). LCMS m/z = 615 [M+H]+. Step 4. Synthesis of 3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-N-((1r,4r)-4- (hydroxymethyl)cyclohexyl)benzenesulfonamide To a stirred solution of methyl (1r,4r)-4-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonamido)cyclohexane-1- carboxylate (Step 3, 3.0 g, 4.88 mmol) in THF (50 mL) was added LiAlH4 (14.6 mL, 9.76 mmol) at -5°C and the reaction mixture stirred at rt for 2 h. The reaction was quenched with saturated NH4Cl solution (250 mL) and extracted with EtOAc (2x 80 mL). The combined organics were dried (Na2SO4) and evaporated to dryness under reduced pressure to afford the title compound as a brown solid (2.7 g, 94%) which was used without further purification. LCMS m/z = 587 [M+H]+. Step 5. Synthesis of 3-fluoro-N-((1r,4r)-4-formylcyclohexyl)-4-((4-(1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide and 3-fluoro-N-((1s,4s)-4-formylcyclohexyl)-4-((4-(1-(2- hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide To a solution of methyl 4-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)- 5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonamido)cyclohexane-1-carboxylate (Step 4, 2.7 g, 4.60 mmol) in DCM (50 mL) was added DMP (3.90 g, 9.21 mmol) and the mixture stirred for 2 h. The reaction mixture filtered through celite bed and the filtrate evaporated to dryness under reduced pressure. The residue was purified by column chromatography (SiO2, 45% EtOAc/PE) to afford the title compounds as a 2:1 mixture of trans to cis isomers as a brown solid (900 mg, 33%). LCMS m/z = 585 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 10.10 (s, 1H), 9.50 (s, 1H), 9.49 (bs, 1H), 8.25 (s, 1H), 8.10-8.01 (m, 3H), 4.94 (s, 1H), 4.18 (s, 1H), 4.11 (s, 1H), 4.03-4.02 (s, 2H), 2.99-2.98 (s, 1H), 2.96-2.95 (m, 1H), 1.85-1.83 (m, 2H), 1.72-1.67 (m, 2H), 1.23-1.15 (s, 4H), 1.08 (s, 6H). Intermediate 15. (1r,4r)-4-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4- yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonamido)cyclohexane-1-carboxylic acid.
Figure imgf000131_0001
To a stirred solution of methyl (1r,4r)-4-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonamido)cyclohexane-1- carboxylate (Intermediate 14, Step 3, 350 mg, 0.57 mmol) in THF (8 mL) and H2O (2 mL) was added LiOH.H2O (119 mg, 2.85 mmol) at 0 °C and the reaction mixture stirred at rt for 4 h. The reaction mixture was neutralised with 1M HCl solution and extracted with EtOAc (3x 40 mL). The combined organics were evaporated to dryness to afford the title compound as a brown solid (300 mg, 88%). LCMS m/z = 601 [M+H]+. Intermediate 16. 3-(1-oxo-4-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)isoindolin-2- yl)piperidine-2,6-dione.
Figure imgf000132_0001
Step 1. Synthesis of tert-butyl 4-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)prop- 2-yn-1-yl)oxy)piperidine-1-carboxylate To a stirred solution of 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1.0 g, 3.10 mmol) and tert-butyl 4-(prop-2-yn-1-yloxy)piperidine-1-carboxylate (1.111 g, 4.64 mmol) in DMF (10 mL) was added cesium carbonate (2.521 g, 7.74 mmol) and the resulting solution purged with nitrogen gas for 15 min. To this was added dichlorobis (triphenylphosphine)palladium (217 mg, 0.31 mmol) and copper(I) iodide (118 mg, 0.62 mmol) under nitrogen and the resulting reaction mixture stirred at 70 °C for 16h. The reaction was quenched with cold water (30 mL) and extracted with EtOAc (3x 30 mL). The combined organics were washed with saturated ammonium chloride solution (2x 30 mL) and dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, EtOAc/PE) to afford the title compound as a brown solid (800 mg, 53%). LCMS m/z = 482 [M+H]+. Step 2. Synthesis of 3-(1-oxo-4-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)isoindolin-2- yl)piperidine-2,6-dione To a stirred solution of tert-butyl 4-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)prop-2-yn-1-yl)oxy)piperidine-1-carboxylate (Step 1, 500 mg, 1.038 mmol) in DCM (5 mL) at 0 ºC was added 4.0 M HCl in dioxane (2.5 mL) and the reaction mixture stirred at rt for 3h. The reaction mixture was evaporated to dryness under reduced pressure and the residue and diluted with cold water (30 mL) and washed with Et2O (3x 30 mL). The aqueous layer was treated with saturated sodium bicarbonate (50 mL) and extracted with 20% IPA/CHCl3 (3x 30 mL). The combined extracts were dried (Na2SO4) and evaporated to dryness under reduced pressure to afford the title compound as a brown solid (290 mg, 73%) as brown solid. LCMS m/z = 382 [M+H]+. Intermediate 17. 4-((2-(2-(2-azidoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione.
Figure imgf000133_0001
To a solution of 2-(2-(2-azidoethoxy)ethoxy)ethan-1-amine (0.35 g, 2.00 mmol) and 2-(2,6- dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (RSC Med Chem, 2021, 12, 1381-1390, 0.55 g, 2.00 mmol) in DMF (5 mL) was added DIPEA (0.54 mL, 3.01 mmol) at 25 °C and the reaction mixture stirred at 90 °C for 16 h. The reaction was quenched with water (15 mL) and extracted with EtOAc (3x 15 mL). The combined organics were dried (Na2SO), concentrated under reduced pressure and the residue purified using column chromatography (SiO2, 35% EtOAc/PE to afford the title compound as a yellow solid (0.22 g, 25%). LCMS m/z = 431 [M+H]+. Intermediate 18. 1-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)piperidine-4-carboxylic acid.
Figure imgf000133_0002
Step 1. Synthesis of tert-butyl 1-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol- 4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)piperidine-4-carboxylate To a stirred solution of tert-butyl 1-((4-amino-3-fluorophenyl)sulfonyl)piperidine-4- carboxylate (0.60 g, 1.67 mmol) and 2-amino-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol- 4-yl)pyrimidine-5-carbonitrile (Intermediate 107, 0.53 g, 1.67 mmol) in dioxane (6 mL) was added Cs2CO3 (1.63 g, 5.02 mmol) at rt. The reaction mixture was purged with nitrogen for 10 min and Pd(OAc)2 (0.037 g, 0.167 mmol) added and stirred under argon at 100 °C for 1 h in a microwave. The reaction mixture was quenched with cold water (100 mL) and extracted with EtOAc (3x 150 mL). The combined organics were washed with water (2x 150 mL), brine (150 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 30% EtOAc/PE) to afford the title compound as a brown liquid (400 mg, 37%). LCMS m/z = 643 [M+H]+. Step 2. Synthesis of 1-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)piperidine-4-carboxylic acid To a stirred solution of tert-butyl 1-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)piperidine-4- carboxylate (Step 1, 0.40 g, 0.62 mmol) in DCM (5 mL) was added TFA (2 mL) at 0 C and the reaction mixture stirred at rt for 4 h. The reaction mixture was concentrated under reduced pressure to afford the title compound as a brown solid (0.35 g, 95%). LCMS m/z = 587 [M+H]+. Intermediate 19. 4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-N-(2-(prop-2-yn-1-yloxy)ethyl)benzenesulfonamide.
Figure imgf000134_0001
Step 1. Synthesis of 4-nitro-N-(2-(prop-2-yn-1-yloxy)ethyl)benzenesulfonamide To a stirred solution of 2-(prop-2-yn-1-yloxy)ethan-1-amine (0.67 g, 6.77 mmol), 4- nitrobenzenesulfonyl chloride (1.50 g, 6.77 mmol) in DCM (2 mL) was added triethylamine (2.36 mL, 16.9 mmol) at rt and stirred for 2 h. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3x 30 mL). The combined organics were dried (Na2SO4), concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 13% EtOAc/PE) to afford the title compound as a pale yellow solid (0.50 g, 26%) as pale yellow solid. LCMS m/z = 283 [M+H]+. Step 2. Synthesis of 4-amino-N-(2-(prop-2-yn-1-yloxy)ethyl)benzenesulfonamide To a stirred solution of 4-nitro-N-(2-(prop-2-yn-1-yloxy)ethyl)benzenesulfonamide (Step 1, 0.50 g, 1.76 mmol) in ethanol (2.5 mL) and water (2.5 mL), were added Ammonium Chloride (1.882 g, 35.2 mmol), Iron Powder (1.964 g, 35.2 mmol) at rt and the reaction mixture heated at 80 ºC for 4 h. The mixture was cooled to rt, diluted with water (50 mL) and extracted with ethyl acetate (3x 50 mL). The combined organics were dried (Na2SO4), concentrated under reduced pressure to afford the title compound (0.40 g, 89%) which was used without further purification. LCMS m/z = 255 [M+H]+. Step 3. Synthesis of 4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-N-(2-(prop-2-yn-1-yloxy)ethyl)benzenesulfonamide To a stirred solution of 4-amino-N-(2-(prop-2-yn-1-yloxy)ethyl)benzenesulfonamide (Step 2, 0.250 g, 0.983 mmol) and 1-(4-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1- yl)-2-methylpropan-2-ol (Intermediate 1, 0.315 g, 0.983 mmol) in IPA (2 mL) was added 4- methylbenzenesulfonic acid (0.169 g, 0.983 mmol) and heated at 90 ºC for 16 h. The reaction mixture was diluted with water (2 mL) and extracted with ethyl acetate (3x 5 mL). The combined organics were dried (Na2SO4), concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 50% EtOAc/PE) to afford the title compound as a pale brown solid (0.18 g, 34%). LCMS m/z = 539 [M+H]+. Intermediate 20. 3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-3-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-N-(2-hydroxyethyl)-N-(prop-2-yn-1-
Figure imgf000135_0001
To a stirred solution of aminoethanol (2.50 g, 40.92 mmol) in DCM (50 mL) was added 3- fluoro-4-nitrobenzenesulfonyl chloride (10.78 g, 45.01 mmol) and triethylamine (11.4 mL, 81.9 mmol) at 0 °C and stirred for 1 h at rt. The reaction was quenched with water (50 mL) and extracted with DCM (3 x 40 mL). The combined organics were dried (Na2SO4), concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 45-50% EtOAc/PE) to afford the title compound (4.70 g, 43%) as a yellow solid. LCMS m/z = 263 [M-H]+ Step 2. Synthesis of 3-fluoro-N-(2-hydroxyethyl)-4-nitro-N-(prop-2-yn-1- yl)benzenesulfonamide To a stirred solution of 3-fluoro-N-(2-hydroxyethyl)-4-nitrobenzenesulfonamide (Step 1, 2.20 g, 8.33 mmol) and t-butylammonium bromide (0.537 g, 1.67 mmol) in THF (30 mL) were added propargyl bromide (1.25 mL, 16.7 mmol) and potassium hydroxide (0.561 g, 9.99 mmol) at rt and stirred for 16 h at rt. The reaction was quenched with water (20 mL) and extracted with EtOAc (3x 20 mL). The combined organic were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 35-40% EtOAc/PE) to afford the title compound as a yellow solid (1.4 g, 56%). LCMS m/z = 303 [M+H]+ Step 3. Synthesis of 4-amino-3-fluoro-N-(2-hydroxyethyl)-N-(prop-2-yn-1- yl)benzenesulfonamide To a stirred solution of 3-fluoro-N-(2-hydroxyethyl)-4-nitro-N-(prop-2-yn-1- yl)benzenesulfonamide (Step 2, 0.60 g, 1.98 mmol) in ethanol (20 mL) and water (20 mL) was added iron powder (2.21 g, 39.7 mmol) and ammonium chloride (2.12 g, 39.7 mmol) and the mixture stirred at 80 °C for 2 h. The reaction mixture was filtered through celite bed and washed with methanol. The filtrate was concentrated under reduced pressure to afford the title compound as an orange solid (0.50 g, 92%). LCMS m/z = 273 [M+H]+ Step 4. Synthesis of 3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-3-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-N-(2-hydroxyethyl)-N-(prop-2-yn-1- yl)benzenesulfonamide To the stirred solution of 4-amino-3-fluoro-N-(2-hydroxyethyl)-N-(prop-2-yn-1- yl)benzenesulfonamide (Step 3, 0.50 g, 1.84 mmol) in IPA (10 mL) were added 1-(3-(2- chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (0.59 g, 1.84 mmol) and 4-methylbenzenesulfonic acid (0.32 g, 1.84 mmol) and the resulting mixture stirred at 90 °C for 16 h. The reaction was quenched with water (10 mL) and extracted with EtOAc (3x 15 mL). The combined organics were dried (Na2SO4) and concentrated under reduced. The residue was purified by column chromatography (SiO2, 35-40% EtOAc/PE) to afford the title compound as a yellow solid (0.14 g, 13%). LCMS m/z = 557 [M+H]+ Intermediate 21. 3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-N-(2-(prop-2-yn-1-yloxy)ethyl)benzenesulfonamide.
Figure imgf000137_0001
Step 1: Synthesis of 3-fluoro-4-nitro-N-(2-(prop-2-yn-1-yloxy)ethyl)benzenesulfonamide. To a stirred solution of 2-(prop-2-yn-1-yloxy)ethan-1-amine hydrochloride (1.50 g, 11.06 mmol) and 3-fluoro-4-nitrobenzenesulfonyl chloride (3.98 g, 16.59 mmol) in DCM (7.5 mL) was added triethylamine (4 mL, 27.66 mmol) dropwise at 0 °C and the resulting reaction mixture stirred at rt for 1 h. The reaction mixture was quenched with water (20 mL) and extracted with DCM (3x 20 mL). The combined organics were washed with brine (40 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by combi-flash chromatography (SiO2, 20-30% EtOAc/PE) to afford the title compound as a semi-solid (2.2 g, 66%). 1H NMR (400 MHz, CDCl3): 8.21 (t, 1H), 7.86-7.81 (m, 2H), 5.07 (t, 1H), 4.13 (d, 2H), 3.61 (t, 2H), 3.31 (q, 2H), 2.48 (t, 1H). Step 2: Synthesis of 4-amino-3-fluoro-N-(2-(prop-2-yn-1-yloxy)ethyl)benzenesulfonamide Iron powder (16.3 g, 291 mmol) and ammonium chloride (15.6 g, 291 mmol) were added to a stirred solution of 3-fluoro-4-nitro-N-(2-(prop-2-yn-1-yloxy)ethyl)benzenesulfonamide (Step 1, 4.40 g, 14.6 mmol) in ethanol (22 mL) and water (22 mL) and stirred at 80 °C for 2 h. The reaction mixture was filtered through a pad of celite and washed with methanol (2x 30 mL). The filtrate was concentrated under reduced pressure and the remaining aqueous solution extracted with DCM (50 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as a brown gum (3.80 g, 96%). LCMS m/z = 273 [M+H]+ Step 3: Synthesis of 3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-N-(2-(prop-2-yn-1-yloxy)ethyl)benzenesulfonamide 1-(4-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 1, 0.46 g, 1.43 mmol) was added at room temperature to a stirred solution of 4- amino-3-fluoro-N-(2-(prop-2-yn-1-yloxy)ethyl)benzenesulfonamide (Step 2, 0.30 g, 1.10 mmol) and p-toluenesulfonic acid (0.21 g, 1.10 mmol) in IPA (3 mL) and the resulting mixture stirred at 90 °C for 16 h. The reaction mixture was evaporated under reduced pressure and the residue purified by combi-flash chromatography (SiO2, 30-40% EtOAc/PE) to afford the title compound as a yellow gum (0.29 g, 47%). LCMS m/z = 557 [M+H]+. Intermediate 22. 4-(9-(2-azidoethyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione.
Figure imgf000138_0001
Step 1. Synthesis of tert-butyl 9-(2-azidoethyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate To a stirred solution of tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (2.50 g, 9.83 mmol) in acetonitrile (25 mL) at rt was added sequentially 2-azidoethyl 4- methylbenzenesulfonate (2.85 mL, 11.79 mmol) and potassium carbonate (4.08 g, 29.5 mmol) and the resulting reaction mixture stirred for 18 h at 80 °C. The reaction was quenched with cold water (50 mL) and extracted with ethyl acetate (2x 50 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 25-30% EtOAc/PE) to afford the title compound as a yellow liquid (2.10 g, 66%). LCMS m/z = 324 [M+H]+. Step 2. Synthesis of 3-(2-azidoethyl)-3,9-diazaspiro[5.5]undecane To a stirred solution of tert-butyl 9-(2-azidoethyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (Step 1, 0.23 g, 0.65 mmol) in DCM (3 mL) was added 4N HCl in dioxane (2 mL) at 0 °C and the resulting mixture stirred for 1 h at rt. The reaction mixture was evaporated to dryness under reduced pressure and the residue was triturated with diethyl ether (5 mL) to afford the title compound as a brown liquid (0.18 g, 96%). 1H-NMR (400 MHz, DMSO-d6): 10.45 (br, 1H), 8.85 (br, 2H), 1.86 (m, 2H), 3.37-3.32 (m, 5H), 3.08-3.01 (m, 6H), 1.82-1.77 (m, 4H), 1.72-1.65 (m, 2H), 1.53-1.51 (m, 2H) Step 3. Synthesis of 4-(9-(2-azidoethyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione To a stirred solution of 3-(2-azidoethyl)-3,9-diazaspiro[5.5]undecane (Step 2, 0.48 g, 1.85 mmol) in DMSO (10 mL) at rt were added 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline- 1,3-dione (0.61 g, 2.22 mmol) and DIPEA (1.65 mL, 9.24 mmol) and the resulting reaction mixture stirred for 18 h at 120 °C. The reaction mixture was quenched with cold water (30 mL) and extracted with ethyl acetate (3x 30 mL). The combined organics were dried (Na2SO4), concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 70-80% EtOAc/PE) to afford the title compound as a yellow solid (0.60 g, 68%). LCMS m/z = 480 [M+H]+. Intermediate 23. 5-(1'-(2-azidoethyl)-[4,4'-bipiperidin]-1-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione.
Figure imgf000139_0001
Step 1. Synthesis of tert-butyl 1'-(2-azidoethyl)-[4,4'-bipiperidine]-1-carboxylate To a stirred solution of tert-butyl [4,4'-bipiperidine]-1-carboxylate (2.00 g ,7.45 mmol) and 2- azidoethyl 4-methylbenzenesulfonate (2.70 g, 11.2 mmol) in MeCN (20 mL) at room temperature was added potassium carbonate (3.09 g, 22.4 mmol) and the resulting mixture stirred at 80 °C for 16 h. The reaction mixture was diluted with water (80 mL) and extracted with ethyl acetate (3x 50 mL). The combined organics were dried (Na2SO4), concentrated under reduced pressure the residue purified by column chromatography (SiO2, 50-60% EtOAc/PE) to afford the title compound as a brown liquid (1.70 g, 68 %). LCMS m/z = 338 [M+H]+. Step 2. 1-(2-azidoethyl)-4,4'-bipiperidine hydrochloride (17b) To a stirred solution of tert-butyl 1'-(2-azidoethyl)-[4,4'-bipiperidine]-1-carboxylate (Step 1, 0.50 g, 1.48 mmol) in DCM (10 mL) was added 4.0 M HCl in dioxane (6 mL) dropwise at 0° C. After addition was completed the reaction mixture was allowed to stir at rt for 2 h. The reaction mixture was concentrated under reduced pressure and the residue triturated with diethyl ether and DCM to afford the title compound as an off-white solid (0.35 g, 87%). Step 3. Synthesis of 5-(1'-(2-azidoethyl)-[4,4'-bipiperidin]-1-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione (Intermediate 17) To a stirred solution of 1-(2-azidoethyl)-4,4'-bipiperidine hydrochloride (Step 2, 0.70 g, 2.58 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (0.66 g, 2.30 mmol) in DMSO (15 mL) was added DIPEA(1.42 mL 7.67 mmol) at rt under nitrogen atmosphere and the resulting mixture stirred at 120 °C for 16 h. The reaction mixture was quenched with cold water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organics were washed with water (2× 50 mL), brine (50 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 70-80% EtOAc/PE) to afford the title compound as a yellow solid (0.40 g, 32 %). LCMS m/z = 494 [M+H]+. Intermediate 24. 4-(1'-(2-azidoethyl)-[4,4'-bipiperidin]-1-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione.
Figure imgf000140_0001
To a stirred solution of 1-(2-azidoethyl)-4,4'-bipiperidine (0.11 g, 0.40 mmol) in DMSO (1.5 mL), were added 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (88.8 g, 0.32 mmol) and DIPEA (0.18 mL, 1.00 mmol) at rt and the resulting mixture stirred for 18 h at 120 °C. The reaction mixture was quenched with cold water (30 mL) and extracted with ethyl acetate (3x 30 mL). The combined organics were dried (Na2SO4), concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 2-8% MeOH/DCM) to afford the title compound as a yellow semi-solid (0.08 g, 40%). LCMS m/z = 494 [M+H]+. Intermediate 25. ((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)glycine.
Figure imgf000141_0001
Step 1. Synthesis of tert-butyl ((3-fluoro-4-nitrophenyl)sulfonyl)glycinate. A solution of tert-butyl glycinate (2.00 g, 15.3 mmol) and triethylamine (3.86 g, 38.2 mmol) in DCM (20 mL) was stirred for 15 min at rt and cooled to 0 °C before 3-fluoro-4- nitrobenzenesulfonyl chloride (5.48 g, 22.9 mmol) was added and stirring continued at 0 °C for 2 h. The reaction mixture was quenched with ice-cold water (20 mL) and extracted with DCM (3x 25 mL). The combined organics were dried (Na2SO4), concentrated under the reduced pressure and the residue purified by Biotage column chromatography (SiO2, 25-30% EtOAc/PE) to afford the title compound as a brown solid (4.00 g, 78%). LCMS m/z = 333 [M+H]+. Step 2: Synthesis of tert-butyl ((4-amino-3-fluorophenyl)sulfonyl)glycinate. To a stirred solution of tert-butyl ((3-fluoro-4-nitrophenyl)sulfonyl)glycinate (Step 1, 2.0 g, 5.98 mmol) in EtOH/H2O (1:1, 40 mL) were added ammonium chloride (6.4 g, 120 mmol) and Iron powder, (6.68 g, 120 mmol) at rt and the resulting reaction mixture stirred at 80 °C for 3 h. The reaction mixture was filtered through a pad of celite, washed with EtOH (2x 20 mL). The filtrate was concentrated under the reduced pressure to obtain the title compound (1.7 g, 93%). LCMS m/z = 303 [M+H]+. Step 3: Synthesis of tert-butyl ((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4- yl)-5-(trifluoromethyl)pyrimidin-2-yl) amino) phenyl) sulfonyl) glycinate. To a stirred solution of tert-butyl ((4-amino-3-fluorophenyl)sulfonyl)glycinate (Step 2, 0.80 g, 2.63 mmol), 1-(4-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2- methylpropan-2-ol (Intermediate 1, 0.67 g, 2.10 mmol) and BINAP (0.33 g, 0.53 mmol) in dioxane (8 mL) was added Cs2CO3 (2.57 g, 7.89 mmol) at rt and the mixture purged with argon for 15 min. Palladium(II) acetate, (0.24 g, 1.05 mmol) was added and again purged with nitrogen for 5 min and the reaction mixture stirred at 120 °C for 3 h under microwave irradiation. The reaction was quenched with ice-cold water (20 mL) and extracted with ethyl acetate (3x 15 mL). The combined organics were washed with water (2x 15 mL), brine (15 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 20-30% EtOAc/PE) to afford the title compound (0.30 g, 19%). LCMS m/z = 589 [M+H]+. Step 4: Synthesis of ((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)glycine. To a stirred solution of tert-butyl ((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl) amino) phenyl) sulfonyl) glycinate (Step 3, 0.3 g, 0.60 mmol) in DCM (3 mL) was added TFA (1.5 mL) at rt and the resulting reaction mixture was stirred for 2 h. The reaction mixture was concentrated under reduced pressure and the residue triturated with PE (20 mL) and further purified by flash chromatography (SiO2, 2-5% MeOH/DCM) to afford the title compound (0.3 g, 95%). LCMS m/z = 533 [M+H]+. Intermediate 26. 2-(2,6-dioxopiperidin-3-yl)-5-(4-(piperidin-4-ylmethyl)piperazin-1- yl)isoindoline-1,3-dione.
Figure imgf000142_0001
Step 1. Synthesis of tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)piperazin-1-yl)methyl)piperidine-1-carboxylate. To a stirred solution of tert-butyl 4-(piperazin-1-ylmethyl)piperidine-1-carboxylate (1.00 g, 3.53 mmol) and 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (1.17 g, 4.23 mmol) in DMSO (10 mL) was added DIPEA (1.37 g, 10.6 mmol) under inert atmosphere at rt and the resulting reaction mixture stirred at 90 °C for 16 h. The reaction mixture was quenched with ice-cold water (10 mL) and extracted with ethyl acetate (3x 15 mL). The combined organics were washed with water (2x 15 mL), brine (15 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by chromatography (SiO2, 10-40 % EtOAc/PE) to afford the title compound (1.2 g, 63%). LCMS m/z = 540 [M+H]+. Step 2. Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(4-(piperidin-4-ylmethyl)piperazin-1- yl)isoindoline-1,3-dione. To a stirred solution of tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)piperazin-1-yl)methyl)piperidine-1-carboxylate (Step 1, 1.20 g, 2.22 mmol) in DCM (12 mL) was added 4 M HCl in dioxane (4.8 mL) at rt and stirred for 2 h. The reaction mixture was concentrated under reduced pressure and the residue triturated with DCM (2 x10 mL) to afford the title compound as a pale yellow solid (1.00 g, 94%). LCMS m/z = 440 [M+H]+. Intermediate 27. 2-methyl-1-(4-(2-((1-((3-(prop-2-yn-1-yloxy)propyl)sulfonyl)piperidin-4- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propan-2-ol.
Figure imgf000143_0001
Step 1. Synthesis of tert-butyl (1-((3-chloropropyl)sulfonyl)piperidin-4-yl)carbamate 3-chloropropane-1-sulfonyl chloride (1.06 g, 5.99 mmol) was added to a stirred solution of tert-butyl piperidin-4-ylcarbamate (1.00 g, 4.99 mmol) and triethylamine (1.99 ml, 14.98 mmol) in DCM (20 mL) at -10 ºC under nitrogen. The reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with DCM (3x 50 mL). The combined organics were dried (Na2SO4), concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 15% EtOAc/PE) to afford the title compound as a white solid (1.50 g, 77%). LCMS m/z = 241 [M+H]+. Step 2. Synthesis of tert-butyl (1-((3-(prop-2-yn-1-yloxy)propyl)sulfonyl)piperidin-4- yl)carbamate Prop-2-yn-1-ol (0.32 g, 5.72 mmol) was added to a stirred solution of tert-butyl (1-((3- chloropropyl)sulfonyl)piperidin-4-yl)carbamate (Step 1, 1.30 g, 3.81 mmol) and Cs2CO3 (3.11 g, 9.53 mmol) in MeCN (10 mL) at rt under nitrogen atmosphere and the resulting mixture stirred at 80 °C for 16 h. The reaction mixture was quenched with cold water (50 mL) and extracted with ethyl acetate (3x 50 mL). The combined organics were washed with water (2x 50 mL), brine (50 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 27 % EtOAc/PE) to afford the title compound as a brown liquid (1.30 g, 94%). LCMS m/z = 305 [M+H]+. Step 3. Synthesis of 1-((3-(prop-2-yn-1-yloxy)propyl)sulfonyl)piperidin-4-amine hydrochloride (14c) To a stirred solution tert-butyl (1-((3-(prop-2-yn-1-yloxy)propyl)sulfonyl)piperidin-4- yl)carbamate (Step 2, 0.2 g, 0.56 mmol) in DCM (12 mL) was added 4.0 M HCl in dioxane (6 mL) drop-wise at 0° C. After addition was completed the reaction mixture was allowed to stir at rt for 2 h. The reaction mixture was concentrated under reduced pressure to obtain the title compound as a brown solid (150 mg, 91%). 1
Figure imgf000144_0001
NMR (400 MHz, DMSO-d6,): 8.03 (bs, 2H), 4.125 (d, 2H), 3.56-3.53 (m, 3H), 3.08-3.07 (m, 2H), 3.07-3.06 (m, 2H), 2.89-2.87 (m, 2H), 1.97-1.90 (m, 5H), 1.53-1.51 (m, 3H). Step 4. Synthesis of 2-methyl-1-(4-(2-((1-((3-(prop-2-yn-1-yloxy)propyl)sulfonyl)piperidin- 4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propan-2-ol. To a stirred solution of 1-((3-(prop-2-yn-1-yloxy)propyl)sulfonyl)piperidin-4-amine hydrochloride (Step 3, 0.30 g, 1.01 mmol) and 1-(4-(2-chloro-5-(trifluoromethyl)pyrimidin-4- yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 1, 389 mg, 1.21 mmol) in dioxane (3 mL) was added DIPEA (0.514 mg, 3.032 mmol) and heated at 90 ºC for 16 h. The mixture was diluted with water (2x 15 mL) and extracted with ethyl acetate (3x 15 mL). The combined organics were dried (Na2SO4), concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 25-30% EtOAc/PE) to afford the title compound as a brown liquid (0.30 g, 54%). LCMS m/z = 545 [M+H]+. Intermediate 28. 3-(4-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)phenyl)piperidine-2,6-dione.
Figure imgf000144_0002
Step 1. Synthesis of 2,6-bis(benzyloxy)-3-(4-nitrophenyl)pyridine. To a stirred solution of 2,6-bis(benzyloxy)-3-bromopyridine (5.0 g, 13.5 mmol), 4- nitrophenyl boronic acid (2.48 g, 14.9 mmol) in dioxane (100 mL) was added solution of potassium phosphate (5.73 g, 27 mmol) in H2O (10 mL) and degassed with argon for 20 min. To the resulting solution was added PdCl2(dppf). DCM (1.10 g, 1.35 mmol) and purged with argon for 2 min and the reaction mixture heated for 16 h at 110°C. The reaction mixture was filtered through a pad of celite and the filtrate concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL), washed with water (2x 50 mL) and brine (50 mL). The combined organics were evaporated under reduced pressure and the residue purified by chromatography (SiO2, 0-3 % EtOAc/PE) to afford the title compound as a yellow solid (4.7 g, 84%). LCMS m/z = 413 [M+H]+. Step 2. Synthesis of 3-(4-aminophenyl)piperidine-2,6-dione. A 100 mL steel pressure vessel was charged with 2,6-bis(benzyloxy)-3-(4- nitrophenyl)pyridine (Step 1, 9.4 g, 22.8 mmol) in EtOH (180 mL) and 10% Palladium on carbon (1.29 g) was added under a nitrogen atmosphere. The vessel was charged with H2 gas (50m psi) and heated at 55 ºC for 24 h. After completion of reaction, the reaction mixture was filtered through a pad of celite and washed with MeOH (200 mL). The combined organics were concentrated under reduced pressure and the residue triturated with Et2O (50 mL) to afford the title compound as a white solid (2.00 g, 81%). LCMS m/z = 205 [M+H]+. Step 3. Synthesis of 3-(4-iodophenyl)piperidine-2,6-dione. To the stirred solution of 3-(4-aminophenyl)piperidine-2,6-dione (Step 2, 2.50 g, 12.24 mmol) in water (40 mL) were added, at 0 ºC, sodium nitrate (2.53 g, 36.72 mmol) and sulfuric acid (3.27 mL, 61.2 mmol) and the resulting mixture stirred at rt for 20 min. To this was added KI (10.16 g, 61.2 mmol) in water (20 mL) and the reaction mixture stirred at 80 ºC for 3 h. The reaction mixture was extracted with ethyl acetate (3x 50 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 20-30% EtOAc/PE) to afford the title compound as a brown solid (1.90 g, 49%). 1H NMR (400 MHz, DMSO-d6,): 10.97 (s, 1H), 7.72 (d, 2H), 7.05 (d, 2H), 3.86-3.83 (m, 1H), 2.69-2.51 (m, 1H), 2.48-2.47 (m, 1H), 2.20-2.17 (m, 1H), 2.03-1.99 (m, 1H). Step 4. Synthesis of tert-butyl 4-((3-(4-(2,6-dioxopiperidin-3-yl)phenyl)prop-2-yn-1- yl)oxy)piperidine-1-carboxylate. 3-(4-iodophenyl)piperidine-2,6-dione (0.50 g, 1.58 mmol) and tert-butyl 4-(prop-2-yn-1- yloxy)piperidine-1-carboxylate (0.684 g, 2.56 mmol), Cs2CO3 (1.55 g, 4.76 mmol) in DMF (5 mL) was purged with N2 for 15 min. Pd(PPh3)2Cl2 (0.11 g, 0.15 mmol) and CuI (0.060 g, 0.32 mmol) were added under N2 and the mixture stirred at 70 °C for 4 h. The reaction was quenched with cold water (25 mL) and extracted with EtOAc (3x 25 mL). The combined organics were washed with brine (25 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by chromatography (SiO2, 40-50% EtOAc/PE) to afford the title compound as a brown solid (0.43 g, 63%). LCMS m/z = 371 [M-56]+. Step 5. Synthesis of 3-(4-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)phenyl)piperidine-2,6-dione hydrochloride. To a stirred solution of tert-butyl 4-((3-(4-(2,6-dioxopiperidin-3-yl)phenyl)prop-2-yn-1- yl)oxy)piperidine-1-carboxylate (Step 4, 1.0 g, 2.35 mmoL) in DCM (10.0 mL) was added 4.0 M HCl in dioxane (5 mL) at 0 °C and the reaction mixture stirred at rt for 4 h. The reaction mixture was evaporated to dryness and the residue quenched with saturated sodium bicarbonate (20 mL) and extracted with 20% IPA/CDCl3 (3x 20 mL). The combined organics were washed with brine (25 mL), dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as a brown solid (0.90 g). LCMS m/z = 327 [M+H]+. Intermediate 29. 1-(((1r,4r)-4-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol- 4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)phenyl)sulfonamido)cyclohexyl)methyl)piperidine-4-carboxylic acid.
Figure imgf000146_0001
Step 1. Synthesis of N-((1r,4r)-4-(bromomethyl)cyclohexyl)-3-fluoro-4- nitrobenzenesulfonamide. To a stirred solution of (1r,4r)-4-(bromomethyl)cyclohexan-1-amine hydrochloride (Intermediate 7, 1.00 g, 5.2 mmol) in DCM (60 mL) were added Et3N (2.25 mL, 15.60 mmol) and 3-fluoro-4-nitrobenzenesulfonyl chloride (1.50 g, 6.25 mmol) at 0 °C and the resulting reaction mixture stirred at 0 °C for 1 h. The reaction mixture was diluted with water (70 mL) and extracted with DCM (3x 50 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 20% EtOAc/PE) to afford the title compound as a brown solid (1.20 g, 58%). LCMS m/z = 394 [M+H]+. Step 2. Synthesis of 4-amino-N-((1r,4r)-4-(bromomethyl)cyclohexyl)-3- fluorobenzenesulfonamide. To a stirred solution of N-((1r,4r)-4-(bromomethyl)cyclohexyl)-3-fluoro-4- nitrobenzenesulfonamide (Step 1, 1.20 g, 3.03 mmol) in EtOH (50 mL) and water (50 mL) was added NH4Cl (3.24 g, 60.7 mmol) and iron powder (3.39 g, 60.7 mmol) at rt and the resulting reaction mixture stirred at 60 °C for 2 h. The reaction mixture was filtered through a pad of celite and the filtrate diluted with water (50 mL) and extracted with EtOAc (3x 50 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as a brown solid (1.00 g, 90%). LCMS m/z = 365 [M+H]+. Step 3. Synthesis of N-((1r,4r)-4-(bromomethyl)cyclohexyl)-3-fluoro-4-((4-(1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide. 4-methylbenzenesulfonic acid (2.55 g, 14.8 mmol) was added to a stirred solution of 4- amino-N-((1r,4r)-4-(bromomethyl)cyclohexyl)-3-fluorobenzenesulfonamide (Step 2, 1.80 g, 4.93 mmol) and 1-(4-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2- methylpropan-2-ol (Intermediate 1, 1.58 g, 4.93 mmol) in THF (20 mL) at rt and stirred at 90 °C for 16 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3x 40 mL). The combined organics were dried (Na2SO4), concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 20-30% EtOAc/PE) to afford the title compound as a white solid (1.70 g, 53%). LCMS m/z = 649 [M+H]+. Step 4. Synthesis of tert-butyl 1-(((1r,4r)-4-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)- 1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)phenyl)sulfonamido)cyclohexyl)methyl)piperidine-4-carboxylate. To a stirred solution of N-((1r,4r)-4-(bromomethyl)cyclohexyl)-3-fluoro-4-((4-(1-(2-hydroxy- 2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide (Step 3, 0.4 g, 0.62 mmol) in dioxane (40 mL) were added Cs2CO3 (0.40 g, 1.23 mmol), KI (0.05 g, 0.31 mmol), and tert-butyl piperidine-4-carboxylate hydrochloride (0.68 g, 3.08 mmol) at rt and the resulting mixture heated at 100 °C for 16 h. The reaction mixture was evaporated under reduced pressure and the residue diluted with water (50 mL) and extracted with EtOAc (3x 50 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure to afford a residue that was purified by column chromatography (SiO2, 24% EtOAc/PER) to afford the title compound as an off- white solid (0.30 g, 65%). LCMS m/z = 754 [M+H]+. Step 5. Synthesis of 1-(((1r,4r)-4-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)phenyl)sulfonamido)cyclohexyl)methyl)piperidine-4-carboxylic acid. TFA (2 mL) was added to a stirred solution of tert-butyl 1-(((1r,4r)-4-((3-fluoro-4-((4-(1-(2- hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)phenyl)sulfonamido)cyclohexyl)methyl)piperidine-4-carboxylate (0.30 g, 0.398 mmol) in DCM (2 mL) at 0 °C and stirred at rt for 4 h. The reaction mixture was concentrated under reduced pressure to afford the title compound as a brown liquid (0.20 g, 72%). LCMS m/z = 698 [M+H]+. Intermediate 30. 1-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)piperidine-4-carbaldehyde.
Figure imgf000148_0001
Step 1. Synthesis of 4-(1,3-dioxolan-2-yl)-1-((3-fluoro-4-nitrophenyl)sulfonyl)piperidine To a stirred solution of 4-(1,3-dioxolan-2-yl)piperidine (2 g,12.7 mmol) and 3-fluoro-4- nitrobenzenesulfonyl chloride (3.66 g, 15.3 mmol) in DCM (60 mL) was added trimethylamine (18.4 mL, 127 mmol) dropwise at 0 °C and the resulting reaction mixture stirred for 1 h at rt. The reaction mixture was quenched with water (60 mL) and extracted with DCM (3x 50 mL). The combined organics were washed with brine (60 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 20-25% EtOAc/PE) to give the title compound as a yellow solid (2.5 g, 54%). LCMS m/z = 361 [M+H]+. Step 2. Synthesis of 4-((4-(1,3-dioxolan-2-yl)piperidin-1-yl)sulfonyl)-2-fluoroaniline To a stirred solution of 4-(1,3-dioxolan-2-yl)-1-((3-fluoro-4-nitrophenyl)sulfonyl)piperidine (Step 2, 3 g, 5.23 mmol) in MeOH (80 mL) was added Palladium on carbon (0.84 g, 7.85 mmol) at rt and the mixture stirred under the atmosphere of H2 (120 PSI) for 6 h at rt. The reaction mixture was filtered through a pad of celite and washed with MeOH (3x 60 mL). The combined filtrate was concentrated under reduced pressure to afford the title compound as a yellow solid (2 g, 87%). LCMS m/z = 331 [M+H]+. Step 3. Synthesis of 1-(4-(2-((4-((4-(1,3-dioxolan-2-yl)piperidin-1-yl)sulfonyl)-2- fluorophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2- ol To a stirred solution of 4-((4-(1,3-dioxolan-2-yl)piperidin-1-yl)sulfonyl)-2-fluoroaniline (Step 2, 0.30 g, 0.91 mmol) and 1-(4-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H- pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 1, 0.23 g, 0.73 mmol) in dioxane (5 mL) was added Cs2CO3 (0.89 g , 2.72 mmol) at 0 °C and the mixture purged with argon for 15 min. To this was added at rt BINAP (0.06 g, 0.09 mmol) and Pd(OAc)2 (0.02 g, 0.09 mmol) and resulting mixture heated at 100 °C under microwave irradiation for 2 h. The reaction mixture was filtered through a pad of celite washed with EtOAc (3x 30 mL). The filtrate was diluted with water (60 mL) and extracted with EtOAc (2x 30 mL). The combined organics were washed with brine (60 mL), dried (Na2SO4) and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (SiO2, 40-50% EtOAc/PE) to afford the title compound as a white semi-solid (0.20 g, 36%). LCMS m/z = 615 [M+H]+. Step 4. Synthesis of 1-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)piperidine-4-carbaldehyde To a stirred solution of 1-(4-(2-((4-((4-(1,3-dioxolan-2-yl)piperidin-1-yl)sulfonyl)-2- fluorophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2- ol (Step 3, 0.70 g, 1.14 mmol) in DCM (15 mL) was added TFA (6 mL) at 0 °C and the resulting reaction mixture stirred for 18 h at rt. The reaction mixture was diluted with ice- cold saturated NaHCO3 (20 mL) and extracted with DCM (2x 30 mL). The combined organics were washed with water (30 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 40-50% EtOAc/PE) to afford the title compound as a brown solid (0.55 g, 85%). LCMS m/z = 571 [M+H]+. Intermediate 31. (1r,4r)-4-((4-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol- 4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonamido)piperidin-1- yl)methyl)cyclohexane-1-carboxylic acid.
Figure imgf000150_0001
Step 1. Synthesis of tert-butyl 4-((3-fluoro-4-nitrophenyl)sulfonamido)piperidine-1- carboxylate To a stirred solution of tert-butyl 4-aminopiperidine-1-carboxylate (4 g, 20.0 mmol) in DCM (20 mL) was added triethylamine (6.06 g, 59.9 mmol) at rt and cooled to 0 °C (solution A). Then a solution of 3-fluoro-4-nitrobenzenesulfonyl chloride (5.742 g, 23.966 mmol, 1.2 equiv.) in DCM (20 mL) (solution B) maintained at 0 °C was added to the solution A at 0 °C. The resulting reaction mixture was stirred at room temperature for 1 h. After completion of reaction, the reaction mixture was quenched with ice-cold water (20 mL) and extracted with DCM (3×50 mL). The combined organic layer was washed with saturated brine solution, dried over Na2SO4 and concentrated under reduced pressure to obtain the crude compound (5.20 g). The crude was purified by flash chromatography, using (100-200 mesh) silica and ethyl acetate in pet ether (50-60%) as eluent to afford 22a (4.20 g, 52.13%) as yellow solid. LCMS m/z = 348 [M+H]+. Step 2. Synthesis of tert-butyl 4-((4-amino-3-fluorophenyl)sulfonamido)piperidine-1- carboxylate 10% Palladium on activated carbon, (3.20 g) was added to a solution of tert-Butyl 4-((3- fluoro-4-nitrophenyl)sulfonamido)piperidine-1-carboxylate (Step 1, 4.0 g, 9.91 mmol) in methanol (60 mL) at rt and reaction mixture was stirred at rt under H2 atmosphere (15 PSI) for 4 h. The reaction mixture was filtered through a celite bed and washed with 30% MeOH in DCM (2x 100 mL). The combined organics were concentrated under reduced pressure to afford the title compound as a brown solid (3.5 g, 94%). LCMS m/z = 372 [M+H]+. Step 3. Synthesis of tert-butyl 4-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonamido)piperidine-1- carboxylate To a stirred solution of tert-butyl 4-((4-amino-3-fluorophenyl)sulfonamido)piperidine-1- carboxylate (Step 2, 2.0 g, 5.36 mmol) and 1-(4-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)- 1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 1, 2.58 g, 8.03 mmol) in THF (20 mL) was added p-toluene sulfonic acid monohydrate (1.12 g, 5.89 mmol) at rt and the mixture stirred at 100 °C for 16 h. After completion of the reaction the reaction mixture was diluted with water (50 mL) and extracted with 20% MeOH in DCM (3x 50 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as a brown solid (1.50 g; 40%). LCMS m/z = 558 [M-100]+. Step 4. Synthesis of 3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-N-(piperidin-4-yl)benzenesulfonamide A solution of tert-butyl 4-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)- 5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonamido)piperidine-1-carboxylate (Step 3, 3.0 g, 4.56 mmol) and formic acid (30 mL) was stirred at 0 °C for 3 h. The reaction mixture was concentrated under reduced pressure and the residue diluted with saturated NaHCO3 solution and extracted with 20% IPA/CHCl3 (2100 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as a brown solid (2.50 g, 98%). LCMS m/z = 558 [M+H]+. Step 5. Synthesis of methyl (1r,4r)-4-((4-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)- 1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonamido)piperidin-1- yl)methyl)cyclohexane-1-carboxylate To a stirred solution of 3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-N-(piperidin-4-yl)benzenesulfonamide (Ste p4, 1.00 g, 1.79 mmol) and methyl (1r,4r)-4-formylcyclohexane-1-carboxylate (0.46 g, 2.69 mmol) in MeOH (10 ml), was added acetic acid (0.01 mL, 0.18 mmol) and MP-Cyanoborohydride (1.00 g) portion wise at room temperature and stirred at rt for 16 h. The reaction mixture was filtered through celite bed and washed with MeOH (2x 20 mL). The filtrate was concentrated under reduced pressure and the residue purified by column chromatography (15% MeOH/DCM) to afford the title compound as a pale brown solid (1.0 g, 78% ). LCMS m/z = 712 [M+H]+. Step 6. Synthesis of (1r,4r)-4-((4-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonamido)piperidin-1- yl)methyl)cyclohexane-1-carboxylic acid To a stirred solution of methyl (1r,4r)-4-((4-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)- 1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonamido)piperidin-1- yl)methyl)cyclohexane-1-carboxylate (Step 5, 0.60 g, 0.84 mmol) in THF (7 mL) and water (7 mL) was added lithium hydroxide (0.14 g, 5.90 mmol) portion wise at rt and the resulting reaction mixture stirred at the same temperature for 4 h. The reaction mixture was washed with diethyl ether (3x 20 mL). Then the aqueous layer was acidified to pH 5 with 1N HCl and extracted with 20% IPA/CHCl3) (3x 100 mL). The combined organics were washed with saturated brine solution (50 mL), dried (Na2SO4) and concentrated in vacuo to afford the title compound as a pale brown solid (0.50 g; 85%). LCMS m/z = 698 [M+H]+. Intermediate 32.3-(4-([4,4'-bipiperidin]-1-yl)phenyl)piperidine-2 dione.
Figure imgf000152_0001
Figure imgf000152_0002
Step 1. Synthesis of tert-butyl 1'-(4-bromophenyl)-[4,4'-bipiperidine]-1-carboxylate. To a stirred solution of tert-butyl [4,4'-bipiperidine]-1-carboxylate (3.00 g, 11.18 mmol) in DCM (60 mL) were added (4-bromophenyl)boronic acid (2.25 g, 11.18 mmol) followed by TEA (4.65 mL, 33.53 mmol) at rt. The reaction mixture was degassed with O2 gas for 15 min and copper (II) acetate (0.81 g, 4.47 mmol) added and stirred at rt for 16 h. The reaction mixture was diluted with water (150 mL) and filtered through a pad of celite and washed with DCM (2x 200 mL). The combined organics were dried (Na2SO4) and concentrated under the reduced pressure. The residue was purified by chromatography (SiO2, 10-50% EtOAc/PE) to afford the title compound as a white solid (3.50 g, 74%). LCMS m/z = 423 [M+H]+. Step 2. Synthesis of tert-butyl 1'-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-[4,4'- bipiperidine]-1-carboxylate To a stirred solution of tert-butyl 1'-(4-bromophenyl)-[4,4'-bipiperidine]-1-carboxylate (Step 1, 3.50 g, 8.27 mmol) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine (5.18 g, 12.40 mmol) in dioxane/water (55 mL, 10:1) was added potassium phosphate (4.39 g, 20.67 mmol). The reaction mixture was purged with Ar for 20 minute and PdCl2(dppf).DCM (0.34 g, 0.41 mmol) added and the resulting reaction mixture stirred for 3 h at 110 °C. The reaction mixture was filtered through a pad of celite and washed with EtOAc (3x 50 mL). The filtrate was washed with water (4x 100 mL), brine (2x 100 mL), dried (Na2SO4) and evaporated to dryness. The residue was purified by chromatography (SiO2, 0-20% EtOAc/PE) to afford the title compound as an off-white solid (2.50 g, 48%). LCMS m/z = 634 [M+H]+. Step 3. Synthesis of tert-butyl 1'-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[4,4'-bipiperidine]-1- carboxylate To a suspension of tert-butyl 1'-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-[4,4'- bipiperidine]-1-carboxylate (Step 2, 2.50 g, 3.94 mmol) in ethanol (50 mL) was added 10% Palladium on activated carbon (2.50 g) and the reaction mixture stirred at rt under H2 (120 psi) atmosphere for 48 h. The reaction mixture was filtered through a pad of celite and washed with methanol (4x 100 mL). The filtrate was concentrated under reduced pressure and the residue triturated with Et2O to afford the title compound as a white solid (1.00 g, 56%). LCMS m/z = 456 [M+H]+. Step 4. Synthesis of 3-(4-([4,4'-bipiperidin]-1-yl)phenyl)piperidine-2,6-dione To a stirred solution of tert-butyl 1'-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[4,4'-bipiperidine]-1- carboxylate (Step 3, 1.00 g, 2.19 mmol) in DCM (10 mL) was added 4N HCl in dioxane (5 mL) dropwise at rt and stirred for 3h. The reaction mixture was evaporated to dryness under the reduced pressure and the residue diluted with saturated solution of aqueous sodium bicarbonate (25 mL) and extracted with 10% IPA/CHCl3. The combined organics were combined, dried (Na2SO4) and evaporated to dryness to afford the title compound as an off- white solid (700 mg, 90%). LCMS m/z = 356 [M+H]+. Intermediate 33. 3-(3-([4,4'-bipiperidin]-1-yl)phenyl)piperidine-2,6-dione.
Figure imgf000154_0001
The title compound was prepared as a pale yellow liquid (900 mg) from (3- bromophenyl)boronic acid and tert-butyl [4,4'-bipiperidine]-1-carboxylate using an analogous 3-Step procedure as described for Intermediate 32. LCMS m/z = 356 [M+H]+. Intermediate 34. 3-(3-(3-((1-((1-((4-aminopiperidin-1-yl)sulfonyl)piperidin-4- yl)methyl)piperidin-4-yl)oxy)prop-1-yn-1-yl)phenyl)piperidine-2,6-dione.
Figure imgf000154_0002
Step 1. Synthesis of tert-butyl (1-((4-(iodomethyl)piperidin-1-yl)sulfonyl)piperidin-4- yl)carbamate To a stirred solution of 4-(iodomethyl)piperidine (6.00 g, 26.7 mmol) in DCM (60 mL) was added triethylamine (11.2 mL, 80 mmol) and tert-butyl (1-(chlorosulfonyl)piperidin-4- yl)carbamate (Intermediate 39, 7.96 g, 26.7 mmol) at 0 °C under nitrogen atmosphere and the reaction mixture stirred at rt for 3 h. The reaction mixture was quenched with water (100 mL) and extracted with DCM (3x 100 mL). The combined organics were dried (Na2SO4), concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 35-45% EtOAc/PE) to afford the title compound as a white solid (5.00 g, 38%). LCMS m/z = 488 [M+H]+. Step 2. Synthesis of tert-butyl (1-((4-((4-((3-(3-(2,6-dioxopiperidin-3-yl)phenyl)prop-2-yn-1- yl)oxy)piperidin-1-yl)methyl)piperidin-1-yl)sulfonyl)piperidin-4-yl)carbamate To a stirred solution of 3-(3-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)phenyl)piperidine-2,6- dione (0.5 g, 1.53 mmol) in dioxane (5 mL) was added DIPEA (0.82 mL, 4.60 mmol) and tert-butyl (1-((4-(iodomethyl)piperidin-1-yl)sulfonyl)piperidin-4-yl)carbamate (Step 1, 1.12 g, 2.30 mmol) and the reaction mixture stirred at 100 °C for 16 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3x 30 mL). The combined organics were washed with brine (30 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 4-5% MeOH/DCM) to afford the title compound as a brown oil (0.80 g, 76%). LCMS m/z = 686 [M+H]+. Step 3. Synthesis of 3-(3-(3-((1-((1-((4-aminopiperidin-1-yl)sulfonyl)piperidin-4- yl)methyl)piperidin-4-yl)oxy)prop-1-yn-1-yl)phenyl)piperidine-2,6-dione hydrochloride 4M HCl in 1,4-dioxane (4 mL) was added to a stirred solution of tert-butyl (1-((4-((4-((3-(3- (2,6-dioxopiperidin-3-yl)phenyl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)piperidin-1- yl)sulfonyl)piperidin-4-yl)carbamate (Step 2, 0.89 g, 1.30 mmol) in DCM (4 mL) at 0 °C and the reaction mixture stirred for 2 h at rt. The reaction mixture was evaporated under reduced pressure and the residue triturated with Et2O (5 mL) to afford the title compound as a brown solid (0.80 g, 98%). LCMS m/z = 586 [M+H]+. Intermediate 35. 4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)piperidine-1-sulfonyl chloride.
Figure imgf000156_0001
Step 1. Synthesis of Synthesis of 2-chloro-4-(1-methyl-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidine A mixture of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (3 g, 13.8 mmol), 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.87 g, 13.8 mmol), Pd(dppf)Cl2 (112 mg, 0.138 mmol), K2CO3 (1.90 g, 13.8 mmol) in dioxane (30 mL) and water (8 mL) was stirred at 50 °C for 3 h. The reaction mixture was evaporated to dryness and the residue purified on silica gel column (25% EtOAc/PE) to afford the title compound as a white solid (1.5 g, 41%). LCMS m/z = 263 [M+H]+; Step 2. Synthesis of tert-butyl 4-((4-(1-methyl-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate A solution of 2-chloro-4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine (Step 1, 1.5 g, 5.71 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (1.48 g, 7.42 mmol), DIPEA (1.10 g, 8.56 mmol) in IPA (30 mL) was stirred at 80 °C for 3 h. The reaction mixture was evaporated to dryness under reduced pressure and the residue purified by column chromatography (SiO2, 5% MeOH/DCM) to afford the title compound as a colourless oil (2.2 g, 90%). LCMS m/z = 427 [M+H]+. Step 3. Synthesis of 4-(1-methyl-1H-pyrazol-4-yl)-N-(piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine To a solution of tert-butyl 4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)piperidine-1-carboxylate (Step 2, 2.2 g, 5.15 mmol) in DCM (20 mL) was added TFA (8 mL) and the reaction mixture stirred at rt for 2 h and evaporated to dryness under reduced pressure. The residue was diluted with DCM. Washed with sat. Na2CO3. The organic layer was separated and dried over Na2SO4. Filtered and concentrated to dryness to afford title compound (1.2 g, yield=71.4%) as a light-yellow oil. LCMS m/z = 327 [M+H]+. Step 4. Synthesis of 4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)piperidine-1-sulfonyl chloride To a solution of 4-(1-methyl-1H-pyrazol-4-yl)-N-(piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine (Step 3, 300 mg, 0.919 mmol) and TEA (371 mg, 3.67 mmol) in DCE (6 mL) was added sulfuroyl dichloride (371 mg, 2.75 mmol) at 0oC and then at 50oC for 16 h. The reaction mixture was quenched with water and extracted with DCM. The combined organics was dried (Na2SO4) and concentrated to dryness to afford title compound as a yellow solid (300 mg, 77%). LCMS m/z = 425 [M+H]+. Intermediate 36. 3-(1-oxo-5-(4-(piperazin-1-ylmethyl)piperidin-1-yl)isoindolin-2- yl)piperidine-2,6-dione.
Figure imgf000157_0001
Step 1: Synthesis of tert-butyl 4-((1-((benzyloxy)carbonyl)piperidin-4-yl)methyl)piperazine- 1-carboxylate. To a solution of benzyl 4-formylpiperidine-1-carboxylate (20 g, 80.9 mmol) and tert-butyl piperazine-1-carboxylate (15.06 g, 80.9 mmol) in DCM (400 mL) was added NaBH(OAc)3 (34.28 g, 162 mmol) and HOAc (5.83 g, 97.1 mmol) and the mixture stirred at 20 °C for 4 h. The reaction mixture was concentrated under reduced pressure and the residue diluted with H2O (300 mL) and extracted with EtOAc (3x 300 mL). The combined organics were washed with brine (2x 150 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 0-40% THF/PE) to afford the title compound as a white solid (33.1 g, 93%). LCMS m/z = 418 [M+H]+. Step 2. Synthesis of tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate. A mixture of tert-butyl 4-((1-((benzyloxy)carbonyl)piperidin-4-yl)methyl)piperazine-1- carboxylate (Step 1, 33 g, 79.03 mmol) and Pd/C (4.21 g, 3.95 mmol, 10% purity) in IPA (400 mL) was degassed and purged with H2 (3x) and the mixture stirred at 25 °C for 10 h under H2. The mixture was filtered and concentrated under reduced pressure to give the title compound as a white solid (21 g, 85%). 1H NMR (400MHz, DMSO-d6): 4.53 (br s, 2H), 3.34-3.22 (m, 4H), 2.94 (br d, 2H), 2.48-2.43 (m, 1H), 2.25 (br t, 4H), 2.08 (br d, 2H), 1.67- 1.53 (m, 3H), 1.38 (s, 9H), 1.05-0.96 (m, 2H). Step 3. Synthesis of tert-butyl 4-((1-(1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-4- yl)methyl)piperazine-1-carboxylate. A mixture of 5-bromoisobenzofuran-1(3H)-one (17.5 g, 82.15 mmol), tert-butyl 4-(piperidin- 4-ylmethyl)piperazine-1-carboxylate (Step 2, 20.95 g, 73.93 mmol), Pd2(dba)3 (3.76 g, 4.11 mmol), Xantphos (2.85 g, 4.93 mmol) and K3PO4 (17.44 g, 82.15 mmol) and tri-tert- butylphosphonium tetrafluoroborate (1.19 g, 4.11 mmol, 0.05 equiv.) in dioxane (400 mL) was degassed and purged with N2 (3x) and the mixture stirred at 100 °C for 18 h under N2. The reaction mixture was concentrated under reduced pressure and the residue diluted with H2O (300 mL) and extracted with DCM (3x 300 mL). The combined organics were washed with brine (2x 250 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 0-10% MeOH/DCM) to afford the title compound as a yellow solid (13 g, 37%). LCMS m/z = 416 [M+H]+. Step 4. Synthesis of 4-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)piperidin-1-yl)-2- (hydroxymethyl)benzoic acid. To a solution of tert-butyl 4-((1-(1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-4- yl)methyl)piperazine-1-carboxylate (Step 3, 13 g, 31.28 mmol) in MeOH (90 mL) and H2O (30 mL) was added NaOH (5.01 g, 125 mmol) and the mixture stirred at 50 °C for 3h. The reaction mixture was concentrated under reduced pressure, the pH adjusted to 3-4 with aqueous HCl (2M) and extracted with EtOAc (3x 150 mL). The combined organic layers were washed with H2O (2x 150 mL), dried (Na2SO4) and concentrated under reduced to afford the title compound as a yellow solid (12 g, 82%) which was used without further purification. Step 5. Synthesis of tert-butyl 4-((1-(3-(hydroxymethyl)-4- (methoxycarbonyl)phenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate. To a solution of 4-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)piperidin-1-yl)-2- (hydroxymethyl)benzoic acid (Step 4, 13 g, 29.98 mmol) in MeOH (50 mL) and EtOAc (50 mL) was added trimethylsilyldiazomethane (2 M, 22.5 mL) and the mixture stirred at -10 °C for 10 min. The reaction mixture was concentrated under reduced pressure and the residue diluted with H2O (100 mL) and extracted with EtOAc (3x 100 mL). The combined organics were washed with brine (2x 100 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 0-40% THF/PE) to give the title compound as a yellow solid (12.5 g, 80%). Step 6. Synthesis of tert-butyl 4-((1-(3-formyl-4-(methoxycarbonyl)phenyl)piperidin-4- yl)methyl)piperazine-1-carboxylate. To a solution of tert-butyl 4-((1-(3-(hydroxymethyl)-4-(methoxycarbonyl)phenyl)piperidin-4- yl)methyl)piperazine-1-carboxylate (Step 5, 12.5 g, 28 mmol) in DCM (130 mL) were added NaHCO3 (2.35 g, 28 mmol, 1.09 mL) and Dess-Martin (10.98 g, 25.9 mmol, 8.01 mL) and the mixture stirred at 0 °C for 1h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography (SiO2, 0-50% THF/PE) to afford the title compound as a yellow oil (7.95 g, 69%). Step 7. Synthesis of tert-butyl 4-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)piperidin-4-yl)methyl)piperazine-1-carboxylate. To a solution of tert-butyl 4-((1-(3-formyl-4-(methoxycarbonyl)phenyl)piperidin-4- yl)methyl)piperazine-1-carboxylate (6.4 g, 14.36 mmol) and 3-aminopiperidine-2,6-dione (3.78g, 23.0 mmol) and NaOAc (3.54 g, 43.1 mmol) in MeOH (40 mL) was added NaBH3CN (1.35 g, 21.5 mmol) and the mixture was stirred at 20-40 °C for 10 h. The reaction mixture was concentrated under reduced pressure and the residue purified by flash chromatography (SiO2, 0-10% MeOH/DCM) to afford the title compound was a white solid (3.5 g, 49%). Step 8. Synthesis of 3-(1-oxo-5-(4-(piperazin-1-ylmethyl)piperidin-1-yl)isoindolin-2- yl)piperidine-2,6-dione trifluoroacetate. A solution of tert-butyl 4-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-4- yl)methyl)piperazine-1-carboxylate (3.2 g, 5.97 mmol) in DCM (21 mL) and TFA (7 mL) was stirred at 0 °C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound as a white solid (2.8 g, 85%). LCMS m/z = 426 [M+H]+. Intermediate 37. 3-(1-oxo-4-(7-(piperidin-4-ylmethyl)-2,7-diazaspiro[3.5]nonan-2- yl)isoindolin-2-yl)piperidine-2,6-dione.
Figure imgf000160_0001
Step 1. Synthesis of tert-butyl 2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2,7- diazaspiro[3.5]nonane-7-carboxylate A mixture of 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1 g, 3.09 mmol), tert- butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (488 mg, 2.16 mmol), Pd-PEPPSI-IHeptCl 3- chloropyridine (120 mg, 123 µmol), Cs2CO3 (3 g, 9.26 mmol) in dioxane (40 mL) was stirred at 100 ℃ for 3 h. The reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was purified using column chromatography to afford title compound as a yellow solid (700 mg, 69%). LCMS m/z = 469 [M+H]+. Step 2. Synthesis of 3-(1-oxo-4-(2,7-diazaspiro[3.5]nonan-2-yl)isoindolin-2-yl)piperidine- 2,6-dione To a solution of tert-butyl 2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2,7- diazaspiro[3.5]nonane-7-carboxylate (700 mg, 1.49 mmol) in DCM (20 mL) was added TFA (8 mL) and stirred at 25 ℃ for 5 h. The reaction mixture was evaporated to dryness and the residue diluted with MTBE (20 mL) and the solid collected by filtration to afford title compound as an off-white solid (650 mg, TFA salt). LCMS m/z = 369 [M+H]+. Step 3. Synthesis of tert-butyl 4-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2,7- diazaspiro[3.5]nonan-7-yl)methyl)piperidine-1-carboxylate To a solution 3-(1-oxo-4-(2,7-diazaspiro[3.5]nonan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (250 mg, 678 µmol), tert-butyl 4-formylpiperidine-1-carboxylate (287 mg, 1.35 mmol), DIPEA (350 mg, 2.71 mmol) in DCM (12 mL) was added STAB (430 mg, 2.03 mmol) and the mixture stirred at 25 ℃ for 3 h. The reaction was quenched with water, evaporated to dryness and the residue purified by prep-TLC (25/1 DCM/MeOH) to afford title compound as a yellow solid (300 mg, 78%). LCMS m/z = 566 [M+H]+. Step 4. Synthesis of 3-(1-oxo-4-(7-(piperidin-4-ylmethyl)-2,7-diazaspiro[3.5]nonan-2- yl)isoindolin-2-yl)piperidine-2,6-dione To a solution of tert-butyl 4-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2,7- diazaspiro[3.5]nonan-7-yl)methyl)piperidine-1-carboxylate (300 mg, 530 µmol) in DCM (8 mL) was added TFA (3 mL). Stirred at 25℃ for 3 h. Concentrated to dryness. The residue was diluted with MTBE (10 mL). Filtered. The solid was dried in vacuum to afford title compound (200 mg, TFA salt) as an off-white solid. LCMS m/z = 466 [M+H]+. Intermediate 38. 4-((4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)piperidin-1- yl)methyl)cyclohexane-1-carboxylic acid.
Figure imgf000161_0001
Step 1. Synthesis of tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oxy)piperidine-1-carboxylate To a solution of 3-(4-hydroxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione (2 g, 7.68 mmol) and tert-butyl 4-(methanesulfonyloxy)piperidine-1-carboxylate (4.27 g, 15.3 mmol) in DMF (20 mL) was added t-BuOK (1.71 g, 15.3 mmol) and the mixture stirred at 100 ºC for 3 h. The reaction mixture was evaporated to dryness and the residue purified by column chromatography (SiO2, 5% MeOH/DCM) to afford the title compound as a light brown solid (1.2 g, 35%). LCMS m/z = 444 [M+H]+. Step 2. Synthesis of 3-(1-oxo-4-(piperidin-4-yloxy)isoindolin-2-yl)piperidine-2,6-dione trifluoroacetate To a solution of tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oxy)piperidine-1-carboxylate (Step 1, 1.2 g, 2.70 mmol) in DCM (15 mL) was added TFA (8 mL) and the mixture stirred at 25 ºC for 2 h. The reaction mixture was evaporated to dryness and the residue diluted with MTBE (30 mL). The solid was collected by filtration to afford the title compound as an off-white solid (1.1 g, TFA salt). LCMS m/z = 344 [M+H]+. Intermediate 39. tert-butyl (1-(chlorosulfonyl)piperidin-4-yl)carbamate.
Figure imgf000162_0001
To a solution of tert-butyl N-(piperidin-4-yl)carbamate (300 mg, 1.49 mmol) and TEA (452 mg, 4.47 mmol) in DCM (10 mL) was added SO2Cl2 (402 mg, 2.98 mmol) dropwise at 0°C and the reaction mixture was stirred at 25 °C for 3 h. The reaction mixture was washed with water and the combined organics evaporated to dryness to afford the title compound as an off-white solid (300 mg, crude) which was used without further purification. Intermediate 40. 3-(4-((1-((1-((4-aminopiperidin-1-yl)sulfonyl)piperidin-4- yl)methyl)piperidin-4-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione.
Figure imgf000162_0002
Step 1. Synthesis of tert-butyl 4-((4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oxy)piperidin-1-yl)methyl)piperidine-1-carboxylate To a solution of 3-(1-oxo-4-(piperidin-4-yloxy)isoindolin-2-yl)piperidine-2,6-dione (Intermediate 38, 800 mg, 2.32 mmol), tert-butyl 4-formylpiperidine-1-carboxylate (989 mg, 4.64 mmol), DIPEA (1.19 g, 9.28 mmol) in DCM (20 mL) was added STAB (1.96 g, 9.28 mmol) at 0 ºC and the reaction mixture stirred at 25 ºC for 3 h. The reaction mixture was diluted with water, evaporated to dryness and the residue purified by column chromatography (SiO2, 10% MeOH/DCM) to afford the title compound as a light brown solid (750 mg, 60%). LCMS m/z = 541 [M+H]+. Step 2. Synthesis of 3-(1-oxo-4-((1-(piperidin-4-ylmethyl)piperidin-4-yl)oxy)isoindolin-2- yl)piperidine-2,6-dione trifluoroacetate To a solution of tert-butyl 4-((4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oxy)piperidin-1-yl)methyl)piperidine-1-carboxylate (Step 1, 750 mg, 1.38 mmol) in DCM (10 mL) was added TFA (4 mL) and stirred at 25 ºC for 2 h. The reaction mixture was evaporated to dryness and the residue triturated with MTBE (15 mL). The solid was collected by filtration to afford the title compound as a light brown solid (600 mg) which was used without further purification. LCMS m/z = 441 [M+H]+. Step 3. Synthesis of tert-butyl (1-((4-((4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oxy)piperidin-1-yl)methyl)piperidin-1-yl)sulfonyl)piperidin-4-yl)carbamate To a solution of 3-(1-oxo-4-((1-(piperidin-4-ylmethyl)piperidin-4-yl)oxy)isoindolin-2- yl)piperidine-2,6-dione trifluoroacetate (Step 2, 200 mg, 0.45 mmol), tert-butyl (1- (chlorosulfonyl)piperidin-4-yl)carbamate (Intermediate 39, 200 mg, crude) in MeCN (15 mL) was added TEA (136 mg, 1.35 mmol) and stirred at 50°C for 16 h. The solution was concentrated to dryness and the residue was purified on prep-TLC (20:1 DCMMeOH) to afford the title compound as an off-white solid (200 mg, 63%). LCMS m/z = 703 [M+H]+. Step 4. Synthesis of 3-(4-((1-((1-((4-aminopiperidin-1-yl)sulfonyl)piperidin-4- yl)methyl)piperidin-4-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione trifluoroacetate To a solution of tert-butyl (1-((4-((4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oxy)piperidin-1-yl)methyl)piperidin-1-yl)sulfonyl)piperidin-4-yl)carbamate (Step 3, 200 mg, 0.284 mmol) in DCM (8 mL) was added TFA (3 mL) and stirred at 25 ºC for 1 h. The reaction mixture was evaporated to dryness and the residue triturated with MTBE (10 mL). The solid was collected by filtration to afford the title compound as a white solid (100 mg). LCMS m/z = 603 [M+H]+. Intermediate 41. 1-((1r,4r)-4-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol- 4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonamido)cyclohexane-1- carbonyl)piperidine-4-carboxylic acid.
Figure imgf000164_0001
Step 1. Synthesis of ethyl 1-((1r,4r)-4-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonamido)cyclohexane-1- carbonyl)piperidine-4-carboxylate. HATU (80.17 mg, 0.21 mmol) was added to a stirred solution of (1r,4r)-4-((3-fluoro-4-((4-(1- (2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)phenyl)sulfonamido)cyclohexane-1-carboxylic acid (Intermediate 15, 150 mg, 0.250 mmol), DIPEA (0.13 mL, 0.75 mmol) and ethyl piperidine-4-carboxylate (39.3 mg, 0.250 mmol) in dry DMF (3 mL) 0 °C and the reaction mixture warmed to rt and stirred for 16 h. The reaction mixture was quenched with cold water (10 mL) and extracted with ethyl acetate (3x 15 mL). The combined organics were washed with water (2x 15 mL), brine (15 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (0-3% MeOH/DCM) to afford the title compound as an off-white solid (100 mg, 82%). LCMS m/z = 740 [M+H]+. Step 2. Synthesis of 1-((1r,4r)-4-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonamido)cyclohexane-1- carbonyl)piperidine-4-carboxylic acid. The title compound was prepared from ethyl 1-((1r,4r)-4-((3-fluoro-4-((4-(1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)phenyl)sulfonamido)cyclohexane-1-carbonyl)piperidine-4-carboxylate (Step 1) using an analogous method to that described for Intermediate 15. LCMS m/z = 712 [M+H]+. Intermediate 42. 1-methyl-3-(1-oxo-4-(piperidin-4-yloxy)isoindolin-2-yl)piperidine-2,6- dione hydrochloride.
Figure imgf000165_0001
Step 1. Synthesis of tert-butyl 4-((2-(1-methyl-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oxy)piperidine-1-carboxylate. A mixture of tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)piperidine- 1-carboxylate (Intermediate 38, Step 1; 0.30 g, 0.68 mmol) and cesium carbonate (0.44 g, 1.35 mmol) in DMF (5 mL) was stirred for 10 min at rt. MeI (0.5 mL, 1.01 mmol) was added and stirred rt for 16 h. The reaction mixture was quenched with water (5 mL) and extracted with EtOAc (2x 15 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure to obtain the title compound (220 mg, 71%). Step 2. Synthesis of 1-methyl-3-(1-oxo-4-(piperidin-4-yloxy)isoindolin-2-yl)piperidine-2,6- dione. The title compound was prepared (100 mg, 58%) from tert-butyl 4-((2-(1-methyl-2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)piperidine-1-carboxylate (Step 1) using an analogous method to that described for Intermediate 54, Step 2. LCMS m/z = 358 [M+H]+. Intermediate 43. 1-((4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)piperidin-1-yl)sulfonyl)piperidine-4-carbaldehyde.
Figure imgf000165_0002
Step 1. Synthesis of ethyl 1-((4-((4-(1-methyl-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)piperidine-4-carboxylate To a stirred solution of 2-chloro-4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine (Intermediate 35, Step 1, 2 g, 7.62 mmol) and ethyl 1-((4-aminopiperidin-1- yl)sulfonyl)piperidine-4-carboxylate (Intermediate 4, Step 2, 2.68 g, 8.38 mmol) in DMSO (30 mL) was added DIPEA (7.96 mL, 22.8 mmol) and the reaction mixture stirred at 80 ºC for 16 h. The reaction was diluted with water (40 mL) and extracted with EtOAc (2x 120 mL). The combined organics were concentrated under reduced pressure and the residue purified using column chromatography (SiO2, 50-60% EtOAc/PE) to afford the title compound as a yellow solid. (1.5 g, 36%). LCMS m/z = 546 [M+H]+. Step 2. Synthesis of (1-((4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)piperidin-1-yl)sulfonyl)piperidin-4-yl)methanol To a stirred solution of ethyl 1-((4-((4-(1-methyl-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)piperidine-4-carboxylate (Step 1, 2.0 g, 3.67 mmol) in THF (30 mL) at 0 oC was added dropwise LAH (2.M solution in THF, 5.4 mL, 11 mmol). The reaction was quenched with sat. ammonium chloride solution and extracted with EtOAc (2x 75 mL). The combined organics evaporated to dryness to afford the title compound (1.4 g, 76%). LCMS m/z = 504 [M+H]+. Step 3. Synthesis of 1-((4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)piperidin-1-yl)sulfonyl)piperidine-4-carbaldehyde A stirred solution of (1-((4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)piperidin-1-yl)sulfonyl)piperidin-4-yl)methanol (Step 2, 1.5 g, 2.98 mmol) and 2- iodoxybenzoic acid (3.34 g, 11.9 mmol, contains stabilizer, 45 wt. %) in DMSO (15 mL) was at rt overnight. The reaction was quenched with ice cold water (20-30 mL) and the solid collected by filtration. The solid was dissolved in EtOAc (100 mL) and washed with 1M sodium bicarbonate solution. The combined organics were dried (Na2SO4) and evaporated to dryness under reduced pressure to obtain the title compound (1 g, 67%). LCMS m/z = 502 [M+H]+. Intermediate 44. 3-(4-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl)piperidine-2,6-dione.
Figure imgf000166_0001
Step 1. Synthesis of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine To a stirred solution of 1-bromo-4-iodobenzene (0.6 g, 2.12 mmol) and 2,6-bis(benzyloxy)-3- (4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)pyridine (1.07 g, 2.55 mmol) in dioxane (5.4 mL) and H2O) (0.6 mL) was added potassium phosphate (1.125 g, 5.30 mmol) and degassed with nitrogen stream for 5 min. Pd(dppf)Cl2.DCM (87 mg, 0.11 mmol) was added and the mixture stirred at 100 °C for 12 h. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (2x 45 mL). The combined organics were dried (Na2SO4) and evaporated to dryness. The residue was purified by column chromatography (SiO2, 5-10% EtOAc/PE) to afford the title compound. LCMS m/z = 446 [M+H]+. Step 2. Synthesis of tert-butyl 6-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-2,6- diazaspiro[3.3]heptane-2-carboxylate To a stirred solution of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (0.5 g, 1.12 mmol) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (0.244 g, 1.23 mmol) in dioxane (10 mL) were added TEA (0.178 mL, 1.23 mmol) and sodium tert-butoxide (0.355 g, 3.70 mmol) and degassed with nitrogen stream for 5 minutes. Tris(dibenzylideneacetone)dipalladium(0) (51 mg, 0.056 mmol) and BINAP (0.070 g, 0.112 mmol) were added and the resulting reaction mixture was heated at 110 °C for 12 h. The reaction was quenched with water (70 mL) and extracted with ethyl acetate (2x 55 mL). The combined organics were dried (Na2SO4) and evaporated to dryness. The residue was purified by column chromatography using (SiO2, 5-10% EtOAc/PE) to afford the title compound. LCMS m/z = 564 [M+H]+. Step 3. Synthesis of tert-butyl 6-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,6- diazaspiro[3.3]heptane-2-carboxylate 10 % Pd/C (0.4 g) was added to a stirred, degassed solution of tert-butyl 6-(4-(2,6- bis(benzyloxy)pyridin-3-yl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (Step 2, 0.4 g, 0.71 mmol) in EtOH (4 mL) and EtOAc (2 mL) and hydrogenated at 120 PSI H2 and stirred at rt for 16 h. The reaction mixture filtered through a pad of celite and washed with MeOH (3x 50 mL) and evaporated to dryness under reduced pressure afford the title compound as a clear oil (0.25 g, 91%). LCMS m/z = 386 [M+H]+. Step 4. Synthesis of 3-(4-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl)piperidine-2,6-dione A solution of tert-butyl 6-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,6-diazaspiro[3.3]heptane-2- carboxylate (Step 3, 0.23 g, 0.60 mmol) in formic acid (2.5 mL) was stirred at rt for 4 h. The reaction mixture was quenched with sat. bicarbonate solution and extracted with EtOAc (2x 50 mL). The combine organics were dried and evaporated to dryness to afford the title compound (160 mg, 94%). LCMS m/z = 286 [M+H]+. Intermediate 45. 1-(3-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)phenyl)dihydropyrimidine- 2,4(1H,3H)-dione.
Figure imgf000168_0001
Step 1. Synthesis of 1-(3-bromophenyl)dihydropyrimidine-2,4(1H,3H)-dione Acrylic acid (5.17 mL, 75.6 mmol) was added to a solution of 3-bromoaniline (10 g, 58.13 mmol) in toluene (100 mL) at rt and the reaction mixture stirred at 100 °C for 16 h. The toluene was removed under vacuum and AcOH (49.9 mL, 872 mmol) and urea (52.37 g, 872 mmol) added at rt and the reaction mixture stirred at 120 °C for 24 h. The reaction mixture was cooled to 0 °C and ice cold water (100 mL) added and stirred for 15 min. The solids were collected by filtration and washed with ice cold water and diethyl ether to afford the title compound (9.2 g, 61%). 1H NMR (400 MHz, DMSO-d6): 10.45 (s, 1H), 7.59 (s, 1H), 7.43- 7.40 (m, 1H), 7.35 (d, 2H), 3.79 (t, 2H), 2.72-2.50 (t, 2H). Step 2. Synthesis of tert-butyl 4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)prop- 2-yn-1-yl)oxy)piperidine-1-carboxylate A mixture of 1-(3-bromophenyl)dihydropyrimidine-2,4(1H,3H)-dione (2.00 g, 7.43 mmol), tert-butyl 4-(prop-2-yn-1-yloxy)piperidine-1-carboxylate (2.69 g, 11.15 mmol) and caesium carbonate (6.05 g, 18.58 mmol) in DMF (20 mL) at rt was purged with nitrogen for 15 min. Pd(PPh3)2Cl2 (0.52 g, 0.74 mmol) and copper(I) iodide (0.28 g, 1.49 mmol) were added under nitrogen atmosphere and the resulting reaction mixture stirred at 70 oC for 16 h. The reaction mixture was quenched with cold water (100 mL) and extracted with EtOAc (3x 100 mL). The combined organics were washed with brine solution (50 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 50-60% EtOAc/PE) to afford to the title compound as a brown solid (1.20 g, 51%). LCMS m/z = 428 [M+H]+. Step 3. Synthesis of 1-(3-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)phenyl)dihydropyrimidine- 2,4(1H,3H)-dione Formic acid (6 mL) was added to tert-butyl 4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)- yl)phenyl)prop-2-yn-1-yl)oxy)piperidine-1-carboxylate (1.2 g, 2.81 mmol) at rt and stirred for 2 h. The formic acid was removed under reduced pressure and the residue diluted with water (20 mL) and extracted with 10% MeOH/CHCl3 (3x 50 mL). The combined organics were washed with brine solution (50 mL), dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as a brown solid (0.68 g, 74%). LCMS m/z = 328 [M+H]+. Intermediate 46. 1-(3-(3-((1-(piperidine-4-carbonyl)piperidin-4-yl)oxy)prop-1-yn-1- yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione.
Figure imgf000169_0001
Step 1. Synthesis of tert-butyl 4-(4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)- yl)phenyl)prop-2-yn-1-yl)oxy)piperidine-1-carbonyl)piperidine-1-carboxylate To a stirred solution of 1-(3-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)phenyl)dihydropyrimidine- 2,4(1H,3H)-dione Intermediate 45 (0.30 g, 0.92 mmol) and 1-(tert- butoxycarbonyl)piperidine-4-carboxylic acid (0.25 g, 1.10 mmol) in DMF (3 mL) were added HATU (0.69 g, 1.83 mmol) and DIPEA (0.48 mL, 2.75 mmol) at rt and the reaction mixture stirred for 16 h. The reaction mixture was quenched with cold water (10 mL) and extracted with EtOAc (3x 25 mL). The combined organics were washed with brine solution (15 mL), dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as a brown solid (0.26 g, 53%). LCMS m/z = 539 [M+H]+. Step 2. Synthesis of 1-(3-(3-((1-(piperidine-4-carbonyl)piperidin-4-yl)oxy)prop-1-yn-1- yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione Formic acid (1.3 mL) was added to tert-butyl 4-(4-((3-(3-(2,4-dioxotetrahydropyrimidin- 1(2H)-yl)phenyl)prop-2-yn-1-yl)oxy)piperidine-1-carbonyl)piperidine-1-carboxylate (Step 1, 0.26 g, 0.48 mmol) at rt and stirred for 2 h. The reaction mixture was evaporated to dryness under reduced pressure and the residue diluted with water (20 mL) and extracted with 10% MeOH/CHCl3 (3x 20 mL). The combined organics were washed with brine (20 mL), dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as a brown solid (0.12 g, 55%). LCMS m/z = 439 [M+H]+. Intermediate 47. 4-amino-N-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin- 4-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)-3-fluorobenzenesulfonamide.
Figure imgf000170_0001
Step 1. Synthesis of tert-butyl (tert-butoxycarbonyl)(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-4-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)carbamate To a stirred solution of 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-1,3-dione (Chem. Comm., 2017, 53, 7577-7580, 1.00 g, 3.64 mmol), sodium bicarbonate (0.30 g, 3.64 mmol) and 5-(tert-butoxycarbonyl)-2,2-dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azahexadecan-16-yl 4- methylbenzenesulfonate (Org. Lett., 2004, 6, 3715-3718, 1.99 g, 3.64 mmol) in DMF (20 mL) added potassium bromide (0.86 g, 7.29 mmol) at rt and the resulting reaction mixture heated at 70 oC for 16h. The reaction mixture was quenched with sat. NH4Cl solution (50 mL) and extracted with EtOAc (2x 20 mL). The combined organics were washed with water (2x 20 mL), brine solution (2x 20 mL), dried (Na2SO4) and concentrated under the reduced pressure. The residue was purified by flash chromatography (SiO2, 1-5% MeOH/DCM) to afford the title compound as a semi-solid (1.40 g, 59 %). LCMS m/z = 648 [M+H]+ Step 2: Synthesis of 4-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethoxy)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione hydrochloride To a stirred solution of tert-butyl (tert-butoxycarbonyl)(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3- yl)-1,3-dioxoisoindolin-4-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)carbamate (0.70 g, 2.55 mmol) in DCM (14 mL) was added 4.0 M HCl in dioxane (2.5 mL) at 0 °C and the reaction mixture allowed to warm to rt and stirred for 3h. The reaction mixture was concentrated under reduced pressure and the residue was triturated with diethyl ether to afford the title compound as an off-white foam (0.55 g, 36 %). LCMS m/z = 650 [M+H]+ Step 3: Synthesis of N-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)-3-fluoro-4-nitrobenzenesulfonamide To a stirred solution 4-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethoxy)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione hydrochloride (0.50 g, 1.02 mmol) in DCM (10 mL) was added triethylamine (0.42 mL, 3.08 mmol) dropwise at -10 °C and stirred for 15 min at same temperature. To this solution was added a solution of 3-fluoro-4- nitrobenzenesulfonyl chloride (0.49 g, 2.05 mmol) in DCM (10 mL) drop wise at -10 °C and the resulting reaction mixture was stirred for 1h at same temperature. The reaction mixture was diluted with water (25 mL) and extracted with DCM (3x 20 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0-3% MeOH/DCM) to afford the title compound as a pale orange solid (0.40 g, 60%). LCMS m/z = 653 [M+H]+ Step 4: Synthesis of 4-amino-N-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)-3-fluorobenzenesulfonamide To a stirred solution of N-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)-3-fluoro-4-nitrobenzenesulfonamide (0.35 g, 0.53 mmol) in EtOH (10 mL) and water (10 mL) was added ammonium chloride (0.57 g, 10.72 mmol) and iron powder (0.59 g, 10.72 mmol) at 0 °C and the resulting reaction mixture stirred at 60 °C for 16h. The reaction mixture was filtered through a pad of celite and washed with EtOAc (2x 10 mL). The filtrate was diluted with water (10 mL) and extracted with EtOAc (20 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure and the residue purified by combi flash chromatography (neutral alumina, 0-3% MeOH/DCM) to afford the title compound as a brown semi-solid (0.12 g; 36 %). LCMS m/z = 623 [M+H]+ Intermediate 48. 3-(4-(3-((1-((1-((4-aminopiperidin-1-yl)sulfonyl)piperidin-4- yl)methyl)piperidin-4-yl)oxy)prop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione.
Figure imgf000172_0001
Step 1: Synthesis of tert-butyl (1-((4-((4-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl) prop-2-yn-1-yl) oxy) piperidin-1-yl) methyl) piperidin-1-yl) sulfonyl) piperidin-4-yl) carbamate To a stirred solution of 3-(1-oxo-4-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)isoindolin-2- yl)piperidine-2,6-dione (Intermediate 16, 0.16 g, 0.28 mmol) in DCM (5 mL) and tert-butyl (1-(chlorosulfonyl) piperidin-4-yl) carbamate (0.12 g, 0.42 mmol) was added triethylamine (0.19 mL, 1.40 mmol) under inert atmosphere at rt and the resulting reaction mixture heated at 35 °C for 12 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (SiO2, 70-100% EtOAc/PE) to afford the title compound as a brown solid (0.17 g, 82%). LCMS m/z = 742 [M+H]+. Step 2: Synthesis 3-(4-(3-((1-((1-((4-aminopiperidin-1-yl)sulfonyl)piperidin-4- yl)methyl)piperidin-4-yl)oxy)prop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione To a stirred solution of tert-butyl (1-((4-((4-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin- 4-yl) prop-2-yn-1-yl) oxy) piperidin-1-yl) methyl) piperidin-1-yl) sulfonyl) piperidin-4-yl) carbamate (0.17 g, 0.23 mmol) in DCM (3 mL) was added TFA (0.42 mL, 5.52 mmol) at 0 °C and the resulting reaction mixture stirred at rt for 8 h. The reaction mixture was concentrated under reduced pressure and the residue triturated with diethyl ether (3x 10mL) to afford the title compound as a brown solid (0.14 g, 83.3%) which was used without purifcation. Intermediate 49. 3-(1-oxo-4-(3-((1-(piperidin-4-ylmethyl)piperidin-4-yl)oxy)prop-1-yn-1- yl)isoindolin-2-yl)piperidine-2,6-dione.
Figure imgf000173_0001
Step 1: Synthesis of tert-butyl 4-((4-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)piperidine-1-carboxylate To a stirred solution of 3-(1-oxo-4-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)isoindolin-2- yl)piperidine-2,6-dione (Intermediate 16, 0.30 g, 0.79 mmol) and tert-butyl 4- formylpiperidine-1-carboxylate (0.21 g, 1.02 mmol) in MeOH (3 mL) were added acetic acid (0.004 mL, 0.079 mmol) followed by MP-cynoborohydride (0.30 g) was added at rt and the resulting reaction mixture was stirred for 16 h at rt. The reaction mixture was filtered and the solid residue was washed with methanol (3x 5 mL). The filtrate was evaporated under reduced pressure to afford the title compound as a red solid (0.15 g, 33%). LCMS m/z = 579 [M+H]+. Step 2: Synthesis of 3-(1-oxo-4-(3-((1-(piperidin-4-ylmethyl)piperidin-4-yl)oxy)prop-1-yn-1- yl)isoindolin-2-yl)piperidine-2,6-dione A solution of tert-butyl 4-((4-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)prop-2- yn-1-yl)oxy)piperidin-1-yl)methyl)piperidine-1-carboxylate (0.19 g, 0.33 mmol) in formic acid (2.5 mL) was stirred at rt for 4 h. The reaction mixture was concentrated under reduced pressure to afford the title compound as a red solid (0.10 g, 64%). LCMS m/z = 479 [M+H]+. Intermediate 50. 3-(3-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)phenyl)piperidine-2,6-dione.
Figure imgf000173_0002
Step 1: Synthesis of tert-butyl 4-((3-(3-(2,6-dioxopiperidin-3-yl)phenyl)prop-2-yn-1- yl)oxy)piperidine-1-carboxylate To a stirred solution of 3-(3-iodophenyl)piperidine-2,6-dione (1.00 g, 3.17 mmol) and tert- butyl 4-(prop-2-yn-1-yloxy)piperidine-1-carboxylate (1.37 g, 5.71 mmol) in DMF (10 mL) was added caesium carbonate (2.59 g, 7.93 mmol) at rt and purged with nitrogen gas for 15 min. Bis(triphenylphosphine)palladium (II) dichloride (0.22 g, 0.32 mmol) and copper(I) iodide (0.12 g, 0.64 mmol) were added at rt and stirred at 70 ºC for 4 h. The reaction mixture was quenched with cold water (50 mL) and extracted with EtOAc (3x 50 mL). The combined organics were washed with ice cold water (3x 50 mL), aqueous saturated solution of ammonium chloride solution (2x 50 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 50-60% EtOAc/PE) to afford the title compound as a brown solid (1.20 g, 88%). LCMS m/z = 427 [M+H]+. Step 2: Synthesis of 3-(3-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)phenyl)piperidine-2,6-dione To a stirred solution tert-butyl 4-((3-(3-(2,6-dioxopiperidin-3-yl)phenyl)prop-2-yn-1- yl)oxy)piperidine-1-carboxylate (Step 1, 1.20 g, 2.81 mmol) in DCM (12 mL) was added 4 M hydrochloric acid in dioxane (6 mL) dropwise at 0 °C and the resulting reaction mixture was allowed to stir at rt for 3 h. The reaction mixture was concentrated under reduced pressure and the residue diluted with aqueous solution of saturated sodium bicarbonate (30 mL) and extracted with 20% IPA/CHCl3 (3x 30 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as a brown solid (0.70 g, 76%). LCMS m/z = 327 [M+H]+. Intermediate 51. 1-(4-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)phenyl)dihydropyrimidine- 2,4(1H,3H)-dione.
Figure imgf000174_0001
Step 1: Synthesis of tert-butyl 4-((3-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)prop- 2-yn-1-yl)oxy)piperidine-1-carboxylate To a stirred solution of 1-(4-bromophenyl)dihydropyrimidine-2,4(1H,3H)-dione (2 g, 7.43 mmol) and tert-butyl 4-(prop-2-yn-1-yloxy)piperidine-1-carboxylate (2.67 g, 11.1 mmol) in MeCN (30 mL) was added caesium carbonate (6.05 g, 18.6 mmol) at rt and purged with argon gas for 15 min before BrettPhos Pd G4 (0.68 g, 0.74 mmol) and copper(I) iodide (0.28 g, 1.49 mmol) added at rt and the mixture stirred at 80 °C for 16 h. The reaction mixture was filtered through celite and washed with EtOAc (2x 50 mL). The filtrate was washed with water (60 mL), brine (60 mL) and dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 50-60% EtOAc/PE) to afford the title compound as a colourless semi-solid (1.20 g, 38%). LCMS m/z = 426 [M+H]+. Step 2: Synthesis of 1-(4-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)phenyl)dihydropyrimidine- 2,4(1H,3H)-dione To a stirred solution of tert-butyl 4-((3-(4-(2,4-dioxotetrahydropyrimidin-1(2H)- yl)phenyl)prop-2-yn-1-yl)oxy)piperidine-1-carboxylate (1.2 g, 4.46 mmol) in DCM (6 mL) was added 4M hydrochloric acid in dioxane (6 mL) at 0 °C and the reaction mixture stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure and the residue diluted with solution of aqueous sodium bicarbonate and extracted with 20% IPA/CHCl3. The combined organics were dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as a brown solid (0.23 g, 15%). LCMS m/z = 328 [M+H]+. Intermediate 52. 3-(4-(2,7-diazaspiro[3.5]nonan-2-yl)phenyl)piperidine-2,6-dione.
Figure imgf000175_0001
Step 1: Synthesis of tert-butyl 2-(4-bromophenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate To a stirred solution of tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (5.0 g, 22.1 mmol) and (4-bromophenyl)boronic acid (8.87 g, 44.2 mmol) in DCM (100 mL) was added triethylamine (9.2 mL, 66.3 mmol) at rt and purged with oxygen for 15 min then copper (II) acetate (1.61 g, 8.83 mmol) was added at rt. The resulting reaction mixture was stirred under oxygen atmosphere at rt for 16 h. The reaction mixture was filtered through celite and washed with DCM (2x 100 mL). The filtrate was dried (Na2SO4) and concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 10-15% EtOAc/PE) to afford the title compound as a colourless semi-solid (6.0 g, 71%). LCMS m/z = 382 [M+H]+. Step 2: Synthesis of tert-butyl 2-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-2,7- diazaspiro[3.5]nonane-7-carboxylate To a stirred solution of tert-butyl 2-(4-bromophenyl)-2,7-diazaspiro[3.5]nonane-7- carboxylate (6.0 g, 15.7 mmol) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine (13.13 g, 31.5 mmol) in dioxane (120 mL) and water (12 mL) was added potassium phosphate (8.35 g, 39.3 mmol) at rt. The reaction mixture was purged with argon for 15 min then PdCl2(dppf).DCM (642 mg, 0.79 mmol) was added at rt and the resulting reaction mixture was stirred under argon at 110 °C for 3 h. The reaction mixture was filtered through celite washed with EtOAc (2x 100 mL). The filtrate was washed with water (250 mL), brine, dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0-6% EtOAc) to afford the title compound as a colourless semi-solid (4.5 g, 48%). LCMS m/z = 592 [M+H]+. Step 3: Synthesis of tert-butyl 2-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,7- diazaspiro[3.5]nonane-7-carboxylate To the stirred solution of tert-butyl 2-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-2,7- diazaspiro[3.5]nonane-7-carboxylate (4.50 g, 7.61 mmol) in ethanol (20 mL) was added Pd/C (4.50 g) and stirred at rt under H2 (120 psi) atmosphere for 48 h. The reaction mixture was filtered through celite bed and washed with methanol (4x 100 mL). The combined filtrate was concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 10-50% EtOAc/PE) to afford the title compound as an off-white solid. (1.90 g, 60%). LCMS m/z = 414 [M+H]+. Step 4: Synthesis of 3-(4-(2,7-diazaspiro[3.5]nonan-2-yl)phenyl)piperidine-2,6-dione To a stirred solution of tert-butyl 2-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,7- diazaspiro[3.5]nonane-7-carboxylate (1.90 g, 4.60 mmol) in DCM (10 mL) was added, 4M hydrochloric acid in dioxane (5 mL) at 0 °C and the resulting reaction mixture stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure and the residue diluted with saturated solution of aqueous sodium bicarbonate and extracted in 20% IPA/CHCl3. The combined organics were dried (Na2SO4) and concentrated under the reduced pressure to afford the title compound as an off-white solid (1.40 g, 97%). LCMS m/z = 314 [M+H]+. Intermediate 53. 3-(3-(2,7-diazaspiro[3.5]nonan-2-yl)phenyl)piperidine-2,6-dione.
Figure imgf000177_0001
The title compound was prepared from tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate using an analogous 4-Step procedure as described for Intermediate 52. LCMS m/z = 314 [M+H]+. Intermediate 54. 2-(2,6-dioxopiperidin-3-yl)-5-(3,9-diazaspiro[5.5]undecan-3- yl)isoindoline-1,3-dione hydrochloride.
Figure imgf000177_0002
Step 1. Synthesis of tert-butyl 9-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3,9- diazaspiro[5.5]undecane-3-carboxylate. To a stirred solution of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (0.50 g, 1.81 mmol) and tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (0.69 g, 2.72 mmol) in DMSO (10 mL) was added DIPEA (1 mL, 5.45 mmol) at rt and the resulting reaction mixture heated at 90 °C for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (3x 30 mL). The combined organics were dried (Na2SO4), concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 30% EtOAc/PE) to afford the title compound as a yellow solid (0.7 g; 75%). LCMS m/z = 511 [M+H]+. Step 2. Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(3,9-diazaspiro[5.5]undecan-3- yl)isoindoline-1,3-dione hydrochloride To a stirred solution of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (0.70 g, 1.37 mmol) in DCM (30 mL) was added 4M HCl in dioxane (7 mL) at 0°C and continued the stirring at same temperature for 2 h. The reaction mixture was concentrated under reduced pressure and the residue triturated with DCM (3x 15 mL) to afford the title compound as a white solid (0.60 g, 98%) as a white solid. LCMS m/z = 411 [M+H]+. Intermediate 55. 3-(3-(3-((3-azaspiro[5.5]undecan-9-yl)oxy)prop-1-yn-1- yl)phenyl)piperidine-2,6-dione.
Figure imgf000178_0001
Step 1. Synthesis of tert-butyl 9-((3-(3-(2,6-dioxopiperidin-3-yl)phenyl)prop-2-yn-1-yl)oxy)- 3-azaspiro[5.5]undecane-3-carboxylate To a stirred solution of 3-(4-bromophenyl)piperidine-2,6-dione (0.50 g, 1.86 mmol) and tert- butyl 9-(prop-2-yn-1-yloxy)-3-azaspiro[5.5]undecane-3-carboxylate (0.86 g, 2.79 mmol) DMF (5 mL) was added Caesium carbonate (1.51 g, 4.66 mmol ) at rt. The resulting solution was purged with nitrogen for 15 min. Dichloro bis(triphenylphosphine)palladium (0.13 g, 0.18 mmol) and CuI (0.07 g, 0.37 mmol) were added under inert atmosphere and stirred at 70 °C for 4 h. The reaction was quenched with ice-cold water (40 mL) and extracted with EtOAc (3x 50 mL). The combined organics were washed with water (2x 40 mL), brine (2x 40 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 50-60 % EtOAc/PE) to afford the title compound as a brown solid (0.25 g, 25%). LCMS m/z = 495 [M+H]+. Step 2. Synthesis of 3-(3-(3-((3-azaspiro[5.5]undecan-9-yl)oxy)prop-1-yn-1- yl)phenyl)piperidine-2,6-dione To a stirred solution of tert-butyl 9-((3-(3-(2,6-dioxopiperidin-3-yl)phenyl)prop-2-yn-1- yl)oxy)-3-azaspiro[5.5]undecane-3-carboxylate (Step 1, 0.25 g, 0.50 mmol) in DCM (2.5 mL) was added 4.0 M HCl in dioxane (0.25 mL) dropwise at 0 °C and the resulting reaction mixture allowed to warm to rt and stirred for 3 h. The reaction mixture was concentrated under reduced pressure and the residue diluted with saturated sodium bicarbonate solution (10 mL), extracted (20% IPA/CHCl3) (3x 20 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure to afford the title compound (0.13 g, 65%). LCMS m/z = 395 [M+H]+. Intermediate 56. 3-(4-(3-((1-(piperidin-4-ylmethyl)piperidin-4-yl)oxy)prop-1-yn-1-
Figure imgf000179_0001
Step 1: Synthesis of tert-butyl 4-((4-((3-(4-(2,6-dioxopiperidin-3-yl)phenyl)prop-2-yn-1- yl)oxy)piperidin-1-yl)methyl)piperidine-1-carboxylate Acetic acid (0.01 g, 0.08 mmol) followed by MP-Cynoborohydride (0.38 g) were added at rt to a solution of 3-(4-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)phenyl)piperidine-2,6-dione Intermediate 28 (0.38 g, 1.16 mmol) and tert-butyl 4-formylpiperidine-1-carboxylate (0.32 g, 1.51 mmol) in methanol (3.8 mL) and the resulting reaction mixture stirred for 16 h at rt. The reaction mixture was filtered and the solid residue was washed with methanol (3x 5 mL). The filtrate was evaporated under reduced pressure and the residue purified by combi-flash (SiO2, 0-10% MeOH/DCM) o afford the title compound as an off-white solid (0.35 g, 57%). LCMS m/z = 524 [M+H]+. Step 2: Synthesis of 3-(4-(3-((1-(piperidin-4-ylmethyl)piperidin-4-yl)oxy)prop-1-yn-1- yl)phenyl)piperidine-2,6-dione To a stirred solution of tert-butyl 4-((4-((3-(4-(2,6-dioxopiperidin-3-yl)phenyl)prop-2-yn-1- yl)oxy)piperidin-1-yl)methyl)piperidine-1-carboxylate (0.35 g, 0.67 mmol) in DCM (3.5 mL) was added 4 M hydrochloric acid in dioxane (1.75 mL) at 0 °C and the reaction mixture was stirred at rt for 3 h. The reaction mixture was concentrated under reduced pressure and the residue diluted with saturated solution of aqueous sodium bicarbonate (30 mL) and extracted with 20% IPA/CHCl3 (3x 20 mL). The combined organics were dried (Na2SO4) and concentrated under the reduced pressure to afford the title compound as an off-white solid (0.28 g, 99%). LCMS m/z = 424 [M+H]+. Intermediate 57. 3-(3-(3-((1-(piperidin-4-ylmethyl)piperidin-4-yl)oxy)prop-1-yn-1- yl)phenyl)piperidine-2,6-dione.
Figure imgf000180_0001
The title compound was prepared from 3-(3-(3-(piperidin-4-yloxy)prop-1-yn-1- yl)phenyl)piperidine-2,6-dione Intermediate 50 using an analogous 2-Step procedure as described for Intermediate 56. LCMS m/z = 424 [M+H]+. Intermediate 58. 1-(2-methyl-3-(3-((1-(piperidin-4-ylmethyl)piperidin-4-yl)oxy)prop-1-yn-
Figure imgf000180_0002
The title compound was prepared from 1-(2-methyl-3-(3-(piperidin-4-yloxy)prop-1-yn-1- yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione Intermediate 11 using an analogous 2-Step procedure as described for Intermediate 56. LCMS m/z = 424 [M+H]+. Intermediate 59. 3-(1-oxo-5-(3-((1-(piperidin-4-ylmethyl)piperidin-4-yl)oxy)prop-1-yn-1- yl)isoindolin-2-yl)piperidine-2,6-dione.
Figure imgf000180_0003
The title compound was prepared from 3-(1-oxo-5-(3-(piperidin-4-yloxy)prop-1-yn-1- yl)isoindolin-2-yl)piperidine-2,6-dione (Intermediate 6) using an analogous 2-Step procedure as described for Intermediate 56. LCMS m/z = 479 [M+H]+. Intermediate 60. 3-(4-(1'-(piperidine-4-carbonyl)-[4,4'-bipiperidin]-1-yl)phenyl)piperidine- 2,6-dione.
Figure imgf000181_0001
Step 1: Synthesis of tert-butyl 4-(1'-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[4,4'-bipiperidine]-1- carbonyl)piperidine-1-carboxylate To a stirred solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (0.07 g, 0.31 mmol) and HATU (0.17 g, 0.46 mmol) in DMF (1 mL) was added at rt 3-(4-([4,4'- bipiperidin]-1-yl)phenyl)piperidine-2,6-dione (Intermediate 32, 0.11 g, 0.31 mmol) and DIPEA (0.11 mg, 0.93 mmol) and the resulting reaction mixture stirred for 16 h. The reaction mixture was diluted with ice-cold water (10 mL) and filtered to afford the title compound as an off-white solid (0.11 g, 65%). LCMS m/z = 567 [M+H]+. Step 2: Synthesis of 3-(4-(1'-(piperidine-4-carbonyl)-[4,4'-bipiperidin]-1- yl)phenyl)piperidine-2,6-dione 4 M hydrochloric acid in dioxane (2.96 mL) was added at 0 °C to a stirred solution of tert- butyl 4-(1'-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[4,4'-bipiperidine]-1-carbonyl)piperidine-1- carboxylate (0.11 g, 0.20 mmol) in DCM (2 mL) and the resulting reaction mixture stirred at rt for 3 h. The reaction mixture was concentrated under reduced pressure and the residue co- distilled with dioxane (2x 5 mL) to afforded the title compound as a white solid (0.09 g, 96%). LCMS m/z = 467 [M+H]+. Intermediate 61. N-(2-chloroethyl)-3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide.
Figure imgf000182_0001
Step 1: Synthesis of N-(2-bromoethyl)-3-fluoro-4-nitrobenzenesulfonamide To a stirred solution of 2-bromoethan-1-amine (2.0 g, 16.1 mmol) and triethylamine (4.89 g, 48.4 mmol) in DCM (50 mL) was added 3-fluoro-4-nitrobenzenesulfonyl chloride (5.79 g, 24.19 mmol) at -10 oC and the reaction mixture stirred at same temperature for 2 h. The reaction mixture was diluted with water (500 mL) and extracted with DCM (3x 50 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 15% EtOAc /PE) to afford the title compound as a brown solid (2.50 g, 47%). LCMS m/z = 328 [M+H]+. Step 2: Synthesis of 4-amino-N-(2-chloroethyl)-3-fluorobenzenesulfonamide To a stirred solution of N-(2-bromoethyl)-3-fluoro-4-nitrobenzenesulfonamide (1.0 g, 3.05 mmol) in ethanol and water (20 mL, 1:1) at rt was added iron powder (3.30 g, 61.13 mmol) and NH4Cl (3.42 g, 61.13 mmol) and the resulting reaction mixture stirred at 60 °C for 2 h. The reaction mixture was passed through a pad of celite and washed with ethanol (2x 10 mL). The combined filtrate was concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 30% EtOAc/PE) to afford the title compound (0.5 g, 65%). LCMS m/z = 253 [M+H]+. Step 3: Synthesis of N-(2-chloroethyl)-3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide (48) To a stirred solution of 4-amino-N-(2-chloroethyl)-3-fluorobenzenesulfonamide (0.50 g, 1.97 mmol) and 1-(4-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2- methylpropan-2-ol Intermediate 1 (0.63 g, 1.97 mmol) in IPA (10 mL) was added TsOH (0.07 g, 0.39 mmol) portion wise at rt and the reaction mixture stirred at 90 oC for 16 h. The reaction mixture was quenched with ice-cold water (10 mL) and extracted with EtOAc (3x 50 mL). The combined organics were washed with water (2x 50 mL), brine (25 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 80% EtOAc/PE) to afford the title compound as a brown solid (0.40 g, 42%). LCMS m/z = 537 [M+H]+. Intermediate 62. 3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-N-(2-(4-(2-oxo-2-(piperazin-1-yl)ethyl)piperidin-1- yl)ethyl)benzenesulfonamide.
Figure imgf000183_0001
Step 1: Synthesis of benzyl 4-(2-(piperidin-4-yl)acetyl)piperazine-1-carboxylate 4.0 M HCl in Dioxane (15 mL) was added at rt to a stirred solution of benzyl 4-(2-(1-(tert- butoxycarbonyl)piperidin-4-yl)acetyl)piperazine-1-carboxylate (1.50 g, 3.36 mmol) in DCM (15 mL) and the resulting reaction mixture stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure to afford the title compound (0.13 g). LCMS m/z = 846 [M+H]+. Step 2: Synthesis of benzyl 4-(2-(1-(2-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonamido)ethyl)piperidin- 4-yl)acetyl)piperazine-1-carboxylate To a stirred solution of benzyl 4-(2-(piperidin-4-yl)acetyl)piperazine-1-carboxylate (0.2 g, 0.57 mmol) and N-(2-chloroethyl)-3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide (Intermediate 61, 0.24 g, 0.46 mmol) in DMF (10 ml) was added DIPEA (0.49 ml, 2.89 mmol) at rt and the resulting reaction mixture stirred at 90 °C for 16 h. The reaction mixture was quenched with ice-cold water (10 mL) and extracted with EtOAc (3x 20 mL). The combined organics were washed with water (2x 20 mL), brine (15 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 6% MeOH in DCM) to afford the title compound (0.18 g, 37%). LCMS m/z = 346 [M+H]+. Step-3 Synthesis of 3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-N-(2-(4-(2-oxo-2-(piperazin-1-yl)ethyl)piperidin-1- yl)ethyl)benzenesulfonamide (47) To a stirred solution of benzyl 4-(2-(1-(2-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)- 1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)phenyl)sulfonamido)ethyl)piperidin-4-yl)acetyl)piperazine-1-carboxylate (0.18 g, 0.21 mmol) in MeOH (5 mL) was added palladium on activated carbon (0.04 g, 0.42 mmol) and stirred under H2 atmosphere at rt for 2 h. The reaction mixture was filtered through a pad of celite and washed with methanol (2x 30 mL). The combined filtrate was concentrated under the reduced pressure to afford the title compound (0.12 g, 82%). LCMS m/z = 712 [M+H]+. Intermediate 63. 2-(2,6-dioxopiperidin-3-yl)-4-(4-(piperidin-4-ylmethyl)piperazin-1- yl)isoindoline-1,3-dione hydrochloride.
Figure imgf000184_0001
Step 1: Synthesis of tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)piperazin-1-yl)methyl)piperidine-1-carboxylate DIPEA (1.37 g, 10.59 mmol) was added to a stirred solution of tert-butyl 4-(piperazin-1- ylmethyl)piperidine-1-carboxylate (1.00 g, 3.53 mmol) and 2-(2,6-dioxopiperidin-3-yl)-4- fluoroisoindoline-1,3-dione (1.17 g, 4.23 mmol) in DMSO (10 mL) at rt and the resulting reaction mixture stirred at 90 °C for 16 h. The reaction mixture was diluted with ice-cold water and extracted with EtOAc (3x 25 mL). The combined organics were washed with ice- cold water (2x 15 mL), brine (20 mL), dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by column chromatography (SiO2, 10-40% EtOAc/PE) to afford the title compound as a yellow solid (1.2 g, 63%). LCMS m/z = 540 [M+H]+. Step 2: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-(4-(piperidin-4-ylmethyl)piperazin-1- yl)isoindoline-1,3-dione hydrochloride: 4.0 M hydrochloric acid in dioxane (4.8 mL) dropwise at 0 °C to a stirred solution tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)methyl)piperidine- 1-carboxylate (1.20 g, 2.22 mmol) in DCM (12 mL) and the resulting reaction mixture stirred at rt for 2 h. The rreaction mixture was concentrated under reduced pressure and the residue was triturated with DCM (2x 5 mL) to afford the title compound as a pale yellow solid (1.00 g, 94%). LCMS m/z = 440 [M+H]+. Intermediate 64. 5-([4,4'-bipiperidin]-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- dione.
Figure imgf000185_0001
The title compound was prepared from 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3- dione and tert-butyl [4,4'-bipiperidine]-1-carboxylate using an analogous 2-Step method to that described for Intermediate 63. LCMS m/z = 440 [M+H]+. Intermediate 65. (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycine.
Figure imgf000185_0002
Step 1: Synthesis of tert-butyl (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycinate DIPEA (9.46 mL, 54.30 mmol) was added at rt to a stirred solution of 2-(2,6-dioxopiperidin- 3-yl)-4-fluoroisoindoline-1,3-dione (5 g,18.1 mmol) and tert-butyl glycinate (4.75 g, 36.20 mmol) in DMSO (50 mL) and the resulting reaction mixture stirred at 90 °C for 16 h. The reaction mixture was diluted with ice-cold water (50 mL) and extracted in EtOAc (3x 50 mL). The combined organics were washed with ice-cold water (2x 50 mL), brine (50 mL), dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by combi- flash (SiO2, 25-30% EtOAc/PE) to afford the title compound (2.5 g, 35%). LCMS m/z = 388 [M+H]+. Step 2: Synthesis of (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycine: TFA (25 mL) was added dropwise at 0 °C to a stirred solution tert-butyl (2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycinate (5 g, 12.9 mmol) in DCM (25 mL) and the resulting reaction mixture stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure and the residue triturated with pentane (2x 5 mL) to afford the title compound (4 g, 94%). LCMS m/z = 332 [M+H]+. Intermediate 66. 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl 4- methylbenzenesulfonate.
Figure imgf000186_0001
Step 1: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-((2-hydroxyethyl)amino)isoindoline-1,3- dione DIPEA (12.7 g, 98.2 mmol) was added at rt to a stirred solution of 2-(2,6-dioxopiperidin-3- yl)-4-fluoroisoindoline-1,3-dione (5.43 g, 19.65 mmol) and 2-aminoethan-1-ol (1.00 g, 16.37 mmol) in DMSO (20 mL) and the resulting reaction mixture stirred at 90 °C for 16 h. The reaction mixture was diluted with ice-cold water (50 mL) and extracted with EtOAc (3x 50 mL). The combined organics were washed with ice-cold water (2x 50 mL), brine (50 mL), dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by combi- flash (SiO2, 25-30% EtOAc/PE) to afford the title compound as a yellow solid (0.35 g, 7%). LCMS m/z = 318 [M+H]+. Step 2: Synthesis of 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl 4- methylbenzenesulfonate TEA (0.39 mL, 2.76 mmol) was added dropwise at 0 °C to a stirred solution of 2-(2,6- dioxopiperidin-3-yl)-4-((2-hydroxyethyl)amino)isoindoline-1,3-dione (0.35 g, 1.10 mmol) and 4-toluenesulfonyl chloride (0.31 mg, 1.66 mmol) in DCM (5 mL) and the resulting reaction mixture stirred at rt for 16 h. The reaction mixture was diluted water (10 mL) and extracted with DCM (2x 10 mL). The combined organics were dried (Na2SO4) and evaporated under reduced pressure and the residue purified by combi-flash (SiO2, 25-30% EtOAc/PE) to afford the title compound as a yellow solid (0.15 g, 29%) as a yellow solid. LCMS m/z = 472 [M+H]+. Intermediate 67. N-(2-(3,9-diazaspiro[5.5]undecan-3-yl)ethyl)-3-fluoro-4-((4-(1-(2- hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide.
Figure imgf000187_0001
Step 1: Synthesis of tert-butyl 9-(2-((3-fluoro-4-nitrophenyl)sulfonamido)ethyl)-3,9- diazaspiro[5.5]undecane-3-carboxylate A solution of 3-fluoro-4-nitrobenzenesulfonyl chloride (3.86 g, 16.13 mmol) in DCM (20 mL) was added dropwise to a stirred solution of tert-butyl 9-(2-aminoethyl)-3,9- diazaspiro[5.5]undecane-3-carboxylate (2.40 g, 8.06 mmol) and TEA (3.3 mL, 24.2 mmol) in DCM (20 mL) at -10 °C and stirred for 2 h at the same temperature. The reaction mixture was extracted with DCM (3x 30 mL), washed with brine solution, dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 60-65% EtOAc/PE) to afford the title compound (1.5 g, 37%). LCMS m/z = 501 [M+H]+. Step 2: Synthesis of tert-butyl 9-(2-((4-amino-3-fluorophenyl)sulfonamido)ethyl)-3,9- diazaspiro[5.5]undecane-3-carboxylate To a stirred solution of tert-butyl 9-(2-((3-fluoro-4-nitrophenyl)sulfonamido)ethyl)-3,9- diazaspiro[5.5]undecane-3-carboxylate (1.40 g, 2.79 mmol) in EtOH (25 mL) was added Fe (3.07 g, 55.9 mmol) and NH4Cl (2.96 g, 55.9 mmol) solution in water (25 mL) at rt and the resulting reaction mixture stirred at 80 ºC for 2 h. The reaction mixture was filtered through celite bed and washed with EtOAc (2x 20 mL) and the filtrate concentrated under reduced pressure to afford the title compound (1.0 g, 76%). LCMS m/z = 471 [M+H]+. Step 3: Synthesis of tert-butyl 9-(2-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonamido)ethyl)-3,9- diazaspiro[5.5]undecane-3-carboxylate To a stirred solution of tert-butyl 9-(2-((4-amino-3-fluorophenyl)sulfonamido)ethyl)-3,9- diazaspiro[5.5]undecane-3-carboxylate (0.86 g, 1.83 mmol) and 1-(4-(2-chloro-5- (trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 1, 0.58 g, 1.83 mmol) in tBuOH (20 mL) was added Cs2CO3 (1.79 g, 5.51 mmol) at rt and the reaction mixture purged with nitrogen for 20 min. Pd2(dba)3 (0.16 g, 0.18 mmol) and XPhos (0.17 g, 0.36 mmol) was added at rt and the resulting reaction mixture heated in a microwave oven at 90 °C for 4 h. The reaction mixture was extracted with EtOAc (3x 30 mL), washed with brine solution, dried Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 5% MeOH in DCM) to afford the title compound as a yellow solid (0.70 g, 50%). LCMS m/z = 755 [M+H]+. Step 4. Synthesis of N-(2-(3,9-diazaspiro[5.5]undecan-3-yl)ethyl)-3-fluoro-4-((4-(1-(2- hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide (53) To a stirred solution of tert-butyl 9-(2-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonamido)ethyl)-3,9- diazaspiro[5.5]undecane-3-carboxylate (Step 3, 0.70 g, 0.93 mmol) in DCM (8 mL) was added 4M hydrochloric acid in dioxane (5 mL) at 0 °C and the reaction mixture stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure to afford the title compound as a yellow oil (0.60 g, 99%). LCMS m/z = 655 [M+H]+. Intermediate 68. tert-butyl 7-(2-aminoethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate.
Figure imgf000188_0001
Step 1. Synthesis of tert-butyl 7-(2-azidoethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate To a stirred solution of tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (2.5 g, 11.04 mmol) and 2-azidoethyl 4-methylbenzenesulfonate (3.19 mL, 13.25 mmol) MeCN (25mL) was added K2CO3 (4.58 g, 33.13 mmol) at rt and the resulting reaction mixture stirred at 80 °C for 18 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2x 10 mL). The combined organics were dried (Na2SO4), concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 0-10% MeOH in DCM) to afford the title compound as a yellow liquid (2.50 g, 77%). LCMS m/z = 296 [M+H]+. Step 2. Synthesis of tert-butyl 7-(2-aminoethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate To a stirred solution of tert-butyl 7-(2-azidoethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (Step 1, 2.00 g, 6.77 mmol) in MeOH (25 mL) was added Palladium on activated carbon (0.72 g, 6.77 mmol) ) at rt and the reaction mixture was stirred under H2 atmosphere at same temperature for 2 h. The reaction mixture was filtered through celite bed and washed with methanol (2x 30 mL). The combined filtrate was concentrated under reduced pressure to afford the title compound as a colourless liquid (1.80 g, 98% ). LCMS m/z = 270 [M+H]+. Intermediate 69. N-(2-(2,7-diazaspiro[3.5]nonan-7-yl)ethyl)-3-fluoro-4-((4-(1-(2-hydroxy- 2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide.
Figure imgf000189_0001
The title compound was prepared from tert-butyl 7-(2-aminoethyl)-2,7- diazaspiro[3.5]nonane-2-carboxylate (Intermediate 68) using an analogous 4-Step procedure as described for Intermediate 67. LCMS m/z = 627 [M+H]+. Intermediate 70. N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-3-fluoro-4-((4-(1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide hydrochloride.
(
Figure imgf000190_0001
Step 1: Synthesis of 5-(tert-butoxycarbonyl)-2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan- 13-yl 4-methylbenzenesulfonate 4-methylbenzenesulfonyl chloride (8.18 g, 42.9 mmol) was added portion wise to a stirred solution of tert-butyl (tert-butoxycarbonyl)(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)carbamate (10 g, 28.6 mmol) and TEA (12 mL, 85.9 mmol) in DCM (100.00 mL) under an inert atmosphere at 0 °C and the reaction mixture was allowed to warm to rt and stirred for 18 h. The reaction mixture was diluted with water (100 mL) and extracted with DCM (2x 100 mL). The combined organics were dried (Na2SO4), concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 20-30 % EtOAc/PE) to afford the title compound as a colourless liquid (12.5 g, 87%). LCMS m/z = 448 [M+H]+. Step 2: Synthesis of tert-butyl (2-(2-(2-azidoethoxy)ethoxy)ethyl)(tert- butoxycarbonyl)carbamate NaN3 (3.87 g, 59.6 mmol) was added to a stirred solution of 5-(tert-butoxycarbonyl)-2,2- dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl 4-methylbenzenesulfonate (10 g, 19.9 mmoL) in DMF (60 mL) at rt and the reaction mixture heated at 60 °C for 16h. The reaction mixture was diluted with water (60 mL) and extracted with EtOAc (3x 60 mL). The combined organics were washed with ice-cold sat. brine solution (3x 60 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 10-25% EtOAc/PE) to afford the title compound as a colourless liquid (6.5 g, 87%). LCMS m/z = 375 [M+H]+. Step 3: Synthesis of tert-butyl (2-(2-(2-aminoethoxy)ethoxy)ethyl)(tert- butoxycarbonyl)carbamate To a solution of tert-butyl (2-(2-(2-azidoethoxy)ethoxy)ethyl)(tert-butoxycarbonyl)carbamate (4.0 g, 10.7 mmoL) and acetic acid (0.61 mL, 10.7 mmoL) in EtOH (180 mL) was added 10% palladium on carbon (0.45 g, 4.27 mmoL) under an inert atmosphere at rt and hydrogenated under H2 gas at 50 psi pressure at rt for 5 h. The reaction mixture was filtered through a celite bed, washed with MeOH (100 mL) and concentrated under reduced pressure. The residue was triturated with diethyl ether (50 mL) to afford the title compound as a colourless liquid (3.5 g; 94%). LCMS m/z = 349 [M+H]+. Step 4: Synthesis of tert-butyl (tert-butoxycarbonyl)(2-(2-(2-((3-fluoro-4- nitrophenyl)sulfonamido)ethoxy)ethoxy)ethyl)carbamate TEA (3.5 mL, 9.75 mmoL) was added to a stirred solution tert-butyl (2-(2-(2- aminoethoxy)ethoxy)ethyl)(tert-butoxycarbonyl)carbamate (3.5 g, 10.0 mmoL) in DCM (35 mL) at 0 °C and stirred for 15 min. A solution of 3-fluoro-4-nitrobenzenesulfonyl chloride (4.81 g, 20.1 mmoL) in DCM (35 mL) was added drop wise at 0 °C and the resulting reaction mixture allowed to warm to rt and stirred for 1h. The reaction mixture was diluted with water (70 mL) and extracted with DCM (3x 70 mL). The combined organics were dried (Na2SO4), concentrated under reduced pressure and the residue purified by chromatography (SiO2, 20- 30% EtOAc/PE) to afford the title compound (3.30 g; 60%).. LCMS m/z = 550 [M+H]+. Step 5: Synthesis of tert-butyl (tert-butoxycarbonyl)(5-((3-fluoro-4-nitrophenyl)sulfonyl)-2,2- dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl)carbamate To a stirred solution of tert-butyl (tert-butoxycarbonyl)(2-(2-(2-((3-fluoro-4- nitrophenyl)sulfonamido)ethoxy)ethoxy)ethyl)carbamate (3.30 g, 5.98 mmoL) in THF (66 mL) was added sodium hydride (598 mg, 60 % NaH, 14.95 mmoL) at 0 °C and stirred for 5 min. The reaction mixture was allowed to warm to rt and stirred for 745 min before di-tert- butyl dicarbonate (5.49 mL, 23.9 mmoL) was added and the reaction mixture stirred at rt for 15 min. The reaction mixture was quenched with ice-cold water (60 mL) and extracted with EtOAc (2x 60 mL). The combined organics were dried (Na2SO4), concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 25-35 % EtOAc/PE) to afford the title compound as a colourless liquid (2.50 g, 64%). LCMS m/z = 552 [M+H]+. Step 6, 7, 8. Synthesis of N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-3-fluoro-4-((4-(1-(2- hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide hydrochloride. The title compound was prepared from tert-butyl (tert-butoxycarbonyl)(5-((3-fluoro-4- nitrophenyl)sulfonyl)-2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl)carbamate using an analogous procedure to Step 2, 3 and 4 as described for Intermediate 67. LCMS m/z = 906 [M+H]+. Intermediate 71. N-(17-amino-3,6,9,12,15-pentaoxaheptadecyl)-3-fluoro-4-((4-(1-(2- hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide hydrochloride.
Figure imgf000192_0001
Step 1: Synthesis of tert-butyl (17-azido-3,6,9,12,15-pentaoxaheptadecyl) (tert- butoxycarbonyl) carbamate To a stirred solution of 17-azido-3,6,9,12,15-pentaoxaheptadecyl 4-methylbenzenesulfonate (4 g, 8.66 mmol) and di-tert-butyl iminodicarboxylate (2.07 g, 9.53 mmol) in DMF (24 mL) was added caesium carbonate (3.38 g, 10.4 mmol) at rt and the reaction mixture stirred at 50 °C for 16h. The reaction mixture was diluted with water (150 mL) and extracted with EtOAc (3x 50 mL). The combined organics were washed with ice-cold sat. brine solution (3x 50 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 10-20% EtOAc/hexane to afford the title compound as a colourless liquid (3.70 g, 84%) LCMS m/z = 524 [M+H]+. Step 2: Synthesis of tert-butyl (17-amino-3,6,9,12,15-pentaoxaheptadecyl) (tert- butoxycarbonyl) carbamate A solution of tert-butyl (17-azido-3,6,9,12,15-pentaoxaheptadecyl) (tert-butoxycarbonyl) carbamate (Step 1, 2.50 g, 4.93 mmol) and acetic acid (1.41 mL, 24.7 mmol) in MeOH (25 mL) was hydrogenated in the presence of 10 % Pd/C (0.52 g, 4.93 mmol) under H2 at 50 psi pressure for 8 h. The reaction mixture was filtered through a pad of celite and washed with MeOH (120 mL). The combined organics were concentrated under reduced pressure and the residue triturated with diethyl ether (50 mL), dried under reduced pressure and purified by column chromatography (alumina, 0-10% MeOH/DCM) to afford the title compound as a colourless liquid (1.40 g, 59%). LCMS m/z = 481 [M+H]+. Step 3: Synthesis of tert-butyl (tert-butoxycarbonyl) (17-((3-fluoro-4-nitrophenyl) sulfonamido)-3,6,9,12,15-pentaoxaheptadecyl)carbamate To a stirred solution of tert-butyl (17-amino-3,6,9,12,15-pentaoxaheptadecyl) (tert- butoxycarbonyl) carbamate (Step 2, 1.4 g, 2.91 mmol) in DCM (14 mL) was added triethylamine (1.01 mL, 7.28 mmol) dropwise at 0 °C and stirred for 15 min. To this was added a solution of 3-fluoro-4-nitrobenzenesulfonyl chloride (1.53 g, 6.40 mmol) in DCM (14 mL) drop wise at 0 °C and the resulting reaction mixture stirred for 1h. The reaction mixture was diluted with water (50 mL) and extracted with DCM (3x 50 mL). The combined organics were dried (Na2SO4), concentrated under reduced pressure and the residue purified by flash column chromatography (SiO2, 50-60% EtOAc/PE to afford the title compound as a brown liquid (1.50 g, 75%). LCMS m/z = 628 [M+H]+. Step 4: Synthesis of tert-butyl (17-((4-amino-3-fluorophenyl) sulfonamido)-3,6,9,12,15- pentaoxaheptadecyl)(tert-butoxycarbonyl)carbamate To a stirred solution of tert-butyl (tert-butoxycarbonyl) (17-((3-fluoro-4-nitrophenyl) sulfonamido)-3,6,9,12,15-pentaoxaheptadecyl)carbamate (Step 3, 1.50 g, 2.19 mmol) in EtOH (15 mL) and water (15 mL) was added ammonium chloride (2.34 g, 43.9 mmol) and Fe powder (2.45 g, 43.9mmoL) at 0 °C and the resulting reaction mixture stirred at 55 °C for 3h. The reaction mixture was filtered through a ped of celite and washed with 10% MeOH/DCM (60 mL). The filtrate was diluted with water (50 mL) and extracted with 10% MeOH/DCM. The combined organics dried (Na2SO4), concentrated under reduced pressure and the residue purified by flash chromatography (SiO2, 60-70 % EtOAc/PE) to afford the title compound as a brown liquid (1.0 g; 69.7%). LCMS m/z = 598 [M+H]+. Step 5: Synthesis of tert-butyl (tert-butoxycarbonyl) (17-((3-fluoro-4-((4-(1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl) sulfonamido)-3,6,9,12,15-pentaoxaheptadecyl) carbamate To a stirred solution of 1-(4-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)- 2-methylpropan-2-ol Intermediate 1 (0.35 g, 1.10 mmol) and tert-butyl (17-((4-amino-3- fluorophenyl) sulfonamido)-3,6,9,12,15-pentaoxaheptadecyl)(tert-butoxycarbonyl)carbamate (Step 4, 0.60 g, 0.91 mmoL) in IPA (6 mL) was added PTSA (0.31 g, 1.83 mmol) at rt and the reaction mixture stirred at 90 °C for 16 h. The reaction mixture was diluted with water (30 mL), extracted with EtOAc (3x 50 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0-10% MeOH/DCM) to afford the title compound as a brown liquid (0.59 g, 68%). LCMS m/z = 738 [M+H]+. Step 6: Synthesis of N-(17-amino-3,6,9,12,15-pentaoxaheptadecyl)-3-fluoro-4-((4-(1-(2- hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl) pyrimidin-2-yl)amino) benzenesulfonamide hydrochloride To a stirred solution tert-butyl (tert-butoxycarbonyl) (17-((3-fluoro-4-((4-(1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl) sulfonamido)-3,6,9,12,15-pentaoxaheptadecyl) carbamate (Step 5, 0.24 g, 0.25 mmol) in DCM (2.4 mL) was added 4.0 M HCl in dioxane (1.2 mL) at 0 °C. Then the reaction mixture was allowed to warm to rt and stirred for 3h. The reaction mixture was concentrated under reduced pressure and the residue triturated with diethyl ether the afford the title compound as an off-white foamy solid (0.20 g, 98%). LCMS m/z = 738 [M+H]+. Intermediate 72. N-(14-amino-3,6,9,12-tetraoxatetradecyl)-3-fluoro-4-((4-(1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide hydrochloride.
Figure imgf000194_0001
The title compound was prepared as an off-white solid (0.40g) from 14-azido-3,6,9,12- tetraoxatetradecyl 4-methylbenzenesulfonate (Chem. Med. Chem., 2009, 4, 749-755, 6.00 g, 14.4 mmol) using an analogous 6-Step procedure as described for Intermediate 71. LCMS m/z = 694 [M+H]+. Intermediate 73. N-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-3-fluoro-4-((4-(1-(2- hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide hydrochloride.
Figure imgf000195_0001
The title compound was prepared as an off-white solid (0.37 g) from 2-(2-(2-(2- azidoethoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (8.5 g, 14.4 mmol) using an analogous 6-Step procedure as described for Intermediate 71. LCMS m/z = 650 [M+H]+. Intermediate 74. 4-((2-(1-(2-azidoethyl)piperidin-4-yl)ethyl)amino)-2-(2,6-dioxopiperidin- 3-yl)isoindoline-1,3-dione.
Figure imgf000195_0002
Step 1. Synthesis of tert-butyl (2-(1-(2-azidoethyl)piperidin-4-yl)ethyl)carbamate Potassium carbonate (1.82 g, 13.14 mmol) was added at rt to a stirred solution of tert-butyl (2-(piperidin-4-yl)ethyl)carbamate (1.0 g, 4.38 mmol) and 2-azidoethyl 4- methylbenzenesulfonate (1.27 g, 5.25 mmol) in MeCN (10 mL) and the reaction mixture stirred at 90°C for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3x 50 mL). The combined organics were washed with water (2x 50 mL), brine (25 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 20-25% EtOAc/PE) to afford the title compound as a colourless liquid (0.80 g, 61%). LCMS m/z = 298 [M+H]+. Step 2. Synthesis of 2-(1-(2-azidoethyl)piperidin-4-yl)ethan-1-amine hydrochloride To a stirred solution of tert-butyl (2-(1-(2-azidoethyl)piperidin-4-yl)ethyl)carbamate (Step 1, 0.80 g, 2.69 mmol) in DCM (8 mL) was added 4M HCl in dioxane (4 mL) at 0 °C and stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure to afford the title compound as a colourless gum (700 mg). 1H NMR (DMSO-d6, 400 MHz): 10.59 (bs, 1H), 3.47-3.45 (m, 2H), 3.25-3.20 (m, 2H), 2.92-2.78 (m, 4H), 1.85-1.82 (m, 2H), 1.61-1.51 (m, 6H). Step 3. Synthesis of 4-((2-(1-(2-azidoethyl)piperidin-4-yl)ethyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione To a stirred solution of 2-(1-(2-azidoethyl)piperidin-4-yl)ethan-1-amine hydrochloride (Step 2, 0.35 g, 1.77 mmol) and 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (0.59 g, 2.13 mmol) in DMSO (7mL) was added DIPEA (1.15 g, 8.87 mmol ) at rt and the reaction mixture stirred at 110 °C for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3x 50 mL). The combined organics were washed with water (2x 50 mL), brine (25 mL), dried and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 5-10 % Methanol/DCM to afford the title compound as a colourless liquid (350 mg, 38%). LCMS m/z = 454 [M+H]+. Intermediate 75. 5-((2-(1-(2-azidoethyl)piperidin-4-yl)ethyl)amino)-2-(2,6-dioxopiperidin- 3-yl)isoindoline-1,3-dione.
Figure imgf000196_0001
The title compound was prepared from 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3- dione and 2-(1-(2-azidoethyl)piperidin-4-yl)ethan-1-amine hydrochloride (Intermediate 74, Step 2) using an analogous method to that described for Intermediate 74, Step 3. LCMS m/z = 454 [M+H]+. Intermediate 76. 5-(9-(2-azidoethyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione.
Figure imgf000197_0001
The title compound was prepared from 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3- dione and 3-(2-azidoethyl)-3,9-diazaspiro[5.5]undecane hydrochloride (Intermediate 22, Step 2) using an analogous method to that described for Intermediate 74, Step 3. LCMS m/z = 480 [M+H]+. Intermediate 77. 5-(4-(2-azidoethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione.
Figure imgf000197_0002
The title compound was prepared as a yellow solid (120 mg, 54%) from 2-(2,6- dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione and 1-(2-azidoethyl)piperazine using an analogous method to that described for Intermediate 74, Step 3. Intermediate 78. Synthesis of 5-(7-(2-azidoethyl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione.
Figure imgf000197_0003
The title compound was prepared as a yellow solid (300 mg, 20%) from 2-(2,6- dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione and 7-(2-azidoethyl)-2,7- diazaspiro[3.5]nonane hydrochloride (Intermediate 81, Step 1) using an analogous method to that described for Intermediate 74, Step 3. LCMS m/z = 452 [M+H]+. Intermediate 79. 3-(3-((2-(2-(2-azidoethoxy)ethoxy)ethyl)amino)phenyl)piperidine-2,6- dione.
Figure imgf000197_0004
To a stirred solution of 3-(3-aminophenyl)piperidine-2,6-dione (0.20 g, 0.98 mmol) in DMF (2 mL), were added DIPEA (0.85 mL, 4.90 mmol) and 2-(2-(2-azidoethoxy)ethoxy)ethyl 4- methylbenzenesulfonate (0.48 g, 1.469 mmol) at rt and the resulting reaction mixture stirred at 110 °C for 18 h. The reaction mixture was diluted with water (25 mL) and extracted with EtOAc (3x 25 mL). The combined organics were washed with brine (25 mL), dried and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 50-60% EtOAc/PE) to afford the title compound as a brown liquid (90 mg, 25%). LCMS m/z = 362 [M+H]+. Intermediate 80. 3-(4-((2-(2-(2-azidoethoxy)ethoxy)ethyl)amino)phenyl)piperidine-2,6- dione.
Figure imgf000198_0001
The title compound was prepared as a brown semi-solid (180 mg, 50%) from 3-(4- aminophenyl)piperidine-2,6-dione and 2-(2-(azidomethoxy)ethoxy)ethyl 4- methylbenzenesulfonate using an analogous method to that described for Intermediate 79. LCMS m/z = 362 [M+H]+. Intermediate 81. 4-(7-(2-azidoethyl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-(2,6-dioxopiperidin- 3-yl)isoindoline-1,3-dione.
Figure imgf000198_0002
Step 1. Synthesis of 7-(2-azidoethyl)-2,7-diazaspiro[3.5]nonane hydrochloride 4M HCl in dioxane (7 mL) was added at 0 °C to a stirred solution of tert-butyl 7-(2- azidoethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (Intermediate 68, Step 1, 1.40 g, 4.74 mmol) in DCM (14 mL) and t reaction mixture stirred at rt for 3 h. The reaction mixture was concentrated under reduced pressure to afford the title compound as an off-white solid (1.60 g) which was used without further purification. Step 2. Synthesis of 4-(7-(2-azidoethyl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione The title compound was prepared as a yellow solid (480 mg, 29%) from 7-(2-azidoethyl)-2,7- diazaspiro[3.5]nonane hydrochloride and 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3- dione using an analogous method as described for Intermediate 74, Step 3. LCMS m/z = 452 [M+H]+. Intermediate 82. 3-(3-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)phenyl)piperidine-2,6-dione.
Figure imgf000199_0001
Step 1: Synthesis of 2-(2-(2-(3-bromophenoxy)ethoxy)ethoxy)ethan-1-ol To a stirred solution of 2-(2-(2-hydroxyethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (RSC Adv., 2020, 10, 21464-21472, 1.00 g, 3.29 mmol) and 3-bromophenol (0.85 g, 4.93 mmol) in MeCN (10 mL) was added potassium carbonate (1.36 g, 9.86 mmol) at rt and the resulting reaction mixture stirred at 80 °C for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3x 50 mL). The combined organics were washed with brine (30 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by combi-flash (SiO2, 5-10% EtOAc/PE) to afford the title compound as a colourless liquid (1.00 g, 99%). LCMS m/z = 307 [M+H]+. Step 2: Synthesis of 2-(2-(2-(3-(2,6-bis(benzyloxy)pyridin-3- yl)phenoxy)ethoxy)ethoxy)ethan-1-ol To a stirred solution of 2-(2-(2-(3-bromophenoxy)ethoxy)ethoxy)ethan-1-ol (Step 1, 1.00 g, 3.28 mmol) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.37 g, 3.28 mmol) in dioxane (10 mL) and water (1 mL) was added solution of potassium phosphate (2.09 g, 9.83 mmol) under argon at rt. The reaction mixture was degassed with argon and PdCl2(dppf).DCM (0.27 g, 0.33 mmol) added and the resulting reaction mixture stirred at 110 °C for 3 h. The reaction mixture was filtered through celite and the celite bed was washed with EtOAc (3x 30 mL). The filtrate was washed with water (50 mL) and brine (30 mL). The organics were dried (Na2SO4), concentrated under reduced pressure and the residue purified by combi-flash (SiO2, 10-20% EtOAc/PE) to afford the title compound as white semi-solid (1.10 g, 65%). LCMS m/z = 516 [M+H]+. Step 3: Synthesis of 3-(3-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)phenyl)piperidine-2,6-dione To a stirred solution of 2-(2-(2-(3-(2,6-bis(benzyloxy)pyridin-3- yl)phenoxy)ethoxy)ethoxy)ethan-1-ol (Step 2, 1.00 g, 3.28 mmol) in ethanol (10 mL) was added Palladium on carbon (0.30 g) at rt under nitrogen atmosphere and the reaction vessel filled with H2 (50 psi) and stirred at rt for 16 h under H2. The reaction mixture was filtered through a celite bed and washed with methanol (3x 50 mL). The filtrate was evaporated under reduced pressure and the residue purified by combi-flash (SiO2, 3-10% MeOH/DCM) to afford the title compound as a colourless liquid (0.35g, 53%). LCMS m/z = 338 [M+H]+. Step 4: Synthesis of 2-(2-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)ethoxy)ethoxy)ethyl 4- methylbenzenesulfonate To a stirred solution of 3-(3-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)phenyl)piperidine-2,6- dione (Step 3, 0.35 g, 1.04 mmol) and p-toluenesulfonyl chloride (0.40 g, 2.08 mmol) in DCM (7 mL) was added DMAP (0.01 g, 0.10 mmol) followed by dropwise addition of TEA (0.43 mL, 3.11 mmol) at 0 °C and the resulting reaction mixture stirred at rt for 16 h. The reaction was quenched with water and extracted in DCM (3x 50 mL). The combined organics were washed with brine (50 mL), dried (Na2SO4) and concentrated under the reduced pressure. The residue was purified by combi-flash (SiO2, 3-10% MeOH/DCM) to afford the title compound as a colourless liquid (0.37 g, 52%). LCMS m/z = 492 [M+H]+. Step 5: Synthesis of 3-(3-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)phenyl)piperidine-2,6-dione To a solution of 2-(2-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)ethoxy)ethoxy)ethyl 4- methylbenzenesulfonate (Step 4, 0.37 g, 0.75 mmol) in DMF (7.4 mL) was added sodium azide (0.07 mg, 1.13 mmol) at rt and the resulting reaction mixture stirred at 60 °C for 3 h. The reaction mixture was diluted with water (50 mL) and extracted using EtOAc (2x 30 mL). The combined organics were washed with ice-cold water (2x 40 mL), dried (Na2SO4) and concentrated under the reduced pressure to afford the title compound as a colourless liquid (0.22 g, 80%). LCMS m/z = 363 [M+H]+. Intermediate 83. 3-(4-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)phenyl)piperidine-2,6-dione.
Figure imgf000200_0001
The title compound was prepared from 2-(2-(2-hydroxyethoxy)ethoxy)ethyl 4- methylbenzenesulfonate (RSC Adv., 2020, 10, 21464-21472) and 4-bromophenol using and analogous 5-Step procedure as described for Intermediate 82. LCMS m/z = 363 [M+H]+. Intermediate 84. 3-(3-(1'-(2-azidoethyl)-[4,4'-bipiperidin]-1-yl)phenyl)piperidine-2,6-dione.
Figure imgf000201_0001
To a stirred solution of 3-(3-([4,4'-bipiperidin]-1-yl)phenyl)piperidine-2,6-dione (Intermediate 33, 0.15 g, 0.38 mmol) in DMF (1.5 mL) was added 2-azidoethyl 4- methylbenzenesulfonate (0.14 g, 0.57 mmol) and DIPEA (0.33 mL, 1.91 mmol) at rt and stirred at 110 °C for 16 h. The reaction mixture was diluted with water (20 mL) and extracted in EtOAc (3x 20 mL). The combined organics were washed with ice-cold water (20 mL), brine (20 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by combi-flash (SiO2, 1-3% MeOH/DCM) to afford the title compound as a brown solid (0.12 g, 74%). LCMS m/z = 425 [M+H]+. Intermediate 85. 3-(3-(4-(2-azidoethyl)piperazin-1-yl)phenyl)piperidine-2,6-dione.
Figure imgf000201_0002
The title compound was prepared (30 mg, 38%) from 3-(3-(piperazin-1-yl)phenyl)piperidine- 2,6-dione using an analogous method to that described for Intermediate 84. LCMS m/z = 343 [M+H]+. Intermediate 86. 3-(3-(9-(2-azidoethyl)-3,9-diazaspiro[5.5]undecan-3-yl)phenyl)piperidine- 2,6-dione.
Figure imgf000201_0003
The title compound was prepared (650 mg, 55%) from 3-(3-(3,9-diazaspiro[5.5]undecan-3- yl)phenyl)piperidine-2,6-dione (Intermediate 10) using an analogous method to that described for Intermediate 84. LCMS m/z = 411 [M+H]+. Intermediate 87. 1-(4-(2-((4-((4-((3,9-diazaspiro[5.5]undecan-3-yl)methyl)piperidin-1- yl)sulfonyl)-2-fluorophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2- methylpropan-2-ol.
Figure imgf000202_0001
Step 1. Synthesis of benzyl 3,9-diazaspiro[5.5]undecane-3-carboxylate hydrochloride. 4M HCl in dioxane (15 mL) at 0 °C to a stirred solution of 3-benzyl 9-(tert-butyl) 3,9- diazaspiro[5.5]undecane-3,9-dicarboxylate (WO2022253309, 3 g, 10.4 mmol ) in DCM (15 mL ) and the reaction mixture stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure and the residue triturated with diethyl ether and DCM to obtain the title compound (2.4 g, 96%). LCMS m/z = 289 [M+H]+. Step 2. Synthesis of benzyl 9-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)-3,9- diazaspiro[5.5]undecane-3-carboxylate. Acetic acid (0.75 mL) was added to a stirred solution of benzyl 3,9-diazaspiro[5.5]undecane- 3-carboxylate hydrochloride (Ste p1, 1.50 g, 5.20 mmol) and tert-butyl 4-formylpiperidine-1- carboxylate (1.11 g, 5.20 mmol) in 1,2-dichloroethane (15 mL) under N2 and stirred at rt for 3 h. Sodium triacetoxyborohydride (3.30 g, 15.60 mmol) was added and reaction mixture stirred at rt for 16 h. The reaction mixture was quenched with water (50 mL) and extracted with DCM (3x 50 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (60-65% EtOAc/PE to afford the title compound as a white solid (1.2 g, 47%). LCMS m/z = 486 [M+H]+. Step 3. Synthesis of benzyl 9-(piperidin-4-ylmethyl)-3,9-diazaspiro[5.5]undecane-3- carboxylate hydrochloride 4.0 M hydrochloric acid in dioxane (5 mL) was added dropwise to a stirred solution benzyl 9- ((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (Step 2, 1.2 g, 2.47 mmol) in DCM (5 mL) at 0 °C and the resulting reaction mixture stirred at rt for 3 h. The reaction mixture was concentrated under reduced pressure to afford the title compound as a brown gum (0.62 g, 59% yield). LCMS m/z = 386 [M-56]+. Step 4: Synthesis of benzyl 9-((1-((3-fluoro-4-nitrophenyl)sulfonyl)piperidin-4-yl)methyl)- 3,9-diazaspiro[5.5]undecane-3-carboxylate To a stirred solution of benzyl 9-(piperidin-4-ylmethyl)-3,9-diazaspiro[5.5]undecane-3- carboxylate hydrochloride (Step 3, 0.85 g, 2.01 mmol) and 3-fluoro-4-nitrobenzenesulfonyl chloride (1.45 g, 6.04 mmol) in DCM (25 mL) was added TEA (0.61 g, 6.04 mmol) dropwise at 0 °C and the resulting reaction mixture stirred at rt for 3 h. The reaction was quenched with water (50 mL) and extracted in DCM (3x 30 mL). The combined organics were washed with brine (40 mL), dried (Na2SO4), concentrated under the reduced pressure and the residue purified by combi-flash (SiO2, 80% EtOAc/PE) to afford the tile compound as a brown gum (1.10 g, 93%). LCMS m/z = 589 [M+H]+. Step 5: Synthesis of benzyl 9-((1-((4-amino-3-fluorophenyl)sulfonyl)piperidin-4-yl)methyl)- 3,9-diazaspiro[5.5]undecane-3-carboxylate To the stirred solution of benzyl 9-((1-((3-fluoro-4-nitrophenyl)sulfonyl)piperidin-4- yl)methyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (Step 4, 1.10 g,1.87 mmol) in EtOH (40 mL) and water (40 mL), iron powder (2.09 g, 37.4 mmol) and ammonium chloride (2.0 g, 37.4 mmol) were added and stirred at 70 °C for 2 h. The reaction mixture was filtered through a celite bed and washed with MeOH (2x 30 mL). The filtrate was concentrated under reduced pressure and the remaining aqueous solution extracted with DCM (50 mL) to afford the title compound as a pale yellow solid (0.80 g, 76%). LCMS m/z = 559 [M+H]+. Step 6: Synthesis of benzyl 9-((1-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)piperidin-4- yl)methyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate 1-(4-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol Intermediate 1 (0.34 g, 1.07 mmol) was added at rt to a stirred solution of benzyl 9-((1-((4- amino-3-fluorophenyl)sulfonyl)piperidin-4-yl)methyl)-3,9-diazaspiro[5.5]undecane-3- carboxylate (Step 5, 0.60 g, 1.07 mmol) and PTSA (0.20 g, 1.07 mmol) in IPA (10 mL) and the resulting reaction mixture stirred at 90 °C for 16 h. The reaction mixture was evaporated under reduced pressure and the residue purified by combi-flash (SiO2, (3-5% MeOH/DCM) to afford the title compound as a brown gum (0.25 g, 27%). LCMS m/z = 841 [M+H]+. Step 7: Synthesis of 1-(4-(2-((4-((4-((3,9-diazaspiro[5.5]undecan-3-yl)methyl)piperidin-1- yl)sulfonyl)-2-fluorophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2- methylpropan-2-ol. To the stirred solution of benzyl 9-((1-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)piperidin-4- yl)methyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (Step 6, 0.30 g, 0.36 mmol) in MeOH (30 mL) were added Pd/C (0.03 g) and hydrogenated under hydrogen at rt for 48 h. The reaction mixture was filtered through a celite pad and washed with MeOH (2x 20 mL). The filtrate was concentrated under reduced pressure and the residue purified by combi-flash (SiO2, 5% MeOH/DCM) to afford the title compound as a pale yellow gum (0.25 g, 28%). LCMS m/z = 709 [M+H]+. Intermediate 88A and Intermediate 88B. Methyl (1r,3r)-3-((3-fluoro-4-((4-(1-(2-hydroxy- 2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)phenyl)sulfonamido)cyclobutane-1-carboxylate and (1r,3r)-3-((3-fluoro-4-((4-(1- (2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)phenyl)sulfonamido)cyclobutane-1-carboxylic acid.
Figure imgf000204_0001
Step 1. Synthesis of methyl (1r,3r)-3-((3-fluoro-4-nitrophenyl)sulfonamido)cyclobutane-1- carboxylate To a stirred solution of methyl (1r,3r)-3-aminocyclobutane-1-carboxylate (3 g, 23.23 mmol) and TEA (9.70 mL, 69.7 mmol) in DCM (20 mL) was added a solution of 3-fluoro-4- nitrobenzenesulfonyl chloride (13.9 g, 58.1 mmol) in DCM (20 mL) at -10 oC under nitrogen and the reaction mixture stirred at rt for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with DCM (3x 50 mL). The combined organics were dried (Na2SO4), concentrated under reduced pressure and the residue was purified by column chromatography (SiO2, 30% EtOAc/PE) to afford the title compound as a red solid (3.00 g, 39%). LCMS m/z = 333 [M+H]+. Step 2. Synthesis of methyl (1r,3r)-3-((4-amino-3-fluorophenyl)sulfonamido)cyclobutane-1- carboxylate To a stirred solution of methyl (1r,3r)-3-((3-fluoro-4-nitrophenyl)sulfonamido)cyclobutane-1- carboxylate (Step 1, 3.0 g, 9.02 mmol) in EtOH (30 mL) and water (30 mL) were added ammonium chloride (9.66 g, 181 mmol) and iron powder (9.93 g, 181 mmol) at rt and the resulting reaction mixture stirred at 80 ºC for 2 h. The reaction mixture was filtered through a pad of celite, washed with EtOAc (2x 50 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as a red solid (2.70 g, 99%). LCMS m/z = 303 [M+H]+. Step 3. Synthesis of methyl (1r,3r)-3-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonamido)cyclobutane-1- carboxylate and (1r,3r)-3-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)- 5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonamido)cyclobutane-1-carboxylic acid To a stirred solution of 1-(4-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)- 2-methylpropan-2-ol Intermediate 1 (0.60 g, 1.87 mmol) and methyl (1r,3r)-3-((4-amino-3- fluorophenyl)sulfonamido)cyclobutane-1-carboxylate (Step 2, 0.85 g, 2.81 mmol) in dioxane (20 mL), was added PTSA (0.36 g, 1.87 mmol) at 0 °C under nitrogen and the resulting reaction mixture stirred at 90 °C for 16 h. The reaction mixture was diluted with water (25 mL) and extracted with EtOAc (3x 25 mL). The combined organics were dried (Na2SO4), concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 40-60% EtOAc/PE) to afford Intermediate 88A as a red solid (0.47 g, 43%). LCMS m/z = 587 [M+H]+ and Intermediate 88B as a white solid (0.23 g, 20%). LCMS m/z = 573 [M+H]+. Intermediate 89. 3-fluoro-N-((1r,3r)-3-formylcyclobutyl)-4-((4-(1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide.
Figure imgf000206_0001
Step 1. Synthesis of 3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-N-((1r,3r)-3- (hydroxymethyl)cyclobutyl)benzenesulfonamide LAH (2.0 M in THF, 1.77 mL, 5.00 mmol) was added dropwise over 10 min at -10° C to a stirred solution of methyl (1r,3r)-3-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonamido)cyclobutane-1- carboxylate (Intermediate 88A, 0.47 g, 0.80 mmol) in THF (15 mL) under nitrogen and the resulting mixture stirred at rt for 1 h. The reaction mixture was quenched with saturated NH4Cl solution (250 mL) and extracted with EtOAc (3x 30 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as a white solid (0.33 g, 73%). LCMS m/z = 559 [M+H]+. Step 2. Synthesis of 3-fluoro-N-((1r,3r)-3-formylcyclobutyl)-4-((4-(1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide To a stirred solution of 3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-N-((1r,3r)-3- (hydroxymethyl)cyclobutyl)benzenesulfonamide (Step 1, 0.20 g, 0.34 mmol) in DMSO (3 mL), was added iodobenzoic acid (0.38 g, 1.36 mmol) portions wise at 0° C and stirred at rt for 2 h. The reaction mixture was quenched with ice-cold water and the solid collected by filtration to afford the title compound as a red solid (0.10 g, 50%). LCMS m/z = 585 [M+H]+. Intermediate 90. 1-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)but-3-yn-1-yl)piperidine-4- carbaldehyde.
Figure imgf000207_0001
Step 1. Synthesis of 3-(3-(4-hydroxybut-1-yn-1-yl)phenyl)piperidine-2,6-dione To a stirred solution of 3-(3-bromophenyl)piperidine-2,6-dione (3 g, 11.19 mmol) and but-3- yn-1-ol (2.35 g, 33.6 mmol) in dry DMSO (10 mL) was added DIPEA.trihydrofluoride (2.35 g, 55.9 mmol) and the solution purged with argon for 15 min. Bis(triphenylphosphine)palladium chloride (2.57 g, 2.24 mmol) and copper(I) iodide (0.64 g, 3.36 mmol) were added under nitrogen and the reaction mixture stirred at 100 °C for 4h. The reaction mixture was quenched with ice cold water (20 mL) and extracted with EtOAc (3x 15 mL). The combined organics were washed with brine solution (15 mL), dried (Na2SO4), concentrated under reduced pressure and the residue purified by flash chromatography (SiO2, 70% EtOAc/PE) as brown liquid (0.98 g, 34%). LCMS m/z = 258 [M+H]+. Step-2 : Synthesis of 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)but-3-yn-1-yl 4- methylbenzenesulfonate To the stirred solution of 3-(3-(4-hydroxybut-1-yn-1-yl)phenyl)piperidine-2,6-dione (Step 1, 2 g, 7.77 mmol) in DCM (30 mL) was added TEA (3.23 mL, 23.3 mmol) at 0 oC followed by the addition of 4-toluenesulfonyl chloride (2.22 g, 11.7 mmol) in DCM (10 mL) and the reaction mixture warmed to rt and stirred for 16 h. The reaction mixture was diluted with DCM (20 mL) and water (40 mL) and stirred for 10 min. The layers were separated and the aqueous layer extracted with DCM (2x 30 mL). The combined organics was washed with brine (50 mL), dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by flash chromatography (SiO2, 80-100% EtOAc/PE) to afford the title compound as a white solid (0.8 g, 25%). LCMS m/z = 412 [M+H]+. Step-3 : Synthesis of 3-(3-(4-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)but-1-yn-1- yl)phenyl)piperidine-2,6-dione To a stirred solution of 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)but-3-yn-1-yl 4- methylbenzenesulfonate (Step 2, 350 mg, 0.88 mmol) and 4-(1,3-dioxolan-2-yl)piperidine (138.5 mg, 0.88 mmol) in DMF (3.5 mL) were added sodium bicarbonate (222 mg, 2.64 mmol) and KBr (21 mg, 0.18 mmol) at rt and the reaction mixture heated 90 °C for 16 h. The reaction mixture was diluted with water (20 mL) and EtOAc (20 mL) and stirred for 10 min. The layers were separated and aqueous layer extracted with EtOAc (2x 20 mL). The combined organics were dried (Na2SO4), concentrated under the reduced pressure and the residue purified by column chromatography (SiO2, 1-3 % MeOH/DCM) as a brown solid (220 mg, 65%). LCMS m/z = 397 [M+H]+. Step 4: Synthesis of 1-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)but-3-yn-1-yl)piperidine-4- carbaldehyde TFA (1 mL) was added to a stirred solution of 3-(3-(4-(4-(1,3-dioxolan-2-yl)piperidin-1- yl)but-1-yn-1-yl)phenyl)piperidine-2,6-dione (Step 3, 110 mg, 0.28 mmol) in DCM (1 mL) and water (0.2 mL) and the reaction mixture stirred at rt for 16h. The reaction mixture was concentrated under reduced pressure to afford the title compound as brown solid (90 mg, 92%) which was used without further purification. LCMS m/z = 353 [M+H]+. Intermediate 91. N-(6-aminohexyl)-3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide.
Figure imgf000208_0001
Step 1: Synthesis of tert-butyl (6-((3-fluoro-4-nitrophenyl)sulfonamido)hexyl)carbamate To a stirred solution of tert-butyl (6-aminohexyl)carbamate (5.0 g, 23.1 mmol) and 3-fluoro- 4-nitrobenzenesulfonyl chloride (8.30 g, 34.7 mmol) in DCM (50mL) was added TEA (4.60 g, 46.2 mmol) dropwise at 0 °C and the resulting reaction mixture stirred at rt for 4 h. The reaction was quenched with water (60 mL) and extracted in DCM (3x 50 mL). The combined organics were washed with brine (60 ml), dried (Na2SO4), concentrated under the reduced pressure and the residue purified by combi-flash (SiO2, 20% EtOAc/PE) to afford the title compound as a yellow solid (3.5 g, 36%). LCMS m/z = 420 [M+H]+. Step 2: Synthesis of tert-butyl (6-((4-amino-3-fluorophenyl)sulfonamido)hexyl)carbamate To a stirred solution of tert-butyl (6-((3-fluoro-4-nitrophenyl)sulfonamido)hexyl)carbamate (Step 1, 0.50 g, 1.19 mmol) in MeOH (5 mL) was added Pd/C (0.10 g) at rt under nitrogen and the reaction vessel was filled with H2 (50 psi) and stirred at rt for 2 h under H2. The reaction mixture was filtered through a pad of celite and washed with MeOH (3x 50 mL). The filtrate was evaporated under reduced pressure and the residue purified by combi-flash (SiO2, 20% EtOAc/PE) to afford the title compound as a brown gum (0.28 g, 60%) LCMS m/z = 390 [M+H]+. Step 3 and 4: Synthesis of 3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-N-(6-((2,2,2-trifluoroacetyl)-l4- azaneyl)hexyl)benzenesulfonamide The title compound was prepared from tert-butyl (6-((4-amino-3- fluorophenyl)sulfonamido)hexyl)carbamate (Step 2, 0.30 g, 0.94 mmol) and 1-(4-(2-chloro-5- (trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol Intermediate 1 (0.36 g, 0.94 mmol) using an analogous 2 -Step method to that described for Intermediate 71, Step 5 and 6. LCMS m/z = 574 [M+H]+. Intermediate 92. N-(5-aminopentyl)-3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide hydrochloride.
Figure imgf000209_0001
Step 1: Synthesis of tert-butyl (5-((3-fluoro-4-nitrophenyl)sulfonamido)pentyl)carbamate The title compound was prepared as a brown liquid (6.0g, 60%) from tert-butyl (5- aminohexyl)carbamate (5 g, 24.71 mmol) and 3-fluoro-4-nitrobenzenesulfonyl chloride (11.84 g, 7.32 mmol) using an analogous method to that described for Intermediate 71, Step 1. Step 2, 3, 4, 5: Synthesis of N-(5-aminopentyl)-3-fluoro-4-((4-(1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide hydrochloride The title compound was prepared from tert-butyl (5-((3-fluoro-4- nitrophenyl)sulfonamido)pentyl)carbamate (Step 1) using an analogous 4-Step procedure as described for Intermediate 70, 55 Steps 5, 6, 7, 8. LCMS m/z = 560 [M+H]+. Intermediate 93. N-(7-aminoheptyl)-3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide hydrochloride.
Figure imgf000210_0001
Step 1 and 2: Synthesis of tert-butyl (7-((4-amino-3- fluorophenyl)sulfonamido)heptyl)carbamate The title compound was prepared from tert-butyl (7-aminoheptyl)carbamate and 3-fluoro-4- nitrobenzenesulfonyl chloride using an analogous 2-Step procedure as described for Intermediate 91, Step 5 and 6. LCMS m/z = 404 [M+H]+. Step 3, 4. Synthesis of N-(7-aminoheptyl)-3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)- 1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide hydrochloride. The title compound was prepared as an off-white solid (80 mg) from tert-butyl (7-((4-amino- 3-fluorophenyl)sulfonamido)heptyl)carbamate (Step 2) using an analogous 2-Step procedure as described for Intermediate 71, Step 5 and 6,. LCMS m/z = 588 [M+H]+. Intermediate 94. N-(4-aminobutyl)-3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide hydrochloride.
Figure imgf000211_0001
The title compound was prepared as a yellow solid (70 mg) from tert-butyl (4- aminobutyl)carbamate and 3-fluoro-4-nitrobenzenesulfonyl chloride using an analogous 4- Step procedure as described for Intermediate 93. LCMS m/z = 546 [M+H]+. Intermediate 95. 1-(4-(2-((4-((4-aminopiperidin-1-yl)sulfonyl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol.
Figure imgf000211_0002
The title compound was prepared as an off-white solid (650 mg) from tert-butyl piperidin-4- ylcarbamate using an analogous 4-Step procedure as described for Intermediate 71, Step 3, 4, 5 and 6. LCMS m/z = 540 [M+H]+. Intermediate 96. 1-(4-(2-((4-((4-(azetidin-3-ylamino)piperidin-1- yl)sulfonyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2- methylpropan-2-ol hydrochloride.
Figure imgf000212_0001
Step 1, 2, 3. Synthesis of 11-((4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)piperidin-4-one. The title compound was prepared as a white solid (0.60 g) from piperidin-4-one using an analogous 3-Step procedure as described for Intermediate 71, Step 3, 4, 5. LCMS m/z = 539 [M+H]+. Step 4. Synthesis of tert-butyl 3-((1-((4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4- yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)piperidin-4-yl)amino)azetidine- 1-carboxylate Acetic acid (0.13 mL) was added to a stirred solution of 11-((4-((4-(1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)phenyl)sulfonyl)piperidin-4-one (Step 3, 0.30 g, 0.55 mmol) and tert-butyl 3- aminoazetidine-1-carboxylate (0.19 g, 1.11 mmol) in 1,2-dichloroethane (6 mL) and stirred at rt for 3 h. To this was added STAB (0.35 g, 1.67 mmol) and the resulting reaction mixture stirred at rt for 16 h. The reaction was quenched with water (20 mL) and extracted in EtOAc (3x 20 mL). The combined organics were washed with water (2x 20 mL), brine (20 mL), dried (Na2SO4) and concentrated under reduced. The residue was purified by combi-flash (SiO2, 60-65% EtOAc/PE) to afford the title compound as a white solid (0.30 g, 77%). LCMS m/z = 695 [M+H]+. Step 5. Synthesis of 1-(4-(2-((4-((4-(azetidin-3-ylamino)piperidin-1- yl)sulfonyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2- methylpropan-2-ol hydrochloride The title compound was prepared as a white solid (0.27 g) from tert-butyl 3-((1-((4-((4-(1-(2- hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)phenyl)sulfonyl)piperidin-4-yl)amino)azetidine-1-carboxylate (Step 4, 0.30 g, 0.43 mmol) using an analogous method to that described for Intermediate 71, Step 6. LCMS m/z = 595 [M+H]+. Intermediate 97. 1-methyl-3-(3-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)phenyl)piperidine- 2,6-dione.
Figure imgf000213_0001
Step 1. Synthesis of tert-butyl 4-((3-(3-(1-methyl-2,6-dioxopiperidin-3-yl)phenyl)prop-2-yn- 1-yl)oxy)piperidine-1-carboxylate To a solution of tert-butyl 4-((3-(3-(2,6-dioxopiperidin-3-yl)phenyl)prop-2-yn-1- yl)oxy)piperidine-1-carboxylate Intermediate 12, Step 1 (1.00 g, 2.35 mmol) in DMF (10 mL) was added potassium carbonate (1.30 g, 9.38 mmol) and the mixture stirred for 10 min before MeI (0.37 g, 2.58 mmol) was added and the resulting reaction mixture stirred at rt for 16 h. The reaction was quenched with ice-cold water (30 mL) and extracted in EtOAc (2x 25 ml). The combined organics were washed with brine (50 mL), dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as a brown semi-solid (0.50 g, 48%). LCMS m/z = 427 [M+H]+. Step 2. Synthesis of 1-methyl-3-(3-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)phenyl)piperidine- 2,6-dione The title compound was prepared as an off-white solid 300 mg, 95%) from tert-butyl 4-((3- (3-(1-methyl-2,6-dioxopiperidin-3-yl)phenyl)prop-2-yn-1-yl)oxy)piperidine-1-carboxylate (Step 1, 0.50 g, 1.843 mmol) using an analogous method to that described for Intermediate 71, Step 6. LCMS m/z = 341 [M+H]+. Intermediate 98. 3-fluoro-N-((1r,4r)-4-formylcyclohexyl)-4-((4-(1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N- methylbenzenesulfonamide.
Figure imgf000214_0001
Step 1: Synthesis of methyl (1r,4r)-4-((3-fluoro-N-methyl-4- nitrophenyl)sulfonamido)cyclohexane-1-carboxylate The title compound was prepared as a brown solid (1.1 g, 53%) from methyl (1r,4r)-4-((3- fluoro-4-nitrophenyl)sulfonamido)cyclohexane-1-carboxylate (Intermediate 14, Step 1; 2.00 g, 5.55 mmol) using an analogous method to that described for Intermediate 97, Step 1. LCMS m/z = 375 [M+H]+. Step 2: Synthesis of methyl (1r,4r)-4-((4-amino-3-fluoro-N- methylphenyl)sulfonamido)cyclohexane-1-carboxylate The title compound was prepared as a black solid (900 mg, 98%) from methyl (1r,4r)-4-((3- fluoro-N-methyl-4-nitrophenyl)sulfonamido)cyclohexane-1-carboxylate (Step 1, 1 g) using an analogous method to that described for Intermediate 71, Step 4. LCMS m/z = 345 [M+H]+. Step 3: Synthesis of methyl (1r,4r)-4-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N- methylphenyl)sulfonamido)cyclohexane-1-carboxylate To a stirred solution of methyl (1r,4r)-4-((4-amino-3-fluoro-N- methylphenyl)sulfonamido)cyclohexane-1-carboxylate (Step 2, 0.90 g, 2.61 mmol) and 1-(4- (2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol Intermediate 1 (1.01 g, 3.14 mmol) in dioxane (20 mL) was added caesium carbonate (2.55 g, 7.84 mmol) at rt and the reaction mixture purged with argon for 10 min before Pd(OAc)2 (0.12 g, 0.52 mmol) and BINAP (0.49 g, 0.78 mmol) were added. The resulting reaction mixture was heated at 100 °C in microwave oven for 2 h. The reaction mixture was filtered through a pad of celite and washed with EtOAc (2x 30 mL). The filtrate was washed with water (50 mL), brine (50 mL) and dried (Na2SO4) and concentrated under reduced pressure. The reside was purified by combi-flash (SiO2, 35% EtOAc/PE) to afford the title compound as a brown solid (0.35 g, 21%). LCMS m/z = 629 [M+H]+. Step 4: Synthesis of 3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-N-((1r,4r)-4-(hydroxymethyl)cyclohexyl)-N- methylbenzenesulfonamide To a stirred solution of methyl (1r,4r)-4-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N- methylphenyl)sulfonamido)cyclohexane-1-carboxylate (Step 3, 0.215 g, 0.350 mmol) in THF (50 mL) was added LiAlH4 (0.64 mL, 1.27 mmol) at 0 °C and the resulting reaction mixture stirred for 2 h. The reaction mixture was quenched with water and extracted in EtOAc (2x 50 mL). The combined organics were concentrated under reduced pressure to afford the title compound as a black gum (0.15 g, 39%). LCMS m/z = 601 [M+H]+. Step 5. Synthesis of 3-fluoro-N-((1r,4r)-4-formylcyclohexyl)-4-((4-(1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N- methylbenzenesulfonamide To the reaction mixture of 3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-N-((1r,4r)-4-(hydroxymethyl)cyclohexyl)-N- methylbenzenesulfonamide (Step 4, 0.35 g, 0.58 mmol) in DCM (10 mL) was added DMP (0.49 g, 1.17 mmol) at rt and the reaction mixture stirred at rt for 2 h. The reaction mixture was filtered through a pad of celite and washed with DCM (2x 20 mL). The filtrate was concentrated under reduced pressure and the residue purified by combi-flash (SiO2, 45% EtOAc/PE) to afford the title compound as a brown solid (0.30 g, 86%). LCMS m/z = 599 [M+H]+. Intermediate 99. N-(2-chloroethyl)-3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methylbenzenesulfonamide.
Figure imgf000216_0001
Step 1. Synthesis of N-(2-chloroethyl)-3-fluoro-N-methyl-4-nitrobenzenesulfonamide.. To a stirred solution of 2-chloro-N-methylethan-1-amine (2.0 g, 21.4 mmol) in DCM (80 mL) at rt was added TEA (9.28 mL, 64.2 mmol) followed, at 0 °C, 3-fluoro-4- nitrobenzenesulfonyl chloride (6.15 g, 25.7 mmol) and the resulting mixture stirred at 0 °C for 1 h. The reaction mixture was diluted with water (80 mL) and extracted with DCM (3x 60 mL). The combined organics were dried (Na2SO4), concentrated under reduced pressure and the residue purified by flash chromatography (SiO2, 20% EtOAc/PE) to the title compound was a brown (2.5 g). LCMS m/z = 297 [M+H]+. Step 2 and 3. Synthesis of N-(2-chloroethyl)-3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)- 1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methylbenzenesulfonamide. The title compound was prepared as a brown gum (80 mg, 77%) from N-(2-chloroethyl)-3- fluoro-N-methyl-4-nitrobenzenesulfonamide (Step 1) and 1-(4-(2-chloro-5- (trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol Intermediate 1 using an analogous 2-Step procedure as described for Intermediate 71, Step 3 and 4. LCMS m/z = 551 [M+H]+. Intermediate 100. 2-methyl-1-(4-(2-((4-(piperazin-1-ylsulfonyl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propan-2-ol.
Figure imgf000216_0002
Step 1. Synthesis of tert-butyl 4-((4-nitrophenyl)sulfonyl)piperazine-1-carboxylate To a stirred solution of 4-nitrobenzenesulfonyl chloride (2.00 g, 0.90 mmol) in DCM (10 mL), was added solution of tert-butyl piperazine-1-carboxylate (2.02 g, 1.08 mmol) in DCM (10 mL) followed by TEA (1.83 g, 1.80 mmol) at 0 °C under nitrogen and the reaction mixture stirred at rt for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with DCM (3x 50 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as an off-white solid (2.8 g, 84%). LCMS m/z = 272 [M-Boc+H]+. Step 2. Synthesis of tert-butyl 4-((4-aminophenyl)sulfonyl)piperazine-1-carboxylate To a stirred solution of tert-butyl 4-((4-nitrophenyl)sulfonyl)piperazine-1-carboxylate (Step 1, 2.80 g, 7.54 mmol) in THF (20 mL) and MeOH (20 mL) was added solution of ammonium chloride (4.03 g, 75.4 mmol) in water (10 mL) followed by Zn dust (4.90 g, 75.4 mmol) at 0 °C and the reaction mixture stirred at rt for 16 h. The reaction mixture was filtered through a pad of celite and washed with EtOAc (2x 50 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as an off- white solid (2.50 g, 97%). LCMS m/z = 242 [M-Boc+H]+. Step 3. Synthesis of 2-methyl-1-(4-(2-((4-(piperazin-1-ylsulfonyl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propan-2-ol The title compound was prepared as a pale yellow solid (110 mg, 73%) from tert-butyl 4-((4- aminophenyl)sulfonyl)piperazine-1-carboxylate (Step 2, 100 mg, 0.29 mmol) using an analogous method to that described for Intermediate 71, Step 5. LCMS m/z = 526 [M+H]+. Intermediate 101. 3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-N-(2-(2-(4-(piperazin-1-ylmethyl)piperidin-1- yl)ethoxy)ethyl)benzenesulfonamide hydrochloride.
Figure imgf000218_0001
Step 1: Synthesis of tert-butyl 4-((1-(2-(2- (((benzyloxy)carbonyl)amino)ethoxy)ethyl)piperidin-4-yl)methyl)piperazine-1-carboxylate To a stirred solution of 2-(2-(((benzyloxy)carbonyl)amino)ethoxy)ethyl 4- methylbenzenesulfonate (0.75 g, 1.91 mmol) and tert-butyl 4-(piperidin-4- ylmethyl)piperazine-1-carboxylate (0.54 g, 1.91 mmol) in MeCN (15 mL) was added potassium carbonate (0.79 g, 5.72 mmol) at rt and the resulting reaction mixture stirred at 80 °C for 16 h. The reaction was quenched with water (50 mL) and extracted with EtOAc (2x 30 mL). The combined organics were dried (Na2SO4), concentrated under the reduced pressure and the residue purified by combi-flash (SiO2, 0-5% MeOH/DCM) to afford the title compound as a colourless solid (0.60 g, 62%). LCMS m/z = 505 [M-H]+. Step 2: Synthesis of tert-butyl 4-((1-(2-(2-aminoethoxy)ethyl)piperidin-4- yl)methyl)piperazine-1-carboxylate To the stirred solution of tert-butyl 4-((1-(2-(2- (((benzyloxy)carbonyl)amino)ethoxy)ethyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (Step 1, 0.60 g, 1.19 mmol) in MeOH (12 mL) were added Pd/C (0.10 g) and stirred at rt for 4 h. The reaction mixture was filtered through a pad of celite bed and washed with MeOH (2x 30 mL). The filtrate was concentrated under reduced pressure and the residue purified by combi-flash (SiO2, 0-5% MeOH/DCM) to afford the title compound as a colourless solid (0.37 g, 84%). 1H NMR (DMSO-d6, 400 MHz): (3.51-3.48 (m, 4H), 3.45-3.43 (m, 4H), 2.85- 2.79 (m, 4H), 2.53-2.41 (m, 6H), 2.25-2.23 (m, 3H), 2.11-2.09 (m, 2H), 1.91-1.89 (m, 2H), 1.65-1.62 (m, 2H), 1.39 (s, 9H), 1.07-1.05 (m, 2H). Step 3 and 4: Synthesis of tert-butyl 4-((1-(2-(2-((4-amino-3- fluorophenyl)sulfonamido)ethoxy)ethyl)piperidin-4-yl)methyl)piperazine-1-carboxylate The title compound was prepared as a colourless solid (0.20 g, 66%) from tert-butyl 4-((1-(2- (2-aminoethoxy)ethyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (Step 2) using an analogous 2-Step procedure as described for Intermediate 91, Step 1 and 2. LCMS m/z = 544 [M+H]+. Step 5 and 6: Synthesis of 3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-N-(2-(2-(4-(piperazin-1-ylmethyl)piperidin-1- yl)ethoxy)ethyl)benzenesulfonamide The title compound was prepared as a brown semi-solid from tert-butyl 4-((1-(2-(2-((4- amino-3-fluorophenyl)sulfonamido)ethoxy)ethyl)piperidin-4-yl)methyl)piperazine-1- carboxylate (Step 4) using an analogous 2-Step procedure as described for Intermediate 71, Step 5 and 6. LCMS m/z = 728 [M+H]+. Intermediate 102. 1-(4-(2-((4-((4-((2-aminoethyl)amino)piperidin-1- yl)sulfonyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2- methylpropan-2-ol hydrochloride.
Figure imgf000219_0001
The title compound was prepared as a white solid (0.27 g) from 1-((4-((4-(1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)phenyl)sulfonyl)piperidin-4-one Intermediate 96, Step 3 (81) using an analogous 2- Step procedure as described for Intermediate 96, Step 4 and 5. LCMS m/z = 583 [M+H]+. Intermediate 103. 1-(4-(2-((4-((3,9-diazaspiro[5.5]undecan-3-yl)sulfonyl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol hydrochloride.
Figure imgf000220_0001
The title compound was prepared as a white solid (0.40 g) from tert-butyl 3,9- diazaspiro[5.5]undecane-3-carboxylate and 4-nitrobenzenesulfonyl chloride using an analogous 4-Step procedure as described for Intermediate 71, Steps 3, 4, 5 and 6. LCMS m/z = 594 [M+H]+. Intermediate 104. 4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-N-(4-(prop-2-yn-1- yloxy)cyclohexyl)benzenesulfonamide.
Figure imgf000220_0002
The title compound was prepared as an off-white solid (0.90 g) from 4-(prop-2-yn-1- yloxy)cyclohexan-1-amine hydrochloride and 4-nitrobenzenesulfonyl chloride using an analogous 3-Step procedures as described for Intermediate 71, Step 1, 2 and 3. LCMS m/z = 593 [M+H]+. Intermediate 105. N-(6-aminohexyl)-4-((5-cyano-4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)pyrimidin-2-yl)amino)-3-fluorobenzenesulfonamide hydrochloride.
Figure imgf000221_0001
Step 1 and 2. Synthesis of tert-butyl (6-((4-amino-3- fluorophenyl)sulfonamido)hexyl)carbamate The title compound was prepared as a yellow gum (0.30 g, 40%) from tert-butyl (6- aminohexyl)carbamate and 3-fluoro-4-nitrobenzenesulfonyl chloride using an analogous 2- Step procedure as described for Intermediate 91, Step 1 and 2. LCMS m/z = 390 [M+H]+. Step 3. Synthesis of tert-butyl (6-((4-((5-cyano-4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonamido)hexyl)carbamate To a solution of tert-butyl (6-((4-amino-3-fluorophenyl)sulfonamido)hexyl)carbamate (Step 2, 0.61 g, 1.56 mmol) in dry THF (5 mL) was added NaH (0.08 g, 0.04 mmol) at 0 °C and stirred for 30 min before 4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-2- (methylsulfonyl)pyrimidine-5-carbonitrile (WO2022266190, 0.50 g, 1.56 mmol) was added under nitrogen atmosphere and allowed stirred at rt for 1 h. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3x 20 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by combi flash (SiO2, 42% EtOAc/PE) to afford the title compound as a brown solid (0.35 g, 36%). LCMS m/z = 631 [M+H]+. Step 4. Synthesis of N-(6-aminohexyl)-4-((5-cyano-4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)pyrimidin-2-yl)amino)-3-fluorobenzenesulfonamide hydrochloride 4 M hydrochloric acid in dioxane (2.0 mL) was added at 0 °C to a stirred solution of tert- butyl (6-((4-((5-cyano-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)-3-fluorophenyl)sulfonamido)hexyl)carbamate (Step 3, 0.40 g, 0.63 mmol) in THF (4 mL) and the resulting reaction mixture stirred at rt for 3 h. The reaction mixture was concentrated under reduced pressure to afford the title compound as a yellow solid (0.35 g, 97%). LCMS m/z = 531 [M+H]+. Intermediate 106. N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)pentyl)-4-iodobenzenesulfonamide.
Figure imgf000222_0001
To a stirred solution of 4-((5-aminopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- dione (Org. Lett., 2019, 21, 3838-3841, 0.20 g, 0.56 mmol) and 4-iodobenzenesulfonyl chloride (0.25 g, 0.84 mmol) in DCM (5 mL) was added DMAP (0.01 g, 0.10 mmol) followed by dropwise addition of TEA (0.156 mL, 1.12 mmol) at 0 °C and the resulting reaction mixture stirred at rt for 2 h. The reaction was quenched with water and extracted with DCM (3x 20 mL). The combined organics were washed with brine (30 mL) and dried (Na2SO4) and concentrated under the reduced pressure. The crude residue was purified by combi-flash (SiO2, 3-10% MeOH/DCM) as a colourless liquid (0.20 g, 57%). LCMS m/z = 625 [M+H]+. Intermediate 107. 2-amino-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrimidine- 5-carbonitrile.
Figure imgf000222_0002
To a stirred solution of 4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-2- (methylsulfonyl)pyrimidine-5-carbonitrile (WO2022266190, 3 g, 9.34 mmol) in dioxane (100 mL) was added 0.5 M ammonia solution in dioxane (54 mL) at 0 °C and the resulting reaction mixture stirred at rt for 1 h. The reaction mixture was diluted with water and extracted in EtOAc (2x 50 mL). The combined organics were washed with brine (50 mL), dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as an off-white solid (2.10 g, 87%). LCMS m/z = 259 [M+H]+. Intermediate 108. N-(14-amino-3,6,9,12-tetraoxatetradecyl)-4-((5-cyano-4-(1-(2-hydroxy- 2-methylpropyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-fluorobenzenesulfonamide hydrochloride.
Figure imgf000223_0001
Step 1: Synthesis of tert-butyl (14-azido-3,6,9,12-tetraoxatetradecyl)(tert- butoxycarbonyl)carbamate To a solution of 14-azido-3,6,9,12-tetraoxatetradecyl 4-methylbenzenesulfonate (6.0 g, 14.4 mmol) in DMF (7.4 mL) was added di-tert-butyl iminodicarbonate (3.45 g, 15.8 mmol) at rt and the resulting reaction mixture stirred at 60 °C for 3 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2x 60 mL). The combined organics were washed with ice-cold water (2x 60 mL), dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as a colourless liquid (2.30 g, 35%). Step 2: Synthesis of tert-butyl (14-amino-3,6,9,12-tetraoxatetradecyl)(tert- butoxycarbonyl)carbamate To a stirred solution of tert-butyl (14-azido-3,6,9,12-tetraoxatetradecyl)(tert- butoxycarbonyl)carbamate (Step 1, 2.30 g, 4.97 mmol) in MeOH (25 mL) was added Pd/C (0.53 g) at rt under nitrogen atmosphere. The reaction vessel was filled with H2 (50 psi) gas and the resulting reaction mixture was stirred at rt for 3 h under H2 gas atmosphere. The reaction mixture was filtered through a pad of celite and washed with MeOH (3x 25 mL). The filtrate was evaporated under reduced pressure and the residue purified by combi-flash (SiO2, 4% MeOH/DCM) to afford the title compound as colourless liquid (2.0g, 92%). LCMS m/z = 437 [M+H]+. Step 3: Synthesis of tert-butyl (14-((4-bromo-3-fluorophenyl)sulfonamido)-3,6,9,12- tetraoxatetradecyl)(tert-butoxycarbonyl)carbamate To a stirred solution of tert-butyl (14-amino-3,6,9,12-tetraoxatetradecyl)(tert- butoxycarbonyl)carbamate (Step 2, 0.50 g, 1.15 mmol) and 4-bromo-3-fluorobenzenesulfonyl chloride (0.63 g, 2.29 mmol) in DCM (15 mL) was added dropwise TEA (0.41 g, 4.01 mmol) at 0 °C and the resulting reaction mixture stirred at rt for 16 h. The reaction was quenched with water and extracted with DCM (3x 20 mL). The combined organics were washed with brine (40 mL), dried (Na2SO4), concentrated under the reduced pressure and the residue purified by combi-flash (SiO2, 50% EtOAc/PE) to afford the title compound as a brown liquid (0.32 g, 41%). LCMS m/z = 671 [M+H]+. Step 4: Synthesis of tert-butyl (tert-butoxycarbonyl)(14-((4-((5-cyano-4-(1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)methyl)-3-fluorophenyl)sulfonamido)- 3,6,9,12-tetraoxatetradecyl)carbamate To a stirred solution of tert-butyl (14-((4-bromo-3-fluorophenyl)sulfonamido)-3,6,9,12- tetraoxatetradecyl)(tert-butoxycarbonyl)carbamate (Step 3, 0.30 g, 0.45 mmol) and 2-amino- 4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile Intermediate 107 (0.92 g, 0.36 mmol) in dioxane (15 mL) was added caesium carbonate (0.43 g, 1.34 mmol) was added at rt. The reaction mixture was purged with argon and Pd2(dba)3 (0.41 g, 0.05 mmol) and XantPhos (0.51 g, 0.09 mmol) added at rt and the resulting reaction mixture heated in a microwave oven at 160 °C for 20 min. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3x 30 mL). The combined organics were dried (Na2SO4), concentrated under reduced pressure and the residue purified by combi-flash (SiO2, 50% EtOAc/PE) to afford the title compound as a light brown solid (0.22 g, 58%). LCMS m/z = 851 [M+H]+. Step 5: Synthesis of N-(14-amino-3,6,9,12-tetraoxatetradecyl)-4-((5-cyano-4-(1-(2-hydroxy- 2-methylpropyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)methyl)-3-fluorobenzenesulfonamide hydrochloride 4 M hydrochloric acid in dioxane (5 mL) was added at 0 °C to a stirred solution of tert-butyl (tert-butoxycarbonyl)(14-((4-((5-cyano-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4- yl)pyrimidin-2-yl)methyl)-3-fluorophenyl)sulfonamido)-3,6,9,12- tetraoxatetradecyl)carbamate (Step 4, 0.22 mg, 0.26 mmol) in DCM (5 mL) and stirred at rt for 3 h. The reaction mixture was concentrated under reduced pressure to afford the title compound as an off-white solid (0.15 g, 84.13%) as an off-white solid. LCMS m/z = 650 [M+H]+. Intermediate 109. (1r,4r)-4-((4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidine)-1-sulfonamido)cyclohexane-1-carboxylic acid
Figure imgf000225_0001
Lithium hydroxide (35.7 mg, 1.49 mmol) was added to a stirred solution of methyl (1r,4r)-4- ((4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)piperidine)-1-sulfonamido)cyclohexane-1-carboxylate (Intermediate 5, Step 3; 300 mg, 0.49 mmol) in THF (4 mL) and water (1 mL) and the mixture stirred for 4h. The reaction mixture was diluted with water (15 mL) and washed with EtOAc (2x 15 mL). The aqueous layer neutralised using 2N HCl and extracted with EtOAc (3x 10 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as a gum (250 mg, 85%). LCMS m/z = 590 [M+H]+. Intermediate 110. 1-((4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)piperidine-4-carboxylic acid.
Figure imgf000225_0002
The title compound was prepared as a gum (300 mg, 88%) from ethyl 1-((4-((4-(1-(2- hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)piperidin-1-yl)sulfonyl)piperidine-4-carboxylate (Intermediate 5, Step 4; 350 mg, 0.57 mmol) using an analogous method to that described for Intermediate 109. LCMS m/z = 601 [M+H]+. Intermediate 111. 3-(5-(4-((1-((4-aminopiperidin-1-yl)sulfonyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione.
Figure imgf000226_0001
The title compound was prepared from 3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine- 2,6-dione (WO2020201080, 0.10 g, 0.30 mmol) and tert-butyl (1-((4-(iodomethyl)piperidin- 1-yl)sulfonyl)piperidin-4-yl)carbamate (Intermediate 34, Step 1; 0.23 g, 0.45 mmol) using an analogous 2-Step procedure as described for Intermediate 2. LCMS m/z = 588 [M+18]+. Intermediate 112. 3-(5-(3-((1-((4-aminopiperidin-1-yl)sulfonyl)piperidin-4-yl)oxy)prop-1- yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride.
Figure imgf000226_0002
The title compound was prepared as a white solid (200 mg) from 3-(1-oxo-5-(3-(piperidin-4- yloxy)prop-1-yn-1-yl)isoindolin-2-yl)piperidine-2,6-dione (Intermediate 6) using an analogous 2-Step procedure as described for Intermediate 115, Step 1 and 2. LCMS m/z = 544 [M+H]+. Intermediate 113. 3-(4-((1-((1-((4-aminopiperidin-1-yl)sulfonyl)piperidin-4- yl)methyl)azetidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione.
Figure imgf000227_0001
Step 1: Synthesis of tert-butyl 3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oxy)azetidine-1-carboxylate To a stirred solution of 3-(4-hydroxy-1-oxoisoindolin-2-yl) piperidine-2,6-dione (0.50 g, 1.92 mmol), NaHCO3 (0.48 g, 5.76 mmol) and KBr (0.27 g, 2.30 mmol) in DMF (5 mL) was added tert-butyl 3-(tosyloxy)azetidine-1-carboxylate (1.88 g, 5.76 mmol) at rt and the resulting reaction mixture stirred at 80 °C for 16 h. The reaction mixture was quenched with ice-cold water (30 mL) and extracted with EtOAc (3x 30 mL). The combined organics were dried (Na2SO4), concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 60- 65% EtOAc/PE) to afford the title compound as a white solid (0.20 g, 25%). LCMS m/z = 416 [M+H]+. Step 2: Synthesis of 3-(4-(azetidin-3-yloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydroacid To a stirred solution of tert-butyl 3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oxy)azetidine-1-carboxylate (Step 1, 0.30 g, 0.72 mmol) in DCM (0.6 mL) was added 4 M HCl in dioxane(0.60 mL) at 0 °C and the reaction mixture was stirred at rt for 2h. The reaction mixture was concentrated under reduced pressure and the residue triturated with diethyl ether (2x 20 mL) to afford the title compound as a white solid (0.30 g, 99 %). LCMS m/z = 316 [M+H]+. Step 3: Synthesis of tert-butyl (1-((4-((3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oxy)azetidin-1-yl)methyl)piperidin-1-yl)sulfonyl)piperidin-4-yl)carbamate To a stirred solution of 3-(4-(azetidin-3-yloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride (Step 2, 0.35 g, 1.11 mmol) and tert-butyl (1-((4-(iodomethyl)piperidin-1- yl)sulfonyl)piperidin-4-yl)carbamate (Intermediate 34, Step 1; 0.70 g, 1.43 mmol) in dioxane (7 mL) was added DIPEA (0.6 mL, 3.33 mmol) at 0 °C and the resulting reaction mixture stirred at 100 °C for 16h. The reaction mixture was diluted with water (30 ml) and extracted with EtOAc (3x 20 mL). The combined organics were washed with brine (20 mL), dried (Na2SO4), concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 4-5% MeOH/DCM) to afford the title compound as a brown solid (0.40 g, 53%). LCMS m/z = 675 [M+H]+. Step 4: Synthesis of 3-(4-((1-((1-((4-aminopiperidin-1-yl)sulfonyl)piperidin-4- yl)methyl)azetidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride To a stirred solution of tert-butyl (1-((4-((3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oxy)azetidin-1-yl)methyl)piperidin-1-yl)sulfonyl)piperidin-4-yl)carbamate (Step 3, 0.40 g, 0.59 mmol) in DCM (8 mL) was added 4 M HCl in dioxane(0.80 mL) at 0 °C and the reaction mixture stirred for 2h at rt. The reaction mixture was concentrated under reduced pressure and the residue triturated with diethyl ether (2x 20 mL) to afford the title compound as a brown solid (0.34 g, 99%). LCMS m/z = 575 [M+H]+. Intermediate 114. 2-chloro-4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl) pyrimidine.
Figure imgf000228_0001
To a stirred solution of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazole (3.00 g, 14.4 mmol) and 2,4-dichloro-5-(trifluoromethyl) pyrimidine (6.88 g, 31.7 mmol) in dioxane (27 mL) was added a solution of sodium carbonate (4.58 g, 43.3mmol) in water (15 mL) at rt. The reaction mixture was purged with nitrogen gas for 15 min and Pd(dppf)Cl2.DCM (0.66 g, 0.72 mmol) added at rt and stirred under inert atmosphere at 80°C for 2 h. The reaction mixture was diluted with water (60 mL) and extracted with EtOAc (3x 60 mL). The combined organics were washed with brine (30 mL), dried (Na2SO4), concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 20-30% EtOAc) to afford the title compound as a white solid (0.50 g, 13%). 1
Figure imgf000228_0002
NMR (DMSO-d6, 400 MHz): 9.05 (s, 1H), 8.53 (m, 1H), 7.99 (m, 1H), 3.96 (s, 3H). Intermediate 115. 2-methyl-1-(4-(2-((1-((4-(prop-2-yn-1-yloxy)piperidin-1- yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1- yl)propan-2-ol.
Figure imgf000229_0001
Step 1: Synthesis of tert-butyl (1-((4-(prop-2-yn-1-yloxy)piperidin-1-yl)sulfonyl)piperidin-4- yl)carbamate TEA (1.45 mL, 6.81 mmol) was added dropwise at 0 °C to a stirred solution of tert-butyl (1- (chlorosulfonyl)piperidin-4-yl)carbamate (Intermediate 39, 1.00 g, 3.35 mmol) and 4-(prop- 2-yn-1-yloxy)piperidine (0.56 g, 4.02 mmol) in DCM (10 mL) and the reaction mixture stirred at rt for 4 h. The reaction was quenched with water (20 mL) and extracted with DCM (3x 20 mL). The combined organics were washed with brine (40 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by combi-flash (SiO2, 15% EtOAc/PE) to afford the title compound as a brown liquid (1.0 g, 74%). LCMS m/z = 402 [M+H]+. Step 2: Synthesis of 1-((4-(prop-2-yn-1-yloxy)piperidin-1-yl)sulfonyl)piperidin-4-amine hydrochloride 4 M hydrochloric acid in dioxane (5 mL) was added dropwise at 0 °C to a stirred solution of tert-butyl (1-((4-(prop-2-yn-1-yloxy)piperidin-1-yl)sulfonyl)piperidin-4-yl)carbamate (Step 1, 700 mg, 1.743 mmol) in DCM (5 mL) and the reaction mixture stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure to afford the title compound as a white solid (0.50 g, 85%). LCMS m/z = 302 [M+H]+. Step 3: Synthesis of 2-methyl-1-(4-(2-((1-((4-(prop-2-yn-1-yloxy)piperidin-1- yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1- yl)propan-2-ol: To a stirred solution of 1-((4-(prop-2-yn-1-yloxy)piperidin-1-yl)sulfonyl)piperidin-4-amine hydrochloride (0.30 g, 0.89 mmol) and 1-(4-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H- pyrazol-1-yl)-2-methylpropan-2-ol Intermediate 1 (0.34 g, 1.07 mmol) in NMP (4.0 mL) was added DIPEA (0.34 g, 2.66 mmol) at rt and the reaction mixture stirred at 100 °C for 16 h. The reaction mixture was concentrated under reduced pressure and the residue partitioned between EtOAc and water (20 mL). The aqueous layer was extracted with EtOAc (3 x 20 mL) and the combined organics dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by combi-flash (20-30% MeOH/DCM) to afford the title compound as a brown solid (0.20 g, 38%). LCMS m/z = 586 [M+H]+. Intermediate 116. 2-methyl-1-(4-(2-((1-((4-((4-(prop-2-yn-1-yloxy)piperidin-1- yl)methyl)piperidin-1-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)- 1H-pyrazol-1-yl)propan-2-ol.
Figure imgf000230_0001
Step 1: Synthesis of tert-butyl (1-((4-((4-(prop-2-yn-1-yloxy)piperidin-1-yl)methyl)piperidin- 1-yl)sulfonyl)piperidin-4-yl)carbamate To a stirred solution of 4-(prop-2-yn-1-yloxy)piperidine hydrochloride (0.80 g, 4.56 mmol) and tert-butyl 4-formylpiperidine-1-carboxylate (0.97 g , 4.56 mmol) in 1,2-dichloroethane (8 mL) was added acetic acid (0.026 mL) at rt and the resulting reaction mixture stirred at rt for 2 h. STAB (1.45 g, 6.83 mmol) was added at 0 °C and the reaction mixture stirred at rt for 16 h. The reaction was quenched with water (30 mL) and extracted in DCM (3x 30 mL). The combined organics were washed with ice-cold water (50 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by combi flash (neutral alumina, 80-90% EtOAc/PE) to afford the title compound as a yellow solid (0.50 g, 33%). LCMS m/z = 337 [M+H]+. Step 2: Synthesis of 1-(piperidin-4-ylmethyl)-4-(prop-2-yn-1-yloxy)piperidine hydrochloride To a stirred solution of tert-butyl (1-((4-((4-(prop-2-yn-1-yloxy)piperidin-1- yl)methyl)piperidin-1-yl)sulfonyl)piperidin-4-yl)carbamate (0.5 g, 1.49 mmol) in DCM (2 mL) was added 4 M hydrochloric acid in dioxane (2 mL) dropwise at 0 °C and the reaction mixture stirred at rt for 2 h. The reaction mixture was evaporated under reduced pressure and the residue triturated with DCM to afforded the title compound as a yellow solid (0.27 g, 78%). 1H NMR (DMSO-d6, 400 MHz): 4.21 (dd, 1H), 3.84 (bs, 1H), 3.67-3.64 (m, 1H), 3.46-3.45 (m, 3H), 3.34-3.24 (m, 3H), 3.01-2.79 (m, 5H), 2.11-2.07 (m, 3H), 1.99-1.96 (m, 3H), 1.84-1.81 (m, 1H), 1.44-1.38 (m, 2H), 1.24-1.22 (m, 2H). Step 3, 4 and 5: Synthesis of 2-methyl-1-(4-(2-((1-((4-((4-(prop-2-yn-1-yloxy)piperidin-1- yl)methyl)piperidin-1-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)- 1H-pyrazol-1-yl)propan-2-ol The title compound was prepared as an off-white solid (0.35 g,) from 1-(piperidin-4- ylmethyl)-4-(prop-2-yn-1-yloxy)piperidine hydrochloride (Step 2) and tert-butyl (1- (chlorosulfonyl)piperidin-4-yl)carbamate (Intermediate 39) using an analogous 3-Step procedure as described for Intermediate 115. LCMS m/z = 683 [M+H]+. Intermediate 117. 3-(3-(3-((1-(1-((4-aminopiperidin-1-yl)sulfonyl)piperidine-4- carbonyl)piperidin-4-yl)oxy)prop-1-yn-1-yl)phenyl)piperidine-2,6-dione hydrochloride.
Figure imgf000231_0001
The title compound was prepared as a white solid (100 mg) from 3-(3-(3-((1-(piperidine-4- carbonyl)piperidin-4-yl)oxy)prop-1-yn-1-yl)phenyl)piperidine-2,6-dione Intermediate 12 and tert-butyl (1-(chlorosulfonyl)piperidin-4-yl)carbamate (Intermediate 39) using an analogous 2-Step procedure as described for Intermediate 115, Step 1 and 2. LCMS m/z = 600 [M+H]+. Intermediate 118. 4-(1,3-dioxolan-2-yl)piperidine-1-sulfonyl chloride.
Figure imgf000231_0002
To a stirred solution of 4-(1,3-dioxolan-2-yl)piperidine (1.0 g, 6.36 mmol) in DCM (10 mL) at -10 oC was added TEA (2.76 mL, 19.08 mmol) followed by sulfuryl chloride (0.62 mL, 7.63mmol) and the reaction mixture stirred at -10 °C for 2 h. The reaction mixture was diluted with water (30 mL) and extracted with DCM (3x 30 mL). The combined organics was dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as a colourless gum (1.4 g, 86%) which was used without further purification. Intermediate 119. 1-((3,3-difluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)- 5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)piperidine-4-carbaldehyde.
Figure imgf000232_0001
Step 1: Synthesis of benzyl 3,3-difluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4- yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate To a stirred solution of benzyl 4-amino-3,3-difluoropiperidine-1-carboxylate (0.2 g, 0.740 mmol) and 1-(4-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2- methylpropan-2-ol Intermediate 1 (0.285 g, 0.888 mmol) in DMSO (2 mL) was added DIPEA (0.644 mL, 3.70 mmol) at rt and the reaction mixture stirred at 110 °C for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3x 15 mL). The combined organics were washed with water (2x 15 mL), brine (15 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 35-45% EtOAc/PE) to afford the title compound as an off white solid (0.3 g, 73%). 1H NMR (DMSO-d6, 400 MHz): 8.59 (d, 3H), 8.22-8.13 (m, 3H), 7.35-7.33 (m, 2H), 5.13 (s, 2H), 4.76 (s, 1H), 4.24-4.18 (m, 1H), 4.10 (s, 2H), 4.04-3.99 (m,1H), 3.32-3.25 (m, 1H), 1.91-1.77 (m, 2H), 1.08 (s, 6H). Step-2 : Synthesis of 1-(4-(2-((3,3-difluoropiperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol To a stirred solution of benzyl 3,3-difluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol- 4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate (Step 1, 0.3 g, 0.54 mmol) in EtOH (6 mL) was added 10% Pd/C (0.058 g, 0.54 mmol) at rt and the reaction mixture stirred at rt for 3h under hydrogen pressure (14 psi). The reaction mixture was filtered through a pad of celite and washed with 10% Methanol/DCM (50 mL), dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as a white solid (0.21 g, 92%). LCMS m/z = 421 [M+H]+. Step-3 : Synthesis of 1-(4-(2-((1-((4-(1,3-dioxolan-2-yl)piperidin-1-yl)sulfonyl)-3,3- difluoropiperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2- methylpropan-2-ol To the stirred solution of 1-(4-(2-((3,3-difluoropiperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Step 2, 0.24 g, 0.57 mmol) in DCM (5 mL) were added sequentially TEA (0.24 mL, 1.71 mmol) and 4-(1,3- dioxolan-2-yl)piperidine-1-sulfonyl chloride (Intermediate 118, 0.32 g, 1.25 mmol) in DCM (2 mL) at 0 °C and the reaction mixture stirred at rt for 1 h. The reaction mixture was diluted with cold water (20 mL) and extracted with DCM (3x 20 mL). The combined organics were washed with water (2x 30 mL), dried (Na2SO4), concentrated under reduced pressure and the residue purified by column chromatography (Neutral alumina, 0-10% MeOH/DCM) to afford the title compound as a brown gum (0.18 g, 50%). LCMS m/z = 640 [M+H]+. Step 4. Synthesis of 1-((3,3-difluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)- 5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)piperidine-4-carbaldehyde. TFA (7.20 mL, 1.41 mmol) was added to a stirred solution of 1-(4-(2-((1-((4-(1,3-dioxolan-2- yl)piperidin-1-yl)sulfonyl)-3,3-difluoropiperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Step 3, 0.18 g, 0.28 mmol) in DCM (1.8 mL) and the reaction mixture stirred at rt for 16 h. The reaction was quenched with water (30 mL) and extracted with DCM (3x 30 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as a brown liquid (160 mg, 95%). LCMS m/z = 596 [M+H]+. Intermediate 120. 3-fluoro-N-((1r,4r)-4-formylcyclohexyl)-4-((4-(1-methyl-1H-pyrazol-4- yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide.
Figure imgf000234_0001
The title compound was prepared as a gummy solid (250 mg) from methyl (1r,4r)-4-((4- amino-3-fluorophenyl)sulfonamido)cyclohexane-1-carboxylate (0.8 g, 2.42 mmol) and 2- chloro-4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine (Intermediate 35, Step 1; 763 mg, 2.91 mmol) using an analogous 3-Step procedure as described for Intermediate 14, Step 3, 4 and 5. LCMS m/z = 527 [M+H]+. Intermediate 121. 4-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione.
Figure imgf000234_0002
Step 1: Synthesis of 2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)oxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate Tosyl chloride (0.70 g, 3.69 mmol) was added portion wise at 0 °C to a stirred solution of 2- (2,6-dioxopiperidin-3-yl)-4-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)isoindoline-1,3-dione (Bioorg. Chem., 2020, 105, 104453, 1.0 g, 2.46 mmol) and TEA (0.85 mL, 6.15 mmol) in DCM (15 mL) under an inert atmosphere and the resulting reaction mixture stirred at rt for 16 h. The reaction mixture was diluted with water (15 mL) and extracted with DCM (3x 15 mL). The combined organics was dried (Na2SO4), concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 60-80 % EtOAc/PE) to afford the title compound as an off white solid (0.30 g, 22%). LCMS m/z = 561 [M-56]+. Step 2: Synthesis of 4-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione To a stirred solution of 2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)oxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (Step 1, 0.20 g, 0.35 mmol) in DMF (5 mL) was added NaN3 (0.70 g, 1.07 mmol) at rt and the reaction mixture heated at 60 °C for 16h. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (3x 20 mL). The combined organics were washed with ice-cold brine (3x 20 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 30-35% EtOAc/PE) to afford the title compound as an off- white solid (0.10 g, 65%). LCMS m/z = 432 [M+H]+. Intermediate 122. 3-(1-oxo-6-(4-(piperidin-4-ylmethyl)piperazin-1-yl)isoindolin-2- yl)piperidine-2,6-dione hydrochloride.
Figure imgf000235_0001
Step 1. Synthesis of tert-butyl 4-(3-oxo-1,3-dihydroisobenzofuran-5-yl)piperazine-1- carboxylate. A mixture of 6-bromoisobenzofuran-1(3H)-one (20 g, 93.88 mmol), tert-butyl piperazine-1- carboxylate (19.23 g, 103.27 mmol), Pd2(dba)3 (4.30 g, 4.69 mmol), Xantphos (3.26 g, 5.63 mmol), K3PO4 (59.79 g, 282 mmol) and tritert-butylphosphonium tetrafluoroborate (1.63 g, 5.63 mmol) in dioxane (500 mL) was degassed and purged with N2 (x3) and the mixture stirred at 100 °C for 24 h under N2. The reaction mixture was filtered and the filtrate concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 1-25% EtOAc/PE) to afford the title compound as a white solid (11 g, 37%). LCMS m/z = 319 [M+H]+. Step 2. Synthesis of 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-(hydroxymethyl)benzoic acid. To a solution of tert-butyl 4-(3-oxo-1,3-dihydroisobenzofuran-5-yl)piperazine-1-carboxylate (Step 1, 20.5 g, 64.4 mmol) in MeOH (250 mL) was added NaOH (12.88 g, 322 mmol) and H2O (50 mL) and the mixture stirred at 50 °C for 2 h. The reaction mixture was concentrated under reduced pressure the pH adjusted to pH=3-4 with aqueous 2M HCl and extracted with EtOAc (3x 300 mL). The combined organics were washed with H2O (3x 30 mL), dried (Na2SO4) and concentrated under reduced pressure to give the title compound as a yellow solid (14.17 g, 60%). LCMS m/z = 337 [M+H]+. Step 3. Synthesis of tert-butyl 4-(4-(hydroxymethyl)-3-(methoxycarbonyl)phenyl)piperazine- 1-carboxylate. To a solution of 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-(hydroxymethyl)benzoic acid (Step 2, 11 g, 32.7 mmol,) in EtOAc (40 mL) and MeOH (40 mL) was added (diazomethyl)trimethylsilane (2M, 81.75 mL) and the mixture stirred at -10 °C for 0.5 h. The reaction mixture was quenched with H2O (18 mL) at 25 °C and extracted with EtOAc (3x 120mL). The combined organics were washed with H2O (3x 80 mL), dried (Na2SO4), concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 1-5% EtOAc/PE) give the title compound as a yellow oil (5 g, 30% yield). 1H NMR (400MHz, CDCl3): 7.44 (d, 1H), 7.29-7.22 (m, 1H), 6.96 (dd, 1H), 4.60 (s, 2H), 3.84 (s, 3H), 3.57-3.44 (m, 4H), 3.15-3.02 (m, 4H), 1.40 (s, 9H). Step 4. Synthesis of tert-butyl 4-(4-formyl-3-(methoxycarbonyl)phenyl)piperazine-1- carboxylate. To a solution of tert-butyl 4-(4-(hydroxymethyl)-3-(methoxycarbonyl)phenyl)piperazine-1- carboxylate (Step 3, 6 g, 17.12 mmol) in DCM (80 mL) was added NaHCO3 (1.44 g, 17.12 mmol) and Dess-Martin Periodinane (8.72 g, 20.55 mmol) and the mixture stirred at 0 °C for 1h. The reaction mixture was filtered, concentrated under reduced pressure and the residue purified by column chromatography (ISCO®; 80 g SepaFlash®, 0-16% EtOAc/PE) to afford the title compound as a pink solid (4 g, 67%). Step 5. Synthesis of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5- yl)piperazine-1-carboxylate. To a solution of tert-butyl 4-(4-formyl-3-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (Step 4, 1.72 g, 4.94 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (1.30 g, 7.90 mmol) in MeOH (100 mL) was added was added AcOH (148 mg, 2.47 mmol) and AcONa (810 mg, 9.87 mmol) and stirred at 20 °C for 10 min before NaBH3CN (931 mg, 14.8 mmol) was added and the mixture stirred at 20 °C for 14 h and at 70 °C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure and the residue was purified by column chromatography (ISCO®; 80 g SepaFlash®, 0-90% EtOAc/PE) to afford the title compound as a white solid (1.2 g, 57%). LCMS m/z = 429 [M+H]+. Step 6. Synthesis of 3-(1-oxo-6-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione hydrochloride. To a solution of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazine-1- carboxylate (Step 5, 1.2 g, 2.80 mmol) in DCM (5 mL) was added was added HCl/dioxane (4 M, 2 mL) at 0 °C and the mixture stirred at 0 °C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound as a white solid (936 mg, 99%). Step 7. Synthesis of tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5- yl)piperazin-1-yl)methyl)piperidine-1-carboxylate. To a solution of 3-(1-oxo-6-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione hydrochloride (Step 6, 936 mg, 2.57 mmol) and tert-butyl 4-formylpiperidine-1-carboxylate (602 mg, 2.82 mmol) in THF (20 mL) and DMF (20 mL) was added AcOH (231 mg, 3.85 mmol), NaOAc (631 mg, 7.70 mmol) and STAB (1.09 g, 5.13 mmol) and the mixture stirred at 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure and the residue purified by column chromatography (ISCO®; 20 g SepaFlash®, 0-90% EtOAc/DCM) to afford the title compound as a white solid (1.1 g, 82%). LCMS m/z = 526 [M+H]+. Step 8. Synthesis of 3-(1-oxo-6-(4-(piperidin-4-ylmethyl)piperazin-1-yl)isoindolin-2- yl)piperidine-2,6-dione hydrochloride. To a solution of tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin- 1-yl)methyl)piperidine-1-carboxylate (Step 7, 1.1 g, 2.09 mmol) in DCM (5 mL) was added HCl/dioxane (4M, 7.85 mL) and the mixture stirred at 0 °C for 2h. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound as a white solid (1 g, 96%) as a white solid. 1H NMR (400MHz, DMSO-d6): 11.09 (br s, 1H), 10.98 (s, 1H), 9.15 (br s, 1H), 9.02 (br d, 1H), 7.49 (d, 1H), 7.37-7.24 (m, 2H), 6.38 (br s, 1H), 5.10 (dd, 1H), 4.42-4.31 (m, 1H), 4.29-4.18 (m, 1H), 3.89 (br d, 2H), 3.59 (br d, 2H), 3.48-3.34 (m, 2H), 3.25 (br d, 2H), 3.18-3.03 (m, 4H), 2.93-2.78 (m, 3H), 2.59 (br d, 1H), 2.38 (dq, 1H), 2.19 (br s, 1H), 2.09-1.94 (m, 3H), 1.54-1.40 (m, 2H). Example 1. Synthesis of 3-(5-(3-((1-((1-((4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol- 4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)piperidin-4- yl)methyl)piperidin-4-yl)oxy)prop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione.
Figure imgf000238_0001
Acetic acid (2.2 mg, 0.37 mmol) was added to a solution of 3-(1-oxo-5-(3-(piperidin-4- yloxy)prop-1-yn-1-yl)isoindolin-2-yl)piperidine-2,6-dione (Intermediate 6, 70 mg, 0.184 mmol) and 1-((4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)piperidine-4-carbaldehyde (Intermediate 4, 113 mg, 0.202 mmol) in DCM (5 mL) and stirred at rt under N216 h. STAB (77.8 mg, 0.37 mmol) was added and stirring continued for 2 h at rt. The mixture was quenched with cold water (10 mL) and extracted with DCM (3x 15 mL). The combined organics were washed with water (2x 15 mL), brine (15 mL), dried (Na2SO4) and evaporated to dryness under reduced pressure. The residue was purified by prep-HPLC purification (Column: X-BRIDGE C18; 250 x 20 mm; 5 µm mobile phase: 0.10 % formic acid in water mobile phase (B):- MeOH , Gradient : (T%B):- 0/15, 10/55, 18/55, 18.01/98, 21/98, 21.1/15, 25/15 Flow: 18.0 mL/min Diluent: ACN+THF) to afford the title compound as a white solid (38 mg, 22%). LCMS m/z = 925 [M+H]+; 1H-NMR (400 MHz, DMSO-d6): 10.99 (s, 1H), 8.54 (d, 1H), 8.19 (d, 1H), 8.13 (s, 1H), 8.02-7.89 (m, 2H), 7.73-7.70 (m, 2H), 7.57-7.55 ( m, 1H), 6.51 (br s, 7H), 6.27 (br s, 1H), 5.13-5.09 (m, 1H), 4.75 (s, 1H), 4.48-4.31 (m, 4H), 4.1 (d, 2H), 3.98 (br s, 1H), 3.55 (m, 5H), 3.03-2.86 (m, 3H), 2.81-2.66 (m, 4H), 2.62-2.57 (m, 1H), 2.41-2.32 (m, 1H), 2.33-2.01 (m, 4H), 1.91-1.90 (m, 5H), 1.74 (d, 2H), 1.55-1.50 (m, 5H), 1.07 (br s, 8H). Example 2. N-((1r,4r)-4-(4-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)prop-2-yn- 1-yl)oxy)piperidine-1-carbonyl)cyclohexyl)-3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)- 1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide
Figure imgf000239_0001
HATU (57.0 mg, 0.150 mmol) was added to a mixture of (1r,4r)-4-((3-fluoro-4-((4-(1-(2- hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)phenyl)sulfonamido)cyclohexane-1-carboxylic acid (Intermediate 15, 75 mg, 0.125 mmol), 3-(1-oxo-5-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)isoindolin-2-yl)piperidine-2,6-dione (Intermediate 6, 42.9 mg, 0.112 mmol) and DIPEA (0.065 mL, 0.375 mmol) in DMF (2 mL) at 0 ºC under N2 and warmed to rt and stirred for 18h. The reaction mixture was quenched with cold water (10 mL) and extracted with EtOAc (3x 15 mL). The combined organics were washed with brine (15 mL), dried (Na2SO4) and evaporated to dryness under reduced pressure. The residue was purified by RP-Prep-HPLC (Column: INRTSIL ODS-3 (250*20 mm),5 µm Mobile phase: 10 mM Ammonium bicarbonate in H2O Mobile phase (B):- ACN , Gradient : (T % B ):-0.1/35, 1/35, 10/65, 10.01/98, 13/98, 13.01/35, 15/35 Flow: 18.0 mL/min) to afford the title compound as an off-white solid (20 mg, 16.6%). LCMS m/z = 964 [M+H]+; 1H-NMR (400 MHz, DMSO-d6): 8.78 (s, 1H), 8.50 (bs, 1H), 8.26 (s, 1H), 8.07 (t, 1H), 7.93 (s, 1H), 7.77-7.67 (m, 4H), 7.57 (d, 1H), 5.14-5.09 (q, 1H), 4.79 (s, 1H), 4.48- 4.44 (m, 3H), 4.33 (m, 1H), 4.12 (s, 2H), 3-77.75 (m, 3H), 3.26-2.88 (m, 4H), 2.67-2.61 (m, 2H), 2.41-2.33 (m, 1H), 1.68-1.57 (m, 4H), 1.39-1.23 (m, 6H), 1.07 (s, 6H). Example 3. N-((1r,4r)-4-((4-(4-((3-(4-(2,6-dioxopiperidin-3-yl)phenyl)prop-2-yn-1- yl)oxy)piperidine-1-carbonyl)piperidin-1-yl)methyl)cyclohexyl)-3-fluoro-4-((4-(1-(2- hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide
Figure imgf000240_0001
HATU (0.055 g, 0.14 mmol) was added to a solution of 1-(((1r,4r)-4-((3-fluoro-4-((4-(1-(2- hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)phenyl)sulfonamido)cyclohexyl)methyl)piperidine-4-carboxylic acid (Intermediate 29, 0.1g, 0.143 mmol), 3-(4-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)phenyl)piperidine-2,6- dione hydrochloride (Intermediate 28, 52 mg, 0.143 mmol) and DIPEA (55.6 mg, 0.43 mmol) in DMF (2 mL) at 0 °C under N2. The reaction mixture was warmed to rt and stirred for 16 h. The reaction was quenched with cold water (10 mL) and extracted with EtOAc (3x 15 mL). The combined organics were washed with water (2x 15 mL), brine (15 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by Prep-HPLC-B to afford the title compound as a white solid (38 mg, 26%). LCMS m/z = 1006 [M+H]+; 1H NMR (DMSO-d6, 400 MHz): 10.86 (s, 1H), 10.09 (s, 1H), 8.78 (s, 1H), 8.36 (brs, 1H), 8.25 (s, 1H), 8.05 (t, 1H), 7.93 (s, 1H), 7.71-7.65 (m, 3H), 7.41 (d, 2H), 7.24 (d, 2H), 4.8 (brs, 1H), 4.42 (s, 2H), 4.12 (s, 2H), 3.73-3.60 (m, 4H), 3.40-3.30 (m, 1H), 3.16-3.09 (m, 1H), 2.93- 2.89 (m, 1H), 2.80-2.70 (m, 2H), 2.72-2.67 (m, 1H), 2.50-2.49 (m, 2H), 2.22-2.18 (m, 1H), 2.03-1.95 (m, 3H), 1.89-1.79 (m, 4H), 1.66-1.64 (d, 4H), 1.50-1.32 (m, 7H), 1.15-1.08 (m, 8H), 0.78-0.75 (m, 2H). Example 4. N-((1r,4r)-4-(4-(4-((3-(3-(2,6-dioxopiperidin-3-yl)phenyl)prop-2-yn-1- yl)oxy)piperidine-1-carbonyl)piperidine-1-carbonyl)cyclohexyl)-3-fluoro-4-((4-(1-(2- hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide
Figure imgf000241_0001
A solution of 3-(3-(3-((1-(piperidine-4-carbonyl)piperidin-4-yl)oxy)prop-1-yn-1- yl)phenyl)piperidine-2,6-dione (Intermediate 12, 70 mg, 0.160 mmol), (1r,4r)-4-((3-fluoro-4- ((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)phenyl)sulfonamido)cyclohexane-1-carboxylic acid (Intermediate 15, 96.1 mg, 0.160 mmol) and DIPEA (0.070 mL, 0.40 mmol) in DMF (4.2 mL) at rt under nitrogen was cooled to 0 ºC and HATU (73 mg, 0.19 mmol) added and the reaction mixture warmed to rt and stirred for 18h. The reaction mixture was quenched with cold water (10 mL) and extracted with EtOAc (3x 15 mL). The combined organics were washed with brine (15 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by prep-HPLC (Column: X-SELECT-C18 (250*19 mm), 5 µm Mobile phase: 0.1% FA in H2O Mobile phase (B):- methanol Flow :-18.00 mL /min , Gradient :- (T % B): 0.01/30, 1/30, 10/68, 13/68, 13.5/98, 15/98, 15.01/30, 17/30, Diluent : Acetonitrile and THF) to afford the title compound as a white solid (7.5 mg, 5%). LCMS m/z = 1020 [M+H]+; 1H-NMR (400 MHz, DMSO-d6): 10.86 (s, 1H), 10.09 (s, 1H), 8.79 (s, 1H), 8.26 (s, 1H), 8.08 (t, 1H), 7.94 (s, 1H), 7.75 (d, 1H), 7.69 (d, 2H), 7.36 (d, 2H), 7.33 (s, 1H), 7.28-7.26 (m, 1H), 4.78 (s, 1H), 4.44 (s, 2H), 4.34-4.31 (m, 1H), 4.12 (s, 2H), 3.91-3.77 (m, 5H), 3.32-2.68 (m, 5H), 2.68 (bs, 1H), 2.51-2.50 (m, 2H), 2.33-2.00 (m, 2H), 1.90-1.83 (m, 2H), 1.69-1.57 (m, 6H), 1.44-1.24 (m, 9H), 1.09 (s, 6H). Example 5. 3-(4-(9-((1-((4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)piperidin-4-yl)methyl)-3,9- diazaspiro[5.5]undecan-3-yl)phenyl)piperidine-2,6-dione
Figure imgf000242_0001
Acetic acid (0.001 mL, 0.018 mmol) was added to a solution of 1-((4-((4-(1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1- yl)sulfonyl)piperidine-4-carbaldehyde (Intermediate 4, 100 mg, 0.179 mmol) and 3-(4-(3,9- diazaspiro[5.5]undecan-3-yl)phenyl)piperidine-2,6-dione (Intermediate 9, 61 mg, 0.179 mmol) in DCE (2 mL) at rt and the mixture stirred at rt for 16 h. To this was added sodium triacetoxyborohydride (75.8 mg, 0.36 mmol) and the mixture stirred at rt for 2 h. The reaction was quenched with ice cold water (50 mL) and extracted with 10% MeOH in DCM (3x 30 mL). The combined organics were washed with brine solution (15 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by prep-HPLC (Column: X-SELECT-C18 (250*19 mm), 5 µm Mobile phase: 0.1% FA in H2O Mobile phase (B): - Acetonitrile Flow :- 18.0mL/min , Gradient :- (T % B):- 0/20, 1/20, 8/52, 8.01/98, 10/98, 10.01/20, 15/20 Diluent :- Acetonitrile and THF) to afford the title compound as a white solid 38 mg, 24%). LCMS m/z = 885 [M+H]+; 1H-NMR (400 MHz, DMSO-d6): 10.76 (s, 1H), 8.57-8.52 (m, 1H), 8.21-8.15 (m, 2H), 8.02-7.88 (m, 2H), 7.02 (d, 2H), 6.87 (d, 2H), 4.75 (s, 1H), 4.10 (d, 2H), 3.91 (s, 2H), 3.73-3.69 (m, 1H), 3.56 (d, 4H), 3.22 (s, 4H), 2.97-2.80 (m , 3H), 2.79 (t, 2H), 2.59-2.50 (m, 1H), 2.42 (s, 1H), 2.33 (d, 4H), 2.18 (d, 2H), 2.02-1.89 (m, 4H), 1.71 (d, 2H), 1.57 (s, 1H), 1.50 (d, 9H), 1.07 (s, 8H). Example 6. 3-(3-(9-((1-((4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)piperidin-4-yl)methyl)-3,9- diazaspiro[5.5]undecan-3-yl)phenyl)piperidine-2,6-dione
Figure imgf000243_0001
Acetic Acid (0.001 mL, 0.018 mmol) was added to a solution of 1-((4-((4-(1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1- yl)sulfonyl)piperidine-4-carbaldehyde (Intermediate 4, 100 mg, 0.179 mmol) and 3-(3-(3,9- diazaspiro[5.5]undecan-3-yl)phenyl)piperidine-2,6-dione (Intermediate 10, 61 mg, 0.179 mmol) in DCE (2 mL) and stirred at rt for 16 h. Sodium triacetoxyborohydride (75.7 mg, 0.36 mmol), was added and the mixture was stirred at rt for 18 h. The reaction mixture was quenched with ice cold water (50 mL) and extracted with 10% MeOH in DCM (3x 30 mL). The combined organics were washed with ice cold water (2x 15 mL), brine (15 mL), dried (Na2SO4) concentrated under reduced pressure. The residue was purified by prep-HPLC (Column: X-BRIDGE-C18 (250*19 mm), 5 µm Mobile phase: 0.1% FA in H2O Mobile phase (B): - Acetonitrile Flow :- 18.0mL/min , Gradient :- (T % B):- 0/10, 1/10, 10/60, 10.01/98, 13/98, 13.01/10, 16/10 Diluent :- Acetonitrile and THF) to afford the title compound as a white solid (48 mg, 30%). LCMS m/z = 885 [M+H]+; 1H-NMR (400 MHz, DMSO-d6): 10.78 (s, 1H), 8.57-8.52 (m, 1H), 8.17-8.14 (m, 1H), 8.02-7.89 (m, 2H), 7.14 (t, 1H), 6.81 (d, 1H), 6.77 (s, 1H), 6.57 (d, 1H), 4.78 (s, 1H), 4.03 (d, 2H), 3.98 (s, 1H), 3.76- 3.72 (m, 1H), 3.57 (t, 4H), 3.14 (d, 4H), 2.97 (t, 2H), 2.80 (t, 2H), 2.76-2.59 (m, 1H), 2.42 (d, 4H), 2.24 (d, 3H), 2.07-1.92 (m, 3H), 1.54-1.49 (m, 10H), 1.07 (m, 8H). Example 7. N-((1r,4r)-4-((9-(4-(2,6-dioxopiperidin-3-yl)phenyl)-3,9- diazaspiro[5.5]undecan-3-yl)methyl)cyclohexyl)-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-sulfonamide
Figure imgf000244_0001
Acetic acid (2.11 mg, 0.035 mmol) was added to solution of 3-(4-(3,9- diazaspiro[5.5]undecan-3-yl)phenyl)piperidine-2,6-dione (Intermediate 9, 60 mg, 0.176 mmol) and N-((1r,4r)-4-formylcyclohexyl)-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-sulfonamide (Intermediate 5, 111 mg, 0.193 mmol) in 1,2-Dichloroethane (5 mL). and the mixture was stirred at rt under nitrogen atmosphere for 16 h. Sodium triacetoxyborohydride (55.9 mg, 0.264 mmol) was added and stirring continued at rt for 2 h. The reaction was quenched with cold water (10 mL) and extracted with DCM (3x 15 mL). The combined organics were washed with water (2x 15 mL), brine (15 mL) and dried (Na2SO4). The filtrate was concentrated under reduced pressure and the residue purified by prep-HPLC (Column:- X- SELECT-C18 (250*19 mm), 5 µm Mobile phase: 0.1% FA in H2O Mobile phase (B): - Acetonitrile Flow :- 22.0 mL/min , Gradient :- (T % B):- 0/20, 2/20, 8/33, 9.7/33, 9.8/98, 12/98, 12.01/20, 15/20 Diluent :- Acetonitrile and THF) to afford the title compound as a white solid (25 mg, 98%). LCMS m/z = 899 [M+H]+; 1H-NMR (400 MHz, DMSO-d6): 10.77 (s, 1H), 8.61-8.50 (m, 2H), 8.19 (d, 1H), 8.02-7.89 (m, 2H), 7.24 (m, 1H), 7.05 (d, 2H), 6.94-6.92 (m, 2H), 4.10-4.09 (m, 2H), 3.90-3.40 (m, 1H), 3.74-3.70 (m, 1H), 3.61 (m, 2H), 3.46 (m, 2H), 3.32-3.14 (m, 4H), 3.03-2.93 (m, 5H), 2.81 (m, 2H), 2.6 (m, 1H), 2.49-2.44 (m, 1H), 2.07-2.01(m, 1H), 2.01-1.69 (m, 12H), 1.61-1.50 (m, 6H), 1.28-1.25 (m, 2H), 1.08-1.02 (m, 8H). Example 8. 3-(5-(3-((1-((4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)piperidin-4-yl)amino)azetidin- 1-yl)-1-oxoisoindolin-2-yl)
Figure imgf000244_0002
e-2,6-dione
Figure imgf000245_0001
Step 1. Synthesis of tert-butyl (1-((4-oxopiperidin-1-yl)sulfonyl)piperidin-4-yl)carbamate. Tert-butyl (1-(chlorosulfonyl) piperidine-4-yl) carbamate (3.014 g, 10.0 mmol) was added to a solution of piperidin-4-one (1 g, 10.0 mmol) in DCM (10 mL) at 0 °C and TEA (4.230 mL, 30.2 mmol) and the reaction mixture stirred at rt for 3 h. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3x 50 mL). The combined organics were dried (Na2SO4) and concentrated under vacuum. The residue was purified by column chromatography (10-50% EtOAc/PE) to afford the title compound as a white solid (1.0 g, 27%). LCMS m/z = 362 [M+H]+. Step 2: Synthesis of 1-((4-aminopiperidin-1-yl) sulfonyl)piperidin-4-one hydrochloride. To a solution of tert-butyl (1-((4-oxopiperidin-1-yl)sulfonyl)piperidin-4-yl)carbamate (Step 1, 0.5 g, 1.38 mmol) in DCM (2.5 mL) at 0 °C was added 4 M HCl in dioxane (2.5 mL) at 0 ºC and the reaction mixture stirred at rt for 3 h. The reaction mixture was concentrated under reduced pressure and the residue triturated in diethyl ether to afford the title compound as a white solid (0.4 g, 97%). LCMS m/z = 261 [M+H]+. Step 3: Synthesis of 1-((4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)piperidin-4-one p-Toluene sulfonic acid monohydrate (0.320 g, 1.69 mmol) was added to a solution of 1-((4- aminophenyl)sulfonyl) piperidine-4-one hydrochloride (Step 2, 0.5 g, 1.69 mmol), and 1-(4- (2-chloro-5-(trifluoromethyl) pyrimidine-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate XX, 0.54 g, 1.69 mmol) in IPA (5 mL) at room temperature under nitrogen atmosphere and the reaction mixture heated at 90 °C for 16 h. The reaction mixture quenched with water (20 mL) and extracted with ethyl acetate (3x 30 mL). The combined organics were washed with brine solution (30 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (90% EtOAc/PE) to afford the title compound as a white solid (0.23 g, 25%). LCMS m/z = 546 [M+H]+. Step 4. Synthesis of tert-butyl (1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)azetidin- 3-yl)carbamate. A mixture of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.280 g, 0.866 mmol) and tert-butyl azetidin-3-ylcarbamate (0.3 g, 1.733 mmol) and cesium carbonate (847 mg, 2.60 mmol) in dioxane (6 mL) was purged with nitrogen gas for 15 min. To this was added Pd-PEPSI-IHept-Cl2 (0.034 g, 0.043 mmol) under a nitrogen and the reaction mixture stirred at 100 °C for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3x 20 mL). The combined organics were washed with brine (20 mL), dried (Na2SO4), concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 50-60% EtOAc/PE) to afford the title compound as a yellow oil (0.1 g, 28%). LCMS m/z = 415 [M+H]+. Step 5. Synthesis of 3-(5-(3-aminoazetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. A solution of tert-butyl (1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl) azetidine-3-yl) carbamate (Step 4, 0.06 g, 0.145 mmol) in formic acid (1.2 mL) was stirred at rt for 6 h. The reaction mixture was concentrated under reduced pressure to afford the title compound as a white solid (0.04 g, 87%). LCMS m/z = 315 [M+H]+. Step 6. Synthesis of 3-(5-(3-((1-((4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)piperidin-4-yl)amino)azetidin- 1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a stirred solution of 3-(5-(3-aminoazetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione (Step 5, 50 mg, 0.159 mmol) in DMSO were added 1-((4-((4-(1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1- yl)sulfonyl)piperidine-4-one (Step 3, 87 mg, 0.159 mmol) and AcOH (0.005 mL) at rt and stirred for 30 min. STAB (67 mg, 0.318 mmol) was added and the reaction mixture stirred for 12 h at rt. The reaction mixture was diluted with water and extracted with EtOAc (2x 50 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by prep-HPLC-U to afford the title compound as a white solid (10 mg, 21%). LCMS m/z = 844 [M+H]+; 1H-NMR (400 MHz, DMSO-d6): 10.92 (s, 1H), 8.57-8.52 (m, 1H), 8.21-8.19 (m, 1H), 8.02-7.89 (m, 2H), 7.47 (d, 1H), 6.48 (m, 2H), 5.0 (m, 1H), 4.75 (s, 1H), 4.32-4.10 (m, 6H), 4.2-3.98 (m, 1H), 3.84-3.79 (m, 1H), 3.54-3.52 (m, 6H), 3.0-2.85 (m, 6H), 2.67 (s, 1H), 2.33 (s, 1H), 1.97-1.89 (m, 3H), 1.83-1.79 (m, 2H), 1.57-1.53 (m, 2H), 1.37 (s, 1H), 1.31- 1.27 (m, 2H), 1.10-1.04 (m, 6H). Example 9. 3-(4-(3-((1-((1-((4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)piperidin-4- yl)methyl)piperidin-4-yl)oxy)prop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione
Figure imgf000247_0001
A mixture of 1-((4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)piperidine-4-carbaldehyde (Intermediate 4, 80 mg, 0.143 mmol), 3-(1-oxo-4-(3-(piperidin-4-yloxy)prop-1-yn-1- yl)isoindolin-2-yl)piperidine-2,6-dione (Intermediate 16, 65.4 mg, 0.172 mmol), AcOH (1.72 mg, 0.029 mmol) and 1,2-dichloroethane (2.4 mL) at rt under N2 and stirred for 16h. The reaction mixture was cooled to 0 ºC and STAB (60.6 mg, 0.286 mmol) was added and the reaction mixture warmed to rt and stirred for 3h. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3x 15 mL). The combined organics were washed with brine (15 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by prep-HPLC (Column: INRTSIL ODS-3 (250*20 mm), 5 µm Mobile phase: 0.1% FA in H2O Mobile phase (B): -Acetonitrile Flow :- 18.0 mL/min , Gradient :- (T % B ):- 0.01/49, 18.5/49-ISOCRATIC Diluent :- Acetonitrile and H2O) to afford the title compound as a white solid (54 mg, 41%). LCMS m/z = 925 [M+H]+; 1H-NMR (400 MHz, DMSO-d6): 11.0 (s, 1H), 8.55 (d, 1H), 8.21-8.13 (m, 2H), 8.02-7.89 (m, 2H), 7.78 (d, 1H), 7.72-7.67 (m, 1H), 7.57 (t, 1H), 7.19-6.90 (m, 3H), 6.51 (s, 21H), 6.16 (s, 6H), 5.16 (d, 1H), 4.75 (s, 1H), 4.503 (t, 2H), 4.33 (d, 1H), 4.10 (d, 2H), 4 (bs, 1H), 3.57 (d, 4H), 3.00-3.92 (m, 5H), 2.810 (t, 2H), 2.60 (d, 2H), 2.41 (d, 7H), 2.07-1.90 (m, 6H), 1.77 (d, 2H), 1.54 (d, 2H), 1.17-1.15 (m, 2H), 1.07 (d, 6H). Example 10. 3-((3-fluoro-4-(4-(1-((4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)- 5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)piperidin-4-yl)piperazin-1- yl)phenyl)amino)piperidine-2,6-dione
Figure imgf000248_0001
Step 1. Synthesis of tert-butyl 4-(1-((4-nitrophenyl)sulfonyl)piperidin-4-yl)piperazine-1- carboxylate. To a stirred solution of 4-nitrobenzenesulfonyl chloride (2.00 g, 9.02 mmol) in DCM (10 mL) was added solution of tert-butyl 4-(piperidin-4-yl) piperazine-1-carboxylate (2.92 g, 10.8 mmol) in DCM (10 mL) followed by triethylamine (1.83 g, 18.1 mmol) at 0 °C and the reaction mixture warmed to rt and stirred for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with DCM (2x 100 mL). The combined organics were washed with brine (50 mL), dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as an off-white solid (3 g, 73%). LCMS m/z = 455 [M+H]+. Step 2. Synthesis of tert-butyl 4-(1-((4-aminophenyl) sulfonyl) piperidin-4-yl) piperazine-1- carboxylate. To a stirred solution of tert-butyl 4-(1-((4-nitrophenyl) sulfonyl) piperidin-4-yl) piperazine-1- carboxylate (Step 1, 3 g, 6.60 mmol) in THF (20 mL) and MeOH (20 mL) was added solution of ammonium chloride (3.53 g, 66.0 mmol) in water (10 mL) followed by Zn dust (4.32 g, 66.0 mmol) and stirred at rt for 16 h. The reaction mixture was filtered through a pad of celite and washed with EtOAc (2x 30 mL). The filtrate was diluted with water (100 mL) and extracted with EtOAc (2x 100 mL). The combined organics were washed with brine (50 mL), dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as an off-white solid (2.50 g, 89%). LCMS m/z = 425 [M+H]+. Step 3. Synthesis of 2-methyl-1-(4-(2-((4-((4-(piperazin-1-yl)piperidin-1- yl)sulfonyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propan-2-ol To a stirred solution of tert-butyl 4-(1-((4-aminophenyl)sulfonyl)piperidin-4-yl)piperazine-1- carboxylate (Step 2, 0.20 g, 0.47 mmol) in IPA (5.0 mL) were added at 0 °C, 1-(4-(2-chloro- 5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 1, 0.18 g, 0.57 mmol) and PTSA (0.08 g, 0.47 mmol) and the resulting mixture stirred at 85 °C for 16 h. The reaction mixture was concentrated under reduced pressure and the residue purified by reverse phase column chromatography (40-50% H2O (0.1% HCO2H)/MeCN) to afford the title compound as a light brown solid (0.22 g, 77%). LCMS m/z = 609 [M+H]+. Step 4. Synthesis of 1-(4-(2-((4-((4-(4-(2-fluoro-4-nitrophenyl)piperazin-1-yl)piperidin-1- yl)sulfonyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2- methylpropan-2-ol. To a stirred solution of 2-methyl-1-(4-(2-((4-((4-(piperazin-1-yl)piperidin-1- yl)sulfonyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propan-2-ol (Step 3, 0.20 g, 0.28 mmol) in DMF (3 mL) was added 1,2-difluoro-4-nitrobenzene (0.06 g, 0.34 mmol) and sodium carbonate (0.09 g, 0.85 mmol) at 0 °C and the reaction mixture stirred at 100 °C for 16 h. The reaction mixture was diluted with water (25 mL) and extracted with DCM (2x 50 mL). The combined organics were washed with brine (50 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0-10% MeOH/DCM) to afford the title compound as a pale brown solid (0.23 g, 94%) as a pale brown solid. LCMS m/z = 748 [M+H]+. Step 5. Synthesis of 1-(4-(2-((4-((4-(4-(4-amino-2-fluorophenyl)piperazin-1-yl)piperidin-1- yl)sulfonyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2- methylpropan-2-ol To a stirred solution of 1-(4-(2-((4-((4-(4-(2-fluoro-4-nitrophenyl)piperazin-1-yl)piperidin-1- yl)sulfonyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2- methylpropan-2-ol (Step 4, 0.20 g, 0.27 mmol) in EtOAc/THF (1:1, 10 mL) was added 10% Pd-C (199 mg, 1.87 mmol) and stirred at rt for 5 h under H2 atmosphere. The reaction mixture was filtered through pad of celite, washed with EtOAc (2x 30 mL). The filtrate was concentrated under reduced pressure and the residue purified by reverse phase column chromatography (25-35% H2O (0.1% HCO2H)/MeCN) to afford the title compound as a pale brown solid (0.19 g, 100%). 1H NMR (400 MHz, DMSO-d6): 10.60 (s, 1H), 8.84 (s, 1H), 8.33 (s, 1H), 8.07-8.05 (m, 3H), 7.73 (d, 2H), 6.66-6.61 (m, 2H), 6.49-6.46 (m, 1H), 4.81 (s, 1H), 4.51 (s, 2H),4.15 (s, 2H), 3.66-3.63 (m, 2H), 2.86 (m, 4H), 2.29-2.18 (m, 4H), 1.81-1.79 (m, 2H), 1.49-1.41 (m, 3H), 1.10 (s, 6H). Step 6. Synthesis of 3-((3-fluoro-4-(4-(1-((4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol- 4-yl)-5-(trifluoromethyl) pyrimidin-2-yl) amino) phenyl) sulfonyl) piperidin-4-yl) piperazin- 1-yl) phenyl)amino)piperidine-2,6-dione: To a stirred solution of 1-(4-(2-((4-((4-(4-(4-amino-2-fluorophenyl) piperazin-1-yl) piperidin- 1-yl) sulfonyl) phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2- methylpropan-2-ol (Step 5, 120 mg, 0.17 mmol) in DMF (5 mL) was added sodium bicarbonate (112 mg, 1.34 mmol) at 0 °C and the reaction mixture stirred at rt for 1 h. 3- bromopiperidine-2,6-dione (160 mg, 0.84 mmol) was added and the resulting mixture stirred at 70 °C for 16 h. The reaction mixture was diluted with water (50 mL), extracted with EtOAc (3x 30 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by prep-HPLC (Column/dimensions : Kinetex C-18 (21*250 mm*5 µm), Mobile phase A : ABC, Mobile phase B: 100% Acetonitrile, Gradient (Time/%B) :0/10, 2/10, 10/35. Flow rate: 18 mL/min, Solubility : WATER+ACN) to afford the title compound as an off-white solid (60 mg, 46%). LCMS m/z = 829 [M+H]+. Example 11 and 12. (S)-3-((3-fluoro-4-(4-(1-((4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)piperidin-4- yl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione and (R)-3-((3-fluoro-4-(4-(1-((4-((4-(1- (2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)phenyl)sulfonyl)piperidin-4-yl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione.
Figure imgf000251_0001
Example 10 was separated by chiral-SFC (Column/dimensions : Kinetex C-18 (21*250 mm *5 µm), Mobile phase A : ABC, Mobile phase B: 100% Acetonitrile, Gradient (Time/%B): 0/10, 2/10, 10/35. Flow rate: 18 mL/min, Solubility : WATER+ACN) to afford: Peak 1 (first eluting isomer), Example 11; (S)-3-((3-fluoro-4-(4-(1-((4-((4-(1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)phenyl)sulfonyl)piperidin-4-yl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione or (R)-3-((3-fluoro-4-(4-(1-((4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)piperidin-4-yl)piperazin-1- yl)phenyl)amino)piperidine-2,6-dione. Off-white solid (10.3 mg, 7%). LCMS m/z = 829 [M+H]+; 1H NMR (400 MHz, DMSO-d6): 10.76 (s, 1H), 10.65 (s, 1H), 8.84 (s, 1H), 8.33 (s, 1H), 8.05 (m, 3H), 7.73 (d, 2H), 6.78 (t, 1H), 6.50-6.46 (m, 1H), 6.40-6.37 (m, 1H), 5.77 (d, 1H), 4.80 (s, 1H), 4.26-4.20 (m, 1H), 4.15 (s, 2H), 3.66-3.64 (m, 2H), 2.78-2.70 (m, 5H), 2.57-2.49 (m, 5H), 2.29-2.21 (m, 3H), 2.09-2.07 (m, 2H), 1.85-1.79 (m, 2H), 1.51-1.45 (m, 2H), 1.02 (s, 6H). Peak 2 (second eluting isomer), Example 12; (R)-3-((3-fluoro-4-(4-(1-((4-((4-(1-(2-hydroxy- 2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)phenyl)sulfonyl)piperidin-4-yl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione or (S)-3-((3-fluoro-4-(4-(1-((4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)piperidin-4-yl)piperazin-1- yl)phenyl)amino)piperidine-2,6-dione. Off-white solid (10.2 mg, 7%). LCMS m/z = 829 [M+H]+; 1H NMR (400 MHz, DMSO-d6): 10.76 (s, 1H), 10.65 (s, 1H), 8.84 (s, 1H), 8.33 (s, 1H), 8.06 (m, 3H), 7.73 (d, 2H), 6.80-6.75 (m, 1H), 6.46-6.50 (m, 1H), 6.37-6.40 (m, 1H), 5.77 (d, 1H) 4.80 (s, 1H), 4.20-4.24 (m, 1H), 4.15 (s, 2H), 3.64 (m, 2H), 2.70-2.78 (m, 4H), 2.49-2.57 (m, 5H), 2.21-2.29 (m, 3H), 2.04-2.09 (m, 1H), 1.79-1.85 (m, 2H), 1.49 (m, 2H) 1.23 (m, 2H), 1.02 (s, 6H). Example 13. 3-(5-(4-((1-((4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)piperidin-1-yl)sulfonyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione
Figure imgf000252_0001
Step1. Synthesis of 2,5-dichloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidine A mixture of 2,4,5-trichloropyrimidine (1 g, 5.45 mmol), 1-methyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.69 g, 8.17 mmol), Pd(dppf)Cl2 (100 mg, 122 µmol), Cs2CO3 (3.55 g, 10.9 mmol) in dioxane (50 mL) and H2O (10 mL) was stirred at 50 ℃ for 2 h. The reaction mixture was evaporated to dryness and the residue purified on silica gel column to afford title compound as an off-white solid (450 mg, 36%). LCMS m/z = 229 [M+H]+ Step2. Synthesis of tert-butyl 4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)piperidine-1-carboxylate A mixture of 2,5-dichloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidine (Step 1, 500mg, 2.18 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (522 mg, 2.61 mmol), DIPEA (845 mg, 6.54 mmol) in DMSO (8 mL) was stirred at 120 ℃ for 2 h. The reaction mixture was evaporated to dryness and the residue purified on C18 column with 20% ACN in water to afford title compound as a white solid (400 mg, 46%). LCMS m/z = 415 [M+H]+ Step 3. Synthesis of 5-chloro-4-(1-methyl-1H-pyrazol-4-yl)-N-(piperidin-4-yl)pyrimidin-2- amine To a solution of tert-butyl 4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)piperidine-1-carboxylate (Step 2, 400 mg, 1.01 mmol) in DCM (8 mL) was added TFA (3 mL) and the reaction mixture stirred at 25 ℃ for 3 h. The reaction mixture was evaporated to dryness and the residue dissolved in DCM and washed (sat Na2CO3), dried (Na2SO4) and concentrated to dryness. The residue was purified on C18 column with 20% ACN in water to afford title compound as a white solid (200 mg, 68%). LCMS m/z = 293 [M+H]+ Step 4. Synthesis of 4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)piperidine-1-sulfonyl chloride A mixture of 5-chloro-4-(1-methyl-1H-pyrazol-4-yl)-N-(piperidin-4-yl)pyrimidin-2-amine (Step 3, 220 mg, 751 µmol), TEA (303 mg, 3.00 mmol) and DCE (8 mL) was stirred at 0 ℃ and SO2Cl2 (303 mg, 2.25 mmol) added slowly and the resulting mixture stirred at 50 ℃ for 2h. The reaction was quenched with water and extracted with DCM. The combined organics were evaporated to dryness and the residue purified on prep-TLC (25:1 DCM/MeOH) to afford the title compound as a yellow solid (120 mg, 41%). LCMS m/z = 391 [M+H]+ Step 5. Synthesis of 3-(5-(4-((1-((4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)piperidin-1-yl)sulfonyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione A mixture of 4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)piperidine-1- sulfonyl chloride (Step 4, 70 mg, 178 µmol), 3-(1-oxo-6-(4-(piperidin-4-ylmethyl)piperazin- 1-yl)isoindolin-2-yl)piperidine-2,6-dione (Intermediate 122, 113 mg, 267 µmol), TEA (54 mg, 534 µmol) in DCE (8 mL) was stirred at 50 ℃ for 2 h. The reaction mixture was evaporated to dryness and the residue purified by prep-HPLC (Xselect CSH C18 OBD 30 x 150 mm, 5 μm; 18-28% MeCN/H2O (0.1% HCO2H)) to afford the title compound as a white solid 28.6 mg, 21%). LCMS m/z = 780 [M+H]+; 1
Figure imgf000253_0001
(DMSO-d6, 400 MHz): 10.99 (s, 1H), 8.53 (s, 1H), 8.29 (s, 1H), 8.16 (s, 1H), 7.43 (d, 1H), 7.34 (d, 1H), 7.26 (dd, 1H), 7.16 (d, 1H), 5.10 (dd, 1H), 4.34 (d, 1H), 4.20 (d, 1H), 3.93 (s, 4H), 3.57 (m, 4H), 3.19 (s, 4H), 3.09-2.74 (m, 5H), 2.62 (m, 3H), 2.38 (m, 3H), 2.21 (m, 2H), 2.04-1.86 (m, 3H), 1.79 (m, 2H), 1.70 (s, 1H), 1.51 (m, 2H), 1.11 (m, 2H). Example 14. 3-(5-(4-((4-((4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)piperidin-1-yl)sulfonyl)piperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione
Figure imgf000254_0001
To a solution of 3-(1-oxo-5-(4-(piperazin-1-ylmethyl)piperidin-1-yl)isoindolin-2- yl)piperidine-2,6-dione (Intermediate 36, 30 mg, 0.070 mmol), 4-((4-(1-methyl-1H-pyrazol- 4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-sulfonyl chloride (Intermediate 35, 59.4 mg, 0.14 mmol) in DCE (8 mL) was added TEA (21.3 mg, 0.211 mmol) and the mixture stirred at 50 °C for 16 h. The mixture was evaporated to dryness and the residue purified by prep-HPLC (Xselect CSH C18 OBD 30 x 150 mm, 6 ^m; 18-34% MeCN/H2O (0.1% HCO2H)) to afford title compound as a white solid (7.6 mg). LCMS m/z = 814 [M+H]+; 1H-NMR (400 MHz, DMSO-d6): 10.96 (s, 1H), 8.55 (d, 1H), 8.22 (d, 1H), 8.02-7.87 (m, 2H), 7.50 (d, 1H), 7.04 (d, 2H), 5.05 (dd, 1H), 4.32 (d, 1H), 4.19 (d, 1H), 4.08-3.84 (m, 6H), 3.60 (m, 2H), 3.16 (s, 4H), 3.11-2.86 (m, 3H), 2.81 (m, 2H), 2.58 (m, 1H), 2.40 (m, 5H), 2.19 (d, 2H), 1.94 (m, 3H), 1.78 (m, 3H), 1.54 (m, 2H), 1.26-1.10 (m, 2H) Example 15. 3-(4-(7-((1-((4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)piperidin-1-yl)sulfonyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione
Figure imgf000255_0001
A mixture of 3-(1-oxo-4-(7-(piperidin-4-ylmethyl)-2,7-diazaspiro[3.5]nonan-2-yl)isoindolin- 2-yl)piperidine-2,6-dione (Intermediate 37, 100 mg, 0.21 mmol), 4-((4-(1-methyl-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-sulfonyl chloride (Intermediate 35, 100 mg, 0.24 mmol) and TEA (86.6 mg, 0.86 mmol) in THF (15 mL) was stirred at 50 ℃ for 3 h. The reaction mixture was evaporated to dryness under reduced pressure and the residue purified on prep-TLC 20:1 DCM/MeOH) followed by prep-HPLC (Xcelect CSH F-pheny OBD, 30 x150 mm, 5 ^m; 20-31% MeCN/H2O (0.1% HCO2H)) to afford title compound as a white solid (13.4 mg, 7.4%). LCMS m/z = 854 [M+H]+; 1H-NMR (400 MHz, DMSO-d6): 11.00 (s, 1H), 8.55 (d, 1H), 8.30-8.11 (m, 1H), 8.01-7.88 (m, 2H), 7.31 (t, 1H), 7.03 (d, 1H), 6.54 (d, 1H), 5.11 (dd, 1H), 4.45 (d, 1H), 4.30 (d, 1H), 3.93 (d, 4H), 3.73 (m, 4H), 3.57 (m, 4H), 3.07-2.86 (m, 3H), 2.80 (m, 2H), 2.64-2.55 (m, 1H), 2.40 (s, 4H), 2.21 (s, 2H), 1.94 (m, 3H), 1.76 (d, 7H), 1.60-1.47 (m, 2H), 1.17-1.01 (m, 2H). Example 16. 3-(5-(4-((1-((2-methyl-4-((4-(1-methyl-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione
Figure imgf000256_0001
Step 1. Synthesis of tert-butyl 2-methyl-4-((4-(1-methyl-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate A mixture of 2-chloro-4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine (Intermediate 43, Step 1; 500 mg, 1.90 mmol), tert-butyl 4-amino-2-methylpiperidine-1- carboxylate (488 mg, 2.28 mmol), DIPEA (491 mg, 3.80 mmol) in IPA (10 mL) was stirred at 100 ºC for 3 h. The reaction mixture was concentrated to dryness and purified column chromatography (SiO2, 50% EtOAc/PE) to afford the title compound as a solid (700 mg, 84%). LCMS m/z = 441 [M+H]+ Step 2. Synthesis of 4-(1-methyl-1H-pyrazol-4-yl)-N-(2-methylpiperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine TFA (3 mL) was added to a solution of tert-butyl 2-methyl-4-((4-(1-methyl-1H-pyrazol-4-yl)- 5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate (Step 1, 300 mg, 681 µmol) in DCM (8 mL) at 0 ºC and stirred at rt for 3 h. The reaction mixture was evaporated to dryness, diluted with DCM, washed (sat. Na2CO3), dried (Na2SO4) and evaporated to dryness to afford the title compound as a brown solid (220 mg, 95%). LCMS m/z = 341 [M+H]+ Step 3. Synthesis of methyl 1-((2-methyl-4-((4-(1-methyl-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)piperidine-4-carboxylate To a solution of 4-(1-methyl-1H-pyrazol-4-yl)-N-(2-methylpiperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine (Step 2, 250 mg, 734 µmol), TEA (147 mg, 1.46 mmol) in MeCN (10 mL) at rt was added methyl 1-(chlorosulfonyl) piperidine-4-carboxylate (265 mg, 1.10 mmol) and the mixture stirred at 80 ºC for 2 h. The reaction was quenched with water and evaporated to dryness and the residue purified by prep-TLC (30:1 DCM/MeOH) to afford title compound as a pale brown solid (200 mg, 50%). LCMS m/z = 546 [M+H]+ Step 4. Synthesis of (1-((2-methyl-4-((4-(1-methyl-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)piperidin-4-yl)methanol DIBAL-H (2M in THF, 0.7 mL, 1.39 mmol) was added to a solution of methyl 1-((2-methyl- 4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1- yl)sulfonyl)piperidine-4-carboxylate (Step 3, 190 mg, 348 µmol) in THF (10 mL) at 0 ºC and stirred at rt for 3 h. The reaction mixture was quenched with water and extracted with DCM. The combined organics were dried (Na2SO4) and concentrated to dryness to afford title compound as a pale brown solid (150 mg, 83%). LCMS m/z = 518 [M+H]+ Step 5. Synthesis of 1-((2-methyl-4-((4-(1-methyl-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)piperidine-4-carbaldehyde Dess-Martin periodinane (246 mg, 577 µmol) was added to a solution of (1-((2-methyl-4-((4- (1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1- yl)sulfonyl)piperidin-4-yl)methanol (Step 4, 150 mg, 289 µmol) in DCM (5 mL) at 0 ºC and stirred for 2 h. The reaction mixture was quenched with water and extracted with DCM. The combined organics were dried (Na2SO4) and concentrated to dryness to afford title compound as a pale brown solid (80 mg crude). LCMS m/z = 516 [M+H]+ Step 6. Synthesis of 3-(5-(4-((1-((2-methyl-4-((4-(1-methyl-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione STAB (162 mg, 772 µmol) was added to a solution of 1-((2-methyl-4-((4-(1-methyl-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)piperidine-4- carbaldehyde (Step 5, 100 mg, 193 µmol), 3-(1-oxo-5-(piperazin-1-yl)isoindolin-2- yl)piperidine-2,6-dione (WO2020201080, 75.8 mg, 231 µmol), DIPEA (99.7 mg, 772 µmol) in DCM (10 mL) and the reaction mixture stirred at rt for 2 h. The reaction was quenched with water and evaporated to dryness. The residue was purified by prep-TLC (10:1 DCM/MeOH) followed by prep-HPLC (Xselect CSH C18 OBD 30 x 150 mm, 6 μm; 20-33% MeCN/H2O (0.1% HCO2H)) to afford the title compound as a white solid (27.2 mg, 17%). LCMS m/z = 828 [M+H]+; 1H NMR (DMSO-d6, 400 MHz): 10.96 (s, 1H), 8.65-8.49 (m, 1H), 8.33-8.13 (m, 1H), 8.07-7.82 (m, 2H), 7.52 (d, 1H), 7.06 (d, 2H), 5.05 (dd, 1H), 4.39- 4.01 (m, 3H), 3.93 (s, 3H), 3.65 (s, 1H), 3.52 (s, 3H), 3.34 (s, 3H), 3.27 (s, 3H), 3.19 (m, 1H), 2.90 (m, 1H), 2.69 (m, 2H), 2.63-2.54 (m, 2H), 2.48 (s, 1H), 2.43-2.30 (m, 1H), 2.19 (m, 2H), 2.04-1.86 (m, 3H), 1.85-1.57 (m, 5H), 1.31 (m, 3H), 1.11 (m, 2H). Example 17. 2-((1-((4-((4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)piperidin- 1-yl)methyl)piperidin-1-yl)sulfonyl)piperidin-4-yl)amino)-4-(1-methyl-1H-pyrazol-4- yl)pyrimidine-5-carbonitrile
Figure imgf000258_0001
A mixture of 3-(4-((1-((1-((4-aminopiperidin-1-yl)sulfonyl)piperidin-4-yl)methyl)piperidin- 4-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Intermediate 40, 100 mg, 165 µmol), 2- chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile (Intermediate 2, 43.4 mg, 198 µmol), DIPEA (63.9 mg, 495 µmol) in DMSO (5 mL) was stirred at 120 ºC for 2 h. The reaction mixture was purified on C18 column with 40% MeCN/H2O followed by prep-HPLC (Xselect CSH C18 OBD, 30 x 150 mm, 5 μm; 28-42% MeCN/H2O (0.1% HCO2H)) to afford the title compound as a white solid (24.2 mg, 17%). LCMS m/z = 786 [M+H]+; 1H-NMR (400 MHz, DMSO-d6): 11.00 (s, 1H), 8.74-8.41 (m, 2H), 8.26-8.17 (m, 2H), 7.46 (t, 1H), 7.30 (dd, 2H), 5.12 (dd, 1H), 4.56 (s, 1H), 4.36 (d, 1H), 4.22 (d, 1H), 4.03 (s, 1H), 3.96 (s, 3H), 3.62-3.56 (m, 4H), 2.95 (m, 3H), 2.79 (t, 2H), 2.66-2.54 (m, 3H), 2.45 (dd, 1H), 2.25 (s, 2H), 2.17 (d, 2H), 1.97 (m, 5H), 1.76 (d, 2H), 1.66 (d, 3H), 1.54 (m, 2H), 1.09 (m, 2H). Example 18 and 19. N-((1s,4s)-4-((4-(4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)- yl)phenyl)prop-2-yn-1-yl)oxy)piperidine-1-carbonyl)piperidin-1-yl)methyl)cyclohexyl)-3- fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin- 2-yl)amino)benzenesulfonamide and N-((1r,4r)-4-((4-(4-((3-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)phenyl)prop-2-yn-1-yl)oxy)piperidine-1- carbonyl)piperidin-1-yl)methyl)cyclohexyl)-3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)- 1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide.
Figure imgf000259_0001
Acetic acid (0.05 mL) was added to a stirred solution of a 2:1 mixture of 3-fluoro-N-((1r,4r)- 4-formylcyclohexyl)-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide and a 2:1 mixture of 3-fluoro-N- ((1r,4r)-4-formylcyclohexyl)-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide and 3-fluoro-N-((1s,4s)-4- formylcyclohexyl)-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide (Intermediate 14, 80 mg, 0.137 mmol) and 1-(3-(3-((1-(piperidine-4-carbonyl)piperidin-4-yl)oxy)prop-1-yn-1- yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (Intermediate 46, 60 mg, 0.137 mmol) in dichloroethane (2 mL) at rt.   The reaction mixture was stirred at rt for 4 h, cooled to 0-5 °C and STAB (60 mg, w/w) added and the reaction mixture stirred for 2 h at rt. The reaction mixture was quenched with cold water (10 mL) and extracted with 10% MeOH in DCM (3x 15 mL). The combined organics were washed with water (2x 15 mL), brine (15 mL) dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by prep-HPLC (INRTSIL ODS-3, 250 x 20 mm, 5µm 0-100% MeCN/H2O (0.1% HCO2H)) to afford the title compounds: Peak 1 (first eluting isomer), Example 18. N-((1s,4s)-4-((4-(4-((3-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)phenyl)prop-2-yn-1-yl)oxy)piperidine-1- carbonyl)piperidin-1-yl)methyl)cyclohexyl)-3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)- 1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide or N- ((1r,4r)-4-((4-(4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)prop-2-yn-1- yl)oxy)piperidine-1-carbonyl)piperidin-1-yl)methyl)cyclohexyl)-3-fluoro-4-((4-(1-(2- hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide (white solid, 22 mg, 16%). LCMS m/z = 1007 [M+H]+; 1H NMR (400 MHz, DMSO-d6): 10.41 (s, 1H), 10.09 (s, 1H), 8.78 (s, 1H), 8.26 (s, 1H), 8.18 (br, 1H), 8.08-8.04 (t, 1H), 7.71-7.66 (m, 3H), 7.42-7.29 (m, 4H), 4.77 (s, 1H), 4.43 (s, 2H), 4.11 (s, 2H), 3.85-3.75 (m, 5H), 3.32-3.25 (m, 1H), 3.10-3.05 (m, 1H), 2.93-2.91(m, 1H), 2.71-2.49 (m, 4H), 2.505-2.501 (m, 1H), 1.98-1.90 (m, 2H), 1.87-1.80 (m, 4H), 1.67-1.64 (m, 4H), 1.51-1.49 (m, 4H) 1.35-1.30 (m, 3H), 1.18-1.15 (m, 2H), 1.12 (s, 6H), 0.81-0.75 (m, 2H). Peak 2 (second eluting isomer), Example 19. N-((1s,4s)-4-((4-(4-((3-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)phenyl)prop-2-yn-1-yl)oxy)piperidine-1- carbonyl)piperidin-1-yl)methyl)cyclohexyl)-3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)- 1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide or N- ((1r,4r)-4-((4-(4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)prop-2-yn-1- yl)oxy)piperidine-1-carbonyl)piperidin-1-yl)methyl)cyclohexyl)-3-fluoro-4-((4-(1-(2- hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide (white solid, 9 mg, 6.5%). LCMS m/z = 1007 [M+H]+; 1H NMR (400 MHz, DMSO-d6): 10.41 (s, 1H), 10.09 (s, 1H), 8.78 (s, 1H), 8.26 (s, 1H), 8.08- 8.04 (t, 1H), 7.93 (s, 1H), 7.70-7.67 (m, 2H), 7.60-7.59 (m, 1H), 7.42-7.29 (m, 4H), 4.77 (s, 1H), 4.44 (s, 2H), 4.11 (s, 2H), 3.81-3.73 (m, 5H), 3.32-3.25 (m, 2H), 3.17-3.10 (m, 1H), 2.78-2.71(m, 2H), 2.70-2.67 (m, 2H), 2.07-2.06 (m, 2H), 1.89-1.83 (m, 4H), 1.42-1.25 (m, 16H), 1.08 (s, 6H). Example 20. 3-(4-(6-((1-((4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)piperidin-1-yl)sulfonyl)piperidin-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2- yl)phenyl)piperidine-2,6-dione
Figure imgf000261_0001
To a stirred solution of 3-(4-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl)piperidine-2,6-dione (Intermediate 44, 150 mg, 0.53 mmol) and 1-((4-((4-(1-methyl-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)piperidine-4-carbaldehyde (Intermediate 43, 527 mg, 1.051 mmol) in MeOH (3 mL) was added two drops of AcOH and heated to 50 °C for 30 min. To this was added MP-Cyanoborohydride (0.52 g) and stirred at rt for 12 h. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to afford the title compound as an off-white solid (10.5 mg, 4.7%). LCMS m/z = 771 [M+H]+; 1H-NMR (400 MHz, DMSO-d6): 10.8 (s, 1H), 8.57-8.51 (m, 1H), 8.26-8.15 (m, 1H), 7.97-7.90 (m, 2H), 6.99 (d, 2H), 6.37 (d, 2H), 4.11-3.99 (brs, 1H), 3.98-3.90 (br s, 3H), 3.90-3.80(br s, 4 H), 3.72-3.65(m, 1H), 3.60-3.50 (br, 4H), 3.30-3.20 (m, 1H), 3.05-2.90 (m, 2H), 2.80-2.74 (m, 2H), 2.72-2.60 (m, 1H), 2.49 (m, 1H), 2.40-2.35 (m, 2 H), 2.18-2.03 (m, 1H), 2.02-1.80 (m, 2H), 1.78-1.65 (m, 3H), 1.60-1.49 (m, 2H), 1.50-1.30 (m, 4H), 1.20-1.0 (m, 2H). Example 21. N-((1r,4r)-4-((4-(4-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)prop- 2-yn-1-yl)oxy)piperidine-1-carbonyl)piperidin-1-yl)methyl)cyclohexyl)-3-fluoro-4-((4-(1-(2- hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide
Figure imgf000261_0002
The title compound was prepared from 3-(1-oxo-4-(3-(piperidin-4-yloxy)prop-1-yn-1- yl)isoindolin-2-yl)piperidine-2,6-dione (Intermediate 16) using an analogous method to that described for Example 19. LCMS m/z = 1061 [M+H]+; 1H NMR (400 MHz, DMSO-d6): 11.00 (s, 1H), 10.09 (s, 1H), 8.78 (s, 1H), 8.26-8.25 (m, 2H), 8.06 (t, 1H), 7.95 (s, 1H), 7.78- 7.76 (m, 1H), 7.73-7.66 (m, 4H), 7.56 (t, 1H), 5.14 (dd, 1H), 4.78 (bs, 1H), 4.51-4.46 (m, 3H), 4.36-4.32 (m, 1H), 4.12 (s, 2H), 3.87-3.70 (m, 3H), 3.12-3.03 (m, 2H), 3.96-3.88 (m, 2H), 2.78-2.74 (m, 2H), 2.61-2.55 (m, 1H), 2.47-2.42 (m, 1H), 1.97-1.91 (m, 3H), 1.86-1.80 (m, 4H), 1.67-1.64 (m, 4H), 1.51 (bs, 4H), 1.36-1.34 (m, 2H), 1.16-1.11 (m, 3H), 1.08 (s, 6H), 0.79-0.76 (m, 2H). Example 22. N-(2-((1-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)ethyl)-4-((4-(1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide
Figure imgf000262_0001
To a stirred solution of 4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-N-(2-(prop-2-yn-1-yloxy)ethyl)benzenesulfonamide (Intermediate 19, 0.1 g, 0.186 mmol) in dry THF (2 mL) was added 4-((2-(2-(2- azidoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Intermediate 17, 0.08 g, 0.19 mmol) at rt. To this was added a solution of CuSO4.5H2O (11.9 mg, 0.07 mmol) and sodium ascorbate (73.6 mg, 0.37 mmol) in water (2 mL) and stirred at rt under N2 for 18 h. The reaction mixture was quenched with cold water (10 mL) and extracted with EtOAc (3×15 mL). The combined organics were washed with brine (15 mL), dried (Na2SO4) and evaporated to dryness under reduced pressure. The residue was purified by Prep-HPLC-C to afford the title compound as a yellow solid (98 mg, 54%). LCMS m/z = 969 [M+H]+; 1H-NMR (400 MHz, DMSO-d6): 11.08 (s, 1H), 10.5 (s, 1H), 8.82 (s, 1H), 8.32 (s, 1H), 8.03-7.97 (dd, 4H), 7.76 (d, 2H), 7.59-7.54 (q, 2H), 7.10 (d, 1H), 7.02 (d, 1H), 6.57 (t, 1H), 5.06-5.01 (dd, 1H), 4.81 (s, 1H), 4.47 (t, 2H), 4.43 (s, 2H), 4.14 (s, 2H), 3.79 (t, 2H), 3.56 (t, 2H), 3.52 (s, 4H), 3.40-3.44 (q, 4H), 2.91-2.83 (m, 3H), 2.55 (s, 2H), 1.98-1.03 (m, 1H), 1.09 (s, 6H). Example 23. N-((1-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methyl)-3-fluoro-4-((4-(1-(2-hydroxy- 2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(2- hydroxyethyl)benzenesulfonamide
Figure imgf000263_0001
To a stirred solution of 3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-3-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-N-(2-hydroxyethyl)-N-(prop-2-yn-1- yl)benzenesulfonamide (Intermediate 20, 0.065 g, 0.12 mmol) and 4-((2-(2-(2- azidoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Intermediate 17, 0.055 g, 0.13 mmol) in THF (2.0 mL) was added the solution of sodium ascorbate (0.046 g, 0.23 mmol) and Copper (II) sulphate pentahydrate (0.007 g, 0.05 mmol) in water (1.0 mL) at rt and stirred at rt for 16 h. The reaction mixture was quenched with cold water (5 mL) and extracted with ethyl acetate (3x 15 mL). The combined organics were washed with water (2x 15 mL), brine (15 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by Prep-HPLC-A to give the title compound as a yellow solid (46 mg, 40%). LCMS m/z = 987 [M+H]+; 1H-NMR (400 MHz, DMSO-d6): 11.08 (s, 1H), 10.13 (s, 1H), 8.79 (s, 1H), 8.11 (t, 1H), 7.98 (s, 1H), 7.92 (s, 1H), 7.69-7.63 (m, 2H), 7.58-7.54 (m, 1H), 7.11 (d, 1H), 7.03 (d, 1H), 6.58 (t, 1H), 5.06-5.02 (m, 1H), 4.82- 4.79 (m, 2H), 4.50-4.45 (m, 4H), 4.12 (s, 2H), 3.76 (t, 2H), 3.57 (t, 2H), 3.51 (s, 3H), 3.49- 3.43 (m, 4H), 3.23 (t, 2H), 2.87-2.83 (m, 1H), 2.60-2.51 (m, 4H), 2.03-2.00 (m, 1H), 1.08 (s, 6H). Example 24. N-(2-((1-(2-(9-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-3,9- diazaspiro[5.5]undecan-3-yl)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)ethyl)-3-fluoro-4-((4-(1- (2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide
Figure imgf000264_0001
To a stirred solution of 3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-N-(2-(prop-2-yn-1-yloxy)ethyl)benzenesulfonamide (Intermediate 21, 0.10 g, 0.18 mmol) and 4-(9-(2-azidoethyl)-3,9-diazaspiro[5.5]undecan-3- yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Intermediate 22, 0.09 g, 0.2 mmol) in THF (3 mL) was added the solution of sodium ascorbate (0.05 g, 0.36 mmol) and Copper (II) Sulphate pentahydrate (0.008 g, 0.07 mmol) in water (1 mL) at rt and the resulting mixture stirred for 16 h. The reaction mixture was quenched with cold water (20 mL) and extracted with ethyl acetate (3x 15 mL). The combined organics were washed with water (2x 15 mL), brine (15 mL) and dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by prep-HPLC-B to afford the title compound as a yellow solid (80 mg, 43%). LCMS m/z = 1036 [M+H]+; 1H-NMR (400 MHz, CDCl3): 11.09 (s, 1H), 10.10 (s, 1H), 8.77 (s, 1H), 8.25 (s, 1H), 8.21 (s, 1H), 8.07 (t, 1H), 8.04 (s, 1H), 7.56 (s, 1H), 7.81 (br, 1H), 7.68- 7.64 (m, 3H), 7.32-7.29 (m, 2H), 5.10-5.60 (m, 1H), 4.78 (br, 1H), 4.47-4.42 (m, 4H), 4.11 (s, 2H), 3.46-3.43 (m, 2H), 3.17 (br, 4H), 2.98-2.97 (m, 2H), 2.88-2.84 (m, 1H), 2.74-2.71 (m, 2H), 2.61-2.54 (m, 2H), 2.40 (br, 4H), 2.03-2.00 (m, 1H), 1.57 (br, 4H), 1.45 (br, 4H), 1.08 (s, 6H). Example 25. N-(2-((1-(2-(1'-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-[4,4'- bipiperidin]-1-yl)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)ethyl)-3-fluoro-4-((4-(1-(2-hydroxy- 2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide
Figure imgf000265_0001
To a stirred solution of 3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-N-(2-(prop-2-yn-1-yloxy)ethyl)benzenesulfonamide (Intermediate 21, 0.07 g, 0.14 mmol) and 4-(1'-(2-azidoethyl)-[4,4'-bipiperidin]-1-yl)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione (Intermediate 24, 0.07 g, 0.15 mmol), in THF (1.3 mL) at rt was added the solution of sodium ascorbate (0.005 g, 0.27 mmol) and copper (II) sulfate pentahydrate (0.001 g, 0.06 mmol) in water (1 mL) and the resulting mixture stirred for 16 h. The reaction mixture was quenched with cold water (20 mL) and extracted with ethyl acetate (3x 15 mL). The combined organics were washed with water (2x 15 mL), brine (15 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by prep-HPLC-C to afford the title compound as a yellow solid (40 m g, 28%). LCMS m/z = 1050 [M+H]+; 1H NMR (DMSO-d6, 400 MHz): 11.08 (s, 1H), 10.1 (s, 1H), 8.76 (s, 1H), 8.25 (s, 1H), 8.08 (t, 1H), 8.02 (s, 1H), 7.96 (s, 1H), 7.81 (t, 1H), 7.67-7.63 (m, 3H), 7.30 (d, 2H), 5.10-5.05 (m, 1H), 4.78 (s, 1H), 4.46-4.41 (m, 4H), 4.11 (s, 2H), 3.72-3.69 (m, 2H), 3.46- 4.43 (m, 2H), 2.66-2.49 (m, 11H), 2.01 (t, 1H), 1.90 (t, 2H), 1.74 (d, 2H), 1.74 (d, 2H), 1.64 (d, 2H), 1.33 (t, 2H), 1.23-1.21 (m, 3H), 1.07 (s, 7H). Example 26. N-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1- yl)methyl)piperidin-1-yl)-2-oxoethyl)-3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide
Figure imgf000266_0001
To a stirred solution of ((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)glycine (Intermediate 25, 0.10 g, 0.19 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-(4-(piperidin-4-ylmethyl)piperazin-1-yl)isoindoline- 1,3-dione (Intermediate 26, 0.12 g, 0.28 mmol) and DIPEA (0.07 g, 0.563 mmol) in dry DMF (1.0 mL) was added HATU (0.09 g, 0.22 mmol) under inert atmosphere at 0°C. The reaction mixture was allowed to warm to rt and stirred for 16 h. The reaction mixture was diluted with ice-cold water (10 mL) and extracted with ethyl acetate (3x 15 mL). The combined organics were washed with water (2x 15 mL), brine (15 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by Prep-HPLC-C to afford the title compound as a yellow solid (53 mg, 3%). LCMS m/z = 954 [M+H]+; 1H NMR (DMSO-d6, 400 MHz): 11.07 (s, 1H), 10.12 (s, 1H), 8.78 (s, 1H), 8.43 (bs, 1H), 8.26 (s, 1H), 8.08 (t, 1H), 7.97 (s, 1H), 7.72-7.66 (m, 4H), 7.32 (s, 1H), 7.23 (d, 1H), 5.04-5.09 (m, 1H), 4.78 (bs, 1H), 4.21 (d, 1H), 4.12 (s, 2H), 3.69-3.84 (m, 3H), 3.32-3.39 (m, 4H), 2.85-2.95(m, 2H), 2.67-2.32(m, 8H), 2.10 (d, 2H), 1.99-2.02 (m, 1H), 1.74-1.63 (m, 3H), 1.08 (bs, 6H). Example 27. 2-(2,6-dioxopiperidin-3-yl)-5-(1'-(2-(4-((3-((4-((4-(1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1- yl)sulfonyl)propoxy)methyl)-1H-1,2,3-triazol-1-yl)ethyl)-[4,4'-bipiperidin]-1-yl)isoindoline- 1,3-dione
Figure imgf000267_0001
A solution of CuSO4.5H2O (8.79 mg, 0.055 mmol) and sodium ascorbate (54.6 mg, 0.28 mmol) in water (1 mL) was added to a stirred solution of 2-methyl-1-(4-(2-((1-((3-(prop-2- yn-1-yloxy)propyl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H- pyrazol-1-yl)propan-2-ol (Intermediate 27, 0.075 g, 0.14 mmol) and 5-(1'-(2-azidoethyl)- [4,4'-bipiperidin]-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Intermediate 23, 0.068 g, 0.14 mmol) in THF (2 mL) at rt and stirred at rt under nitrogen atmosphere for 18 h. The mixture was quenched with cold water (10 mL) and extracted with ethyl acetate (3x 15 mL). The combined organics were washed with water (2x 15 mL), brine (15 mL), dried (Na2SO4) and evaporated to dryness under reduced pressure. The residue was purified by Prep-HPLC-C to afford the tittle compound as a yellow solid (10 mg, 15%). LCMS m/z = 1038 [M+H]+; 1H NMR (DMSO-d6, 400 MHz): 11.07 (s, 1H), 8.53 (d, 1H), 8.20 (d, 1H), 8.07 (s, 1H), 8.06-7.90 (m, 3H), 7.63 (d, 1H), 7.28 (s, 1H), 7.20 (d, 1H), 5.20-5.10 (m, 1H), 4.76 (s, 1H), 4.52 (s, 1H), 4.45 (t, 2H), 4.10-4.04 (m, 5H), 3.60-3.52 (m, 4H), 3.06-2.83 (m, 9H), 2.71-2.67 (m, 2H), 2.56 (m, 2H), 1.99-1.87 (m, 7H), 1.75 (d, 2H), 1.63-1.54 (m, 4H), 1.24-1.08 (m, 12H). Example 28. (E)-3-(4-(3-((1-((1-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)piperidin-4- yl)methyl)piperidin-4-yl)oxy)prop-1-en-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione
Figure imgf000268_0001
A mixture of 3-(1-oxo-4-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)isoindolin-2-yl)piperidine-2,6- dione (Intermediate 16, 0.10 g, 0.26 mmol), 1-((3-fluoro-4-((4-(1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)- piperidine-4-carbaldehyde (Intermediate 30, 0.14 g, 0.26 mmol) and acetic acid (0.2 mL) in 1,2-dichloroethane (2 mL) at rt under argon was stirred for 4 h at rt. After 4 h, STAB (0.16 g, 0.79 mmol) was added at rt and stirred for 12 h at rt. The reaction mixture was quenched with cold water (20 mL) and extracted EtOAc (3x 20 mL). The combined organics were washed with water (2x 20 mL), brine (20 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by Prep-HPLC-B to afford the title compound as a white solid (36 mg, 15%). LCMS m/z = 938 [M+H]+; 1H NMR (DMSO-d6, 400 MHz): 11.03 (s, 1H), 10.18 (s, 1H), 8.79 (s, 1H), 8.38 (s, 1H), 8.27 (s, 1H), 8.17 (t, 1H), 7.96 (s, 1H), 7.66-7.59 (m, 3H), 7.54-7.50 (m, 1H), 7.44 (d, 1H), 6.57 (d, 1H), 6.00-5.94 (m, 1H), 5.15- 5.10 (m, 1H), 4.44 (d, 1H), 4.27 (d, 1H), 4.17 (d, 2H), 4.11 (s, 2H), 3.65 (d, 2H), 3.27 (m, 1H), 2.92-2.88 (m, 1H), 2.61 (d, 3H).2.41 (m, 1H), 2.27 (m, 2H), 2.04-1.98 (m, 3H), 1.90 (t, 2H), 1.73 (d, 4H), 1.46-1.23 (m, 3H), 1.07 (bs, 8H). Example 29. N-(1-(((1r,4r)-4-(9-(4-(2,6-dioxopiperidin-3-yl)phenyl)-3,9- diazaspiro[5.5]undecane-3-carbonyl)cyclohexyl)methyl)piperidin-4-yl)-3-fluoro-4-((4-(1-(2- hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide
Figure imgf000269_0001
To a stirred solution of 3-(4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)piperidine-2,6-dione (Intermediate 9, 0.048 g, 0.14 mmol), (1r,4r)-4-((4-((3-fluoro-4-((4-(1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)- sulfonamido)piperidin-1-yl)methyl)cyclohexane-1-carboxylic acid (Intermediate 31, 0.10 g, 0.14 mmol) and DIPEA (0.064 mL, 0.36 mmol) in dry DMF (2 mL) was added HATU (0.065 g, 0.17 mmol) under inert atmosphere at 0 °C and the reaction mixture stirred at rt for 18 h. The reaction mixture was diluted with ice-cold water (10 mL) and extracted with ethyl acetate (3x 15 mL). The combined organics were washed with water (2x 15 mL), saturated brine solution (15 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by Prep-HPLC-D to afford the title compound as a white solid (9 mg, 6%). LCMS m/z = 1021 [M+H]+; 1H NMR (DMSO-d6, 400 MHz): 10.77 (s, 1H), 10.12 (s, 1H), 8.25 (s, 1H), 8.06 (t, 1H), 7.93 (s, 1H), 7.78 (d, 1H), 7.68 (s, 2H), 7.03 (d, 2H), 6.88 (d, 2H), 4.79 (s, 1H), 4.12 (s, 2H), 3.73-3.69 (m, 1H), 3.43 (bs, 4H), 3.12-2.97 (m, 5H), 2.67- 2.59 (m, 3H), 2.50-2.46 (m, 2H), 2.13-1.97 (m, 4H), 1.91-1.57 (m, 12H), 1.44-1.27 (m, 9H), 1.08 (s, 6H), 0.91-0.82 (m, 2H). Example 30. N-(1-(((1r,4r)-4-(1'-(4-(2,6-dioxopiperidin-3-yl) phenyl)-[4,4'-bipiperidine]-1- carbonyl) cyclohexyl) methyl) piperidin-4-yl)-3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)- 1H-pyrazol-4-yl)-5-(trifluoromethyl) pyrimidin-2-yl)amino)benzenesulfonamide
Figure imgf000270_0001
To a stirred solution of (1r,4r)-4-((4-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonamido)piperidin-1- yl)methyl)cyclohexane-1-carboxylic acid (Intermediate 31, 0.20 g, 0.28 mmol), 3-(4-([4,4'- bipiperidin]-1-yl)phenyl)piperidine-2,6-dione (Intermediate 32, 0.10 g, 0.28 mmol) and DIPEA (0.13 mL, 0.71 mmol) in dry DMF (2 mL) was added HATU (0.06 g, 0.17 mmol) portion wise under inert atmosphere at 0 °C and the reaction mixture was allowed to warm to rt and stirred for 16 h. The reaction mixture was diluted with ice-cold water (10 mL) and extracted with ethyl acetate (3x 15 mL). The combined organics were washed with water (2x 5 mL), brine (15 mL), dried (Na2SO4) and evaporated to dryness. The residue was purified by RP-Prep-HPLC-I to afford the title compound as a white solid (53 mg, 24%). LCMS m/z = 1035 [M+H]+; 1H NMR (DMSO-d6, 400 MHz): 10.76 (s, 1H), 10.19 (s, 1H), 8.78 (s, 1H), 8.25 (s, 1H), 8.06 (t, 1H), 7.92 (s, 1H), 7.76 (s, 1H), 7.68 (d, 3H), 7.02 (d, 2H), 4.5-4.4 (m, 1H), 4.12 (s, 2H), 4.0-3.9 (s, 1H), 3.73-3.67 (m, 4H), 2.96-2.92 (m, 3H), 2.67-2.41 (m, 8H), 2.01-1.97 (m, 4H), 1.81-1.72 (m, 8H), 1.62-1.54 (m, 4H), 1.37-1.22 (m, 9H), 1.08 (s, 6H), 1.05-0.87 (m, 3H). Example 31. 3-(4-(2-(4-((4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)piperidin-1-yl)sulfonyl)piperidin-1-yl)-2-oxoethoxy)-1-oxoisoindolin-2- yl)piperidine-2,6-dione
Figure imgf000271_0001
Step 1. Synthesis of tert-butyl 4-((4-(((benzyloxy)carbonyl)amino)piperidin-1- yl)sulfonyl)piperidine-1-carboxylate 4-Chlorosulfonylpiperidine-1-carboxylic acid tert-butyl ester (540 mg, 1.90 mmol) was added to a solution of benzyl piperidin-4-ylcarbamate (446 mg, 1.90 mmol) and Et3N (796 µL, 5.71 mmol) in DCM (7 mL) and the mixture stirred at rt for 2 h. The reaction mixture was loaded directly onto a silica gel column purified by silica gel chromatography (0-10% MeOH/DCM) to afford the title compound (700 mg). LCMS m/z = 382 [M-100]+. Step 2. Synthesis of tert-butyl 4-((4-aminopiperidin-1-yl)sulfonyl)piperidine-1-carboxylate Pd/C (155 mg, 1.45 mmol) was added to a solution of tert-butyl 4-((4- (((benzyloxy)carbonyl)amino)piperidin-1-yl)sulfonyl)piperidine-1-carboxylate (Step 1, 700 mg, 1.45 mmol) in EtOH (20 mL) and stirred at rt overnight under a balloon atmosphere of H2. The reaction mixture was filtered through a pad of celite (2x) and evaporated to dryness. The residue was purified by silica gel chromatography chromatography (0-10% MeOH (1% NH4OH (aq)/DCM) to afford the title compound (400 mg, 79%). LCMS m/z = 292 [M-56]+. Step 3. Synthesis of tert-butyl 4-((4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)piperidin-1-yl)sulfonyl)piperidine-1-carboxylate A solution of 2,5-dichloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidine (Intermediate 3, 16 mg, 0.070 mmol) and tert-butyl 4-((4-aminopiperidin-1-yl)sulfonyl)piperidine-1-carboxylate (Step 2, 25 mg, 0.072 mmol) in MeCN (200 µL) and DIPEA (36.6 µl, 0.210 mmol) was stirred at 90 °C overnight in a sealed tube. The reaction mixture was purified by silica gel chromatography (10-100% EtOAc/Hex) to afford the title compound (20 mg, 51%). LCMS m/z = 540 [M+H]+. Step 4. Synthesis of 5-chloro-4-(1-methyl-1H-pyrazol-4-yl)-N-(1-(piperidin-4- ylsulfonyl)piperidin-4-yl)pyrimidin-2-amine hydrochloride Hydrochloric acid, 4M in 1,4-dioxane (500 µL, 2.0 mmol) was added to tert-butyl 4-((4-((5- chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)piperidin-1- yl)sulfonyl)piperidine-1-carboxylate (Step 3, 20 mg, 0.037 mmol) in dioxane (0.5 mL) and the reaction mixture stirred at rt overnight. The reaction mixture was evaporated to dryness to afford the title compound (18 mg, 100%). LCMS m/z = 440 [M+H]+. Step 5. Synthesis of 3-(4-(2-(4-((4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)piperidin-1-yl)sulfonyl)piperidin-1-yl)-2-oxoethoxy)-1-oxoisoindolin-2- yl)piperidine-2,6-dione 2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetic acid (Intermediate 8, 14 mg, 0.044 mmol) and HATU (17 mg, 0.045 mmol) were dissolved in DMF (200 µL) and stirred at rt for 5 min. 5-chloro-4-(1-methyl-1H-pyrazol-4-yl)-N-(1-(piperidin-4- ylsulfonyl)piperidin-4-yl)pyrimidin-2-amine hydrochloride (Step 4, 18 mg, 0.038 mmol) and DIPEA (20 µL, 0.115 mmol) were added and the mixture stirred at rt overnight. The reaction mixture was diluted with DMSO and purified by RP-silica gel chromatography (10-100% H2O/MeCN) to afford the title compound (8 mg, 2.5%). LCMS m/z = 740 [M+H]+; 1H NMR (500 MHz, DMSO-d6): 10.91 (s, 1H), 8.45 (s, 1H), 8.23 (s, 1H), 8.09 (bs, 1H), 7.41-7.38 (t, 1H), 7.26-7.25 (d, 1H), 7.11-7.09 (d, 1H), 5.06-4.93 (m, 4H), 4.35-4.32 (m, 2H), 4.22-4.18 (m, 2H), 3.86 (s, 3H), 3.59-3.56 (m, 2H), 3.41-3.38 (m, 4H), 3.07-3.02 (m, 2H), 2.88-2.81 (m, 1H), 2.62-2.54 (m, 2H), 2.44-2.36 (m, 2H), 2.29 (m, 1H), 1.96-1.94 (m, 2H), 1.87-1.85 (m, 1H), 1.61-1.58 (m, 1H), 1.44-1.35 (m, 2H). Example 32. 3-(4-(2-(4-((4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)piperidin-1-yl)-2-oxoethoxy)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione
Figure imgf000272_0001
The title compound was prepared from 2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oxy)acetic acid (Intermediate 8) using an analogous method to that described for Example 31. LCMS m/z = 832 [M+H]+; 1H NMR (500 MHz, DMSO-d6, ): 10.90 (s, 1H), 8.51-8.46 (d, 1H), 8.14-8.11 (d, 1H), 7.97-7.82 (m, 2H), 7.41(t, 1H), 7.26-7.25 (d, 1H), 7.10-7.09 (d, 1H), 5.06-4.93 (m, 4H), 4.37-4.18 (m, 4H), 4.04 (s, 2H), 4.00-3.94 (m, 1H), 3.88-3.85 (m, 1H), 3.60-3.57 (m, 2H), 3.43-3.36 (m, 1H), 3.07-3.00 (m, 3H), 2.88-2.81 (m, 1H), 2.62-2.50 (m, 2H), 2.40-2.34 (m, 1H), 1.96-1.94 (m, 3H), 1.90-1.83 (m, 1H), 1.63-1.54 (m, 1H), 1.49- 1.42 (m, 2H), 1.37-1.34 (m, 1H), 1.00 (s, 6H). Example 33. 3-(4-(2-(4-((6-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)- 2-azaspiro[3.3]heptan-2-yl)sulfonyl)piperidin-1-yl)-2-oxoethoxy)-1-oxoisoindolin-2- yl)piperidine-2,6-dione
Figure imgf000273_0001
Step 1. Synthesis of tert-butyl 6-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate A solution of 2,5-dichloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidine (Intermediate 3, 100 mg, 0.44 mmol), tert-butyl 6-amino-2-azaspiro[3.3]heptane-2-carboxylate (93 mg, 0.44 mmol), DIPEA (229 mL, 1.31 mmol) in MeCN (1 mL) was stirred at 90 °C overnight. The reaction mixture was purified using column chromatography (10-100% EtOAc/Hex) to afford the title compound (113 mg, 63%). LCMS m/z = 405 [M+H]+. Step 2. Synthesis of N-(5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)-2- azaspiro[3.3]heptan-6-amine TFA (0.2 mL) was added to tert-butyl 6-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin- 2-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate (Step 1, 105 mg, 0.259 mmol) DCM (0.75 mL) and the reaction mixture was stirred at rt for 2 h. The reaction was quenched with saturated NaHCO3 (aq) and extracted with 3:1 CHCl3/IPA. The combined organics were dried (MgSO4) and evaporated tot dryness to give the title compound (79 mg, 100%). LCMS m/z = 305 [M+H]+. Step 3. Synthesis of tert-butyl 4-((6-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)-2-azaspiro[3.3]heptan-2-yl)sulfonyl)piperidine-1-carboxylate A solution of N-(5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)-2- azaspiro[3.3]heptan-6-amine (Step 2, 79 mg, 0.259 mmol), tert-butyl 4- (chlorosulfonyl)piperidine-1-carboxylate (88 mg, 0.311 mmol) and triethylamine (108 µl, 0.778 mmol) in DCM (0.75 mL) was stirred at rt overnight. The reaction mixture was purified by silica gel chromatography (0-10% MeOH/DCM) to afford the title compound (60 mg, 42%). LCMS m/z = 552 [M+H]+. Step 4. Synthesis of N-(5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)-2-(piperidin- 4-ylsulfonyl)-2-azaspiro[3.3]heptan-6-amine TFA (84 µL) was added to tert-butyl 4-((6-((5-chloro-4-(1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)-2-azaspiro[3.3]heptan-2-yl)sulfonyl)piperidine-1-carboxylate (Step 3, 60 mg, 0.109 mmol) in DCM (0.5 mL) and stirred at rt for 2 h. The reaction was quenched with saturated NaHCO3 (aq) and extracted with a solution of 3:1 CHCl3/IPA. The combined organics were concentrated and purified using RP-silica gel chromatography (10-100% H2O/MeCN) to give the title compound (28 mg, 57%). LCMS m/z = 452 [M+H]+. Step 5. Synthesis of 3-(4-(2-(4-((6-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)-2-azaspiro[3.3]heptan-2-yl)sulfonyl)piperidin-1-yl)-2-oxoethoxy)-1-oxoisoindolin- 2-yl)piperidine-2,6-dione 2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetic acid (Intermediate 8, 20 mg, 0.063 mmol) and HATU (24 mg, 0.063 mmol) were dissolved in DMF (0.5 mL) and stirred at rt for 5 min. To this were added N-(5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)- 2-(piperidin-4-ylsulfonyl)-2-azaspiro[3.3]heptan-6-amine (Step 4, 28 mg, 0.062 mmol) and DIPEA (32.5 µL, 0.186 mmol) and stirred at rt overnight. The reaction mixture was diluted with DMSO and purified by RP-silica gel chromatography (10-100% H2O/MeCN) to afford the title compound (8.8 mg, 19%). LCMS m/z = 752 [M+H]+; 1H NMR (DMSO-d6, 500 MHz): 10.91 (s, 1H), 8.44 (s, 1H), 8.20 (s, 1H), 8.09 (bs, 1H), 7.40-7.37 (t, 1H), 7.26-7.24 (d, 1H), 7.11-7.08 (d, 1), 5.06-4.93 (m, 4H), 4.35-4.28 (m, 2H), 4.21-4.12 (m, 2H), 3.89-3.83 (m, 5H), 3.76 (s, 2H), 3.34-3.29 (m, 1H), 3.06-3.01 (m, 1H), 2.88-2.81 (m, 1H), 2.61-2.34 (m, 7H), 2.13-2.09 (m, 2H), 1.95-1.92 (m, 2H), 1.61-1.56 (m, 1H), 1.37-1.32 (m, 1H). Example 34. 3-(4-(2-(6-((4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)piperidin-1-yl)sulfonyl)-2-azaspiro[3.3]heptan-2-yl)-2-oxoethoxy)-1-oxoisoindolin- 2-yl)piperidine-2,6-dione
Figure imgf000275_0001
The title compound was prepared from using an analogous 5-Step procedure as that described for Example 43. LCMS m/z = 752 [M+H]+; 1H NMR (DMSO-d6, 500 MHz): 10.90 (s, 1H), 8.45 (s, 1H), 8.22 (s, 1H), 8.08 (bs, 1H), 7.42-7.38 (t, 1H), 7.28-7.24 (d, 1H), 7.08-7.07 (d, 1H), 5.05-5.02 (m, 2H), 4.68 (s, 2H), 4.37-4.33 (m, 2H), 4.23-4.19 (m, 4H), 3.91-3.81 (m, 4H), 3.86 (m, 3H), 3.52-3.49 (m, 2H), 2.88-2.81 (m, 4H), 2.56-2.51 (m, 2H), 1.97-1.92 (m, 2H), 1.88-1.83 (m, 2H), 1.45-1.38 (m, 2H). Example 35. 3-(4-(2-(3-((4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)piperidin-1-yl)sulfonyl)pyrrolidin-1-yl)-2-oxoethoxy)-1-oxoisoindolin-2- yl)piperidine-2,6-dione
Figure imgf000276_0001
Step 1. Synthesis of tert-butyl 4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)piperidine-1-carboxylate. A mixture of 2,5-dichloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidine (Intermediate 3, 530 mg, 2.31 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (510 mg, 2.55 mmol) in MeCN (5 mL) and DIPEA (1212 µL, 6.94 mmol) was sealed and stirred at 90 °C overnight. The reaction was cooled to room temperature and loaded directly onto a silica column and purified by chromatography (10-100% EtOAc/Hex) to afford the title compound. (130 mg, 14%). LCMS m/z = 393 [M+H]+. Step 2. Synthesis of 5-chloro-4-(1-methyl-1H-pyrazol-4-yl)-N-(piperidin-4-yl)pyrimidin-2- amine hyrdochloride. HCl (4 M in dioxane, 2 mL) was added to a solution of tert-butyl 4-((5-chloro-4-(1-methyl- 1H-pyrazol-4-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate (Step 1, 130 mg, 0.331 mmol) in dioxane (2 mL). and stirred at rt overnight. The reaction mixture was concentrated to give the title compound (109 mg, 100 %). LCMS m/z = 293 [M+H]+. Step 3. Synthesis of tert-butyl 3-((4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)piperidin-1-yl)sulfonyl)pyrrolidine-1-carboxylate. 3-Chlorosulfonyl-pyrrolidine-1-carboxylic acid tert-butyl ester (49.2 mg, 0.182 mmol) was added to a solution of 5-chloro-4-(1-methyl-1H-pyrazol-4-yl)-N-(piperidin-4-yl)pyrimidin-2- amine hydrochloride (Step 2, 30 mg, 0.091 mmol) and TEA (38.1 µL, 0.273 mmol) in DCM (400 µL) and stirred at rt overnight. The reaction mixture was loaded onto a silica gel column and purified by column chromatography (0-10% MeOH/DCM) to afford the title compound (37 mg, 38%). LCMS m/z = 526 [M+H]+. Step 4. Synthesis of 5-chloro-4-(1-methyl-1H-pyrazol-4-yl)-N-(1-(pyrrolidin-3- ylsulfonyl)piperidin-4-yl)pyrimidin-2-amine hydrochloride. HCl (4 M in dioxane, 400 ^L) was added to a solution of tert-butyl 3-((4-((5-chloro-4-(1- methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)pyrrolidine-1- carboxylate (Step 3, 37 mg, 0.070 mmol) in 1,4-dioxane (400 µL) and stirred at rt overnight. The reaction mixture was evaporated to dryness to afford the title compound (32.5 mg, 100%). LCMS m/z = 426 [M+H]+. Step 5. Synthesis of 3-(4-(2-(3-((4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)piperidin-1-yl)sulfonyl)pyrrolidin-1-yl)-2-oxoethoxy)-1-oxoisoindolin-2- yl)piperidine-2,6-dione. A solution of 2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetic acid (Intermediate 8, 33.6 mg, 0.105 mmol) and O-(7-Azabenzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (40.1 mg, 0.105 mmol) in DMF (250 µL) was stirred at rt for 5 min and 5-chloro-4-(1-methyl-1H-pyrazol-4-yl)-N-(1-(pyrrolidin-3- ylsulfonyl)piperidin-4-yl)pyrimidin-2-amine hydrochloride (Step 4, 32.5 mg, 0.070 mmol) and DIPEA (36.8 µl, 0.211 mmol) added and stirred at rt overnight. The reaction mixture was diluted with DMSO and purified twice using a silica gel reverse-phase chromatography (10-100% H2O/MeCN) to afford the title compound (24 mg, 47%). LCMS m/z = 726 [M+H]+; 1H NMR (DMSO-d6, 500 MHz): 10.90 (s, 1H), 8.45 (s, 1H), 8.23 (s, 1H), 8.09 (bs, 1H), 7.40-7.37 (t, 1H), 7.27-7.25 (d, 1H), 7.13-7.08 (d, 1H), 5.06-5.02 (m, 2H), 4.91-4.87 (m, 2H), 4.36-4.32 (m, 2H), 4.23-4.19 (m, 2H), 4.06-4.03 (m, 1H), 3.97-3.94 (m, 1H), 3.86 (s, 2H), 3.70-3.63 (m, 2H), 3.61-3.55 (m, 2H), 3.53-3.46 (m, 2H), 3.31-3.29 (m, 1H), 3.06-2.98 (m, 1H), 2.88-2.81 (m, 1H), 2.57-2.47 (m, 2H), 2.23-2.17 (m, 1H), 2.05-2.01 (m, 1H), 1.95- 1.87 (m, 2H), 1.50-1.40 (m, 2H). Example 36. 3-(4-(2-(3-((4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)piperidin-1-yl)sulfonyl)piperidin-1-yl)-2-oxoethoxy)-1-oxoisoindolin-2- yl)piperidine-2,6-dione
Figure imgf000278_0001
The title compound was prepared using an analogous 5-Step procedure as described in Example 35. LCMS m/z = 740 [M+H]+; 1H NMR (DMSO-d6, 500 MHz): 10.91 (s, 1H), 8.45 (s, 1H), 8.22 (s, 1H), 8.08 (bs, 1H), 7.40-7.37 (t, 1H), 7.26-7.25 (d, 1H), 7.11-7.09 (d, 1H), 5.06-5.00 (m, 3H), 4.97-4.94 (m, 1H), 4.49-4.47 (m, 1H), 4.34-4.31 (m, 1H), 4.24-4.19 (m, 1H), 4.08-4.05 (m, 1H), 3.86 (s, 3H), 3.72-3.69 (m, 1H), 3.60-3.58 (m, 2H), 3.05-3.00 (m, 2H), 2.88-2.82 (m, 2H), 2.71-2.66 (m, 1H), 2.57-2.50 (m, 2H), 2.07-2.05 (m, 1H), 1.95-1.93 (m, 1H), 1.88-1.84 (m, 2H), 1.77-1.74 (m, 2H), 1.69-1.62 (m, 2H), 1.47-1.42 (m, 2H). Example 37. 3-(3-(3-((1-((1-((4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)piperidin-4- yl)methyl)piperidin-4-yl)oxy)prop-1-yn-1-yl)phenyl)piperidine-2,6-dione
Figure imgf000278_0002
A solution of 3-(3-(3-((1-((1-((4-aminopiperidin-1-yl)sulfonyl)piperidin-4- yl)methyl)piperidin-4-yl)oxy)prop-1-yn-1-yl)phenyl)piperidine-2,6-dione hydrochloride (Intermediate 34, 0.20 g, 0.32 mmol), 1-(4-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H- pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 1, 0.15 g, 0.48 mmol) and DIPEA (0.17 mL, 0.97 mmol) in DMSO (4 mL) was stirred at 100 °C for 16 h. The reaction mixture was quenched with cold water (20 mL) and extracted with ethyl acetate (3x 20 mL). The combined organics were washed with water (2x 20 mL), brine (20 mL), dried (Na2SO4) and evaporated to dryness under reduced pressure. The residue was purified by Prep-HPLC-B to afford the title compound as a white solid (66 mg, 21%). LCMS m/z = 870 [M+H]+; 1H NMR (DMSO-d6, 400 MHz): 10.85 (s, 1H), 8.54 (m, 1H), 8.21-8.13 (m, 2H), 8.02-7.85 (m, 2H), 7.37-7.31 (m, 3H), 7.28-7.24 (m, 1H), 4.70 (bs, 1H), 4.39 (s, 2H), 4.10 (m, 2H), 3.90- 3.86 (m, 2H), 3.58-3.49 (m, 6H), 3.03-2.97 (m, 2H), 2.77 (t, 2H), 2.69-2.62 (m, 3H), 2.53 (m, 1H), 2.32-2.21 (m, 1H), 2.11 (m, 2H), 2.06-1.95 (m, 3H), 1.92-1.85 (m, 5H), 1.74 (d, 2H), 1.61-1.45 (m, 5H), 1.07 (s, 8H). Example 38. N-((1r,4r)-4-((1'-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[4,4'-bipiperidin]-1- yl)methyl)cyclohexyl)-3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide
Figure imgf000279_0001
AcOH (0.001 mL, 0.017 mmol) was added to a stirred solution of a 2:1 mixture of 3-fluoro- N-((1r,4r)-4-formylcyclohexyl)-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide and 3-fluoro-N-((1s,4s)-4- formylcyclohexyl)-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide (Intermediate 14, 0.10 g, 0.17 mmol) and 3-(4-([4,4'-bipiperidin]-1-yl)phenyl)piperidine-2,6-dione (Intermediate 32, 0.07 g, 0.20 mmol) in dry DCE (2 mL) at rt and stirred for 18 h. STAB (0.11 g, 0.51 mmol) was added to the reaction mixture and stirred for 1 h at rt. The reaction was quenched with cold water (10 mL) and extracted with ethyl acetate (3x 15 mL). The combined organics were washed with water (2x 15 mL), brine (15 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by Prep-HPLC-I to afford the title compound as a white solid (43 mg, 28%). LCMS m/z = 690 [M+H]+; 1H NMR (DMSO-d6, 400 MHz): 10.75 (bs, 1H), 10.09 (bs, 1H), 8.78 (bs, 1H), 8.25 (s, 1H), 8.15 (s, 1H), 8.06 (t, 1H), 7.71- 7.65 (m, 3H), 7.03 (d, 2H), 6.87 (d, 2H), 6.52 (s, 4H), 6.52 (s, 4H), 6.28 (s, 1H), 4.77 (s, 1H), 4.11 (s, 2H), 3.72-3.65 (m, 3H), 2.93-2.91 (s, 1H), 2.81-2.79 (m, 1H), 2.50-2.49 (m, 2H), 2.10-1.99 (m, 4H), 1.76 -1.61 (m, 9H), 1.24-1.02 (m, 10H), 0.79 (s, 2H). Example 39. N-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-2,7-diazaspiro [3.5]nonan-7-yl)ethyl)-3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide
Figure imgf000280_0001
To a stirred solution of N-(2-(2,7-diazaspiro[3.5]nonan-7-yl)ethyl)-3-fluoro-4-((4-(1-(2- hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide (Intermediate 69, 0.11 g, 0.17 mmol) and 2-(2,6- dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (0.04 g, 0.15 mmol) in DMSO (1.1 mL) was added DIPEA (0.08 mL, 0.43 mmol) under inert atmosphere at rt. The resulting reaction mixture was stirred at 120 °C for 16 h. The reaction mixture was quenched with ice-cold water (10 mL) and extracted with EtOAc (3x 15 mL). The combined organic layer was washed with water (2x 15 mL), brine (15 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by Prep-HPLC-B to afford the title compound as a yellow solid (30 mg, 19%). LCMS m/z = 883 [M+H]+; 1H-NMR (400 MHz, DMSO-d6): 11.06 (s, 1H), 10.12 (s, 1H), 8.32 (s, 1H), 8.25 (s, 1H), 8.09 (t, 1H), 7.96 (s, 1H), 7.71-7.67 (m, 2H), 7.60 (bs, 1H), 7.55-7.52 (m, 1H), 7.09 (d, 1H), 6.74 (d, 1H), 5.02 (dd, 1H), 4.77 (bs, 1H), 4.11 (s, 2H), 3.85 (s, 4H), 2.92-2.82 (m, 3H), 2.59-2.55 (m, 2H), 2.33-2.25 (m, 6H), 1.99-1.97 (m, 1H), 1.67 (bs, 4H), 1.07 (s, 6H). Example 40-55. The title compounds were prepared as yellow solids from 2-(2,6-dioxopiperidin-3-yl)-4- fluoroisoindoline-1,3-dione (Isoindoline-A) or 2-(2,6-dioxopiperidin-3-yl)-5- fluoroisoindoline-1,3-dione (Isoindoline-B) and the appropriate amines using an analogous method to that described for Example 39. Amines: Intermediate 70, N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-3-fluoro-4-((4-(1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide hydrochloride; Intermediate 71, N-(17-amino-3,6,9,12,15- pentaoxaheptadecyl)-3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide hydrochloride; Intermediate 73, N-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-3-fluoro-4-((4-(1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide hydrochloride; Intermediate 87: 1-(4-(2-((4-((4-((3,9- diazaspiro[5.5]undecan-3-yl)methyl)piperidin-1-yl)sulfonyl)-2-fluorophenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol; Intermediate 108: N-(14-amino-3,6,9,12-tetraoxatetradecyl)-4-((5-cyano-4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)pyrimidin-2-yl)amino)-3-fluorobenzenesulfonamide hydrochloride; Intermediate 67, N-(2-(3,9-diazaspiro[5.5]undecan-3-yl)ethyl)-3-fluoro-4-((4-(1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide; Intermediate 96, 1-(4-(2-((4-((4-(azetidin-3- ylamino)piperidin-1-yl)sulfonyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H- pyrazol-1-yl)-2-methylpropan-2-ol hydrochloride; Intermediate 102, 1-(4-(2-((4-((4-((2- aminoethyl)amino)piperidin-1-yl)sulfonyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)- 1H-pyrazol-1-yl)-2-methylpropan-2-ol hydrochloride; Intermediate 72: N-(14-amino- 3,6,9,12-tetraoxatetradecyl)-3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)- 5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide hydrochloride; Intermediate 96, 1-(4-(2-((4-((4-(azetidin-3-ylamino)piperidin-1-yl)sulfonyl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol hydrochloride; Intermediate 69, N-(2-(2,7-diazaspiro[3.5]nonan-7-yl)ethyl)-3-fluoro-4-((4-(1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide; Intermediate 62, 3-fluoro-4-((4-(1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(2-(4-(2-oxo-2- (piperazin-1-yl)ethyl)piperidin-1-yl)ethyl)benzenesulfonamide; Intermediate 67, N-(2-(3,9- diazaspiro[5.5]undecan-3-yl)ethyl)-3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide; Intermediate 103, 1-(4-(2-((4-((3,9-diazaspiro[5.5]undecan-3-yl)sulfonyl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol hydrochloride; Intermediate 101, 3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-N-(2-(2-(4-(piperazin-1-ylmethyl)piperidin-1- yl)ethoxy)ethyl)benzenesulfonamide hydrochloride
Figure imgf000282_0001
Figure imgf000283_0001
Figure imgf000284_0001
Figure imgf000285_0001
Figure imgf000286_0001
Figure imgf000287_0001
Figure imgf000288_0001
Figure imgf000289_0001
Figure imgf000290_0001
Example 56. 3-(3-(3-((1-(1-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4- yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)piperidine-4- carbonyl)piperidin-4-yl)oxy)prop-1-yn-1-yl)phenyl)piperidine-2,6-dione
Figure imgf000291_0001
To a stirred solution of 1-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)- 5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)piperidine-4-carboxylic acid (Intermediate 18, 75 mg, 0.13 mmol) and 3-(3-(3-(piperidin-4-yloxy)prop-1-yn-1- yl)phenyl)piperidine-2,6-dione (Intermediate 50, 56 mg, 0.15 mmol) in dry DMF (1.5 mL) was added DIPEA (0.38 mL, 0.38 mmol) and the reaction mixture cooled to 0 °C and HATU (0.06 g, 0.14 mmol) added. The reaction mixture was warmed to rt and stirred for 16 h, quenched with cold water (10 mL) and extracted in EtOAc (3x 15 mL). The combined organics were washed with water (2x 15 mL), brine (15 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by HPLC-A to afford the title compound as a white solid (28 mg, 24%). LCMS m/z = 895 [M+H]+; 1H NMR (DMSO-d6, 400 MHz) 10.85 (s, 1H), 10.21 (s, 1H), 8.80 (s, 1H), 8.52 (bs, 1H), 8.28 (s, 1H), 8.21 (t, 1H), 7.98 (s, 1H),7.63 (t, 1H), 7.34-7.31 (m, 3H), 7.27-7.25 (m, 1H), 4.79 (s, 1H), 4.42 (s, 2H), 4.12 (s, 2H), 3.89-3.85 (m, 1H), 3.74-3.71 (m, 1H), 3.74-3.63 (m, 4H), 3.23-3.19 (m, 1H), 3.05-3.11 (m, 1H), 2.69-2.65 (m, 2H), 2.64-2.62 (m, 1H), 2.49-2.48 (m, 2H), 2.39-2.22 (m, 1H), 2.02-2.03 (m, 1H), 1.81 (bs, 2H), 1.81-1.67 (m, 2H), 1.57-1.54 (m, 2H), 1.38-1.35 (m, 2H), 1.08 (s, 6H). Example 57-84. The title compounds were prepared as white solids from the appropriate carboxylic acid and amine using an analogous method to that described for Example 56. Carboxylic acid: Intermediate 8: 2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetic acid; Intermediate 18: 1-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)piperidine-4-carboxylic acid; Intermediate 29: 1-(((1r,4r)-4-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4- yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)phenyl)sulfonamido)cyclohexyl)methyl)piperidine-4-carboxylic acid; Intermediate 31: (1r,4r)-4-((4-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonamido)piperidin-1- yl)methyl)cyclohexane-1-carboxylic acid; Intermediate 15: (1r,4r)-4-((3-fluoro-4-((4-(1-(2- hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)phenyl)sulfonamido)cyclohexane-1-carboxylic acid; Intermediate 88B (1r,3r)-3- ((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonamido)cyclobutane-1-carboxylic acid; Intermediate 109: (1r,4r)-4-((4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidine)-1-sulfonamido)cyclohexane-1-carboxylic acid; Intermediate 110: 1-((4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)piperidine-4-carboxylic acid; Intermediate 41: 1-((1r,4r)-4-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4- yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonamido)cyclohexane-1- carbonyl)piperidine-4-carboxylic acid; Amine: Intermediate 6: 3-(1-oxo-5-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)isoindolin-2-yl)piperidine- 2,6-dione; Intermediate 9: 3-(4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)piperidine-2,6- dione; Intermediate 10: 3-(3-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)piperidine-2,6-dione; Intermediate 16: 3-(1-oxo-4-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)isoindolin-2-yl)piperidine- 2,6-dione; Intermediate 28: 3-(4-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)phenyl)piperidine-2,6- dione; Intermediate 45: 1-(3-(3-(piperidin-4-yloxy)prop-1-yn-1- yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; Intermediate 50: 3-(3-(3-(piperidin-4- yloxy)prop-1-yn-1-yl)phenyl)piperidine-2,6-dione; Intermediate 56: 3-(4-(3-((1-(piperidin-4- ylmethyl)piperidin-4-yl)oxy)prop-1-yn-1-yl)phenyl)piperidine-2,6-dione; Intermediate 57: 3- (3-(3-((1-(piperidin-4-ylmethyl)piperidin-4-yl)oxy)prop-1-yn-1-yl)phenyl)piperidine-2,6- dione; Intermediate 58: 1-(2-methyl-3-(3-((1-(piperidin-4-ylmethyl)piperidin-4-yl)oxy)prop- 1-yn-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; Intermediate 59: 3-(1-oxo-5-(3-((1- (piperidin-4-ylmethyl)piperidin-4-yl)oxy)prop-1-yn-1-yl)isoindolin-2-yl)piperidine-2,6- dione; 3-(4-(piperazin-1-yl)phenyl)piperidine-2,6-dione (WO2023025091); 3-(3-(piperazin-1-yl)phenyl)piperidine-2,6-dione (US20200129627);
Figure imgf000293_0001
Figure imgf000294_0001
Figure imgf000295_0001
Figure imgf000296_0001
Figure imgf000297_0001
Figure imgf000298_0001
Figure imgf000299_0001
Figure imgf000300_0001
Figure imgf000301_0001
Figure imgf000302_0001
Figure imgf000303_0001
Figure imgf000304_0001
Figure imgf000305_0001
Figure imgf000306_0001
Figure imgf000307_0002
Examples 85 and 86. N-((1r,4r)-4-((4-(4-((3-(3-(2,6-dioxopiperidin-3-yl)phenyl)prop-2-yn- 1-yl)oxy)piperidine-1-carbonyl)piperidin-1-yl)methyl)cyclohexyl)-3-fluoro-4-((4-(1-(2- hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonate and N-((1s,4s)-4-((4-(4-((3-(3-(2,6-dioxopiperidin-3- yl)phenyl)prop-2-yn-1-yl)oxy)piperidine-1-carbonyl)piperidin-1-yl)methyl)cyclohexyl)-3- fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin- 2-yl)amino)benzenesulfonamide
Figure imgf000307_0001
Figure imgf000308_0001
To a solution of 3-(3-(3-((1-(piperidine-4-carbonyl)piperidin-4-yl)oxy)prop-1-yn-1- yl)phenyl)piperidine-2,6-dione (Intermediate 12, 50 mg, 0.114 mmol) in DCM (10 mL) were added a 2:1 mixture of 3-fluoro-N-((1r,4r)-4-formylcyclohexyl)-4-((4-(1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide and 3-fluoro-N-((1s,4s)-4-formylcyclohexyl)-4-((4-(1-(2- hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide (Intermediate 14, 66 mg, 0.114 mmol) and AcOH (0.05 mL) and stirred for 4 h at rt. Then reaction mixture was cooled to 0-5°C and STAB (36.3 mg, 0.171 mmol) added and stirred for 30 min. The reaction was quenched with water (20 mL) and extracted with DCM (2x 20 mL). The combined organics were dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by Prep-HPLC-E to afford: Peak 1 (first eluting isomer), Example 85, white solid (20 mg, 17%). N-((1r,4r)-4-((4-(4-((3- (3-(2,6-dioxopiperidin-3-yl)phenyl)prop-2-yn-1-yl)oxy)piperidine-1-carbonyl)piperidin-1- yl)methyl)cyclohexyl)-3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide. LCMS m/z = 1006 [M+H]+; 1H-NMR (400 MHz, DMSO-d6): 10.85 (s, 1H), 10.09 (s, 1H), 8.78 (s, 1H), 8.25 (s, 1H), 8.07-8.03 (t, 1H), 7.79 (s, 1H), 7.71-7.65 (m, 3H), 7.35-7.25 (m, 4H), 4.77 (s, 1H), 4.43 (s, 2H), 4.11 (s, 2H), 3.89-3.74 (m, 4H), 3.30-3.07 (m, 3H), 2.75-2.66 (m, 3H), 2.50-2.51 (m, 1H), 2.32-1.13 (m, 22H), 1.10 (s, 6H), 0.78-7.075 (m, 2H). Peak 2 (second eluting isomer), Example 86, white solid (8 mg, 7%). N-((1s,4s)-4-((4-(4- ((3-(3-(2,6-dioxopiperidin-3-yl)phenyl)prop-2-yn-1-yl)oxy)piperidine-1-carbonyl)piperidin- 1-yl)methyl)cyclohexyl)-3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide. LCMS m/z = 1006 [M+H]+; 1H-NMR (400 MHz, DMSO-d6): 10.85 (s, 1H), 10.08 (s, 1H), 8.78 (s, 1H), 8.25 (s, 1H), 8.08-8.06 (t, 1H), 7.93 (s, 1H), 7.70-7.59 (m, 3H), 7.35-7.26 (m, 4H), 4.77 (s, 1H), 4.43 (s, 2H), 4.11 (s, 2H), 3.90-3.73 (m, 4H), 3.30-3.08 (m, 3H), 2.79-2.54 (m, 4H), 2.32-1.84 (m, 8H),1.53-1.23 (m, 16H), 1.08 (s, 6H), 1.03-1.00 (m, 2H). Example 87. 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-(5-((3- fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin- 2-yl)amino)phenyl)sulfonamido)pentyl)acetamide
Figure imgf000309_0001
To a stirred solution of N-(5-aminopentyl)-3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)- 1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide hydrochloride (Intermediate 92, 140 mg, 0.24 mmol), (2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)glycine (Intermediate 65, 77.8 mg, 0.24 mmol), DIPEA (60.8 mg, 0.47 mmol) and dry DMF (1.0 mL) at rt under nitrogen atmosphere was added HATU (114 mg, 0.30 mmol) under nitrogen atmosphere at 0 °C and the reaction mixture warmed to rt and stirred for 18 h. The reaction mixture was diluted with ice-cold water (10 mL) and extracted with EtOAc (3x 15 mL). The combined organics were washed with water (2x 15 mL), saturated brine solution (15 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by HPLC-A to afford the title compound as a white solid (51 mg, 25%). LCMS m/z = 873 [M+H]+; 1H NMR (DMSO-d6, 400 MHz): 11.09 (s, 1H), 10.1 (s, 1H), 8.77 (s, 1H), 8.25 (s, 1H), 8.11-8.03 (m, 2H), 7.9 (s, 1H), 7.66-7.55 (m, 4H), 7.05 (d, 1H), 6.92 (t, 1H), 6.83 (d, 1H), 5.08-5.04 (m,1H), 4.77 (s, 1H), 4.11 (s, 2H), 3.89 (d, 2H), 3.07-3.02 (m, 2H), 2.90-2.84 (m, 1H), 2.77-2.72 (m, 2H), 2.56-2.49 (m, 2H), 2.04-2.00 (m, 1H), 1.40-1.35 ( m, 4H ), 1.23 (d, 2H), 1.07 (s, 6H). Example 88-97. The title compounds were prepared as yellow solids from Intermediate 65 (2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycine or 2-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)oxy)acetic acid ACS Med. Chem. Lett., 2022, 13, 1621-1627 and the appropriate amine using an analogous method to that described for Example 87. Amine: Intermediate 67, N-(2-(3,9-diazaspiro[5.5]undecan-3-yl)ethyl)-3-fluoro-4-((4-(1-(2-hydroxy- 2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide; Intermediate 69, N-(2-(2,7-diazaspiro[3.5]nonan-7-yl)ethyl)- 3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide; Intermediate 73, N-(2-(2-(2-(2- aminoethoxy)ethoxy)ethoxy)ethyl)-3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide hydrochloride; Intermediate 92, N-(5-aminopentyl)-3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide hydrochloride; Intermediate 93, N-(7-aminoheptyl)-3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide hydrochloride; Intermediate 94, N-(4-aminobutyl)-3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide hydrochloride; Intermediate 95, 1-(4-(2-((4-((4-aminopiperidin-1-yl)sulfonyl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol; Intermediate 105, N-(6-aminohexyl)-4-((5-cyano-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrimidin- 2-yl)amino)-3-fluorobenzenesulfonamide.
Figure imgf000310_0001
Figure imgf000311_0001
Figure imgf000312_0001
Figure imgf000313_0001
Figure imgf000314_0001
Figure imgf000315_0002
Example 98. 3-(4-((1-((1-((4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)piperidin-4- yl)methyl)piperidin-4-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione
Figure imgf000315_0001
A mixture of 3-(4-((1-((1-((4-aminopiperidin-1-yl)sulfonyl)piperidin-4-yl)methyl)piperidin- 4-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride (Intermediate 40, 200mg, 0.31 mmol) and 1-(4-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2- methylpropan-2-ol (Intermediate 1, 151 mg, 0.47 mmol) and DIPEA (0.17 mL, 0.94 mmol) in DMSO (4 mL) at rt under nitrogen was stirred at 100 °C for 16 h. The reaction mixture was quenched with cold water (20 mL) and extracted with EtOAc (3x 20 mL). The combined organics were washed with water (2x 20 mL), brine (20 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by HPLC-A to afford the title compound as a yellow solid (20 mg, 7%). LCMS m/z = 887 [M+H]+; 1H NMR (DMSO-d6, 400 MHz): 10.97 (s, 1H), 8.58-8.52 (m, 1H), 8.22-8.17 (m, 1H), 8.02-7.89 (m, 2H), 7.46 (t, 1H), 7.31-7.28 (m, 2H), 5.13-5.08 (m, 1H), 4.56 (bs, 1H), 4.37-4.33 (m, 1H), 4.23-4.19 (m, 1H), 4.09 (d, 2H), 3.98 (bs, 1H), 3.58-3.51 (m, 4H), 3.06-2.89 (m, 2H), 2.86-2.76 (m, 2H), 2.74-2.55 (m, 4H), 2.49-2.42 (m, 1H), 2.24-2.15 (m, 4H), 1.99-1.84 (m, 5H), 1.78-1.67 (m, 2H), 1.67-1.65 (m, 3H), 1.59-1.49 (m, 2H), 1.12-1.03 (m, 9H). Example 99-104. The title compounds were prepared from 1-(4-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)- 1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 1) or 2-chloro-4-(1-methyl-1H-pyrazol- 4-yl)-5-(trifluoromethyl) pyrimidine (Intermediate 114) and the appropriate amines using an analogous method to that described for Example 98. Amines: Intermediate 40, 3-(4-((1-((1-((4-aminopiperidin-1-yl)sulfonyl)piperidin-4- yl)methyl)azetidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; Intermediate 47, 4- amino-N-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)-3-fluorobenzenesulfonamide; Intermediate 48, 3-(4-(3- ((1-((1-((4-aminopiperidin-1-yl) sulfonyl) piperidin-4-yl) methyl) piperidin-4-yl) oxy) prop- 1-yn-1-yl)-1-oxoisoindolin-2-yl) piperidine-2,6-dione; Intermediate 111, 3-(5-(4-((1-((4- aminopiperidin-1-yl)sulfonyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione; Intermediate 113, 3-(4-((1-((1-((4-aminopiperidin-1- yl)sulfonyl)piperidin-4-yl)methyl)azetidin-3-yl)oxy)-1-oxoisoindol; Intermediate 117, 3-(3- (3-((1-(1-((4-aminopiperidin-1-yl)sulfonyl)piperidine-4-carbonyl)piperidin-4-yl)oxy)prop-1- yn-1-yl)phenyl)piperidine-2,6-dione;
Figure imgf000317_0001
Figure imgf000318_0001
Figure imgf000319_0001
Example 105. N-(2-((1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)ethyl)piperidin-1-yl)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)ethyl)-3-fluoro-4-((4-(1- (2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide
Figure imgf000320_0001
To a stirred solution of 3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-N-(2-(prop-2-yn-1-yloxy)ethyl)benzenesulfonamide (Intermediate 21, 70 mg, 0.13 mmol) and 4-((2-(1-(2-azidoethyl)piperidin-4-yl)ethyl)amino)- 2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Intermediate 74, 62.7 mg, 0.14 mmol) in THF (2 mL) was added the solution of sodium ascorbate (49.8 mg, 0.25 mmol) and Copper (II) Sulphate (8.03 mg, 0.05 mmol) in water (1 mL) at rt and the resulting reaction mixture stirred for 16 h. The reaction was quenched with cold water (20 mL) and extracted with EtOAc (3x 15 mL). The combined organics were washed with water (2x 15 mL), brine (15 mL), dried (Na2SO4). The combined organics were concentrated under reduced pressure and the residue purified by HPLC-C to afford the title compound as a yellow solid (37 mg, 29%). LCMS m/z = 1010 [M+H]+; 1H NMR (DMSO-d6, 400 MHz): 11.08 (s, 1H), 10.10 (s, 1H), 8.77 (s, 1H), 8.38 (bs, 1H), 8.25 (s, 1H), 8.07 (t, 1H), 8.02 (s, 1H), 7.96 (s, 1H), 7.81 (bs, 1H), 7.67-7.64 (m, 2H), 7.54-7.58 (m, 1H), 7.06 (d, 1H), 7.01 (d, 1H), 6.47 (t, 1H), 5.03-5.06 (m, 1H), 4.8 (bs, 1H), 4.41-4.4.46 (m, 4H), 4.11 (s, 2H), 3.44 (m, 2H), 3.30 (m, 2H), 2.97 (s, 2H), 2.82-2.88 (m, 3H), 2.66-2.67 (m, 2H), 2.56-2.60 (m, 2H), 1.90-1.96 (m, 2H), 1.64 (m, 2H), 1.47 (m, 2H), 1.13(m, 1H), 1.09 (m, 2H), 1.075 (s, 6H). Example 106. 2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-(4-((3-((4-((4-(1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1- yl)sulfonyl)propoxy)methyl)-1H-1,2,3-triazol-1-yl)ethyl)piperazin-1-yl)isoindoline-1,3-dione
Figure imgf000321_0001
Step 1. Synthesis of tert-butyl 4-(2-(4-((2-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)- 1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)phenyl)sulfonamido)ethoxy)methyl)-1H-1,2,3-triazol-1-yl)ethyl)piperazine-1- carboxylate. The title compound was prepared from 3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(2-(prop-2-yn-1- yloxy)ethyl)benzenesulfonamide Intermediate 21 and tert-butyl 4-(2-azidoethyl)piperazine-1- carboxylate using an analogous method to that described for Example 105. LCMS m/z = 812 [M+H]+. Step 2. Synthesis of 3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-N-(2-((1-(2-(piperazin-1-yl)ethyl)-1H-1,2,3-triazol- 4-yl)methoxy)ethyl)benzenesulfonamide hydrochloride. To a stirred solution of tert-butyl 4-(2-(4-((2-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)- 1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)phenyl)sulfonamido)ethoxy)methyl)-1H-1,2,3-triazol-1-yl)ethyl)piperazine-1- carboxylate (Step 1, 0.25 g, 0.308 mmol) in DCM (5 mL), was added 4.0 M HCl in dioxane (2.5 mL) at 0 °C and stirred at rt for 2 h. The reaction mixture was concentrated and co- distilled with dichloromethane (2x 50 mL) under reduced pressure. The residue was washed with diethyl ether to afford the title compound as a pale brown semi-solid (190 mg, 82%). LCMS m/z = 712 [M+H]+. Step 3. 2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-(4-((3-((4-((4-(1-(2-hydroxy-2-methylpropyl)- 1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1- yl)sulfonyl)propoxy)methyl)-1H-1,2,3-triazol-1-yl)ethyl)piperazin-1-yl)isoindoline-1,3- dione. To a stirred solution of 3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-N-(2-((1-(2-(piperazin-1-yl)ethyl)-1H-1,2,3-triazol- 4-yl)methoxy)ethyl)benzenesulfonamide hydrochloride (Step 2, 50 mg, 0.070 mmol) and 2- (2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (23 mg, 0.085 mmol) in DMSO (0.25 mL) was added DIPEA (0.059 mL, 0.352 mmol) at rt under N2 and stirred at 120 °C for 16 h. The reaction mixture was quenched with water (15 mL) and extracted with ethyl acetate (3x 15 mL). The combined organics were dried over anhydrous sodium sulphate, concentrated under reduced pressure and was purified by Prep-HPLC (Sunfire C-18150 x 19 mm, 5 mm; 0-100% MeCN/H2O (0.1% HCO2H)) to afford the title compound as a yellow solid (6.0 mg, 9%). LCMS m/z = 968 [M+H]+; 1H NMR (DMSO-d6, 400 MHz): 11.07 (s, 1H), 10.10 (s, 1H), 8.77 (s, 1H), 8.25 (s, 1H), 8.09 (s, 1H), 8.06 (d, 2H), 7.96 (s, 1H), 7.79 (m, 1H), 7.67- 7.63 (m, 3H), 7.35 (d, 1H), 7.25-7.22 (dd, 1H), 5.08-5.04 (m, 1H), 4.77 (s, 1H), 4.52-4.47 (m, 4H), 4.11 (s, 2H), 3.46-3.40 (m, 6H), 2.97 (m, 2H), 2.88-2.77 (m, 3H), 2.67-2.49 (m, 6H), 2.01 (m, 1H), 1.07 (bs, 6H). Example 107-126. The title compounds were prepared from 3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(2-(prop-2-yn-1- yloxy)ethyl)benzenesulfonamide (Intermediate 21), 2-methyl-1-(4-(2-((1-((3-(prop-2-yn-1- yloxy)propyl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol- 1-yl)propan-2-ol (Intermediate 27) or 4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)- 5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(2-(prop-2-yn-1- yloxy)ethyl)benzenesulfonamide (Intermediate 19) and the appropriate azide using an analogous method to that described for Example 105. Intermediate 23, 5-(1'-(2-azidoethyl)-[4,4'-bipiperidin]-1-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione; Intermediate 83, 3-(4-(2-(2-(2- azidoethoxy)ethoxy)ethoxy)phenyl)piperidine-2,6-dione; Intermediate 75, 5-((2-(1-(2- azidoethyl)piperidin-4-yl)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- dione;Intermediate 76, 5-(9-(2-azidoethyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione; Intermediate 78, 5-(7-(2-azidoethyl)-2,7- diazaspiro[3.5]nonan-2-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; Intermediate 79, 3-(3-((2-(2-(2-azidoethoxy)ethoxy)ethyl)amino)phenyl)piperidine-2,6-dione;Intermediate 80, 3-(4-((2-(2-(2-azidoethoxy)ethoxy)ethyl)amino)phenyl)piperidine-2,6-dione; Intermediate 81, 4-(7-(2-azidoethyl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione;Intermediate 82, 2-(2-(2-(3-(2,6-dioxopiperidin-3- yl)phenoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate; Intermediate 84, 3-(3-(1'-(2- azidoethyl)-[4,4'-bipiperidin]-1-yl)phenyl)piperidine-2,6-dione; Intermediate 85, 3-(3-(4-(2- azidoethyl)piperazin-1-yl)phenyl)piperidine-2,6-dione;Intermediate 86, 3-(3-(9-(2- azidoethyl)-3,9-diazaspiro[5.5]undecan-3-yl)phenyl)piperidine-2,6-dione; Intermediate 121, 4-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;
Figure imgf000323_0001
Figure imgf000324_0001
Figure imgf000325_0001
Figure imgf000326_0001
Figure imgf000327_0001
Figure imgf000328_0001
Figure imgf000329_0001
Figure imgf000330_0001
Figure imgf000331_0001
Figure imgf000332_0001
Figure imgf000333_0001
Figure imgf000334_0002
Example 127. N-((1r,4r)-4-((4-((4-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)-3-fluoro-4- ((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide
Figure imgf000334_0001
To a stirred solution of a 2:1 mixture of 3-fluoro-N-((1r,4r)-4-formylcyclohexyl)-4-((4-(1-(2- hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide and 3-fluoro-N-((1s,4s)-4-formylcyclohexyl)-4-((4-(1-(2- hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide (Intermediate 14, 80 mg, 0.14 mmol) and 3-(1-oxo-4-(3-((1- (piperidin-4-ylmethyl)piperidin-4-yl)oxy)prop-1-yn-1-yl)isoindolin-2-yl)piperidine-2,6-dione (Intermediate 49, 85.1 mg, 0.18 mmol) in methanol (0.8 mL) were added acetic acid (0.01 mL, 0.01 mmol) followed by MP-Cyanoborohydride (80 mg, w/w) at rt and the resulting reaction mixture stirred at rt for 16 h. The reaction mixture was filtered and solids washed with methanol (3x 5 mL). The filtrate was concentrated under reduced pressure and the residue purified by HPLC-B to afford the title compound as a white solid (3 mg, 2%). LCMS m/z = 1047 [M+H]+; 1H NMR (DMSO-d6, 400 MHz): 11.00 (s, 1H), 10.02 (s, 1H), 8.78 (s, 1H), 8.25 (s, 1H), 8.13 (s, 1H), 8.08 (t, 1H), 7.93 (s, 1H) 7.77 (d, 1H), 7.72-7.66 (m, 3H), 7.57 (t, 1H), 5.18-5.13 (dd, 1H), 4.77 (s, 1H), 4.51-4.45 (m, 3H), 4.34-4.30 (m, 1H), 4.11 (s, 1H), 3.55-3.48 (m, 1H), 2.95-2.87 (m, 5H), 2.60 (s, 2H), 2.36-2.32 (m, 2H), 2.17-2.04 (m, 9H).1.90-1.86 (m, 2H), 1.67-1.65 (m, 6H), 1.46-1.39 (m, 4H).1.23-1.02 (m, 11H). Example 128-152 The title compounds were prepared from the appropriate aldehyde and the appropriate amine using an analogous method to that described for Example 127. Aldehydes: Intermediate 4: 1-((4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)piperidine-4-carbaldehyde; Intermediate 14: 2:1 mixture of 3-fluoro-N-((1r,4r)-4-formylcyclohexyl)-4-((4-(1-(2- hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide and 3-fluoro-N-((1s,4s)-4-formylcyclohexyl)-4-((4-(1-(2- hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide; Intermediate 43: 1-((4-((4-(1-methyl-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)piperidine-4-carbaldehyde; Intermediate 98; 3-fluoro-N-((1r,4r)-4-formylcyclohexyl)-4-((4-(1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N- methylbenzenesulfonamide; Intermediate 119: 1-((3,3-difluoro-4-((4-(1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1- yl)sulfonyl)piperidine-4-carbaldehyde; Amines: Intermediate 6: 3-(1-oxo-5-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)isoindolin-2-yl)piperidine- 2,6-dione; Intermediate 9: 3-(4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)piperidine-2,6- dione; Intermediate 10: 3-(3-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)piperidine-2,6-dione; Intermediate 16: 3-(1-oxo-4-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)isoindolin-2-yl)piperidine- 2,6-dione; Intermediate 28:3-(4-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)phenyl)piperidine-2,6- dione; Intermediate 33: 3-(3-([4,4'-bipiperidin]-1-yl)phenyl)piperidine-2,6-dione; Intermediate 45: 1-(3-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)phenyl)dihydropyrimidine- 2,4(1H,3H)-dione; Intermediate 46: 1-(3-(3-((1-(piperidine-4-carbonyl)piperidin-4- yl)oxy)prop-1-yn-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; Intermediate 50: 3-(3- (3-(piperidin-4-yloxy)prop-1-yn-1-yl)phenyl)piperidine-2,6-dione; Intermediate 51: 1-(4-(3- (piperidin-4-yloxy)prop-1-yn-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; Intermediate 53: 3-(3-(2,7-diazaspiro[3.5]nonan-2-yl)phenyl)piperidine-2,6-dione; Intermediate 55: 3-(3-(3-((3-azaspiro[5.5]undecan-9-yl)oxy)prop-1-yn-1- yl)phenyl)piperidine-2,6-dione; Intermediate 60: 3-(4-(1'-(piperidine-4-carbonyl)-[4,4'- bipiperidin]-1-yl)phenyl)piperidine-2,6-dione; Intermediate 97: 1-methyl-3-(3-(3-(piperidin- 4-yloxy)prop-1-yn-1-yl)phenyl)piperidine-2,6-dione; Intermediate 123: 1-(2-methyl-3-(3-((1- (piperidine-4-carbonyl)piperidin-4-yl)oxy)prop-1-yn-1-yl)phenyl)dihydropyrimidine- 2,4(1H,3H)-dione; Intermediate 126:1-methyl-3-(1-oxo-4-(piperidin-4-yloxy)isoindolin-2- yl)piperidine-2,6-dione; 4-(prop-2-yn-1-yloxy) piperidine hydrochloride; 1-methyl-3-(1-oxo- 5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (WO2018102725);
Figure imgf000336_0001
Figure imgf000337_0001
Figure imgf000338_0001
Figure imgf000339_0001
Figure imgf000340_0001
Figure imgf000341_0001
Figure imgf000342_0001
Figure imgf000343_0001
Figure imgf000344_0001
Figure imgf000345_0001
Figure imgf000346_0001
Figure imgf000347_0001
Figure imgf000348_0001
Example 153. 3-(4-(3-((1-((1-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol- 4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)piperidin-4- yl)methyl)piperidin-4-yl)oxy)prop-1-yn-1-yl)phenyl)piperidine-2,6-dione
Figure imgf000349_0001
To a stirred solution of 1-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)- 5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)piperidine-4-carbaldehyde (Intermediate 30, 100 mg, 0.17 mmol) and 3-(4-(3-(piperidin-4-yloxy)prop-1-yn-1- yl)phenyl)piperidine-2,6-dione (Intermediate 28, 86 mg, 0.26 mmol) in DCE (2 mL) was added acetic acid (0.01 mL, 0.02 mmol) at rt and the reaction mixture stirred at rt for 16 h. STAB (74 mg, 0.35 mmol) was added and the resulting mixture was stirred for 2 h at rt. The reaction was quenched with cold water (10 mL) and extracted with 10% MeOH in DCM (3x 15 mL). The combined organics were washed with water (2x 15 mL), brine (15 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by HPLC-P to afford the title compound as a white solid (20 mg, 13%). LCMS m/z = 881 [M+H]+; 1H NMR (DMSO-d6, 400 MHz): 10.85 (s, 1H), 10.19 (bs, 1H), 8.79 (s, 1H), 8.39 (bs, 1H), 8.18 (t, 1H), 7.97 (s, 1H), 7.61 (t, 2H), 7.39 (d, 2H), 7.23 (t, 2H), 4.37 (s, 2H), 4.12 (s, 2H), 3.89 (dd, 1H), 3.67-3.64 (m, 2H), 3.47-3.39 (m, 1H), 2.67-2.58 (m, 4H), 2.30-2.17 (m, 3H), 2.07- 1.97 (m, 5H), 1.83-1.73 (m, 4H), 1.53-1.41 (m, 3H), 1.10-1.07 (m, 8H). Example 154-162. The title compounds were prepared from the appropriate aldehyde and appropriate amines using an analogous method to that described for Example 153. Aldehydes: Intermediate 5: N-((1r,4r)-4-formylcyclohexyl)-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-sulfonamide; Intermediate 30:1-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)piperidine-4-carbaldehyde; Intermediate 120: 3-fluoro-N-((1r,4r)-4-formylcyclohexyl)-4-((4-(1-methyl-1H-pyrazol-4- yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide; Amines: Intermediate 6; 3-(1-oxo-5-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)isoindolin-2-yl)piperidine- 2,6-dione; Intermediate 9; 3-(4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)piperidine-2,6- dione; Intermediate 10; 3-(3-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)piperidine-2,6-dione; Intermediate 16; 3-(1-oxo-4-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)isoindolin-2-yl)piperidine- 2,6-dione; Intermediate 28; 3-(4-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)phenyl)piperidine-2,6- dione; Intermediate 45; 1-(3-(3-(piperidin-4-yloxy)prop-1-yn-1- yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; Intermediate 50; 3-(3-(3-(piperidin-4- yloxy)prop-1-yn-1-yl)phenyl)piperidine-2,6-dione;
Figure imgf000350_0001
Figure imgf000351_0001
Figure imgf000352_0001
Figure imgf000353_0001
Figure imgf000354_0001
Example 163. N-(4-((3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)prop-2-yn-1- yl)oxy)cyclohexyl)-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide
Figure imgf000355_0001
A mixture of 4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-N-(4-(prop-2-yn-1- yloxy)cyclohexyl)benzenesulfonamide (Intermediate 104, 200 mg, 0.34 mmol), 2-(2,6- dioxopiperidin-3-yl)-4-iodoisoindoline-1,3-dione (190 mg, 0.51 mmol) and caesium carbonate (330 mg, 1.01 mmol) in DMF (2 mL) was purged with nitrogen gas for 15 min. PdCl2(PPh3)2 (240 mg, 0.03 mmol) and CuI (13mg, 0.07 mmol) were added and the reaction mixture stirred at 80 °C for 3 h. The reaction mixture was quenched with cold water (20 mL) and extracted with EtOAc (3x 30 mL). The combined organics were washed with ice cold water (2x 20 mL), brine (20 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by HPLC-B to afford the title compound as a white solid (100 mg, 37 %). LCMS m/z = 849 [M+H]+; 1H NMR (DMSO-d6, 400 MHz): 11.12 (s, 1H), 10.56 (s, 1H), 8.82 (s, 1H), 8.32 (bs, 1H), 8.03 (s, 1H), 7.99-7.97 (m, 2H), 7.91-7.85 (m, 3H), 7.79 (d, 2H), 7.51 (d, 1H), 5.15-5.10 (m, 1H), 4.81 (s, 1H), 4.42 (s, 2H), 4.14 (s, 2H), 3.46-3.31 (m, 1H), 2.97-2.84 (m, 2H), 2.67-2.56 (m, 2H), 2.06-2.03 (m, 1H), 1.98-1.93 (m, 2H), 1.64-1.60 (m, 2H), 1.25-1.15 (m, 4H), 1.10 (s, 6H). Example 164-165. The title compounds were prepared from 2-(2,6-dioxopiperidin-3-yl)-4-iodoisoindoline-1,3- dione and the appropriate alkyne using an analogous method to that described for Example 163.
Figure imgf000355_0002
Figure imgf000356_0001
Example 166. N-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin- 1-yl)methyl)piperidin-1-yl)ethyl)-3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol- 4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide
Figure imgf000357_0001
A mixture of N-(2-chloroethyl)-3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4- yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide (Intermediate 61, 293 mg, 0.55 mmol), 2-(2,6-dioxopiperidin-3-yl)-4-(4-(piperidin-4-ylmethyl)piperazin-1- yl)isoindoline-1,3-dione hydrochloride (Intermediate 63, 200 mg, 0.46 mmol) and DIPEA (176 mg, 1.36 mmol) in dry DMF (5 mL) at rt under nitrogen was stirred for 16 h. The reaction mixture was quenched with cold water (15 mL) and extracted with EtOAc (3x 15 mL). The combined organics were washed with ice cold water (2x 15 mL), brine (15 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by HPLC-B to afford the title compound as a yellow solid (15 mg, 7%). LCMS m/z = 940 [M+H]+; 1H NMR (DMSO-d6, 400 MHz): 11.07 (s, 1H), 10.12 (s, 1H), 8.78 (s, 1H), 8.25 (s, 1H), 8.16 (s, 1H), 8.09 (t, 1H), 7.96 (s, 1H), 7.68 (t, 3H), 7.58 (bs, 1H), 7.36-7.30 (m, 2H), 6.54 (bs, 2H), 6.28 (s, 1H), 5.10-5.06 (m, 1H ), 4.78 (s, 1H), 4.12 (s, 2H), 3.32-3.17 (m, 4H), 2.91-2.83 (m, 3H), 2.73-2.67 (m, 2H), 2.61-2.56 (m, 2H), 2.50-2.40 (m, 4H), 2.33-2.32 (m, 2H), 2.03-2.00 (m, 1H), 1.88-1.83 (m, 2H), 1.63-1.59 (m, 2H), 1.45 (bs, 1H), 1.08 (s, 6H). Example 167. N-(2-(1'-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-[4,4'- bipiperidin]-1-yl)ethyl)-3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide
Figure imgf000357_0002
The title compound was prepared (11 mg, 5%) from N-(2-chloroethyl)-3-fluoro-4-((4-(1-(2- hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide (Intermediate 61) and 5-([4,4'-bipiperidin]-1-yl)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione (Intermediate 64) using an analogous method to that described for Example 166. LCMS m/z = 925 [M+H]+; 1H NMR (DMSO-d6, 400 MHz): 11.10 (bs, 1H), 10.15 (bs, 1H), 8.77 (s, 1H), 8.36 (bs, 2H), 8.26 (s, 1H), 8.10 (t, 1H), 7.96 (s, 1H), 7.70-7.58 (m, 3H), 7.33 (s, 1H), 7.20-7.17 (m, 1H), 5.08-5.05 (m, 1H), 4.78 (bs, 1H), 4.12 (s, 2H), 4.04-4.01 (m, 2H), 2.95-2.80 (m, 5H), 2.77-2.73 (m, 2H), 2.51-2.48 (m, 2H), 2.29-2.25 (m, 2H), 2.35-1.95 (m, 1H), 1.70-1.69 (m, 3H), 1.58-1.51 (m, 2H), 1.24 (bs, 1H), 1.12-1.01 (m, 9H), 0.96-0.93 (m, 1H). Example 168. N-(2-(9-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)ethyl)-3,9-diazaspiro[5.5]undecan-3-yl)ethyl)-3-fluoro-4-((4-(1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide
Figure imgf000358_0001
A mixture of N-(2-(3,9-diazaspiro[5.5]undecan-3-yl)ethyl)-3-fluoro-4-((4-(1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide (Intermediate 67, 166.6 mg, 0.26 mmol), 2-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl 4-methylbenzenesulfonate (Intermediate 66, 80 mg, 0.170 mmol) and sodium bicarbonate (71.3 mg, 0.85 mmol) in dry MeCN (1.6 mL) at rt under nitrogen was stirred at 70 °C for 16 h. The reaction mixture was quenched with cold water (30 mL) and extracted with EtOAc (3x 30 mL). The combined organics were washed with ice cold water (2x 30 mL), brine (30 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by HPLC-R to afford the title compound as a yellow solid (55 mg, 34%). LCMS m/z = 954 [M+H]+; 1H NMR (DMSO-d6, 400 MHz): 11.09 (s, 1H), 10.14 (s, 1H), 8.78 (s, 1H), 8.26 (s, 1H), 8.13-8.09 (m, 2H), 7.96 (s, 1H), 7.71-7.57 (m, 4H), 7.10 (d, 1H), 7.05 (d, 1H), 6.77 (s, 1H), 5.08-5.03 (m, 1H), 4.78 (s, 1H), 4.12 (s, 2H), 3.44-3.43 (m, 1H) 3.32 (s, 2H), 2.89 (s, 4H), 2.67-2.54 (m, 9H), 2.46-2.41 (m, 1H), 2.02 (m, 1H), 1.45 (bs, 8H), 1.23 (s, 1H), 1.08 (bs, 6H). Example 169. N-(2-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1- yl)methyl)piperidin-1-yl)ethyl)-3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4- yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methylbenzenesulfonamide
Figure imgf000359_0001
A mixture of N-(2-chloroethyl)-3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4- yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methylbenzenesulfonamide (Intermediate 99, 130 mg, 0.24 mmol), 3-(4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)piperidine-2,6- dione hydrochloride (WO2022133285, 80 mg, 0.19 mmol), DIPEA (0.14 mg, 0.79 mmol), KI (49 mg, 0.29 mmol in dry DMF (1.6 mL) at rt under nitrogen was stirred at 100 °C for 16 h. The reaction mixture was quenched with cold water (10 mL) and extracted with EtOAc (3x 15 mL). The combined organics were washed with ice cold water (2x 20 mL), brine (20 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by HPLC-B to afford the title compound as a white solid (7 mg, 4%). LCMS m/z = 885 [M+H]+; 1H NMR (DMSO-d6, 400 MHz): 10.78 (s, 1H), 10.25 (bs, 1H), 8.79 (s, 1H), 8.27 (s, 1H), 8.16 (t, 1H), 7.97 (s, 1H), 7.74 (dd, 1H), 7.68 (dd, 1H), 7.04 (d, 2H), 6.87 (d, 2H), 4.83 (bs, 1H), 4.12 (s, 2H), 3.72 (dd, 1H), 3.19-3.12 (m, 2H), 3.09 (bs, 4H), 2.87-2.81 (m, 2H), 2.78 (s, 3H), 2.62-2.57 (m, 2H), 2.47-2.42 (m, 6H), 2.15-2.10 (m, 4H), 1.92-1.88 (m, 2H), 1.66-1.63 (m, 2H), 1.5 (bs, 1H), 1.04 (s, 8H). Example 170. 4-((5-cyano-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)-N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)pentyl)benzenesulfonamide
Figure imgf000360_0001
To a stirred solution of N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)pentyl)-4-iodobenzenesulfonamide (Intermediate 106, 170 mg, 0.27 mmol) and 2- amino-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile (Intermediate 107, 70 mg, 0.27 mmol) in dioxane (5 mL) and was added Cs2CO3 (270 mg, 0.82 mmol) at rt. The reaction mixture was initially purged with argon for 20 min before Pd2(dba)3 (20 mg, 0.03 mmol), Xanthphos (50 mg, 0.082 mmol) were added. The reaction mixture was heated in a microwave oven at 160 °C for 2 h. The reaction was quenched with ice-cold water (20 mL) and extracted in EtOAc (3x 25 mL). The combined organics were washed with water (2x 20 mL), brine (30 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by HPLC-J to afford the title compound as a yellow solid (45 mg, 22%). LCMS m/z = 755 [M+H]+; 1H NMR (DMSO-d6, 400 MHz): 11.10 (s, 1H), 10.68 (s, 1H), 8.89 (s, 1H), 8.58 (s, 1H), 8.28 (s, 1H), 8.00 (d, 2H), 7.79 (d, 2H), 7.55-7.51 (q, 1H), 7.47 (t, 1H), 7.03-6.97 (m, 2H), 6.48 (t, 1H), 5.05-5.01 (m, 1H), 4.84 (s, 1H), 4.17 (s, 2H), 3.31-3.19 (m, 2H), 2.87-2.86 (m, 1H), 2.84 -2.74 (m, 2H), 2.73-2.49 (m, 2H), 2.03-1.99 ( m, 1H), 1.50-1.37 ( m, 4H), 1.30-1.27 (q, 2H), 1.10 (s, 6H). Example 171. 3-(3-(3-((1-((1-((4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)piperidin-1-yl)sulfonyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)prop-1-yn-1- yl)phenyl)piperidine-2,6-dione
Figure imgf000361_0001
DIPEA (0.11 mL, 0.62 mmol) was added to a solution of 3-(3-(3-((1-((1-((4-aminopiperidin- 1-yl)sulfonyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)prop-1-yn-1-yl)phenyl)piperidine-2,6- dione hydrochloride (Intermediate 34, 120 mg, 0.21 mmol) and 2,5-dichloro-4-(1-methyl-1H- pyrazol-4-yl)pyrimidine (Intermediate 3, 28.2 mg, 0.12 mmol) in DMSO (2 mL) at rt under nitrogen atmosphere and the resulting mixture stirred at 100 °C for 16 h. The reaction mixture was diluted with cold water (20 mL) and extracted with EtOAc (3x 20 mL). The combined organics were washed with water (2x 20 mL), brine (20 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by HPLC-A to afford the title compound as a white solid (13 mg, 8%). LCMS m/z = 778 [M+H]+; 1H NMR (DMSO-d6, 400 MHz): 10.84 (s, 1H), 8.51(s, 1H), 8.32-8.15 (m, 2H), 7.40-7.26 (m, 5H), 4.39 (s, 1H), 3.92-3.86 (m, 4H), 3.57-2.54 (m, 5H), 2.96 (s, 2H), 2.81-2.75 (m, 2H), 2.69-2.67 (m, 4H), 2.45 (s, 2H), 2.24 (t, 2H), 2.12-2.01 (m, 5H).1.93-1.85 (m, 2H), 1.73 (m, 2H), 1.45-1.51 (m, 6H), 1.08-1.05 (m, 2H). Example 172. N-((1r,3r)-3-((9-(3-(2,6-dioxopiperidin-3-yl)phenyl)-3,9- diazaspiro[5.5]undecan-3-yl)methyl)cyclobutyl)-3-fluoro-4-((4-(1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide
Figure imgf000361_0002
To a stirred solution of 3-(3-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)piperidine-2,6-dione (Intermediate 10, 70 mg, 0.20 mmol) and 3-fluoro-N-((1r,3r)-3-formylcyclobutyl)-4-((4-(1- (2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide (Intermediate 89, 114.1 mg, 0.20 mmol) in DCM (3.5 mL) was added STAB (86.9 mg, 0.41 mmol) under nitrogen at rt and the reaction mixture stirred at rt for 16 h. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (3x 20 mL). The combined organics were washed with water (2x 20 mL), brine (20 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by HPLC-A to afford the title compound as an off-white solid (28 mg, 15%). LCMS m/z = 882 [M+H]+; 1H NMR (DMSO-d6, 400 MHz): 10.77 (s, 1H), 10.11 (s, 1H), 8.78 (s, 1H), 8.25 (s, 1H), 8.02-8.09 (m, 1H), 7.91-7.94 (s, 2H), 7.64 (m, 2H), 7.11 (t, 1H), 6.75-6.77 (m, 2H), 6.56 (d, 1H), 4.78 (bs, 1H), 4.11 (s, 2H), 3.75-3.71 (m, 1H), 3.56-3.54 (m, 1H), 3.67 (m, 4H), 2.60-2.50 (m, 1H), 2.49-2.42 (m, 2H), 2.25-1.80 (m, 11H), 1.44-1.42 (m, 9H), 1.08 (s, 6H). Example 173. N-(1-((1-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)but-3-yn-1-yl)piperidin-4- yl)methyl)piperidin-4-yl)-3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide
Figure imgf000362_0001
To a stirred solution of 1-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)but-3-yn-1-yl)piperidine-4- carbaldehyde 73 (Intermediate 90, 100 mg, 0.28 mmol) and 3-fluoro-4-((4-(1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(piperidin-4- yl)benzenesulfonamide 22d (Intermediate 31, Step 4; 158.2 mg, 0.284 mmol) in MeOH (2 mL) were added acetic acid (85.2 mg, 1.42 mmol) and MP-Cyanoborohydride (180.4 mg, 0.85 mmol) at rt under nitrogen and the reaction mixture stirred at rt for 16 h. The reaction mixture was filtered and solid residue washed with methanol (3x 5 mL). The filtrate was concentrated under reduced pressure and the residue purified by HPLC-B to afford the title compound as a white solid (46 mg, 18%). LCMS m/z = 894 [M+H]+; 1H NMR (DMSO-d6, 400 MHz): 10.83 (s, 1H), 10.08 (s, 1H), 8.78 (s, 1H), 8.25 (s, 1H), 8.16 (s, 1H), 8.06 (t, 1H), 7.92 (s, 1H), 7.75 (d, 1H), 7.67-7.66 (m, 2H), 7.32-7.18 (m, 4H), 4.77 (s, 1H), 4.11 (s, 2H), 3.87-3.83 (m, 1H), 2.98 (s, 1H), 2.86-2.83 (m, 2H), 2.69-2.61 (m, 3H), 2.54-2.52 (m, 5H), 2.25-2.16 (m, 1H), 2.03-1.90 (m, 5H), 1.85-1.80 (m, 2H), 1.61-1.54 (m, 4H), 1.40-1.35 (m, 3H), 1.08-0.98 (m, 7H). Example 174. N-((1r,4r)-4-((9-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3,9- diazaspiro[5.5]undecan-3-yl)methyl)cyclohexyl)-3-fluoro-4-((4-(1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide
Figure imgf000363_0001
To a stirred solution of 2-(2,6-dioxopiperidin-3-yl)-5-(3,9-diazaspiro[5.5]undecan-3- yl)isoindoline-1,3-dione hydrochloride (Intermediate 54, 150 mg, 0.33 mmol) and N-((1r,4r)- 4-(bromomethyl)cyclohexyl)-3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4- yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide (Intermediate 29, Step 3; 330 mg, 0.50 mmol) in DMF (2 mL) was added DIPEA (0.18 mL, 1.00 mmol) at rt and the resulting reaction mixture stirred at 90 °C for 16 h. The reaction mixture was diluted with ice-cold water (10 mL) and extracted in EtOAc (3x 15 mL). The combined organics were washed with water (2x 15 mL), brine (15 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by HPLC-B to afford the title compound as a yellow solid (42 mg, 13%). LCMS m/z = 979 [M+H]+; 1H NMR (DMSO-d6, 400 MHz): 11.06 (bs, 1H), 10.10 (bs, 1H), 8.78 (bs, 1H), 8.27-8.25 (m, 2H), 8.06 (t, 1H), 7.93 (s, 1H), 7.71-7.62 (m, 4H), 7.31-7.25 (m, 1H), 7.21-7.18 (dd, 1H), 5.07-5.03 (m, 1H), 4.98-4.60 (bs, 1H), 4.12 (s, 2H), 3.80-3.15 (m, 4H), 3.00-2.83 (m, 2H), 2.67-2.53 (m, 2H), 2.32-2.25 (m, 4H), 2.01-1.99 (m, 3H), 1.67-1.64 (m, 4H), 1.48-1.44 (m, 8H), 1.25-1.05 (m, 8H), 0.75-0.63 (m, 2H). Example 175. 2-(2,6-dioxopiperidin-3-yl)-4-(2-(4-((4-((4-(1-(2-hydroxy-2-methylpropyl)- 1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)piperazin-1-yl)- 2-oxoethoxy)isoindoline-1,3-dione
Figure imgf000364_0001
To a stirred solution of 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetic acid [ACS Med. Chem. Lett., 2022, 13, 1621-1627] (88 mg, 0.27 mmol) in DMF (2 mL) was added 2-methyl-1-(4-(2-((4-(piperazin-1-ylsulfonyl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propan-2-ol (Intermediate 100, 70 mg, 0.13 mmol) followed by DIPEA (0.09 g, 0.66 mmol) at 0 °C under nitrogen. After 10 minutes, PyBOP (139 mg, 0.27 mmol) was added at rt and the resulting reaction mixture stirred at rt for 2 h. The reaction mixture was diluted with water (30 mL) and extracted with 10% MeOH/DCM (2x 50 mL). The combined organics were washed with brine, dried (Na2SO4), concentrated under vacuum and the residue purified by HPLC-T to afford the title compound as an off-white solid (13 mg, 12%). LCMS m/z = 840 [M+H]+; 1H NMR (DMSO-d6, 400 MHz): 11.12 (bs, 1H), 10.76 (s, 1H), 8.84 (s, 1H), 8.34 (bs, 1H), 8.07-8.03 (m, 3H), 7.75-7.68 (m, 3H), 7.40 (d, 1H), 7.25 (d, 1H), 5.13-5.02 (m, 4H), 4.15 (s, 2H), 3.55 (bs, 4H), 2.98-2.80 (m, 5H), 2.59-2.54 (m, 1H), 2.52-2.49 (m, 1H), 2.05-2.02 (m, 1H), 1.11 (s, 6H). Example 176. 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)-N-(6-((3- fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-
Figure imgf000364_0002
HATU (36.9 mg, 0.097 mmol) was added to a solution of N-(6-aminohexyl)-3-fluoro-4-((4- (1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide hydrochloride (Intermediate 91, 50 mg, 0.08 mmol), 2-((2- (2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetic acid (ACS Med. Chem. Lett., 2022, 13, 1621-1627, 30 mg, 0.09 mmol), DIPEA (0.04 mL, 0.22 mmol) in dry DMF (1 mL) at 0 ºC under nitrogen. The reaction mixture was warmed to rt and stirred for 16 h, quenched with cold water (10 mL) and extracted with EtOAc (3x 15 mL). The combined organics were washed with ice cold water (2x 15 mL), brine (15 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by HPLC-A to afford the title compound as a yellow solid (20 mg, 30%). LCMS m/z = 887
Figure imgf000365_0001
NMR (DMSO-d6, 400 MHz): 11.05 (s, 1H), 10.10 (s, 1H), 8.77 (s, 1H), 8.25 (s, 1H), 8.08 (t, 1H), 8.00 (t, 1H), 7.95 (s, 1H), 7.65-7.56 (m, 4H), 7.33 (t, 1H), 6.92 (s, 1H), 6.84 (d, 1H), 5.05-5.00 (m, 1H), 4.77 (s, 1H), 4.11 (s, 2H), 3.80 (d, 2H), 3.07-3.02 (m, 2H), 2.87-2.83 (m, 1H), 2.77-2.73 (m, 2H), 2.87- 2.55 (m, 2H), 1.98 (t, 2H), 1.34 (d, 2H), 1.19 (bs, 5H), 1.08 (bs, 6H). Example 177. 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-N-(6-((3- fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin- 2-yl)amino)phenyl)sulfonamido)hexyl)acetamide
Figure imgf000365_0002
The title compound was prepared as a white solid (58 mg, 25%) from (2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-5-yl)glycine (WO2022100710) and 2-((2-(2,6-dioxopiperidin-3- yl)-1,3-dioxoisoindolin-4-yl)oxy)acetic acid (ACS Med. Chem. Lett., 2022, 13, 1621-1627) using an analogous method to that described for Example 176. HPLC-I; LCMS m/z = 888 [M+H]+; 1H NMR (DMSO-d6, 400 MHz): 11.05 (s, 1H), 10.1 (s, 1H), 8.77 (s, 1H), 8.25 (s, 1H), 8.08 (t, 1H), 7.95 (s, 2H), 7.91 (t, 1H), 7.79 (t, 1H), 7.66-7.63 (m, 2H), 7.48 (d, 1H), 7.37 (d, 1H), 5.12-5.09 (m, 1H), 4.79-4.75 (m, 3H), 4.11 (s, 2H), 3.13-3.08 (q, 2H), 2.94-2.85 (m, 1H), 2.77 (bs, 2H), 2.61-2.57 (m, 2H), 2.04-2.01 (m, 1H), 1.39-1.37 (s, 4H), 1.23 (bs, 4H), 1.08 (s, 6H). Example 178. 3-(5-(3-((1-((4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin- 2-yl)amino)piperidin-1-yl)sulfonyl)piperidin-4-yl)oxy)prop-1-yn-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione
Figure imgf000366_0001
DIPEA (0.12 mL, 0.50 mmol) was added to a stirred solution of 3-(5-(3-((1-((4- aminopiperidin-1-yl)sulfonyl)piperidin-4-yl)oxy)prop-1-yn-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (Intermediate 112, 90 mg, 0.166 mmol) and 2-chloro-4-(1-methyl- 1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine (Intermediate 35, Step 1; 48 mg, 0.182 mmol) in dioxane (2 mL) was added DIPEA (0.12 mL, 0.497 mmol) at rt and the resulting reaction mixture stirred at 100 ºC for 16 h. The reaction mixture was diluted with water (5 mL) and extracted with 10% MeOH/DCM (3x 10 mL). The combined organics were washed with brine (10 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by HPLC-B to afford the title compound as a white solid (39 mg, 31%). LCMS m/z = 770 [
Figure imgf000366_0002
400 MHz): 10.99 (bs, 1H), 8.57-8.51 (m, 1H), 8.26- 8.154 (m, 1H), 7.98-7.89 (m, 2H), 7.74-7.72 (m, 2H), 7.59-7.57 (d, 1H), 5.14-5.09 (m, 1H), 4.49 (s, 2H), 4.48-4.31 (m, 1H), 4.1-3.9 (m, 4H), 3.80 - 3.70 (m, 1H), 3.60-3.52 (m, 2H), 3.45-3.35 (m, 2H), 3.15-2.80 (m, 5H), 2.70-2.53 (m, 1H), 2.4 -2.30 (m, 1H), 2.10-1.90 (m, 5H), 1.70-1.50 (m, 4H). Example 179. 3-(5-(4-((2-methyl-1-((4-((4-(1-methyl-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione
Figure imgf000367_0001
Step 1. Synthesis of methyl 2-methyl-1-((4-((4-(1-methyl-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)piperidine-4-carboxylate A mixture of 4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)piperidine-1-sulfonyl chloride (Intermediate 35, 200 mg, 470 µmol), methyl 2- methyl-piperidine-4-carboxylate hydrochloride (109 mg, 564 µmol), TEA (142 mg, 1.41 mmol) in MeCN (10 mL) was stirred at 50 ºC for 6 h. The reaction mixture was evaporated to dryness and the residue diluted with DCM and washed with water. The combined organics were dried (Na2SO4) and evaporated to dryness to afford title compound as a brown solid (160 mg, 62%). LCMS m/z = 546 [M+H]+ Step 2. Synthesis of (2-methyl-1-((4-((4-(1-methyl-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)piperidin-4-yl)methanol DIBAL-H (2M in THF, 073 mL, 1.46 mmol) was added to a solution of methyl 2-methyl-1- ((4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1- yl)sulfonyl)piperidine-4-carboxylate (Step 1, 160 mg, 293 µmol) in THF (15 mL) at 0 ºC and stirred at rt for 4 h. The reaction was quenched with water and evaporated to dryness. The residue was purified by prep-TLC (20:1 DCM/MeOH) to afford the title compound was a white solid (100 mg, 66%). LCMS m/z = 518 [M+H]+ Step 3. Synthesis of 2-methyl-1-((4-((4-(1-methyl-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)piperidine-4-carbaldehyde Dess-Martin periodinane (97.9 mg, 231 µmol) was added to a solution of (2-methyl-1-((4- ((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1- yl)sulfonyl)piperidin-4-yl)methanol (Step 2, 100 mg, 193 µmol) in DCM (1 mL) at 0 ºC and the reaction mixture stirred at rt for 2 h. The reaction mixture was evaporated to dryness and the residue purified on prep-TLC (20:1 DCM/MeOH) to afford the title compound as a yellow solid (75 mg, 75%). LCMS m/z = 516 [M+H]+ Step 4. Synthesis of 3-(5-(4-((2-methyl-1-((4-((4-(1-methyl-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione STAB (34.1 mg, 162 μmol) was added to a mixture of 2-methyl-1-((4-((4-(1-methyl-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)piperidine-4- carbaldehyde (Step 3, 70 mg, 135 μmol), 3-(1-oxo-5-(piperazin-1-yl)isoindolin-2- yl)piperidine-2,6-dione hydrochloride (49.2 mg, 135 μmol), DIPEA (26.1 mg, 202 μmol) in DCM (10 mL) at 0 ºC and stirred at rt for 2 h. The reaction was quenched with water and concentrated to dryness. The residue was purified by prep-TLC (20:1 DCM/MeOH) followed by prep-HPLC (Xselect CSH C18 OBD 30 x 150 mm, 6 μm; 20-32% MeCN/H2O (0.1% HCO2H)) to afford the title compound as a white solid (8.4 mg). LCMS m/z = 828 [M+H]+; 1H NMR (DMSO-d6, 400 MHz): 10.95 (s, 1H), 8.55 (d, 1H), 8.22 (d, 1H), 7.94 (m, 2H), 7.52 (m, 1H), 7.06 (m, 2H), 5.05 (m, 1H), 4.33 (m, 1H), 4.20 (m, 1H), 3.93 (s, 5H), 3.54 (s, 3H), 3.29 (m, 5H), 3.04-2.71 (m, 5H), 2.60 (s, 3H), 2.40-2.11 (m, 4H), 1.88 (m, 6H), 1.56 (m, 2H), 1.31 (s, 2H), 1.17 (s, 2H). Example 180. 3-(6-(4-((1-((4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin- 2-yl)amino)piperidin-1-yl)sulfonyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione
Figure imgf000369_0001
A mixture of 3-(1-oxo-6-(4-(piperidin-4-ylmethyl)piperazin-1-yl)isoindolin-2-yl)piperidine- 2,6-dione (Intermediate 122, 50 mg, 117 µmol), 4-((4-(1-methyl-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-sulfonyl chloride (Intermediate 35, 99.4 mg, 234 µmol), TEA (35.5 mg, 351 µmol) in DCE (8 mL) was stirred at 50 ºC for 16 h. The reaction mixture was evaporated to dryness and the residue purified by prep-TLC (10:1 DCM/MeOH) followed by prep-HPLC (Xselect CSH C18 OBD 30 x 150 mm, 6 μm; 20-33% MeCN/H2O (0.1% HCO2H)) to afford the title compound as a white solid (6.3 mg). LCMS m/z = 814 [M+H]+; 1H NMR (DMSO-d6, 400 MHz): 10.98 (s, 1H), 8.55 (d, 1H), 8.25 (d, 1H), 8.16 (s, 0.335H), 8.01-7.90 (m, 2H), 7.43 (d, 1H), 7.26 (dd, 1H), 7.16 (d, 1H), 5.10 (dd, 1H), 4.38-4.14 (m, 2H), 3.93 (m, 4H), 3.58 (m, 4H), 3.20 (m, 4H), 3.10-2.54 (m, 5H), 2.55- 2.45 (m, 4H), 2.42-2.28 (m, 2H), 2.21 (m, 2H), 2.02-1.85 (m, 3H), 1.83-1.73 (m, 2H), 1.70 (s, 1H), 1.54 (m, 2H), 1.12 (m, 2H). Biological Example 1. CDK2 Degradation Assays in OVCAR3 Cells OVCAR3 cells were cultured in RPMI medium with 20% FBS with penicillin- streptomycin to appropriate confluency before they were harvested for assay use. An appropriate amount of OVCAR3 cells were seeded in each well which contains 30 µL of DMEM complete medium in a 384-well Opti-plate. The cells were incubated overnight at 37 °C in a 5% CO2 incubator. On the day of the assay, the compound solutions were diluted to appropriate concentrations on an intermediate plate.10 µL of the intermediate compound solutions were transferred to the corresponding wells on the cell-culture plate. The plates were incubated for either 6 h or 16 h at 37 °C in a 5% CO2 incubator. After incubation, the supernatant was removed. The cells were lysed by using ice cold AlphaLISA lysis buffer with protease/phosphatase inhibitors. A fraction of the lysate was used for CDK2 AlphaLISA. For AlphaLISA measurement, an appropriate amount of lysate was transferred to a Opti-plate.5 µL of acceptor beads were added to each well, followed by the addition of donor beads. The plate was then incubated in dark at room temperature overnight before being read by an EnVision plate reader Excitation 680 nm; Emission 520 to 620 nm. Table 2. CDK2 degradation assay data.
Figure imgf000370_0001
Figure imgf000371_0001
Figure imgf000372_0001
Figure imgf000373_0001
Other known biological assays can be used to assess the compounds of the disclosure, including, but not limited to, protein selectivity, degradation of other proteins, and protein inhibitory activity. Various modifications of the disclosure, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference, including all patent, patent applications, and publications, cited in the present application is incorporated herein by reference in its entirety.

Claims

What is claimed is: 1. A compound of Formula (II),
Figure imgf000374_0001
or a pharmaceutically acceptable salt thereof, wherein R1 is selected from C1-C6alkyl, C3-C6cycloalkyl, and 3 to 6-membered heterocyclyl, wherein the C1-C6alkyl is optionally substituted with 1 to 3 Ra1, wherein C3-C6cycloalkyl is optionally substituted with 1 to 4 Rb1, wherein the 3 to 6-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc1 and then is optionally substituted on a ring carbon with 1 to 4 Rb1; R2 is selected from H, D, C1-C4alkyl, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 3 Ra2; R3 is selected from H, D, halo, CN, C1-C4alkyl, and C3-C6cyclcoalkyl; R4 is selected from H, D, halo, OH, CN, C1-C4alkyl, C1-C4alkoxy, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 4 groups each independently selected from D, halo, OH and CN; R5 is selected from H, D, halo, OH, CN, C1-C4alkyl, C1-C4alkoxy, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 4 groups each independently selected from D, halo, OH and CN; R6 is H or D; R7 is selected from H, D, C1-C4alkyl, and C(=O)-C1-4alkyl; Ring A is selected from C3-C10cycloalkyl, 3 to 12-membered heterocyclyl, C5- C12spirocycloalkyl, 5 to 12-membered spiroheterocyclyl, 6 to 12-membered aryl, and 5 to 12-membered heteroaryl, wherein the C3-C10cycloalkyl, C5-C12spirocycloalkyl, and 6 to 12-membered aryl are each optionally substituted with 1 to 4 Rb2, and wherein the 3 to 12-membered heterocyclyl, 5 to 12-membered spiroheterocyclyl, and 5 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc2 and then are optionally substituted on a ring carbon with 1 to 4 Rb2; L is a linker moiety; Ring B is:
Figure imgf000375_0001
Each Y1 is independently selected from C(Rd5)2 and NRc12; Y2 is C(Re3)2 or C(=O); W is CH or N; Each Ra1 and Ra2 is independently selected from D, halo, OH, C3-C6cycloalkyl, and 3 to 6- membered heterocyclyl, wherein the C3-C6cycloalkyl is optionally substituted with D, OH, or -CH2OH, wherein the 3 to 6-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc13 and then is optionally substituted on a ring carbon with D, OH, or -CH2OH; Each Rb1, Rb2, and Rb8 is independently selected from D, halo, OH, CN, N(Rc14)2, C1-C4alkyl, and C1-C4alkoxy, or two Rb1 or Rb2 attached to the same atom, form a =O, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 4 groups each independently selected from D, halo, OH and CN; Each Rc1, Rc2, Rc12, Rc13, and Rc14 is independently selected from H, D, C1-C4alkyl, and C(=O)-C1-4alkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 4 groups each independently selected from D and OH; Each Rd5 is independently selected from H, D, halo, OH, C1-C4alkyl, and C3-C6cycloalkyl; Each Re3 is independently selected from H, D, and C1-C4alkyl; m is 0, 1, or 2; and t is an integer from 0 to 4.
2. The compound of claim 1, wherein the compound is of Formula (III):
Figure imgf000376_0001
or a pharmaceutically acceptable salt thereof, wherein R1 is selected from C1-C6alkyl, C3-C6cycloalkyl, and 3 to 6-membered heterocyclyl, wherein the C1-C6alkyl is optionally substituted with 1 to 3 Ra1, wherein C3-C6cycloalkyl is optionally substituted with 1 to 4 Rb1, wherein the 3 to 6-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc1 and then is optionally substituted on a ring carbon with 1 to 4 Rb1; R2 is selected from H, D, C1-C4alkyl, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 3 Ra2; R3 is selected from H, D, halo, CN, C1-C4alkyl, and C3-C6cyclcoalkyl; R4 is selected from H, D, halo, OH, CN, C1-C4alkyl, C1-C4alkoxy, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 4 groups each independently selected from D, halo, OH and CN; R5 is selected from H, D, halo, OH, CN, C1-C4alkyl, C1-C4alkoxy, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 4 groups each independently selected from D, halo, OH and CN; R6 is H or D; R7 is selected from H, D, C1-C4alkyl, and C(=O)-C1-4alkyl; Ring A is selected from C3-C10cycloalkyl, 3 to 12-membered heterocyclyl, C5- C12spirocycloalkyl, 5 to 12-membered spiroheterocyclyl, 6 to 12-membered aryl, and 5 to 12-membered heteroaryl, wherein the C3-C10cycloalkyl, C5-C12spirocycloalkyl, and 6 to 12-membered aryl are each optionally substituted with 1 to 4 Rb2, and wherein the 3 to 12-membered heterocyclyl, 5 to 12-membered spiroheterocyclyl, and 5 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc2 and then are optionally substituted on a ring carbon with 1 to 4 Rb2; L1 is selected from a covalent bond, -S(=O)2-, -*NRc3-S(=O)2-, -*S(=O)2-NRc3-, -*S(=O)2- NRc3-(C(Rd1)2)n-, -*S(=O)2-(C(Rd1)2)n-O-(C(Rd1)2)n-, -*NRc3-S(=O)2-(C(Rd1)2)n-O- (C(Rd1)2)n-, and -*S(=O)2-NRc3-(C(Rd1)2)n-O-(C(Rd1)2)n-, wherein * denotes the point of attachment of L1 to Ring A; X1 is selected from a covalent bond, C3-C10cycloalkyl, 3 to 12-membered heterocyclyl, 6 to 12-membered aryl, and 5 to 12-membered heteroaryl, wherein the C3-C10cycloalkyl and 6 to 12-membered aryl are each optionally substituted with 1 to 4 Rb3, and wherein the 3 to 12-membered heterocyclyl and 5 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc4 and then are optionally substituted on a ring carbon with 1 to 4 Rb3; L2 is selected from a covalent bond, -(C(Rd2)2)n-, -*NRc5-(C(Rd2)2)n-, -*(C(Rd2)2)n-C(=O)-, - *(C(Rd2)2)n-O-(C(Rd2)2)n-, and -*(C(Re1)2C(Re1)2O)r-(C(Rd2)2)n-, wherein * denotes the point of attachment of L2 to X1; X2 is selected from a covalent bond, C3-C10cycloalkyl, 3 to 12-membered heterocyclyl, 6 to 12-membered aryl, and 5 to 12-membered heteroaryl, wherein the C3-C10cycloalkyl and 6 to 12-membered aryl are each optionally substituted with 1 to 4 Rb4, and wherein the 3 to 12-membered heterocyclyl and 5 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc6 and then are optionally substituted on a ring carbon with 1 to 4 Rb4; or X1– L2– X2 form a C5-C12spirocycloalkyl or 5 to 12-membered spiroheterocyclyl, wherein the C5-C12spirocycloalkyl is optionally substituted with 1 to 4 Rb5, and wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc7 and then are optionally substituted on a ring carbon with 1 to 4 Rb5; L3 is selected from -O-, -(C(Rd3)2)n-, -*NRc8-(C(Rd3)2)n-, -*C(=O)-(C(Rd3)2)n-, and - *(C(Re2)2C(Re2)2O)r-(C(Rd3)2)n-, wherein * denotes the point of attachment of L3 to X2; Each X3 is selected from C3-C10cycloalkyl, 3 to 12-membered heterocyclyl, 6 to 12- membered aryl, and 5 to 12-membered heteroaryl, wherein the C3-C10cycloalkyl and 6 to 12-membered aryl are each optionally substituted with 1 to 4 Rb6, and wherein the 3 to 12-membered heterocyclyl and 5 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc9 and then are optionally substituted on a ring carbon with 1 to 4 Rb6; or X2– L3– X3 form a C5-C12spirocycloalkyl or 5 to 12-membered spiroheterocyclyl, wherein the C5-C12spirocycloalkyl is optionally substituted with 1 to 4 Rb7, and wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc10 and then are optionally substituted on a ring carbon with 1 to 4 Rb7; or Two X3 form a C5-C12spirocycloalkyl or 5 to 12-membered spiroheterocyclyl, wherein the C5-C12spirocycloalkyl is optionally substituted with 1 to 4 Rb7, and wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc10 and then are optionally substituted on a ring carbon with 1 to 4 Rb7; L4 is selected from a covalent bond, -O-, -C(=O)-, -(C(Rd4)2)n-, -NRc11-, -*NRc11-(C(Rd4)2)n-, -*(C(Rd4)2)n-NRc11-, -*O-(C(Rd4)2)n-, -*(C(Rd4)2)n-O-, -*C(=O)-(C(Rd4)2)n-, - *(C(Rd4)2)n-C(=O)-, -*C2-C6alkenylene-(O)s-, -*C2-C6alkynylene-(O)s-, -*O- (C(Rd4)2)n-C(=O)-, -*O-(C(Rd4)2)n-C(=O)-NRc11-, -*O-(C(Rd4)2)n-NRc11-C(=O)-, - *NRc11-(C(Rd4)2)n-C(=O)-NRc11-, -*NRc11-(C(Rd4)2)n-C(=O)-, and -*NRc11-(C(Rd4)2)n- NRc11-C(=O)- wherein * denotes the point of attachment of L4 to Ring B; wherein no more than three of L1, X1, L2, X2, and L4 can simultaneously be a covalent bond; Ring B is
Figure imgf000378_0001
Each Y1 is independently selected from C(Rd5)2 and NRc12; Y2 is C(Re3)2 or C(=O); W is CH or N; Each Ra1 and Ra2 is independently selected from D, halo, OH, C3-C6cycloalkyl, and 3 to 6- membered heterocyclyl, wherein the C3-C6cycloalkyl is optionally substituted with D, OH, or -CH2OH, and wherein the 3 to 6-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc13 and then is optionally substituted on a ring carbon with D, OH, or -CH2OH; Each Rb1, Rb2, Rb3, Rb4, Rb5, Rb6, Rb7, and Rb8 is independently selected from D, halo, OH, CN, N(Rc14)2, C1-C4alkyl, and C1-C4alkoxy, or two Rb1, Rb2 Rb3, Rb4, Rb5, Rb6, or Rb7 attached to the same atom, form a =O, wherein the C1-C4alkyl and C1-C4alkoxy each optionally substituted with 1 to 4 groups each independently selected from D, halo, OH and CN; Each Rc1, Rc2, Rc3, Rc4, Rc5, Rc6, Rc7, Rc8, Rc9, Rc10, Rc11, Rc12, Rc13, and Rc14 is independently selected from H, D, C1-C4alkyl, and C(=O)-C1-4alkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 4 groups each independently selected from D and OH; Each Rd1, Rd2, Rd3, Rd4, and Rd5 is independently selected from H, D, halo, OH, C1-C4alkyl, and C3-C6cycloalkyl; Each Re1, Re2, and Re3 is independently selected from H, D, and C1-C4alkyl; m is 0, 1, or 2; n is an integer from 0 to 8; p is 0 or 1; q is 0, 1, or 2; r is an integer from 1 to 6; s is 0 or 1; and t is an integer from 0 to 4.
3. The compound of claim 2, wherein the compound is of Formula (IV):
Figure imgf000379_0001
wherein t is an integer from 0 to 4, or a pharmaceutically acceptable salt thereof.
4. The compound of claim 3, wherein the compound is of Formula (IVa),(IVb), (IVc), or (IVd):
Figure imgf000380_0001
or a pharmaceutically acceptable salt thereof.
5. The compound of claim 2, wherein the compound is of Formula (V):
Figure imgf000381_0001
wherein t is an integer from 0 to 3,
6. The compound of claim 5, wherein the compound is of Formula (Va), (Vb), (Vc), (Vd), (Ve), or (Vf):
Figure imgf000381_0002
Figure imgf000382_0001
or a pharmaceutically acceptable salt thereof.
7. The compound of any one of claims 2 to 6, wherein R1 is selected from C1-C6alkyl, C3-C6cycloalkyl, and 3 to 6-membered heterocyclyl, wherein the C1-C6alkyl is optionally substituted with 1 or 2 Ra1, and wherein the 3 to 6- membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc1; R2 is selected from H, D, C1-C4alkyl, and C3-C6cyclcoalkyl, wherein the C1-C6alkyl is optionally substituted with 1 or 2 Ra2; R3 is selected from H, D, C1-C4alkyl, and C3-C6cyclcoalkyl; R4 is selected from H, D, halo, OH, CN, C1-C4alkyl, C1-C4alkoxy, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 3 groups each independently selected from D, halo, OH and CN; R5 is selected from H, D, halo, OH, CN, C1-C4alkyl, C1-C4alkoxy, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 3 groups each independently selected from D, halo, OH and CN; R6 is H or D; R7 is selected from H, D, C1-C4alkyl, and C(=O)-C1-4alkyl; Ring A is selected from C3-C8cycloalkyl, 3 to 10-membered heterocyclyl, 5 to 10-membered spiroheterocyclyl, 6 to 10-membered aryl, and 5 to 10-membered heteroaryl, wherein the C3-C8cycloalkyl and 6 to 10-membered aryl are each optionally substituted with 1 to 3 Rb2, and wherein the 3 to 10-membered heterocyclyl, 5 to 10-membered spiroheterocyclyl, and 5 to 10-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc2 and then are optionally substituted on a ring carbon with 1 to 3 Rb2; L1 is selected from -S(=O)2-, -*S(=O)2-NRc3-, -*S(=O)2-NRc3-(C(Rd1)2)n-, -*S(=O)2- (C(Rd1)2)n-O-(C(Rd1)2)n-, and -*S(=O)2-NRc3-(C(Rd1)2)n-O-(C(Rd1)2)n-, wherein * denotes the point of attachment of L1 to Ring A; X1 is selected from a covalent bond, C3-C8cycloalkyl, 3 to 10-membered heterocyclyl, 6 to 10-membered aryl, and 5 to 10-membered heteroaryl, wherein the C3-C8cycloalkyl and 6 to 10-membered aryl are each optionally substituted with 1 to 3 Rb3, and wherein the 3 to 10-membered heterocyclyl and 5 to 10-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc4 and then are optionally substituted on a ring carbon with 1 to 3 Rb3; L2 is selected from a covalent bond, -(C(Rd2)2)n-, -*NRc5-(C(Rd2)2)n-, -*(C(Rd2)2)n-C(=O)-, - *(C(Rd2)2)n-O-(C(Rd2)2)n-, and -*(C(Re1)2C(Re1)2O)r-(C(Rd2)2)n-, wherein * denotes the point of attachment of L2 to X1; X2 is selected from a covalent bond, C3-C8cycloalkyl, 3 to 10-membered heterocyclyl, 6 to 10-membered aryl, and 5 to 10-membered heteroaryl, wherein the C3-C8cycloalkyl and 6 to 10-membered aryl are each optionally substituted with 1 to 3 Rb4, and wherein the 3 to 10-membered heterocyclyl and 5 to 10-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc6 and then are optionally substituted on a ring carbon with 1 to 3 Rb4; or X1– L2– X2 form a 5 to 10-membered spiroheterocyclyl, wherein the 5 to 10-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc7 and then are optionally substituted on a ring carbon with 1 to 3 Rb5; L3 is selected from -O-, -(C(Rd3)2)n-, -*NRc8-(C(Rd3)2)n-, -*C(=O)-(C(Rd3)2)n-, and - *(C(Re2)2C(Re2)2O)r-(C(Rd3)2)n-, wherein * denotes the point of attachment of L3 to X2; X3 is selected from C3-C8cycloalkyl, 3 to 10-membered heterocyclyl, 6 to 10-membered aryl, and 5 to 10-membered heteroaryl, wherein the C3-C8cycloalkyl and 6 to 10-membered aryl are each optionally substituted with 1 to 3 Rb6, and wherein the 3 to 10-membered heterocyclyl and 5 to 10-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc9 and then are optionally substituted on a ring carbon with 1 to 3 Rb6; or X2– L3– X3 form a 5 to 10-membered spiroheterocyclyl, wherein the 5 to 10-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc10 and then are optionally substituted on a ring carbon with 1 to 3 Rb7; or L4 is selected from a covalent bond, -O-, -C(=O)-, -(C(Rd4)2)n-, -NRc11-, -*NRc11-(C(Rd4)2)n-, -*O-(C(Rd4)2)n-, -*(C(Rd4)2)n-O-, -*C(=O)-(C(Rd4)2)n-, -*C2-C6alkenylene-(O)s-, -*C2- C6alkynylene-(O)s-, -*O-(C(Rd4)2)n-C(=O)-, -*O-(C(Rd4)2)n-C(=O)-NRc11-, -* NRc11- (C(Rd4)2)n-C(=O)-NRc11-, and -*NRc11-(C(Rd4)2)n-C(=O)- wherein * denotes the point of attachment of L4 to Ring B; wherein at least one of X1 and X2 is not a covalent bond; Y2 is C(Re3)2 or C(=O); Each Ra1 and Ra2 is independently selected from D, halo, OH, C3-C6cycloalkyl, and 3 to 6- membered heterocyclyl, wherein the 3 to 6-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc13; Each Rb1, Rb2, Rb3, Rb4, Rb5, Rb6, Rb7, and Rb8 is independently selected from D, halo, OH, CN, N(Rc14)2, C1-C4alkyl, and C1-C4alkoxy, or two Rb1, Rb2 Rb3, Rb4, Rb5, Rb6, or Rb7 attached to the same atom, form a =O, wherein the C1-C4alkyl and C1-C4alkoxy each optionally substituted with 1 to 3 groups each independently selected from D, halo, OH and CN; Each Rc1, Rc2, Rc3, Rc4, Rc5, Rc6, Rc7, Rc8, Rc9, Rc10, Rc11, Rc13, and Rc14 is independently selected from H, D, C1-C4alkyl, and C(=O)-C1-4alkyl; Each Rd1, Rd2, Rd3, and Rd4 is independently selected from H, D, halo, OH, C1-C4alkyl, and C3-C6cycloalkyl; Each Re1, Re2, and Re3 is independently selected from H, D, and C1-C4 alkyl; n is an integer from 0 to 4; p is 0 or 1; q is 0, 1, or 2; r is an integer from 1 to 6; s is 0 or 1; and t is an integer from 0 to 3.
8. The compound of any one of claims 2 to 6, wherein R1 is C1-C6alkyl, wherein the C1-C6alkyl is optionally substituted with 1 or 2 Ra1; R2 is selected from H, D, and C1-C4alkyl, wherein the C1-C6alkyl is optionally substituted with 1 or 2 Ra2; R3 is selected from H, D, and C1-C4alkyl; R4 is selected from H, D, halo, OH, CN, and C1-C4alkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 3 groups each independently selected from D, halo, OH, and CN; R5 is selected from H, D, halo, OH, CN, and C1-C4alkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 3 groups each independently selected from D, halo, OH, and CN; R6 is H or D; R7 is selected from H, D, and C1-C4alkyl; Ring A is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, 6-membered aryl, and 5 or 6-membered heteroaryl, wherein the C3-C6cycloalkyl and 6-membered aryl are each optionally substituted with 1 to 3 Rb2, and wherein the 3 to 6-membered heterocyclyl and 5 or 6-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc2 and then are optionally substituted on a ring carbon with 1 to 3 Rb2; L1 is selected from -S(=O)2-, -*S(=O)2-NRc3-, -*S(=O)2-NRc3-(C(Rd1)2)n-, -*S(=O)2- (C(Rd1)2)n-O-(C(Rd1)2)n-, and -*S(=O)2-NRc3-(C(Rd1)2)n-O-(C(Rd1)2)n-, wherein * denotes the point of attachment of L1 to Ring A; X1 is selected from a covalent bond, C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, 6- membered aryl, and 5 or 6-membered heteroaryl, wherein the C3-C6cycloalkyl and 6- membered aryl are each optionally substituted with 1 to 3 Rb3, and wherein the 3 to 6- membered heterocyclyl and 5 or 6-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc4 and then are optionally substituted on a ring carbon with 1 to 3 Rb3; L2 is selected from a covalent bond, -(C(Rd2)2)n-, -*NRc5-(C(Rd2)2)n-, -*(C(R2d)2)n-C(=O)-, - *(C(Rd2)2)n-O-(C(Rd2)2)n-, and -*(C(Re1)2C(Re1)2O)r-(C(Rd2)2)n-, wherein * denotes the point of attachment of L2 to X1; X2 is selected from a covalent bond, C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, 6- membered aryl, and 5 or 6-membered heteroaryl, wherein the C3-C6cycloalkyl and 6- membered aryl are each optionally substituted with 1 to 3 Rb4, and wherein the 3 to 6- membered heterocyclyl and 5 or 6-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc6 and then are optionally substituted on a ring carbon with 1 to 3 Rb4; or X1– L2– X2 form a 5 to 10-membered spiroheterocyclyl, wherein the 5 to 10-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc7 and then are optionally substituted on a ring carbon with 1 to 3 Rb5; L3 is selected from -O-, -(C(Rd3)2)n-, -*NRc8-(C(Rd3)2)n-, -*C(=O)-(C(Rd3)2)n-, and - *(C(Re2)2C(Re2)2O)r-(C(Rd3)2)n-, wherein * denotes the point of attachment of L3 to X2; X3 is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, 6-membered aryl, and 5 or 6-membered heteroaryl, wherein the C3-C6cycloalkyl and 6-membered aryl are each optionally substituted with 1 to 3 Rb6, and wherein the 3 to 6-membered heterocyclyl and 5 or 6-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc9 and then are optionally substituted on a ring carbon with 1 to 3 Rb6; or X2– L3– X3 form a 5 to 10-membered spiroheterocyclyl, wherein the 5 to 10-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc10 and then are optionally substituted on a ring carbon with 1 to 3 Rb7; or L4 is selected from a covalent bond, -O-, -C(=O)-, -(C(Rd4)2)n-, -NRc11-, -*NRc11-(C(Rd4)2)n-, -*O-(C(Rd4)2)n-, -*(C(Rd4)2)n-O-, -*C(=O)-(C(Rd4)2)n-, -*C2-C6alkenylene-(O)s-, -*C2- C6 alkynylene-(O)s-, -*O-(C(Rd4)2)n-C(=O)-, -*O-(C(Rd4)2)n-C(=O)-NRc11-, -* NRc11- (C(Rd4)2)n-C(=O)-NRc11-, wherein * denotes the point of attachment of L4 to Ring B; wherein at least one of X1 and X2 is not a covalent bond; Y2 is C(Re3)2 or C(=O); Each Ra1 and Ra2 is independently selected from H, D, OH, and C1-C4alkyl; Each Rb2, Rb3, Rb4, Rb5, Rb6, Rb7, and Rb8 is independently selected from D, halo, OH, CN, C1-C4alkyl, and C1-C4alkoxy, or two Rb2 Rb3, Rb4, Rb5, Rb6, or Rb7 attached to the same atom, form a =O, wherein the C1-C4alkyl and C1-C4alkoxy each optionally substituted with 1 to 3 groups each independently selected from D, halo, OH and CN; Each Rc2, Rc3, Rc4, Rc5, Rc6, Rc7, Rc8, Rc9, Rc10, and Rc11 is independently selected from H, D, and C1-C4alkyl; Each Rd1, Rd2, Rd3, and Rd4 is independently selected from H, D, and C1-C4alkyl; Each Re1, Re2, and Re3 is independently H or D; n is an integer from 0 to 4; p is 0 or 1; q is 0, 1, or 2; r is an integer from 1 to 6; s is 1; and t is an integer from 0 to 3.
9. The compound of claim 2, wherein the compound is of Formula (VI):
Figure imgf000388_0001
or a pharmaceutically acceptable salt thereof.
10. The compound of claim 2, wherein the compound is of Formula (VII):
Figure imgf000388_0002
or a pharmaceutically acceptable salt thereof, wherein t is an integer from 0 to 4.
11. The compound of claim 10, wherein the compound is of Formula (VIIa) or (VIIb):
Figure imgf000388_0003
or a pharmaceutically acceptable salt thereof.
12. The compound of claim 2, wherein the compound is of Formula (VIII):
Figure imgf000389_0001
or a pharmaceutically acceptable salt thereof, wherein t is an integer from 0 to 3.
13. The compound of claim 12, wherein the compound is of Formula (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), or (VIIIf):
Figure imgf000389_0002
Figure imgf000390_0001
or a pharmaceutically acceptable salt thereof.
14. The compound of claim 2, wherein the compound is of Formula (IX):
Figure imgf000390_0002
or a pharmaceutically acceptable salt thereof.
15. The compound of any one of claims 10 to 14, wherein R1 is selected from C1-C6alkyl, C3-C6cycloalkyl, and 3 to 6-membered heterocyclyl, wherein the C1-C6alkyl is optionally substituted with 1 or 2 Ra1, and wherein the 3 to 6- membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc1; R2 is selected from H, D, C1-C4alkyl, and C3-C6cyclcoalkyl, wherein the C1-C6alkyl is optionally substituted with 1 or 2 Ra2; R3 is selected from H, D, C1-C4alkyl, and C3-C6cyclcoalkyl; R4 is selected from H, D, halo, OH, CN, C1-C4alkyl, C1-C4alkoxy, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 3 groups each independently selected from D, halo, OH and CN; R5 is selected from H, D, halo, OH, CN, C1-C4alkyl, C1-C4alkoxy, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 3 groups each independently selected from D, halo, OH and CN; R6 is H or D; R7 is selected from H, D, C1-C4alkyl, and C(=O)-C1-4alkyl; Ring A is selected from C3-C8cycloalkyl, 3 to 10-membered heterocyclyl, 5 to 10-membered spiroheterocyclyl, 6 to 10-membered aryl, and 5 to 10-membered heteroaryl, wherein the C3-C8cycloalkyl and 6 to 10-membered aryl are each optionally substituted with 1 to 3 Rb2, and wherein the 3 to 10-membered heterocyclyl, 5 to 10-membered spiroheterocyclyl, and 5 to 10-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc2 and then are optionally substituted on a ring carbon with 1 to 3 Rb2; L1 is selected from -S(=O)2-, -*S(=O)2-NRc3-, -*S(=O)2-NRc3-(C(Rd1)2)n-, -*S(=O)2- (C(Rd1)2)n-O-(C(Rd1)2)n-, and -*S(=O)2-NRc3-(C(Rd1)2)n-O-(C(Rd1)2)n-, wherein * denotes the point of attachment of L1 to Ring A; X1 is selected from a covalent bond, C3-C8cycloalkyl, 3 to 10-membered heterocyclyl, 6 to 10-membered aryl, and 5 to 10-membered heteroaryl, wherein the C3-C8cycloalkyl and 6 to 10-membered aryl are each optionally substituted with 1 to 3 Rb3, and wherein the 3 to 10-membered heterocyclyl and 5 to 10-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc4 and then are optionally substituted on a ring carbon with 1 to 3 Rb3; L2 is selected from a covalent bond, -(C(Rd2)2)n-, -*NRc5-(C(Rd2)2)n-, -*(C(Rd2)2)n-C(=O)-, - *(C(Rd2)2)n-O-(C(Rd2)2)n-, and -*(C(Re1)2C(Re1)2O)r-(C(Rd2)2)n-, wherein * denotes the point of attachment of L2 to X1; X2 is selected from a covalent bond, C3-C8cycloalkyl, 3 to 10-membered heterocyclyl, 6 to 10-membered aryl, and 5 to 10-membered heteroaryl, wherein the C3-C8cycloalkyl and 6 to 10-membered aryl are each optionally substituted with 1 to 3 Rb4, and wherein the 3 to 10-membered heterocyclyl and 5 to 10-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc6 and then are optionally substituted on a ring carbon with 1 to 3 Rb4; or X1– L2– X2 form a 5 to 10-membered spiroheterocyclyl, wherein the 5 to 10-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc7 and then are optionally substituted on a ring carbon with 1 to 3 Rb5; L4 is selected from a covalent bond, -O-, -C(=O)-, -(C(Rd4)2)n-, -NRc11-, -*NRc11-(C(Rd4)2)n-, -*O-(C(Rd4)2)n-, -*(C(Rd4)2)n-O-, -*C(=O)-(C(Rd4)2)n-, -*C2-C6alkenylene-(O)s-, -*C2- C6 alkynylene-(O)s-, -*O-(C(Rd4)2)n-C(=O)-, -*O-(C(Rd4)2)n-C(=O)-NRc11-, -* NRc11- (C(Rd4)2)n-C(=O)-NRc11-, wherein * denotes the point of attachment of L4 to Ring B; wherein at least one of X1 and X2 is not a covalent bond; Y2 is C(Re3)2 or C(=O); Each Ra1 and Ra2 is independently selected from D, halo, OH, C3-C6cycloalkyl, and 3 to 6- membered heterocyclyl, wherein the 3 to 6-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc13; Each Rb2, Rb3, Rb4, Rb5, and Rb8 is independently selected from D, halo, OH, CN, N(Rc14)2, C1-C4alkyl, and C1-C4alkoxy, or two Rb2 Rb3, Rb4, or Rb5 attached to the same atom, form a =O, wherein the C1-C4alkyl and C1-C4alkoxy each optionally substituted with 1 to 3 groups each independently selected from D, halo, OH and CN; Each Rc1, Rc2, Rc3, Rc4, Rc5, Rc6, Rc7, Rc11, Rc13, and Rc14 is independently selected from H, D, C1-C4alkyl, and C(=O)C1-4alkyl; Each Rd1, Rd2, and Rd4 is independently selected from H, D, halo, OH, C1-C4alkyl, and C3- C6cycloalkyl; Each Re1 and Re3 is independently selected from H, D, and C1-C4 alkyl; n is an integer from 0 to 4; r is an integer from 1 to 6; s is 0 or 1; and t is an integer from 0 to 3.
16. The compound of any one of claims 10 to 14, wherein R1 is C1-C6alkyl, wherein the C1-C6alkyl is optionally substituted with 1 or 2 Ra1; R2 is selected from H, D, and C1-C4alkyl, wherein the C1-C6alkyl is optionally substituted with 1 or 2 Ra2; R3 is selected from H, D, and C1-C4alkyl; R4 is selected from H, D, halo, OH, CN, and C1-C4alkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 3 groups each independently selected from D, halo, OH, and CN; R5 is selected from H, D, halo, OH, CN, and C1-C4alkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 3 groups each independently selected from D, halo, OH, and CN; R6 is H or D; R7 is selected from H, D, and C1-C4alkyl; Ring A is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, 6-membered aryl, and 5 or 6-membered heteroaryl, wherein the C3-C6cycloalkyl and 6-membered aryl are each optionally substituted with 1 to 3 Rb2, wherein the 3 to 6-membered heterocyclyl and 5 or or 6-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc2 and then are optionally substituted on a ring carbon with 1 to 3 Rb2; L1 is selected from -S(=O)2-, -*S(=O)2-NRc3-, -*S(=O)2-NRc3-(C(Rd1)2)n-,-*S(=O)2- (C(Rd1)2)n-O-(C(Rd1)2)n-, and -*S(=O)2-NRc3-(C(Rd1)2)n-O-(C(Rd1)2)n-, wherein * denotes the point of attachment of L1 to Ring A; X1 is selected from a covalent bond, C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, 6- membered aryl, and 5 or 6-membered heteroaryl, wherein the C3-C6cycloalkyl and 6- membered aryl are each optionally substituted with 1 to 3 Rb3, and wherein the 3 to 6- membered heterocyclyl and 5 or 6-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc4 and then are optionally substituted on a ring carbon with 1 to 3 Rb3; L2 is selected from a covalent bond, -(C(Rd2)2)n-, -*NRc5-(C(Rd2)2)n-, -*(C(Rd2)2)n-C(=O)-, - *(C(Rd2)2)n-O-(C(Rd2)2)n-, and -*(C(Re1)2C(Re1)2O)r-(C(Rd2)2)n-, wherein * denotes the point of attachment of L2 to X1; X2 is selected from a covalent bond, C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, 6- membered aryl, and 5 or 6-membered heteroaryl, wherein the C3-C6cycloalkyl and 6- membered aryl are each optionally substituted with 1 to 3 Rb4, and wherein the 3 to 6- membered heterocyclyl and 5 or 6-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc6 and then are optionally substituted on a ring carbon with 1 to 3 Rb4; or X1– L2– X2 form a 5 to 10-membered spiroheterocyclyl, wherein the 5 to 10-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc7 and then are optionally substituted on a ring carbon with 1 to 3 Rb5; L4 is selected from a covalent bond, -O-, -C(=O)-, -(C(Rd4)2)n-, -NRc11-, -*NRc11-(C(Rd4)2)n-, -*O-(C(Rd4)2)n-, -*(C(Rd4)2)n-O-, -*C(=O)-(C(Rd4)2)n-, -*C2-C6alkenylene-(O)s-, -*C2- C6 alkynylene-(O)s-, -*O-(C(Rd4)2)n-C(=O)-, -*O-(C(Rd4)2)n-C(=O)-NRc11-, -*NRc11- (C(Rd4)2)n-C(=O)-NRc11-, wherein * denotes the point of attachment of L4 to Ring B; wherein at least one of X1 and X2 is not a covalent bond; Y2 is C(Re3)2 or C(=O); Each Ra1 and Ra2 is independently selected from H, D, and C1-C4alkyl; Each Rb2, Rb3, Rb4, Rb5, and Rb8 is independently selected from D, halo, OH, CN, C1-C4alkyl, and C1-C4alkoxy, or two Rb2, Rb3, Rb4, or Rb5 attached to the same atom, form a =O, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 3 groups each independently selected from D, halo, OH and CN; Each Rc2, Rc3, Rc4, Rc5, Rc6, Rc7, Rc11, Rc13, and Rc14 is independently selected from H, D, and C1-C4alkyl; Each Rd1, Rd2, Rd3, and Rd4 is independently selected from H, D, and C1-C4alkyl; Each Re1 and Re3 is independently H or D; n is an integer from 0 to 4; r is an integer from 1 to 6; s is 1; and t is an integer from 0 to 3.
17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R1 is C1-C6alkyl optionally substituted with 1 or 2 Ra1.
18. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R1 is C1-C6alkyl optionally substituted with OH.
19. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R1 is CH3 or CH2C(CH3)2OH.
20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein R2 is H or C1-C4alkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 3 Ra2.
21. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein R2 is H.
22. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein R3 is H.
23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein R4 is selected from H, D, halo, OH, CN, C1-C4alkyl, and C1-C4alkoxy, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 4 groups each independently selected from D, halo, OH and CN.
24. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein R4 is C1-C4alkyl, CN, or halo, wherein said C1-C4alkyl is optionally substituted with 1 to 3 groups each independently selected from halo.
25. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein R4 is CH3, CHF2, CF3, CN, or Cl.
26. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein R4 is CF3.
27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein R5 is selected from H, D, halo, OH, CN, C1-C4alkyl, and C1-C4alkoxy, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 4 groups each independently selected from D, halo, OH and CN.
28. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein R5 is selected from H, D, halo, OH, and CN.
29. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein R5 is H.
30. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, wherein R6 is H.
31. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt thereof, wherein R7 is selected from H, D, and C1-C4alkyl.
32. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt thereof, wherein R7 is H or C1-C4alkyl.
33. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt thereof, wherein R7 is methyl.
34. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt thereof, wherein R7 is H.
35. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, C5- C12spirocycloalkyl, 5 to 12-membered spiroheterocyclyl, phenyl, and 5 or 6-membered heteroaryl, wherein the C3-C6cycloalkyl, C5-C12spirocycloalkyl, and phenyl are each optionally substituted with 1 to 4 Rb2, and wherein the 3 to 6-membered heterocyclyl, 5 to 12- membered spiroheterocyclyl, and 5 or 6-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc2 and then are optionally substituted on a ring carbon with 1 to 4 Rb2.
36. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from C3-C6cycloalkyl optionally substituted with 1 to 4 Rb2.
37. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein Ring A is cyclohexyl optionally substituted with 1 to 4 Rb2.
38. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein Ring A is cyclohexyl.
39. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl optionally substituted with 1 to 4 Rb2.
40. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl.
41. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from 3 to 6-membered heterocyclyl optionally substituted with 1 to 4 Rb2.
42. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein Ring A is piperidinyl optionally substituted with 1 to 4 Rb2.
43. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein Ring A is piperidinyl.
44. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from 5 to 12-membered spiroheterocyclyl optionally substituted with 1 to 4 Rb2.
45. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein Ring A is 6 to 11-membered spiroheterocyclyl optionally substituted with 1 to 4 Rb2.
46. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein Ring A is 2-azaspiro[3.3]heptanyl optionally substituted with 1 to 4 Rb2.
47. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein Ring A is 2-azaspiro[3.3]heptanyl.
48. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from 5 or 6-membered heteroaryl optionally substituted with 1 to 4 Rb2.
49. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein Ring A is pyridinyl optionally substituted with 1 to 4 Rb2.
50. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein Ring A is pyridinyl.
51. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein Ring A is cyclohexyl, phenyl, piperidinyl, 2-azaspiro[3.3]heptanyl, or pyridinyl, each of which is optionally substituted with 1 to 4 Rb2.
52. The compound of any one of claims 1-51, or a pharmaceutically acceptable salt thereof, wherein Rb2 is selected from C1-C4alkyl and halo.
53. The compound of any one of claims 1-51, or a pharmaceutically acceptable salt thereof, wherein Rb2 is C1-C4alkyl.
54. The compound of any one of claims 1-51, or a pharmaceutically acceptable salt thereof, wherein Rb2 is selected from F and methyl.
55. The compound of any one of claims 1-54, or a pharmaceutically acceptable salt thereof, wherein L1 is selected from -S(=O)2-, -*S(=O)2-NRc3-, -*S(=O)2-(C(Rd1)2)n-O- (C(Rd1)2)n-, and -*S(=O)2-NRc3-(C(Rd1)2)n-O-(C(Rd1)2)n-.
56. The compound of any one of claims 1-54, or a pharmaceutically acceptable salt thereof, wherein L1 is selected from -S(=O)2- and -*S(=O)2-NRc3-.
57. The compound of any one of claims 1-54, or a pharmaceutically acceptable salt thereof, wherein L1 is selected from -S(=O)2- and -*S(=O)2-NH-.
58. The compound of any one of claims 1-54, or a pharmaceutically acceptable salt thereof, wherein L1 is -S(=O)2-.
59. The compound of any one of claims 1-54, or a pharmaceutically acceptable salt thereof, wherein L1 is -*S(=O)2-NRc3-.
60. The compound of any one of claims 1-54, or a pharmaceutically acceptable salt thereof, wherein L1 is -*S(=O)2-(C(Rd1)2)n-O-(C(Rd1)2)n-.
61. The compound of any one of claims 1-54, or a pharmaceutically acceptable salt thereof, wherein L1 is -*S(=O)2-(CH2)3-O-CH2-.
62. The compound of any one of claims 1-54, or a pharmaceutically acceptable salt thereof, wherein L1 is -*S(=O)2-NRc3-(C(Rd1)2)n-O-(C(Rd1)2)n-.
63. The compound of any one of claims 1-54, or a pharmaceutically acceptable salt thereof, wherein L1 is -*S(=O)2-NH-(CH2)2-O-CH2-.
64. The compound of any one of claims 1-63, or a pharmaceutically acceptable salt thereof, wherein X1 is a covalent bond.
65. The compound of any one of claims 1-63, or a pharmaceutically acceptable salt thereof, wherein X1 is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, 6- membered aryl, and 5 or 6-membered heteroaryl, wherein the C3-C6cycloalkyl and 6- membered aryl are each optionally substituted with 1 to 3 Rb3, and wherein the 3 to 6- membered heterocyclyl and 5 or 6-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc4 and then are optionally substituted on a ring carbon with 1 to 3 Rb3.
66. The compound of any one of claims 1-63, or a pharmaceutically acceptable salt thereof, wherein X1 is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, and 5 or 6-membered heteroaryl, wherein the C3-C6cycloalkyl is optionally substituted with 1 to 3 Rb3, wherein the 3 to 6-membered heterocyclyl and 5 or 6-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc4 and then are optionally substituted on a ring carbon with 1 to 3 Rb3.
67. The compound of any one of claims 1-63, or a pharmaceutically acceptable salt thereof, wherein X1 is selected from C3-C6cycloalkyl optionally substituted with 1 to 3 Rb3.
68. The compound of any one of claims 1-63, or a pharmaceutically acceptable salt thereof, wherein X1 is cyclobutyl or cyclohexyl.
69. The compound of any one of claims 1-63, or a pharmaceutically acceptable salt thereof, wherein X1 is selected from 3 to 6-membered heterocyclyl optionally substituted with 1 to 3 Rb3.
70. The compound of any one of claims 1-63, or a pharmaceutically acceptable salt thereof, wherein X1 is pyrrolidinyl, piperidinyl, or piperazinyl.
71. The compound of any one of claims 1-63, or a pharmaceutically acceptable salt thereof, wherein X1 is selected from 5 or 6-membered heteroaryl optionally substituted with 1 to 3 Rb3.
72. The compound of any one of claims 1-63, or a pharmaceutically acceptable salt thereof, wherein X1 is 1,2,3-triazolyl.
73. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt thereof, wherein L2 is selected from -*(C(Re1)2C(Re1)2O)r-(C(Rd2)2)n-, -(C(Rd2)2)n-, - *(C(Rd2)2)n-C(=O)-, -*NRc5-(C(Rd2)2)n-, and -*(C(Rd2)2)n-O-(C(Rd2)2)n-.
74. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt thereof, wherein L2 is selected from -*(CH2CH2O)r-(CH2)n-, -(CH2)n-, -*(CH2)n-C(=O)-, - *NRc5-(CH2)n-, and -*(CH2)n-O-(CH2)n-.
75. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt thereof, wherein L2 is -*(C(Re1)2C(Re1)2O)r-(C(Rd2)2)n-.
76. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt thereof, wherein L2 is -*(CH2CH2O)r-(CH2)n-.
77. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt thereof, wherein L2 is -(C(Rd2)2)n-.
78. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt thereof, wherein L2 is -(CH2)n-.
79. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt thereof, wherein L2 is -*(C(Rd2)2)n-O-(C(Rd2)2)n-.
80. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt thereof, wherein L2 is -*(CH2)n-O-(CH2)n-.
81. The compound of any one of claims 1-80, or a pharmaceutically acceptable salt thereof, wherein X2 is a covalent bond.
82. The compound of any one of claims 1-80, or a pharmaceutically acceptable salt thereof, wherein X2 is selected from C3-C10cycloalkyl, 3 to 12-membered heterocyclyl, 6 to 12-membered aryl, and 5 to 12-membered heteroaryl, wherein the C3-C10cycloalkyl and 6 to 12-membered aryl are each optionally substituted with 1 to 4 Rb4, and wherein the 3 to 12- membered heterocyclyl and 5 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc6 and then are optionally substituted on a ring carbon with 1 to 4 Rb4.
83. The compound of any one of claims 1-80, or a pharmaceutically acceptable salt thereof, wherein X2 is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, and 5 to 6-membered heteroaryl, wherein the C3-C6cycloalkyl is optionally substituted with 1 to 4 Rb4, and wherein the 3 to 6-membered heterocyclyl and 5 to 6-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc6 and then are optionally substituted on a ring carbon with 1 to 4 Rb4.
84. The compound of any one of claims 1-80, or a pharmaceutically acceptable salt thereof, wherein X2 is selected from C3-C6cycloalkyl optionally substituted with 1 to 3 Rb4.
85. The compound of any one of claims 1-80, or a pharmaceutically acceptable salt thereof, wherein X2 is cyclohexyl.
86. The compound of any one of claims 1-80, or a pharmaceutically acceptable salt thereof, wherein X2 is selected from 3 to 6-membered heterocyclyl optionally substituted with 1 to 3 Rb4.
87. The compound of any one of claims 1-80, or a pharmaceutically acceptable salt thereof, wherein X2 is azetidinyl, piperidinyl, or piperazinyl.
88. The compound of any one of claims 1-80, or a pharmaceutically acceptable salt thereof, wherein X2 is selected from 5 or 6-membered heteroaryl optionally substituted with 1 to 3 Rb4.
89. The compound of any one of claims 1-80, or a pharmaceutically acceptable salt thereof, wherein X2 is 1,2,3-triazolyl.
90. The compound of any one of claims 1-89, or a pharmaceutically acceptable salt thereof, wherein L3 is selected from -O-, -*C(=O)-(C(Rd3)2)n-, -(C(Rd3)2)n-, and - *(C(Re2)2C(Re2)2O)r-(C(Rd3)2)n-.
91. The compound of any one of claims 1-89, or a pharmaceutically acceptable salt thereof, wherein L3 is -O-.
92. The compound of any one of claims 1-89, or a pharmaceutically acceptable salt thereof, wherein L3 is -*C(=O)-(C(Rd3)2)n-.
93. The compound of any one of claims 1-89, or a pharmaceutically acceptable salt thereof, wherein L3 is -*C(=O)-(CH2)n-.
94. The compound of any one of claims 1-89, or a pharmaceutically acceptable salt thereof, wherein L3 is -(C(Rd3)2)n-.
95. The compound of any one of claims 1-89, or a pharmaceutically acceptable salt thereof, wherein L3 is -(CH2)n-.
96. The compound of any one of claims 1-89, or a pharmaceutically acceptable salt thereof, wherein L3 is -*(C(Re2)2C(Re2)2O)r-(C(Rd3)2)n-.
97. The compound of any one of claims 1-89, or a pharmaceutically acceptable salt thereof, wherein L3 is -*(CH2CH2O)r-(CH2)n-.
98. The compound of any one of claims 1-97, or a pharmaceutically acceptable salt thereof, wherein X3 is selected from 3 to 6-membered heterocyclyl having 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc9 and then is optionally substituted on a ring carbon with 1 to 3 Rb6.
99. The compound of any one of claims 1-97, or a pharmaceutically acceptable salt thereof, wherein X3 is selected from piperazinyl and piperidinyl, each optionally substituted on a ring carbon with 1 to 3 Rb6.
100. The compound of any one of claims 1-97, or a pharmaceutically acceptable salt thereof, wherein X3 is selected from piperazinyl and piperidinyl.
101. The compound of any one of claims 1-80, or a pharmaceutically acceptable salt thereof, wherein X2– L3– X3 form a C5-C12spirocycloalkyl or 5 to 12-membered spiroheterocyclyl, wherein the C5-C12spirocycloalkyl is optionally substituted with 1 to 4 Rb7, and wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc10 and then are optionally substituted on a ring carbon with 1 to 4 Rb7.
102. The compound of any one of claims 1-80, or a pharmaceutically acceptable salt thereof, wherein X2– L3– X3 form a 5 to 12-membered spiroheterocyclyl, wherein the 5 to 12- membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc10 and then are optionally substituted on a ring carbon with 1 to 4 Rb7.
103. The compound of any one of claims 1-80, or a pharmaceutically acceptable salt thereof, wherein X2– L3– X3 form a 10 to 11-membered spiroheterocyclyl, wherein the 10 to 11-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from N and NRc10.
104. The compound of any one of claims 1-97, or a pharmaceutically acceptable salt thereof, wherein two X3 form a C5-C12spirocycloalkyl or 5 to 12-membered spiroheterocyclyl, wherein the C5-C12spirocycloalkyl is optionally substituted with 1 to 4 Rb7, and wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc10 and then are optionally substituted on a ring carbon with 1 to 4 Rb7.
105. The compound of any one of claims 1-97, or a pharmaceutically acceptable salt thereof, wherein two X3 form a 5 to 12-membered spiroheterocyclyl, wherein the 5 to 12- membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc10 and then are optionally substituted on a ring carbon with 1 to 4 Rb7.
106. The compound of any one of claims 1-97, or a pharmaceutically acceptable salt thereof, wherein two X3 form 3,9-diazaspiro[5.5]undecane optionally substituted on a ring carbon with 1 to 4 Rb7.
107. The compound of any one of claims 1-106, or a pharmaceutically acceptable salt thereof, wherein L4 is a covalent bond.
108. The compound of any one of claims 1-106, or a pharmaceutically acceptable salt thereof, wherein L4 is selected from -O-, -C(=O)-, -(C(Rd4)2)n-, -NRc11-, -*NRc11-(C(Rd4)2)n-, -*(C(Rd4)2)n-NRc11-, -*O-(C(Rd4)2)n-, -*(C(Rd4)2)n-O-, -*C(=O)-(C(Rd4)2)n-, -*(C(Rd4)2)n- C(=O)-, -*C2-C6alkenylene-(O)s-, -*C2-C6alkynylene-(O)s-, -*O-(C(Rd4)2)n-C(=O)-, -*O- (C(Rd4)2)n-C(=O)-NRc11-, -*O-(C(Rd4)2)n-NRc11-C(=O)-, -*NRc11-(C(Rd4)2)n-C(=O)-NRc11-, - *NRc11-(C(Rd4)2)n-C(=O)-, and -*NRc11-(C(Rd4)2)n-NRc11-C(=O)-.
109. The compound of any one of claims 1-106, or a pharmaceutically acceptable salt thereof, wherein L4 is selected from -O-, -NRc11-, -*NRc11-(C(Rd4)2)n-C(=O)-NRc11-, -*C2- C6alkynylene-(O)s-, -*NRc11-(C(Rd4)2)n-, -*O-(C(Rd4)2)n-C(=O)-, -*NRc11-(C(Rd4)2)n-C(=O)-, and -*O-(C(Rd4)2)n-C(=O)-NRc11-.
110. The compound of any one of claims 1-106, or a pharmaceutically acceptable salt thereof, wherein L4 is selected from -O-, -NH-, -*NH-(CH2)n-C(=O)-NH-, -*C2- C6alkynylene-(O)s-, -*NH-(CH2)n-, -*O-(CH2)n-C(=O)-, -*NH-(CH2)n-C(=O)-, and -*O- (CH2)n-C(=O)-NH-.
111. The compound of any one of claims 1-106, or a pharmaceutically acceptable salt thereof, wherein L4 is selected from -O- and -NRc11-.
112. The compound of any one of claims 1-106, or a pharmaceutically acceptable salt thereof, wherein L4 is -*NRc11-(C(Rd4)2)n-C(=O)-NRc11-.
113. The compound of any one of claims 1-106, or a pharmaceutically acceptable salt thereof, wherein L4 is -*O-(C(Rd4)2)n-C(=O)-NRc11-.
114. The compound of any one of claims 1-106, or a pharmaceutically acceptable salt thereof, wherein L4 is -*C2-C6alkynylene-O-.
115. The compound of any one of claims 1-106, or a pharmaceutically acceptable salt thereof, wherein L4 is -*C2-C6alkynylene-.
116. The compound of any one of claims 1-115, or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl optionally substituted with 1 to 4 Rb2 and L1 is -*S(=O)2- NRc3-.
117. The compound of any one of claims 1-115, or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl optionally substituted with 1 to 4 Rb2, L1 is -*S(=O)2-NRc3- , and X1 is C3-C8cycloalkyl.
118. The compound of any one of claims 1-115, or a pharmaceutically acceptable salt thereof, wherein Ring A is piperidinyl optionally substituted with 1 to 4 Rb2 and L1 is - S(=O)2-.
119. The compound of any one of claims 1-115, or a pharmaceutically acceptable salt thereof, wherein Ring A is piperidinyl optionally substituted with 1 to 4 Rb2, L1 is -S(=O)2-, and X1 is 3 to 10-membered heterocyclyl.
120. The compound of any one of claims 1-119, or a pharmaceutically acceptable salt thereof, wherein Ring
Figure imgf000406_0001
.
121. The compound of any one of claims 1-119, or a pharmaceutically acceptable salt thereof, wherein Ring
Figure imgf000406_0002
122. The compound of any one of claims 1-121, or a pharmaceutically acceptable salt thereof, wherein Rb8 is halo or C1-C4alkyl.
123. The compound of any one of claims 1-121, or a pharmaceutically acceptable salt thereof, wherein Rb8 is F or methyl.
124. The compound of any one of claims 1-121, or a pharmaceutically acceptable salt thereof, wherein Rb8 is methyl.
125. The compound of any one of claims 1-124, or a pharmaceutically acceptable salt thereof, wherein W is CH.
126. The compound of any one of claims 1-124, or a pharmaceutically acceptable salt thereof, wherein W is N.
127. The compound of any one of claims 1-126, or a pharmaceutically acceptable salt thereof, wherein Y1 is C(Rd5)2.
128. The compound of any one of claims 1-126, or a pharmaceutically acceptable salt thereof, wherein Y1 is CH2.
129. The compound of any one of claims 1-126, or a pharmaceutically acceptable salt thereof, wherein Y1 is NRc12.
130. The compound of any one of claims 1-126, or a pharmaceutically acceptable salt thereof, wherein Y1 is NH.
131. The compound of any one of claims 1-130, or a pharmaceutically acceptable salt thereof, wherein Y2 is C(Re3)2.
132. The compound of any one of claims 1-130, or a pharmaceutically acceptable salt thereof, wherein Y2 is CH2.
133. The compound of any one of claims 1-130, or a pharmaceutically acceptable salt thereof, wherein Y2 is C(=O).
134. The compound of any one of claims 1-133, or a pharmaceutically acceptable salt thereof, wherein m is 0.
135. The compound of any one of claims 1-133, or a pharmaceutically acceptable salt thereof, wherein m is 1 or 2.
136. The compound of any one of claims 1-135, or a pharmaceutically acceptable salt thereof, wherein n is 0.
137. The compound of any one of claims 1-135, or a pharmaceutically acceptable salt thereof, wherein n is an integer from 1 to 8.
138. The compound of any one of claims 1-135, or a pharmaceutically acceptable salt thereof, wherein n is an integer from 1 to 4.
139. The compound of any one of claims 1-135, or a pharmaceutically acceptable salt thereof, wherein n is an integer from 1 to 2.
140. The compound of any one of claims 1-139, or a pharmaceutically acceptable salt thereof, wherein p is 0.
141. The compound of any one of claims 1-139, or a pharmaceutically acceptable salt thereof, wherein p is 1.
142. The compound of any one of claims 1-141, or a pharmaceutically acceptable salt thereof, wherein q is 0.
143. The compound of any one of claims 1-141, or a pharmaceutically acceptable salt thereof, wherein q is 1 or 2.
144. The compound of any one of claims 1-143, or a pharmaceutically acceptable salt thereof, wherein r is an integer from 1 to 3.
145. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt thereof, wherein s is 0.
146. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt thereof, wherein s is 1.
147. The compound of any one of claims 1-146, or a pharmaceutically acceptable salt thereof, wherein t is 0.
148. The compound of any one of claims 1-146, or a pharmaceutically acceptable salt thereof, wherein t is an integer from 1 to 3.
149. The compound of claim 1, wherein the compound is selected from the following:
Figure imgf000409_0001
Figure imgf000410_0001
Figure imgf000411_0001
Figure imgf000412_0001
Figure imgf000413_0001
Figure imgf000414_0001
Figure imgf000415_0001
Figure imgf000416_0001
Figure imgf000417_0001
Figure imgf000418_0001
Figure imgf000419_0001
Figure imgf000420_0001
Figure imgf000421_0001
Figure imgf000422_0001
Figure imgf000423_0001
HO N N N F N F F
Figure imgf000424_0001
Figure imgf000425_0001
Figure imgf000426_0001
Figure imgf000427_0001
Figure imgf000428_0001
Figure imgf000429_0001
Figure imgf000430_0001
Figure imgf000431_0001
Figure imgf000432_0001
Figure imgf000433_0001
Figure imgf000434_0001
, or a pharmaceutically acceptable salt of any of the aforementioned.
150. A pharmaceutical composition comprising a compound of any one of claims 1-149, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
151. A method of degrading CDK2, comprising contacting CDK2 with a compound of any one of claims 1-149, or a pharmaceutically acceptable salt thereof.
152. A method of treating cancer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1-149, or a pharmaceutically acceptable salt thereof.
153. The method of claim 152, wherein the cancer is selected from anal cancer, breast cancer, colorectal cancer, endometrial cancer, gastric cancer, liver cancer, lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, and uterine cancer.
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Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015197028A1 (en) 2014-06-28 2015-12-30 Sunshine Lake Pharma Co., Ltd. Compounds as hepatitis c virus (hcv) inhibitors and uses thereof in medicine
WO2020023782A1 (en) * 2018-07-27 2020-01-30 Biotheryx, Inc. Bifunctional compounds as cdk modulators
US20200129627A1 (en) 2016-12-23 2020-04-30 Arvinas Operations, Inc. Compounds and methods for the targeted degradation of rapidly accelerated fibrosarcoma polypeptides
WO2020201080A1 (en) 2019-03-29 2020-10-08 Astrazeneca Ab Estrogen receptor degrading protacs
WO2021155050A1 (en) * 2020-01-29 2021-08-05 Biotheryx, Inc. Kinase modulators, pharmaceutical compositions, and therapeutic applications
WO2022155593A1 (en) * 2021-01-15 2022-07-21 H. Lee Moffitt Cancer Center And Research Institute, Inc. Inhibitors and degraders of janus kinase 2
WO2022253309A1 (en) 2021-06-03 2022-12-08 首药控股(北京)股份有限公司 Substituted heterocyclic compounds and application thereof
WO2022266190A1 (en) 2021-06-16 2022-12-22 Blueprint Medicines Corporation Substituted pyrimidinyl-pyrazoles as cdk2 inhibitors
WO2023025091A1 (en) 2021-08-24 2023-03-02 Biofront Ltd (Cayman) Hpk1 degraders, compositions thereof, and methods of using the same
CN115873001A (en) * 2022-11-24 2023-03-31 上海市皮肤病医院 A novel use of a JAK degrader based on proteolytic targeting chimera technology (PROTAC)
WO2023143482A1 (en) * 2022-01-29 2023-08-03 上海辉启生物医药科技有限公司 2-aminopyrimidine compound or salt, preparation method therefor and use thereof
WO2023249970A1 (en) * 2022-06-21 2023-12-28 Nikang Therapeutics, Inc. Bifunctional compounds containing pyrimidine derivatives for degrading cyclin-dependent kinase 2 via ubiquitin proteasome pathway

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015197028A1 (en) 2014-06-28 2015-12-30 Sunshine Lake Pharma Co., Ltd. Compounds as hepatitis c virus (hcv) inhibitors and uses thereof in medicine
US20200129627A1 (en) 2016-12-23 2020-04-30 Arvinas Operations, Inc. Compounds and methods for the targeted degradation of rapidly accelerated fibrosarcoma polypeptides
WO2020023782A1 (en) * 2018-07-27 2020-01-30 Biotheryx, Inc. Bifunctional compounds as cdk modulators
WO2020201080A1 (en) 2019-03-29 2020-10-08 Astrazeneca Ab Estrogen receptor degrading protacs
WO2021155050A1 (en) * 2020-01-29 2021-08-05 Biotheryx, Inc. Kinase modulators, pharmaceutical compositions, and therapeutic applications
WO2022155593A1 (en) * 2021-01-15 2022-07-21 H. Lee Moffitt Cancer Center And Research Institute, Inc. Inhibitors and degraders of janus kinase 2
WO2022253309A1 (en) 2021-06-03 2022-12-08 首药控股(北京)股份有限公司 Substituted heterocyclic compounds and application thereof
WO2022266190A1 (en) 2021-06-16 2022-12-22 Blueprint Medicines Corporation Substituted pyrimidinyl-pyrazoles as cdk2 inhibitors
WO2023025091A1 (en) 2021-08-24 2023-03-02 Biofront Ltd (Cayman) Hpk1 degraders, compositions thereof, and methods of using the same
WO2023143482A1 (en) * 2022-01-29 2023-08-03 上海辉启生物医药科技有限公司 2-aminopyrimidine compound or salt, preparation method therefor and use thereof
WO2023249970A1 (en) * 2022-06-21 2023-12-28 Nikang Therapeutics, Inc. Bifunctional compounds containing pyrimidine derivatives for degrading cyclin-dependent kinase 2 via ubiquitin proteasome pathway
CN115873001A (en) * 2022-11-24 2023-03-31 上海市皮肤病医院 A novel use of a JAK degrader based on proteolytic targeting chimera technology (PROTAC)

Non-Patent Citations (30)

* Cited by examiner, † Cited by third party
Title
"Physician's Desk Reference", 2003
ACS MEDICINAL CHEMISTRY LETTERS, vol. 3, no. 2, 2012, pages 129 - 134
AN S ET AL., EBIOMEDICINE, vol. 36, 2018, pages 553 - 562
BÉKÉS, M. ET AL., NAT. REV. DRUG DISCOV., vol. 21, no. 3, 2022, pages 181 - 200
BIOORG. CHEM., vol. 105, 2020, pages 104453
B�K�S MIKL�S ET AL: "PROTAC targeted protein degraders: the past is prologue", NATURE REVIEWS DRUG DISCOVERY, NATURE PUBLISHING GROUP, GB, vol. 21, no. 3, 18 January 2022 (2022-01-18), pages 181 - 200, XP037710236, ISSN: 1474-1776, [retrieved on 20220118], DOI: 10.1038/S41573-021-00371-6 *
BONDESON, D. P. ET AL., NAT CHEM BIOL., vol. 11, no. 8, 2015, pages 611 - 617
CHEM. COMM., vol. 53, 2017, pages 7577 - 7580
CHEM. MED. CHEM., vol. 4, 2009, pages 749 - 755
DING, L. ET AL., INT. J. MOL. SCI., vol. 21, no. 6, 2020, pages 1960
FREEMAN-COOK, K. ET AL., CANCER CELL, vol. 39, no. 6, 2021, pages 1404 - 1421
GOEL, S. ET AL., NAT. REV. CANCER
LAI, A. CCREWS, C.M., NAT. REV. DRUG DISCOV., vol. 16, no. 2, 2017, pages 101 - 114
Mack Publishing Co.; "GenBank", Database accession no. NM_001238
NAKAYAMA, K. ET AL., INT. J. ONCOL., vol. 48, no. 2, 2016, pages 506 - 516
OHTSUBO ET AL., MOL. CELL. BIOL., vol. 15, 1995, pages 2612 - 2624
OOI, A. ET AL., HUM. PATHOL., vol. 61, 2016, pages 58 - 67
ORG. LETT., vol. 21, 2019, pages 3838 - 3841
ORG. LETT., vol. 6, 2004, pages 3715 - 3718
PAIVA S-L. ET AL., CURR. OP. IN CHEM. BIO., vol. 50, 2010, pages 111 - 119
RSC ADV., vol. 10, 2020, pages 21464 - 21472
RSC MED CHEM, vol. 12, 2021, pages 1381 - 1390
S. M. BERGE ET AL., J. PHARM. SCI., vol. 66, 1977, pages 1 - 19
SHERR, C.J. ET AL., CANCER DISCOV, vol. 6, no. 4, 2016, pages 353 - 367
T.W. GREENEP.G.M. WUTS: "Protective Groups in Organic Synthesis", 1999, WILEY & SONS, INC.
TENG, M. ET AL., ANGEW. CHEM. IN. ED., vol. 59, no. 33, 2020, pages 13865 - 13870
WANG LIGUO ET AL: "Discovery of a first-in-class CDK2 selective degrader for AML differentiation therapy", NATURE CHEMICAL BIOLOGY, NATURE PUBLISHING GROUP US, NEW YORK, vol. 17, no. 5, 4 March 2021 (2021-03-04), pages 567 - 575, XP037433854, ISSN: 1552-4450, [retrieved on 20210304], DOI: 10.1038/S41589-021-00742-5 *
WANG, B. ET AL., FRONT. ONCOL., vol. 11, 2021, pages 405
WANG, L. ET AL., NAT. CHEM. BIOL., vol. 17, no. 5, 2021, pages 567 - 575
YUAN, K. ET AL., ACTA PHARM. SIN. B, vol. 11, no. 1, 2000, pages 30 - 54

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