EP4702014A1 - Bifunctional compounds for degrading braf via ubiquitin proteosome pathway - Google Patents

Bifunctional compounds for degrading braf via ubiquitin proteosome pathway

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Publication number
EP4702014A1
EP4702014A1 EP24730823.2A EP24730823A EP4702014A1 EP 4702014 A1 EP4702014 A1 EP 4702014A1 EP 24730823 A EP24730823 A EP 24730823A EP 4702014 A1 EP4702014 A1 EP 4702014A1
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Prior art keywords
fluorophenyl
piperidin
sulfonamide
pyridin
dioxopiperidin
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EP24730823.2A
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German (de)
French (fr)
Inventor
Ge Peng
Jeffrey Wu
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Nurix Therapeutics Inc
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Nurix Therapeutics Inc
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Publication of EP4702014A1 publication Critical patent/EP4702014A1/en
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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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

This disclosure relates to compounds of formula (I) useful for ex vivo, in vitro, or in vivo degradation of BRAF via a ubiquitin proteolytic pathway. This disclosure also provides pharmaceutically acceptable compositions comprising said compounds, and methods of using the compositions in the treatment of various diseases, conditions, and/or disorders. (I)

Description

WHAT IS CLAIMED IS: 1. A compound of Formula (I) (I) wherein R1 is alkyl, aryl, amino, alkylamino, dialkylamino, cycloalkyl, or heterocycloalkyl, each unsubstituted or substituted with one or more halogen or hydroxyl; R1a is halogen; R1b is hydrogen, haloalkyl, or halogen; R2 is hydrogen, alkyl, cycloalkyl, haloalkyl, or -[Ar1-Z1]n-Z2-Cy1-Z3-L-UBM; X1 is carbon or nitrogen; X2 is carbon or nitrogen; X3 is sulfur, nitrogen, oxygen, or carbon; the bonds among X1, X2, and X3 comprise single and double bonds, and the ring containing X1, X2, and X3 is aromatic; X4 is carbon or nitrogen; X5 is hydrogen or -NR3R4; R3 is hydrogen or alkyl where alkyl is unsubstituted or substituted with hydroxyl; R4 is hydrogen, alkyl, cycloa -Cy1-Z3-L-UBM wherein Ar1 is arylene or het bstituted or substituted with one or more alkyl or one or more h Z1 is a bond or -CH2- n is zero or one; Z2 is absent, -C(O)-, - -, - 0 y , 1-10 alkylene-C(Me)(Me)-, three- to six-membered cycloalkylene, three- to six-membered cycloalkylene-C1-10 alkylene, heterocycloalkylene, or -C(Me)(Me)-; Cy1 is absent or heterocycloalkylene, unsubstituted or substituted with one or more alkyl or one or more halogen; Z3 is absent, C1-10 alkylene, or -C(O)-; L is a linker according to –L1-L2-L3-L4– or –L4-L3-L2-L1–, wherein –L1– is absent, -N(R10)-, -C(R11)2-, -C(O)-, -C1-8 alkylene-, -C2-8 alkynylene-, -C6-10 aryl-, -C4-10 heteroaryl-, -Q1-, or -Q2-; each –L2–, –L3–, and –L4– is independently, absent, -N(R10)-, -C(R11)2-, -C(O)-, -O-, -(CH2CH2-O)1-8-, -C1-8 alkylene-, -C2-8 alkynylene-, -C6-10 aryl-, -C4-10 heteroaryl-, -Q1-, -Q2-, or -Q3-; each R10 is independently, hydrogen or methyl; each R11 is, independently, hydrogen, methyl, aryl, or heteroaryl; each -Q1- is a three- to seven-membered heterocycloalkylene comprising at least one nitrogen and is unsubstituted or substituted with one or more methyl, hydroxyl, or halogen; each -Q2- is a five- to thirteen-membered bicyclic heterocycloalkylene comprising at least one nitrogen, wherein the five- to thirteen-membered bicyclic heterocycloalkylene is optionally a spiro bicyclic heterocycloalkylene ring; each -Q3- is a three- to six-membered cycloalkylene; UBM is a ubiquitin ligase binding moiety; wherein at least one of R2 or R4 is -[Ar1-Z1]n-Z2-Cy1-Z3-L-UBM; or a stereoisomer and/or pharmaceutical salt thereof. 2. The compound of claim 1, having the following Formula (I) (I) wherein R1 is alkyl, aryl, amino, alkylamino, dialkylamino, cycloalkyl, or heterocycloalkyl, each unsubstituted or substituted with one or more halogen or hydroxyl; R1a is halogen; R1b is hydrogen or halogen; R2 is hydrogen, alkyl, cycloalkyl, haloalkyl, or -[Ar1-Z1]n-Z2-Cy1-Z3-L-UBM; X1 is carbon or nitrogen; X2 is carbon or nitrogen; X3 is sulfur, nitrogen, oxygen, or carbon; the bonds among X1, X2, and X3 comprise single and double bonds, and the ring containing X1, X2, and X3 is aromatic; X4 is carbon or nitrogen; X5 is hydrogen or -NR3R4; R3 is hydrogen or alkyl where alkyl is unsubstituted or substituted with hydroxyl; R4 is hydrogen, alkyl, cycloalkyl, or -[Ar1-Z1]n-Z2-Cy1-Z3-L-UBM wherein Ar1 is arylene or heteroarylene, each unsubstituted or substituted with one or more alkyl or one or more halogen; Z1 is a bond or -CH2-; n is zero or one; Z2 is absent, -C(O)-, -O- C1 10 alk lene C1 10 alkylene-C(Me)(Me)-, three- to six-membered cycloalkylene, t d cycloalkylene-C1-10 alkylene, heterocycloalkylene, or -C(Me)( Cy1 is absent or heterocy uted or substituted with alkyl; Z3 is absent, C1-10 alkyle L is a linker according to 4-L3-L2-L1–, wherein –L1– is absent , -N( )-, -C( )2-, -C(O)-, -C1-8 alkylene-, -C2-8 alkynylene-, -C6-10 aryl-, -C4-10 heteroaryl-, -Q1-, or -Q2-; each –L2–, –L3–, and –L4– is independently, absent, -N(R10)-, -C(R11)2-, -C(O)-, -O-, -(CH2CH2-O)1-8-, -C1-8 alkylene-, -C2-8 alkynylene-, -C6-10 aryl-, -C4-10 heteroaryl-, -Q1-, -Q2-, or -Q3-; each R10 is independently, hydrogen or methyl; each R11 is, independently, hydrogen, methyl, aryl, or heteroaryl; each -Q1- is a three- to seven-membered heterocycloalkylene comprising at least one nitrogen and is unsubstituted or substituted with methyl, hydroxyl, or halogen; each -Q2- is a five- to thirteen-membered bicyclic heterocycloalkylene comprising at least one nitrogen, wherein the five- to thirteen-membered bicyclic heterocycloalkylene is optionally a spiro bicyclic heterocycloalkylene ring; each -Q3- is a three- to six-membered cycloalkylene; UBM is a ubiquitin ligase binding moiety; wherein at least one of R2 or R4 is -[Ar1-Z1]n-Z2-Cy1-Z3-L-UBM; or a stereoisomer and/or pharmaceutical salt thereof. 3. The compound of claim 2, wherein X1 is nitrogen; X2 is carbon, X3 is sulfur; and X4 is carbon or nitrogen. 4. The compound of claim 3, wherein R1 is alkyl; R1a is fluoro; R2 is -[Ar1-Z1]n-Z2-Cy1-Z3-L-UBM; n is zero; Z2 is absent; and Cy1 is an unsubstituted heterocycloalkylene. 5. The compound of claim 4, wherein Z3 is -C(O)-. 6. The compound of claim 5, wherein L1 is Q1. 7. The compound of claim 6, wherein L2 is -C(O)-. 8. The compound of claim 7, wherein L3 is Q1; and L4 is absent. 9. The compound of any one of claims 4-8, wherein R1 is -CH2CH2CH3. 10. The compound of claim 2, wherein X1 is carbon or nitrogen; X2 is nitrogen, and X3 is carbon or nitrogen. 11. The compound of claim 10, wherein X1 is carbon; X2 is nitrogen, and X3 is nitrogen. 12. The compound of claim 11, wherein R1 is alkyl; R1a is fluoro; R2 is -[Ar1-Z1]n-Z2-Cy1-Z3-L-UBM; Ar1 is ; Z1 is a bond; n is one; Z2 and Z3 are absent; and Cy1 is an unsubstituted heterocycloalkylene. 13. The compound of claim 12, wherein X4 is carbon and X5 is hydrogen. 14. The compound of claim 13, wherein L1 is -C(R11)2-. 15. The compound of claim 14, wherein is R11 hydrogen. 16. The compound of claim 15, wherein L2 is Q1; and L3 and L4 are absent. 17. The compound of any one of claims 11-16, wherein R1 is -CH2CH2CH3. 18. The compound of claim 2, wherein X1 is nitrogen; X2 is carbon, X3 is sulfur; and X4 is nitrogen. 19. The compound of claim 18, wherein R1 is alkyl; R1a is fluoro; R2 is alkyl; n is zero; Z2 is absent; and Cy1 is an unsubstituted heterocy 20. The compound of claim 19, wh - or -C(O)-. 21. The compound of claim 20, wherein L1 is Q1, -C(R11)2-, or -CH2CH2CH2CH2CH2-, or Q3. 22. The compound of claim 21, wherein L2 is absent, Q1, Q2, -C(R11)2-, -C(O)-, or -O-. 23. The compound of claim 22, wherein L3 is absent, Q1, or -CH2CH2CH2-; and L4 is absent. 24. The compound of any one of claims 19-23, wherein R1 is -CH2CH2CH3. 25. The compound of claim 2, wherein UBM binds an E3 ubiquitin ligase. 26. The compound of claim 2, wherein UBM binds SCFβ-TRCP, VHL, MDM2, IAP, or CRBN. 27. The compound of claim 2, wherein UBM binds VHL. 28. The compound of claim 27, wherein UBM binds VHL and has the following chemical formula wherein designates attachment to L; Z4 is a bond, -CH2-, -C(O)-, -C(O)N(R12)-, or -N(R12)-, wherein R12 is hydrogen or methyl; X6 is C-H or nitrogen; R8 is alkyl, alkenyl, alkylene, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, - S(O)(R13), or -S(O)2(R13); wherein R13 is hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, aryl, heterocycle, or heteroaryl, wherein each alkyl, alkenyl, alkylene, alkynyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl is unsubstituted or substituted; R9 is hydrogen, unsubstituted or substituted C1-8 alkyl, or -AA1-AA2-R14 wherein each AA1 and AA2 is an amino acid residue, and R14 is hydrogen or methyl. 29. The compound of claim 27, wherein UBM binds VHL and has the following chemical formula wherein designates attachment to L; Z5 is a bond, -CH2-, -C(O)-, -C(O)N(R12)-, -N(R12)-, or -O-, wherein R12 is hydrogen or methyl; A is phenyl or C4-heteroaryl; X7 is -CH2, -NR12, oxygen, or sulfur, wherein R12 is hydrogen or methyl; p is zero or one; R15 is unsubstituted or substituted C1-8 alkyl, -AA1-AA2-R14, wherein each AA1 and AA2 is an amino acid residue, and R14 is hydrogen or methyl. 30. The compound of claim 27, wherein UBM binds VHL and has the following chemical formula wherein designates attachment to L; Z6 is a bond, -CH2-, -C(O)-, -C(O)N(R12)-, or N(R12), wherein R12 is hydrogen or methyl; W is , , or wherein, designates attachment to X8, wherein designates attachment to X9, and wherein, designates attachment to Z6; X8 is carbon or nitrogen; X9 is C–H or -CH2-; R16 is hydrogen, –OH, halogen, –NH2, -C1-3 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C1-3 alkoxy, -C1-3 thioalkyl, -C1-3 alkylamine, -C6-10 aryl, cycloalkyl, heterocycloalkyl, or heteroaryl; R17 is -C(O)N(H)-C6-10 aralkyl, -C(O)CH(t-butyl)-N(H)-C3-6 cycloalkyl, -C(O)-CH(t-butyl)-N(H)C(O)-C3-C6 cycloalkyl, , , , , or -AA1-AA2-R14, wherein each AA1 and AA2 is an amino acid residue and R14 is hydrogen or methyl; and R18 is halogen or . 31. The compound of claim 2, wherein UBM binds CRBN. 32. The compound of claim 31, wherein UBM binds CRBN and has the following chemical formula or wherein X6 absent or NR3; X7 absent or -C(O)-; and X8 is arylene or heteroarylene. 33. The compound of claim 32, wherein UBM binds CRBN and is selected from the group consisting of , , , , , , , , , , , , , and wherein X9 is absent or halogen; and m is one, two, three, or four. 34. A compound of Formula (II) (II) wherein R1 is alkyl, aryl, amino, alkylamino, dialkylamino, cycloalkyl, or heterocycloalkyl, each unsubstituted or substituted with one or more halogen or hydroxyl; R1a is halogen; R1b is hydrogen or halogen; R2 is -[Ar1-Z1]n-Z2-Cy1-Z3-L-UBM wherein Ar1 is arylene or heteroarylene, each unsubstituted or substituted with one or more alkyl or one or more halogen; Z1 is a bond or -CH2-; n is zero or one; Z2 is absent, -C(O)-, -O-, C1-10 alkylene, C1-10 alkylene-C(Me)(Me)-, three- to six-membered cycloalkylene, three- to six-membered cycloalkylene-C1-10 alkylene, heterocycloalkylene, or -C(Me)(Me)-; Cy1 is absent or heterocycloalkylene, unsubstituted or substituted with alkyl; Z3 is absent, C1-10 alkylene, or -C(O)-; L is a linker according to –L1-L2-L3-L4– or –L4-L3-L2-L1–, wherein –L1– is absent, -N(R10)-, -C(R11)2-, -C(O)-, -C1-8 alkylene-, -C2-8 alkynylene-, -C6-10 aryl-, -C4-10 heteroaryl-, -Q1-, or -Q2-; each –L2–, –L3–, and –L4– is independently, absent, -N(R10)-, -C(R11)2-, -C(O)-, -O-, -(CH2CH2-O)1-8-, -C1-8 alkylene-, -C2-8 alkynylene-, -C6-10 aryl-, -C4-10 heteroaryl-, -Q1-, -Q2-, or -Q3-; each R10 is independently, hydrogen or methyl; each R11 is, independently, hydrogen, methyl, aryl, or heteroaryl; each -Q1- is a three- to seven-membered heterocycloalkylene comprising at least one nitrogen and is unsubstituted or substituted with methyl, hydroxyl, or halogen; each -Q2- is a five- to thirteen-membered bicyclic heterocycloalkylene comprising at least one nitrogen, wherein the five- to thirteen-membered bicyclic heterocycloalkylene is optionally a spiro bicyclic heterocycloalkylene ring; each -Q3- is a three- to six-membered cycloalkylene; UBM is a ubiquitin ligase binding moiety; X1 is nitrogen or oxygen; X3 is sulfur when X1 is nitrogen; oxygen when X1 is nitrogen; or nitrogen when X1 is oxygen; the bonds among X1 and X3 comprise single and double bonds, and the ring containing X1 and X3 is aromatic; X4 is carbon or nitrogen; X5 is hydrogen or -NR3R4; R3 is hydrogen or alkyl where alkyl is unsubstituted or substituted with hydroxyl; R4 is hydrogen, alkyl, or cycloalkyl; or a stereoisomer and/or pharmaceutical salt thereof. 35. The compound of claim 34, wherein X1 is nitrogen; X3 is oxygen; and X4 is carbon or nitrogen. 36. The compound of claim 34, wherein X1 is oxygen; X3 is nitrogen; and X4 is carbon or nitrogen. 37. The compound of claim 34, wherein X1 is nitrogen; X3 is sulfur; and X4 is carbon or nitrogen. 38. The compound of claim 37, wherein R1 is alkyl; R1a is fluoro; R2 is -[Ar1-Z1]n-Z2-Cy1-Z3-L-UBM; n is zero; Z2 is absent; and Cy1 is an unsubstituted heterocycloalkylene. 39. The compound of claim 38, wherein Z3 is -C(O)-. 40. The compound of claim 39, wherein L1 is Q1. 41. The compound of claim 40, wherein L2 is -C(O)-. 42. The compound of claim 41, wherein L3 is Q1 and L4 is absent. 43. The compound of any one of claims 38-42, wherein R1 is -CH2CH2CH3. 44. The compound of claim 34, wherein UBM binds an E3 ubiquitin ligase. 45. The compound of claim 34, wherein UBM binds SCFβ-TRCP, VHL, MDM2, IAP, or CRBN. 46. The compound of claim 45, wherein UBM binds VHL. 47. The compound of claim 46, wherein UBM binds VHL and has the following chemical formula wherein designates attachment to L; Z4 is a bond, -CH2-, -C(O)-, -C(O)N(R12)-, or -N(R12)-, wherein R12 is hydrogen or methyl; X6 is C-H or nitrogen; R8 is alkyl, alkenyl, alkylene, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, - S(O)(R13), or -S(O)2(R13); wherein R13 is hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, aryl, heterocycle, or heteroaryl, wherein each alkyl, alkenyl, alkylene, alkynyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl is unsubstituted or substituted; R9 is hydrogen, unsubstituted or substituted C1-8 alkyl, or -AA1-AA2-R14 wherein each AA1 and AA2 is an amino acid residue, and R14 is hydrogen or methyl. 48. The compound of claim 46, wherein UBM binds VHL and has the following chemical formula wherein designates attachment to L; Z5 is a bond, -CH2-, -C(O)-, -C(O)N(R12)-, -N(R12)-, or -O-, wherein R12 is hydrogen or methyl; A is phenyl or C4-heteroaryl; X7 is -CH2, -NR12, oxygen, or sulfur, wherein R12 is hydrogen or methyl; p is zero or one; R15 is unsubstituted or substituted C1-8 alkyl, -AA1-AA2-R14, wherein each AA1 and AA2 is an amino acid residue, and R14 is hydrogen or methyl. 49. The compound of claim 46, wherein UBM binds VHL and has the following chemical formula wherein designates attachment to L; Z6 is a bond, -CH2-, -C(O)-, -C(O)N(R12)-, or N(R12), wherein R12 is hydrogen or methyl; W is , , or wherein, designates attachment to X8, wherein designates attachment to X9, and wherein, designates attachment to Z6; X8 is carbon or nitrogen; X9 is C–H or -CH2-; R16 is hydrogen, –OH, halogen, –NH2, -C1-3 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C1-3 alkoxy, -C1-3 thioalkyl, -C1-3 alkylamine, -C6-10 aryl, cycloalkyl, heterocycloalkyl, or heteroaryl; R17 is -C(O)N(H)-C6-10 aralkyl, -C(O)CH(t-butyl)-N(H)-C3-6 cycloalkyl, -C(O)-CH(t-butyl)-N(H)C(O)-C3-C6 cycloalkyl, , , , , or -AA1-AA2-R14, wherein each AA1 and AA2 is an amino acid residue and R14 is hydrogen or methyl; and R18 is halogen or . 50. The compound of claim 34, wherein UBM binds CRBN. 51. The compound of claim 50, wherein UBM binds CRBN and has the following chemical formula or wherein X6 is absent or NR3; X7 is absent or -C(O)-; and X8 is arylene or heteroarylene. 52. The compound of claim 51, wherein UBM binds CRBN and is selected from the group consisting of , , , , , , , , , , , , , and wherein X9 is absent or halogen; and m is one, two, three, or four. 53. The compound of claim 2 Formula (I) or claim 34 Formula (II), wherein L comprises at least one -Q1-; at least one -Q2-; at least one -Q3-; at least one -C(R11)2-; or at least one C1-8 alkylene-. 54. The compound of claim 53, wherein L is selected from the group consisting of a. -Q1-; b. -Q1-C(O)-Q1-; c. -C(R11)2-Q1-; d. -Q1-C(R11)2-Q1-; e. -C(R11)2-O-; f. -Q3-O-; g. -C(R11)2-Q1-Q1-; h. -Q1-Q1-; i. -C(R11)2-Q2-; j. -C1-8 alkylene-; k. -C(R11)2-Q1-C1-8 alkylene-; l. -Q3-C(R11)2-; m. -C(R11)2-; n. -Q2-; o. -Q1-C(O)-C(R11)2-; p. -Q1-C(O)-Q3-O-; q. -Q1-C(O)-C(R11)2-Q1-; r. -Q1-C(R11)2-Q3-O-; and s. -Q1-C(R11)2-. 55. The compound of claim 54, wherein -Q1- is or wherein R19 is hydrogen, hydroxyl, halogen, or unsubstituted alkyl, n1 is one or two, n2 is one or two, and n3 is one or two. 56. The compound of claim 55, wherein -Q1- is selected from the group consisting of , , , and , wherein R19 is hydrogen, hydroxyl, fluoro, or methyl. 57. The compound of claim 54, wherein -Q2- is , wherein n4 is one or two, n5 is one or two, and n6 is one or two.
58. The compound of claim 57, wherein -Q2- is selected from the group consisting of and . 59. The compound of claim 54, wherein -Q3- is , wherein n7 is one or two, and n8 is one or two. 60. The compound of claim 59, wherein -Q3- is selected from the group consisting of , , , and . 61. The compound of claim 54, wherein each R11 is, independently, hydrogen or methyl. 62. The compound of claim 61, wherein both R11 are hydrogen; one R11 is hydrogen and one R11 is methyl; or both R11 are methyl. 63. The compound of claim 54, wherein -C1-8 alkylene- is selected from the group consisting of -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, - CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2-, and -CH2CH2CH2CH2CH2CH2CH2CH2-. 64. The compound of claim 54, wherein the linker L is selected from , , , , , , , , , , , , , , , , , , , , , , , , , ,
, , , , , , , , , , , and , wherein indicates attachment to Z3, and indicates attachment to UBM. 65. The compound of any one of claims 2-9, 31-33, or 53-64 selected from the group consisting of (S)-N-(3-(5-(2-aminopyrimidin-4-yl)-2-(1-(1-(1-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(5-(2-aminopyrimidin-4-yl)-2-(1-(1-(1-(5- (2,6-dioxopiperidin-3-yl)pyridin-2-yl)-4-methylpiperidine-4-carbonyl)piperidine-4- carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(5-(2- aminopyrimidin-4-yl)-2-(1-(1-(1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4- carbonyl)-4-methylpiperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide, (R)-N-(3-(5-(2-aminopyrimidin-4-yl)-2-(1-(1-(1-(4- (2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)-4-methylpiperidine-4- carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(2-(1- (1-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)piperidine-4- carbonyl)piperidin-4-yl)-5-(pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1- sulfonamide, (S)-N-(3-(2-(1-(1-(1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4- carbonyl)-4-methylpiperidine-4-carbonyl)piperidin-4-yl)-5-(pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide, and (S)-N-(3-(2-(1-(1-(1-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidine-4-carbonyl)-4-methylpiperidine-4-carbonyl)piperidin-4-yl)-5- (pyridin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide. 66. The compound of any one of claims 2, 31-33, or 53-64 selected from the group consisting of (R)-N-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-(2-(4-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)propyl)piperazin-1-yl)acetyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)- 2-fluorophenyl)propane-1-sulfonamide, N-(3-(5-(2-aminopyrimidin-4-yl)-2-(1-((1S,4r)-4-((6- ((S)-2,6-dioxopiperidin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)cyclohexane-1- carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(2-(1- (1-((1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperidine-4- carbonyl)piperidin-4-yl)-5-(pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1- sulfonamide, (R)-N-(3-(5-(2-aminopyrimidin-4-yl)-2-(1-(2-(4-(2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-5-yl)piperazin-1-yl)acetyl)-4-methylpiperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide, (R)-N-(3-(5-(2-aminopyrimidin-4-yl)-2-(1-(2-(1'-(2- (2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-[1,4'-bipiperidin]-4-yl)acetyl)-4- methylpiperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(5-(2- aminopyrimidin-4-yl)-2-(1-(1-((1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)methyl)piperidine-4-carbonyl)-4-methylpiperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(5-(2-aminopyrimidin-4-yl)-2-(1-((1-(2-(6- (2,6-dioxopiperidin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)acetyl)piperidin-4- yl)methyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(5-(2- aminopyrimidin-4-yl)-2-(3-((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)-3- azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(2- (1-(1-((1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperidine-4- carbonyl)piperidin-4-yl)-5-(pyridin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1- sulfonamide, (R)-N-(3-(5-(2-aminopyrimidin-4-yl)-2-(1-(2-(1'-(2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-5-yl)-[1,4'-bipiperidin]-4-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide, (R)-N-(3-(5-(2-aminopyrimidin-4-yl)-2-(1-(2-(4-(2- (2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)acetyl)piperidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (R)-N-(3-(5-(2-aminopyrimidin-4- yl)-2-(2-(1-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4- yl)azetidine-3-carbonyl)piperidin-4-yl)propan-2-yl)thiazol-4-yl)-2-fluorophenyl)propane-1- sulfonamide, N-(3-(5-(2-aminopyrimidin-4-yl)-2-(1-((1-((1R,4r)-4-(3-((R)-2,6- dioxopiperidin-3-yl)phenoxy)cyclohexane-1-carbonyl)piperidin-4-yl)methyl)piperidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (R)-N-(3-(5-(2-aminopyrimidin-4- yl)-2-(3-((1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)-3- azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(5- (2-aminopyrimidin-4-yl)-2-(1-(1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)- 4-hydroxypiperidin-4-yl)acetyl)azetidin-3-yl)piperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(1-(2-(1-(5- (2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)acetyl)piperidin-4-yl)phenyl)thiazol-4- yl)-2-fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(4-((1- (4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)thiazol-4- yl)-2-fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(1-(2- (1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)acetyl)piperidin-4- yl)phenyl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(5-(2- aminopyrimidin-4-yl)-2-(4-(1-(1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4- carbonyl)piperidin-4-yl)phenyl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (S)-N- (3-(5-(2-aminopyrimidin-4-yl)-2-(4-(1-((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)methyl)piperidin-4-yl)phenyl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, N-(3- (5-(2-aminopyrimidin-4-yl)-2-(3-(((1S,4r)-4-((5-((S)-2,6-dioxopiperidin-3-yl)pyridin-2- yl)oxy)cyclohexyl)methyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide, (R)-N-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(4-(1-(4- (2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)piperazin-1-yl)phenyl)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide, (R)-5-(4-(9-(5-(2-aminopyrimidin-4-yl)-4-(2-fluoro-3- (propylsulfonamido)phenyl)thiazol-2-yl)-3-azaspiro[5.5]undecane-3-carbonyl)piperidin-1- yl)-N-(2,6-dioxopiperidin-3-yl)picolinamide, N-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-(2-((S)-1- (5-((S)-2,6-dioxopiperidin-3-yl)pyridin-2-yl)pyrrolidin-3-yl)ethyl)-3-azaspiro[5.5]undecan-9- yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(5-(2-aminopyrimidin-4-yl)- 2-(1-(1-(2-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)acetyl)azetidin-3- yl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(5-(2- aminopyrimidin-4-yl)-2-(3-(1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4- carbonyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(1-((1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2- yl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)thiazol-4-yl)-2-fluorophenyl)propane-1- sulfonamide, (S)-N-(3-(2-(1-(1-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4- carbonyl)piperidine-4-carbonyl)piperidin-4-yl)-5-(pyridin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(2-(1-(1-((1-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidin-4-yl)methyl)piperidine-4-carbonyl)piperidin-4-yl)-5-(2- (methylamino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (R)-N-(3- (5-(2-aminopyrimidin-4-yl)-2-(2-(2-(1'-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)-[1,4'-bipiperidin]-4-yl)acetyl)-2-azaspiro[3.5]nonan-7-yl)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(2-(1-(1-(1-(5-(2,6-dioxopiperidin-3- yl) i i 2 l i i i 4 l i i i 4 l i i i 4 l i in-4- yl) -4-yl)-2- (1-((1-(((1S,4r)-4-(4-((S)-2,6-dioxopiperidin-3-yl)phenoxy)cyclohexyl)methyl)piperidin-4- yl)meth l i idi 4 l thi l 4 l 2 fl h nyl)propane-1-sulfonamide, (R)-N-(3-(5- (2-am ridin-3-yl)-1,3-dioxoisoindolin-5- yl)piperidine-4-carbonyl)-2-azaspiro[3.5]nonan-7-yl)thiazol-4-yl)-2-fluorophenyl)propane-1- sulfonamide, (S)-N-(3-(2-(1-(1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4- yl)acetyl)piperidine-4-carbonyl)piperidin-4-yl)-5-(pyrimidin-4-yl)thiazol-4-yl)-2- fluoropheny pane-1-sulfonamide, (S)-N-(3-(5-(2-aminopyrimidin-4-yl)-2-(2-(1-(1-(1-(5- (2,6-dioxopi din-3-yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidin- 4-yl)ethyl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (R)-N-(3-(5-(2- aminopyrimidin-4-yl)-2-(2-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)piperazin-1-yl)acetyl)-2-azaspiro[3.5]nonan-7-yl)thiazol-4-yl)-2-fluorophenyl)propane-1- sulfonamide, (R)-N-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(4-(1-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)phenyl)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(2-(1-(1-(1-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidin-4-yl)-5-(pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (R)-N-(3-(5-(2-aminopyrimidin-4- yl)-2-(1-(1-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)piperidine-4- carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamidef, (R)-N-(3-(5-(2- aminopyrimidin-4-yl)-2-(4-(4-((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)phenyl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (S)-N- (3-(5-(2-aminopyrimidin-4-yl)-2-(1-((1-(1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2- yl)piperidine-4-carbonyl)piperidin-4-yl)methyl)piperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide, (R)-N-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(4-(2-(1-(5- (2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)acetyl)piperazin-1-yl)phenyl)thiazol-4- yl)-2-fluorophenyl)propane-1-sulfonamide, (R)-N-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-(2-(1'- (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-[1,4'-bipiperidin]-4-yl)acetyl)-3- azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(5- (2-aminopyrimidin-4-yl)-2-(1-(1-((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)methyl)piperidine-4-carbonyl)-4-methylpiperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(2-(1-(1-(1-(4-(2,6-dioxopiperidin-3- yl)phenyl)piperidine-4-carbonyl)-4-methylpiperidine-4-carbonyl)piperidin-4-yl)-5-(2- (isopropylamino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (R)-N- (3-(5-(2-aminopyrimidin-4-yl)-2-(3-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)piperazin-1-yl)acetyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1-sulfonamide, N-(3-(5-(2-aminopyrimidin-4-yl)-2-(1-((1-((1R,4r)-4-(4-((R)-2,6- dioxopiperidin-3-yl)phenoxy)cyclohexane-1-carbonyl)piperidin-4-yl)methyl)piperidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (R)-N-(3-(5-(2-aminopyrimidin-4- yl)-2-(2-(6-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)hexanoyl)-2- azaspiro[3.5]nonan-7-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, N-(3-(2-(1-(1- (1-(5-((S)-2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4- carbonyl)piperidin-4-yl)-5-(2-(((R)-1-hydroxypropan-2-yl)amino)pyrimidin-4-yl)thiazol-4- yl)-2-fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(4-((1- (5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)thiazol- 4-yl)-2-fluorophenyl)propane-1-sulfonamide, rac-(3R)-3-{6-[4-(4-{4-[5-(2-aminopyrimidin- 4-yl)-4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-1,3-thiazol-2-yl]piperidine-1- carbonyl}piperidine-1-carbonyl)piperidin-1-yl]pyridin-3-yl}piperidine-2,6-dione, rac-(3R)-3- {6-[4-(4-{4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-5-{2-[(propan-2- yl)amino]pyrimidin-4-yl}-1,3-thiazol-2-yl]piperidine-1-carbonyl}piperidine-1- carbonyl)piperidin-1-yl]pyridin-3-yl}piperidine-2,6-dione, (S)-N-(3-(5-(2-aminopyrimidin-4- yl)-2-(1-(1-((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperidine-4- carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(5-(2- aminopyrimidin-4-yl)-2-(1-(1-((1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)methyl)piperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1- sulfonamide, (R)-N-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-((1-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)piperidin-4-yl)methyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide, (R)-N-(3-(5-(2-aminopyrimidin-4-yl)-2-(1-(2-(2-(2- (2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)acetyl)-4- methylpiperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (R)-N-(3-(5-(2- aminopyrimidin-4-yl)-2-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)piperidine-4-carbonyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1-sulfonamide, (R)-N-(3-(2-(1-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)- 2,7-diazaspiro[3.5]nonan-7-yl)acetyl)piperidin-4-yl)-5-(2-(methylamino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (R)-N-(3-(5-(2-aminopyrimidin-4- yl)-2-(3-(6-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)hexanoyl)-3- azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (R)-N-(3-(5- (2-aminopyrimidin-4-yl)-2-(1-(1-(2-(1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)acetyl)-4-methylpiperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(2-(1-(1-(1-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidin-4-yl)-5-(2- (methylamino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (R)-N-(3- (5-(2-aminopyrimidin-4-yl)-2-(1-(1-(2-(1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin- 4-yl)acetyl)piperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1- sulfonamide, (S)-N-(3-(2-(1-(1-(1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4- carbonyl)piperidine-4-carbonyl)piperidin-4-yl)-5-(2-(isopropylamino)pyrimidin-4-yl)thiazol- 4-yl)-2-fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(5-(2-(cyclopropylamino)pyrimidin-4- yl)-2-(1-(1-(1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4- carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(2-(1- (1-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)-4-methylpiperidine-4- carbonyl)piperidin-4-yl)-5-(pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1- sulfonamide, N-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-(2-((R)-1-(4-((S)-2,6-dioxopiperidin-3- yl)phenyl)pyrrolidin-3-yl)acetyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide, (R)-N-(3-(5-(2-aminopyrimidin-4-yl)-2-(2-(2-(2-(2- (2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)acetyl)-2- azaspiro[3.5]nonan-7-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (R)-N-(3-(5-(2- aminopyrimidin-4-yl)-2-(1-((1-(2-(1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)acetyl)piperidin-4-yl)methyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1- sulfonamide, (R)-N-(3-(5-(2-aminopyrimidin-4-yl)-2-(1-(2-(2-(2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide, (R)-N-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-(1-(1-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidine-4- carbonyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (R)-N-(3-(2-(1-(1-((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperidine-4- carbonyl)piperidin-4-yl)-5-(2-(methylamino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide, (R)-N-(3-(5-(2-aminopyrimidin-4-yl)-2-(1-(1-(1-(2- (2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)azetidine-3- carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (R)-N-(3-(5-(2- aminopyrimidin-4-yl)-2-(2-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)piperidin-4-yl)azetidine-3-carbonyl)-2-azaspiro[3.5]nonan-7-yl)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(5-(2-aminopyrimidin-4-yl)-2-(1-(1-((1-(1- (2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin- 4-yl)methyl)piperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1- sulfonamide, (R)-N-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-(2-(2-(2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)acetyl)-3-azaspiro[5.5]undecan-9- yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (R)-N-(3-(5-(2-aminopyrimidin-4- yl)-2-(2-(1-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7- diazaspiro[3.5]nonan-7-yl)acetyl)piperidin-4-yl)propan-2-yl)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide, and (R)-4-((4-(5-(2-aminopyrimidin-4-yl)-4-(2-fluoro- 3-(propylsulfonamido)phenyl)thiazol-2-yl)piperidin-1-yl)methyl)-N-(2,6-dioxopiperidin-3- yl)benzamide. 67. The compound of any one of claims 2, 18-24, 31-33, or 53-64 selected from the group consisting of (R)-4-(4-((6-((4-(2-(tert-butyl)-4-(2-fluoro-3-(propylsulfonamido)phenyl)thiazol-5- yl)pyrimidin-2-yl)amino)-2-azaspiro[3.3]heptan-2-yl)methyl)piperidin-1-yl)-N-(2,6- dioxopiperidin-3-yl)benzamide, N-(3-(2-(tert-butyl)-5-(2-((2-(2-((S)-1-(5-((S)-2,6- dioxopiperidin-3-yl)pyridin-2-yl)pyrrolidin-3-yl)ethyl)-2-azaspiro[3.3]heptan-6- yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (R)-N-(3-(2- (tert-butyl)-5-(2-((2-(2-(1'-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-[1,4'- bipiperidin]-4-yl)acetyl)-2-azaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide, (R)-N-(3-(2-(tert-butyl)-5-(2-((2-(1-(1-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidine-4- carbonyl)-2-azaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide, (R)-N-(3-(2-(tert-butyl)-5-(2-((2-(1-(1-(2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)azetidine-3-carbonyl)-2- azaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1- sulfonamide, (R)-N-(3-(2-(tert-butyl)-5-(2-((2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)acetyl)-2-azaspiro[3.3]heptan-6- yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (R)-N-(3-(2- (tert-butyl)-5-(2-((2-(6-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)hexanoyl)-2- azaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1- sulfonamide, (R)-N-(3-(2-(tert-butyl)-5-(2-((2-((1-((1-(4-(2,6-dioxopiperidin-3- yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)-2-azaspiro[3.3]heptan-6- yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (R)-N-(3-(2- (tert-butyl)-5-(2-((2-(2-(4-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)propyl)piperazin-1-yl)acetyl)-2-azaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4- yl)-2-fluorophenyl)propane-1-sulfonamide, (R)-N-(3-(2-(tert-butyl)-5-(2-((2-(1-((1-(4-(2,6- dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)-4-fluoropiperidine-4-carbonyl)-2- azaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1- sulfonamide, (R)-N-(3-(2-(tert-butyl)-5-(2-((2-((1-(1-(4-(2,6-dioxopiperidin-3- yl)phenyl)piperidine-4-carbonyl)piperidin-4-yl)methyl)-2-azaspiro[3.3]heptan-6- yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(2- (tert-butyl)-5-(2-((1'-((1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)- [1,4'-bipiperidin]-4-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1- sulfonamide, (R)-N-(3-(2-(tert-butyl)-5-(2-((7-(2-(4-(4-((2,6-dioxopiperidin-3- yl)amino)phenyl)piperidin-1-yl)acetyl)-7-azaspiro[3.5]nonan-2-yl)amino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, N-(3-(2-(tert-butyl)-5-(2-((7- (((1S,4r)-4-(4-((S)-2,6-dioxopiperidin-3-yl)phenoxy)cyclohexyl)methyl)-7- azaspiro[3.5]nonan-2-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1- sulfonamide, (R)-N-(3-(2-(tert-butyl)-5-(2-((7-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2- dihydroisoquinolin-6-yl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)amino)pyrimidin- 4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (R)-N-(3-(2-(tert-butyl)-5-(2-((7- ((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2- yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, and (R)-N-(3- (2-(tert-butyl)-5-(2-((7-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin- 1-yl)acetyl)-7-azaspiro[3.5]nonan-2-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide. 68. The compound of any one of claims 2, 31-33, or 53-64 selected from the group consisting of (S)-N-(3-(2-(tert-butyl)-5-(2-((4-(1-((1-(5-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidin-4- yl)methyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1-sulfonamide, (R)-N-(3-(2-(tert-butyl)-5-(2-((4-(1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-5-yl)oxy)acetyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide, (R)-N-(3-(2-(tert-butyl)-5-(2-((4-(1-(2-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetyl)piperidin-4- yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (R)-N- (3-(2-(tert-butyl)-5-(2-((4-(1-(2-(4-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperazin-1- yl)acetyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1-sulfonamide, N-(3-(2-(tert-butyl)-5-(2-((4-(1-(2-((S)-1-(5-((S)-2,6-dioxopiperidin-3- yl)pyridin-2-yl)pyrrolidin-3-yl)ethyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4- yl)-2-fluorophenyl)propane-1-sulfonamide, (R)-4-(4-((4-(4-((4-(2-(tert-butyl)-4-(2-fluoro-3- (propylsulfonamido)phenyl)thiazol-5-yl)pyrimidin-2-yl)amino)phenyl)piperidin-1- yl)methyl)piperidin-1-yl)-N-(2,6-dioxopiperidin-3-yl)benzamide, (R)-5-(4-((4-(4-((4-(2-(tert- butyl)-4-(2-fluoro-3-(propylsulfonamido)phenyl)thiazol-5-yl)pyrimidin-2- yl)amino)phenyl)piperidin-1-yl)methyl)piperidin-1-yl)-N-(2,6-dioxopiperidin-3- yl)picolinamide, N-(3-(2-(tert-butyl)-5-(2-((4-(1-(((1S,4r)-4-((5-((S)-2,6-dioxopiperidin-3- yl)pyridin-2-yl)oxy)cyclohexyl)methyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol- 4-yl)-2-fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(2-(tert-butyl)-5-(2-((4-(1-((1-(4-(2,6- dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)amino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, N-(3-(2-(tert-butyl)-5-(2-((4-(1-(2- ((S)-1-(4-((S)-2,6-dioxopiperidin-3-yl)phenyl)pyrrolidin-3-yl)acetyl)piperidin-4- yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, N-(3- (2-(tert-butyl)-5-(2-((4-(1-(2-((R)-1-(4-((S)-2,6-dioxopiperidin-3-yl)phenyl)pyrrolidin-3- yl)acetyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1-sulfonamide, N-(3-(2-(tert-butyl)-5-(2-((4-(1-((R)-1-(5-((S)-2,6-dioxopiperidin-3- yl)pyridin-2-yl)pyrrolidine-3-carbonyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4- yl)-2-fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(2-(tert-butyl)-5-(2-((4-(1-(1-(4-(2,6- dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)piperidin-4- yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (R)-N- (3-(2-(tert-butyl)-5-(2-((4-(1-(2-(1'-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)- [1,4'-bipiperidin]-4-yl)acetyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(2-(tert-butyl)-5-(2-((4-(1-(1-(5-(2,6- dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)piperidin-4- yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, N-(3- (2-(tert-butyl)-5-(2-((4-(1-(2-((S)-1-(1-((R)-2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-5-yl)pyrrolidin-3-yl)acetyl)piperidin-4- yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (R)-N- (3-(2-(tert-butyl)-5-(2-((4-(1-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro- 1H-benzo[d]imidazol-4-yl)piperidine-4-carbonyl)piperidin-4-yl)phenyl)amino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(2-(tert-butyl)-5-(2-((4-(1- (1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)azetidine-3-carbonyl)piperidin-4- yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (R)-N- (3-(2-(tert-butyl)-5-(2-((4-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)piperidine-4-carbonyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide, (R)-N-(3-(2-(tert-butyl)-5-(2-((4-(1-(2-(2-(2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7- yl)acetyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1-sulfonamide, (R)-N-(3-(2-(tert-butyl)-5-(2-((4-(1-(6-(2-(2,6-dioxopiperidin-3-yl)-3- oxoisoindolin-5-yl)hexanoyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide, (R)-N-(3-(2-(tert-butyl)-5-(2-((4-(1-(2-(4-(2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)acetyl)piperidin-4- yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (S)-5- (4-((4-(((4-(2-(tert-butyl)-4-(2-fluoro-3-(propylsulfonamido)phenyl)thiazol-5-yl)pyrimidin-2- yl)amino)methyl)piperidin-1-yl)methyl)piperidin-1-yl)-N-(2,6-dioxopiperidin-3- yl)picolinamide, (S)-5-(4-((4-(1-((4-(2-(tert-butyl)-4-(2-fluoro-3- (propylsulfonamido)phenyl)thiazol-5-yl)pyrimidin-2-yl)amino)-2-methylpropan-2- yl)piperidin-1-yl)methyl)piperidin-1-yl)-N-(2,6-dioxopiperidin-3-yl)picolinamide, (R)-N-(3- (2-(tert-butyl)-5-(2-(((1-((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)methyl)piperidin-4-yl)methyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1-sulfonamide, (R)-N-(3-(2-(tert-butyl)-5-(2-((2-(1-((1-(4-(2,6-dioxopiperidin-3- yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-2-methylpropyl)amino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, 5-(4-(((R)-3-(((4-(2-(tert-butyl)-4-(2- fluoro-3-(propylsulfonamido)phenyl)thiazol-5-yl)pyrimidin-2-yl)amino)methyl)pyrrolidin-1- yl)methyl)piperidin-1-yl)-N-((S)-2,6-dioxopiperidin-3-yl)picolinamide, N-(3-(2-(tert-butyl)- 5-(2-(((1r,4r)-4-((4-((1-(4-((S)-2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)methyl)cyclohexyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide, N-(3-(2-(tert-butyl)-5-(2-(((1s,4s)-4-(4-(1-(5-((S)-2,6- dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)piperazin-1- yl)cyclohexyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, N- (3-(2-(tert-butyl)-5-(2-(((1r,4r)-4-(4-(1-(5-((S)-2,6-dioxopiperidin-3-yl)pyridin-2- yl)piperidine-4-carbonyl)piperazin-1-yl)cyclohexyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide, N-(3-(2-(tert-butyl)-5-(2-(((1r,4r)-4-(4-((1-(5-((S)-2,6- dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-1- yl)cyclohexyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, N- (3-(2-(tert-butyl)-5-(2-(((1s,4s)-4-(4-((1-(5-((S)-2,6-dioxopiperidin-3-yl)pyridin-2- yl)piperidin-4-yl)methyl)piperazin-1-yl)cyclohexyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide, (3R)-3-{4-[4-({4-[6-({4-[2-tert-butyl-4-(3- {[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-1,3-thiazol-5-yl]pyrimidin-2- yl}amino)pyridin-3-yl]piperazin-1-yl}methyl)piperidin-1-yl]phenyl}piperidine-2,6-dione, (3S)-3-{4-[4-({4-[6-({4-[2-tert-butyl-4-(3-{[ethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)-1,3-thiazol-5-yl]pyrimidin-2-yl}amino)pyridin-3-yl]piperazin-1- yl}methyl)piperidin-1-yl]phenyl}piperidine-2,6-dione, rac-(3S)-3-{6-[4-({4-[6-({4-[2-tert- butyl-4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-1,3-thiazol-5-yl]pyrimidin-2- yl}amino)pyridin-3-yl]piperazin-1-yl}methyl)piperidin-1-yl]pyridin-3-yl}piperidine-2,6- dione, rac-(3S)-3-(2-{[(1r,4r)-4-{4-[6-({4-[2-tert-butyl-4-(3- {[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-13-thiazol-5-yl]pyrimidin-2- yl}amino)pyridin-3-yl]piperazine-1-car hyl}-1,2,3,4- tetrahydroisoquinolin-6-yl)piperidine-2, (2-{[(1r,4r)-4-{4-[6-({4-[2-tert- butyl-4-(3-{[ethyl(methyl)sulfamoyl]am 1,3-thiazol-5-yl]pyrimidin-2- yl}amino)pyridin-3-yl]piperazine-1-car hyl}-1,2,3,4- tetrahydroisoquinolin-7-yl)piperidine-2, 2-(tert-butyl)-5-(2-((2-(2-(4-(4- ((2,6-dioxopiperidin-3-yl)amino)phenyl y y -1,2,3,4-tetrahydroisoquinolin- 6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (R)-5-(4-(6- ((4-(2-(tert-butyl)-4-(2-fluoro-3-(propylsulfonamido)phenyl)thiazol-5-yl)pyrimidin-2- yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidin-1-yl)-N-(2,6-dioxopiperidin-3- yl)picolinamide, N-(3-(2-(tert-butyl)-5-(2-((2-((R)-1-(5-((S)-2,6-dioxopiperidin-3-yl)pyridin- 2-yl)pyrrolidine-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(2-(tert-butyl)-5-(2-((2-(2- (4-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperazin-1-yl)acetyl)-1,2,3,4- tetrahydroisoquinolin-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1- sulfonamide, (S)-N-(3-(2-(tert-butyl)-5-(2-((1-((1-(2-(6-(2,6-dioxopiperidin-3-yl)-3,4- dihydroisoquinolin-2(1H)-yl)acetyl)piperidin-4-yl)methyl)-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, N-(3-(2-(tert- butyl)-5-(2-((1-((1-((1S,4r)-4-(4-((S)-2,6-dioxopiperidin-3-yl)phenoxy)cyclohexane-1- carbonyl)piperidin-4-yl)methyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide, N-(3-(2-(tert-butyl)-5-(2-((1-((1-((1S,4r)-4-((5-((S)-2,6- dioxopiperidin-3-yl)pyridin-2-yl)oxy)cyclohexane-1-carbonyl)piperidin-4-yl)methyl)-1H- pyrazol-4-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (R)- N-(3-(2-(tert-butyl)-5-(2-((1-((1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin- 1-yl)acetyl)piperidin-4-yl)methyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- ropane-1-sulfonamide, (R)-5-(4-(4-((4-((4-(2-(tert-butyl)-4-(2-fluoro-3- (propylsulfonamido)phenyl)thiazol-5-yl)pyrimidin-2-yl)amino)-1H-pyrazol-1- yl)methyl)piperidine-1-carbonyl)piperidin-1-yl)-N-(2,6-dioxopiperidin-3-yl)picolinamide, N- (3-(2-(tert-butyl)-5-(2-((1-((1-((R)-1-(5-((S)-2,6-dioxopiperidin-3-yl)pyridin-2-yl)pyrrolidine- 3-carbonyl)piperidin-4-yl)methyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(2-(tert-butyl)-5-(2-((1-((1-(2-(4-(4-(2,6- dioxopiperidin-3-yl)pyridin-2-yl)piperazin-1-yl)acetyl)piperidin-4-yl)methyl)-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, N-(3-(2-(tert- butyl)-5-(2-((1-((1-(2-((S)-1-(4-((S)-2,6-dioxopiperidin-3-yl)phenyl)pyrrolidin-3- yl)acetyl)piperidin-4-yl)methyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide, N-(3-(2-(tert-butyl)-5-(2-((1-((1-(2-((R)-1-(4-((S)-2,6- dioxopiperidin-3-yl)phenyl)pyrrolidin-3-yl)acetyl)piperidin-4-yl)methyl)-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, N-(3-(2-(tert- butyl)-5-(2-((1-(1-((1S,4r)-4-(4-((S)-2,6-dioxopiperidin-3-yl)phenoxy)cyclohexane-1- carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfona utyl)-5-(2-((1-(1-((1S,4r)-4-((5-((S)-2,6- dioxopiperidin-3-yl)pyridin-2-y carbonyl)piperidin-4-yl)-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)thiazol l)propane-1-sulfonamide, (R)-N-(3-(2- (tert-butyl)-5-(2-((1-(1-(2-(4-(4- 3-yl)amino)phenyl)piperidin-1- yl)acetyl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide, (R)-5-(4-(4-(4-((4-(2-(tert-butyl)-4-(2-fluoro-3- (propylsulfonamido)phenyl)thiazol-5-yl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine- 1-carbonyl)piperidin-1-yl)-N-(2,6-dioxopiperidin-3-yl)picolinamide, N-(3-(2-(tert-butyl)-5- (2-((1-(1-((R)-1-(5-((S)-2,6-dioxopiperidin-3-yl)pyridin-2-yl)pyrrolidine-3- carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide, N-(3-(2-(tert-butyl)-5-(2-((1-(1-(2-((S)-1-(4-((S)-2,6- dioxopiperidin-3-yl)phenyl)pyrrolidin-3-yl)acetyl)piperidin-4-yl)-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(2- (tert-butyl)-5-(2-((3-(1-(2-(6-(2,6-dioxopiperidin-3-yl)-3,4-dihydroisoquinolin-2(1H)- yl)acetyl)piperidin-4-yl)p ol-4-yl)-2-fluorophenyl)propane- 1-sulfonamide, (1-(2-(4-(4-((2,6-dioxopiperidin-3- yl)amino)phenyl)piperidin-1-yl)acetyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4- yl)-2-fluorophenyl)propane-1-sulfonamide, N-(3-(2-(tert-butyl)-5-(2-((3-(1-((R)-1-(5-((S)- 2,6-dioxopiperidin-3-yl)pyridin-2-yl)pyrrolidine-3-carbonyl)piperidin-4- yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (S)-N- (3-(2-(tert-butyl)-5-(2-((3-((1-(2-(6-(2,6-dioxopiperidin-3-yl)-3,4-dihydroisoquinolin-2(1H)- yl)acetyl)piperidin-4-yl)oxy)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(2-(tert-butyl)-5-(2-((3-((1-(1-(4-(2,6- dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)piperidin-4- yl)oxy)phenyl)amino)pyrimidin fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(2-(tert-butyl)-5-(2-((3 piperidin-3-yl)phenyl)piperidine-4- carbonyl)piperidin-4-yl)oxy)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide, N-(3-(2-(tert-butyl)-5-(2-((3-((1-((1S,4r)-4-(4-((S)-2,6- dioxopiperidin-3-yl)phenoxy)cyclohexane-1-carbonyl)piperidin-4- yl)oxy)phenyl)amino)pyrimidin-4-yl)thia (3-(2-(tert-butyl)-5-(2-((3-((1-((1S,4r)-4- yl)oxy)cyclohexane-1-carbonyl)piperidin yl)-2-fluorophenyl)propane-1-sulfonamid ( namide, ( -5- dioxopiperidin-3-yl)picolinamide, N-(3-(2-(tert-butyl)-5-(2-((3-((1-((R)-1-(5-((S)-2,6- dioxopiperidin-3-yl)pyridin-2-yl)pyrrolidine-3-carbonyl)piperidin-4- yl)oxy)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(2-(tert-butyl)-5-(2-((3-((1-(2-(4-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperazin- 1-yl)acetyl)piperidin-4-yl)oxy)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide, N-(3-(2-(tert-butyl)-5-(2-((3-((1-(2-((S)-1-(4-((S)-2,6- y l)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (R)-N-(3-(2-(tert-butyl)-5-(2-((4-(1- ((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperidin-4 yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1- e, (S)-N- (3-(2-(tert-butyl)-5-(2-((4-(4-((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-3-fluorophenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide, (R)-N-(3-(2-(tert-butyl)-5-(2-((4-(4-((1-(4-(2,6- dioxopiperidin-3-yl)phenyl)pip yl)-3- fluorophenyl)amino)pyrimidin yl)propane-1-sulfonamide, (2S,4R)-1-((S)-2-(5-(4-(4-((4-( (propylsulfonamido)phenyl)thi phenyl)piperidin-1-yl)-5- oxopentanamido)-3,3-dimethyl 4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide, (R)-N-(3-(2-(tert-butyl)-5-(2-((2-((1-(2-(2,6- dioxopiperidin-3-yl)-1-oxo-1,2-dihydroisoquinolin-6-yl)piperidin-4-yl)methyl)-1,2,3,4- tetrahydroisoquinolin-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1- sulfonamide, N-(3-(2-(tert-butyl)-5-(2-((1-((1-(((1S,4r)-4-(4-((S)-2,6-dioxopiperidin-3- yl)phenoxy)cyclohexyl)methyl)piperidin-4-yl)methyl)-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (R)-N-(3-(2-(tert-butyl)-5-(2-((1-((1- ((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroisoquinolin-6-yl)piperidin-4- 1-sulfonamide, N-(3-(2-(tert-butyl)-5-(2-((3-(1-(2-((R)-1-(5-((S)-2,6-dioxopiperidin-3- yl)pyridin-2-yl)pyrrolidin-3-yl)ethyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4- e-1-sulfonamide, N-(3-(2-(tert-butyl)-5-(2-((3-(1-(2-((S)-1-(5-((S)- ridin-2-yl)pyrrolidin-3-yl)ethyl)piperidin-4- -4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (S)-N- (1-((1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)-4-methylpiperidin- )phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- p y p p - - ulfonamide, N-(3-(2-(tert-butyl)-5-(2-((3-((1-(((1S,4r)-4-(4-((S)-2,6- dioxopiperidin-3-yl)phenoxy)cyclo yl)oxy)phenyl)amino)pyrimidin-4- nyl)propane-1-sulfonamide, (R)-N-(3-(2-(tert-butyl)-5-(2-((3-(( -3-yl)-1-oxo-1,2- dihydroisoquinolin-6-yl)piperidin- xy)phenyl)amino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)pro -(2-(tert-butyl)-5-(2-((3-((1-(2- ((R)-1-(5-((S)-2,6-dioxopi yrrolidin-3-yl)ethyl)piperidin-4- yl)oxy)phenyl)amino)pyri fluorophenyl)propane-1-sulfonamide, N- (3-(2-(tert-butyl)-5-(2-((3- oxopiperidin-3-yl)pyridin-2- yl)pyrrolidin-3-yl)ethyl)pi mino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-1-s 3-(2-(tert-butyl)-5-(2-((3-((1-((1-(5-(2,6- dioxopiperidin-3-yl)pyridi n-2-yl)-4-methylpiperidin-4-yl)methyl)piperidin-4- yl)oxy)phenyl)amino)pyrimid rophenyl)propane-1-sulfonamide, (R)-5-(4-((4-(4-((4-(2-(tert-bu ulfonamido)phenyl)thiazol-5- yl)pyrimidin-2-yl)amino)-1H- l)methyl)piperidin-1-yl)-N-(2,6- dioxopiperidin-3-yl)picolinam -((4-((4-(2-(tert-butyl)-4-(2-fluoro-3- (propylsulfonamido)phenyl)th amino)-1H-pyrazol-1- yl)methyl)piperidin-1-yl)methyl)piperidin-1-yl)-N-(26-dioxopiperidin-3-yl)picolinamide, (S)-N-(3-(2-(tert-butyl)-5-(2-((4-( -3-yl)phenyl)piperidine-4- carbonyl)piperazin-1-yl)-3-fluoro -yl)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfonam -(1-((1-(4-(2,6-dioxopiperidin-3- yl)phenyl)piperidin-4-yl)methyl) o)pyrimidin-4-yl)-2- methylthiazol-4-yl)-2-fluorophen (R)-N-(3-(5-(2-((4-(1-((1-(4-(2,6- dioxopiperidin-3-yl)phenyl)piperidin-4 henyl)amino)pyrimidin-4- yl)-2-methylthiazol-4-yl)-2-fluorophen (S)-N-(3-(5-(2-((5-(4-((1- (5-(2,6-dioxopiperidin-3-yl)pyridin-2-y perazin-1-yl)pyridin-2- yl)amino)pyrimidin-4-yl)-2-methylthia ropane-1-sulfonamide, (S)- N-(3-(5-(2-((5-(4-((1-(4-(2,6-dioxopipe -4-yl)methyl)piperazin-1- yl)pyridin-2-yl)amino)pyrimidin-4-yl)- - e y a o - -y - - uorophenyl)propane-1- sulfonamide, (R)-N-(3-(5-(2-((5-(4- 3-yl)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)pyridin-2-yl)ami lthiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide, -5-(2-((4-(4-((1-(4-(2,6- dioxopiperidin-3-yl)phenyl)piperidin-4-yl) yl)amino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-1- -(tert-butyl)-5-(2-((4-(4- ((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperazin-1- yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (S)-N- (3-(2-(tert-butyl)-5-(2-((4-(4-(1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4- carbonyl)piperazin-1-yl)-3-fluorophenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide, rac-(3R)-3-[6-(4-{4-[6-({4-[2-tert-butyl-4-(3- {[ethy -2-fluorophenyl)-1,3-thiazol-5-y yl}am 1-carbonyl}piperidin-1-yl)pyrid dione, (1-(1-(5-(2,6-dioxopiperidin-3-y carbon ino)pyrimidin-4-yl)-2-methylth fluoro ide, N-(3-(2-(tert-butyl)-5- dioxop iperidin-3-yl)pyridin-2-yl)pyrrolidine-3-carbonyl)piperazin -1-yl)-3- fluorophenyl)amino)pyrimidin- yl)propane-1-sulfonamide, (R)- N-(3-(5-(2-((4-(1-((1-(5-(2,6-di piperidin-4- yl)methyl)piperidin-4-yl)pheny hylthiazol-4-yl)-2- fluorophenyl)propane-1-sulfon -5-(2-((4-(4-((R)-1-(5-((R)-2,6- dioxopiperidin-3-yl)pyridin-2-y zin-1-yl)-3- fluorophenyl)amino)pyrimidin- yl)propane-1-sulfonamide, rac- 2 (1H)-yl)acetyl)piperazin-1-yl)-3-fluorophenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-1-s yl)-5-(2-((4-(4-((1S,4r)-4-((5-((S)-2,6- dioxopiperidin-3-yl)pyridi bonyl)piperazin-1-yl)-3- fluorophenyl)amino)pyrim rophenyl)propane-1-sulfonamide, (R)- N-(3-(2-(tert-butyl)-5-(2-( idin-3-yl)pyridin-2-yl)piperidin-4- yl)acetyl)piperazin-1-yl)-3 in-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(2-(tert-butyl)-5-(2-((4-(4-((1-(5-(26- dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperaz yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)p - (3-(2-(tert-butyl)-5-(2-((4-(4-(2-(1-(4-((2,6-dioxopiperidin-3-yl yl)acetyl)piperazin-1-yl)-3-fluorophenyl)amino)pyrimidin-4-yl fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(2-(tert - dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-1-yl)-3- fluorophenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (S)- N-(3-(5-(2-((4-(1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4- yl)acetyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl) fluorophenyl)propane-1-sulfonamide, {4-[4-(3- {[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-2-m din-2- yl}amino)pyridin-3-yl]piperazin-1-yl}methyl)piperidin 2,6- dione, rac-(3S)-3-[6-(4-{4-[6-({4-[2-tert-butyl-4-( mino}-2- fluorophenyl)-1,3-thiazol-5-yl]pyrimidin-2-yl}amino)pyridin-3-yl]piperazine-1-carbonyl}-4- methylpiperidin-1-yl)pyridin-3-yl]piperidine-2,6-dione, - {[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-2-methyl-1, yl}amino)pyridin-3-yl]piperazin-1-yl}methyl)piperidin-1-yl]ph rac-(3S)-3-[6-(4-{4-[6-({4-[4-(3-{[ethyl(methyl)sulfamoyl]ami methyl-1,3-thiazol-5-yl]pyrimidin-2-yl}amino)pyridin-3-yl]pip 1-yl)pyridin-3-yl]piperidine-2,6-dione, rac-(3R)-3-{6-[4-(2-{4-[6-({4-[4-(3- [ th l(m th l) lf m l] min 2 fl r h n l) 2 m th l 13 thi z l 5 l] rimidin 2 1-sulfonamide, rac-(3S)-3-{6-[4-({4-[6-({4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2- fluorop imidin-2-yl}amino)pyridin-3-yl]piperazin-1- yl}met 3-yl}piperidine-2,6-dione, rac-(3S)-3-{4-[4-({4- [6-({4- o}-2-fluorophenyl)-2-methyl-1,3-thiazol-5- yl]pyri azin-1-yl}methyl)-4-fluoropiperidin-1- yl]phenyl}piperidine-2,6-dione, (S)-N-(3-(5-(2-((4-(4-((1-(5-(2,6-dioxopiperidin-3-yl)pyridin- 2-yl)-4-methylpiperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-2- methylthiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(5-(2-((4-(4-((1-(4-(2,6- dioxopiperidin-3-yl)phenyl)-4-fluoropiperidin-4-yl)methyl)piperazin-1- yl)phenyl)amino)pyrimidin-4-yl)-2-methylthiazol-4-yl)-2-fluorophenyl)propane-1- d ione, rac-(3R)-3-[2-(2-{4-[4-({4-[2-tert-butyl-4-(3-{[ethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)-1,3-thiazol-5 2-fluorophenyl]piperazin-1-yl}-2- oxoethyl)-1,2,3,4-tetrahydr -2,6-dione, and (3R)-3-{6-[4-({4-[6- ({4-[4-(3-{[ethyl(methyl)s enyl)-2-methyl-1,3-thiazol-5- yl]pyrimidin-2-yl}amino)p ethyl)piperidin-1-yl]pyridin-3- yl}piperidine-2,6-dione. 69. The compound of any one of claims 2 10-17 31-33 or 53-64 selected from the group l)piperidin-4- nyl)propane- l)piperidin-4- nyl)propane- -yl)piperidin- fluorophenyl)propane-1-sulfonamide. 70. The compound of any one of 3-64 selected from the group consisting of (R)-N-(3-(1-(4- ridin-3-yl)phenyl)piperidine-4- carbonyl)piperazine-1-carbonyl)phenyl yrazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide, 4-((1-(4-(2,6-dioxopiperidin-3- yl)phenyl)piperidin-4-yl)methyl)pipera )-3-(pyridin-4-yl)-1H-pyrazol- 4-yl)-2-fluorophenyl)propane-1-sulfona (4-(1-(4-(2,6-dioxopiperidin-3- yl)phenyl)piperidine-4-carbonyl)piperazin-1-yl)phenyl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide, (R)-N-(3-(1-(4-((1-(1-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)oxy)phenyl)-3-(pyridin-4-yl)-1H- pyrazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(1-(4-(4-((1-(5-(2,6- dioxopiperidin-3-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)methyl)piperazin-1-yl)phenyl)-3- (pyridin-4-yl)-1H-pyrazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (R)-N-(3-(1-(4-(4- ((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperazine-1-carbonyl)phenyl)- 3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(1-(1-(1- (1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidin- 4-yl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(1- (4-(4-((1-(4-(2,6-dioxopiperidin-3-yl)-3-fluorophenyl)piperidin-4-yl)methyl)piperazin-1- yl)phenyl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (S)-N- (3-(1-(4-(1-((1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin- 4-yl)phenyl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (S)- N-(3-(1-(1-(1-(1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4- carbonyl)piperidin-4-yl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2-fluorophenyl)propane-1- sulfonamide, (S)-N-(3-(1-(4-(4-((1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidin-4- yl)methyl)piperazin-1-yl)phenyl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2-fluorophenyl)propane- 1-sulfonamide, (S)-N-(3-(1-(6-(4-((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)pyridin-3-yl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide, (R)-N-(3-(1-(4-(4-(2-(1-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidin-4-yl)a bonyl)phenyl)-3-(pyridin-4-yl)-1H- pyrazol-4-yl)-2-fluorophenyl)pr , (S)-N-(3-(1-(1-(1-((1-(5-(2,6- dioxopiperidin-3-yl)pyridin-2-y yl)piperidine-4-carbonyl)piperidin-4-yl)- 3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(1-(4-(4- ((1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-3- (pyridin-4-yl)-1H-pyrazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(1-(6-(4- ((1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3- yl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(1-(4- (1-((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)-3- (pyridin-4-yl)-1H-pyrazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(1-(4-(1- ((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)-3- (pyridin-4-yl)-1H-pyrazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(1-(4-(1- ((1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)-3- (pyridin-4-yl)-1H-pyrazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(1-(4-(4- ( peridin-4-yl)methyl)piperazin-1-yl)phenyl)-3- ( henyl)propane-1-sulfonamide, (S)-N-(3-(1-(1-(1-(1- ( 5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)-4-methylpiperidine-4- carbonyl)piperidin-4-yl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2-fluorophenyl)propane-1- sulfonamide, (S)-N-(3-(1-(4-(1-((1-(4-(2,6-dioxopiperidin-3-yl)-3-fluorophenyl)piperidin-4- yl)methyl)piperidin-4-yl)phenyl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2-fluorophenyl)propane- 1-sulfonamide, and (R)-N-(3-(1-(4-(4-((1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin- 4-yl)methyl)piperazin-1-yl)phenyl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide. 71. The compound of any one of claims 34, 37-45, or 50-54 selected from the group (S)-N-(3-(5-(2-aminopyrimidin-4-yl)-2-(1-(1-(1-(5-(2,6-dioxopiperidin-3- idine-4-carbonyl)piperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(5-(2-aminopyrimidin-4-yl)-2-(1-(1-(1-(5- (2,6-dioxopiperidin-3-yl)pyridin-2-yl)-4-methylpiperidine-4-carbonyl)piperidine-4- carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(5-(2- aminopyrimidin-4-yl)-2-(1-(1-(1-(5-( carbonyl)-4-methylpiperidine-4-carbo fluorophenyl)propane-1-sulfonamide, (2,6-dioxopiperidin-3-yl)phenyl)pipe N-(3-(2-(1- - iperidine-4- carbonyl)-4-methylpiperidine-4-carbonyl)piperidin-4-yl)-5-(pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide, and (S)-N-(3-(2-(1-(1-(1-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidine-4-carbonyl)-4-methylpiperidine-4-carbonyl)piperidin-4-yl)-5- (pyridin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide. 72. The compound of any one of claims 34, 37, 44, 45, or 50-64 selected from the group consisting of (R)-N-(3-(5-(2-aminopyrimidin-4-yl 2 3 2 4 3 2 26 di i idi 3 l)- 1,3-dioxoisoindolin-4-yl)propyl)piperazin-1-yl)a 4-yl)-2-fluorophenyl)propane-1-sulfonamide, N - 4-((6-((S)-2,6-dioxopiperidin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)cyclohexane-1- carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(2-(1- (1-((1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperidine-4- fluorophenyl)propane-1-sulfonamide, (R)-N-(3-(5-(2-aminopyrimidin 1-(2-(1'-(2- (2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-[1,4'-bipiperidin]-4-y 4- methylpiperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(5-(2- aminopyrimidin-4-yl)-2-(1-(1-((1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)methyl)piperidine-4-carbonyl)-4-methylpiperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide (S)-N-(3-(5-(2-aminopyrimidin-4-yl)-2-(1-((1-(2-(6- (2,6-dioxopiperidin-3-yl)-3,4-d )-yl)acetyl)piperidin-4- yl)methyl)piperidin-4-yl)thiazo propane-1-sulfonamide, (S)-N-(3-(5-(2- aminopyrimidin-4-yl)-2-(3-((1- -3-yl)phenyl)piperidin-4-yl)methyl)-3- azaspiro[5.5]undecan-9-yl)thia l)propane-1-sulfonamide, (S)-N-(3-(2- (1-(1-((1-(5-(2,6-dioxopiperidi eridin-4-yl)methyl)piperidine-4- carbonyl)piperidin-4-yl)-5-(pyridin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1- sulfonamide, (R)-N-(3-(5-(2-aminopyrimidin-4-yl)-2-(1-(2-(1'-(2-(2,6-diox 1,3-dioxoisoindolin-5-yl)-[1,4'-bipiperidin]-4-yl)acetyl)piperidin-4-yl)thiazol fluorophenyl)propane-1-sulfonamide, (R)-N-(3-(5-(2-aminopyrimidin-4- (2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)acetyl)pipe yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (R)-N-(3-(5-(2-am yl)-2-(2-(1-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperi - - y s d y y a (2-aminopyrimidin-4-yl)-2-(1-(1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)- 4-hydroxypiperidin-4-yl)acetyl)azetidin-3-yl)piperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(1-(2-(1-(5- (2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)acetyl)piperidin-4-yl)phenyl)thiazol-4- yl)-2-fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(4-((1- (4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)thiazol-4- yl)- (1-( yl)p ami car (3-( yl) (5-(2-aminopyrimidin-4-yl)-2-(3-(((1S,4r)-4-((5-((S)-2,6-dioxopiperidin-3-yl)pyridin-2- yl)oxy)cy ro[5.5]undecan-9-yl)thiazol-4-yl)-2- fluoroph e, (R)-N-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(4-(1-(4- (2,6-diox eridine-4-carbonyl)piperazin-1-yl)phenyl)thiazol-4-yl)-2- fluoroph e, (R)-5-(4-(9-(5-(2-aminopyrimidin-4-yl)-4-(2-fluoro-3- (propylsu 2-yl)-3-azaspiro[5.5]undecane-3-carbonyl)piperidin-1- yl)-N-(2,6 -dioxopiperidin-3-yl)picolinamide, N-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-(2-((S)-1- (5-((S)-2,6-dioxopiperidin-3-yl)pyridin-2-y zaspiro[5.5]undecan-9- yl)thiazol-4-yl)-2-fluorophenyl)propane-1-s -aminopyrimidin-4-yl)- 2-(1-(1-(2-(1-(4-(2,6-dioxopiperidin-3-yl)p )azetidin-3- yl)piperidin-4-yl)thiazol-4-yl)-2-fluorophen , (S)-N-(3-(5-(2- aminopyrimidin-4-yl)-2-(3-(1-(5-(2,6-dioxo l)piperidine-4- carbonyl)-3-azaspiro[5.5]undecan-9- l)thiazol-4- l)-2-fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(5-(2-aminopyrimidin-4-y piperidin-3-yl)pyridin-2- yl)piperidin-4-yl)methyl)piperidin- -fluorophenyl)propane-1- sulfonamide, (S)-N-(3-(2 eridin-3-yl)phenyl)piperidine-4- carbonyl)piperidine-4-carbonyl)pip l)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamid (1-((1-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidin-4-yl)methyl)pip in-4-yl)-5-(2- (methylamino)pyrimidin-4-yl)thiazol-4-y -1-sulfonamide, (R)-N-(3- (5-(2-aminopyrimidin-4-yl)-2-(2-(2-(1'-( -1,3-dioxoisoindolin-5- yl)-[1,4'-bipiperidin]-4-yl)acetyl)-2-azas -4-yl)-2- fluorophenyl)propane-1-sulfonamide, -(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidine-4-carbonyl)pip erd ne- -carbony )p per din-4-yl)-5-(pyridin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, N-(3-(5-(2-aminopyrimidin-4-yl)-2- (1-((1-(((1S,4r)-4-(4-((S)-2,6-dioxopiperidin-3-yl)phenoxy)cyclohexyl)methyl)piperidin-4- yl)methyl)piperidin-4-yl)thiazol-4-yl)-2-fluoropheny (2-aminopyrimidin-4-yl)-2-(2-(1-(2-(2,6-dioxopiperi yl)piperidine-4-carbonyl)-2-azaspiro[3.5]nonan-7-yl sulfonamide, (S)-N-(3-(2-(1-(1-(2-(1-(4-((2,6-dioxo yl)acetyl)piperidine-4-carbonyl)piperidin-4-yl)-5-(p fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(5-( 2-aminopyrimidin-4-yl)-2-(2-(1-(1-(1-(5- (2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbon iperidin- 4-yl)ethyl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfona -(3-(5-(2- aminopyrimidin-4-yl)-2-(2-(2-(4-(2-(2,6-dioxopiperidin-3 yl)piperazin-1-yl)acetyl)-2-azaspiro[3.5]nonan-7-yl)thiazo pane-1- sulfonamide, (R)-N-(3-(5-(2-aminopyrimidin-4-yl)- eridin-3- yl)pyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)phenyl)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(2-(1-(1-( yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperi yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (R)-N- yl)-2-(1-(1-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-car carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-su aminopyrimidin-4-yl)-2-(4-(4-((1-(4 henyl)piperidin-4- yl)methyl)piperazin-1-yl)phenyl)thi ropane-1-sulfonamide, (S)-N- (3-(5-(2-aminopyrimidin-4-yl)-2-(1 in-3-yl)pyridin-2- yl)piperidine-4-carbonyl)piperidin- hiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamid rimidin-4-yl)-2-(4-(4-(2-(1-(5- (2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)acetyl)piperazin-1-yl)phenyl)thiazol-4- -(1'- ( -(5- ( f , , n-3- yl)phenyl)piperidine-4-carbonyl)-4-methylpiperidine-4-carbonyl)piperidin-4-yl)-5-(2- (isopropylamino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (R)-N- (3-(5-(2-aminopyrimidin-4-yl)-2-(3-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)piperazin-1-yl)acetyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1-sulfonamide, -4-yl)-2-(1-((1-((1R,4r)-4-(4-((R)-2,6- dioxopiperidin-3-yl)phenoxy iperidin-4-yl)methyl)piperidin-4- yl)thiazol-4-yl)-2-fluorophen (R)-N-(3-(5-(2-aminopyrimidin-4- yl)-2-(2-(6-(2-(2,6-dioxopip -5-yl)hexanoyl)-2- azaspiro[3.5]nonan-7-yl)thia opane-1-sulfonamide, N-(3-(2-(1-(1- (1-(5-((S)-2,6-dioxopiperidin ne-4-carbonyl)piperidine-4- carbonyl)piperidin-4-yl)-5-(2 -(((R)-1-hydroxypropan-2-yl)amino)pyrimidin-4-yl)thiazol-4- (4-(4-((1- l)thiazol- yrimidin- dine-1- c-(3S)-3- {-[-(-{-[-(-{[ety(mety)su amoy]amno}-- uoropeny)--{-[(propan-2- yl)amino]pyrimidin-4-yl}-1,3-thiazol-2-yl]piperidine-1-carbonyl}piperidine-1- a zaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (R)-N-(3-(5- (2-aminopyrimidin-4-yl)-2-(1-(1-(2-(1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)acetyl)-4-methylpiperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)prop (S)-N-(3-(2-(1-(1-(1-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)pi e-4-carbonyl)piperidin-4-yl)-5-(2- (methylamino)py uorophenyl)propane-1-sulfonamide, (R)-N-(3- (5-(2-aminopyrim 6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin- 4-yl)acetyl)piperi l)thiazol-4-yl)-2-fluorophenyl)propane-1- sulfonamide, (S)-N-(3-(2-(1-(1-(1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4- carbonyl)piperidine-4-carbony ylamino)pyrimidin-4-yl)thiazol- 4-yl)-2-fluorophenyl)propane- -(cyclopropylamino)pyrimidin-4- yl)-2-(1-(1-(1-(5-(2,6-dioxopip idine-4-carbonyl)piperidine-4- carbonyl)piperidin-4-yl)thiazol e-1-sulfonamide, (S)-N-(3-(2-(1- (1-(1-(4-(2,6-dioxopiperidin-3- yl)-4-methylpiperidine-4- carbonyl)piperidin-4-yl)-5-(pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1- sulfonamide, N-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-(2-((R)-1-(4-((S)-2,6-dioxopiperidin-3- yl)phenyl)pyrrolidin-3-yl)acetyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide, (R)-N-(3-(5-(2-aminopyrimidin-4-yl)-2-(2-(2-(2-(2- (2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)acetyl)-2- azaspiro[3.5]nonan 7 l thi l 4 l 2 fl henyl)propane-1-sulfonamide, (R)-N-(3-(5-(2- aminopyrimidin-4- opiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)acetyl)piperidin azol-4-yl)-2-fluorophenyl)propane-1- sulfonamide, (R -yl)-2-(1-(2-(2-(2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindoli n-7-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propa -(5-(2-aminopyrimidin-4-yl)-2-(3-(1-(1-(2,6- dioxopiperidin-3-y , -1H-benzo[d]imidazol-4-yl)piperidine-4- carbonyl)-3-a de, (R)-N-(3-(2-( -4- carbonyl)pip fluorophenyl -(2- (2,6-dioxopip carbonyl)pip -(2- aminopyrimid in-4-yl)-2-(2-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)piperidin-4-yl)azetidine-3-carbonyl)-2-azaspiro[3.5]nonan-7-yl)thiazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide, (S)-N-(3-(5-(2-aminopyrimidin-4-yl)-2-(1-(1-((1-(1- (2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin- 4-yl)methyl)piperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1- sulfonamide, (R)-N-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-(2-(2-(2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)acetyl)-3-azaspiro[5.5]undecan-9- yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (R)-N-(3-(5-(2-aminopyrimidin-4- yl)-2-(2-(1-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7- diazaspiro[3.5]nonan-7-yl)acetyl)piperidin-4-yl)propan-2-yl)thiazol-4-yl) fluorophenyl)propane-1-sulfonamide, and (R)-4-((4-(5-(2-aminopyrimid 3-(propylsulfonamido)phenyl)thiazol-2-yl)piperidin-1-yl)methyl)-N-(2,6- yl)benzamide. 73. The compound of claim 1, wherein X1 is carbon; X2 is nitrogen, carbon; and X5 is hydrogen. 74. The compound of claim 73, wherein R1 is alkyl, dialkylamino, cycloalkyl, or heterocycloalkyl each unsubstituted or substituted with one or more halogen; R1a is halogen; R1b is hydrogen, haloalkyl or halogen; R2 is -[Ar1-Z1]n-Z2-Cy1-Z3-L-UBM; Ar1 is arylene or heteroarylene, each unsubstituted or substituted with one or more halogen; Z1 is a bond; n is one; Z2 is absent; Cy1 is r heterocycloalkylene, unsubstituted or substituted with one or more alkyl or one or more halogen; Z3 is absent or C1-10 alkylene; L is a linker according to –L1-L2-L3-L4– or –L4-L3-L2-L1–, wherein –L1– is -Q1- or -Q2-; each –L2–, –L3–, and –L4– is independently, absent, -C1-8 alkylene-, or -Q1-; each -Q1- is a three- to seven-membered heterocycloalkylene comprising at least one nitrogen and is unsubstituted or substituted with one or more methyl or halogen; each -Q2- is a five- to thirteen-membered bicyclic heterocycloalkylene comprising at least one nitrogen, wherein the five- to thirteen-membered bicyclic heterocycloalkylene is optionally a spiro bicyclic heterocycloalkylene ring; and UBM is a ubiquitin ligase binding moiety; or a stereoisomer and/or pharmaceutical salt thereof. 75. The compound of claim 73 or 74, wherein R1 is selected from the group consisting of propyl, ethylmethylamino, sec-butyl, , , , , , , , , , , , , , , , and . 76. The compound of any one of claims 73-75, wherein R1a is chloro or fluoro; and R1b is 8 . p , g formula X7 absent or -C(O)-; and X8 is arylene or heteroarylene. 82. The compound of claim 81, wherein UBM binds CRBN and is selected from the consi of , , , , , , , X9 is absent or h l d m is one, two, 83. The co y one of claims 1 or , compound is selected from the group consisting of (R)-N-(5-chloro-3-(1-(4-(4-((1-(5-(2,4-dioxotetrahydropyrimidin- 1(2H)-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-3-(pyridin-4-yl)-1H- pyrazol-4-yl)-2-fluorophenyl)-3-fluoropyrrolidine-1-sulfonamide; (R)-N-(5-chloro-3-(1-(4-(4- ((1-(5-((R)-2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-1- yl)phenyl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2-fluorophenyl)-3-fluoropyrrolidine-1- sulfonamide; rac-(R)-N-(5-chloro-3-(1-(4-( -((1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2- yl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2- fluorophenyl)pyrrolidine-1-sulfonamide; rac-(R)-N-(5-chloro-3-(1-(4-(4-((1-(5-(2,6- dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-1-yl)-2-fluorophenyl)-3- (pyridin-4-yl)-1H-pyrazol-4-yl)-2-fluorophenyl)pyrrolidine-1-sulfonamide; rac-(R)-N-(3-(1- (4-(4-((1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-1- yl)phenyl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2,5-difluorophenyl)pyrrolidine-1-sulfonamide; N-(5-chloro-3-(1-(4-((R)-4-((1-(5-((RS)-2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- f r r f ( f ( f ( ( [ [ yl]phenyl}-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2-fluorophenyl]propane-1-sulfonamide; N-[5-
N-{5-chloro-3-[1-(5-{4-[(1-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4- yl)methyl]piperazin-1-yl}pyridin-2-yl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl]-2- fluorophenyl}pyrrolidine-1-sulfonamide; N-[5-chloro-3-(1-{5-[4-({1-[4-(2,4-dioxo-1,3- diazinan-1-yl)phe -4-yl)- 1H-pyrazol-4-yl)- -(5-{4-[(1- {5-[(3R)-2,6-diox }pyridin- 2-yl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl]-2-fluorophenyl}pyrrolidine-1-sulfonamide; N-(3-(1- (4-((R)-4-((1-(5-((RS)-2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)-3- methylpiperazin-1-yl)-2-fluorophenyl)-3-(pyridin-4-yl)- difluorophenyl)pyrrolidine-1-sulfonamide; N-{ dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl] (pyridin-4-yl)-1H-pyrazol-4-yl]-2-fluorophenyl}pyrrolid chloro-3-[1-(4-{4-[(1-{4-[(3R)-2,6-dioxopiperidin-3-yl] yl)methyl]piperazin-1-yl}phenyl)-3-(pyridin-4-yl)-1H-p fluoropyrrolidine-1-sulfonamide; (3R)-N-[5-chloro-3-(1-{4-[4-({1-[4-(2,4-dioxo-1,3- diazinan-1-yl)phenyl]piperidin-4-yl}methyl)piperazin-1-yl]phenyl}-3-(pyridin-4-yl)-1H- pyrazol-4-yl)-2-fluorophenyl]-3-fluoropyrrolidine-1-sulfonamide; (3R)-N-{5-chloro-3-[1-(4- {4-[(1-{5-[(3R)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-1- yl}phenyl)- yrrolidine-1- sulfonamid 2,6-dioxopiperidin-3- yl]phenyl}p -4-yl)-1H-pyrazol-4- yl]-2-fluorophenyl}-3-fluoropyrrolidine-1-sulfonamide; (3R)-N-[5-chloro-3-(1-{5-[4-({1-[4- (2,4-dioxo-1,3-diazinan-1-yl)phenyl]pipe yl)piperazin-1-yl]pyridin-2-yl}-3- (pyridin-4-yl)-1H-pyrazol-4-yl)-2-fluoro pyrrolidine-1-sulfonamide; (3R)-N- {5-chloro-3-[1-(5-{4-[(1-{5-[(3RS)-2,6-d -yl]pyridin-2-yl}piperidin-4- yl)methyl]piperazin-1-yl}pyridin-2-yl)-3 H-pyrazol-4-yl]-2-fluorophenyl}-3- fluoropyrrolidine-1-sulfonamide; -chloro-3- -(5-{4-[(1-{5-[(3R)-2,6- dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-1-yl}pyridin-2-yl)-3- (pyridin-4-yl)-1H-pyrazol-4-yl]-2-fluorophenyl}-3-fluoropyrrolidine-1-sulfonamide; (3R)-N- {5-chloro-3-[1-(5-{4-[(7-{4-[(3RS)-2,6-dioxopiperidin-3-yl]phenyl}-7-azaspiro[3.5]nonan-2- n-1-yl}pyridin-2-yl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl]-2-fluorophenyl}-3- f -sulfonamide; N-{3-[1-(4-{4-[(1-{4-[(3R)-2,6-dioxopiperidin-3- n-4-yl)methyl]piperazin-1-yl}phenyl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl]- }pyrrolidine-1-sulfonamide; N-[3-(1-{4-[4-({1-[4-(2,4-dioxo-1,3-diazinan- in-4-yl}methyl)piperazin-1-yl]phenyl}-3-(pyridin-4-yl)-1H-pyrazol-4-yl)- ]pyrrolidine-1-sulfonamide; N-{3-[1-(4-{4-[(1-{5-[(3R)-2,6- d ioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-1-yl}phenyl)-3-(pyridin-4- yl)-1H-pyrazol-4-yl]-2,5-difluorophenyl}pyrrolidi -(5-{4-[(1- {4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin din-2-yl)- 3-(pyridin-4-yl)-1H-pyrazol-4-yl]-2,5-difluorophen amide; (3R)-N-[3-(1-{5-[4-({1-[4-(2,4-dioxo-1,3-diazinan yl}methyl)piperazin-1-yl]pyridin-2-yl}-3-(pyridin- difluorophenyl]-3-fluoropyrrolidine-1-sulfonamide (3RS)-2,6- dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)me thyl]piperazin-1-yl}pyridin-2-yl)-3- (pyridin-4-yl)-1H-pyrazol-4-yl]-2,5-difluorophenyl}-3-fluoropyrrolidine-1-sulfonamide; (3R)-N-{3-[1-(5-{4-[(1-{5-[(3R)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4- perazin-1-yl}pyridin-2-yl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl]-2,5- yl}-3-fluoropyrrolidine-1-sulfonamide; (3R)-3-(4-{4-[(4-{4-[4-(5-chloro-3- yl)sulfamoyl]amino}-2-fluorophenyl)-3-(pyrdin-4-yl)-1H-pyrazol-1- yl]phenyl}piperazin-1-yl)methyl]piperidin-1-yl}phenyl)piperidine-2,6-dione; 1-(4-{4-[(4-{4- [4-(5-chloro-3-{[ethyl(methyl)su }-2-fluorophenyl)-3-(pyridin-4-yl)-1H- pyrazol-1-yl]phenyl}piperazin-1 eridin-1-yl}phenyl)-1,3-diazinane-2,4-dione; rac-(3R)-3-(6-{4-[(4-{4-[4-(5-ch methyl)sulfamoyl]amino}-2-fluorophenyl)-3- (pyridin-4-yl)-1H-pyrazol-1-yl]p n-1-yl)methyl]piperidin-1-yl}pyridin-3- yl)piperidine-2,6-dione; R)-3-(6-{4-[(4-{4-[4-(5-chloro-3- {[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-3-(pyridin-4-yl)-1H-pyrazol-1- yl]henl}ierazin-1-l)methl]ieridin-1-l} ridin-3-l)ieridine-26-dione (3R)-3-(4- { 1 d (pyridin-4-yl)-1H-pyrazol-1-yl]pyridin-3-yl}piperazin-1-yl)methyl]piperidin-1-yl}phenyl)- 1,3-diazinane-2,4-dione; rac-(3R)-3-(6-{4-[(4-{6-[4-(5-chloro-3- {[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl]pyridin- 3-yl}piperazin-1-yl)methyl]piperidin-1-yl}pyridin-3-yl)piperidine-2,6-dione; 1-(6-{4-[(4-{6- [4-(5-c hyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-3-(pyridin-4-yl)-1H- pyrazo n-3-yl}piperazin-1-yl)methyl]piperidin-1-yl}pyridin-3-yl)-1,3-diazinane- 2,4-di (3R)-3-(6-{4-[(4-{6-[4-(5-chloro-3-{[ethyl(methyl)sulfamoyl]amino}-2- fluoro ridin-4-yl)-1H-pyrazol-1-yl]pyridin-3-yl}pipe n-1- yl)met -1-yl}pyridin-3-yl)piperidine-2,6-dione; (3 )-N-[5-chloro-3-(1-{4-[(3R)- 4-({1-[4-(2,4-dioxo-1,3-diazinan-1-yl eridin-4-yl}methyl)-3-methylpiperazin-1- yl]phenyl}-3-(pyridin-4-yl)-1H-pyraz uorophenyl]-3-fluoropyrrolidine-1- sulfonamide; N-[5-c -[(3R)-4-[(1-{4-[(3R)-2,6-dioxopiperidin-3- yl]phenyl}piperidin-4-yl)methyl]-3-m in-1-yl]phenyl}-3-(pyridin-4-yl)-1H- pyrazol-4-yl)-2-fluorophenyl]pyrroli amide; ( )-N-[5-chloro-3-(1-{4-[(3R)-4- [(1-{4-[(3R)-2,6-dioxopiperidin-3-yl] pey}pperidin-4-yl) methyl]-3-methylpiperazin-1- yl]phenyl}-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2-fluorophenyl]-3-fluo sulfonamide; (3R)-N-[5-chloro-3-(1-{4-[(3R)-4-[(1-{5-[(3 eridin-3- yl]pyridin-2-yl}piperidin-4-yl)methyl]-3-methylpiperazin-1-yl]phen -yl)-1H- pyrazol-4-yl)-2-fluorophenyl]-3-fluoropyrrolidine-1-sulfonamide; N {4-[(3R)- 4-({1-[4-(2,4-dioxo-1,3-diazinan-1-yl)phenyl]piperidin-4-yl}methyl) -- ypp azin-1- y -yl)-2-fluorophenyl]pyrrolidine-1-sulfonamide; ( - - -c oo-- -{- -- -{-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4- yl)methyl]-3-methylpiperazin-1-yl]pyridin-2-yl}-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2- fluoropheny olidine-1-sulfonamide; (3R)-N-[5-chloro-3-(1-{5-[(3R)-4-[(1-{5- [(3RS)-2,6- 3-yl]pyridin-2-yl}piperidin-4-yl)methyl]-3-methylpiperazin-1- yl]pyridin-2 -4-yl)-1H-pyrazol-4-yl)-2-fluorophenyl]-3-fluoropyrrolidine-1- sulfonamid 3R)-N-[5-chloro-3-(1-{5-[(3R)-4-({1-[4-(2,4-dioxo-1,3-diazinan-1- yl)phenyl]p ethyl)-3-methylpiperazin-1-yl]pyridin-2-yl}-3-(pyridin-4-yl)-1H- pyrazol-4-y yl]-3-fluoropyrrolidine-1-sulfonamide; N-[5-chloro-3-(1-{5-[(3R)- 4-[(1-{5-[(3 iperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]-3- methylpiper azin-1-yl]pyridin-2-yl}-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2- fluorophenyl]pyrrolidine-1-sulfonamide; N-[5-chloro-3 dioxo-1,3- diazinan-1-yl)phenyl]piperidin-4-yl}methyl)-3-methylp 3- (pyridin-4-yl)-1H-pyrazol-4-yl)-2-fluorophenyl]pyrrolid loro-3-(1- {5-[(3R)-4-[(1-{5-[(3R)-2,6-dioxopiperidin-3-yl]pyridin ]-3- methylpiperazin-1-yl]pyridin-2-yl}-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2- fluorophenyl]pyrrolidine-1-sulfonamide; N-[5-chloro-3-(1-{5-[(3R)-4-[(1-{4-[(3R)-2,6- dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]-3-methylpiperazin-1-yl]pyridin-2-yl}-3- zol-4-yl)-2-fluorophenyl]pyrrolidine-1-sulfonamide; (RS)-N-(5-chloro- 2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin- n-4-yl)-1H-pyrazol-4-yl)-2-fluorophenyl)butane-2-sulfonamide; rac- -{4-[4-({1-[4-(2,4-dioxo-1,3-diazinan-1-yl)phenyl]piperidin-4- -yl]phenyl}-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2-fluorophenyl]butane- )-N-(5-chloro-3-(1-(4-(4-((1-(5-((S)-2,6-dioxopiperidin-3-yl)pyridin-2- yl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2- fluorophenyl)butane-2-sulfo - dioxopiperidin-3-yl]phenyl} 1H-pyrazol-4-yl]-2-fluoroph - [(3R)-2,6-dioxopiperidin-3- (pyridin-4-yl)-1H-pyrazol-4 - chloro-3-[1-(4-{4-[(1-{5-[(3 yl)methyl]piperazin-1-yl}phenyl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl]-2-fluorophenyl}-3- fluoroazetidine-1-sulfonamide; N-{5-chloro-3-[1-(4-{4-[(1-{4-[(3R)-2,6-dioxopiperidin-3- yl]phenyl}piperidin-4-yl)methyl]piperazin-1-yl}phenyl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl]-2- fluorophenyl}-3-fluoroazetidine-1-sulfonamide; (3R)-N-{5-chloro-3-[1-(4-{4-[(1-{5-[(3R)- 2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-1-yl}-2-fluorophenyl)- 3-(pyridin-4-yl)-1H-pyrazol-4-yl]-2-fluorophenyl}-3-fluoropyrroli amide; (3R)- N-{5-chloro-3-[1-(4-{4-[(1-{5-[(3RS)-2,6-dioxopiperidin-3-yl]pyri ridin-4- yl)methyl]piperazin-1-yl}-2-fluorophenyl)-3-(pyridin-4-yl)-1H-py fluorophenyl}-3-fluoropyrrolidine-1-sulfonamide; (3R)-N-{5-chlo [(1-{4-[(3R)- 2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]piperazin-1- henyl)-3- (pyridin-4-yl)-1H-pyrazol-4-yl]-2-fluorophenyl}-3-fluoropyrrolidi ide; rac- - {5-chloro-3-[1-(4-{4-[(1-{5-[(3R)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4- yl)methyl]piperazin-1-yl}-2-fluorophenyl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl]-2- fluoroph l fl idine-1-sulfonamide; N-{5-chloro-3-[1-(4-{4-[(1-{4-[(3R)-2,6- dioxop }piperidin-4-yl)methyl]piperazin-1-yl}-2-fluorophenyl)-3- (pyridi -yl]-2-fluorophenyl}-3-fluoroazetidine-1-sulfonamide; N-[5- chloro- ,4-dioxo-1,3-diazinan-1-yl)phenyl]piperidin-4- yl}met -fluorophenyl}-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2- fluorop dine-1-sulfonamide; N-{3-[1-(4-{4-[(1-{4-[(3R)-2,6- dioxopi p - -y p y}piperidin-4-yl)methyl]piperazin-1-yl}-2-fluorophe nyl)-3- (pyridin-4-yl)-1H-pyrazol-4-yl]-2,5-difluorophenyl}pyrr (4-{4-[(1-{5-[(3R)-2,6-dioxopiperidin-3-yl]pyridin-2-yl yl}-2-fluorophenyl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl]-2 sulfonamide; N-{3-[1-(5-{4-[(1-{4-[(3R)-2,6-dio yl)methyl]piperazin-1-yl}pyrimidin-2-yl)-3-(pyridin-4-y difluorophenyl}pyrrolidine-1-sulfonamide; dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]p y y y (pyridin-4-yl)-1H-pyrazol-4-yl]-2,5-difluorophenyl}pyrrolidine-1-sulfonamide; N-{5-chloro- 3-[1-(4-{4-[(1-{4-[(3R)-2,6-dioxopiperidin-3-yl]-3-fluorophenyl}piperidin-4- yl)met yl}phenyl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl]-2- fluoro ne-1-sulfonamide; rac-N-{5-chloro-3-[1-(4-{4-[(1-{5-[(3R)-2,6- dioxop ridin-2-yl}piperidin-4-yl)methyl]-1,4-diazepan-1-yl}-2-fluorophenyl)- 3-(pyr razol-4-yl]-2-fluorophenyl}pyrrolidine-1-sulfonamide; N-{5-chloro-3- [1-(4- 2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]-1,4-diazepan-1- yl}-2-f luorophenyl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl]-2-fluorophenyl}pyrrolidine-1- sulfonamide; rac-N-{5-chloro-3-[1-(4-{4-[(1-{4-[(3R)-2,6-dioxopiperidin-3-yl]-2- fluorophenyl}piperidin-4-yl)methyl]piperazin-1-yl}phenyl)-3-(pyridin-4-yl)-1H-pyrazol-4- yl]-2-fluorophenyl}pyrrolidine-1-sulfonamide; rac-N-{5-chloro-3-[1-(4-{4-[(1-{4-[(3R)-2,6- dioxopiperidin-3-yl]-3-fluorophenyl}pi zin-1-yl}phenyl)-3- (pyridin-4-yl)-1H-pyrazol-4-yl]-2-fluor onamide; N-[5- (difluoromethyl)-3-[1-(4-{4-[(1-{4-[(3R phenyl}piperidin-4- yl)methyl]piperazin-1-yl}phenyl)-3-(py l]-2- fluorophenyl]pyrrolidine-1-sulfonamide yl)-3-[1-(4-{4-[(1-{5-[(3R)- 2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-1-yl}ph (pyridin-4-yl)-1H-pyrazol-4-yl]-2-fluorophenyl]pyrrolidine-1-sulfonamide; N- - (6-{4-[(1-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]pipe yl}pyridin-3-yl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl]-2-fluorophenyl}pyrrolidine sulfonamide; rac-N-{5-chloro-3-[1-(6-{4-[(1-{5-[(3R)-2,6-dioxopiperidin - yl}piperidin-4-yl)methyl]piperazin-1-yl}pyridin-3-yl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl]-2- fluorophenyl}pyrrolidine-1-sulfonamide; N-{5-chloro-3-[1-(4-{4-[(1-{4-[(3R)-2,6- dioxopiperidin-3-yl]phe l i i i 4 l)methyl]piperazin-1-yl}-2,5-difluorophenyl)-3- (pyridin-4-yl)-1H-pyraz enyl}pyrrolidine-1-sulfonamide; rac-N-{5-chloro- 3-[1-(4-{4-[(1-{5-[(3R)- -3-yl]pyridin-2-yl}piperidin-4- yl)methyl]piperazin-1-y yl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl]-2- fluorophenyl}pyrrolidine- -su onam de; N-[5-chloro-3-(1-{4-[4-({1-[5-(2,4-dioxo-1,3- diazinan-1-yl)pyridin-2-yl]piperidin-4-yl}methyl)piperazin-1-yl]p din-4-yl)- 1H-pyrazol-4-yl)-2-fluorophenyl]pyrrolidine-1-sulfonamide; N-[ hyl)-3-(1-{4- [4-({1-[4-(2,4-dioxo-1,3-diazinan-1-yl)phenyl]piperidin-4-yl}met -yl]-2- fluorophenyl}-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2-fluorophenyl] ulfonamide; rac-N-[5-(difluoromethyl)-3-[1-(4-{4-[(1-{5-[(3R)-2,6-dioxopiper n- -y ]pyr din-2- yl}piperidin-4-yl)methyl]piperazin-1-yl}-2-fluorophenyl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl]- 2-fluorophenyl]pyrrolidine-1-sulfonamide; N-[5-chloro-3-(1-{5-[4-({1-[4-(2,4-dioxo-1,3- diazin yl]piperidin-4-yl}methyl)piperazin-1-yl]pyrimidin-2-yl}-3-(pyridin-4-yl)- 1H-py -fluorophenyl]pyrrolidine-1-sulfonamide; rac-N-{5-chloro-3-[1-(5-{4-[(1- {5-[(3 piperidin-3-yl]pyridin-2-yl}piperidin-4-yl)m hyl]piperazin-1- yl}pyrimidin-2-yl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl]-2-fluorophenyl}pyrrolidine-1- sulfonamide; N-{5-chloro-3-[1-(5-{4 )-2,6-dioxopiperidin-3-yl]phenyl}piperidin- 4-yl)methyl]piperazin-1-yl}pyrimidi ridin-4-yl)-1H-pyrazol-4-yl]-2- fluorophenyl}pyrrolidine-1-sulfonam -[5-chloro-3-(1-{4-[4-({1-[4-(2,4-dioxo-1,3- diazinan-1-yl)phenyl]piperidin-4-yl} azin-1-yl]- fluorophenyl}-3-(pyridin-4- yl)-1H-pyrazol-4-yl)-2-fluorophenyl]pyrrolidine-1-sulfonamide; N-[5-(difluoromethyl)-3-[1- ( -1-yl}-2- namide; idin-4- f uorop eny }pyrro d ne- -su onam de; N-{5-c oro-3-[ -( -{ -[( -{ -[(3R)-2,6- dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]piperazin-1-yl}-3-fluorophenyl)-3- (pyridin-4-yl)-1H-pyrazol-4-yl]-2-fluorophenyl}pyrrolidine-1-sulfonamide; (3R)-N-[5- chloro-3-(1-{4-[4-({1-[4-(2,4-dioxo-1,3-diazinan-1-yl)phenyl]piperidin-4- yl}methyl)piperazin-1-yl]-3-fluorophenyl}-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2- fluorophenyl]-3-fl {4-[(1-{5- [(3RS)-2,6-dioxop 3- fluorophenyl)-3-(p ne-1- sulfonamide; (3R)-N-{5-chloro-3-[1-(4-{4-[(1-{4-[(3R)-2,6-dioxopiperidin-3- yl]phenyl}piperidin-4-yl)methyl]piperazin-1-yl}-3-fluorophenyl)-3-(pyridin-4-yl)-1H- pyrazol-4-yl]-2-fluorophenyl}-3-fluoropyrrolidine-1-sul -(1-{4-[4- ({1-[5-(2,4-dioxo-1,3-diazinan-1-yl)pyridin-2-yl]piperid - yl]phenyl}-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2-fluorop sulfonamide; N-[5-chloro-3-(1-{4-[4-({1-[5-(2 pyridin-2- yl]piperidin-4-yl}methyl)piperazin-1-yl]-2-fluorophenyl}-3-(pyridin-4-yl)-1H-pyrazol-4-yl)- 2-fluorophenyl]-3-fluoroazetidine-1-sulfonamide; N-[5-chloro-3-(1-{4-[4-({1-[5-(2,4-dioxo- 1,3-diazinan-1-yl)pyridin-2-yl]piperidin-4-yl}methyl)piperazin-1-yl]-2-fluorophenyl}-3- ( razol-4-yl)-2-fluorophenyl]pyrrolidine-1-sulfonamide; (3R)-N-[5-chloro- 4-dioxo-1,3-diazinan-1-yl)pyridin-2-yl]piperidin-4-yl}methyl)piperazin- }-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2-fluorophenyl]-3- f ulfonamide; N-{5-chloro-3-[1-(4-{4-[(1-{5-[(3R)-2,6-dioxopiperidin-3- idin-4-yl)methyl]piperazin-1-yl}phenyl)-3-(pyridin-4-yl)-1H-pyrazol-4- y yclopentanesulfonamide; rac-N -{5-chloro-3-[1-(4-{4-[(1-{5-[(3R)-2,6- dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-1-yl}phenyl)-3-(pyridin-4- yl)-1H-pyrazol-4-yl]-2-fluorophenyl}cyclopentanesulfonamide; N-{5-chloro-3-[1-(4-{4-[(1- {4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]piperazin-1-yl}phenyl)-3- (pyridin-4-yl)-1H-pyrazol-4-yl]-2-fluorophenyl}cyclopentanesulfonamide; (3R)-3-(6-{4-[(4- {4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2,5-difluorophenyl)-3-(pyridin-4-yl)-1H-pyrazol- 1-yl]phenyl}piperazin-1-yl)methyl]piperidin-1-yl}pyridin-3-yl)piperidine-2,6-dione; rac- (3R)-3-(6-{4-[(4-{4-[4-(3-{[ oyl]amino}-2,5-difluorophenyl)-3-(pyridin- 4-yl)-1H-pyrazol-1-yl]pheny hyl]piperidin-1-yl}pyridin-3-yl)piperidine- 2,6-dione; (3R)-3-(4-{4-[(4 thyl)sulfamoyl]amino}-2,5-difluorophenyl)- 3-(pyridin-4-yl)-1H-pyrazol- in-1-yl)methyl]piperidin-1- yl}phenyl)piperidine-2,6-dio 4-[(3R)-4-[(1-{4-[(3R)-2,6-dioxopiperidin-3- yl]phenyl}piperidin-4-yl)me zin-1-yl]p nyl}-3-(pyridin-4-yl)-1H- pyrazol-4-yl)-2-fluoropheny mide; (3R)-3-(6-{4-[(4-{4-[4-(3- { fl ( p 2 y 1 2- y)pper n--y)me y)-,- me ypperazn--y)-- uoropeny)--(pyr n--y)- 1H-pyrazol-4-yl)-2-fluorophenyl)pyrrolidine-1-sulfonamide; N-{5-chloro-3-[1-(5-{4-[(1-{5- [(3S)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-1-yl}pyridin-2- yl)-3-(pyrid N-{5- chloro-3-[1 - yl)methyl]p fluoropheny -[(3R)-2,6- dioxopiperi yl)-3- (pyridin-4-y {5-chloro- 3-[1-(4-{4-[ yl)methyl]p iperazin-1-yl}phenyl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl]-2- fluorophenyl}pyrrolidine-1-sulfonamide; ra 4-{4-[(1-{4-[(3R)-2,6- dioxopiperidin-3-yl]-3,5-difluorophenyl}piperidin- n-1-yl}phenyl)-3- (pyridin-4-yl)-1H-pyrazol-4-yl]-2-fluorophenyl}py ide; and N-[5-chloro- 3-(1-{4-[4-({1-[5-(2,4-dioxo-1,3-diazinan-1-yl)pyr -yl}methyl)piperazin- 1-yl]phenyl}-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2-f ntanesulfonamide. 84. A pharmaceutical composition comprising e compoun o any one of the previous claims and a pharmaceutically acceptable carrier, excipient, and/or diluent. 85. A method of treating a disease or disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound or composition of any one of the previous claims. r is cancer. us claims for use in therapy. s claims for use in the treatment embodiment, the linker wherein ' n ca es a ac men o , an indicates attachment to UBM.
[000105] In certain embodiments, the compound of Formula (I) is selected from the group consisting of (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(l-(l-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(l-(l-(5- (2,6-dioxopiperidin-3-yl)pyridin-2-yl)-4-methylpiperidine-4-carbonyl)piperidine-4- carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(5-(2- aminopyrimidin-4-yl)-2-(l -(l-(l-(5-(2,6-di oxopiperi din-3 -yl)pyri din-2 -yl)piperidine-4- carbonyl)-4-methylpiperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(l-(l-(4- (2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)-4-methylpiperidine-4- carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(l- (l-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)piperidine-4- carbonyl)piperidin-4-yl)-5-(pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (5)-7V-(3-(2-(l-(l-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4- carbonyl)-4-methylpiperidine-4-carbonyl)piperidin-4-yl)-5-(pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, and (5)-7V-(3-(2-(l-(l-(l-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidine-4-carbonyl)-4-methylpiperidine-4-carbonyl)piperidin-4-yl)-5- (pyridin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide. In certain embodiments, the compond of Formula (I) is selected from the group consisting of (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-(2-(4-(3-(2-(2,6-di oxopiperi din-3-yl)- 1,3- dioxoisoindolin-4-yl)propyl)piperazin-l-yl)acetyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)- 2-fluorophenyl)propane- 1 -sulfonamide, N-(3 -(5 -(2-aminopyrimidin-4-yl)-2-( 1 -(( 15,4r)-4-((6- ((5)-2,6-dioxopiperidin-3-yl)-3,4-dihydroisoquinolin-2(lJ7)-yl)methyl)cyclohexane-l- carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(l- (l-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperidine-4- carbonyl)piperidin-4-yl)-5-(pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (7?)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(2-(4-(2-(2,6-dioxopiperidin-3-yl)- 1.3-dioxoisoindolin-5-yl)piperazin-l-yl)acetyl)-4-methylpiperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(2-(r-(2- (2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)-[l,4'-bipiperidin]-4-yl)acetyl)-4- methylpiperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(5-(2- aminopyrimidin-4-yl)-2-(l-(l-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)methyl)piperidine-4-carbonyl)-4-methylpiperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-((l-(2-(6- (2,6-dioxopiperidin-3-yl)-3,4-dihydroisoquinolin-2(U7)-yl)acetyl)piperidin-4- yl)methyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-7V-(3-(5-(2- aminopyrimidin-4-yl)-2-(3-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)-3- azaspiro[5.5 ]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (S)-N-(3-(2- (l-(l-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperidine-4- carbonyl)piperidin-4-yl)-5-(pyridin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(2-(r-(2-(2,6-dioxopiperidin-3-yl)-
1.3-dioxoisoindolin-5-yl)-[l,4'-bipiperidin]-4-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(2-(4-(2- (2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperazin-l-yl)acetyl)piperidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4- yl)-2-(2-( 1 -( 1 -(1 -(2-(2,6-dioxopiperi din-3 -yl)- 1 ,3-dioxoisoindolin-5-yl)piperidin-4- yl)azetidine-3-carbonyl)piperidin-4-yl)propan-2-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, 7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-((l-((17?,4r)-4-(3-((7?)-2,6- dioxopiperi din-3 -yl)phenoxy)cy cl ohexane-l-carbonyl)piperidin-4-yl)methyl)piperi din-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4- yl)-2-(3-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)-3- azaspiro[5.5 ]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(5- (2-aminopyrimidin-4-yl)-2-(l-(l-(2-(l-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)- 4-hydroxypiperidin-4-yl)acetyl)azetidin-3-yl)piperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(l-(2-(l-(5- (2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)acetyl)piperidin-4-yl)phenyl)thiazol-4- yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(4-((l- (4-(2, 6-dioxopiperi din-3 -yl)phenyl)piperidin-4-yl)methyl)piperazin-l-yl)phenyl)thi azol -4- yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(l-(2- (l-(4-((2,6-dioxopiperi din-3 -yl)amino)phenyl)piperidin-4-yl)acetyl)piperi din-4- yl)phenyl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(5-(2- aminopyrimidin-4-yl)-2-(4-(l-(l-(5-(2,6-dioxopiperi din-3-yl)pyri din-2 -yl)piperidine-4- carbonyl)piperidin-4-yl)phenyl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (S)-N- (3-(5-(2-aminopyrimidin-4-yl)-2-(4-(l-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)methyl)piperidin-4-yl)phenyl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, N-(3- (5-(2-aminopyrimidin-4-yl)-2-(3-(((15,4r)-4-((5-((S)-2,6-dioxopiperidin-3-yl)pyridin-2- yl)oxy)cyclohexyl)methyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(4-(l-(4- (2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)piperazin-l-yl)phenyl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-5-(4-(9-(5-(2-aminopyrimidin-4-yl)-4-(2-fluoro-3- (propylsulfonamido)phenyl)thiazol-2-yl)-3-azaspiro[5.5]undecane-3-carbonyl)piperidin-l- yl)-N-(2,6-dioxopiperidin-3-yl)picolinamide, 7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-(2-((5)- l-(5-((5)-2,6-dioxopiperidin-3-yl)pyridin-2-yl)pyrrolidin-3-yl)ethyl)-3-azaspiro[5.5]undecan- 9-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(5-(2-aminopyrimidin-4- yl)-2-(l-(l-(2-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)acetyl)azetidin-3- yl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-7V-(3-(5-(2- aminopyrimidin-4-yl)-2-(3-(l -(5-(2,6-di oxopiperidin-3-yl)pyri din-2 -yl)piperidine-4- carbonyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(l-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2- yl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (5)-7V-(3-(2-(l-(l-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4- carbonyl)piperidine-4-carbonyl)piperidin-4-yl)-5-(pyridin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(l-(l-((l-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidin-4-yl)methyl)piperidine-4-carbonyl)piperidin-4-yl)-5-(2- (methylamino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (R)-N-(3 - (5-(2-aminopyrimidin-4-yl)-2-(2-(2-(l'-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)-[l,4'-bipiperidin]-4-yl)acetyl)-2-azaspiro[3.5]nonan-7-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(l-(l-(l-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidin-4-yl)-5-(pyridin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, 7V-(3-(5-(2-aminopyrimidin-4-yl)-2- (l-((l-(((15,4r)-4-(4-((5)-2,6-dioxopiperidin-3-yl)phenoxy)cyclohexyl)methyl)piperidin-4- yl)methyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-N-(3-(5- (2-aminopyrimidin-4-yl)-2-(2-(l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)piperidine-4-carbonyl)-2-azaspiro[3.5]nonan-7-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (5)-7V-(3-(2-(l-(l-(2-(l-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4- yl)acetyl)piperidine-4-carbonyl)piperidin-4-yl)-5-(pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(2-(l-(l-(l-(5- (2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidin- 4-yl)ethyl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-N-(3-(5-(2- aminopyrimidin-4-yl)-2-(2-(2-(4-(2-(2, 6-dioxopiperi din-3-yl)- 1,3 -di oxoisoindolin-5- yl)piperazin-l-yl)acetyl)-2-azaspiro[3.5]nonan-7-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (7?)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(4-(l-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidine-4-carbonyl)piperazin-l-yl)phenyl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(l-(l-(l-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidin-4-yl)-5-(pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4- yl)-2-(l-(l-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)piperidine-4- carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-N-(3-(5-(2- aminopyrimidin-4-yl)-2-(4-(4-((l-(4-(2, 6-dioxopiperi din-3-yl)phenyl)piperidin-4- yl)methyl)piperazin-l-yl)phenyl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (S)-N- (3-(5-(2-aminopyrimidin-4-yl)-2-(l-((l-(l-(5-(2,6-dioxopiperidin-3-yl)pyri din-2- yl)piperidine-4-carbonyl)piperidin-4-yl)methyl)piperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(4-(2-(l-(5- (2, 6-dioxopiperi din-3 -yl)pyri din-2 -yl)piperi din-4-yl)acetyl)piperazin- l-yl)phenyl)thi azol-4- yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-(2-(r- (2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)-[l,4'-bipiperidin]-4-yl)acetyl)-3- azaspiro[5.5 ]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(5- (2-aminopyrimidin-4-yl)-2-(l-(l-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)methyl)piperidine-4-carbonyl)-4-methylpiperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(l-(l-(l-(4-(2,6-dioxopiperidin-3- yl)phenyl)piperidine-4-carbonyl)-4-methylpiperidine-4-carbonyl)piperidin-4-yl)-5-(2- (isopropylamino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-N- (3-(5-(2-aminopyrimidin-4-yl)-2-(3-(2-(4-(2-(2, 6-dioxopiperi din-3-yl)-l,3-dioxoisoindolin-5- yl)piperazin-l-yl)acetyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, 7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-((l-((17?,4r)-4-(4-((7?)-2,6- dioxopiperi din-3 -yl)phenoxy)cy cl ohexane-l-carbonyl)piperidin-4-yl)methyl)piperi din-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4- yl)-2-(2-(6-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)hexanoyl)-2- azaspiro[3.5]nonan-7-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, 7V-(3-(2-(l-(l- (l-(5-((5)-2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4- carbonyl)piperidin-4-yl)-5-(2-(((7?)-l-hydroxypropan-2-yl)amino)pyrimidin-4-yl)thiazol-4- yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(4-((l- (5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-l-yl)phenyl)thiazol- 4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, rac-(37?)-3 - { 6-[4-(4-{4-[5-(2-aminopyrimidin- 4-yl)-4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3-thiazol-2-yl]piperidine-l- carbonyl}piperidine-l-carbonyl)piperidin-l-yl]pyridin-3-yl}piperidine-2, 6-dione, ,rac-(37?)-3- {6-[4-(4-{4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-5-{2-[(propan-2- yl)amino]pyrimidin-4-yl } - 1 ,3 -thiazol-2-yl]piperidine- 1 -carbonyl } piperi dine- 1 - carbonyl)piperidin-l-yl]pyridin-3-yl}piperidine-2, 6-dione (5)-7V-(3-(5-(2-aminopyrimidin-4- yl)-2-(l-(l-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperidine-4- carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(5-(2- aminopyrimidin-4-yl)-2-(l-(l-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)methyl)piperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-((l-(2-(2,6-dioxopiperidin-3-yl)-l- oxoisoindolin-5-yl)piperidin-4-yl)methyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(2-(2-(2- (2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)acetyl)-4- methylpiperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-N-(3-(5-(2- aminopyrimidin-4-yl)-2-(3-(l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)piperidine-4-carbonyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (7?)-7V-(3-(2-(l-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)- 2,7 -di azaspiro [3.5 ]nonan-7 -yl)acetyl)piperidin-4-yl)-5-(2-(methylamino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4- yl)-2-(3-(6-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)hexanoyl)-3- azaspiro[5.5 ]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-N-(3-(5- (2-aminopyrimidin-4-yl)-2-(l-(l-(2-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)acetyl)-4-methylpiperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(l-(l-(l-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidin-4-yl)-5-(2- (methylamino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (R)-N-(3 - (5-(2-aminopyrimidin-4-yl)-2-(l-(l-(2-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin- 4-yl)acetyl)piperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (5)-7V-(3-(2-(l-(l-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4- carbonyl)piperidine-4-carbonyl)piperidin-4-yl)-5-(2-(isopropylamino)pyrimidin-4-yl)thiazol- 4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(5-(2-(cyclopropylamino)pyrimidin-4- yl)-2-(l-(l-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4- carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(l- (l-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)-4-methylpiperidine-4- carbonyl)piperidin-4-yl)-5-(pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, 7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-(2-( (R)-l-(4-((,S)-2,6-dioxopiperidin-3- yl)phenyl)pyrrolidin-3-yl)acetyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(2-(2-(2-(2- (2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)acetyl)-2- azaspiro[3.5]nonan-7-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (R)-N-(3-(5-(2- aminopyrimidin-4-yl)-2-(l-((l-(2-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)acetyl)piperidin-4-yl)methyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (7?)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(2-(2-(2-(2,6-dioxopiperidin-3-yl)- l,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-(l-(l-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-17/-benzo[d]imidazol-4-yl)piperidine-4- carbonyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (R)-7V-(3-(2-(l-(l-((l-(4-(2,6-dioxopiperi din-3 -yl)phenyl)piperi din-4-yl)methyl)piperi dine-4- carbonyl)piperidin-4-yl)-5-(2-(methylamino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(l-(l-(2- (2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperidin-4-yl)azetidine-3- carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-N-(3-(5-(2- aminopyrimidin-4-yl)-2-(2-(l-(l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)piperidin-4-yl)azetidine-3-carbonyl)-2-azaspiro[3.5]nonan-7-yl)thiazol-4-yl)-2- fluorophenyl)propane- 1 -sulfonamide, (S)-N-(3 -(5-(2-aminopyrimidin-4-yl)-2-(l -( 1 -(( 1 -( 1 - (2, 6-dioxopiperi din-3 -yl)-3-methyl-2-oxo-2, 3 -dihydro- l/7-benzo[J]imidazol-4-yl)piperi din- 4-yl)methyl)piperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-(2-(2-(2-(2,6-dioxopiperidin-3-yl)- l,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)acetyl)-3-azaspiro[5.5]undecan-9- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4- yl)-2-(2-(l-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)-2,7- diazaspiro[3.5]nonan-7-yl)acetyl)piperidin-4-yl)propan-2-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, and (R)-4-((4-(5-(2-aminopyrimidin-4-yl)-4-(2-fluoro- 3-(propylsulfonamido)phenyl)thiazol-2-yl)piperidin-l-yl)methyl)-7V-(2,6-dioxopiperidin-3- yl)benzamide. In certain embodiments, the compound of Formula (I) is selected from the group consisting of (R)-4-(4-((6-((4-(2-(tert-butyl)-4-(2-fluoro-3-(propylsulfonamido)phenyl)thiazol-5- yl)pyrimidin-2-yl)amino)-2-azaspiro[3.3]heptan-2-yl)methyl)piperidin-l-yl)-7V-(2,6- di oxopiperi din-3 -yl)benzamide, 7V-(3-(2-(tert-butyl)-5-(2-((2-(2-((5)-l-(5-((5)-2,6- dioxopiperidin-3-yl)pyridin-2-yl)pyrrolidin-3-yl)ethyl)-2-azaspiro[3.3]heptan-6- yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (R)-N-(3-(2- (tert-butyl)-5-(2-((2-(2-(l'-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)-[l,4'- bipiperidin]-4-yl)acetyl)-2-azaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(2-(tert-butyl)-5-(2-((2-(l-(l-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-17/-benzo[d]imidazol-4-yl)piperidine-4- carbonyl)-2-azaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(2-(tert-butyl)-5-(2-((2-(l-(l-(2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperidin-4-yl)azetidine-3-carbonyl)-2- azaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (R)-7V-(3-(2-(tert-butyl)-5-(2-((2-(2-(2-(2-(2,6-di oxopiperi din-3 -yl)- 1,3- dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)acetyl)-2-azaspiro[3.3]heptan-6- yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (R)-N-(3-(2- (tert-butyl)-5-(2-((2-(6-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)hexanoyl)-2- azaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (R)-7V-(3-(2-(tert-butyl)-5-(2-((2-((l-((l-(4-(2,6-dioxopiperidin-3- yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)-2-azaspiro[3.3]heptan-6- yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (R)-N-(3-(2- (tert-butyl)-5-(2-((2-(2-(4-(3-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)propyl)piperazin-l-yl)acetyl)-2-azaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4- yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(2-(tert-butyl)-5-(2-((2-(l-((l-(4-(2,6- dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)-4-fluoropiperidine-4-carbonyl)-2- azaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (R)-7V-(3-(2-(tert-butyl)-5-(2-((2-((l-(l-(4-(2,6-dioxopiperidin-3- yl)phenyl)piperidine-4-carbonyl)piperidin-4-yl)methyl)-2-azaspiro[3.3]heptan-6- yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, S)-N-(3-(2- (tert-butyl)-5-(2-((r-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)- [ 1 ,4'-bipiperidin]-4-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 - sulfonamide, (R)-7V-(3-(2-(tert-butyl)-5-(2-((7-(2-(4-(4-((2,6-dioxopiperidin-3- yl)amino)phenyl)piperidin-l-yl)acetyl)-7-azaspiro[3.5]nonan-2-yl)amino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, 7V-(3-(2-(Zert-butyl)-5-(2-((7- (((15,4r)-4-(4-((5)-2,6-dioxopiperidin-3-yl)phenoxy)cyclohexyl)methyl)-7- azaspiro[3.5]nonan-2-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, ( ?)-7V-(3-(2-(tert-butyl)-5-(2-((7-((l-(2-(2,6-dioxopiperidin-3-yl)-l-oxo-l,2- dihydroisoquinolin-6-yl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)amino)pyrimidin- 4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(2-(terZ-butyl)-5-(2-((7- ((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2- yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, and (R)-N-(3- (2-(tert-butyl)-5-(2-((7-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperazin- l-yl)acetyl)-7-azaspiro[3.5]nonan-2-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide. In certain embodiments, the compound of Formula (I) is selected from the group consisting of
(5)-7V-(3-(2-(tert-butyl)-5-(2-((4-(l-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidin-4- yl)methyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (R)-7V-(3-(2-(tert-butyl)-5-(2-((4-(l-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-5-yl)oxy)acetyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(2-(tert-butyl)-5-(2-((4-(l-(2-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)oxy)acetyl)piperidin-4- yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (R)-N- (3-(2-(tert-butyl)-5-(2-((4-(l-(2-(4-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperazin-l- yl)acetyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, 7V-(3-(2-(tert-butyl)-5-(2-((4-(l-(2-((5)-l-(5-((, )-2,6-dioxopiperidin-3- yl)pyridin-2-yl)pyrrolidin-3-yl)ethyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4- yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-4-(4-((4-(4-((4-(2-(tert-butyl)-4-(2-fluoro-3- (propylsulfonamido)phenyl)thiazol-5-yl)pyrimidin-2-yl)amino)phenyl)piperidin-l- yl)methyl)piperi din- l-yl)-7V-(2,6-dioxopiperi din-3 -yl)benzamide, (R)-5-(4-((4-(4-((4-(2-(7ert- butyl)-4-(2-fluoro-3-(propylsulfonamido)phenyl)thiazol-5-yl)pyrimidin-2- yl)amino)phenyl)piperidin-l-yl)methyl)piperidin-l-yl)-7V-(2,6-dioxopiperidin-3- yl)picolinamide, 7V-(3-(2-(terZ-butyl)-5-(2-((4-(l-(((15,4r)-4-((5-((5)-2,6-dioxopiperidin-3- yl)pyridin-2-yl)oxy)cyclohexyl)methyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol- 4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(tert-butyl)-5-(2-((4-(l-((l-(4-(2,6- dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)amino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, 7V-(3-(2-(tert-butyl)-5-(2-((4-(l-(2-
((5)-l-(4-((5)-2,6-dioxopiperidin-3-yl)phenyl)pyrrolidin-3-yl)acetyl)piperidin-4- yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, 7V-(3- (2-(tert-butyl)-5-(2-((4-(l-(2-( (R)-l-(4-((5)-2,6-dioxopiperidin-3-yl)phenyl)pyrrolidin-3- yl)acetyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, 7V-(3-(2-( ert-butyl)-5-(2-((4-(l-( (R)-l-(5-((, )-2,6-dioxopiperidin-3- yl)pyridin-2-yl)pyrrolidine-3-carbonyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4- yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(terZ-butyl)-5-(2-((4-(l-(l-(4-(2,6- dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)piperidin-4- yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (R)-N- (3-(2-(terZ-butyl)-5-(2-((4-(l-(2-(l'-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)- [l,4'-bipiperidin]-4-yl)acetyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(tert-butyl)-5-(2-((4-(l-(l-(5-(2,6- dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)piperidin-4- yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, N-(3- (2-(tert-butyl)-5-(2-((4-(l-(2-((5)-l-(l-( (R)-2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-l/Z-benzo[ ]imidazol-5-yl)pyrrolidin-3-yl)acetyl)piperidin-4- yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (R)-N- (3-(2-(terZ-butyl)-5-(2-((4-(l-(l-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro- l/Z-benzo[ ]imidazol-4-yl)piperidine-4-carbonyl)piperidin-4-yl)phenyl)amino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(terZ-butyl)-5-(2-((4-(l- (l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)azetidine-3-carbonyl)piperidin-4- yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (R)-N- (3-(2-(terZ-butyl)-5-(2-((4-(l-(l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)piperidine-4-carbonyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(2-(terZ-butyl)-5-(2-((4-(l-(2-(2-(2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7- yl)acetyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-
1 -sulfonamide, (R)-7V-(3-(2-(tert-butyl)-5-(2-((4-(l-(6-(2-(2,6-dioxopiperidin-3-yl)-3- oxoisoindolin-5-yl)hexanoyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(2-(terZ-butyl)-5-(2-((4-(l-(2-(4-(2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperazin-l-yl)acetyl)piperidin-4- yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (S)-5- (4-((4-(((4-(2-(tert-butyl)-4-(2-fluoro-3-(propylsulfonamido)phenyl)thiazol-5-yl)pyrimidin-2- yl)amino)methyl)piperidin- 1 -yl)methyl)piperidin- 1 -yl)-7V-(2,6-dioxopiperi din-3 - yl)picolinamide, (5)-5-(4-((4-(l-((4-(2-(tert-butyl)-4-(2-fluoro-3-
(propylsulfonamido)phenyl)thiazol-5-yl)pyrimidin-2-yl)amino)-2-methylpropan-2- yl)piperi din- l-yl)methyl)piperi din- l-yl)-7V-(2,6-dioxopiperi din-3 -yl)picolinamide, (R)-N-(3- (2-(tert-butyl)-5-(2-(((l-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)methyl)piperidin-4-yl)methyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (R)-7V-(3-(2-(terZ-butyl)-5-(2-((2-(l-((l-(4-(2,6-dioxopiperidin-3- yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-2-methylpropyl)amino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, 5-(4-(( (R)-3-(((4-(2-(tert-butyl)-4-(2- fluoro-3-(propylsulfonamido)phenyl)thiazol-5-yl)pyrimidin-2-yl)amino)methyl)pyrrolidin-l- yl)methyl)piperi din- l-yl)-7V-((5)-2,6-dioxopiperi din-3 -yl)picolinamide, 7V-(3-(2-(tert-butyl)- 5-(2-(((lr,4r)-4-((4-((l-(4-((5)-2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)methyl)piperazin-l-yl)methyl)cyclohexyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, 7V-(3-(2-(Zert-butyl)-5-(2-(((15,45)-4-(4-(l-(5-((5)-2,6- dioxopiperi din-3 -yl)pyri din-2-yl)piperi dine-4-carbonyl)piperazin- 1- yl)cyclohexyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, N- (3-(2-(terZ-butyl)-5-(2-(((lr,4r)-4-(4-(l-(5-((5)-2,6-dioxopiperidin-3-yl)pyridin-2- yl)piperidine-4-carbonyl)piperazin-l-yl)cyclohexyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, 7V-(3-(2-(terZ-butyl)-5-(2-(((lr,4r)-4-(4-((l-(5-((5)-2,6- dioxopiperi din-3 -yl)pyri din-2-yl)piperi din-4-yl)methyl)piperazin- 1- yl)cyclohexyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, N- (3-(2-(terZ-butyl)-5-(2-(((15,45)-4-(4-((l-(5-((5)-2,6-dioxopiperidin-3-yl)pyridin-2- yl)piperidin-4-yl)methyl)piperazin-l-yl)cyclohexyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (37?)-3-{4-[4-({4-[6-({4-[2-tert-butyl-4-(3-
{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3-thiazol-5-yl]pyrimidin-2- yl } amino)pyri din-3 -yl]piperazin- 1 -yl }methyl)piperidin- 1 -yl]phenyl }piperidine-2, 6-dione, (35)-3-{4-[4-({4-[6-({4-[2-tert-butyl-4-(3-{[ethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)-l,3-thiazol-5-yl]pyrimidin-2-yl}amino)pyridin-3-yl]piperazin-l- yl}methyl)piperidin-l-yl]phenyl}piperidine-2, 6-dione, rac-(35)-3-{6-[4-({4-[6-({4-[2-tert- butyl-4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3-thiazol-5-yl]pyrimidin-2- yl } amino)pyri din-3 -yl]piperazin- 1 -yl }methyl)piperidin- 1 -yl]pyri din-3 -yl }piperidine-2,6- dione, rac-(3 S)-3 -(2- { [( 1 r,4r)-4- {4-[6-({4-[2-tert-butyl-4-(3 -
{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3-thiazol-5-yl]pyrimidin-2- yl }amino)pyri din-3 -yl]piperazine-l -carbonyl }cy cl ohexyl]methyl}- 1,2, 3,4- tetrahydroisoquinolin-6-yl)piperidine-2, 6-dione, rac-(3S)-3-(2-{[(lr,4r)-4-{4-[6-({4-[2-tert- butyl-4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3-thiazol-5-yl]pyrimidin-2- yl }amino)pyri din-3 -yl]piperazine-l -carbonyl }cy cl ohexyl]methyl}- 1,2, 3,4- tetrahydroisoquinolin-7-yl)piperidine-2, 6-dione, (R)-7V-(3-(2-(terZ-butyl)-5-(2-((2-(2-(4-(4- ((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-l-yl)acetyl)-l,2,3,4-tetrahydroisoquinolin- 6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, ( ?)-5-(4-(6- ((4-(2-(tert-butyl)-4-(2-fluoro-3-(propylsulfonamido)phenyl)thiazol-5-yl)pyrimidin-2- yl)amino)-l,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidin-l-yl)-7V-(2,6-dioxopiperidin-3- yl)picolinamide, V-(3-(2-(ferZ-butyl)-5-(2-((2-( (R)-l-(5-((5)-2,6-dioxopiperidin-3-yl)pyridin- 2-yl)pyrrolidine-3-carbonyl)-l,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(terZ-butyl)-5-(2-((2-(2- (4-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperazin-l-yl)acetyl)-l, 2,3,4- tetrahydroisoquinolin-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (5)-7V-(3-(2-(tert-butyl)-5-(2-((l-((l-(2-(6-(2,6-dioxopiperidin-3-yl)-3,4- dihydroisoquinolin-2(lJ7)-yl)acetyl)piperidin-4-yl)methyl)-lJH-pyrazol-4- yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, N-(3-(2-(tert- butyl)-5-(2-((l-((l-((15,4r)-4-(4-((5)-2,6-dioxopiperidin-3-yl)phenoxy)cyclohexane-l- carbonyl)piperidin-4-yl)methyl)-lJH-pyrazol-4-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, 7V-(3-(2-(ter -butyl)-5-(2-((l-((l-((15',4r)-4-((5-((, )-2, 6- dioxopiperi din-3 -yl)pyridin-2-yl)oxy)cy cl ohexane-l-carbonyl)piperidin-4-yl)methyl)- 1H- pyrazol-4-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (R)- 7V-(3-(2-(terZ-butyl)-5-(2-((l-((l-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin- l-yl)acetyl)piperidin-4-yl)methyl)-lJH-pyrazol-4-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-5-(4-(4-((4-((4-(2-(tert-butyl)-4-(2-fluoro-3- (propylsulfonamido)phenyl)thiazol-5-yl)pyrimidin-2-yl)amino)-l//-pyrazol-l- yl)methyl)piperi dine- l-carbonyl)piperidin-l-yl)-7V-(2,6-dioxopiperi din-3 -yl)picolinamide, N- (3-(2-(terZ-butyl)-5-(2-((l -((1 -((/?)- 1 -(5-((5)-2,6-dioxopiperidin-3-yl)pyridin-2-yl)pyrrolidine- 3-carbonyl)piperidin-4-yl)methyl)-lJH-pyrazol-4-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(tert-butyl)-5-(2-((l-((l-(2-(4-(4-(2,6- dioxopiperidin-3-yl)pyridin-2-yl)piperazin-l-yl)acetyl)piperidin-4-yl)methyl)-lJH-pyrazol-4- yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, N-(3-(2-(tert- butyl)-5-(2-((l-((l-(2-((5)-l-(4-((5)-2,6-dioxopiperidin-3-yl)phenyl)pyrrolidin-3- yl)acetyl)piperidin-4-yl)methyl)-lJH-pyrazol-4-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, 7V-(3-(2-(Zert-butyl)-5-(2-((l-((l-(2-( (R)-l-(4-((5)-2,6- dioxopiperi din-3 -yl)phenyl)pyrrolidin-3-yl)acetyl)piperidin-4-yl)m ethyl)- l/f-pyrazol-4- yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, N-(3-(2-(tert- butyl)-5 -(2-(( 1 -( 1 -(( 15,4r)-4-(4-((5)-2, 6-dioxopiperi din-3 -yl)phenoxy)cy clohexane- 1 - carbonyl)piperidin-4-yl)-lJH-pyrazol-4-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, 7V-(3-(2-(tert-butyl)-5-(2-((l-(l-((15',4r)-4-((5-((5)-2,6- dioxopiperidin-3-yl)pyridin-2-yl)oxy)cyclohexane-l-carbonyl)piperidin-4-yl)-lJH-pyrazol-4- yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (7?)-7V-(3-(2- (tert-butyl)-5-(2-((l-(l-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-l- yl)acetyl)piperidin-4-yl)-lJH-pyrazol-4-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-5-(4-(4-(4-((4-(2-(tert-butyl)-4-(2-fluoro-3- (propylsulfonamido)phenyl)thiazol-5-yl)pyrimidin-2-yl)amino)-l/Z-pyrazol-l-yl)piperidine- l-carbonyl)piperidin-l-yl)-N-(2,6-dioxopiperidin-3-yl)picolinamide, 7V-(3-(2-(tert-butyl)-5- (2-((l-(l-( (R)-l-(5-((5)-2,6-dioxopiperidin-3-yl)pyridin-2-yl)pyrrolidine-3- carbonyl)piperidin-4-yl)-lJH-pyrazol-4-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, 7V-(3-(2-(tert-butyl)-5-(2-((l-(l-(2-((5)-l-(4-((5)-2,6- dioxopiperi din-3 -yl)phenyl)pyrrolidin-3 -yl)acetyl)piperi din-4-yl)- l/f-pyrazol-4- yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-7V-(3-(2- (tert-butyl)-5-(2-((3-(l-(2-(6-(2,6-dioxopiperidin-3-yl)-3,4-dihydroisoquinolin-2(lJ7)- yl)acetyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (R)-7V-(3-(2-(tert-butyl)-5-(2-((3-(l-(2-(4-(4-((2,6-dioxopiperidin-3- yl)amino)phenyl)piperidin-l-yl)acetyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4- yl)-2-fluorophenyl)propane- 1 -sulfonamide, N-(3 -(2-(tert-butyl)-5 -(2-((3 -( 1 -((R)- 1 -(5-((5)-
2,6-dioxopiperidin-3-yl)pyridin-2-yl)pyrrolidine-3-carbonyl)piperidin-4- yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (S)-N- (3-(2-(7er -butyl)-5-(2-((3-((l-(2-(6-(2,6-dioxopiperidin-3-yl)-3,4-dihydroisoquinolin-2(lJ7)- yl)acetyl)piperidin-4-yl)oxy)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane- 1 -sulfonamide, (S)-N-(3 -(2-(ter -butyl)-5 -(2-((3 -(( 1 -( 1 -(4-(2, 6- dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)piperidin-4- yl)oxy)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (S)-N-(3 -(2-(tert-butyl)-5 -(2-((3 -(( 1 -( 1 -(3 -(2, 6-dioxopiperi din-3 -yl)phenyl)piperidine-4- carbonyl)piperidin-4-yl)oxy)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, jV-(3-(2-(tert-butyl)-5-(2-((3-((l-((15,4r)-4-(4-((5)-2,6- dioxopiperi din-3 -yl)phenoxy)cy cl ohexane-1 -carbonyl)piperi din-4- yl)oxy)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, N- (3-(2-(ter -butyl)-5-(2-((3-((l-((15,4r)-4-((5-((, )-2,6-dioxopiperidin-3-yl)pyridin-2- yl)oxy)cy cl ohexane-1 -carbonyl)piperidin-4-yl)oxy)phenyl)amino)pyrimidin-4-yl)thi azol -4- yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(2-(terZ-butyl)-5-(2-((3-((l-(2-(4-(4-
((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-l-yl)acetyl)piperidin-4- yl)oxy)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (R)-5-(4-(4-(3-((4-(2-(terZ-butyl)-4-(2-fluoro-3-(propylsulfonamido)phenyl)thiazol-5- yl)pyrimidin-2-yl)amino)phenoxy)piperidine-l-carbonyl)piperidin-l-yl)-7V-(2,6- dioxopiperidin-3-yl)picolinamide, 7V-(3-(2-(tert-butyl)-5-(2-((3-((l-( (R)-l-(5-((5)-2,6- dioxopiperidin-3-yl)pyridin-2-yl)pyrrolidine-3-carbonyl)piperidin-4- yl)oxy)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-7V-(3-(2-(tert-butyl)-5-(2-((3-((l-(2-(4-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperazin- l-yl)acetyl)piperidin-4-yl)oxy)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, 7V-(3-(2-(terZ-butyl)-5-(2-((3-((l-(2-((5)-l-(4-((5)-2,6- dioxopiperidin-3-yl)phenyl)pyrrolidin-3-yl)acetyl)piperidin-4- yl)oxy)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, 7V- (3-(2-(terZ-butyl)-5-(2-((3-((l-(2-( (R)-l-(4-((5)-2,6-dioxopiperidin-3-yl)phenyl)pyrrolidin-3- yl)acetyl)piperidin-4-yl)oxy)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(terZ-butyl)-5-(2-((4-(l-((l-(4-(2,6- dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)amino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(2-(terZ-butyl)-5-(2-((4-(l- ((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperidin-4- yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (S)-N- (3-(2-(terZ-butyl)-5-(2-((4-(4-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)methyl)piperazin-l-yl)-3-fluorophenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(2-(terZ-butyl)-5-(2-((4-(4-((l-(4-(2,6- dioxopiperi din-3 -yl)phenyl)piperi din-4-yl)m ethyl)piperazin- 1 -yl)-3- fluorophenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (25,47?)-l-((5)-2-(5-(4-(4-((4-(2-(terZ-butyl)-4-(2-fluoro-3- (propylsulfonamido)phenyl)thiazol-5-yl)pyrimidin-2-yl)amino)phenyl)piperidin-l-yl)-5- oxopentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-7V-((5)-l-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide, (R)-7V-(3-(2-(terZ-butyl)-5-(2-((2-((l-(2-(2,6- dioxopiperi din-3-yl)- 1 -oxo-1, 2-dihydroisoquinolin-6-yl)piperidin-4-yl)methyl)-l, 2,3,4- tetrahydroisoquinolin-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, 7V-(3-(2-(terZ-butyl)-5-(2-((l-((l-(((15,4r)-4-(4-((5)-2,6-dioxopiperidin-3- yl)phenoxy)cyclohexyl)methyl)piperidin-4-yl)methyl)-lJH-pyrazol-4-yl)amino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (R)-N-(3 -(2-(7ert-butyl)-5 -(2-(( 1 -(( 1 - ((l-(2-(2,6-dioxopiperidin-3-yl)-l-oxo-l,2-dihydroisoquinolin-6-yl)piperidin-4- yl)methyl)piperidin-4-yl)methyl)-lJH-pyrazol-4-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-5-(4-((4-((4-((4-(2-(terZ-butyl)-4-(2-fluoro-3- (propylsulfonamido)phenyl)thiazol-5-yl)pyrimidin-2-yl)amino)-l/Z-pyrazol-l- yl)methyl)piperi din- l-yl)methyl)piperi din- l-yl)-7V-(2,6-dioxopiperi din-3 -yl)picolinamide, N- (3 -(2-(ter -butyl)-5 -(2-(( 1 -(( 1 -(2-((R)~ 1 -(5 -((5)-2, 6-dioxopiperi din-3 -yl)pyridin-2- yl)pyrrolidin-3-yl)ethyl)piperidin-4-yl)methyl)-lJ7-pyrazol-4-yl)amino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(2-(terZ-butyl)-5-(2-((l-(l- ((l-(2-(2,6-dioxopiperidin-3-yl)-l-oxo-l,2-dihydroisoquinolin-6-yl)piperidin-4- yl)methyl)piperidin-4-yl)-lJH-pyrazol-4-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-5-(4-((4-(4-((4-(2-(tert-butyl)-4-(2-fluoro-3- (propylsulfonamido)phenyl)thiazol-5-yl)pyrimidin-2-yl)amino)-l/Z-pyrazol-l-yl)piperidin-l- yl)methyl)piperi din- l-yl)-7V-(2, 6-dioxopiperi din-3 -yl)picolinamide, TV-(3-(2-(te/7-butyl)-5-(2- ((l-(l-(2-( (R)-l-(5-((5)-2,6-dioxopiperidin-3-yl)pyridin-2-yl)pyrrolidin-3-yl)ethyl)piperidin- 4-yl)-lJH-pyrazol-4-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, 7V-(3-(2-(tert-butyl)-5-(2-((l-(l-(2-((5)-l-(5-(() )-2,6-dioxopiperidin-3- yl)pyridin-2-yl)pyrrolidin-3-yl)ethyl)piperidin-4-yl)-lJH-pyrazol-4-yl)amino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(2-(terZ-butyl)-5-(2-((3-(l- ((l-(2-(2,6-dioxopiperidin-3-yl)-l-oxo-l,2-dihydroisoquinolin-6-yl)piperidin-4- yl)methyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, N-(3 -(2-(ter -butyl)-5 -(2-((3 -(1 -(2-((R)~ 1 -(5 -((5 -2,6-dioxopiperi din-3 - yl)pyridin-2-yl)pyrrolidin-3-yl)ethyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4- yl)-2-fluorophenyl)propane- 1 -sulfonamide, N-(3 -(2-(ter -butyl)-5 -(2-((3 -( 1 -(2-((5)- 1 -(5 -((5)- 2,6-dioxopiperidin-3-yl)pyridin-2-yl)pyrrolidin-3-yl)ethyl)piperidin-4- yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (S)-N- (3-(2-(terZ-butyl)-5-(2-((3-(l-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)-4-methylpiperidin- 4-yl)methyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, 7V-(3-(2-(terZ-butyl)-5-(2-((3-((l-(((15,4r)-4-(4-((5)-2, 6- dioxopiperidin-3-yl)phenoxy)cyclohexyl)methyl)piperidin-4- yl)oxy)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (R)-7V-(3-(2-(tert-butyl)-5-(2-((3-((l-((l-(2-(2,6-dioxopiperidin-3-yl)-l-oxo-l,2- dihydroisoquinolin-6-yl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)phenyl)amino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, 7V-(3-(2-(terZ-butyl)-5-(2-((3-((l-(2- ( (R)-l-(5-((5)-2,6-dioxopiperidin-3-yl)pyridin-2-yl)pyrrolidin-3-yl)ethyl)piperidin-4- yl)oxy)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, N- (3-(2-(terZ-butyl)-5-(2-((3-((l-(2-((5)-l-(5-((5)-2,6-dioxopiperidin-3-yl)pyridin-2- yl)pyrrolidin-3-yl)ethyl)piperidin-4-yl)oxy)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane- 1 -sulfonamide, (S)-N-(3 -(2-(tert-butyl)-5 -(2-((3 - (( 1 - (( 1 - (5 - (2 , 6- dioxopiperidin-3-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)methyl)piperidin-4- yl)oxy)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (R)-5-(4-((4-(4-((4-(2-(tert-butyl)-4-(2-fluoro-3-(propylsulfonamido)phenyl)thiazol-5- yl)pyrimidin-2-yl)amino)-l/Z-pyrazol-l-yl)piperidin-l-yl)methyl)piperidin-l-yl)-N-(2,6- dioxopiperidin-3-yl)picolinamide, (R)-5-(4-((4-((4-((4-(2-(tert-butyl)-4-(2-fluoro-3-
(propylsulfonamido)phenyl)thiazol-5-yl)pyrimidin-2-yl)amino)-l/Z-pyrazol-l- yl)methyl)piperi din- l-yl)methyl)piperi din- l-yl)-7V-(2,6-dioxopiperi din-3 -yl)picolinamide, (5)-7V-(3-(2-(tert-butyl)-5-(2-((4-(4-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4- carbonyl)piperazin-l-yl)-3-fluorophenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(5-(2-((4-(l-((l-(4-(2,6-dioxopiperidin-3- yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)-2- methylthiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-((4-(l-((l-(4-(2,6- dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)amino)pyrimidin-4- yl)-2-methylthiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-7V-(3-(5-(2-((5-(4-((l- (5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-l-yl)pyridin-2- yl)amino)pyrimidin-4-yl)-2-methylthiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)- 7V-(3-(5-(2-((5-(4-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperazin-l- yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylthiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, ( ?)-7V-(3-(5-(2-((5-(4-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)methyl)piperazin-l-yl)pyri din-2 -yl)amino)pyrimi din-4-yl)-2-methylthi azol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(2-(terZ-butyl)-5-(2-((4-(4-((l-(4-(2,6- dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperazin-l-yl)phenyl)amino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(terZ-butyl)-5-(2-((4-(4- ((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperazin-l- yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (S)-N- (3-(2-(terZ-butyl)-5-(2-((4-(4-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4- carbonyl)piperazin-l-yl)-3-fluorophenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, rac-(37?)-3-[6-(4-{4-[6-({4-[2-tert-butyl-4-(3-
{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3-thiazol-5-yl]pyrimidin-2- yl}amino)pyridin-3-yl]piperazine-l-carbonyl}piperidin-l-yl)pyridin-3-yl]piperidine-2,6- dione, (5)-7V-(3-(5-(2-((4-(l-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4- carbonyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)-2-methylthiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, 7V-(3-(2-(tert-butyl)-5-(2-((4-(4-( (R)-l-(5-( (R)-2,6- dioxopiperi din-3 -yl)pyridin-2-yl)pyrrolidine-3 -carbonyl)piperazin- 1 -y l)-3 - fluorophenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (R)- 7V-(3-(5-(2-((4-(l-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)methyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)-2-methylthiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, 7V-(3-(2-(terZ-butyl)-5-(2-((4-(4-((R)-l -(5-(( ?)-2,6- dioxopiperi din-3 -yl)pyridin-2-yl)pyrrolidine-3 -carbonyl)piperazin- 1 -y l)-3 - fluorophenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, rac- (35)-3-[6-(3-{4-[6-({4-[2-tert-butyl-4-(3-{ [ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)- l,3-thiazol-5-yl]pyrimidin-2-yl}amino)pyridin-3-yl]piperazine-l-carbonyl}azetidin-l- yl)pyri din-3 -yl]piperidine-2, 6-dione, (5)-7V-(3-(2-(tert-butyl)-5-(2-((4-(4-(2-(l-(4-((2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)piperazin-l-yl)- 3 -fluorophenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (T?)-7V-(3-(2-(te/7-butyl)-5-(2-((4-(4-(2-(6-(2,6-dioxopiperidin-3-yl)-3,4-dihydroisoquinolin- 2(lH)-yl)acetyl)piperazin-l-yl)-3-fluorophenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, 7V-(3-(2-(tert-butyl)-5-(2-((4-(4-((15',4r)-4-((5-((5)-2,6- dioxopiperi din-3 -yl)pyridin-2-yl)oxy)cy cl ohexane-1 -carbonyl)piperazin- l-yl)-3- fluorophenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (R)- 7V-(3-(2-(tert-butyl)-5-(2-((4-(4-(2-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)acetyl)piperazin-l-yl)-3-fluorophenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(terZ-butyl)-5-(2-((4-(4-((l-(5-(2,6- di oxopiperi din-3 -yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin- 1- yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (S)-N- (3-(2-(terZ-butyl)-5-(2-((4-(4-(2-(l-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4- yl)acetyl)piperazin-l-yl)-3-fluorophenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(terZ-butyl)-5-(2-((4-(4-((l-(5-(2,6- di oxopiperi din-3 -yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin- l-yl)-3- fluorophenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (5)- 7V-(3-(5-(2-((4-(l-(2-(l-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4- yl)acetyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)-2-methylthiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, rac-(35)-3-{6-[4-({4-[6-({4-[4-(3-
{ [ethyl (methyl)sulfamoyl]amino}-2-fluorophenyl)-2-methyl-l, 3-thi azol-5-yl]pyrimidin-2- yl } amino)pyri din-3 -yl]piperazin- 1 -yl }methyl)piperidin- 1 -yl]pyri din-3 -yl }piperidine-2,6- dione, rac-(35)-3-[6-(4-{4-[6-({4-[2-tert-butyl-4-(3-{[ethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)-l, 3-thi azol-5-yl]pyrimidin-2-yl}amino)pyridin-3-yl]piperazine-l -carbonyl }-4- methylpiperi din- l-yl)pyri din-3 -yl]piperidine-2, 6-dione, (37?)-3-{4-[4-({4-[6-({4-[4-(3- { [ethyl (methyl)sulfamoyl]amino}-2-fluorophenyl)-2-methyl-l, 3-thi azol-5-yl]pyrimidin-2- yl } amino)pyri din-3 -yl]piperazin- 1 -yl }methyl)piperidin- 1 -yl]phenyl }piperidine-2, 6-dione, rac-(35)-3-[6-(4-{4-[6-({4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fhrorophenyl)-2- methyl-1, 3-thi azol-5-yl]pyrimidin-2-yl}amino)pyridin-3-yl]piperazine-l -carbonyl Jpiperi din- l-yl)pyri din-3 -yl]piperidine-2, 6-dione, rac-(37?)-3-{6-[4-(2-{4-[6-({4-[4-(3-
{ [ethyl (methyl)sulfamoyl]amino}-2-fluorophenyl)-2-methyl-l, 3-thi azol-5-yl]pyrimidin-2- yl}amino)pyridin-3-yl]piperazin-l-yl}-2-oxoethyl)piperidin-l-yl]pyridin-3-yl}piperidine-2,6- dione, (5)-7V-(3-(2-(tert-butyl)-5-(2-((4-(4-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine- 4-carbonyl)piperazin-l-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(tert-butyl)-5-(2-((4-(l-(l-(4-(2,6- dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)piperidin-4-yl)phenyl)amino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, rac-(35)-3-[4-(4-{4-[6-({4-[2-tert- butyl-4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3-thiazol-5-yl]pyrimidin-2- yl}amino)pyridin-3-yl]piperazine-l-carbonyl}piperidin-l-yl)phenyl]piperidine-2, 6-dione, (R)-7V-(3-(2-(tert-butyl)-5-(2-((4-(l-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)methyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-
1 -sulfonamide, rac-(35)-3-{6-[4-({4-[6-({4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)-2 -methyl- 1 ,3 -thiazol-5-yl]pyrimidin-2-yl } amino)pyri din-3 -yl]piperazin- 1 - yl}methyl)-4-methylpiperidin-l-yl]pyridin-3-yl}piperidine-2, 6-dione, rac-(35)-3-{4-[4-({4- [6-({4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-2-methyl-l,3-thiazol-5- yl]pyrimidin-2-yl}amino)pyridin-3-yl]piperazin-l-yl}methyl)-4-fluoropiperidin-l- yl]phenyl}piperidine-2, 6-dione, (5 -7V-(3-(5-(2-((4-(4-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-
2-yl)-4-methylpiperidin-4-yl)methyl)piperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2- methylthiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(5-(2-((4-(4-((l-(4-(2,6- dioxopiperi din-3 -yl)phenyl)-4-fluoropiperidin-4-yl)m ethyl)piperazin-l - yl)phenyl)amino)pyrimidin-4-yl)-2-methylthiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, rac-(37?)-3-{6-[6-({4-[6-({4-[2-tert-butyl-4-(3-
{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3-thiazol-5-yl]pyrimidin-2- yl}amino)pyridin-3-yl]piperazin-l-yl}methyl)-2-azaspiro[3.3]heptan-2-yl]pyridin-3- yl}piperidine-2, 6-dione, (37?)-3-{6-[4-({4-[6-({4-[2-tert-butyl-4-(3-
{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3-thiazol-5-yl]pyrimidin-2- yl } amino)pyri din-3 -yl]piperazin- 1 -yl }methyl)piperidin- 1 -yl]pyri din-3 -yl }piperidine-2,6- dione, rac-(37?)-3-[2-(2-{4-[4-({4-[2-tert-butyl-4-(3-{[ethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)-l,3-thiazol-5-yl]pyrimidin-2-yl}amino)-2-fluorophenyl]piperazin-l-yl}-2- oxoethyl)-l,2,3,4-tetrahydroisoquinolin-6-yl]piperidine-2,6-dione, and (37?)-3-{6-[4-({4-[6- ({4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-2-methyl-l,3-thiazol-5- yl]pyrimidin-2-yl}amino)pyridin-3-yl]piperazin-l-yl}methyl)piperidin-l-yl]pyridin-3- yl}piperidine-2, 6-dione. In certain embodiments, the compound of Formula (I) is selected from the group consisting of (5)-7V-(3-(l-(4-(4-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)methyl)piperazin-l-yl)phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, ( ?)-7V-(3-(l-(4-(4-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)methyl)piperazin-l-yl)phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, and (5)-7V-(3-(l-(4-(4-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin- 4-yl)methyl)piperazin-l-yl)phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide. In certain embodiments, the compound of Formula (I) is selected from the group consisting of (R)-7V-(3-(l-(4-(4-(l-(4-(2,6-dioxopiperidin-3- yl )phenyl)pi peri di ne-4-carbonyl)piperazine-l -carbonyl )phenyl)-3-(pyri di n-4-yl)-U7-pyrazol - 4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(l-(4-(4-((l-(4-(2,6-dioxopiperidin-3- yl)phenyl)piperidin-4-yl)methyl)piperazine-l-carbonyl)phenyl)-3-(pyridin-4-yl)-l/7-pyrazol- 4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(l-(4-(4-(l-(4-(2,6-dioxopiperidin-3- yl)phenyl)piperidine-4-carbonyl)piperazin-l-yl)phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(l-(4-((l-(l-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)oxy)phenyl)-3-(pyridin-4-yl)-U7- pyrazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(l-(4-(4-((l-(5-(2,6- dioxopiperidin-3-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)methyl)piperazin-l-yl)phenyl)-3- (pyridin-4-yl)-lJ7-pyrazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (7?)-7V-(3-(l-(4-(4- ((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperazine-l-carbonyl)phenyl)-
3 -(pyridin-4-yl)- lZ7-pyrazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (S)-N-(3 -( 1 -(1 -( 1 - (l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidin-
4-yl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(l-
(4-(4-((l-(4-(2,6-dioxopiperidin-3-yl)-3-fluorophenyl)piperidin-4-yl)methyl)piperazin-l- yl)phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (S)-N- (3-(l-(4-(l-((l-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin- 4-yl)phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)- 7V-(3-(l-(l-(l-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4- carbonyl)piperidin-4-yl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (5)-7V-(3-(l-(4-(4-((l-(4-(2,6-dioxopiperi din-3 -yl)-2-fluorophenyl)piperi din-4- yl)methyl)piperazin-l-yl)phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (5)-7V-(3-(l-(6-(4-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)methyl)piperazin-l-yl)pyri din-3 -yl)-3-(pyri din-4-yl)- 1/7-pyrazol -4-yl)-2- fluorophenyl)propane-l -sulfonamide, (7?)-7V-(3-(l-(4-(4-(2-(l-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidin-4-yl)acetyl)piperazine-l-carbonyl)phenyl)-3-(pyridin-4-yl)-l/7- pyrazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (S)-N-(3 -( 1 - ( 1 - ( 1 -(( 1 - ( 5 -(2 , 6 - dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperidine-4-carbonyl)piperidin-4-yl)- 3 -(pyridi n-4-yl)- l//-pyrazol -4-yl )-2-fluorophenyl)propane- l -sulfonamide, (5)-7V-(3-(l-(4-(4- ((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-l-yl)phenyl)-3- (pyridin-4-yl)-lJ7-pyrazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-7V-(3-(l-(6-(4- ((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-l-yl)pyridin-3- yl)-3-(pyridin-4-yl)-l//-pyrazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(l-(4- (l-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)-3- (pyridin-4-yl)- 1 //-pyrazol -4-yl )-2-fl uorophenyl Jpropane- 1 -sulfonamide, (S)-N-(3 -(1 -(4-( 1 -
((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)-3- (pyridin-4-yl)- 1 //-pyrazol -4-yl )-2-fl uorophenyl Jpropane- 1 -sulfonamide, (S)-N-(3 -(1 -(4-( 1 -
((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)-3- (pyridin-4-yl)-l//-pyrazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(l-(4-(4- ((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperazin-l-yl)phenyl)-3- (pyridin-4-yl)- I //-py razol -4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (S)-N-(3 -( 1 -( 1 -( 1 -( 1 - (5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)-4-methylpiperidine-4- carbonyl)piperidin-4-yl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (5)-7V-(3-(l-(4-(l-((l-(4-(2,6-dioxopiperidin-3-yl)-3-fluorophenyl)piperidin-4- yl)methyl)piperidin-4-yl)phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, and (7?)-7V-(3-(l-(4-(4-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin- 4-yl)methyl)piperazin-l-yl)phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2- fluoropheny l)prop ane- 1 - sulfonami de .
[000106] In certain embodiments, the compound of Formula (II) is selected from the group consisting of (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(l-(l-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(l-(l-(5- (2,6-dioxopiperidin-3-yl)pyridin-2-yl)-4-methylpiperidine-4-carbonyl)piperidine-4- carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(5-(2- aminopyrimidin-4-yl)-2-(l -(l-(l-(5-(2,6-di oxopiperi din-3 -yl)pyri din-2 -yl)piperidine-4- carbonyl)-4-methylpiperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(l-(l-(4- (2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)-4-methylpiperidine-4- carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(l- (l-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)piperidine-4- carbonyl)piperidin-4-yl)-5-(pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (5)-7V-(3-(2-(l-(l-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4- carbonyl)-4-methylpiperidine-4-carbonyl)piperidin-4-yl)-5-(pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, and (5)-7V-(3-(2-(l-(l-(l-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidine-4-carbonyl)-4-methylpiperidine-4-carbonyl)piperidin-4-yl)-5- (pyridin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide. In certain embodiments, the compound of Formula (II) is selected from the group consisting of (R)-N-(3-(5-(2- aminopyrimidin-4-yl)-2-(3 -(2-(4-(3 -(2-(2,6-dioxopiperi din-3 -yl)- 1 ,3 -dioxoi soindolin-4- yl)propyl)piperazin-l-yl)acetyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, 7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-((15',4r)-4-((6- ((5)-2,6-dioxopiperidin-3-yl)-3,4-dihydroisoquinolin-2(lJ7)-yl)methyl)cyclohexane-l- carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(l- (l-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperidine-4- carbonyl)piperidin-4-yl)-5-(pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-
1.3-dioxoisoindolin-5-yl)piperazin-l-yl)acetyl)-4-methylpiperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(2-(r-(2- (2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)-[l,4'-bipiperidin]-4-yl)acetyl)-4- methylpiperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(5-(2- aminopyrimidin-4-yl)-2-(l-(l-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)methyl)piperidine-4-carbonyl)-4-methylpiperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-((l-(2-(6- (2,6-dioxopiperidin-3-yl)-3,4-dihydroisoquinolin-2(lJ7)-yl)acetyl)piperidin-4- yl)methyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)- V-(3-(5-(2- aminopyrimidin-4-yl)-2-(3-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)-3- azaspiro[5.5 ]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (S)-N-(3-(2- (l-(l-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperidine-4- carbonyl)piperidin-4-yl)-5-(pyridin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(2-(r-(2-(2,6-dioxopiperidin-3-yl)-
1.3-dioxoisoindolin-5-yl)-[l,4'-bipiperidin]-4-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(2-(4-(2- (2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperazin-l-yl)acetyl)piperidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4- yl)-2-(2-( 1 -( 1 -(1 -(2-(2,6-dioxopiperi din-3 -yl)- 1 ,3-dioxoisoindolin-5-yl)piperidin-4- yl)azetidine-3-carbonyl)piperidin-4-yl)propan-2-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, 7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-((l-((17?,4r)-4-(3-( (R)-2,6- dioxopiperi din-3 -yl)phenoxy)cy cl ohexane-l-carbonyl)piperidin-4-yl)methyl)piperi din-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4- yl)-2-(3-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)-3- azaspiro[5.5 ]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)- V-(3-(5- (2-aminopyrimidin-4-yl)-2-(l-(l-(2-(l-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)- 4-hydroxypiperidin-4-yl)acetyl)azetidin-3-yl)piperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(l-(2-(l-(5- (2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)acetyl)piperidin-4-yl)phenyl)thiazol-4- yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(4-((l- (4-(2, 6-dioxopiperi din-3 -yl)phenyl)piperidin-4-yl)methyl)piperazin-l-yl)phenyl)thi azol -4- yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(l-(2- (l-(4-((2,6-dioxopiperi din-3 -yl)amino)phenyl)piperi din-4-yl)acetyl)piperi din-4- yl)phenyl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)- V-(3-(5-(2- aminopyrimidin-4-yl)-2-(4-(l-(l-(5-(2,6-dioxopiperi din-3-yl)pyri din-2 -yl)piperidine-4- carbonyl)piperidin-4-yl)phenyl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (S)-N- (3-(5-(2-aminopyrimidin-4-yl)-2-(4-(l-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)methyl)piperidin-4-yl)phenyl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, N-(3- (5-(2-aminopyrimidin-4-yl)-2-(3-(((15,4r)-4-((5-((5)-2,6-dioxopiperidin-3-yl)pyridin-2- yl)oxy)cyclohexyl)methyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(4-(l-(4- (2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)piperazin-l-yl)phenyl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-5-(4-(9-(5-(2-aminopyrimidin-4-yl)-4-(2-fluoro-3- (propylsulfonamido)phenyl)thiazol-2-yl)-3-azaspiro[5.5]undecane-3-carbonyl)piperidin-l- yl)-7V-(2,6-dioxopiperidin-3-yl)picolinamide, 7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-(2-((5)-l- (5-((5)-2,6-dioxopiperidin-3-yl)pyridin-2-yl)pyrrolidin-3-yl)ethyl)-3-azaspiro[5.5]undecan-9- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)- 2-(l-(l-(2-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)acetyl)azetidin-3- yl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)- V-(3-(5-(2- aminopyrimidin-4-yl)-2-(3-(l -(5-(2,6-di oxopiperidin-3-yl)pyri din-2 -yl)piperidine-4- carbonyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(l-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2- yl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (5)-7V-(3-(2-(l-(l-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4- carbonyl)piperidine-4-carbonyl)piperidin-4-yl)-5-(pyridin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(l-(l-((l-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidin-4-yl)methyl)piperidine-4-carbonyl)piperidin-4-yl)-5-(2- (methylamino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (R)-N-(3 - (5-(2-aminopyrimidin-4-yl)-2-(2-(2-(l'-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)-[l,4'-bipiperidin]-4-yl)acetyl)-2-azaspiro[3.5]nonan-7-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(l-(l-(l-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidin-4-yl)-5-(pyridin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, 7V-(3-(5-(2-aminopyrimidin-4-yl)-2- (l-((l-(((15,4r)-4-(4-((5)-2,6-dioxopiperidin-3-yl)phenoxy)cyclohexyl)methyl)piperidin-4- yl)methyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-N-(3- 5- (2-aminopyrimidin-4-yl)-2-(2-(l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)piperidine-4-carbonyl)-2-azaspiro[3.5]nonan-7-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (5)-7V-(3-(2-(l-(l-(2-(l-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4- yl)acetyl)piperidine-4-carbonyl)piperidin-4-yl)-5-(pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(2-(l-(l-(l-(5- (2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidin- 4-yl)ethyl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (R)-N-(3- 5-(2- aminopyrimidin-4-yl)-2-(2-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)piperazin-l-yl)acetyl)-2-azaspiro[3.5]nonan-7-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, ( ?)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(4-(l-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidine-4-carbonyl)piperazin-l-yl)phenyl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(l-(l-(l-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidin-4-yl)-5-(pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4- yl)-2-(l-(l-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)piperidine-4- carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-N-(3-(5-(2- aminopyrimidin-4-yl)-2-(4-(4-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)methyl)piperazin-l-yl)phenyl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (S)-N- (3-(5-(2-aminopyrimidin-4-yl)-2-(l-((l-(l-(5-(2,6-dioxopiperidin-3-yl)pyri din-2- yl)piperidine-4-carbonyl)piperidin-4-yl)methyl)piperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(4-(2-(l-(5- (2, 6-dioxopiperi din-3 -yl)pyri din-2 -yl)piperi din-4-yl)acetyl)piperazin- l-yl)phenyl)thi azol-4- yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-(2-(r- (2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)-[l,4'-bipiperidin]-4-yl)acetyl)-3- azaspiro[5.5 ]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)- V-(3-(5- (2-aminopyrimidin-4-yl)-2-(l-(l-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)methyl)piperidine-4-carbonyl)-4-methylpiperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(l-(l-(l-(4-(2,6-dioxopiperidin-3- yl)phenyl)piperidine-4-carbonyl)-4-methylpiperidine-4-carbonyl)piperidin-4-yl)-5-(2- (isopropylamino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-N- (3-(5-(2-aminopyrimidin-4-yl)-2-(3-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)piperazin-l-yl)acetyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, 7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-((l-((17?,4r)-4-(4-(( ?)-2,6- dioxopiperi din-3 -yl)phenoxy)cy cl ohexane-l-carbonyl)piperidin-4-yl)methyl)piperi din-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4- yl)-2-(2-(6-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)hexanoyl)-2- azaspiro[3.5]nonan-7-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, 7V-(3-(2-(l-(l- (l-(5-((5)-2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4- carbonyl)piperidin-4-yl)-5-(2-((( ?)-l-hydroxypropan-2-yl)amino)pyrimidin-4-yl)thiazol-4- yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(4-((l- (5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-l-yl)phenyl)thiazol- 4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, rac-(35)-3 - { 6- [4 - (4 - {4-[5-(2-aminopyrimidin- 4-yl)-4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3-thiazol-2-yl]piperidine-l- carbonyl}piperidine-l-carbonyl)piperidin-l-yl]pyridin-3-yl}piperidine-2, 6-dione, rac-(35)-3- {6-[4-(4-{4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-5-{2-[(propan-2- yl)amino]pyrimidin-4-yl } - 1 ,3 -thiazol-2-yl]piperidine- 1 -carbonyl } piperi dine- 1 - carbonyl)piperidin-l-yl]pyridin-3-yl}piperidine-2, 6-dione, (5)-7V-(3-(5-(2-aminopyrimidin-4- yl)-2-(l-(l-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperidine-4- carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)- V-(3-(5-(2- aminopyrimidin-4-yl)-2-(l-(l-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)methyl)piperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-((l-(2-(2,6-dioxopiperidin-3-yl)-l- oxoisoindolin-5-yl)piperidin-4-yl)methyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(2-(2-(2- (2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)acetyl)-4- methylpiperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-N-(3- 5-(2- aminopyrimidin-4-yl)-2-(3-(l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)piperidine-4-carbonyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, ( ?)-7V-(3-(2-(l-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)- 2,7 -di azaspiro [3.5 ]nonan-7 -yl)acetyl)piperidin-4-yl)-5-(2-(methylamino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4- yl)-2-(3-(6-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)hexanoyl)-3- azaspiro[5.5 ]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-N-(3-(5- (2-aminopyrimidin-4-yl)-2-(l-(l-(2-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)acetyl)-4-methylpiperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(l-(l-(l-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidin-4-yl)-5-(2- (methylamino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (R)-N-(3 - (5-(2-aminopyrimidin-4-yl)-2-(l-(l-(2-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin- 4-yl)acetyl)piperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (5)-7V-(3-(2-(l-(l-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4- carbonyl)piperidine-4-carbonyl)piperidin-4-yl)-5-(2-(isopropylamino)pyrimidin-4-yl)thiazol- 4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(5-(2-(cyclopropylamino)pyrimidin-4- yl)-2-(l-(l-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4- carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(l- (l-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)-4-methylpiperidine-4- carbonyl)piperidin-4-yl)-5-(pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, 7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-(2-( (R)-l-(4-(() )-2,6-dioxopiperidin-3- yl)phenyl)pyrrolidin-3-yl)acetyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(2-(2-(2-(2- (2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)acetyl)-2- azaspiro[3.5]nonan-7-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (R)-N-(3-(5-(2- aminopyrimidin-4-yl)-2-(l-((l-(2-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)acetyl)piperidin-4-yl)methyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(2-(2-(2-(2,6-dioxopiperidin-3-yl)- l,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-(l-(l-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-17/-benzo[d]imidazol-4-yl)piperidine-4- carbonyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, ( ?)-7V-(3-(2-(l-(l-((l-(4-(2,6-dioxopiperi din-3 -yl)phenyl)piperidin-4-yl)methyl)piperidine-4- carbonyl)piperidin-4-yl)-5-(2-(methylamino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(l-(l-(2- (2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperidin-4-yl)azetidine-3- carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-N-(3-(5-(2- aminopyrimidin-4-yl)-2-(2-(l-(l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)piperidin-4-yl)azetidine-3-carbonyl)-2-azaspiro[3.5]nonan-7-yl)thiazol-4-yl)-2- fluorophenyl)propane- 1 -sulfonamide, (S)-N-(3 -(5-(2-aminopyrimidin-4-yl)-2-(l -( 1 -(( 1 -( 1 - (2, 6-dioxopiperi din-3 -yl)-3-methyl-2-oxo-2, 3 -dihydro- l/Z-benzo[d]imidazol-4-yl)piperi din- 4-yl)methyl)piperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, ( ?)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-(2-(2-(2-(2,6-dioxopiperidin-3-yl)- l,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)acetyl)-3-azaspiro[5.5]undecan-9- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4- yl)-2-(2-(l-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)-2,7- diazaspiro[3.5]nonan-7-yl)acetyl)piperidin-4-yl)propan-2-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, and (/?)-4-((4-(5-(2-aminopyrimidin-4-yl)-4-(2-fluoro- 3-(propylsulfonamido)phenyl)thiazol-2-yl)piperidin-l-yl)methyl)-N-(2,6-dioxopiperidin-3- yl)benzamide.
[000107] In certain embodiments of Formula (I), X1 is carbon; X2 is nitrogen, X3 is nitrogen; X4 is carbon; and X5 is hydrogen. In certain embodiments of Formula (I), R1 is alkyl, dialkylamino, cycloalkyl, or heterocycloalkyl each unsubstituted or substituted with one or more halogen; Rla is halogen; Rlb is hydrogen, haloalkyl or halogen; R2 is -[Ar1-Z1]n-Z2-Cy1- Z3-L-UBM; Ar1 is arylene or heteroarylene, each unsubstituted or substituted with one or more halogen; Z1 is a bond; n is one; Z2 is absent; Cy1 is absent or heterocycloalkylene, unsubstituted or substituted with one or more alkyl or one or more halogen; Z3 is absent or Ci-io alkylene; L is a linker according to -L4-L2-L3-L4- or -L4-L3-L2-L4-, wherein -L1- is -Q1- or -Q2-; each -L2-, -L3-, and -L4- is independently, absent, -Ci-8 alkylene-, or -Q1-; each -Q1- is a three- to seven-membered heterocycloalkylene comprising at least one nitrogen and is unsubstituted or substituted with one or more methyl or halogen; each -Q2- is a five- to thirteen-membered bicyclic heterocycloalkylene comprising at least one nitrogen, wherein the five- to thirteen-membered bicyclic heterocycloalkylene is optionally a spiro bicyclic heterocycloalkylene ring; and UBM is a ubiquitin ligase binding moiety; or a stereoisomer and/or pharmaceutical salt thereof. [000108] In certain embodiments of Formula (I), R1 is selected from the group consisting propyl. In one embodiment, R1 is ethylmethylamino. In one embodiment, R1 is ec-butyl. In one embodiment, R1 is . In one embodiment, R1 is one embodiment, R1 is . In one embodiment, R1 is embodiment,
R1 is . In one embodiment, R1 is . In one embodiment, [000109] In certain embodiments of Formula (I), Rla is chloro or fluoro; and Rlb is hydrogen, chloro, fluoro, or haloalkyl. In certain embodiments of Formula (I), Ar1 is arylene or heteroarylene unsubstituted or substituted with one or two halogen. In certain embodiments of Formula (I), UBM binds an E3 ubiquitin ligase. In certain embodiments of Formula (I), UBM binds SCFP-TRCP, VHL, MDM2, IAP, or CRBN. In certain embodiments of Formula (I), UBM binds CRBN. In certain embodiments of Formula (I), UBM binds CRBN and has the following chemical formula wherein X6 absent or NR3; X7 absent or -C(O)-; and X8 is arylene or heteroarylene. In certain embodiments of Formula (I), UBM binds CRBN and is selected from the group consisting absent or halogen; and m is one, two, three, or four. In one embodiment, UBM binds CRBN wherein X9 is absent or halogen; and m is one, two, three, or four. In one embodiment, UBM binds CRBN and is wherein X9 is absent. In one embodiment, UBM binds wherein X9 is halogen; and m is one. In one embodiment, UBM binds wherein X9 is halogen; and m is two.
In one embodiment, UBM binds wherein X9 is halogen; and m is three. In one embodiment, UBM binds wherein X9 is halogen; and m is four. In one embodiment, UBM binds one embodiment, UBM binds CRBN and is . In one embodiment, UBM binds CRBN and is . In one embodiment, UBM binds one embodiment, UBM binds , embodiment, UBM binds wherein X9 is absent or halogen; and m is one, two, three, or four. In one embodiment, UBM binds wherein X9 is absent. In one embodiment, UBM binds wherein
X9 is halogen; and m is one. In one embodiment, UBM binds wherein X9 is halogen; and m is two. In one embodiment, UBM binds CRBN and is wherein X9 is halogen; and m is three. In one embodiment, UBM binds , , embodiment, UBM binds one embodiment, UBM binds CRBN ,
[0001 10] In certain embodiments of Formula (I), the compound is selected from the group consisting of (R)-7V-(5-chloro-3-(l-(4-(4-((l-(5-(2,4-dioxotetrahydropyrimidin-l(2J7)- yl)pyridin-2-yl)piperidin-4-yl )methyl)piperazin-l -yl)phenyl )-3-(pyridin-4-yl)-l //-pyrazol-4- yl)-2-fluorophenyl)-3 -fluoropyrrolidine- 1 -sulfonamide; (R)-N-(5 -chi oro-3 -( 1 -(4-(4-((l -(5-
((7?)-2, 6-dioxopiperi din-3 -yl)pyri din-2-yl)piperi din-4-yl)m ethyl)piperazin- l-yl)phenyl)-3- (pyridin-4-yl)-lJ7-pyrazol-4-yl)-2-fluorophenyl)-3-fluoropyrrolidine-l -sulfonamide; rac-(7?)- 7V-(5-chloro-3-(l-(4-(4-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)methyl)piperazin- 1 -yl)phenyl)-3 -(pyridin-4-yl)- l/7-pyrazol-4-yl)-2- fluorophenyl)pyrrolidine-l -sulfonamide; rac- (R)-7V-(5-chloro-3-(l-(4-(4-((l-(5-(2,6- dioxopiperi din-3 -yl)pyri din-2-yl)piperi din-4-yl)methyl)piperazin- 1 -yl)-2-fluorophenyl)-3 - (pyridin-4-yl)-lJ7-pyrazol-4-yl)-2-fluorophenyl)pyrrolidine-l-sulfonamide; rac-(7?)-7V-(3-(l- (4-(4-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-l- yl)phenyl)-3-(pyridin-4-yl)-lJH-pyrazol-4-yl)-2,5-difluorophenyl)pyrrolidine-l-sulfonamide; 7V-(5-chloro-3-(l-(4-( (R)-4-((l-(5-((7?5)-2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)methyl)-3-methylpiperazin-l-yl)phenyl)-3-(pyridin-4-yl)-lJH-pyrazol-4-yl)-2- fluorophenyl)pyrrolidine-l -sulfonamide; (7?)-7V-(3-(l-(4-(4-((l-(4-(2,6-dioxopiperidin-3-yl)- 2-fluorophenyl)piperidin-4-yl)methyl)piperazin-l-yl)-2-fluorophenyl)-3-(pyridin-4-yl)-lJH- pyrazol-4-yl)-2,5-difluorophenyl)cyclopentanesulfonamide; rac-(7?)-7V-(3-(l-(4-(4-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)methyl)piperazin-l-yl)-3-fluorophenyl)-3-(pyridin-4-yl)-lJH-pyrazol-4-yl)-2,5- difluorophenyl)cyclopentanesulfonamide; rac-(7?)-7V-(5-chloro-3-(l-(4-(4-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)methyl)piperazin-l-yl)-3-fluorophenyl)-3-(pyridin-4-yl)-lJH-pyrazol-4-yl)-2- fluorophenyl)cyclopentanesulfonamide;
(R)-N-(5 -chi oro-3 -( 1 -(4-(4-(( 1 -(4-(2, 6-dioxopiperi din-3 -yl)-2-fluorophenyl)piperidin-4- yl)methyl)piperazin-l-yl)-3-fluorophenyl)-3-(pyridin-4-yl)-lJH-pyrazol-4-yl)-2- fluorophenyl)cyclopentanesulfonamide;
(R)-N-(5 -chi oro-3 -( 1 -(4-(4-(( 1 -(4-(2, 6-dioxopiperi din-3 -yl)-2-fluorophenyl)piperidin-4- yl)methyl)-l,4-diazepan-l-yl)-2-fluorophenyl)-3-(pyridin-4-yl)-lJH-pyrazol-4-yl)-2- fluorophenyl)pyrrolidine-l -sulfonamide; (7?)-7V-(3-(l-(4-(4-((l-(4-(2,6-dioxopiperidin-3-yl)- 2-fluorophenyl)piperidin-4-yl)methyl)-l,4-diazepan-l-yl)-2-fluorophenyl)-3-(pyridin-4-yl)- lZZ-pyrazol-4-yl)-2,5-difluorophenyl)pyrrolidine-l-sulfonamide; 7V-[5-chloro-3-(l-{4-[(37?)- 4-[(l-{4-[(37?)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]-3-methylpiperazin-l- yl]phenyl} -3 -(pyridin-4-yl)-lJH-pyrazol-4-yl)-2-fluorophenyl]propane-l -sulfonamide; 7V-[5- chloro-3-(l-{4-[(37?)-4-[(l-{5-[(37?5)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4- yl )methyl ]-3 -methyl pi perazi n- 1 -yl ]phenyl } -3 -(pyri di n-4-yl )- l //-pyrazol -4-yl )-2- fluorophenyl] prop aned -sulfonamide; 7V-[5-chloro-3-(l-{4-[(37?)-4-({ l-[4-(2,4-dioxo-l,3- diazinan- 1 -yl)phenyl]piperidin-4-yl }methyl)-3 -methylpiperazin- 1 -yl]phenyl } -3 -(pyridin-4- yl)-lJ7-pyrazol-4-yl)-2-fluorophenyl]propane-l -sulfonamide; 7V-[5-chloro-3-(l-{4-[(35)-4- [(l-{4-[(37?)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]-3-methylpiperazin-l- yl]phenyl} -3 -(pyridin-4-yl)-lJ7-pyrazol-4-yl)-2-fluorophenyl]propane-l -sulfonamide; 7V-[5- chloro-3-(l-{4-[(35)-4-[(l-{5-[(37?5')-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4- yl)methyl]-3-methylpiperazin-l-yl]phenyl}-3-(pyridin-4-yl)-lJ7-pyrazol-4-yl)-2- fluorophenyl]propane-l -sulfonamide; 7V-[5-chloro-3-(l-{4-[(35)-4-({l-[4-(2,4-dioxo-l,3- diazinan- 1 -yl)phenyl]piperidin-4-yl }methyl)-3 -methylpiperazin- 1 -yl]phenyl } -3 -(pyridin-4- yl)-l//-pyrazol-4-yl)-2-fluorophenyl]propane-l -sulfonamide; 7V-{5-chloro-3-[l-(4-{4-[(l-{4- [(37?)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}-2-fluorophenyl)- 3-(pyridin-4-yl)-lJ7-pyrazol-4-yl]-2-fluorophenyl}pyrrolidine-l -sulfonamide; 7V-{5-chloro-3- [l-(4-{4-[(l-{4-[(37?)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]piperazin-l- yl }phenyl)-3 -(pyridin-4-yl)- U7-pyrazol-4-yl]-2-fluorophenyl } pyrrol i dine- 1 -sulfonamide; N- [5-chloro-3-(l-{4-[4-({l-[4-(2,4-dioxo-l,3-diazinan-l-yl)phenyl]piperidin-4- yl}methyl)piperazin-l-yl]phenyl}-3-(pyridin-4-yl)-U7-pyrazol-4-yl)-2- fluorophenyl]pyrrolidine-l -sulfonamide; rac-7V-{5-chloro-3-[l-(4-{4-[(l-{4-[(37?)-2,6- dioxopiperidin-3-yl]phenyl}-4-fluoropiperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3- (pyridin-4-yl)-l//-pyrazol-4-yl]-2-fluorophenyl}pyrrolidine-l -sulfonamide; 7V-{5-chloro-3- [l-(4-{4-[(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-
1-yl}phenyl)-3-(pyridin-4-yl)-lJ7-pyrazol-4-yl]-2-fluorophenyl}pyrrolidine-l-sulfonamide; 7V-{5-chloro-3-[l-(5-{4-[(l-{4-[(37?)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4- yl)methyl]piperazin-l-yl}pyridin-2-yl)-3-(pyridin-4-yl)-U7-pyrazol-4-yl]-2- fluorophenyl}pyrrolidine-l-sulfonamide; 7V-[5-chloro-3-(l-{5-[4-({l-[4-(2,4-dioxo-l,3- diazinan- 1 -yl)phenyl]piperidin-4-yl } methylpiperazin- 1 -yl]pyri din-2 -yl } -3 -(pyridin-4-yl)- l/Z-pyrazol-4-yl)-2-fluorophenyl]pyrrolidine-l -sulfonamide; rac-7V-{5-chloro-3-[l-(5-{4-[(l- {5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l-yl}pyridin-
2-yl)-3-(pyridin-4-yl)-lJH-pyrazol-4-yl]-2-fluorophenyl}pyrrolidine-l-sulfonamide; 7V-(3-(l-
(4-( (R)-4-((l-(5-((7?5)-2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)-3- methylpiperazin- 1 -yl)-2-fluorophenyl)-3 -(pyridin-4-yl)- 1 H-py razol-4-yl)-2, 5 - difluorophenyl)pyrrolidine- 1 -sulfonamide; N- { 5 -chi oro-3 - [l-(5-{4-[(l-{ 5 - [ (37?) -2 , 6 - dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l-yl}pyridin-2-yl)-3- (pyridin-4-yl )-l //-pyrazol-4-yl]-2-fluorophenyl } pyrrolidine-1 -sulfonamide; (3R)-N-{5- chloro-3-[l-(4-{4-[(l-{4-[(37?)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4- yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4-yl)-lJH-pyrazol-4-yl]-2-fluorophenyl}-3- fluoropyrrolidine-1 -sulfonamide; (37?)-7V-[5-chloro-3-(l-{4-[4-({l-[4-(2,4-dioxo-l,3- diazinan- 1 -yl)phenyl]piperidin-4-yl }methyl)piperazin- 1 -yl]phenyl } -3 -(pyridin-4-yl)- 1H- pyrazol-4-yl)-2-fluorophenyl]-3 -fluoropyrrolidine- 1 -sulfonamide; (3R)-N- { 5-chl oro-3 -[ 1 -(4- {4-[(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l- yl }phenyl)-3 -(pyridin-4-yl)- lZ7-pyrazol-4-yl]-2-fluorophenyl } -3 -fluoropyrrolidine- 1 - sulfonamide; (37?)-7V-{5-chloro-3-[l-(5-{4-[(l-{4-[(37?)-2,6-dioxopiperidin-3- yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}pyridin-2-yl)-3-(pyridin-4-yl)-lJH-pyrazol-4- yl]-2-fluorophenyl}-3-fluoropyrrolidine-l-sulfonamide; (37?)-zV-[5-chloro-3-(l-{5-[4-({ l-[4- (2,4-dioxo-l,3-diazinan-l-yl)phenyl]piperidin-4-yl}methyl)piperazin-l-yl]pyridin-2-yl}-3- (pyridin-4-yl)-lJ7-pyrazol-4-yl)-2-fluorophenyl]-3-fluoropyrrolidine-l -sulfonamide; (3R)-N- {5-chloro-3-[l-(5-{4-[(l-{5-[(37?5)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4- yl)methyl]piperazin-l-yl}pyridin-2-yl)-3-(pyridin-4-yl)-U7-pyrazol-4-yl]-2-fluorophenyl}-3- fluoropyrrolidine- 1 -sulfonamide; (37?)-7V-{5-chloro-3-[l-(5-{4-[(l-{5-[(37?)-2,6- dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l-yl}pyridin-2-yl)-3- (pyridin-4-yl)-17/-pyrazol-4-yl]-2-fluorophenyl J-3-fluoropyrrolidine-l -sulfonamide; (3R)-N- {5-chloro-3-[l-(5-{4-[(7-{4-[(37?5)-2,6-dioxopiperidin-3-yl]phenyl}-7-azaspiro[3.5]nonan-2- yl)methyl]piperazin-l-yl}pyridin-2-yl)-3-(pyridin-4-yl)-177-pyrazol-4-yl]-2-fluorophenyl}-3- fluoropyrrolidine- 1 -sulfonamide; 7V-{3-[l-(4-{4-[(l-{4-[(37?)-2,6-dioxopiperidin-3- yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4-yl)-lJH-pyrazol-4-yl]-
2.5-difluorophenyl}pyrrolidine-l-sulfonamide; 7V-[3-(l-{4-[4-({l-[4-(2,4-dioxo-l,3-diazinan- l-yl)phenyl]piperidin-4-yl}methyl)piperazin-l-yl]phenyl}-3-(pyridin-4-yl)-lJH-pyrazol-4-yl)-
2.5-difluorophenyl]pyrrolidine-l-sulfonamide; 7V-{3-[l-(4-{4-[(l-{5-[(37?)-2,6- dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4- yl)- IT/-pyrazol-4-yl]-2,5-difluorophenyl Jpyrrolidine- I -sulfonamide; (37?)-7V-{3-[l-(5-{4-[(l - {4-[(37?)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}pyridin-2-yl)- 3-(pyridin-4-yl)-lJH-pyrazol-4-yl]-2,5-difluorophenyl}-3-fluoropyrrolidine-l-sulfonamide; (37?)-7V-[3-(l-{5-[4-({l-[4-(2,4-dioxo-l,3-diazinan-l-yl)phenyl]piperidin-4- yl}methyl)piperazin-l-yl]pyridin-2-yl}-3-(pyridin-4-yl)-177-pyrazol-4-yl)-2,5- difluorophenyl]-3-fluoropyrrolidine-l-sulfonamide; (37?)-7V-{3-[l-(5-{4-[(l-{5-[(3R5)-2,6- dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l-yl}pyridin-2-yl)-3- (pyri di n-4-yl )-l //-pyrazol -4-yl ]-2,5-difl uoropheny 1 } -3 -fl uoropyrrol i di ne-1 -sulfonamide; (3/?)-7V-{3-[l-(5-{4-[(l-{5-[(3/?)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4- yl )methyl ]pi perazin- 1 -yl } pyri di n-2-yl )-3 -fpyri di n-4-yl )- l //-pyrazol -4-yl ]-2,5- difluorophenyl } -3 -fluoropyrrolidine- 1 -sulfonamide; (3R)-3 -(4- { 4- [(4- { 4- [4 - (5 -chi oro-3 -
[ [ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-3-(pyridin-4-yl)-l/7-pyrazol-l- yl]phenyl}piperazin-l-yl)methyl]piperidin-l-yl}phenyl)piperidine-2, 6-dione; l-(4-{4-[(4-{4- [4-(5-chloro-3-{ [ethyl(methyl)sulfamoyl]amino[-2-fluorophenyl)-3-(pyridin-4-yl)-l/7- pyrazol-l-yl]phenyl}piperazin-l-yl)methyl]piperidin-l-yl}phenyl)-l,3-diazinane-2, 4-dione; rac-(37?)-3-(6-{4-[(4-{4-[4-(5-chloro-3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-3- (pyridin-4-yl)- I /7-pyrazol - 1 -yl]phenyl } piperazin- 1 -yl)methyl]piperidin- 1 -yl }pyri din-3 - yl)piperidine-2, 6-dione; (37?)-3-(6-{4-[(4-{4-[4-(5-chloro-3-
{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-3-(pyridin-4-yl)-177-pyrazol-l- yl]phenyl}piperazin-l-yl)methyl]piperidin-l-yl}pyridin-3-yl)piperidine-2, 6-dione; (37?)-3-(4- {4-[(4-{6-[4-(5-chloro-3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-3-(pyridin-4-yl)- I /7-pyrazol - 1 -yl]pyri din-3 -yl } piperazin- 1 -yl)methyl]piperidin- 1 -yl } phenyl )pi peri di ne-2, 6- dione; l-(4-{4-[(4-{6-[4-(5-chloro-3-{[ethyl(methyl)sulfamoyl]amino}-2-fhrorophenyl)-3- (pyridin-4-yl)-177-pyrazol-l-yl]pyridin-3-yl}piperazin-l-yl)methyl]piperidin-l-yl}phenyl)-
1.3-diazinane-2, 4-dione; rac-(37?)-3-(6-{4-[(4-{6-[4-(5-chloro-3-
{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-3-(pyridin-4-yl)-177-pyrazol-l-yl]pyridin-
3-yl}piperazin-l-yl)methyl]piperidin-l-yl}pyridin-3-yl)piperidine-2, 6-dione; l-(6-{4-[(4-{6- [4-(5-chloro-3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-3-(pyridin-4-yl)-177- pyrazol-l-yl]pyridin-3-yl}piperazin-l-yl)methyl]piperidin-l-yl}pyridin-3-yl)-l,3-diazinane-
2.4-dione; (37?)-3-(6-{4-[(4-{6-[4-(5-chloro-3-{[ethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)-3 -(pyridin-4-yl)- I /7-pyrazol - 1 -yl]pyri din-3 -yl } piperazin- 1 - yl)methyl]piperidin-l-yl}pyridin-3-yl)piperidine-2, 6-dione; (37?)-7V-[5-chloro-3-(l-{4-[(37?)-
4-({ 1 -[4-(2,4-dioxo- 1 ,3 -diazinan- 1 -yl)phenyl]piperidin-4-yl }methyl)-3 -methylpiperazin- 1 - yl]phenyl} -3 -(pyridin-4-yl)-177-pyrazol-4-yl)-2-fluorophenyl]-3 -fluoropyrrolidine- 1- sulfonamide; 7V-[5-chloro-3-(l-{4-[(37?)-4-[(l-{4-[(37?)-2,6-dioxopiperidin-3- yl]phenyl}piperidin-4-yl)methyl]-3-methylpiperazin-l-yl]phenyl}-3-(pyridin-4-yl)-177- pyrazol-4-yl)-2-fluorophenyl]pyrrolidine-l -sulfonamide; (37?)-7V-[5-chloro-3-(l-{4-[(37?)-4- [(l-{4-[(37?)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]-3-methylpiperazin-l- yl]phenyl} -3 -(pyridin-4-yl)-177-pyrazol-4-yl)-2-fluorophenyl]-3 -fluoropyrrolidine- 1- sulfonamide; (37?)-7V-[5-chloro-3-(l-{4-[(37?)-4-[(l-{5-[(37?5)-2,6-dioxopiperidin-3- y 1 ] py ri din-2-y 1 } piperi din-4-y l)methy 1 ] -3 -methylpiperazin- 1 -yl]phenyl } -3 -(pyridin-4-yl)- 1H- pyrazol-4-yl)-2-fluorophenyl]-3-fluoropyrrolidine-l-sulfonamide; /V-[5-chloro-3-(l-{4-[(37?)- 4-({ 1 -[4-(2,4-dioxo- 1 ,3 -diazinan- 1 -yl)phenyl]piperidin-4-yl }methyl)-3 -methylpiperazin- 1 - yl]phenyl } -3 -(pyri di n-4-yl)-l//-pyrazol -4-yl )-2-fluorophenyl]pyrroli di ne-1 -sulfonamide; (37?)-7V-[5-chloro-3-(l-{5-[(37?)-4-[(l-{4-[(37?)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4- yl)methyl]-3 -methylpiperazin- 1 -yl]pyri din-2 -yl } -3 -(pyridin-4-yl)- l/7-pyrazol-4-yl)-2- fluorophenyl]-3-fluoropyrrohdine-l-sulfonamide; (37?)-7V-[5-chloro-3-(l-{5-[(37?)-4-[(l-{5- [(37?5)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]-3-methylpiperazin-l- yl]pyridin-2-yl } -3 -(pyridin-4-yl)- l/7-pyrazol-4-yl)-2-fluorophenyl]-3 -fluoropyrrolidine- 1 - sulfonamide; (37?)-7V-[5-chl oro-3 -(1 - { 5-[(37?)-4-({ 1 -[4-(2,4-dioxo- 1 ,3 -diazinan- 1 - yl)phenyl]piperidin-4-yl}methyl)-3 -methylpiperazin- 1 -yl]pyridin-2-yl } -3 -(pyri din-4-yl)- 1/7- pyrazol-4-yl)-2-fluorophenyl]-3-fluoropyrrolidine-l-sulfonamide; 7V-[5-chloro-3-(l-{5-[(37?)- 4-[(l-{5-[(37?5)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]-3- methylpiperazin-l-yl]pyri din-2 -yl} -3 -(pyri din-4-yl)-l/7-pyrazol-4-yl)-2- fluorophenyl]pyrrolidine- 1 -sulfonamide; 7V-[5-chloro-3 -( 1 -{ 5 - [(37?)-4-( { 1 -[4-(2,4-dioxo- 1,3- diazinan- 1 -yl)phenyl]piperidin-4-yl }methyl)-3 -methylpiperazin- 1 -yl]pyridin-2-yl }-3- (pyridin-4-yl)-l//-pyrazol-4-yl)-2-fluorophenyl]pyrrolidine-l -sulfonamide; 7V-[5-chloro-3-(l- {5-[(37?)-4-[(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]-3- methylpiperazin-l-yl]pyri din-2 -yl} -3 -(pyri din-4-yl)-l/7-pyrazol-4-yl)-2- fluorophenyl]pyrrolidine-l -sulfonamide; 7V-[5-chloro-3-(l-{5-[(37?)-4-[(l-{4-[(37?)-2,6- dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]-3-methylpiperazin-l-yl]pyridin-2-yl}-3- (pyridin-4-yl)-l//-pyrazol-4-yl)-2-fluorophenyl]pyrrolidine-l -sulfonamide; (/7S')-A-(5-chloro- 3-(l-(4-(4-((l-(5-((7?)-2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin- 1 -yl)phenyl)-3 -(pyridin-4-yl)- I //-py razol -4-yl )-2-fl uorophenyl )butane-2-sulfonami de; rac-
(27?)-7V-[5-chl oro-3 -(1 - { 4- [4-({ 1 -[4-(2,4-dioxo- 1 ,3 -diazinan- 1 -yl)phenyl]piperidin-4- yl}methyl)piperazin-l-yl]phenyl}-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2-fluorophenyl]butane- 2-sulfonamide; rac- (R)-7V-(5-chloro-3-(l-(4-(4-((l-(5-((5)-2,6-dioxopiperidin-3-yl)pyridin-2- yl)piperidin-4-yl)methyl)piperazin-l-yl)phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2- fluorophenyl)butane-2-sulfonamide; (2/7S')-A-{5-chloro-3-[l-(4-{4-[(l-{4-[(3/?)-2,6- dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4-yl)- l//-pyrazol-4-yl]-2-fluorophenyl}butane-2-sulfonamide; 7V-{5-chloro-3-[l-(4-{4-[(l-{5- [(37?)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3- (pyridin-4-yl)-l/7-pyrazol-4-yl]-2-fluorophenyl}-3-fluoroazetidine-l-sulfonamide; rac-/V-{5- chloro-3-[l-(4-{4-[(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4- yl)methyl]piperazin- l-yl Jphenyl)-3-(pyridin-4-yl)- l//-pyrazol-4-yl]-2-fliiorophenyl J-3- fluoroazetidine- 1 -sulfonamide; V-{5-chloro-3-[l-(4-{4-[(l-{4-[(37?)-2,6-dioxopiperidin-3- yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4-yl)-177-pyrazol-4-yl]-2- fluorophenyl } -3 -fluoroazetidine- 1 -sulfonamide; (3R)-N- { 5 -chi oro-3 -[ 1 -(4- { 4- [( 1 - { 5 -[(37?)-
2.6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l-yl}-2-fluorophenyl)- 3-(pyridin-4-yl)-177-pyrazol-4-yl]-2-fluorophenyl}-3-fluoropyrrolidine-l-sulfonamide; (37?)-V-{5-chloro-3-[l-(4-{4-[(l-{5-[(37?S)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4- yl)methyl]piperazin-l-yl}-2-fluorophenyl)-3-(pyridin-4-yl)-177-pyrazol-4-yl]-2- fluorophenyl} -3 -fluoropyrrolidine- 1 -sulfonamide; (37?)- V-{5-chloro-3-[l-(4-{4-[(l-{4-[(37?)-
2.6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}-2-fluorophenyl)-3- (pyridin-4-yl)-17f-pyrazol-4-yl]-2-fluorophenyl}-3-fluoropyrrolidine-l-sulfonamide; rac- V- {5-chloro-3-[l-(4-{4-[(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4- yl)methyl]piperazin-l-yl}-2-fluorophenyl)-3-(pyridin-4-yl)-177-pyrazol-4-yl]-2- fluorophenyl} -3 -fluoroazetidine- 1 -sulfonamide; V-{5-chloro-3-[l-(4-{4-[(l-{4-[(37?)-2,6- dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}-2-fluorophenyl)-3- (pyridin-4-yl)-177-pyrazol-4-yl]-2-fluorophenyl}-3-fluoroazetidine-l-sulfonamide; 7V-[5- chl oro-3-(l-{4-[4-({l-[4-(2,4-di oxo-1, 3-diazinan-l -yl)phenyl]piperidin-4- yl }methyl)piperazin- 1 -yl]-2-fluorophenyl } -3 -(pyridin-4-yl)- 177-pyrazol-4-yl)-2- fluorophenyl]-3 -fluoroazetidine- 1 -sulfonamide; V-{3-[l-(4-{4-[(l-{4-[(37?)-2,6- dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}-2-fluorophenyl)-3- (pyridin-4-yl)-177-pyrazol-4-yl]-2,5-difluorophenyl}pyrrolidine-l-sulfonamide; rac-7V-{3-[l- (4-{4-[(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l- yl } -2-fluorophenyl)-3 -(pyridin-4-yl)- 177-pyrazol-4-yl]-2, 5 -difluorophenyl (pyrrolidine- 1 - sulfonamide; V-{3-[l-(5-{4-[(l-{4-[(37?)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4- yl)methyl]piperazin-l-yl}pyrimidin-2-yl)-3-(pyridin-4-yl)-177-pyrazol-4-yl]-2,5- difluorophenyl } pyrrolidine- 1 -sulfonamide; rac- V- {3-[l-(5-{4-[(l-{5 -[(37?)-2,6- dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l-yl}pyrimidin-2-yl)-3- (pyridin-4-yl)-177-pyrazol-4-yl]-2,5-difluorophenyl}pyrrolidine-l-sulfonamide; V-{5-chloro- 3-[l-(4-{4-[(l-{4-[(37?)-2,6-dioxopiperidin-3-yl]-3-fluorophenyl}piperidin-4- yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4-yl)-177-pyrazol-4-yl]-2- fluorophenyl}pyrrolidine-l-sulfonamide; rac- V-{5-chloro-3-[l-(4-{4-[(l-{5-[(37?)-2,6- dioxopiperi din-3 -yl]pyridin-2-yl }piperidin-4-yl)methyl]- 1 ,4-diazepan- 1 -yl } -2-fluorophenyl)- 3-(pyridin-4-yl)-l//-pyrazol-4-yl]-2-fluorophenyl Jpyrrolidine- I -sulfonamide; 7V-{5-chloro-3- [l-(4-{4-[(l-{4-[(37?)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]-l,4-diazepan-l- yl } -2-fluorophenyl)-3 -(pyridin-4-yl)- lZ7-pyrazol-4-yl]-2-fluorophenyl J pyrrol i di ne- 1 - sulfonamide; rac-7V-{5-chloro-3-[l-(4-{4-[(l-{4-[(37?)-2,6-dioxopiperidin-3-yl]-2- fluorophenyl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4-yl)-lJH-pyrazol-4- yl]-2-fluorophenyl}pyrrolidine-l-sulfonamide; rac-7V-{5-chloro-3-[l-(4-{4-[(l-{4-[(37?)-2,6- dioxopiperidin-3-yl]-3-fluorophenyl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3- (pyridin-4-yl)-lJ7-pyrazol-4-yl]-2-fluorophenyl}pyrrolidine-l-sulfonamide; 7V-[5-
(difluoromethyl)-3-[l-(4-{4-[(l-{4-[(37?)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4- yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4-yl)-lJH-pyrazol-4-yl]-2- fluorophenyl]pyrrolidine-l -sulfonamide; rac-7V-[5-(difluoromethyl)-3-[l-(4-{4-[(l-{5-[(37?)- 2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3- (pyridin-4-yl)- l//-pyrazol-4-yl]-2-fluorophenyl]pyrrolidine- l -sulfonamide; 7V-{5-chloro-3-[l- (6-{4-[(l-{4-[(37?)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]piperazin-l- yl}pyridin-3-yl)-3-(pyridin-4-yl)-lJH-pyrazol-4-yl]-2-fluorophenyl}pyrrolidine-l- sulfonamide; rac-7V-{5-chloro-3-[l-(6-{4-[(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2- yl}piperidin-4-yl)methyl]piperazin-l-yl}pyridin-3-yl)-3-(pyridin-4-yl)-lJH-pyrazol-4-yl]-2- fluorophenyl}pyrrolidine-l-sulfonamide; 7V-{5-chloro-3-[l-(4-{4-[(l-{4-[(37?)-2,6- dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}-2,5-difluorophenyl)-3- (pyridin-4-yl)-lJ7-pyrazol-4-yl]-2-fluorophenyl}pyrrolidine-l-sulfonamide; rac-7V-{5-chloro- 3-[l-(4-{4-[(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4- yl)methyl]piperazin-l-yl}-2,5-difluorophenyl)-3-(pyridin-4-yl)-lJH-pyrazol-4-yl]-2- fluorophenyl}pyrrolidine-l-sulfonamide; 7V-[5-chloro-3-(l-{4-[4-({l-[5-(2,4-dioxo-l,3- diazinan- 1 -yl)pyri din-2 -y 1 ] piperi din-4-yl }methyl)piperazin- 1 -yl]phenyl } -3 -(pyridin-4-yl)- l/Z-pyrazol-4-yl)-2-fluorophenyl]pyrrolidine-l -sulfonamide; 7V-[5-(difluoromethyl)-3-(l-{4- [4-({l-[4-(2,4-dioxo-l,3-diazinan-l-yl)phenyl]piperidin-4-yl}methyl)piperazin-l-yl]-2- fluorophenyl} -3 -(pyridin-d-y^-l/f-pyrazoM-y^-Z-fluorophenylJpyrrolidine-l -sulfonamide; rac-7V-[5-(difluoromethyl)-3-[l-(4-{4-[(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2- yl}piperidin-4-yl)methyl]piperazin-l-yl}-2-fluorophenyl)-3-(pyridin-4-yl)-lJH-pyrazol-4-yl]- 2-fluorophenyl]pyrrolidine-l -sulfonamide; 7V-[5-chloro-3-(l-{5-[4-({l-[4-(2,4-dioxo-l,3- diazinan- 1 -yl)phenyl]piperidin-4-yl }methyl)piperazin- 1 -yl]pyrimidin-2-yl } -3 -(pyridin-4-yl)- l/Z-pyrazol-4-yl)-2-fluorophenyl]pyrrolidine-l -sulfonamide; rac-7V-{5-chloro-3-[l-(5-{4-[(l- {5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l- yl Jpyrimidin-2-yl)-3-(pyridin-4-yl)- l//-pyrazol-4-yl]-2-fluorophenyl Jpyrrolidine- I- sulfonamide; 7V-{5-chloro-3-[l-(5-{4-[(l-{4-[(37?)-2,6-dioxopiperidin-3-yl]phenyl}piperidin- 4-yl)methyl]piperazin-l-yl}pyrimidin-2-yl)-3-(pyridin-4-yl)-lJH-pyrazol-4-yl]-2- fluorophenyl}pyrrolidine-l -sulfonamide; 7V-[5-chloro-3-(l-{4-[4-({l-[4-(2,4-dioxo-l,3- diazinan- 1 -yl)phenyl]piperidin-4-yl }methyl)piperazin- 1 -y 1 ] -3 -fluorophenyl } -3 -(pyridin-4- yl)-l//-pyrazol-4-yl)-2-fluorophenyl]pyrrolidine-l -sulfonamide; 7V-[5-(difluoromethyl)-3-[l- (4-{4-[(l-{4-[(37?)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}-2- fluorophenyl)-3-(pyridin-4-yl)-lJH-pyrazol-4-yl]-2-fluorophenyl]pyrrolidine-l -sulfonamide; rac-7V-{5-chloro-3-[l-(4-{4-[(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4- yl)methyl]piperazin- 1 -yl } -3 -fluorophenyl)-3 -(pyridin-4-yl)- l/7-pyrazol-4-yl]-2- fluorophenyl}pyrrolidine-l-sulfonamide; 7V-{5-chloro-3-[l-(4-{4-[(l-{4-[(37?)-2,6- dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}-3-fluorophenyl)-3- (pyridin-4-yl)-lJ7-pyrazol-4-yl]-2-fluorophenyl}pyrrolidine-l-sulfonamide; (3R)-N-[5- chloro-3-(l-{4-[4-({l-[4-(2,4-di oxo-1, 3-diazinan-l -yl)phenyl]piperidin-4- yl } methyl)piperazin- 1 -yl] -3 -fluorophenyl } -3 -(py ridin-4-yl)- l/7-pyrazol-4-yl)-2- fhiorophenyl]-3-fhroropyrrohdine-l-sulfonamide; (37?)-7V-{5-chloro-3-[l-(4-{4-[(l-{5- [(37?5)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l-yl}-3- fluorophenyl)-3 -(pyridin-4-yl)- lZ7-pyrazol-4-yl]-2-fluorophenyl } -3 -fluoropyrrolidine- 1 - sulfonamide; (37?)-N-{5-chloro-3-[l-(4-{4-[(l-{4-[(37?)-2,6-dioxopiperidin-3- yl]phenyl }piperidin-4-yl)methyl]piperazin- 1 -yl } -3 -fluorophenyl)-3 -(pyridin-4-yl)- 1H- pyrazol-4-yl]-2-fhiorophenyl}-3-fhroropyrrolidine-l-sulfonamide; 7V-[5-chloro-3-(l-{4-[4- ({1 -[5-(2,4-dioxo- 1 ,3 -diazinan- 1 -yl)pyri din-2 -y 1 ]piperi din-4-yl }methyl)piperazin- 1 - yl]phenyl} -3 -(pyridin-4-yl)- lZ7-pyrazol-4-yl)-2-fluorophenyl]-3 -fluoroazetidine- 1- sulfonamide; 7V-[5-chloro-3-(l-{4-[4-({l-[5-(2,4-dioxo-l,3-diazinan-l-yl)pyridin-2- yl]piperidin-4-yl}methyl)piperazin-l-yl]-2-fluorophenyl}-3-(pyridin-4-yl)-lJH-pyrazol-4-yl)-
2-fluorophenyl] -3 -fluoroazetidine- 1 -sulfonamide; 7V-[5-chloro-3-(l-{4-[4-({l-[5-(2,4-dioxo- l,3-diazinan-l-yl)pyridin-2-yl]piperidin-4-yl}methyl)piperazin-l-yl]-2-fluorophenyl}-3- (pyridin-4-yl)-l//-pyrazol-4-yl)-2-fluorophenyl]pyrrolidine-l -sulfonamide; (37?)-7V-[5-chloro-
3-(l-{4-[4-({l-[5-(2,4-dioxo-l,3-diazinan-l-yl)pyridin-2-yl]piperidin-4-yl}methyl)piperazin- l-yl]-2-fluorophenyl}-3-(pyridin-4-yl)-lJ7-pyrazol-4-yl)-2-fluorophenyl]-3- fluoropyrrolidine-1 -sulfonamide; 7V-{5-chloro-3-[l-(4-{4-[(l-{5-[(37?)-2,6-dioxopiperidin-3- yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4-yl)-lJH-pyrazol-4- yl]-2-fhrorophenyl}cyclopentanesulfonamide; rac-7V-{5-chloro-3-[l-(4-{4-[(l-{5-[(37?)-2,6- dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4- yl)-l//-pyrazol-4-yl]-2-fluorophenyl } cyclopentanesulfonamide; 7V-{5-chloro-3-[l-(4-{4-[(l- {4-[(37?)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3- (pyridin-4-yl)-U7-pyrazol-4-yl]-2-fluorophenyl}cyclopentanesulfonamide; (37?)-3-(6-{4-[(4- {4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2,5-difluorophenyl)-3-(pyridin-4-yl)-lJH-pyrazol- 1 -yl]phenyl } piperazin- 1 -yl)methyl]piperidin- 1 -yl }pyri din-3 -yl)piperidine-2, 6-dione; rac-
(37?)-3-(6-{4-[(4-{4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2,5-difluorophenyl)-3-(pyridin- 4-yl)- I //-py razol - 1 -yl]phenyl } piperazin- 1 -yl)methyl]piperidin- 1 -yl }pyri din-3 -yl)piperidine- 2, 6-dione; (37?)-3-(4-{4-[(4-{4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2,5-difluorophenyl)- 3 -(pyridin-4-yl)- 1 //-pyrazol - 1 -yl]phenyl } piperazin- 1 -yl)methyl]piperidin- 1 - yl}phenyl)piperidine-2, 6-dione; 7V-[3-(l-{4-[(37?)-4-[(l-{4-[(37?)-2,6-dioxopiperidin-3- yl]phenyl }piperidin-4-yl)methyl]-3-methylpiperazin-l -yl]phenyl }-3-(pyridin-4-yl)-lJ7- pyrazol-4-yl)-2-fluorophenyl]propane-l -sulfonamide; (37?)-3-(6-{4-[(4-{4-[4-(3-
{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-3-(pyridin-4-yl)-lJ7-pyrazol-l-yl]-3- fluorophenyl } piperazin- 1 -yl)methyl]piperidin- 1 -yl }pyri din-3 -yl)piperidine-2, 6-dione; (3S)-3 - (6-{4-[(4-{4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-3-(pyridin-4-yl)-lJH- pyrazol-l-yl]-2-fluorophenyl}piperazin-l-yl)methyl]piperidin-l-yl}pyridin-3-yl)piperidine- 2,6-dione; rac-(7?)-N-(3-(l-(4-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l- yl)methyl)piperidin-l-yl)phenyl)-3-(pyridin-4-yl)-lJH-pyrazol-4-yl)-2-fluorophenyl)propane-
1 -sulfonamide; 7V-(5-chloro-3-(l-(4-((37?,57?)-4-((l-(5-((7?5)-2,6-dioxopiperidin-3-yl)pyridin-
2-yl)piperidin-4-yl)methyl)-3,5-dimethylpiperazin-l-yl)-2-fluorophenyl)-3-(pyridin-4-yl)- l/Z-pyrazol-4-yl)-2-fluorophenyl)pyrrolidine-l -sulfonamide; 7V-{5-chloro-3-[l-(5-{4-[(l-{5- [(35)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l-yl}pyridin-2- yl)-3-(pyridin-4-yl)-lJH-pyrazol-4-yl]-2-fluorophenyl}pyrrolidine-l-sulfonamide; N-{5- chloro-3-[l-(4-{4-[(l-{4-[(35)-2,6-dioxopiperidin-3-yl]-3-fluorophenyl}piperidin-4- yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4-yl)-lJH-pyrazol-4-yl]-2- fluorophenyl}pyrrolidine-l-sulfonamide; rac-7V-{5-chloro-3-[l-(4-{4-[(l-{4-[(37?)-2,6- dioxopiperidin-3-yl]-2,3-difluorophenyl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3- (pyridin-4-yl)-lJ7-pyrazol-4-yl]-2-fluorophenyl}pyrrolidine-l-sulfonamide; rac-7V-{5-chloro-
3-[l-(4-{4-[(l-{4-[(37?)-2,6-dioxopiperidin-3-yl]-2,5-difluorophenyl}piperidin-4- yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4-yl)-lJH-pyrazol-4-yl]-2- fluorophenyl}pyrrolidine-l-sulfonamide; rac-7V-{5-chloro-3-[l-(4-{4-[(l-{4-[(37?)-2,6- dioxopiperidin-3-yl]-3,5-difluorophenyl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3- (pyridin-4-yl)4J7-pyrazol-4-yl]-2-fluorophenyl (pyrrolidine- 1 -sulfonamide; and 7V-[5-chloro- 3-(l-{4-[4-({ l-[5-(2,4-dioxo-l,3-diazinan-l-yl)pyridin-2-yl]piperidin-4-yl}methyl)piperazin- l-yl]phenyl}-3-(pyridin-4-yl)-lJ/-pyrazol-4-yl)-2-fluorophenyl]cyclopentanesulfonamide.
Linkers
[0001 1 1 ] In Formula (I) or (II), L is a linker. The linker can be any linker suitable for linking the right and left portions of a molecule or Formula herein. In certain embodiments, the linker does not interfere with the harness or hook functions of a molecule or Formula herein. In certain embodiments, the linker provides useful solubility, flexibility, and/or distance between the portions of a molecule or Formula herein. In certain embodiments, L is a linker according to -L1L2L3L4L5L6-!?- or In certain embodiments, L is a linker according to -L1L2L3-L4 -L5-L;6- or -L6L5L4L3-!?-!?-. In certain embodiments, L is a linker according to In certain embodiments, L is a linker according to
-L1-L2-L3-L,4- or -L4-L3-L2-L1-. In certain embodiments, L is a linker according to -L1-L2- L3- or -L3-L2-L1-. In certain embodiments, L is a linker according to -L1-L2- or -L2-L1-. In certain embodiments, L is a linker according to -L1-, -L2-, -L3-, -L4-, -L5-, -L6-, -L7-, or other combinations as would be appreciated by a person of skill in the art. For example, in certain embodiments, L is a linker according to -L1-L3-L6-, -L7-L5-L1-, or -L1-L3-L6-L2-. Each group Lx is described in detail below. In certain embodiments, the linker L comprises at least one heterocyclic group. In certain embodiments, the linker L comprises one heterocyclic group. In certain embodiments, the linker L comprises two heterocyclic groups. In certain embodiments, the linker L comprises three heterocyclic groups. In certain embodiments, the linker L comprises at least one spiro bicyclic heterocycloalkylene group. In certain embodiments, the linker L comprises one spiro bicyclic heterocycloalkylene group. In certain embodiments, the linker L comprises two spiro bicyclic heterocycloalkylene groups. In certain embodiments, the linker L comprises three spiro bicyclic heterocycloalkylene groups. In certain embodiments, the linker L comprises at least one heterocycloalkylene group and at least one spiro bicyclic heterocycloalkylene. The remaining groups of or within the linker are selected for chemical compatibility with adjacent groups, as will be recognized by those of skill in the art. [0001 12] In certain embodiments, L is a linker according to -L^L^L^lAlAlAL7-. In certain embodiments, L is a linker according to -L7-L6-L5-L4-L3-L2-L1-. In certain embodiments, -L1- is absent, -N(R10)-, -C(R11)2-, -C(O)-, -Ci-8 alkylene-, -C2-8 alkynylene-, -Ce-Cio aryl-, -heteroaryl-, -C4-C10 heteroaryl-, -Q1-, or -Q2-; each -L2-, -L3-, -L4-, and -L5- is independently, absent, -N(R10)-, -C(Rn)2-, -C(O)-, -O-, -(CH2-CH2-O)I-8-, C1-8 alkylene-, -C2-8 alkynylene-, -Ce-Cio aryl-, substituted -Ce-Cio aryl-, -heteroaryl-, -C4-C10 heteroaryl-, -Q1-, -Q2-, or -Q3-; each -L6- and -L7- is independently, absent, -N(R10)-, -C(R10)2-, -C(O)-, -C(O)-N(R10)-, -N(R10)-C(O)-, -heteroaryl-, -C4-C10 heteroaryl-, or -C(R11)2-C(O)-N(R10)-. In certain embodiments, L comprises at least one -Q1-. In certain embodiments, L comprises one -Q1-. In certain embodiments, L comprises two -Q1-. In certain embodiments, L comprises three -Q1-. In certain embodiments, L comprises at least one -Q2-. In certain embodiments, L comprises one -Q2-. In certain embodiments, L comprises two -Q2-. In certain embodiments, L comprises three -Q2-. In certain embodiments, L comprises at least one -Q1- and at least one -Q2-. In certain embodiments, L comprises one -Q1- and one -Q2-.
[0001 13] In certain embodiments, each -Q1- is an unsubstituted or substituted three- to seven-membered heterocycloalkylene comprising at least one nitrogen; each -Q2- is a five- to thirteen-membered bicyclic heterocycloalkylene comprising at least one nitrogen, wherein the five- to thirteen-membered bicyclic heterocycloalkylene is optionally a spiro bicyclic heterocycloalkylene ring; each -Q3- is a three- to six-membered cycloalkylene; each R10 is hydrogen or methyl; and each R11 is independently, hydrogen, methyl, aryl, substituted aryl, or heteroaryl. In certain embodiments, R10 is hydrogen. In certain embodiments, R10 is methyl. In certain embodiments, one R11 is hydrogen. In certain embodiments, both R11 are hydrogen. In certain embodiments, one R11 is methyl. In certain embodiments, one R11 is hydrogen and the other is methyl. In certain embodiments, both R11 are methyl. In certain embodiments, one R11 is aryl. In certain embodiments, one R11 is hydrogen or methyl and the other is aryl. In certain embodiments, both R11 are aryl. In certain embodiments, R11 is a substituted aryl. In certain embodiments, one R11 is heteroaryl. In certain embodiments, one R11 is hydrogen or methyl and the other is heteroaryl. In certain embodiments, both R11 are heteroaryl.
[0001 14] In certain embodiments of Formula (I) or (II), L comprises at least one -Q1- according t , wherein n1 is one or two, and n2 is one or two. [0001 15] In certain embodiments of Formula (I) or (II), L comprises at least one -Q1-.
[000116] In certain embodiments of Formula (I) or (II), L is selected from
-Q^N^-Cfb-Q^QO)-;
-NtMe^Q^Clb-Q^CXO)-;
-Q2-CH2-Q1-C(O)-;
-Q1-CH2-Q1-C(O)-;
-Qi-Qi-C(O)-;
-Q^CFh-N^e^Q^QO)-;
-Q1-CH2-Q1-CH2-C(O)-N(Me)-;
-Q^CHi-Q2-;
-Q1-CH2-CH2-Q1-;
-(^-CFh-CFh-Q2-;
Q>-C(())-Q'
-Qi-QC^-Q2-;
-Q1-CH2-Q1-N(Me)-C(O)-;
-CH2-CH2-CH2-CH2-Q1-C(O)-;
-Qi-C(O)-;
-Q1-C(O)-Q1-CH(C6H5)-;
-C=CCH2-Q1-C(O)-;
-Q^Cfb-Q^NH-QO)-;
-CFh-CFh-CFh-Q^QO)-;
-Q1-CH2-Q1-C(Me)-C(O)-N(Me)-;
-CH2-Q1-;
-Q^QCO-Q^CIb-;
-N(H)-(CH2)s-C(O)-Q1-CH(C6H5)-;
-N(H)-(CH2)2-O-(CH2)2-C(O)-Q1-CH(C6H5)-;
-Q1-(CH2)3-C(O)-Q1-CH(C6H5)-;
-Q2-C(O)-Q1-CH(C6H5)-;
-Q2-CH2-C(O)-Q1-CH(C6H5)-;
-Q2-(CH2)3-C(O)-Q1-CH(C6H5)-;
-Q2-(CH2)2-C(O)-Q1-CH(C6H5)-;
-(CH2)6-Q1-CH(C6H5)-; -Q1-Q1-C(O)-Q1-CH(C6H5)-;
-Q1-CH2-C(O)-Q1-CH(C6H5)-;
-Q1-(CH2)2-C(O)-Q1-CH(C6H5)-;
-(CH2)3-C(O)-Q1-CH(C6H5)-;
-(CH2)4-C(O)-Q1-CH(C6H5)-;
-(CH2)5-C(O)-Q1-CH(C6H5)-;
-(CH2)6-C(O)-Q1-CH(C6H5)-;
-(CH2)3-Q1-CH2-C(O)-Q1-CH(C6H5)-;
-(CH2)3-O-Q3-C(O)-Q1-CH(C6H5)-;
-(CH2)3-O-(CH2)2-C(O)-Q1-CH(C6H5)-;
-(CH2)3-O-(CH2)2-C(O)-Q1-CH(pyrid-2-yl)-;
-(CH2)4-Q1-CH(C6H5)-;
-(CH2)5-Q1-CH(C6H5)-;
-(CH2)6-Q1-CH(pyrid-2-yl)-;
-(CH2)7-Q1-CH(C6H5)-;
-(CH2)7-Q1-CH(Me)-C(O)-N(Me)-;
-N(H)-(CH2)2-O-(CH2)2-Q1-CH(Me)-C(O)-N(Me)-;
-(CH2)3-O-(CH2)2-C(O)-Q1- CH(Me)-C(O)-N(Me)-;
-N(H)-(CH2)2-O-(CH2)2-Q1-CH(C6H5)-;
-N(H)-(CH2)2-[O-(CH2)2]2-C(O)-Q1-CH(C6H5)-;
-N(H)-(CH2)2-[O-(CH2)2]3-C(O)-Q1-CH(C6H5)-;
-N(H)-(CH2)2-[O-(CH2)2]4-C(O)-Q1-CH(C6H5)-;
-N(H)-(CH2)2-[O-(CH2)2]5-C(O)-Q1-CH(C6H5)-;
-N(H)-(CH2)2-[O-(CH2)2]6-C(O)-Q1-CH(C6H5)-;
-N(H)-(CH2)2-[O-(CH2)2]7-C(O)-Q1-CH(C6H5)-;
-N(H)-(CH2)2-[O-(CH2)2]8-C(O)-Q1-CH(C6H5)-;
-N(H)-Q3-O-(CH2)2-CH2-;
-N(H)-(CH2)3-Q1-(CH2)2-;
-C(O)-N(H)-[(CH2)3-O]3-(CH2)2-NH-;
-C(O)-N(H)-[(CH2)3-O]3-(CH2)2-;
-Q1-C(O)-[(CH2)2-O]3-(CH2)2-NH-;
-Q1-(CH2)3-O-CH2-;
-Qi-CCOXCeHeHDHs-; -Q1-(2-pyridyl)-
-N(H)-Q3-X-(2-pyridyl)-
-N(H)-Q3-X-(4-pyridyl)
-CH=C-(CH2)2-Q1-;
-Q1-;
-C(O)-(CH2-CH2-O)-(CH2)2-C(O)-Q1-CH(C6H5)-;
-N(H)-C(O)-(CH2-CH2-O)4-(CH2)2-C(O)-Q1-CH(C6H5)-;
-N(H)-C(O)-(CH2-CH2-O)5-(CH2)2-C(O)-Q1-CH(C6H5)-;
-(CH2-CH2-O)5-(CH2)2-C(O)-Q1-CH(C6H5)-;
-(CH2-CH2-O)-(CH2)2-C(O)-Q1-CH(C6H5)-;
-(CH2-CH2-O)4-(CH2)2-C(O)-Q1-CH(C6H5)-;
-(CH2)4-Q1-CH(C6H5)-;
-(CH2)3-Q1-CH(C6H5)-;
-(CH2)6-Q1-CH(C6H5)-;
-(CH2)5-Q1-CH(C6H5)-;
-(CH2-CH2-O)-(CH2)2-Q1-CH(C6H5)-;
-C(O)-(CH2-CH2-O)4-(CH2)2-Q1-CH(C6H5)-;
-C(O)-(CH2-CH2-O)5-(CH2)2-C(O)-Q1-CH(C6H5)-;
-C(O)-(CH2-CH2-O)6-(CH2)2-C(O)-Q1-CH(C6H5)-;
-C(O)-(CH2-CH2-O)3-(CH2)2-C(O)-Q1-CH(C6H5)-;
-(CH2)5-C(O)-Q1-CH(C6H5)-;
-(CH2-CH2-O)3-(CH2)2-C(O)-Q1-CH(C6H5)-; -(CH2)7-C(O)-Q1-CH(C6H5)-;
-C(O)-(CH2)-Q1-CH2-C(O)-Q1-CH(C6H5)-;
-(CH2)2-C(O)-Q1-CH(C6H5)-;
-C(O)-(CH2)2-Q1-(CH2)2-C(O)-Q1-CH(C6H5)-;
-C(O)-(CH2)9-C(O)-Q1-CH(C6H5)-;
-C(O)-(CH2)7-C(O)-Q1-CH(C6H5)-;
-C(O)-(CH2)5-C(O)-Q1-CH(C6H5)-;
-C(O)-(CH2-CH2-O)2-(CH2)2-C(O)-Q1-CH(C6H5)-;
-CH2-C(O)-Q1-CH(C6H5)-;
-(CH2)3-C(O)-Q1-CH(C6H5)-;
-(CH2)4-C(O)-Q1-CH(C6H5)-; and -QM-pyridyl-
. In some embodiments, X is oxygen or sulfur.
[0001 17] In certain embodiments of Formula (I) or Formula (II), L comprises at least one
(I) or Formula (II), L comprises at least one - certain embodiments of
Formula (I) or Formula (II), L comprises at least one embodiments of Formula (I) or Formula (II), L comprises at least one
In certain embodiments of Formula (I) or Formula (II), L comprises at least one -Q1- as embodiments of Formula (I) or Formula (II), L comprises at least one certain embodiments of Formula (I) or Formula (II), L comprises at least one -Q1- as In certain embodiments of Formula (I) or Formula (II), L comprises at least one [0001 18] In certain embodiments of Formula (I) or Formula (II), L comprises at least one
-Q2- according t wherein n3 is one or two.
[0001 19] In certain embodiments of Formula (I) or Formula (II), L comprises at least one
-Q2- according t
[000120] In certain embodiments of Formula (I) or Formula (II), L comprises at least one
-Q2- according t , wherein n4 is one or two, n5 is one or two, and n6 is one or two.
[000121] In certain embodiments of Formula (I) or Formula (II), L comprises at least one
-Q2- according t
[000122] In certain embodiments of Formula (I) or Formula (II), L comprises at least one
-Q2- according to wherein n8 is one or two.
[000123] In certain embodiments of Formula (I) or Formula (II), L comprises at least one
-Q2- according t
[000124] In certain embodiments of Formula (I) or Formula (II), L comprises at least one
-Q2- according t wherein n18 and n19 is two, or n18 is two and n19 is three, or n18 is three and n19 is two. [000125] In certain embodiments of Formula (I) or Formula (II), L comprises at least one
-Q2- according t
[000126] In certain embodiments of Formula (I) or Formula (II), L comprises at least one n22/ \ / \n23 |_N N-|
-Q2- according to n24 , wherein n22 is zero to two; n23 is zero to two, and n24 is one or two, or wherein n22 is two and each n23 and n24 is one; or n22 is two and each n23 and n24 is two.
[000127] In certain embodiments of Formula (I) or Formula (II), L comprises at least one
-Q2- according t
[000128] In certain embodiments of Formula (I) or Formula (II), L comprises at least one
-Q2- according t
[000129] In certain embodiments of Formula (I) or Formula (II), L comprises at least one
-Q3- according t , wherein n1 is one or two, and n2 is one or two.
[000130] In certain embodiments of Formula (I) or Formula (II), L comprises at least one
-Q3- selected from the group consisting bodiments of Formula (I) or Formula (II), L comprises at least one certain embodiments of Formula (I) or Formula (II), L comprises at least one comprises at least one
Pharmaceutical Compositions
[000131] The compounds described herein can be formulated into pharmaceutical compositions that further comprise a pharmaceutically acceptable carrier, diluent, adjuvant, or vehicle. In one embodiment, this disclosure provides a pharmaceutical composition comprising one or more compounds described herein, and a pharmaceutically acceptable carrier, diluent, adjuvant, or vehicle. In one embodiment, this disclosure provides a pharmaceutical composition comprising an effective amount of one or more compounds of this disclosure, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent, adjuvant, or vehicle. Pharmaceutically acceptable carriers include, for example, pharmaceutical diluents, excipients, or carriers suitably selected with respect to the intended form of administration, and consistent with conventional pharmaceutical practices.
[000132] According to another embodiment, this description provides a composition comprising one or more compounds herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. Pharmaceutical compositions of this description comprise a therapeutically effective amount of one or more compounds of Formula (I) or (II), wherein a “therapeutically effective amount” is an amount that is (a) effective to measurably degrade BRAF (or reduce the amount of BRAF) in a biological sample or in a patient; or (b) effective in treating and/or ameliorating a disease or disorder that is mediated by BRAF.
[000133] It will also be appreciated that certain compounds of this disclosure can exist in free form (e.g., a neutral compound) for treatment, or where appropriate, as a pharmaceutically acceptable derivative (e.g., a salt) thereof. According to this disclosure, a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any other adduct/educt or derivative that upon administration to a patient in need is capable of providing, directly or indirectly, one or more compounds as otherwise described herein, or a metabolite, or residue thereof.
[000134] As used herein, the term “pharmaceutically acceptable salt” refers to those salts that are, within the scope of sound medical practice or judgment, suitable for use in contact with cells, tissues, and/or the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like.
[000135] Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this description include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts include salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid; or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid; or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, -toluenesulfonate, undecanoate, and valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium (NH4 +), and N+(CI-4 alkyl)4 salts. This description also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersable products may be obtained by such quaternization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. [000136] A pharmaceutically acceptable carrier may contain inert ingredients that do not unduly inhibit the biological activity of the compounds described herein. The pharmaceutically acceptable carriers should be biocompatible, for example, non-toxic, non-inflammatory, non- immunogenic, and/or devoid of other undesired reactions or side-effects upon administration to a subject. Standard pharmaceutical formulation techniques can be employed.
[000137] The pharmaceutically acceptable carrier, adjuvant, or vehicle, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion, or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, and the like, as suited to the particular dosage form desired. Remington’s Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions, and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds described herein, such as by producing any undesirable biological effect, or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, the use of such conventional carrier medium is contemplated to be within the scope of this description. As used herein, the phrase “side effects” encompasses unwanted and adverse effects of a therapy (e.g., a prophylactic or therapeutic agent). Side effects are usually unwanted, but unwanted effects are not necessarily adverse or unbeneficial. An adverse effect from a therapy (e.g., prophylactic or therapeutic agent) might be harmful, uncomfortable, or risky. Side effects include, but are not limited to, fever, chills, lethargy, gastrointestinal toxicities (including gastric and intestinal ulcerations and erosions), nausea, vomiting, neurotoxicities, nephrotoxicities or renal toxicities (including such conditions as papillary necrosis and chronic interstitial nephritis), hepatic toxicities (including elevated serum liver enzyme levels), myelotoxicities (including leukopenia, myelosuppression, thrombocytopenia, and anemia), dry mouth, metallic taste, prolongation of gestation, weakness, somnolence, pain (including muscle pain, bone pain, and headache), hair loss, asthenia, dizziness, extra-pyramidal symptoms, akathisia, cardiovascular disturbances, and sexual dysfunction.
[000138] Some examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as Tween 80, phosphates, glycine, sorbic acid, or potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, or zinc salts), colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, methylcellulose, hydroxypropyl methylcellulose, wool fat, sugars such as lactose, glucose, and sucrose; starches such as com starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen -free water; isotonic saline; Ringer’s solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring, and perfuming agents. Preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.
[000139] As used herein, the term “measurably degrade” means a measurable reduction in (a) BRAF activity, between a sample comprising one or more compounds of this description and BRAF versus an equivalent sample comprising BRAF in the absence of said compound(s); or (b) the concentration of BRAF in a sample over time.
Administration
[000140] The compositions of this disclosure may be administered orally, parenterally, via inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. As used herein, the term “parenteral” includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrastemal, intrathecal, intraocular, intrahepatic, intralesional, and intracranial injection or infusion techniques. Compositions can be administered orally, intraperitoneally, or intravenously. Sterile injectable forms of the compositions of this disclosure may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3 -butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. [000141] For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans, and other emulsifying agents or bioavailability enhancers that are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
[000142] The pharmaceutically acceptable compositions of this disclosure may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions, or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring, or coloring agents may also be added.
[000143] Alternatively, the pharmaceutically acceptable compositions of this disclosure may be administered in the form of suppositories for rectal or vaginal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal or vaginal temperature and therefore will melt in the rectum or vaginal cavity to release the drug. Such materials include cocoa butter, polyethylene glycol, or a suppository wax that is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity and releases the active compound.
[000144] The pharmaceutically acceptable compositions of this disclosure may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, skin, or lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
- I l l - [000145] Topical application for the lower intestinal tract can be via a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
[000146] For topical applications, the pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax, and water. Alternatively, the pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.
[000147] For ophthalmic use, the pharmaceutically acceptable compositions may be formulated, for example, as micronized suspensions in isotonic, pH adjusted sterile saline or other aqueous solution, or as solutions in isotonic, pH adjusted sterile saline or other aqueous solution, either with or without a preservative such as benzyl alkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum. The pharmaceutically acceptable compositions of this disclosure may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
[000148] In certain embodiments, the compositions of this disclosure are administered orally. The pharmaceutically acceptable compositions of this description may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions, or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring, or coloring agents may also be added.
[000149] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the biologically active compounds herein, the liquid dosage forms may contain inert diluents commonly used in the art, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 -butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
[000150] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the biologically active compound(s) described herein are mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate, and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents, for example, cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also comprise buffering agents.
[000151] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. Solid dosage forms optionally may contain opacifying agents. These solid dosage forms can also be of a composition such that they release the active ingredient(s) only, for example, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
[000152] The active compounds herein can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, for example, tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition such that they release the active ingredient(s) only, for example, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
[000153] The compounds of the description are formulated in dosage unit form for ease of administration and uniformity of dosage. As used herein, the phrase “dosage unit form” refers to a physically discrete unit of agent appropriate for the subject, cell, tissue, or patient to be treated. It will be understood, however, that the total daily usage of the compounds, and compositions of this disclosure will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular subject, cell, tissue, patient, or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound(s) employed; the specific composition(s) employed; the age, body weight, general health, sex, and diet of the subject, cell, tissue, and/or patient; the time of administration, route of administration, and rate of excretion of the specific compound(s) employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound(s) employed, and like factors well known in the medical arts. [000154] The amount of the compounds of this disclosure that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the subject, cell, tissue, and/or host treated, the particular mode of administration, and other factors. The compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the compound(s) or inhibitor(s) can be administered to a subject, cell, tissue, and/or patient receiving these compositions.
[000155] Depending upon the particular condition or disease to be treated or prevented, additional therapeutic agents, which are normally administered to treat or prevent that condition, may also be present in the compositions of this disclosure. As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition, are known as “appropriate for the disease, or condition, being treated.”
[000156] The compound or composition can be administered concurrently with, prior to, or subsequent to, one or more additional therapeutically active agents. In general, each agent will be administered at a dose and/or on a time schedule determined for that agent. It will further be appreciated that the additional therapeutically active agent utilized in this combination can be administered together in a single composition or administered separately in different composition. The particular combination to employ in a regimen will take into account compatibility of the compounds described herein with the additional therapeutically active agent and/or the desired therapeutic effect to be achieved. In general, it is expected that additional therapeutically active agents utilized in combination will be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually. Additional therapeutically active agents include, but are not limited to, small organic molecules such as drug compounds (e.g., compounds approved by the Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In certain embodiments, the additional therapeutically active agent is a cancer agent (e.g., a biotherapeutic or chemo therapeutic cancer agent). In other embodiments, the additional therapeutically active agent is an anti-inflammatory agent. [000157] The amount of additional therapeutic agent present in the compositions of this disclosure will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. The amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
Methods of Use
[000158] The bifunctional compounds described herein are useful for degrading BRAF in biological samples, or in patients via a ubiquitin proteolytic pathway. Thus, an embodiment of this disclosure provides a method of treating a BRAF-mediated disease or disorder. As used herein, the term “BRAF-mediated disease or disorder” means any disease, disorder, or other deleterious condition in which BRAF is known to play a role. In some instances, an BRAF- mediated disease or disorder is a proliferative disorder or an autoimmune disorder. Examples of proliferative disorders include cancer.
[000159] In one aspect, provided herein are methods of treating or preventing cancer in a subject in need thereof. In certain embodiments, the methods comprise the step of orally administering to the subject an amount of a bifunctional compounds(s) described herein capable of inducing proteolytic degradation of BRAF. In certain embodiments, the amount is effective to treat or prevent the cancer.
[000160] In certain embodiments, the cancer is any cancer described below. In particular embodiments, the cancer comprises a solid tumor. In certain embodiments, the cancer is a B cell malignancy. In certain embodiments, the cancer is selected from the group consisting of chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), transformed CLL or Richter’s transformation, small cell lymphoma, follicular lymphoma (FL), diffuse large B- cell lymphoma (DLBCL), non-Hodgkin lymphoma, mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), Waldenstrom macroglobulinemia (WM), and central nervous system (CNS) lymphoma. In certain embodiments, the cancer is chronic lymphocytic leukemia. In certain embodiments, the cancer is small cell lymphoma. In certain embodiments, the cancer is follicular lymphoma. In certain embodiments, the cancer is diffuse large B-cell lymphoma. In certain embodiments, the cancer is non-Hodgkin lymphoma. In certain embodiments, the cancer is mantle cell lymphoma. In certain embodiments, the cancer is marginal zone lymphoma. In certain embodiments, the cancer is Waldenstrom macroglobulinemia. In certain embodiments, the cancer is small lymphocytic lymphoma (SLL). In certain embodiments, the cancer is CNS lymphoma. In certain embodiments, the cancer is transformed CLL or Richter’s transformation. In certain embodiments, the cancer is chronic lymphocytic leukemia (CLL).
[000161] In another aspect, provided herein are methods of degrading BRAF in a subj ect in need thereof. The methods comprise the step of orally administering to the subject an amount of a bifunctional compound(s) described herein and capable of inducing proteolytic degradation of BRAF. In certain embodiments, the amount is effective to degrade BRAF in the subject. The BRAF can be expressed in any cells or tissues of the subject.
[000162] In another aspect, provided herein are methods of preventing B cell activation in a subject in need thereof. The methods comprise the step of orally administering to the subject an amount of a bifunctional compound(s) described herein and capable of inducing proteolytic degradation of BRAF. In certain embodiments, the amount is effective to prevent B cell activation. In certain embodiments, the B cell expresses CD69. In certain embodiments, the B cell expresses CD86. In certain embodiments, the B cell expresses CD69 and CD86.
[000163] In the methods, the bifunctional compound(s) described herein comprise a moiety capable of specifically binding BRAF and further comprise a moiety capable of recruiting a ubiquitin ligase to degrade the BRAF. Particular compounds with each capability are described herein. The compounds can be administered in any form, including pharmaceutically acceptable salts and pharmaceutical compositions.
[000164] The bifunctional compound(s) described herein can be administered in any dose deemed suitable by the practitioner of skill. In certain embodiments, the dose is 0.1-1000 mg/kg. In certain embodiments, the dose is 0.1-900 mg/kg. In certain embodiments, the dose is 0.1-800 mg/kg. In certain embodiments, the dose is 0.1-700 mg/kg. In certain embodiments, the dose is 0.1-600 mg/kg. In certain embodiments, the dose is 0.1-500 mg/kg. In certain embodiments, the dose is 0.1-400 mg/kg. In certain embodiments, the dose is 0.1-300 mg/kg. In certain embodiments, the dose is 0.1-200 mg/kg. In certain embodiments, the dose is 0.1- 100 mg/kg. In certain embodiments, the dose is selected from the group consisting of 100 mg/kg, 200 mg/kg, 300 mg/kg, 450 mg/kg, 600 mg/kg, 800 mg/kg, and 1000 mg/kg. In certain embodiments, the dose is about 25 mg/kg. In certain embodiments, the dose is about 50 mg/kg. In certain embodiments, the dose is about 75 mg/kg. In certain embodiments, the dose is about 100 mg/kg. In certain embodiments, the dose is about 150 mg/kg. In certain embodiments, the dose is about 200 mg/kg. In certain embodiments, the dose is about 250 mg/kg. In certain embodiments, the dose is about 300 mg/kg. In certain embodiments, the dose is about 400 mg/kg. In certain embodiments, the dose is about 450 mg/kg. In certain embodiments, the dose is about 500 mg/kg. In certain embodiments, the dose is about 600 mg/kg. In certain embodiments, the dose is about 700 mg/kg. In certain embodiments, the dose is about 750 mg/kg. In certain embodiments, the dose is about 800 mg/kg. In certain embodiments, the dose is about 900 mg/kg. In certain embodiments, the dose is about 1000 mg/kg.
[000165] The dose can be administered on a schedule deemed suitable by the person of skill in the art. In certain embodiments, the dose is administered once per day. In certain embodiments, the dose is administered twice per day. In certain embodiments, the dose is administered three times per day. In certain embodiments, the dose is administered four times per day. In certain embodiments, the dose is administered in divided doses. In certain embodiments, the dose is administered in two divided doses per day. In certain embodiments, the dose is administered in three divided doses per day. In certain embodiments, the dose is administered in four divided doses per day.
[000166] Dosing can continue for any length of time deemed suitable by the person of skill in the art. In certain embodiments, the dose is administered daily for fourteen days. In certain embodiments, the dose is administered daily for thirteen days. In certain embodiments, the dose is administered daily for twelve days. In certain embodiments, the dose is administered daily for eleven days. In certain embodiments, the dose is administered daily for ten days. In certain embodiments, the dose is administered daily for nine days. In certain embodiments, the dose is administered daily for eight days. In certain embodiments, the dose is administered daily for seven days. In certain embodiments, the dose is administered daily for six days. In certain embodiments, the dose is administered daily for five days. In certain embodiments, the dose is administered daily for four days. In certain embodiments, the dose is administered daily for three days. In certain embodiments, the dose is administered daily for two days. In certain embodiments, the dose is administered for one day.
[000167] In the dosing schedule, the doses can be administered on consecutive days or cyclicly, according to the judgment of the practitioner of skill. In certain embodiments, the doses are administered on consecutive days. In certain embodiments, the doses are administered with an interval between doses. In certain embodiments, the interval is one day. In certain embodiments, the interval is two days. In certain embodiments, the interval is three days. In certain embodiments, the interval is four days. In certain embodiments, the interval is five days. In certain embodiments, the interval is six days.
[000168] In certain embodiments, the dose is administered weekly. In certain embodiments, the dose is administered twice per week. In certain embodiments, the dose is administered three times per week.
[000169] In certain embodiments, the dose(s) are administered for a period of time with a first interval between dose(s), and then the dose(s) are re-administered for a period of time following the first interval between dose(s), wherein this dosing regimen can be repeated (i.e., cyclicly or cyclically, for example, after a second, third, etc. interval between subsequent administrations of dose(s)) according to the judgment of the practitioner of skill. For example, in one embodiment, a first dose is administered for one week, followed by a first interval of one week without the first dose administration; then, a second dose is re-administered for another week, followed by a second interval of one week without the first or second dose administration, and so on cyclically. Other perturbations for first, second, third, etc. dose(s) followed by perturbations for first, second, third, etc. interval(s), and combinations thereof, are contemplated herein as would be appreciated by the practitioner of skill and the need of the subject, cell, tissue, and/or patient. For example, in one embodiment, a first dose is administered daily for one week, followed by a first interval of three weeks without the first daily dose administration; then, a second dose is re-administered biweekly for another week, followed by a second interval of four weeks without the first daily or second biweekly dose administration, and so on cyclically.
[000170] The compound can be administered by any route of administration deemed suitable by the practioner of skill. In certain embodiments, the dose is administered orally. Formulations and techniques for administration are described elsewhere herein.
[000171 ] In certain embodiments, term “cancer” includes, but is not limited to, the following cancers: epidermoid Oral: buccal cavity, lip, tongue, mouth, pharynx, squamous cell carcinoma of the head and neck (HNSCC); Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; Lung: bronchogenic carcinoma (squamous cell or epidermoid, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma, non-small cell lung cancer (NSCLC); Gastrointestinal: gastric cancer, esophagus (squamous cell carcinoma, larynx, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel or small intestines (adenocarcinoma, lymphoma, carcinoid tumors, Karposi’s sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel or large intestines (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), colon, colon-rectum, colorectal, microsatellite stable colorectal cancer (MSS CRC), rectum; Genitourinary tract: kidney (adenocarcinoma, Wilm’s tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma), metastatic castrate-resistant prostate cancer (mCRPC), muscle-invasive urothelial cancer; Liver: hepatoma (hepatocellular carcinoma), cholangiocar cinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, biliary passages; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing’s sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma (MM), malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical cancer, cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma), breast, triple-negative breast cancer (TNBC), platinum-resistant epithelial ovarian cancer (EOC); Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin’s disease, non-Hodgkin’s lymphoma (malignant lymphoma) hairy cell; lymphoid disorders (e.g., mantle cell lymphoma, Waldenstrom’s macroglobulinemia, Marginal zone lymphoma, and Follicular lymphoma); Skin: malilymphgnant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi’s sarcoma, keratoacanthoma, moles or dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; Thyroid gland: papillary thyroid carcinoma, follicular thyroid carcinoma; medullary thyroid carcinoma, undifferentiated thyroid cancer, multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, familial medullary thyroid cancer, pheochromocytoma, paraganglioma; Adrenal glands: neuroblastoma; and metatstaic melanoma.
[000172] In certain embodiments, the term “autoimmune disease” includes, but is not limited to, the following autoimmune diseases: uticaria, graft-versus-host disease (GVHD), acute graft-versus-host disease, pemphigus vulgaris, achalasia, Addison’s disease, Adult Still’s disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti- GBM/anti-TBM nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune dysautonomia, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, axonal and neuronal neuropathy (AMAN), Balo disease, Behcet’s disease, benign mucosal pemphigoid, bullous pemphigoid, Castleman disease (CD), Celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic recurrent multifocal osteomyelitis (CRMO), Churg-Strauss Syndrome (CSS) or Eosinophilic Granulomatosis (EGPA), cicatricial pemphigoid, Cogan’s syndrome, cold agglutinin disease, congenital heart block, coxsackie myocarditis, CREST syndrome, Crohn’s disease, dermatitis herpetiformis, dermatomyositis, Devic’s disease (neuromyelitis optica), discoid lupus, Dressier’s syndrome, endometriosis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture’s syndrome, granulomatosis with polyangiitis, Graves’ disease, Guillain-Barre syndrome, Hashimoto’s thyroiditis, hemolytic anemia, Henoch-Schonlein purpura (HSP), herpes gestationis or pemphigoid gestationis (PG), hidradenitis suppurativa (HS) (Acne Inversa), hypogammalglobulinemia, IgA nephropathy, IgG4-related sclerosing disease, immune thrombocytopenic purpura (ITP), inclusion body myositis (IBM), interstitial cystitis (IC), juvenile arthritis, juvenile diabetes (Type 1 diabetes), juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, ligneous conjunctivitis, linear IgA disease (LAD), lupus, lyme disease (chronic), Meniere’s disease, microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), Mooren’s ulcer, Mucha-Habermann disease, Multifocal Motor Neuropathy (MMN) or MMNCB, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, palindromic rheumatism (PR), PANDAS, paraneoplastic cerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, pars planitis (peripheral uveitis), Parsonnage-Tumer syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia (PA), POEMS syndrome, polyarteritis nodosa, polyglandular syndromes type I, II, or III, polymyalgia rheumatica, polymyositis, postmyocardial infarction syndrome, postpericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, progesterone dermatitis, psoriasis, psoriatic arthritis, pure red cell aplasia (PRC A), pyoderma gangrenosum, Raynaud’s phenomenon, reactive arthritis, reflex sympathetic dystrophy, relapsing polychondritis, restless legs syndrome (RLS), retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleritis, scleroderma, Sjogren’s syndrome, sperm and testicular autoimmunity, stiff person syndrome (SPS), subacute bacterial endocarditis (SBE), Susac’s syndrome, sympathetic ophthalmia (SO), Takayasu’s arteritis, temporal arteritis (giant cell arteritis), thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome (THS), transverse myelitis, Type 1 diabetes, ulcerative colitis (UC), undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vitiligo, Vogt-Koyanagi-Harada Disease, and Wegener’s granulomatosis (or Granulomatosis with Poly angiitis (GPA)).
[000173] In certain embodiments, the term “inflammatory disease” includes, but is not limited to, the following inflammatory diseases: encephalitis, myelitis, meningitis, arachnoiditis, neuritis, dacryoadenitis, scleritis, episcleritis, keratitis, retinitis, chorioretinitis, blepharitis, conjunctivitis, uveitis, otitisexterna, otitismedia, labyrinthitis, mastoiditis, endocarditis, myocarditis, pericarditis, vasculitis, arteritis, phlebitis, capillaritis, sinusitis, rhinitis, pharyngitis, laryngitis, tracheitis, bronchitis, bronchiolitis, pneumonitis, pleuritis, mediastinitis, stomatitis, gingivitis, gingivostomatitis, glossitis, tonsillitis, sialadenitis/parotitis, cheilitis, pulpitis, gnathitis, esophagitis, gastritis, gastroenteritis, enteritis, colitis, enterocolitis, duodenitis, ileitis, caecitis, appendicitis, proctitis, hepatitis, ascendingcholangitis, cholecystitis, pancreatitis, peritonitis, dermatitis, folliculitis, cellulitis, hidradenitis, arthritis, dermatomyositis, myositis, synovitis/tenosynovitis, bursitis, enthesitis, fasciitis, capsulitis, epicondylitis, tendinitis, panniculitis, osteochondritis/osteitis/osteomyelitis, spondylitis, periostitis, chondritis, nephritis, glomerulonephritis, pyelonephritis, ureteritis, cystitis, urethritis, oophoritis, salpingitis, endometritis, parametritis, cervicitis, vaginitis, vulvitis, mastitis, orchitis, epididymitis, prostatitis, seminalvesiculitis, balanitis, posthitis, balanoposthitis, chori oamnionitis, funisitis, omphalitis, insulitis, hypophysitis, thyroiditis, parathyroiditis, adrenalitis, lymphangitis, and lymphadenitis.
Articles of Manufacture and Kits
[000174] Also provided are articles of manufacture comprising any of the compounds or pharmaceutical compositions described herein. The articles of manufacture include suitable containers or packaging materials for the compounds or pharmaceutical compositions. Examples of a suitable container include, but are not limited to, a bottle, a vial, a syringe, an intravenous bag, or a tube.
[000175] Also provided are kits comprising any of the compounds or pharmaceutical compositions described herein. The kits can contain the compounds or pharmaceutiucal compositions in suitable containers or packaging materials, including, but not limited to, a bottle, a vial, a syringe, an intravenous bag, or a tube. The kits can comprise the compounds or pharmaceutiucal compositions for administration to a subject, cell, tissue, and/or individual in single-dose form or in multiple-dose form. The kits can further comprise instructions or a label for administering the compounds or pharmaceutiucal compositions to a subject, cell, tissue, and/or individual according to any of the methods disclosed herein. The kits can further comprise equipment for administering the compounds or pharmaceutiucal compositions to a subject, cell, tissue, and/or individual, including, but not limited to, needles, syringes, tubing, or intravenous bags. The kits can further comprise instructions for producing any of the compounds or pharmaceutiucal compositions disclosed herein.
[000176] Also provided are articles of manufacture comprising any of the compounds or pharmaceutical compositions described herein. The articles of manufacture include suitable containers or packaging materials for the compounds or pharmaceutical compositions. The articles of manufacture include suitable containers or packaging materials for the compounds or pharmaceutical compositions. Examples of a suitable container include, but are not limited to, a bottle, a vial, a syringe, an intravenous bag, or a tube. [000177] This disclosure will be more fully understood by reference to the following Examples. They should not, however, be construed as limiting the scope of this disclosure. It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims.
EXAMPLES
[000178] Additional embodiments are disclosed in further detail in the following examples, which are not in any way intended to limit the scope of the claims.
Analytical Methods and Instrumentation
[000179] Proton nuclear magnetic resonance (NMR) spectra were obtained on Bruker Ascend™ 500 MHz spectrometer. NMR spectra are reported as follows: chemical shift 5 (ppm), multiplicity, coupling constant J (Hz), and (relative) integration. The abbreviations s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, and br = broad are used throughout. Mass spectral data were measured using the following systems: Waters Acquity i-class ultraperformance liquid chromatography (UPLC) system with Acquity Photo Diode Array Detector, Acquity Evaporative Light Scattering Detector (ELSD), and Waters ZQ Mass Spectrometer. Data was acquired using Waters MassLynx 4.1 software and purity was characterized by UV wavelength 220 nm, evaporative light scattering detection (ELSD), and electrospray positive ion (ESI) (column: Acquity UPLC BEH Cl 8 1.7 p i 2.1 x 50 mm). Solvents used: acetonitrile/water, containing 0.1% formic acid; flow rate 0.7 mL/min. Preparatory HPLC purifications were conducted with a flow rate of 15 mL/min and detection by UV wavelength at 214 nm and 254 nm (Column: Jupiter© 10 pM Proteo 90 A, 250 x 21.2 mm A, solvent: acetonitrile/water, containing a modifier such as 0.1% trifluoroacetic acid).
[000180] Abbreviations used in the examples include:
Table 1. Compounds
Attorney Docket No. : 121843.00271
NU-3200 PCT
-207-
1100573566\5\AMERICAS
[000181 ] Synthesis of \- !2- (2-:iiiiiiiopyriiiiidin-4-yl)-4-|2-nuoro-3-(propane-l - sulfonamido)phenyl]-l.,3-thiazol-2-yl]-2-niethylpropynoxane-4-carboxaniide
[000182] Step-1: Synthesis of tert-butyl 7V-(2-carbamoyl-2.,2- dimethylethyl)carbamate (2)
To a mixture of 3-[(tert-butoxycarbonyl)amino]-2,2-dimethylpropanoic acid (5 g, 23.01 mmol, 1 equiv) and NEUCl (6.15g, 115.06 mmol, 5 equiv) in DMF (50 mL) was added HATU (13.13 g, 34.52 mmol, 1.5 equiv) and DIEA (8.92 g, 69.03 mmol, 3 equiv) at room temperature. The resulting mixture was stirred for one hour at room temperature. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford tert-butyl A-(2-carbamoyl-2,2-dimethylethyl)carbamate (3.5 g, crude) as a yellow oil. [000183] Step-2: Synthesis o butyl /V-(2-carbamothioyl-2.,2- dimethylethyl)carbamate (3)
To a mixture of tert-butyl A-(2-carbamoyl-2,2-dimethylethyl)carbamate (3.5 g, 16.183 mmol, 1 equiv) in THF (40 mL) was added Lawesson’s Reagent (3.27 g, 8.091 mmol, 0.5 equiv) at room temperature. The resulting mixture was stirred overnight at room temperature. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EtOAc(5: l) to afford tert-butyl A-(2-carbamothioyl-2,2-dimethylethyl)carbamate (1.6 g, 38.30%) as a white solid. LCMS: C10H20N2O2S requires: 232.1, found: m/z = 233.1 [M+H]+.
[000184] Step-3: Synthesis of tert-butyl A-]2-[5-(2-chloropyrimidin-4-yl)-4-(2- fluoro-3-][(prop-2-en-l-yloxy)carbonyl]amino}phenyl)-l.,3-thiazol-2-yl]-2- methylpropyBcarbamate (4)
To a mixture of tert-butyl A-(2-carbamothioyl-2,2-dimethylethyl)carbamate (370 mg, 1.59 mmol, 1 equiv) and NBS (283 mg, 1.59 mmol, 1 equiv) in DMA (5 mL) was added prop-2-en- 1-yl 7V-{3-[2-(2-chloropyrimidin-4-yl)acetyl]-2-fluorophenyl}carbamate (556 mg, 1.59 mmol, 1 equiv) at room temperature. The resulting mixture was stirred for 2 h at 60 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EtOAc (5: 1) to afford tert-butyl A-{2-[5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-3-{[(prop-2-en-l- yloxy)carbonyl]amino}phenyl)-l,3-thiazol-2-yl]-2-methylpropyl}carbamate (200 mg, 20.11%) as a white solid. LCMS: C26H29CIFN5O4S requires: 561.2, found: m/z = 562.1 [M+H]+.
[000185] Step-4: Synthesis of prop-2-en-l-yl 7V-]3-[2-(l-amino-2-methylpropan-2- yl)-5-(2-chloropyrimidin-4-yl)-l.,3-thiazol-4-yl]-2-fluorophenvncarbaniate (5)
A solution of tert-butyl A-{2-[5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-3-{[(prop-2-en-l- yloxy)carbonyl]amino}phenyl)-l,3-thiazol-2-yl]-2-methylpropyl}carbamate (190 mg, 0.338 mmol, 1 equiv) in HC1/ 1,4 -di oxane (5 mL, 4 M) was stirred for one hour at room temperature. The resulting mixture was concentrated under reduced pressure to afford prop-2-en-l-yl N-{3- [2-(l-amino-2-methylpropan-2-yl)-5-(2-chloropyrimidin-4-yl)-l,3-thiazol-4-yl]-2- fluorophenyl (carbamate (110 mg, crude) as a yellow oil. LCMS: C21H21CIFN5O2S requires: 461.1, found: m/z = 462.0 [M+H]+. [000186] Step-5: Synthesis of prop-Z-en-l-yl 7V-]3-[5-(2-chloroDyrimidin-4-yl)-2-[2- methyl-l- 4-ylformamido)propan-2-yl]-l.,3-thiazol-4-yl]-2- fluorophenyBcarbamate (6)
To a mixture of prop-2-en-l-yl 7V-{3-[2-(l-amino-2-methylpropan-2-yl)-5-(2- chloropyrimidin-4-yl)-l,3-thiazol-4-yl]-2-fluorophenyl}carbamate (200 mg, 0.43 mmol, 1 equiv) and oxane-4-carboxylic acid (84 mg, 0.64 mmol, 1.5 equiv) in DMF (2 mL) was added HATU (246 mg, 0.64 mmol, 1.5 equiv) and DIEA (279 mg, 2.16 mmol, 5 equiv) at room temperature. The resulting mixture was stirred for one hour at room temperature. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EtOAc (5: 1) to afford prop-2-en-l-yl A-{3-[5-(2-chloropyrimidin-4-yl)-2-[2-methyl-l-(oxan-4- ylformamido)propan-2-yl]-l,3-thiazol-4-yl]-2-fhiorophenyl}carbamate (150 mg, 53.11%) as a yellow oil. LCMS: C27H29CIFN5O4S requires: 573.2, found: m/z = 574.1 [M+H]+.
[000187] Step-6: Synthesis of A-]2-[4-(3-amino-2-fluorophenyl)-5-(2- chloropyrimidin-4-yl)-l.,3-thiazol-2-yl]-2-methylpropynoxane-4-carboxamide (7)
To a mixture of prop-2-en-l-yl A-{3-[5-(2-chloropyrimidin-4-yl)-2-[2-methyl-l-(oxan-4- ylformamido)propan-2-yl]-l,3-thiazol-4-yl]-2-fluorophenyl}carbamate (140 mg, 0.244 mmol, 1 equiv) and Pd(PPh3)2C12 (3.42 mg, 0.005 mmol, 0.02 equiv) in DCM (2 mL) was added HOAc (35.15 mg, 0.586 mmol, 2.4 equiv) and w-BusSnH (106.47 mg, 0.366 mmol, 1.5 equiv) at 0 °C. The resulting mixture was stirred for 0.5 h at 0 °C. The reaction was quenched by the addition of saturated NaHCCL aqueous at 0 °C. The resulting mixture was extracted with CH2Q2. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford N-{2- [4-(3-amino-2-fluorophenyl)-5-(2-chloropyrimidin-4-yl)-l,3-thiazol-2-yl]-2- methylpropyl }oxane-4-carboxamide (120 mg, crude) as a yellow oil. LCMS: C23H25CIFN5O2S requires: 489.1, found: m/z = 490.1 [M+H]+.
[000188] Step-7: Synthesis of 7V-(2-(5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-3- (propylsulfon:iniido)phenyl)thi:izol-2-yl)-2-niethylpropyl)tetr:ihvdro-2//-pyran-4- carboxamide (8)
To a mixture of A-{2-[4-(3-amino-2-fluorophenyl)-5-(2-chloropyrimidin-4-yl)-l,3-thiazol-2- yl]-2-methylpropyl}oxane-4-carboxamide (80 mg, 0.163 mmol, 1 equiv) in DCM (2 mL) was added TEA (49.56 mg, 0.489 mmol, 3 equiv) and propane- 1 -sulfonyl chloride (34.92 mg, 0.244 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford 7V-(2-(5- (2-chloropyrimidin-4-yl)-4-(2-fluoro-3-(propylsulfonamido)phenyl)thiazol-2-yl)-2- methylpropyl)tetrahydro-2J/-pyran-4-carboxamide (100 mg, crude) as a brown oil. LCMS: C26H31CIFN5O4S2 requires: 595.1, found: m/z = 596.1 [M+H]+.
[000189] Step-8: Synthesis of tert-butyl 7V-(4-14-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-2-[2-methyl-l-(oxan-4-ylformamido)propan-2-yl]-l.,3-thiazol-5- vnpyrimidin-2-yl)carbamate (9)
To a mixture of 7V-{2-[5-(2-chloropyrimidin-4-yl)-4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-l,3-thiazol-2-yl]-2-methylpropyl}oxane-4-carboxamide (70 mg, 0.117 mmol, 1 equiv) and tert-butyl carbamate (20.63 mg, 0.176 mmol, 1.5 equiv) in dioxane (2 mL) was added Pd(OAc)2 (2.64 mg, 0.012 mmol, 0.1 equiv), CS2CO3 (61.21 mg, 0.187 mmol, 1.6 equiv), and BINAP (21.94 mg, 0.035 mmol, 0.3 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 3 h at 90 °C under the nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC CFEChiEtOAc (1 : 1) to afford tert-butyl 7V-(4-{4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-2-[2-methyl-l-(oxan-4-ylformamido)propan-2-yl]-l,3-thiazol-5- yl}pyrimidin-2-yl)carbamate (45 mg, 50.96%) as a white solid. LCMS: C31H41FN6O6S2 requires: 676.3, found: m/z = 677.2 [M+H]+.
[000190] Step-9: Synthesis of \-!2-|5-(2-aniinopyrimidin-4-yl)-4-|2-nuoro-3- (propane-l-sulfonamido)phenyl]-l.,3-thiazol-2-yl]-2-niethylpropyl}oxane-4-carboxaniide
A solution of tert-butyl A-(4-{4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-2-[2-methyl-l- (oxan-4-ylformamido)propan-2-yl]-l,3-thiazol-5-yl}pyrimidin-2-yl)carbamate (35 mg, 0.052 mmol, 1 equiv) in HCl/l,4-di oxane (5 mL, 4 M) was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography with FEChMeCN (3: 1) to afford 7V-{2-[5-(2- aminopyrimidin-4-yl)-4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-l,3-thiazol-2-yl]-2- methylpropyl }oxane-4-carboxamide (28.8 mg, 92.71%) as an off-white solid. LCMS: C26H33FN6O4S2 requires: 576.2, found: m/z = 577.2 [M+H]+.
1H NMR (400 MHz, CD3OD) 5 8.10 - 8.08 (m, 1H), 7.71 - 7.67 (m, 1H), 7.53 - 7.51 (m, 1H), 7.40 - 7.36 (m, 1H), 6.67 - 6.64 (m, 1H), 3.92 - 3.88 (m, 2H), 3.56 - 3.54 (m, 2H), 3.42 - 3.33 (m, 2H), 3.18 - 3.14 (m, 2H), 2.57 - 2.42 (m, 1H), 1.90 - 1.84 (m, 2H), 1.74 - 1.62 (m, 4H), 1.52 (s, 6H), 1.06 - 1.04 (m, 3H).
[000191] Synthesis of 7V-(3-(5-(2-aminoDyrimidin-4-yl)-2-(2-(DiDeridin-4-yl)DroDan- 2-yl)thiazol-4-yl)-2-fluoroDhenyl)DroDane-l-sulfonamide
[000192] Step-1: Synthesis of tert-butyl 4-(2-(4-(3-(((allyloxy)carbonyl)amino)-2- fluoroDhenyl)-5-(2-chloroDyrimidin-4-yl)thiazol-2-yl)DroDan-2-yl)Diperidine-l- carboxylate (3)
To a mixture of prop-2-en-l-yl A-{3-[2-(2-chloropyrimidin-4-yl)acetyl]-2- fluorophenyl} carbamate (2.4 g, 6.98 mmol, 1 equiv) in DMA (20.0 mL) was added NBS (1.24 g, 6.98 mmol, 1 equiv) for 15 min at room temperature followed by the addition of tert-butyl 4-(l-carbamothioyl-l-methylethyl)piperidine-l-carboxylate (2.0 g, 6.98 mmol, 1 equiv) at room temperature. The resulting mixture was stirred for 2 h at 60 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (3: 1) to afford tert-butyl 4-{2-[5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-3-{[(prop-2-en-l- yloxy)carbonyl]amino}phenyl)-l,3-thiazol-2-yl]propan-2-yl}piperidine-l-carboxylate (1.80 g, 41.84%) as a white solid. LCMS: C30H35CIFN5O4S requires: 615.2, found: m/z = 616.2 [M+H]+.
[000193] Step-2: Synthesis of tert-butyl 4-]2-[4-(3-amino-2-fluorophenyl)-5-(2- chloropyrimidin-4-yl)-l.,3-thiazol-2-yl]propan-2-vnpiperidine-l-carboxylate (4)
To a mixture of tert-butyl 4-{2-[5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-3-{[(prop-2-en-l- yloxy)carbonyl]amino}phenyl)-l,3-thiazol-2-yl]propan-2-yl}piperidine-l-carboxylate (1.0 g, 1.623 mmol, 1 equiv) and HOAc (243.66 mg, 4.058 mmol, 2.5 equiv) in DCM (4 mL) was added Pd(PPh3)2Ch (22.78 mg, 0.032 mmol, 0.02 equiv) and w-BusSnH (755.83 mg, 2.597 mmol, 1.6 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 0.5 h at room temperature under the nitrogen atmosphere. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous ISfeSC After filtration, the filtrate was concentrated under reduced pressure to afford tert-butyl 4-{2-[4-(3-amino-2-fluorophenyl)-5-(2-chloropyrimidin-4-yl)-l,3-thiazol-2- yl]propan-2-yl (piperidine- 1 -carboxylate (700 mg, crude) as a brown oil. The crude product was used in the next step directly without further purification. LCMS: C26H31CIFN5O2S requires: 531.2, found: m/z = 532.2 [M+H]+.
[000194] Step-3: Synthesis of tert-butyl 4-]2-[5-(2-chloropyrimidin-4-yl)-4-[2-fluoro- 3-(propane-l-sulfonamido)phenyl]-l.,3-thiazol-2-yl]propan-2-vnpiperidine-l- carboxylate (5)
To a mixture of tert-butyl 4-{2-[4-(3-amino-2-fluorophenyl)-5-(2-chloropyrimidin-4-yl)-l,3- thiazol-2-yl]propan-2-yl( piperidine- 1 -carboxylate (1.6 g, 3.007 mmol, 1 equiv) and pyridine (0.24 g, 3.007 mmol, 1.0 equiv) in DCM (15 mL) was added propane- 1 -sulfonyl chloride (0.43 g, 3.007 mmol, 1.0 equiv) dropwise at 0 °C. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product was dissolved in THF (5 mL), ACN (5 mL), and H2O (5 mL). ISfeCCL (3.7 g, 35.190 mmol, 6 equiv) was added at room temperature. The resulting mixture was stirred at 50 °C overnight. The resulting mixture was concentrated under vacuum. The resulting mixture was extracted with DCM. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (5: 1) to afford tert-butyl 4-{2-[5-(2-chloropyrimidin-4-yl)-4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-l,3-thiazol- 2-yl]propan-2-yl (piperidine- 1 -carboxylate (1.0 g, 52.11%) as a yellow solid. LCMS: C29H37CIFN5O4S2 requires: 637.2, found: m/z = 638.2 [M+H]+.
[000195] Step-4: Synthesis of tert-butyl 4-|2-(5-!2-|(tert- butoxycarbonyl)amino]pyrimidin-4-vn-4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]- l,3-thiazol-2-yl)propan-2-yl]piperidine-l-carboxylate (6)
To a mixture of tert-butyl 4-{2-[5-(2-chloropyrimidin-4-yl)-4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-l,3-thiazol-2-yl]propan-2-yl}piperidine-l-carboxylate (1.0 g, 1.567 mmol, 1 equiv) and BocNEE (917.79 mg, 7.835 mmol, 5.0 equiv) in 1,4-dioxane (10 mL) was added BrettPhos Pd G3 (142.0 mg, 0.157 mmol, 0.1 equiv) and CS2CO3 (E02g, 3.134 mmol, 2.0 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C overnight under the nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 : 1) to afford tert-butyl 4-[2-(5-{2-[(tert-butoxycarbonyl)amino]pyrimidin-4- yl}-4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-l,3-thiazol-2-yl)propan-2-yl]piperidine-l- carboxylate (800 mg, 82.51%) as a yellow solid. LCMS: C34H47FN6O6S2 requires: 718.3, found: m/z = 719.1 [M+H]+.
[000196] Step-5: Synthesis of \-!3-|5-(2-aniinopyriniidin-4-yl)-2-|2-(piperidin-4- yl)propan-2-yl]-l.,3-thiazol-4-yl]-2-fluorophenvnpropane-l-sulfonaniide hydrochloride
To a mixture of tert-butyl 4-[2-(5-{2-[(tert-butoxycarbonyl)amino]pyrimidin-4-yl}-4-[2- fluoro-3-(propane-l-sulfonamido)phenyl]-l,3-thiazol-2-yl)propan-2-yl]piperidine-l- carboxylate (800 mg, 1.113 mmol, 1 equiv) in DCM (8 mL) was added HC1 (gas) in 1,4- dioxane (2 mL, 4 M). The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% formic acid (FA)), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford A-{3-[5-(2-aminopyrimidin-4-yl)-2-[2-(piperidin-4-yl)propan-2-yl]-l,3- thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide hydrochloride (553 mg, 89.52%) as a yellow solid. LCMS : C24H31FN6O2S2 requires: 518.2, found: m/z = 519.2 [M+H]+.
'H NMR (400 MHz, CD3OD) 5 8.10 (d, J= 6.8 Hz, 1H), 7.69 (d, J= 1.6 Hz, 1H), 7.52 - 7.49 (m, 1H), 7.40 - 7.36 (m, 1H), 6.66 - 6.64 (m, 1H), 3.51 - 3.40 (m, 2H), 3.23 - 3.13 (m, 2H), 3.05 - 2.85 (m, 2H), 2.24 - 2.16 (m, 1H), 2.01 - 1.82 (m, 4H), 1.71 - 1.65 (m, 2H), 1.55 (s, 6H), 1.10 - 1.07 (m, 3H).
[000197] Synthesis of 7V-(3-(5-(2-aminoDyrimidin-4-yl)-2-(DiDeridin-4-yl)thiazol-4- yl)-2-fluoroDhenyl)DroDane-l-sulfonamide hydrochloride salt
[000198] Step-1: Synthesis of tert-butyl 4-[5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-3- f[(DroD-2-en-l-yloxy)carbonyl]amino} phenyl)-l.,3-thiazol-2-yl]DiDeridine-l-carboxylate
To a mixture of prop-2-en-l-yl 7V-{3-[2-(2-chloropyrimidin-4-yl)acetyl]-2-fluorophenyl} carbamate (1.1 g, 3.145 mmol, 1.00 equiv) and NBS (559.8 mg, 3.145 mmol, 1.0 equiv) in DMA (13 mL) was added tert-butyl 4-carbamothioylpiperidine-l -carboxylate (922.2 mg, 3.774 mmol, 1.20 equiv) at room temperature. The resulting mixture was stirred for 2 h at 60 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 : 1) to afford tert-butyl 4-[5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-3-{[(prop- 2-en-l-yloxy)carbonyl]amino} phenyl)- 1, 3 -thiazol-2-yl]piperi dine- 1-carboxylate (580 mg, 32.12%) as a yellow solid. LCMS: C27H29CIFN5O4S requires: 573.2, found: m/z = 574.2 [M+H]+.
[000199] Step-2: Synthesis of tert-butyl 4-[4-(3-amino-2-fluorophenyl)-5-(2- chloropyrimidin-4-yl)-l.,3-thiazol-2-yl]piperidine-l-carboxylate (3)
To a mixture of tert-butyl 4-[5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-3-{[(prop-2-en-l- yloxy)carbonyl] amino}phenyl)-l,3-thiazol-2-yl]piperidine-l-carboxylate (600 mg, 1.045 mmol, 1 equiv) and HOAc (156.9 mg, 2.612 mmol, 2.5 equiv) in DCM (8 mL) was added Pd(PPh3)2Ch (14.7 mg, 0.021 mmol, 0.02 equiv) and w-BusSnH (486.7 mg, 1.672 mmol, 1.6 equiv) in portions at 0 °C. The resulting mixture was stirred for 0.5 h at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum to afford tert- butyl 4-[4-(3-amino-2-fluorophenyl)-5-(2-chloropyrimidin-4-yl)-l,3-thiazol-2-yl]piperidine- 1-carboxylate (510 mg, crude) as a red oil. The resulting mixture was used in the next step directly without further purification. LCMS: C23H25CIFN5O2S requires: 489.1, found: m/z = 490.1 [M+H]+.
[000200] Step-3: Synthesis of tert-butyl 4-(5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-3- (propylsulfonamido)phenyl)thiazol-2-yl)piperidine-l-carboxylate (4)
To a mixture of tert-butyl 4-[4-(3-amino-2-fluorophenyl)-5-(2-chloropyrimidin-4-yl)-l,3- thiazol-2-yl]piperidine- 1-carboxylate (2 g, 4.082 mmol, 1 equiv) and TEA (1.24 g, 12.246 mmol, 3 equiv) in DCM (20 mL) was added propane- 1 -sulfonyl chloride (873.08 mg, 6.123 mmol, 1.5 equiv) dropwise at 0 °C. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. To the crude product in H2O (7 mL), MeCN (7 mL), and THF (7 mL) was added Na2CO3 (1.06 g, 10.065 mmol, 2.46 equiv) at room temperature. The resulting mixture was stirred at 50 °C overnight. The resulting mixture was extracted with DCM. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CEECh MeOH (10: 1) to afford tert-butyl 4-(5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-3- (propylsulfonamido)phenyl)thiazol-2-yl)piperidine-l-carboxylate (1.58 g, 64.93%) as ayellow solid. LCMS: C26H31CIFN5O4S2 requires: 595.1, found: m/z = 596.1 [M+H]+. [000201 ] Step-4: Synthesis of tert-butyl 4-(5-(2-((tert- butoxycarbonyl)amino)pyrimidin-4-yl)-4-(2-fluoro-3-
(propylsulfonamido)phenyl)thiazol-2-yl)piperidine-l-carboxylate (5)
To a mixture of tert-butyl 4-(5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-3- (propylsulfonamido)phenyl)thiazol-2-yl)piperidine-l-carboxylate (1 g, 1.677 mmol, 1 equiv) and tert-butyl carbamate (982.6 mg, 8.385 mmol, 5 equiv) in 1,4-dioxane (10 mL) was added BrettPhos Pd G3 (152 mg, 0.168 mmol, 0.1 equiv) and CS2CO3 (1.1 g, 3.354 mmol, 2 equiv) at room temperature. The resulting mixture was stirred for 2 h at 80 °C under a nitrogen atmosphere. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 : 1) to afford tert-butyl 4-(5-(2-((te/7- butoxycarbonyl)amino)pyrimidin-4-yl)-4-(2-fluoro-3-(propylsulfonamido)phenyl)thiazol-2- yl)piperidine-l -carboxylate (850 mg, 74.87%) as a yellow solid. LCMS: C31H41FN6O6S2 requires: 676.3, found: m/z = 677.3 [M+H]+.
[000202] Step-5: Synthesis of A-13-[5-(2-aminopyrimidin-4-yl)-2-(piperidin-4-yl)- l,3-thiazol-4-yl]-2-fluorophenvnpropane-l-sulfonamide hydrochloride
To a mixture of tert-butyl 4-(5-(2-((terZ-butoxycarbonyl)amino)pyrimidin-4-yl)-4-(2-fluoro-3- (propylsulfonamido)phenyl)thiazol-2-yl)piperidine-l-carboxylate (1.5 g, 2.217 mmol, 1 equiv) in DCM (3 mL) was added HC1 (gas) in 1,4-dioxane (12 mL, 4 M) at room temperature. The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% formic acid (FA)), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford A-{3-[5-(2-aminopyrimidin-4-yl)-2-(piperidin-4-yl)-l,3-thiazol-4-yl]-2- fluorophenyl (propane- 1 -sulfonamide hydrochloride salt (649.6 mg, 57.13%) as a yellow solid. LCMS: C21H25FN6O2S2 requires: 476.3, found: m/z = 477.3 [M+H]+. 'H NMR (400 MHz, CD3OD) 5 8.09 (d, J= 6.0 Hz, 1H), 7.68 - 7.66 (m, 1H), 7.49 - 7.28 (m, 2H), 6.65 - 6.63 (m, 1H), 3.60 - 3.48 (m, 3H), 3.28 - 3.16 (m, 2H), 3.17 - 3.05 (m, 2H), 2.49 - 2.39 (m, 2H), 2.21 - 2.09 (m, 2H), 1.94 - 1.78 (m, 2H), 1.14 - 0.98 (m, 3H).
[000203] Synthesis of 7V-12-fluoro-3-[2-(piperidin-4-yl)-5-(pyrimidin-4-yl)-l.,3- thiazol-4-vHphenvnpropane-l-sulfonamide hydrochloride salt
[000204] Step-1: Synthesis of tert-butyl 4-14-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-5-(pyrimidin-4-yl)-l.,3-thiazol-2-vnpiperidine-l-carboxylate (2)
To a mixture of tert-butyl 4-[5-(2-chloropyrimidin-4-yl)-4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-l,3-thiazol-2-yl]piperidine-l-carboxylate (700 mg, 1.174 mmol, 1 equiv) and NH4OAC (905.14 mg, 11.740 mmol, 10 equiv) in MeOH (10 mL) was added Pd/C (700 mg) at room temperature. The resulting mixture was stirred for 30 min at 40 °C. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by C18 silica gel column chromatography eluted with CHjCN^O (1 : 1) to afford tert- butyl 4-{4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-5-(pyrimidin-4-yl)-l,3-thiazol-2- yl}piperidine-l-carboxylate (450 mg, 68.23%) as a yellow solid. LCMS: C26H32FN5O4S2 requires: 561.2, found: m/z = 562.2 [M+H]+.
[000205 ] Step-2: Synthesis of 7V-12-fluoro-3-[2-(piperidin-4-yl)-5-(pyrimidin-4-yl)- l,3-thiazol-4-yl]phenvnpropane-l-sulfonamide hydrochloride
A mixture of tert-butyl 4-{4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-5-(pyrimidin-4-yl)-
1.3-thiazol-2-yl}piperidine-l-carboxylate (450 mg, 0.801 mmol, 1 equiv) in HCl/l,4-di oxane (5 mL, 4 N) was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure. This resulted in A-{2-fluoro-3-[2-(piperidin-4-yl)-5-(pyrimidin-4-yl)-
1.3-thiazol-4-yl]phenyl}propane-l-sulfonamide hydrochloride salt (300.1 mg, crude) as a yellow solid. LCMS: C21H24FN5O2S2 requires: 461.1, found: m/z = 462.1 [M+H]+. 'H NMR (400 MHz, CD3OD) 5 9.30 - 9.28 (m, 1H), 8.76 - 8.74 (m, 1H), 7.71 - 7.67 (m, 1H), 7.50 - 7.38 (m, 3H), 3.60 - 3.55 (m, 3H), 3.27 - 3.22 (m, 2H), 3.16 - 3.12 (m, 2H), 2.48 - 2.43 (m, 2H), 2.20 - 2.14 (m, 2H), 1.89 - 1.83 (m, 2H), 1.06 - 1.03 (m, 3H). [000206] Synthesis of 7V-13-[5-(2-aminoDyrimidin-4-yl)-2-[4-(DiDeridin-4-yl)phenyl]- l,3-thiazol-4-yl]-2-fluoroDhenynDroDane-l-sulfonamide
[000207] Step-1: Synthesis o butyl 4-(4-carbamoylDhenyl)Diperidine-l- carboxylate (2)
To a mixture of 4-[l-(tert-butoxycarbonyl)piperidin-4-yl]benzoic acid (5 g, 16.37 mmol, 1 equiv) and NH4CI (4.37 g, 81.86 mmol, 5 equiv) in DMF (50 mL) was added HATU (9.33 g, 24.55 mmol, 1.5 equiv) and DIEA (6.34 g, 49.11 mmol, 3 equiv) at room temperature. The resulting mixture was stirred for one hour at room temperature. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The product was washed with EtOAc. The precipitated solids were collected by filtration to afford tert-butyl 4-(4-carbamoylphenyl)piperidine-l -carboxylate (4.8 g, 96.31%) as a white solid. LCMS: C17H24N2O3 requires: 304.2, found: m/z = 305.2 [M+H]+.
[000208] Step-2: Synthesis of tert-butyl 4-(4-carbamothioylphenyl)piperidine-l- carboxylate (3)
To a mixture of tert-butyl 4-(4-carbamoylphenyl)piperidine-l -carboxylate (3 g, 9.85 mmol, 1 equiv) in THF (30 mL) was added Lawesson’s Reagent (1.99 g, 4.92 mmol, 0.5 equiv) at room temperature. The resulting mixture was stirred overnight at 50 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with aqueous NaHCOs and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CEECh EtOAc (4: 1) to afford tert-butyl 4-(4-carbamothioylphenyl)piperidine-l -carboxylate (2.2 g, 69.66%) as a white solid. LCMS: C17H24N2O2S requires: 320.1, found: m/z = 321.2 [M+H]+.
[000209] Step-3: Synthesis of tert-butyl 4-]4-[5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-
3-][(prop-2-en-l-yloxy)carbonyl]amino}phenyl)-l.,3-thiazol-2-yl]phenvnpiperidine-l- carboxylate (5)
To a mixture of prop-2-en-l-yl A-{3-[2-(2-chloropyrimidin-4-yl)acetyl]-2- fluorophenyl} carbamate (1.8 g, 5.14 mmol, 1 equiv) in DMA (20 mL) was added tert-butyl 4- (4-carbamothioylphenyl)piperidine-l -carboxylate (1.98 g, 6.17 mmol, 1.2 equiv) and NBS (1.83 g, 10.29 mmol, 2 equiv) at room temperature. The resulting mixture was stirred for 2 h at 60 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (5: 1) to afford tert-butyl 4-{4-[5-(2-chloropyrimidin-
4-yl)-4-(2-fluoro-3-{[(prop-2-en-l-yloxy)carbonyl]amino}phenyl)-l,3-thiazol-2- yl]phenyl}piperidine-l-carboxylate (1.8 g, 48.95%) as a yellow solid. LCMS: C33H33CIFN5O4S requires: 649.2, found: m/z = 650.2 [M+H]+.
[000210] Step-4: Synthesis of tert-butyl 4-]4-[4-(3-amino-2-fluorophenyl)-5-(2- chloropyrimidin-4-yl)- 1.,3-thiazol-2-yl] phenyl] piperidine- 1-carboxylate (6) To a mixture of tert-butyl 4-{4-[5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-3-{[(prop-2-en-l- yloxy)carbonyl]amino}phenyl)-l,3-thiazol-2-yl]phenyl}piperidine-l-carboxylate (1.8 g, 2.76 mmol, 1 equiv) and HOAc (415 mg, 6.93 mmol, 2.5 equiv) in DCM (20 mL) was added n- BusSnH (1.29 g, 4.43 mmol, 1.6 equiv) and Pd(PPh3)2Ch (39 mg, 0.05 mmol, 0.02 equiv) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred for 30 min at room temperature. The reaction was quenched with saturated aqueous NaHCCL at 0 °C. The resulting mixture was extracted with CH2Q2. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford tert-butyl 4-{4-[4-(3-amino-2-fluorophenyl)-5-(2-chloropyrimidin-4-yl)-
1.3-thiazol-2-yl]phenyl}piperidine-l-carboxylate (1.5 g, crude) as a brown solid. LCMS: C29H29CIFN5O2S requires: 565.2, found: m/z = 566.2 [M+H]+.
[000211 ] Step-5: Synthesis of tert-butyl 4-(4-(5-(2-chloropyrimidin-4-yl)-4-(2-fluoro- 3-(propylsulfonamido)phenyl)thiazol-2-yl)phenyl)piperidine-l-carboxylate (7)
To a mixture of tert-butyl 4-{4-[4-(3-amino-2-fluorophenyl)-5-(2-chloropyrimidin-4-yl)-l,3- thiazol-2-yl]phenyl}piperidine-l-carboxylate (1.5 g, 2.65 mmol, 1 equiv) in DCM (15 mL) was added propane- 1 -sulfonyl chloride (755 mg, 5.30 mmol, 2 equiv) and TEA (804 mg, 7.95 mmol, 3 equiv) at 0 °C. The resulting mixture was stirred for one hour at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was dissolved in THF (5 mL), H2O (5 mL), and MeCN (5 mL). ISfeCCL (1.13 g, 10.68 mmol, 5 equiv) was added at room temperature. The resulting mixture was stirred overnight at 50 °C. The resulting mixture was concentrated under vacuum. The residue was extracted with DCM. The combined organic layers were washed with water and dried over anhydrous ISfeSC After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with DCM:MeOH (10: 1) to afford tert-butyl 4-(4-(5-(2- chloropyrimidin-4-yl)-4-(2-fluoro-3-(propylsulfonamido)phenyl)thiazol-2- yl)phenyl)piperidine-l -carboxylate (1.1 g, 73.77%) as a yellow solid. LCMS: C32H35CIFN5O4S2 requires: 671.2, found: m/z = 672.2 [M+H]+.
[000212] Step-6: Synthesis of tert-butyl 4-[4-(5- [(tert- butoxycarbonyl)amino]pyrimidin-4-vn-4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-
1.3-thiazol-2-yl)phenyl]piperidine-l-carboxylate (8)
To a mixture of tert-butyl 4-{4-[5-(2-chloropyrimidin-4-yl)-4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-l,3-thiazol-2-yl]phenyl}piperidine-l-carboxylate (600 mg, 0.89 mmol, 1 equiv) and tert-butyl carbamate (522.80 mg, 4.465 mmol, 5 equiv) in dioxane (6 mL) was added BrettPhos Pd G3 (81 mg, 0.089 mmol, 0.1 equiv) and CS2CO3 (581 mg, 1.78 mmol, 2 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 2 h at 80 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 : 1) to afford tert-butyl 4-[4-(5-{2-[(tert-butoxycarbonyl)amino]pyrimidin-4-yl}-4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-l,3-thiazol-2-yl)phenyl]piperidine-l-carboxylate (400 mg, 53.57%) as a yellow solid. LCMS: C37H45FN6O6S2 requires: 752.2, found: m/z = 753.3 [M+H]+.
[000213] Step-7: Synthesis of 7V-13-[5-(2-aminoDyrimidin-4-yl)-2-[4-(DiDeridin-4- Yl)phenyl]-l.,3-thiazol-4-yl]-2-fluoroDhenynDroDane-l-sulfonamide
A mixture of tert-butyl 4-[4-(5-{2-[(tert-butoxycarbonyl)amino]pyrimidin-4-yl}-4-[2-fluoro- 3-(propane-l-sulfonamido)phenyl]-l,3-thiazol-2-yl)phenyl]piperidine-l -carboxylate (400 mg, 0.53 mmol, 1 equiv) in HCl/l,4-di oxane (5 mL, 4 M) was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 pm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 38% B in 8 min; Wave Length: 220/254 nm; Rti (min): 6.75 to afford A-{3-[5-(2-aminopyrimidin-4-yl)-2-[4-(piperidin-4-yl)phenyl]-l,3- thiazol-4-yl]-2-fhiorophenyl}propane-l-sulfonamide (223.7 mg, 70.01%) as a yellow solid. LCMS: C27H29FN6O2S2 requires: 552.2, found: m/z = 553.2 [M+H]+. 'H NMR (400 MHz, DMSO-tL) 5 8.15 - 8.06 (m, 1H), 7.98 - 7.93 (m, 2H), 7.56 - 7.52 (m, 1H), 7.40 - 7.37 (m, 2H), 7.24 - 7.16 (m, 2H), 6.79 (s, 2H), 6.18 - 6.16 (m, 1H), 3.21 - 3.12 (m, 2H), 2.97 - 2.93 (m, 2H), 2.77 - 2.69 (m, 3H), 1.80 - 1.71 (m, 2H), 1.69 - 1.57 (m, 4H), 0.94 - 0.90 (m, 3H).
[000214] Synthesis of 4-[2-tert-butyl-4-(3-llethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)-l.,3-thiazol-5-yl]-A-(4-13.,8-diazabicvclo[3.2.1]octan-8-vn-3- fluoroDhenyl)Dyrimidin-2-amine; trifluoroacetic acid salt
[000215] Step-1: Synthesis of tert-butyl 8-(2-fluoro-4-nitrophenyl)-3.,8- diazabicyclo[3.2.1]octane-3-carboxylate (2)
To a mixture of l,2-difluoro-4-nitrobenzene (1.0 g, 6.286 mmol, 1 equiv) and DIEA (2.44 g, 18.858 mmol, 3.0 equiv) in DMSO (10 mL) was added tert-butyl 3,8- diazabicyclo[3.2.1]octane-3-carboxylate (1.33 g, 6.286 mmol, 1.0 equiv) in portions at room temperature. The resulting mixture was stirred for 3 h at 100 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CEECh MeOH (10: 1) to afford tert-butyl 8-(2-fluoro-4-nitrophenyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (1.2 g, 54.33%) as a yellow solid. LCMS: C17H22FN3O4 requires: 351.2, found: m/z = 352.2 [M+H]+.
[000216] Step-2: Synthesis of tert-butyl 8-(4-amino-2-fluorophenyl)-3.,8- diazabicyclo[3.2.1]octane-3-carboxylate (3)
To a mixture of tert-butyl 8-(2-fluoro-4-nitrophenyl)-3,8-diazabicyclo[3.2.1]octane-3- carboxylate (600 mg, 1.708 mmol, 1 equiv) in EtOH (10 mL) was added Pd/C (299.84 mg, 2.818 mmol, 1.65 equiv) in portions at room temperature. The resulting mixture was stirred for 3 h at room temperature under a hydrogen atmosphere. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CFLCL MeOH (10: 1) to afford tert-butyl 8-(4-amino-2- fluorophenyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (400 mg, 72.89%) as a yellow solid. LCMS: C17H24FN3O2 requires: 321.2, found: m/z = 322.2 [M+H]+.
[000217] Step-3: Synthesis of tert-butyl 8-|4-(!4-|2-tert-butyl-4-(3- flethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l.,3-thiazol-5-yl]pyrimidin-2- vnamino)-2-fluorophenyl]-3.,8-diazabicvclo[3.2.1]octane-3-carboxylate (5)
To a mixture of tert-butyl 8-(4-amino-2-fluorophenyl)-3,8-diazabicyclo[3.2.1]octane-3- carboxylate (380 mg, 1.182 mmol, 1 equiv) and ({3-[2-tert-butyl-5-(2-chloropyrimidin-4-yl)- l,3-thiazol-4-yl]-2-fluorophenyl}sulfamoyl)(ethyl)methylamine (629.49 mg, 1.300 mmol, 1.1 equiv) in 1,4-dioxane (4 mL) was added BrettPhos Pd G3 (107.18 mg, 0.118 mmol, 0.1 equiv) and CS2CO3 (770.46 mg, 2.364 mmol, 2.0 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 80 °C under the nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CthCh MeOH (5: 1) to afford tert- butyl 8-[4-({4-[2-tert-butyl-4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3- thiazol-5-yl]pyrimidin-2-yl}amino)-2-fluorophenyl]-3,8-diazabicyclo[3.2.1]octane-3- carboxylate (385 mg, 42.35%) as a yellow solid. LCMS: C37H46F2N8O4S2 requires: 768.3, found: m/z = 769.3 [M+H]+.
[000218] Step-4: Synthesis of 4-[2-tert-butyl-4-(3-][ethyl(methyl)sulfamoyl]amino}- 2-fluorophenyl)-l.,3-thiazol-5-yl]-7V-(4-f3.,8-diazabicvclo[3.2.1]octan-8-vn-3- fluorophenyl)pyrimidin-2-amine; trifluoroacetic acid
To a mixture of tert-butyl 8-[4-({4-[2-tert-butyl-4-(3-{[ethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)-l,3-thiazol-5-yl]pyrimidin-2-yl}amino)-2-fluorophenyl]-3,8- diazabicyclo[3.2.1]octane-3-carboxylate (380 mg, 0.494 mmol, 1 equiv) in DCM (3 mL) was added TFA (3 mL) dropwise at room temperature. The resulting mixture was stirred for one hour at room temperature. The resulting mixture was concentrated under reduced pressure to afford 4-[2-tert-butyl-4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3-thiazol-5- yl]-A-(4-{3,8-diazabicyclo[3.2.1]octan-8-yl}-3-fluorophenyl)pyrimidin-2-amine; trifluoroacetic acid salt (350 mg, crude) as a red solid. LCMS: C32H38F2N8O2S2 requires: 668.3, found: m/z = 669.3 [M+H]+. 'H NMR (300 MHz, CD3OD) 5 8.24 (d, J = 4.8 Hz, 1H), 7.72 - 7.62 (m, 2H), 7.32 (d, J= 8.4 Hz, 2H), 7.20 (d, J = 8.7 Hz, 1H), 6.95 - 7.82 (m, 1H), 6.60 - 6.50 (m, 1H), 4.28 (s, 2H), 3.49 - 3.38 (m, 2H), 3.28 - 3.17 (m, 4H), 2.82 - 2.76 (m, 3H), 2.32 -2.21 (m, 2H), 2.09 - 1.98 (m, 2H), 1.58 - 1.52 (m, 9H), 1.18 - 1.02 (m, 3H). [000219] Synthesis of A-13-[5-(2-aminoDyrimidin-4-yl)-2-(4-methylpiDeridin-4-yl)- l,3-thiazol-4-yl]-2-fluoroDhenynDroDane-l-sulfonamide
[000220] Step-1: Synthesis of tert-butyl 4-carbamothioyl-4-methylDiDeridine-l- carboxylate (2)
To a mixture of tert-butyl 4-carbamoyl-4-methylpiperidine-l -carboxylate (4 g, 16.5 mmol, 1 equiv) in THF (40 mL) was added Lawesson’s Reagent (3.34 g, 8.25 mmol, 0.5 equiv) at room temperature. The resulting mixture was stirred overnight at 50 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (3 : 1) to afford tert-butyl 4-carbamothioyl-4-methylpiperidine-l -carboxylate (2.1 g, 44.31%) as a yellow oil. LCMS: C12H22N2O2S requires: 258.1, found: m/z = 259.0 [M+H]+.
[000221 ] Step-2: Synthesis of tert-butyl 4-[5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-3- f[(prop-2-en-l-yloxy)carbonyl]amino}phenyl)-l.,3-thiazol-2-yl]-4-methylpiperidine-l- carboxylate (4)
To a mixture of prop-2-en-l-yl A-{3-[2-(2-chloropyrimidin-4-yl)acetyl]-2- fluorophenyl} carbamate (3 g, 8.57 mmol, 1 equiv) in DMA (30 mL) was added NBS (1.53 g,
8.57 mmol, 1 equiv) and tert-butyl 4-carbamothioyl-4-methylpiperidine-l -carboxylate (2.66 g, 10.29 mmol, 1.2 equiv) at room temperature. The resulting mixture was stirred for 2 h at 60 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (3: 1) to afford tert-butyl 4-[5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-3-{[(prop- 2-en-l-yloxy)carbonyl]amino}phenyl)-l,3-thiazol-2-yl]-4-methylpiperidine-l -carboxylate (2.1 g, 36.63%) as a yellow solid. LCMS: C28H31CIFN5O4S requires: 587.2, found: m/z = 588.1 [M+H]+.
[000222] Step-3: Synthesis of tert-butyl 4-(4-(3-amino-2-fluorophenyl)-5-(2- chloropyrimidin-4-yl)thiazol-2-yl)-4-methylpiperidine-l-carboxylate (5)
To a mixture of tert-butyl 4-[5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-3-{[(prop-2-en-l- yloxy)carbonyl]amino}phenyl)-l,3-thiazol-2-yl]-4-methylpiperidine-l-carboxylate (2.1 g,
3.57 mmol, 1 equiv) and Pd PPtr^Ch (50.13 mg, 0.07 mmol, 0.02 equiv) in DCM (30 mL) was added HO Ac (514.6 mg, 8.57 mmol, 2.4 equiv) and w-BusSnH (1.56 g, 5.35 mmol, 1.5 equiv) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred for 0.5 h at 0 °C under the nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 : 1) to afford tert-butyl 4-(4-(3-amino-2-fluorophenyl)-5-(2-chloropyrimidin-4-yl)thiazol-2-yl)-4- methylpiperidine- 1 -carboxylate (1.6 g, 92.82%) as a yellow oil. LCMS: C24H27CIFN5O2S requires: 503.2, found: m/z = 504.1 [M+H]+.
[000223] Step-4: Synthesis of tert-butyl 4-(5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-3- (propylsulfonamido)phenyl)thiazol-2-yl)-4-methylpiperidine-l-carboxylate (6) To a mixture of tert-butyl 4-[4-(3-amino-2-fluorophenyl)-5-(2-chloropyrimidin-4-yl)-l,3- thiazol-2-yl]-4-methylpiperidine-l-carboxylate (1.6 g, 3.17 mmol, 1 equiv) in DCM (20 mL) was added TEA (963.7 mg, 9.52 mmol, 3 equiv) and propane- 1 -sulfonyl chloride (679.0 mg, 4.76 mmol, 1.5 equiv) at 0 °C. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. To the crude product in THF (10 mL), MeCN (10 mL), and H2O (10 mL) was added ISfeCCL (2 g, 19.25 mmol, 10 equiv) at room temperature. The resulting mixture was stirred overnight at 50 °C. The resulting mixture was extracted with DCM. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE: EtOAc (5: 1) to afford tert-butyl 4-[5-(2-chloropyrimidin-4-yl)-4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-l,3-thiazol-2-yl]-4-methylpiperidine-l-carboxylate (1.1 g, 92.38%) as a yellow solid. LCMS: C27H33CIFN5O4S2 requires: 609.2, found: m/z = 610.1 [M+H]+.
[000224] Step-5: Synthesis of tert-butyl 4-(5-!2-|(tert- butoxycarbonyl)amino]pyrimidin-4-vn-4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]- l,3-thiazol-2-yl)-4-methylpiperidine-l-carboxylate (7)
To a mixture of tert-butyl 4-[5-(2-chloropyrimidin-4-yl)-4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-l,3-thiazol-2-yl]-4-methylpiperidine-l-carboxylate (1 g, 1.63 mmol, 1 equiv) and Pd2(dba)3 (150 mg, 0.16 mmol, 0.1 equiv) in dioxane (10 mL) was added XPhos (156.2 mg, 0.32 mmol, 0.2 equiv), CS2CO3 (LI g, 3.27 mmol, 2 equiv) and tert-butyl carbamate (287.9 mg, 2.45 mmol, 1.5 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 80 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (9: 1) to afford tert-butyl 4-(5-{2-[(tert-butoxycarbonyl)amino]pyrimidin-4-yl}-4- [2-fluoro-3 -(propane- 1 -sulfonamido)phenyl]- 1 ,3 -thiazol-2-yl)-4-m ethylpiperidine- 1 - carboxylate (1 g, 77.72%) as a brown solid. LCMS: C32H43FN6O6S2 requires: 690.3, found: m/z = 691.2 [M+H]+.
[000225] Step-6: Synthesis of 7V-f3-[5-(2-aminopyrimidin-4-yl)-2-(4- methylpiperidin-4-yl)-l.,3-thiazol-4-yl]-2-fluorophenvnpropane-l-sulfonaniide
A mixture of tert-butyl 4-(5-{2-[(tert-butoxycarbonyl)amino]pyrimidin-4-yl}-4-[2-fluoro-3- (propane-l-sulfonamido)phenyl]-l,3-thiazol-2-yl)-4-methylpiperidine-l-carboxylate (1 g, 1.44 mmol, 1 equiv) in HCl/l,4-di oxane (10 mL, 4 M) was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with JtChMeCN (1 :3) to afford 7V-{3-[5-(2- aminopyrimidin-4-yl)-2-(4-methylpiperidin-4-yl)-l, 3-thi azol -4-yl]-2-fluorophenyl (propane- 1-sulfonamide (614.8 mg, 84.49%) as a yellow solid. LCMS: C22H27FN6O2S2 requires: 490.2, found: m/z = 491.1 [M+H]+.
'H NMR (400 MHz, CD3OD) 5 8.11 (d, J= 6.4 Hz, 1H), 7.71 - 7.67 (m, 1H), 7.53 - 7.50 (m, 1H), 7.40 - 7.36 (m, 1H), 6.67 - 6.64 (m, 1H), 3.42 - 3.35 (m, 3H), 3.32 - 3.30 (m, 1H), 3.18
- 3.14 (m, 2H), 2.56 - 2.50 (m, 2H), 2.15 - 2.08 (m, 2H), 1.90 - 1.84 (m, 2H), 1.62 (s, 3H), 1.08 - 1.04 (m, 3H).
[000226] Synthesis of 7V-13- [5-(2-aminoDyrimidin-4-yl)-2-12-azasDiro [3.5] nonan-7- vn-l,3-thiazol-4-yl]-2-fluoroDhenvnDroDane-l-sulfonamide; trifluoroacetic acid salt
[000227] Step-1: Synthesis o butyl 7-carbamoyl-2-azasDiro[3.5]nonane-2- carboxylate (2) To a mixture of 2-(tert-butoxycarbonyl)-2-azaspiro[3.5]nonane-7-carboxylic acid (4 g, 14.85 mmol, 1 equiv) and HATU (8.47 g, 22.28 mmol, 1.5 equiv) in DMF (40 mL) was added NH4CI (3.97 g, 74.26 mmol, 5 equiv) and the mixture was stirred for 15 min. Then, DIEA (5.76 g, 44.55 mmol, 3 equiv) was added. The resulting mixture was stirred at room temperature for one hour. The residue was purified by reverse phase flash chromatography eluted with ACbFFhO (1 : 1) to afford tert-butyl 7-carbamoyl-2-azaspiro[3.5]nonane-2-carboxylate (3.5 g, 87.82%) as a white solid. LCMS: C14H24N2O3 requires: 268.2, found: m/z = 269.3 [M+H]+.
[000228] Step-2: Synthesis of tert-butyl 7-carbamothioyl-2-azaspiro[3.5]nonane-2- carboxylate (3)
To a mixture of tert-butyl 7-carbamoyl-2-azaspiro[3.5]nonane-2-carboxylate (3.5 g, 13.04 mmol, 1 equiv) in THF (40 mL) was added Lawesson’s Reagent (2.64 g, 6.53 mmol, 0.5 equiv). The resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with DCM:MeOH (10: 1) to afford tert-butyl 7-carbamothioyl- 2-azaspiro[3.5]nonane-2-carboxylate (2.5 g, 51.89%) as a white solid. LCMS: C14H24N2O2S requires: 284.2, found: m/z = 285.2 [M+H]+.
[000229] Step-3: Synthesis of tert-butyl 7-[5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-3- l[(prop-2-en-l-yloxy)carbonyl]amino}phenyl)-l.,3-thiazol-2-yl]-2-azaspiro[3.5]nonane-2- carboxylate (4)
To a mixture of prop-2-en-l-yl A-{3-[2-(2-chloropyrimidin-4-yl)acetyl]-2- fluorophenyl] carbamate (3.07 g, 8.78 mmol, 1 equiv) in DMA (20 mL) was added NBS (1.56 g, 8.78 mmol, 1 equiv) and the mixture was stirred for 15 min. Then, tert-butyl 7- carbamothioyl-2-azaspiro[3.5]nonane-2-carboxylate (2.5 g, 8.79 mmol, 1 equiv) was added. The resulting mixture was stirred at 60 °C for 2 h. The residue was purified by reverse phase flash chromatography eluted with ACN/FLO (1 : 1) to afford tert-butyl 7-[5-(2-chloropyrimidin- 4-yl)-4-(2-fluoro-3-{[(prop-2-en-l-yloxy)carbonyl]amino}phenyl)-l,3-thiazol-2-yl]-2- azaspiro[3.5]nonane-2-carboxylate (1.4 g, 19.48%) as ayellow solid. LCMS: C30H33CIFN5O4S requires: 613.2, found: m/z = 614.2 [M+H]+.
[000230] Step-4: Synthesis of tert-butyl 7-[4-(3-amino-2-fluorophenyl)-5-(2- chloropyrimidin-4-yl)-l.,3-thiazol-2-yl]-2-azaspiro[3.5]nonane-2-carboxylate (5)
To a mixture of tert-butyl 7-[5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-3-{[(prop-2-en-l- yloxy)carbonyl]amino}phenyl)-l,3-thiazol-2-yl]-2-azaspiro[3.5]nonane-2-carboxylate (1.4 g, 2.28 mmol, 1 equiv) in DCM (10 mL) was added HOAc (329 mg, 5.47 mmol, 2.4 equiv) and Pd(PPh3)2Cl2 (32 mg, 0.046 mmol, 0.02 equiv). Then, w-BusSnH (995 mg, 3.42 mmol, 1.5 equiv) was added at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for one hour. The reaction was quenched with saturated aqueous NaHCCL at 0 °C. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 : 1) to afford tert-butyl 7-[4-(3- amino-2-fluorophenyl)-5-(2-chloropyrimidin-4-yl)-l,3-thiazol-2-yl]-2-azaspiro[3.5]nonane- 2-carboxylate (750 mg, 58.96%) as a yellow solid. LCMS: C26H29C1FNSO2S requires: 529.2, found: m/z = 530.4 [M+H]+.
[000231] Step-5: Synthesis of tert-butyl 7-[5-(2-chloropyrimidin-4-yl)-4-[2-fluoro-3- (propane-l-sulfonamido)phenyl]-l.,3-thiazol-2-yl]-2-azaspiro[3.5]nonane-2-carboxylate (6)
To a mixture of tert-butyl 7-[4-(3-amino-2-fluorophenyl)-5-(2-chloropyrimidin-4-yl)-l,3- thiazol-2-yl]-2-azaspiro[3.5]nonane-2-carboxylate (750 mg, 1.42 mmol, 1 equiv) and TEA (430 mg, 4.25 mmol, 3 equiv) in DCM (10 mL) was added propane- 1 -sulfonyl chloride (605 mg, 4.25 mmol, 3 equiv) at 0 °C. The resulting mixture was stirred at room temperature for one hour. The resulting mixture was concentrated under vacuum. To the above mixture was added THF (10 mL), ACN (10 mL), and Na2CC>3 (2249 mg, 21.22 mmol, 15 equiv) in H2O (10 mL). The resulting mixture was stirred at 50 °C overnight. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 : 1) to afford tert-butyl 7-[5-(2-chloropyrimidin-4-yl)-4-[2-fluoro-3- (propane-l-sulfonamido)phenyl]-l,3-thiazol-2-yl]-2-azaspiro[3.5]nonane-2-carboxylate (750 mg, 79.15%) as a yellow solid. LCMS: C29H35C1FNSO4S2 requires: 635.2, found: m/z = 636.2 [M+H]+.
[000232] Step-6: Synthesis of tert-butyl 7-(5- [(tert- butoxycarbonyl)amino]pyrimidin-4-vn-4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]- l,3-thiazol-2-yl)-2-azaspiro[3.5]nonane-2-carboxylate (7)
To a mixture of tert-butyl 7-[5-(2-chloropyrimidin-4-yl)-4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-l,3-thiazol-2-yl]-2-azaspiro[3.5]nonane-2-carboxylate (750 mg, 1.18 mmol, 1 equiv) and tert-butyl carbamate (691 mg, 5.9 mmol, 5 equiv) in 1,4-dioxane (10 mL) was added Cs2CO3 (768 mg, 2.36 mmol, 2 equiv) and BrettPhos Pd G3 (107 mg, 0.12 mmol, 0.1 equiv). The resulting mixture was stirred at 80 °C for one hour under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with DCM:MeOH (10: 1) to afford tert-butyl 7-(5-{2-[(tert- butoxycarbonyl)amino]pyrimidin-4-yl}-4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-l,3- thiazol-2-yl)-2-azaspiro[3.5]nonane-2-carboxylate (800 mg, 85.19%) as a yellow solid. LCMS: C34H45FN6O6S2 requires: 716.3, found: m/z = 717.2 [M+H]+.
[000233] Step-7: Synthesis of 7V-]3-[5-(2-aminoDyrimidin-4-yl)-2-]2- azasDiro[3.5]nonan-7-yn-l.,3-thiazol-4-yl]-2-fluoroDhenynDroDane-l-sulfonamide; trifluoroacetic acid
To a mixture of tert-butyl 7-(5-{2-[(tert-butoxycarbonyl)amino]pyrimidin-4-yl}-4-[2-fluoro- 3-(propane-l-sulfonamido)phenyl]-l,3-thiazol-2-yl)-2-azaspiro[3.5]nonane-2-carboxylate (500 mg, 0.7 mmol, 1 equiv) in DCM (6 mL) was added TFA (2 mL) at 0 °C. The resulting mixture was stirred at 0 °C for one hour. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase flash chromatography eluted with ACbFFhO (1 : 1) to afford A-{3-[5-(2-aminopyrimidin-4-yl)-2-{2-azaspiro[3.5]nonan-7-yl}-l,3-thiazol-4-yl]- 2-fluorophenyl}propane-l-sulfonamide; trifluoroacetic acid salt (211 mg, 47.54%) as a yellow solid. LCMS: C24H29FN6O2S2 requires: 516.2, found: m/z = 517.2 [M+H]+.
'H NMR (400 MHz, DMSO-tL) 8 8.05 (d, J= 5.2 Hz, 1H), 7.51 - 7.42 (m, 1H), 7.13 - 7.05 (m, 1H), 6.92 - 6.84 (m, 1H), 6.71 (s, 2H), 6.14 (d, J= 5.2 Hz, 1H), 3.53 (s, 2H), 3.45 (s, 2H), 2.97 (s, 1H), 2.91 - 2.82 (m, 2H), 2.08 - 1.97 (m, 4H), 1.74 - 1.61 (m, 2H), 1.60 - 1.41 (m, 4H), 0.97 - 0.83 (m, 3H).
[000234] Synthesis of A-]3-[5-(2-aminoDyrimidin-4-yl)-2-]3-azaspiro[5.5]undecan- 9-yl}-l.,3-thiazol-4-yl]-2-fluoroDhenvnDroDane-l-sulfonaniide
[000235] Step-1: Synthesis of tert-butyl 9-carbamoyl-3-azaspiro[5.5]undecane-3- carboxylate (2)
To a mixture of 3-(tert-butoxycarbonyl)-3-azaspiro[5.5]undecane-9-carboxylic acid (3 g, 10.09 mmol, 1 equiv) and HATU (5.75 g, 15.13 mmol, 1.5 equiv) in DMF (30 mL) was added NH4CI (2.7 g, 50.44 mmol, 5 equiv) and the mixture was stirred for 15 min. Then, DIEA (3.91 g, 30.26 mmol, 3 equiv) was added. The resulting mixture was stirred at room temperature for one hour. The residue was purified by reverse phase flash chromatography eluted with ACbTEhO (1 : 1) to afford tert-butyl 9-carbamoyl-3-azaspiro[5.5]undecane-3-carboxylate (2.1 g, 70.23%) as a yellow solid. LCMS: C16H28N2O3 requires: 296.2, found: m/z = 297.2 [M+H]+.
[000236] Step-2: Synthesis of tert-butyl 9-carbamothioyl-3-azaspiro[5.5]undecane-3- carboxylate (3)
To a mixture of tert-butyl 9-carbamoyl-3-azaspiro[5.5]undecane-3-carboxylate (2.2 g, 7.42 mmol, 1 equiv) in THF (30 mL) was added Lawesson’s Reagent (1.5 g, 3.71 mmol, 0.5 equiv). The resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (2: 1) to afford tert-butyl 9-carbamothioyl-3- azaspiro[5.5 ]undecane-3 -carboxylate (1.43 g, 55.49%) as an off-white solid. LCMS: C16H28N2O2S requires: 312.2, found: m/z = 313.3 [M+H]+. [000237] Step-3: Synthesis of tert-butyl 9-[5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-3- l[(prop-2-en-l-yloxy)carbonyl]amino}phenyl)-l.,3-thiazol-2-yl]-3- azaspiro[5.5]nndecane-3-carboxylate (4)
To a mixture of prop-2-en-l-yl A-{3-[2-(2-chloropyrimidin-4-yl)acetyl]-2- fluorophenyl} carbamate (1.3 g, 3.72 mmol, 1 equiv) in DMA (10 mL) was added NBS (662 mg, 3.72 mmol, 1 equiv) and the mixture was stirred for 15 min. Then, tert-butyl 9- carbamothioyl-3-azaspiro[5.5]undecane-3-carboxylate (1.51 g, 4.83 mmol, 1.3 equiv) was added. The resulting mixture was stirred at 60 °C for 2 h. The residue was purified by reverse phase flash chromatography eluted with ACbFEhO (1 : 1) to afford tert-butyl 9-[5-(2- chloropyrimidin-4-yl)-4-(2-fluoro-3-{[(prop-2-en-l-yloxy)carbonyl]amino}phenyl)-l,3- thiazol-2-yl]-3-azaspiro[5.5]undecane-3-carboxylate (1.14 g, 38.68%) as a yellow solid. LCMS: C32H37CIFN5O4S requires: 641.2, found: m/z = 642.4 [M+H]+.
[000238] Step-4: Synthesis of tert-butyl 9-[4-(3-amino-2-fluorophenyl)-5-(2- chloropyrimidin-4-yl)-l.,3-thiazol-2-yl]-3-azaspiro[5.5]undecane-3-carboxylate (5)
To a mixture of tert-butyl 9-[5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-3-{[(prop-2-en-l- yloxy)carbonyl]amino}phenyl)-l,3-thiazol-2-yl]-3-azaspiro[5.5]undecane-3-carboxylate (1.3 g, 2.02 mmol, 1 equiv) in DCM (10 mL) was added HOAc (0.29 g, 4.83 mmol, 2.4 equiv) and Pd(PPh3)2Ch (28 mg, 0.04 mmol, 0.02 equiv). Then, w-Bu3SnH (884 mg, 3.04 mmol, 1.5 equiv) was added at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for one hour. The reaction was quenched with saturated aqueous NaHCCL at 0 °C. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 : 1) to afford tert-butyl 9-[4-(3-amino-2- fluorophenyl)-5-(2-chloropyrimidin-4-yl)-l,3-thiazol-2-yl]-3-azaspiro[5.5]undecane-3- carboxylate (1.02 g, 90%) as a yellow solid. LCMS: C28H33CIFN5O2S requires: 557.2, found: m/z = 558.2 [M+H]+.
[0002 9] Step-5: Synthesis of tert-butyl 9-[5-(2-chloropyrimidin-4-yl)-4-[2-fluoro-3- (propane-l-snlfonamido)phenyl]-l.,3-thiazol-2-yl]-3-azaspiro[5.5]undecane-3- carboxylate (6)
To a mixture of tert-butyl 9-[4-(3-amino-2-fluorophenyl)-5-(2-chloropyrimidin-4-yl)-l,3- thiazol-2-yl]-3-azaspiro[5.5]undecane-3-carboxylate (1 g, 1.79 mmol, 1 equiv) and TEA (0.54 g, 5.38 mmol, 3 equiv) in DCM (15 mL) was added propane- 1 -sulfonyl chloride (0.38 g, 2.69 mmol, 1.5 equiv) at 0 °C. The resulting mixture was stirred at room temperature for one hour. The resulting mixture was concentrated under vacuum. To the above mixture was added THF (10 mL), ACN (10 mL), and ISfeCCL (2.85 g, 26.85 mmol, 15 equiv) in H2O (10 mL). The resulting mixture was stirred at 50 °C overnight. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 : 1) to afford tert-butyl 9-[5-(2-chloropyrimidin-4-yl)-4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-l,3-thiazol-2-yl]-3-azaspiro[5.5]undecane-3-carboxylate (1.12 g, 89.40%) as a yellow solid. LCMS: C31H39CIFN5O4S2 requires: 663.2, found: m/z = 664.2 [M+H]+.
[000240] Step-6: Synthesis of tert-butyl 9-(5-!2-|(tert- butoxycarbonyl)amino]pyrimidin-4-vn-4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]- l,3-thiazol-2-yl)-3-azaspiro[5.5]undecane-3-carboxylate (7)
To a mixture of tert-butyl 9-[5-(2-chloropyrimidin-4-yl)-4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-l,3-thiazol-2-yl]-3-azaspiro[5.5]undecane-3-carboxylate (1.1 g, 1.66 mmol, 1 equiv) and tert-butyl carbamate (0.97 g, 8.28 mmol, 5 equiv) in 1,4-dioxane (10 mL) was added CS2CO3 (1.08 g, 3.32 mmol, 2 equiv) and BrettPhos Pd G3 (150 mg, 0.17 mmol, 0.1 equiv). The resulting mixture was stirred at 80 °C for one hour under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 : 10) to afford tert-butyl 9-(5-{2-[(tert- butoxycarbonyl)amino]pyrimidin-4-yl}-4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-l,3- thiazol-2-yl)-3-azaspiro[5.5]undecane-3-carboxylate (1.2 g, 84.63%) as a yellow solid. LCMS: C36H49FN6O6S2 requires: 744.3, found: m/z = 745.3 [M+H]+.
[000241 ] Step-7: Synthesis of 7V-]3-[5-(2-aminopyrimidin-4-yl)-2-f3- azaspiro[5.5]undecan-9-vn-l.,3-thiazol-4-yl]-2-fluorophenvnpropane-l-sulfonaniide
To a mixture of tert-butyl 9-(5-{2-[(tert-butoxycarbonyl)amino]pyrimidin-4-yl}-4-[2-fluoro- 3-(propane-l-sulfonamido)phenyl]-l,3-thiazol-2-yl)-3-azaspiro[5.5]undecane-3-carboxylate (1.2 g, 1.61 mmol, 1 equiv) in DCM (12 mL) was added TFA (4 mL) at 0 °C. The resulting mixture was stirred at 0 °C for one hour. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase flash chromatography eluted with ACbFEhO (0.1% NH4HCO3) (1 : 1) to afford A-{3-[5-(2-aminopyrimidin-4-yl)-2-{3-azaspiro[5.5]undecan-9- yl}-l,3-thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide (520.8 mg, 57.69%) as a light yellow solid. LCMS: C26H33FN6O2S2 requires: 544.2, found: m/z = 545.3 [M+H]+. 'H NMR (400 MHz, CD3OD) 5 8.04 (d, J= 5.2 Hz, 1H), 7.70 - 7.60 (m, 1H), 7.34 - 7.21 (m, 2H), 6.28 (d, J = 5.2 Hz, 1H), 3.19 - 2.91 (m, 7H), 2.09 - 2.00 (m, 2H), 1.98 - 1.67 (m, 8H), 1.57 - 1.50 (m, 2H), 1.46 - 1.34 (m, 2H), 1.05 - 0.97 (m, 3H).
[000242] Synthesis of 7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(piperidin-4-yl)thiazol-4- yl)-2-fluorophenyl)propane-l-sulfonamide hydrochloride salt
[000243] Step-1: Synthesis of tert-butyl 4-[5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-3- l[(prop-2-en-l-yloxy)carbonyl]amino} phenyl)-l.,3-thiazol-2-yl]piperidine-l-carboxylate
To a mixture of prop-2-en-l-yl 7V-{3-[2-(2-chloropyrimidin-4-yl)acetyl]-2-fluorophenyl} carbamate (1.1 g, 3.145 mmol, 1.00 equiv) and NBS (559.8 mg, 3.145 mmol, 1.0 equiv) in DMA (13 mL) was added tert-butyl 4-carbamothioylpiperidine-l -carboxylate (922.2 mg, 3.774 mmol, 1.20 equiv) at room temperature. The resulting mixture was stirred for 2 h at 60 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 : 1) to afford tert-butyl 4-[5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-3-{[(prop- 2-en-l-yloxy)carbonyl]amino} phenyl)- 1, 3 -thiazol-2-yl]piperi dine- 1-carboxylate (580 mg, 32.12%) as a yellow solid. LCMS: C27H29CIFN5O4S requires: 573.2, found: m/z = 574.2 [M+H]+.
[000244] Step-2: Synthesis of tert-butyl 4-[4-(3-amino-2-fluorophenyl)-5-(2- chloropyrimidin-4-yl)-l.,3-thiazol-2-yl]piperidine-l-carboxylate (3)
To a mixture of tert-butyl 4-[5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-3-{[(prop-2-en-l- yloxy)carbonyl] amino}phenyl)-l,3-thiazol-2-yl]piperidine-l-carboxylate (600 mg, 1.045 mmol, 1 equiv) and HOAc (156.9 mg, 2.612 mmol, 2.5 equiv) in DCM (8 mL) was added Pd(PPh3)2Ch (14.7 mg, 0.021 mmol, 0.02 equiv) and w-BusSnH (486.7 mg, 1.672 mmol, 1.6 equiv) in portions at 0 °C. The resulting mixture was stirred for 0.5 h at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum to afford tert- butyl 4-[4-(3-amino-2-fluorophenyl)-5-(2-chloropyrimidin-4-yl)-l,3-thiazol-2-yl]piperidine- 1-carboxylate (510 mg, crude) as a red oil. The resulting mixture was used in the next step directly without further purification. LCMS: C23H25CIFN5O2S requires: 489.1, found: m/z = 490.1 [M+H]+.
[000245] Step-3: Synthesis of tert-butyl 4-(5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-3- (propylsulfonamido)phenyl)thiazol-2-yl)piperidine-l-carboxylate (4)
To a mixture of tert-butyl 4-[4-(3-amino-2-fluorophenyl)-5-(2-chloropyrimidin-4-yl)-l,3- thiazol-2-yl]piperidine- 1-carboxylate (2 g, 4.082 mmol, 1 equiv) and TEA (1.24 g, 12.246 mmol, 3 equiv) in DCM (20 mL) was added propane- 1 -sulfonyl chloride (873.08 mg, 6.123 mmol, 1.5 equiv) dropwise at 0 °C. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. To the crude product in H2O (7 mL), MeCN (7 mL), and THF (7 mL) was added Na2CO3 (1.06 g, 10.065 mmol, 3.0 equiv) at room temperature. The resulting mixture was stirred at 50 °C overnight. The resulting mixture was extracted with DCM. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CEECh MeOH (10: 1) to afford tert-butyl 4-(5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-3- (propylsulfonamido)phenyl)thiazol-2-yl)piperidine-l-carboxylate_(1.58 g, 69.85%) as ayellow solid. LCMS: C26H31CIFN5O4S2 requires: 595.1, found: m/z = 596.1 [M+H]+. [000246] Step-4: Synthesis of tert-butyl 4-(5-(2-((tert- butoxycarbonyl)amino)pyrimidin-4-yl)-4-(2-fluoro-3-
(propylsulfonamido)phenyl)thiazol-2-yl)piperidine-l-carboxylate (5)
To a mixture of tert-butyl 4-(5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-3- (propylsulfonamido)phenyl)thiazol-2-yl)piperidine-l-carboxylate_(1.0 g, 1.677 mmol, 1 equiv) and B0CNH2 (982.57 mg, 8.385 mmol, 5 equiv) in 1,4-dioxane (12 mL) was added BrettPhos Pd G3 (152.1 mg, 0.168 mmol, 0.1 equiv) at room temperature. The resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 : 1) to afford tert-butyl 4-(5-(2-((tert-butoxycarbonyl)amino)pyrimidin-4- yl)-4-(2-fluoro-3-(propylsulfonamido)phenyl)thiazol-2-yl)piperidine-l-carboxylate (850 mg, 87.86%) as a white solid. LCMS: CsiEUiFNeOeS? requires: 676.3, found: m/z = 677.3 [M+H]+. [000247] Step-5: Synthesis of A-13-[5-(2-aminopyrimidin-4-yl)-2-(piperidin-4-yl)- l,3-thiazol-4-yl]-2-fluorophenvnpropane-l-sulfonamide hydrochloride
To a mixture of tert-butyl 4-(5-(2-((tert-butoxycarbonyl)amino)pyrimidin-4-yl)-4-(2-fluoro-3- (propylsulfonamido)phenyl)thiazol-2-yl)piperidine-l-carboxylate (1.5 g, 2.263 mmol, 1 equiv) in DCM (3 mL) was added HC1 (gas) in 1,4-dioxane (12 mL, 4 M) at room temperature. The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford 7V-{3-[5- (2-aminopyrimidin-4-yl)-2-(piperidin-4-yl)-l,3-thiazol-4-yl]-2-fluorophenyl}propane-l- sulfonamide hydrochloride salt (649.6 mg, 54.60%) as a yellow solid. LCMS: C21H25FN6O2S2 requires: 476.3, found: m/z = 477.3 [M+H]+.
'H NMR (400 MHz, CD3OD) 5 8.09 (d, J= 6.0 Hz, 1H), 7.68 - 7.66 (m, 1H), 7.49 - 7.28 (m, 2H), 6.65 - 6.63 (m, 1H), 3.60 - 3.48 (m, 3H), 3.28 - 3.16 (m, 2H), 3.17 - 3.05 (m, 2H), 2.49 - 2.39 (m, 2H), 2.21 - 2.09 (m, 2H), 1.94 - 1.78 (m, 2H), 1.14 - 0.98 (m, 3H).
[000248] Synthesis of A-(3-H-[4-(azetidin-3-yl)phenyl]-3-(pyridin-4-yl)pyrazol-4- vn-2-fluorophenyl)propane-l-sulfonamide; trifluoroacetic acid salt
[000249] Step-1: Synthesis of tert-butyl 3-]4-[4-(3-amino-2-fluorophenyl)-3- (pyridin-4-yl)pyrazol-l-yl]phenvnazetidine-l-carboxylate (2)
To a mixture of tert-butyl 3-{4-[4-bromo-3-(pyridin-4-yl)pyrazol-l-yl]phenyl}azetidine-l- carboxylate (100 mg, 0.22 mmol, 1 equiv) and 2-fluoro-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)aniline (78 mg, 0.33 mmol, 1.5 equiv) in dioxane (3 mL) was added CsF (67 mg, 0.44 mmol, 2 equiv) in H2O (0.3 mL) and Pd(AMPHOS)2Ch (31 mg, 0.044 mmol, 0.2 equiv). The resulting mixture was stirred at 95 °C for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 : 10) to afford tert-butyl 3-{4-[4-(3-amino-2- fluorophenyl)-3-(pyridin-4-yl)pyrazol-l-yl]phenyl} azetidine- 1 -carboxylate (100 mg, 89.09%) as a yellow solid. LCMS: C28H28FN5O2 requires: 485.2, found: m/z = 486.3 [M+H]+.
[000250] Step-2: Synthesis of tert-butyl 3-(4-]4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-3-(pyridin-4-yl)pyrazol-l-vnphenyl)azetidine-l-carboxylate (3) To a mixture of tert-butyl 3-{4-[4-(3-amino-2-fluorophenyl)-3-(pyridin-4-yl)pyrazol-l- yl]phenyl}azetidine-l-carboxylate (60 mg, 0.12 mmol, 1 equiv) and TEA (38 mg, 0.37 mmol, 3 equiv) in DCM (3 mL) was added propane- 1 -sulfonyl chloride (53 mg, 0.37 mmol, 3 equiv) at 0 °C. The resulting mixture was stirred at room temperature for one hour. The resulting mixture was concentrated under vacuum. To the above mixture was added THF (1.5 mL), ACN (1.5 mL), and ISfeCCL (196 mg, 1.86 mmol, 15 equiv) in H2O (1.5 mL). The resulting mixture was stirred at 50 °C overnight. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 : 1) to afford tert-butyl 3 -(4- { 4- [2-fluoro-3 -(propane- 1 -sulfonamido)phenyl] -3 -(pyri din-4-yl)pyrazol- 1 - yl}phenyl)azetidine-l -carboxylate (50 mg, 64.97%) as a yellow solid. LCMS: C31H34FN5O4S requires: 591.2, found: m/z = 592.3 [M+H]+.
[000251 ] Step-3: Synthesis of 7V-(3-fl-[4-(azetidin-3-yl)Dhenyl]-3-(Dyridin-4- yl)Dyrazol-4-yl}-2-fluoroDhenyl)DroDane-l-sulfonamide; trifluoroacetic acid
To a mixture of tert-butyl 3-(4-{4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-3-(pyridin-4- yl)pyrazol-l-yl}phenyl)azetidine-l-carboxylate (45 mg, 0.076 mmol, 1 equiv) in DCM (4 mL) was added TFA (1 mL) at 0 °C. The resulting mixture was stirred at 0 °C for one hour. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase flash chromatography eluted with ACN iFEO (1 : 1) to afford N-(3-{ 1 -[4-(azetidin-3-yl)phenyl]- 3 -(pyridin-4-yl)pyrazol-4-yl}-2-fluorophenyl)propane-l -sulfonamide; trifluoroacetic acid salt (18 mg, 37.24%) as a white solid. LCMS: C26H26FN5O2S requires: 491.2, found: m/z = 492.2 [M+H]+. 'H NMR (400 MHz, CD3OD) 5 8.66 - 8.41 (m, 3H), 7.95 (d, J= 8.4 Hz, 2H), 7.72 - 7.46 (m, 5H), 7.37 - 7.17 (m, 2H), 4.27 - 4.16 (m, 1H), 4.16 - 4.08 (m, 2H), 4.07 - 3.94 (m, 2H), 3.14 - 2.92 (m, 2H), 1.94 - 1.64 (m, 2H), 1.12 - 0.80 (m, 3H).
[000252] Synthesis of 7V-I3- [5-(2-aminoDyrimidin-4-yl)-2- [l-(piperidine-4- carbonyl)Diperidin-4-yl]-l.,3-thiazol-4-yl]-2-fluoroDhenvnDroDane-l-sulfonaniide hydrochloride salt
[000253] Step-1: Synthesis of tert-butyl 4-14-[5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-
3-l[(prop-2-en-l-yloxy)carbonyl]amino}phenyl)-l,3-thiazol-2-yl]piperidine-l- carbonyllpiperidine-l-carboxylate (3)
To a mixture of prop-2-en-l-yl A-{3-[5-(2-chloropyrimidin-4-yl)-2-(piperidin-4-yl)-l,3- thiazol-4-yl]-2-fluorophenyl}carbamate (2 g, 4.22 mmol, 1 equiv) and l-(tert- butoxycarbonyl)piperidine-4-carboxylic acid (1.45 g, 6.33 mmol, 1.5 equiv) in DMF (20 mL) was added HATU (2.41 g, 6.33 mmol, 1.5 equiv) and DIEA (2.73 g, 21.10 mmol, 5 equiv) at room temperature. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CEECh MeOEl (10: 1) to afford tert-butyl 4-{4-[5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-3- {[(prop-2-en-l-yloxy)carbonyl]amino}phenyl)-l,3-thiazol-2-yl]piperidine-l- carbonyl}piperidine-l-carboxylate (1.4 g, 43.58%) as a brown oil. LCMS: C33H38CIFN6O5S requires: 684.2, found: m/z = 685.3 [M+H]+.
[000254] Step-2: Synthesis of te -butyl 4-14-[4-(3-amino-2-fluorophenyl)-5-(2- chloropyrimidin-4-yl)-l.,3-thiazol-2-yl]piperidine-l-carbonvnpiperidine-l-carboxylate (4)
To a mixture of tert-butyl 4-{4-[5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-3-{[(prop-2-en-l- yloxy)carbonyl]amino}phenyl)-l,3-thiazol-2-yl]piperidine-l-carbonyl}piperidine-l- carboxylate (1.1 g, 1.60 mmol, 1 equiv) and HO Ac (241 mg, 4.01 mmol, 2.5 equiv) in DCM (10 mL) was added Pd(PPh3)2C12 (22 mg, 0.032 mmol, 0.02 equiv) and w-BusSnH (747 mg, 2.56 mmol, 1.6 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 30 min at room temperature. The reaction was quenched by the addition of saturated aqueous NaHCOs at 0 °C. The resulting mixture was extracted with CH2Q2. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (5: 1) to afford tert-butyl 4-{4-[4-(3- amino-2-fluorophenyl)-5-(2-chloropyrimidin-4-yl)-l,3-thiazol-2-yl]piperidine-l- carbonyl}piperidine-l-carboxylate (700 mg, 63.83%) as ayellow oil. LCMS: C29H34CIFN6O3S requires: 600.2, found: m/z = 601.3 [M+H]+.
[000255] Step-3: Synthesis of tert-butyl 4-(4-(5-(2-chloropyrimidin-4-yl)-4-(2-fluoro- 3-(propylsulfonamido)phenyl)thiazol-2-yl)piperidine-l-carbonyl)piperidine-l- carboxylate (5)
To a mixture of tert-butyl 4-{4-[4-(3-amino-2-fluorophenyl)-5-(2-chloropyrimidin-4-yl)-l,3- thiazol-2-yl]piperidine-l-carbonyl}piperidine-l-carboxylate (700 mg, 1.16 mmol, 1 equiv) in DCM (7 mL) was added TEA (353 mg, 3.49 mmol, 3 equiv) and propane- 1 -sulfonyl chloride (199 mg, 1.39 mmol, 1.2 equiv) at 0 °C. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was dissolved in THF (3 mL), H2O (3 mL), and MeCN (3 mL). Na2COs (456 mg, 4.30 mmol, 5 equiv) was added at room temperature. The resulting mixture was stirred overnight at 50 °C. The resulting mixture was concentrated under vacuum. The residue was extracted with DCM. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford tert-butyl 4-(4- (5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-3-(propylsulfonamido)phenyl)thiazol-2- yl)piperi dine- l-carbonyl)piperi dine- l-carboxylate_(800 mg, crude) as a brown solid. LCMS: C32H40CIFN6O5S2 requires: 706.2, found: m/z = 707.2 [M+H]+.
[000256] Step-4: Synthesis of tert-butyl 4-[4-(5-|2-[(tert- butoxycarbonyl)amino]pyrimidin-4-vn-4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]- l,3-thiazol-2-yl)piperidine-l-carbonyl]piperidine-l-carboxylate (6)
To a mixture of tert-butyl 4-{4-[5-(2-chloropyrimidin-4-yl)-4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]- 1 ,3 -thiazol-2-yl]piperidine- 1 -carbonyl } piperi dine- 1 -carboxylate (1 g, 1.41 mmol, 1 equiv) and tert-butyl carbamate (828 mg, 7.07 mmol, 5 equiv) in dioxane (10 mL) was added BrettPhos Pd G3 (128 mg, 0.14 mmol, 0.1 equiv) and CS2CO3 (921 mg, 2.82 mmol, 2 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 2 h at 80 °C. The resulting mixture was then extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous ISfeSCU. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CFECb MeOH (10: 1) to afford tert-butyl 4-[4-(5-{2-[(tert- butoxycarbonyl)amino]pyrimidin-4-yl}-4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-l,3- thiazol-2-yl)piperi dine- l-carbonyl]piperi dine- 1 -carboxylate (700 mg, 56.55%) as a yellow solid. LCMS: C37H50FN7O7S2 requires: 787.3, found: m/z = 788.3 [M+H]+.
[000257] Step-5: Synthesis of A-]3-[5-(2-aminopyrimidin-4-yl)-2-[l-(piperidine-4- carbonyl)piperidin-4-yl]-l.,3-thiazol-4-yl]-2-fluorophenvnpropane-l-sulfonaniide hydrochloride
A mixture of tert-butyl 4-[4-(5-{2-[(terZ-butoxycarbonyl)amino]pyrimidin-4-yl}-4-[2-fluoro- 3 -(propane- 1 -sulfonamido)phenyl]- 1 ,3 -thiazol-2-yl)piperidine- 1 -carbonyl]piperidine- 1 - carboxylate (700 mg, 0.761 mmol, 1 equiv) in HC1 in 1,4-dioxane (10 mL, 4 M) was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure to afford A-{3-[5-(2-aminopyrimidin-4-yl)-2-[l-(piperidine-4-carbonyl)piperidin-4-yl]-l,3- thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide hydrochloride salt (544.7 mg, crude) as a yellow solid. LCMS: C27H34FN7O3S2 requires: 587.2, found: m/z = 588.2 [M+H]+.
1 H NMR (400 MHz, CD3OD) 5 8.09 - 8.06 (m, 1H), 7.72 - 7.68 (m, 1H), 7.46 - 7.40 (m, 1H), 7.38 - 7.36 (m, 1H), 6.62 - 6.61 (m, 1H), 4.65 - 4.62 (m, 1H), 4.30 - 4.20 (m, 1H), 3.77 - 3.70 (m, 1H), 3.69 - 3.61 (m, 2H), 3.69 - 3.50 (m, 1H), 3.47 - 3.38 (m, 3H), 3.32 - 3.12 (m, 5H), 2.92 - 2.90 (m, 1H), 2.28 - 2.23 (m, 3H), 1.91 - 1.84 (m, 3H), 1.82 - 1.70 (m, 1H), 1.07 - 1.04 (m, 3H).
(24 mg, 0.035 mmol, 0.02 equiv) and w-BusSnH (811 mg, 2.78 mmol, 1.6 equiv) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred for 30 min at room temperature. The reaction was quenched by saturated aqueous NaHCCL at 0 °C. The resulting mixture was extracted with CH2Q2. The combined organic layers were washed with water and dried over anhydrous ISfeSC After filtration, the filtrate was concentrated under reduced pressure to afford tert-butyl 4-[4-(3-amino-2-fluorophenyl)-5-(2-chloropyrimidin-4-yl)-l,3-thiazol-2- yl]piperidine-l -carboxylate (1.5 g, crude) as a brown solid. LCMS: C23H25CIFN5O2S requires: 489.1, found: m/z = 490.1 [M+H]+.
[000260] Step-2: Synthesis of tert-butyl 4-(5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-3- (propylsulfonamido)phenyl)thiazol-2-yl)piperidine-l-carboxylate (3)
To a mixture of tert-butyl 4-[4-(3-amino-2-fluorophenyl)-5-(2-chloropyrimidin-4-yl)-l,3- thiazol-2-yl]piperidine-l -carboxylate (1.5 g, 3.06 mmol, 1 equiv) in DCM (15 mL) was added TEA (929 mg, 9.18 mmol, 3 equiv) and propane- 1 -sulfonyl chloride (436 mg, 3.06 mmol, 1 equiv) at 0 °C. The resulting mixture was stirred for one hour at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was dissolved in THF (5 mL), H2O (5 mL), and MeCN (5 mL). ISfeCCL (1.13 g, 10.68 mmol, 5 equiv) was added at room temperature. The resulting mixture was stirred overnight at 50 °C. The resulting mixture was concentrated under vacuum. The residue was extracted with DCM. The combined organic layers were washed with water and dried over anhydrous ISfeSC After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with DCM:MeOH (10: 1) to afford tert-butyl 4-(5-(2-chloropyrimidin- 4-yl)-4-(2-fluoro-3 -(propylsulfonamido)phenyl)thiazol-2-yl)piperidine- 1 -carboxylate (2 g, 93.03%) as a brown solid. LCMS: C26H31CIFN5O4S2 requires: 595.2, found: m/z = 596.2 [M+H]+.
[000261 ] Step-3: Synthesis of A-]3-[5-(2-chloropyrimidin-4-yl)-2-(piperidin-4-yl)- l,3-thiazol-4-yl]-2-fluorophenvnpropane-l-sulfonamide (4)
A mixture of tert-butyl 4-[5-(2-chloropyrimidin-4-yl)-4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-l,3-thiazol-2-yl]piperidine-l-carboxylate (1.7 g, 2.85 mmol, 1 equiv) in HC1 in 1,4-di oxane (20 mL, 4 M) was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford A-{3-[5-(2-chloropyrimidin-4-yl)-2- (piperidin-4-yl)-l,3-thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide (1.4 g, crude) as a yellow oil. LCMS: C21H23CIFN5O2S2 requires: 495.1, found: m/z = 496.2 [M+H]+. [000262] Step-4: Synthesis of tert-butyl 4-G4-[5-(2-chloroDyrimidin-4-yl)-4-[2- fluoro-3-(propane-l-sulfonamido)phenyl]-l.,3-thiazol-2-yl]piperidin-l- vnmethyl)piperidine-l-carboxylate (5)
To a mixture of A-{3-[5-(2-chloropyrimidin-4-yl)-2-(piperidin-4-yl)-l,3-thiazol-4-yl]-2- fluorophenyl} propane- 1 -sulfonamide (1.4 g, 2.82 mmol, 1 equiv) in DCM (10 mL) was added tert-butyl 4-formylpiperidine-l -carboxylate (902 mg, 4.23 mmol, 1.5 equiv) and NaOAc (231 mg, 2.82 mmol, 1 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for one hour at room temperature. To the above mixture was added NaBH(OAc)3 (1.2 g, 5.64 mmol, 2 equiv) at 0 °C. The resulting mixture was stirred for 2 h at room temperature. The reaction was quenched by the addition of water at 0 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CEEChiMeOH (10: 1) to afford tert-butyl 4-({4-[5-(2-chloropyrimidin-4-yl)-4-[2-fluoro-3- (propane- 1 -sulfonamido)phenyl]- 1 ,3 -thiazol-2-yl]piperidin- 1 -yl }methyl)piperidine- 1 - carboxylate (1.2 g, 55.19%) as a yellow solid. LCMS: C32H42CIFN6O4S2 requires: 692.2, found: m/z = 693.3 [M+H]+.
[000263] Step-5: Synthesis of tert-butyl 4-f[4-(5- [(tert- butoxycarbonyl)amino]pyrimidin-4-vn-4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]- l,3-thiazol-2-yl)piperidin-l-yl]methvnpiperidine-l-carboxylate (6)
To a mixture of tert-butyl 4-({4-[5-(2-chloropyrimidin-4-yl)-4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]- 1 ,3 -thiazol-2-yl]piperidin- 1 -yl }methyl)piperidine- 1 -carboxylate (1.2 g, 1.73 mmol, 1 equiv) and tert-butyl carbamate (1.01 g, 8.65 mmol, 5 equiv) in 1,4-dioxane (10 mL) was added BrettPhos Pd G3 (156 mg, 0.17 mmol, 0.10 equiv) and CS2CO3 (1.13 g, 3.46 mmol, 2 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 2 h at 80 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography with EEOiMeCN (1 :7) to afford tert-butyl 4- {[4-(5-{ 2- [(tertbutoxy carbonyl)amino]pyrimidin-4-yl}-4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-l, 3- thiazol-2-yl)piperidin-l-yl]methyl (piperidine- 1 -carboxylate (700 mg, 49.64%) as a yellow solid. LCMS: C37H52FN7O6S2 requires: 773.3, found: m/z = 774.3 [M+H]+. [000264] Step-6: Synthesis of \-!3-|5-(2-aiiiiiiopyriiiiidiii-4-yl)-2-| l-(piperidiii-4- ylmethyl)piperidin-4-yl]-l.,3-thiazol-4-yl]-2-fluorophenvnpropane-l-sulfonaniide hydrochloride
A mixture of tert-butyl 4-{[4-(5-{2-[(tert-butoxycarbonyl)amino]pyrimidin-4-yl}-4-[2-fluoro- 3 -(propane- 1 -sulfonamido)phenyl]- 1 ,3 -thiazol-2-yl)piperidin- 1 -yl]methyl (piperidine- 1 - carboxylate (700 mg, 1.034 mmol, 1 equiv) in HCl/l,4-di oxane (10 mL, 4 M) was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure to afford 7V-{3-[5-(2-aminopyrimidin-4-yl)-2-[l-(piperidin-4-ylmethyl)piperidin-4-yl]-l,3- thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide hydrochloride salt (596.3 mg, crude) as a yellow solid. LCMS: C27H36FN7O2S2 requires: 573.2, found: m/z = 574.3 [M+H]+.
1 H NMR (400 MHz, CD3OD) 5 8.15 - 8.12 (m, 1H), 7.74 - 7.70 (m, 1H), 7.48 - 7.40 (m, 1H), 7.38 - 7.33 (m, 1H), 6.64 - 6.62 (m, 1H), 3.90 - 3.83 (m, 2H), 3.77 - 3.68 (m, 1H), 3.65 - 3.53 (m, 1H), 3.48 - 3.40 (m, 2H), 3.30 - 3.19 (m, 3H), 3.17 - 3.09 (m, 4H), 2.61 - 2.42 (m, 5H), 2.20 - 2.10 (m, 2H), 1.89 - 1.83 (m, 2H), 1.75 - 1.61 (m, 2H), 1.07 - 1.03 (m, 3H).
[000265] Synthesis of N- (3- 12-tert-hu t yl-5-(2- ! [ 1 -(piperidin-4-yl)pyrazol-4- yl]amino}pyrimidin-4-yl)-l.,3-thiazol-4-yl]-2-fluoroDhenvnDroDane-l-sulfonaniide hydrochloride salt
[000266] Step-1: Synthesis of prop-2-en-l-yl 7V-13-[2-tert-butyl-5-(2- chloroDyrimidin-4-yl)-l.,3-thiazol-4-yl]-2-fluoroDhenyncarbamate(2)
To a mixture of 2,2-dimethylpropanethioamide (0.97 g, 8.234 mmol, 1.2 equiv) in DMA (10 mL) was added NBS (1.22 g, 6.862 mmol, 1.0 equiv) at 0 °C. The resulting mixture was stirred for 15 min at room temperature. To the above mixture was added prop-2-en-l-yl 7V-{3-[2-(2- chloropyrimidin-4-yl)acetyl]-2-fluorophenyl}carbamate (2.4 g, 6.862 mmol, 1.0 equiv) at room temperature. The resulting mixture was stirred for additional 2 h at 60 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CEEChiMeOH (10: 1) to afford prop-2-en-l-yl A-{3-[2-terLbutyl-5-(2-chloropyrimidin-4-yl)- l,3-thiazol-4-yl]-2-fluorophenyl}carbamate (2.6 g, 84.78%) as a yellow solid. LCMS: C21H20CIFN4O2S requires: 446.1, found: m/z = 447.1 [M+H]+.
[000267] Step-2: Synthesis of 3-|2-/,cr/,-biityl-5-(2-cliloi opyi iiiiidiii-4-yl)-L3-tliiazol-
4-yl]-2-fluoroaniline (3)
To a mixture of prop-2-en-l-yl A-{3-[2-tert-butyl-5-(2-chloropyrimidin-4-yl)-l,3-thiazol-4- yl]-2-fluorophenyl}carbamate (2.5 g, 5.594 mmol, 1 equiv) and HOAc (0.84 g, 13.985 mmol, 2.5 equiv) in DCM (30 mL) was added w-BusSnH (2.61 g, 8.950 mmol, 1.6 equiv) and Pd(PPh3)2Cl2 (78.52 mg, 0.112 mmol, 0.02 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 0.5 h at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure to afford 3-[2-tert- butyl-5-(2-chloropyrimidin-4-yl)-l,3-thiazol-4-yl]-2-fluoroaniline (2.4 g, crude) as a yellow oil. The crude product was used in the next step directly without further purification. LCMS: C17H16CIFN4S requires: 362.1, found: m/z = 363.1 [M+H]+.
[000268] Step-3: Synthesis of \-!3-|2-/crt-biityl-5-(2-cliloi opyi iiiiidin-4-yl)-1.3- thiazol-4-yl]-2-fluorophenynpropane-l-sulfonamide (4)
To a mixture of 3-[2-tert-butyl-5-(2-chloropyrimidin-4-yl)-l,3-thiazol-4-yl]-2-fluoroaniline (2.4 g, 5.117 mmol, 1 equiv) and TEA (1.55 g, 15.351 mmol, 3.0 equiv) in DCM (30 mL) was added propane- 1 -sulfonyl chloride (1.46 g, 10.234 mmol, 2.0 equiv) at room temperature. The resulting mixture was stirred for one hour at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was dissolved in THF (10 mL), CH3CN (10 mL), and H2O (10 mL). Na2CC>3 (5.42 g, 51.170 mmol, 10.0 equiv) was added at room temperature. The resulting mixture was stirred at 50 °C overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2:MeOH (10: 1) to afford A-{3-[2-tert-butyl-5-(2- chloropyrimidin-4-yl)-l,3-thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide (2.0 g, 83.33%) as a yellow solid. LCMS: C2OH22C1FN402S2 requires: 468.1, found: m/z = 469.1 [M+H]+.
[000269] Step-4: Synthesis of tert-butyl 4-14-[(4-12-tert-butyl-4-[2-fluoro-3- (propane-l-sulfonamido)phenyl]-l.,3-thiazol-5-vnpyriniidin-2-yl)aniino]pyrazol-l- vnpiperidine-l-carboxylate (6)
To a mixture of A-{3-[2-tert-butyl-5-(2-chloropyrimidin-4-yl)-l,3-thiazol-4-yl]-2- fluorophenyl (propane- 1 -sulfonamide (500 mg, 1.099 mmol, 1 equiv) and tert-butyl 4-(4- aminopyrazol-l-yl)piperidine-l -carboxylate (351.26 mg, 1.319 mmol, 1.2 equiv) in dioxane (5 mL) was added DavePhos (129.75 mg, 0.330 mmol, 0.3 equiv), Pd2(dba)3 (150.96 mg, 0.165 mmol, 0.15 equiv) and Z-BuONa (158.43 mg, 1.648 mmol, 1.5 equiv) at room temperature under a nitrogen atmosphere. The final reaction mixture was irradiated with microwave radiation for 2 h at 120 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2:MeOH (10: 1) to afford tert-butyl 4-{4-[(4-{2-tert-butyl- 4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-l,3-thiazol-5-yl}pyrimidin-2- yl)amino]pyrazol-l-yl}piperidine-l-carboxylate (600 mg, 78.12%) as a white solid. LCMS: C33H43FN8O4S2 requires: 698.3, found: m/z = 699.3 [M+H]+.
[000270] Step-5: Synthesis of \-!3-|2-tert-biityl-5-(2-!| l-(piperidiii-4-yl)pyrazol-4- yl]amino}pyrimidin-4-yl)-l.,3-thiazol-4-yl]-2-fluorophenvnpropane-l-sulfonaniide hydrochloride
To a mixture of tert-butyl 4-{4-[(4-{2-tert-butyl-4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]- 1 ,3 -thiazol-5-yl }pyrimidin-2-yl)amino]pyrazol- 1 -yl } piperidine- 1 - carboxylate (550 mg, 0.787 mmol, 1 equiv) in DCM (3 mL) was added HC1 (gas) in 1,4- dioxane (3 mL, 4 N) at room temperature. The resulting mixture was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol/L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford 7V-{3-[2-tert-butyl-5-(2-{[l-(piperidin-4-yl)pyrazol-4- yl]amino}pyrimidin-4-yl)-l,3-thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide hydrochloride salt (409.3 mg, 81.88%) as a yellow solid. LCMS: C28H35FN8O2S2 requires: 598.2, found: m/z = 599.3 [M+H]+. 'HNMR (400 MHz, CD3OD) 5 8.38 - 7.74 (m, 2H), 7.71 - 7.63 (m, 2H), 7.52 (s, 1H), 7.38 - 7.32 (m, 1H), 6.77 (s, 1H), 4.57 (s, 1H), 3.64 - 3.54 (m, 2H), 3.32 - 3.22 (m, 2H), 3.10 (s, 2H), 2.42 - 2.26 (m, 4H), 1.92 - 1.78 (m, 2H), 1.56 (s, 9H), 1.04 - 0.96 (m, 3H).
[000271 ] Synthesis of 7V-(3-12-tert-butyl-5-[2-(l.,2.,3.,4-tetrahvdroisoquinolin-6- ylamino)pyrimidin-4-yl]-l.,3-thiazol-4-vn-2-fluoroDhenyl)DroDane-l-sulfonaniide hydrochloride salt
[000272] Step-1: Synthesis of tert-butyl 6-[(4-]2-tert-butyl-4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-l.,3-thiazol-5-ynDyrimidin-2-yl)amino]-3.,4-dihydro-IH- isoquinoline-2-carboxylate (3)
To a mixture of tert-butyl 6-amino-3,4-dihydro-17/-isoquinoline-2-carboxylate (444 mg, 1.79 mmol, 1.2 equiv) and 7V-{3-[2-tert-butyl-5-(2-chloropyrimidin-4-yl)-l,3-thiazol-4-yl]-2- fluorophenyl (propane- 1 -sulfonamide (700 mg, 1.49 mmol, 1 equiv) in dioxane (5 mL) was added Pd2(dba)s (205 mg, 0.22 mmol, 0.15 equiv), DavePhos (176 mg, 0.44 mmol, 0.3 equiv), and Z-BuONa (215 mg, 2.24 mmol, 1.5 equiv) at room temperature under a nitrogen atmosphere. The final reaction mixture was irradiated with microwave radiation for 2 h at 120 °C under the nitrogen atmosphere. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous ISfeSCU After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (5: 1) to afford tert-butyl 6-[(4-{2-tert-butyl-4-[2- fhioro-3-(propane-l-sulfonamido)phenyl]-l,3-thiazol-5-yl}pyrimidin-2-yl)amino]-3,4- dihydro-l/Z-isoquinoline-2-carboxylate (700 mg, 61.99%) as a yellow solid. LCMS: C34H41FN6O4S2 requires: 680.3, found: m/z = 681.3 [M+H]+.
[000273] Step-2: Synthesis of A-(3-]2-tert-butyl-5-[2-(l.,2.,3.,4-tetrahvdroisoquinolin- 6-ylamino)pyrimidin-4-yl]-l.,3-thiazol-4-vn-2-fluorophenyl)propane-l-sulfonamide hydrochloride
A mixture of tert-butyl 6-[(4-{2-tert-butyl-4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-l,3- thiazol-5-yl}pyrimidin-2-yl)amino]-3,4-dihydro-17/-isoquinoline-2-carboxylate (700 mg, 1.028 mmol, 1 equiv) in HCl/l,4-di oxane (10 mL, 4 M) was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with MeCbTEhO (7: 1) to afford N-(3-{2-tert- butyl-5-[2-(l,2,3,4-tetrahydroisoquinolin-6-ylamino)pyrimidin-4-yl]-l,3-thiazol-4-yl}-2- fluorophenyl)propane-l -sulfonamide hydrochloride salt (401.2 mg, 66.86%) as a yellow solid. LCMS: C29H33FN6O2S2 requires: 580.2, found: m/z = 581.2 [M+H]+.
1H NMR (400 MHz, CD3OD) 5 8.25 - 8.20 (m, 1H), 7.66 - 7.61 (m, 1H), 7.52 - 7.41 (m, 2H), 7.39 - 7.34 (m, 2H), 7.25 - 7.23 (m, 1H), 6.78 - 6.76 (m, 1H), 4.40 (s, 2H), 3.58 - 3.55 (m, 2H), 3.32 - 3.20 (m, 2H), 3.11 - 3.07 (m, 2H), 1.86 - 1.80 (m, 3H), 1.54 (s, 9H), 1.50 - 1.30 (m, 1H), 1.04 - 1.01 (m, 3H).
[000274] Synthesis of A-13-[2-tert-butyl-5-(2-l[3-(Diperidin-4- yl)Dhenyl]amino}pyrimidin-4-yl)-l.,3-thiazol-4-yl]-2-fluoroDhenyl} _ propane-1- sulfonamide hydrochloride salt
[000275] Step-1: Synthesis of tert-butyl 4-13-[(4-12-tert-butyl-4-[2-fluoro-3-
(DroDane-l-sulfonamido)Dhenyl]-l.,3-thiazol-5-ynDyrimidin-2- vDaminolDhenynpiperidine-l-carboxylate (3)
To a mixture of A-{3-[2-ZerZ-butyl-5-(2-chloropyrimidin-4-yl)-l,3-thiazol-4-yl]-2- fluorophenyl} propane- 1 -sulfonamide (500 mg, 1.066 mmol, 1 equiv) and tert-butyl 4-(3- aminophenyl)piperidine-l -carboxylate (353.59 mg, 1.279 mmol, 1.2 equiv) in dioxane (5 mL) was added DavePhos (125.87 mg, 0.320 mmol, 0.3 equiv), Pd2(dba)s (146.44 mg, 0.160 mmol, 0.15 equiv) and Z-BuONa (153.69 mg, 1.599 mmol, 1.5 equiv) at room temperature under a nitrogen atmosphere. The final reaction mixture was irradiated with microwave radiation for 2 h at 120 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous ISfeSCU After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 : 1) to afford tert-butyl 4-{3-[(4-{2-tert-butyl-4-[2- fluoro-3-(propane-l-sulfonamido)phenyl]-l,3-thiazol-5-yl(pyrimidin-2- yl)amino]phenyl (piperidine- 1 -carboxylate (650 mg, 86.00%) as a yellow solid. LCMS: C36H45FN6O4S2 requires: 708.3, found: m/z = 709.3 [M+H]+.
[000276] Step-2: Synthesis of Az-f3-[2-tert-butyl-5-(2-f[3-(Diperidin-4- yl)Dhenyl]amino}Dyrimidin-4-yl)-l.,3-thiazol-4-yl]-2-fluoroDhenyl}DroDane-l- sulfonamide hydrochloride
To a mixture of tert-butyl 4-{3-[(4-{2-tert-butyl-4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]- 1 ,3 -thiazol-5-yl (pyrimidin-2-yl)amino]phenyl (piperidine- 1 -carboxylate (550 mg, 0.776 mmol, 1 equiv) in DCM (3 mL) was added HCI (gas) in 1,4-dioxane (3 mL, 4 N) at room temperature. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH3CN:H2O (70:30) to afford 7V-{3-[2-tert-butyl-5- (2-{[3-(piperidin-4-yl)phenyl]amino(pyrimidin-4-yl)-l,3-thiazol-4-yl]-2-fluorophenyl( propane- 1 -sulfonamide hydrochloride salt (447 mg, 89.29%) as a yellow solid. LCMS: C31H37FN6O2S2 requires: 608.2, found: m/z = 609.3 [M+H]+. 'H NMR (400 MHz, CD3OD) 5 8.20 (d, J = 6.4 Hz, 1H), 7.78 - 7.68 (m, 1H), 7.52 - 7.28 (m, 5H), 7.18 (d, J = 7.2 Hz, 1H), 6.70 (d, J= 6.0 Hz, 1H), 3.58 - 3.48 (m, 2H), 3.26 - 3.18 (m, 2H), 3.15 - 3.05 (m, 2H), 2.99 - 2.92 (m, 1H), 2.25 - 2.12 (m, 2H), 2.07 - 1.92 (m, 2H), 1.89 - 1.78 (m, 2H), 1.54 (s, 9H), 1.08 - 1.05 (m, 3H).
[000277] Synthesis of Az-|3-[2-tert-butyl-5-(2-f[3-(Diperidin-4- Dhenyl]amino}pyrimidin-4-yl)-l.,3-thiazol-4-yl]-2-fluoroDhenvnDroDane-l- sulfonamide hydrochloride salt
[000278] Step-1: Synthesis of tert-butyl 4-]3-[(4-]2-tert-butyl-4-[2-fluoro-3- (propane-l-sulfonamido)phenyl]-l.,3-thiazol-5-vnpyrimidin-2- yl)amino]phenoxy}piperidine-l-carboxylate (3)
To a mixture of tert-butyl 4-(3-aminophenoxy)piperidine-l-carboxylate (374 mg, 1.27 mmol, 1.2 equiv) and 7V-{3-[2-tert-butyl-5-(2-chloropyrimidin-4-yl)-l,3-thiazol-4-yl]-2- fluorophenyl (propane- 1 -sulfonamide (500 mg, 1.06 mmol, 1 equiv) in dioxane (5 mL) was added Pd2(dba)s (146 mg, 0.16 mmol, 0.15 equiv), DavePhos (125 mg, 0.32 mmol, 0.3 equiv) and LBuONa (153 mg, 1.59 mmol, 1.5 equiv) at room temperature under a nitrogen atmosphere. The final reaction mixture was irradiated with microwave radiation for 2 h at 120 °C under nitrogen atmosphere. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous ISfeSC After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (4: 1) to afford tert-butyl 4-{3-[(4-{2-tert-butyl-4-[2- fhioro-3-(propane-l-sulfonamido)phenyl]-l,3-thiazol-5-yl(pyrimidin-2- yl)amino]phenoxy(piperidine-l-carboxylate (500 mg, 58.23%) as a yellow solid. LCMS: C36H45FN6O5S2 requires: 724.2, found: m/z = 725.3 [M+H]+.
[000279] Step-2: Synthesis of 7V-]3-[2-tert-butyl-5-(2-H3-(piperidin-4- yloxy)phenyl]amino}pyrimidin-4-yl)-l.,3-thiazol-4-yl]-2-fluorophenvnpropane-l- sulfonamide hydrochloride
A mixture of tert-butyl 4-{3-[(4-{2-tert-butyl-4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]- l,3-thiazol-5-yl(pyrimidin-2-yl)amino]phenoxy(piperidine-l-carboxylate (500 mg, 0.69 mmol, 1 equiv) in HCl/l,4-di oxane (10 mL, 4 M) was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure to afford A-{3-[2-tert-butyl-5- (2-{[3-(piperidin-4-yloxy)phenyl]amino(pyrimidin-4-yl)-l,3-thiazol-4-yl]-2- fluorophenyl (propane- 1 -sulfonamide hydrochloride salt (414.0 mg, crude) as an orange solid. LCMS: C31H37FN6O3S2 requires: 624.2, found: m/z = 625.2 [M+H]+. 1H NMR (400 MHz, CD3OD) 5 8.15 - 8.12 (m, 1H), 7.66 - 7.62 (m, 1H), 7.46 - 7.41 (m, 1H), 7.40 - 7.34 (m, 3H), 7.07 - 7.05 (m, 2H), 6.73 - 6.70 (m, 1H), 4.86 - 4.77 (m, 1H), 3.47 - 3.41 (m, 2H), 3.36 - 3.26 (m, 2H), 3.09 - 3.05 (m, 2H), 2.23 - 2.20 (m, 2H), 2.10 - 2.04 (m, 2H), 1.97- 1.86 (m, 2H), 1.53 (s, 9H), 1.04 - 1.00 (m, 3H).
[000280] Synthesis of 7V-13-[2-tert-butyl-5-(2-H3-(pyrrolidin-3- yl)phenyl]amino}pyrimidin-4-yl)-l.,3-thiazol-4-yl]-2-fluorophenyl}propane-l- sulfonamide hydrochloride salt
[000281 ] Step-1: Synthesis of tert-butyl 3-(4-nitrophenyl)-2.,5-dihvdropyrrole-l- carboxylate (2)
To a mixture of tert-butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,5-dihydropyrrole- 1-carboxylate (1 g, 3.388 mmol, 1 equiv) and Pd(dppf)C12 (148.73 mg, 0.203 mmol, 0.06 equiv) in dioxane (9 mL) and H2O (3 mL) was added CS2CO3 (2.21 g, 6.776 mmol, 2 equiv) and 3- bromo-1 -nitrobenzene (684.33 mg, 3.388 mmol, 1 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 90 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous ISfeSC After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (4: 1) to afford tert-butyl 3-(3-nitrophenyl)-2,5-dihydropyrrole-l-carboxylate (700 mg, 67.62%) as a yellow solid.
[000282] Step-2: Synthesis of tert-butyl 3-(3-aminophenyl)pyrrolidine-l-carboxylate (3)
To a mixture of tert-butyl 3-(3-nitrophenyl)-2,5-dihydropyrrole-l-carboxylate (1.4 g, 4.82 mmol, 1 equiv) in DMF (5 mL) and EtOH (5 mL) was added Pd/C (1.4 g) at room temperature. The resulting mixture was stirred overnight at room temperature under a hydrogen atmosphere. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CEECh MeOH (10: 1) to afford tert-butyl 3-(3-aminophenyl)pyrrolidine-l-carboxylate (900 mg, 64.02%) as a yellow solid. LCMS: C15H22N2O2 requires: 262.2, found: m/z = 263.1 [M+H]+.
[000283] Step-3: Synthesis of tert-butyl 3-]3-[(4-]2-tert-butyl-4-[2-fluoro-3- (propane-l-sulfonamido)phenyl]-l.,3-thiazol-5-vnpyrimidin-2- yl)amino]phenvnpyrrolidine-l-carboxylate (5)
To a mixture of tert-butyl 3 -(3 -aminophenyl)pyrrolidine-l -carboxylate (268 mg, 1.02 mmol, 1.2 equiv) and A-{3-[2-tert-butyl-5-(2-chloropyrimidin-4-yl)-l,3-thiazol-4-yl]-2- fluorophenyl (propane- 1 -sulfonamide (400 mg, 0.85 mmol, 1 equiv) in dioxane (5 mL) was added Pd2(dba)s (117 mg, 0.12 mmol, 0.15 equiv), DavePhos (100 mg, 0.25 mmol, 0.3 equiv) and t-BuONa (122 mg, 1.28 mmol, 1.5 equiv) at room temperature under a nitrogen atmosphere. The final reaction mixture was irradiated with microwave radiation for 2 h at 120 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (5: 1) to afford tert-butyl 3-{3-[(4-{2-tert-butyl-4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]- 1 ,3 -thiazol-5-yl (pyrimidin-2-yl)amino]phenyl (pyrrolidine- 1 - carboxylate (220 mg, 33.41%) as a yellow solid. LCMS: C35H43FN6O4S2 requires: 694.3, found: m/z = 695.2 [M+H]+. [000284] Step-4: Synthesis of \-!3-|2-ter/,-biityl-5-(2-!|3-(pyrrolidin-3- yl)Dhenyl]amino}Dyrimidin-4-yl)-l.,3-thiazol-4-yl]-2-fluoroDhenyl}DroDane-l- sulfonamide hydrochloride
A mixture of tert-butyl 3-{3-[(4-{2-tertebutyl-4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]- l,3-thiazol-5-yl}pyrimidin-2-yl)amino]phenyl}pyrrolidine-l-carboxylate (400 mg, 0.576 mmol, 1 equiv) in HCl/l,4-di oxane (5 mL, 4 M) was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure to afford 7V-{3-[2-tert-butyl-5- (2-{[3-(pyrrolidin-3-yl)phenyl]amino}pyrimidin-4-yl)-l,3-thiazol-4-yl]-2- fluorophenyl (propane- 1 -sulfonamide hydrochloride (313.1 mg, crude) as a yellow solid. LCMS: C30H35FN6O2S2 requires: 594.2, found: m/z = 595.2 [M+H]+.
'H NMR (300 MHz, CD3OD) 5 8.26 (d, J= 5.1 Hz, 1H), 7.65 - 7.62 (m, 2H), 7.56 - 7.53 (m, 1H), 7.44 - 7.41 (m, 1H), 7.38 - 7.26 (m, 2H), 7.00 - 6.97 (m, 1H), 6.52 - 6.50 (m, 1H), 3.75 - 3.71 (m, 1H), 3.59 - 3.55 (m, 2H), 3.48 - 3.40 (m, 1H), 3.28 - 3.21 (m, 1H), 3.06 - 3.01 (m, 2H), 2.60 - 2.50 (m, 1H), 2.25 - 2.06 (m, 1H), 1.85 - 1.70 (m, 2H), 1.54 (s, 9H), 1.02 - 0.97 (m, 3H).
[000285] Synthesis of A-f3-[2-tert-butyl-5-(2-f[l-(Diperidin-4-ylmethyl)Dyrazol-4- yl]amino}pyrimidin-4-yl)-l.,3-thiazol-4-yl]-2-fluoroDhenvnDroDane-l-sulfonaniide hydrochloride salt
[000286] Step-1: Synthesis of tert-butyl 4-[(4-nitropyrazol-l-yl)methyl]piperidine-l- carboxylate (2)
To a mixture of 4-nitropyrazole (2 g, 17.68 mmol, 1 equiv) and tert-butyl 4- (hydroxymethyl)piperidine-l -carboxylate (3.81 g, 17.68 mmol, 1 equiv) in THF (20 mL) was added DIAD (3.58 g, 17.68 mmol, 1 equiv) and PPF13 (4.64 g, 17.68 mmol, 1 equiv) at room temperature. The resulting mixture was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 : 1) to afford tert-butyl 4-[(4-nitropyrazol-l- yl)methyl]piperidine-l-carboxylate (2 g, 32.79%) as a yellow solid. LCMS: C14H22N4O4 requires: 310.2, found: m/z = 311.2 [M+H]+.
[000287] Step-2: Synthesis of tert-butyl 4-[(4-aminopyrazol-l-yl)methyl]piperidine- 1-carboxylate (3)
To a mixture of tert-butyl 4-[(4-nitropyrazol-l-yl)methyl]piperidine-l-carboxylate (2 g, 6.44 mmol, 1 equiv) in MeOH (10 mL) was added Pd/C (1.0 g) at room temperature. The resulting mixture was stirred for 1 h at room temperature under a hydrogen atmosphere. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CFLCL MeOH (10: 1) to afford tertbutyl 4-[(4-aminopyrazol-l-yl)methyl]piperidine-l -carboxylate (1 g, 49.81%) as a pink solid. LCMS: C14H24N4O2 requires: 280.2, found: m/z = 281.1 [M+H]+. [000288] Step-3: Synthesis of tert-butyl 4-(]4-[(4-]2-tert-butyl-4-[2-fluoro-3- (propane-l-sulfonamido)phenyl]-l.,3-thiazol-5-vnpyrimidin-2-yl)amino]pyrazol-l- vnmethyl)piperidine-l-carboxylate (4)
To a mixture of tert-butyl 4-[(4-aminopyrazol-l-yl)methyl]piperidine-l -carboxylate (358 mg, 1.27 mmol, 1.2 equiv) and A-{3-[2-tert-butyl-5-(2-chloropyrimidin-4-yl)-l,3-thiazol-4-yl]-2- fluorophenyl (propane- 1 -sulfonamide (500 mg, 1.06 mmol, 1 equiv) in dioxane (5 mL) was added Pd2(dba)s (146 mg, 0.16 mmol, 0.15 equiv), DavePhos (125 mg, 0.32 mmol, 0.3 equiv), and Z-BuONa (153 mg, 1.59 mmol, 1.5 equiv) at room temperature under nitrogen atmosphere. The final reaction mixture was irradiated with microwave radiation for 2 h at 120 °C under nitrogen atmosphere. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous ISfeSCU After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (6: 1) to afford Zc/V-butyl 4-({4-[(4-{2-tert-butyl-4-[2- fluoro-3-(propane-l-sulfonamido)phenyl]-l,3-thiazol-5-yl}pyrimidin-2-yl)amino]pyrazol-l- yl}methyl)piperidine-l -carboxylate (500 mg, 59.21%) as a yellow oil. LCMS: C34H45FN8O4S2 requires: 712.3, found: m/z = 713.3 [M+H]+.
[000289] Step-4: Synthesis of A-]3-[2-tert-butyl-5-(2-][l-(piperidin-4- ylmethyl)pyrazol-4-yl]amino}pyrimidin-4-yl)-l.,3-thiazol-4-yl]-2-fluorophenyl}propane- 1-sulfonamide hydrochloride
A mixture of tert-butyl 4-({4-[(4-{2-tert-butyl-4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]- 1 ,3 -thiazol-5-yl }pyrimidin-2-yl)amino]pyrazol- 1 -yl } methyl)piperidine- 1-carboxylate (500 mg, 0.70 mmol, 1 equiv) in HC1/ 1,4 -di oxane (10 mL, 4 M) was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography with MeCbTEhO (9: 1) to afford 7V-{3-[2-tert-butyl-5-(2-{[l-(piperidin-4-ylmethyl)pyrazol-4-yl]amino}pyrimidin-4- yl)-l,3-thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide hydrochloride salt (369.1 mg, 85.19%) as an orange solid. LCMS: C29H37FN8O2S2 requires: 612.3, found: m/z = 613.3 [M+H]+. ‘HNMR (400 MHz, CD3OD) 5 8.48 - 8.17 (m, 1H), 7.75 - 7.64 (m, 3H), 7.60 - 7.53 (m, 1H), 7.42 - 7.38 (m, 1H), 6.84 - 6.57 (m, 1H), 4.26 - 4.14 (m, 2H), 3.46 - 3.33 (m, 2H), 3.19 - 2.98 (m, 4H), 2.41 - 2.20 (m, 1H), 1.93 - 1.79 (m, 4H), 1.65 - 1.56 (m, 11H), 1.09 - 1.05 (m, 3H).
[000290] Synthesis of A-(2-fluoro-3-H-[4-(piperidin-4-yl)phenyl]-3-(pyridin-4- yl)pyrazol-4-yl}phenyl)propane-l-sulfonamide hydrochloride salt
[000291 ] Step-1: Synthesis of tert-butyl 4-[4-(4,4.,5.,5-tetramethyl-l.,3.,2- dioxaborolan-2-yl)phenyl] piperidine-l-carboxylate (2)
To a mixture of tert-butyl 4-(4-bromophenyl)piperidine-l -carboxylate (6 g, 17.634 mmol, 1 equiv) and bis(pinacolato)diboron (13.4 g, 52.902 mmol, 3 equiv) in dioxane (60 mL) was added Pd(dppf)C12-CH2C12 (1.4 g, 1.763 mmol, 0.1 equiv) and KOAc (5.2 g, 52.902 mmol, 3 equiv) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 85 °C overnight under the nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (82: 18) to afford tert-butyl 4-[4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]piperidine-l -carboxylate (4.8 g, 70.28%) as a yellow oil. LCMS: C22H34BNO4 requires: 387.3, found: m/z = 388.2 [M+H]+.
[000292] Step-2: Synthesis of tert-butyl 4-]4-[4-bromo-3-(pyridin-4-yl)pyrazol-l- yl]phenvnpiperidine-l-carboxylate (4)
To a mixture of tert-butyl 4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl]piperidine-l -carboxylate (2.5 g, 6.454 mmol, 1 equiv) and 4-(4-bromo- IT/-pyrazol- 3-yl)pyridine (2.2 g, 9.681 mmol, 1.5 equiv) in pyridine (20 mL) was added molecular sieves 4A (2.2 g) and Cu(OAc)2 (820.3 mg, 12.908 mmol, 2 equiv) in portions at room temperature under an oxygen atmosphere. The resulting mixture was stirred at 100 °C under the oxygen atmosphere overnight. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (70:30) to afford tertbutyl 4-{4-[4-bromo-3-(pyridin-4-yl)pyrazol-l-yl]phenyl}piperidine-l-carboxylate (2 g, 64.10%) as a light yellow solid. LCMS: C24H2?BrN4O2 requires: 482.1, found: m/z = 483.1 [M+H]+.
[000293] Step-3: Synthesis of tert-butyl 4-]4-[4-(3-amino-2-fluorophenyl)-3- (pyridin-4-yl)pyrazol-l-yl]phenvnpiperidine-l-carboxylate (6)
To a mixture of tert-butyl 4-{4-[4-bromo-3-(pyridin-4-yl)pyrazol-l-yl]phenyl}piperidine-l- carboxylate (1.5 g, 3.103 mmol, 1 equiv) and 2-fhioro-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)aniline (1.5 g, 6.206 mmol, 2 equiv) in dioxane (15 mL) and H2O (1.5 mL) was added Pd(AMPHOS)2C12 (0.44 g, 0.621 mmol, 0.2 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 95 °C under the nitrogen atmosphere for 2 h. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (45:55) to afford tert-butyl 4-{4-[4- (3 -amino-2-fluorophenyl)-3 -(pyridin-4-yl)pyrazol- 1 -yl]phenyl (piperidine- 1 -carboxylate (1.0 g, 62.75%) as a yellow solid. LCMS: C30H32FN5O2 requires: 513.3, found: m/z = 514.3 [M+H]+. [000294] Step-4: Synthesis of tert-butyl 4-(4-]4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-3-(pyridin-4-yl)pyrazol-l-vnphenyl)piperidine-l-carboxylate (7)
To a mixture of tert-butyl 4-{4-[4-(3-amino-2-fluorophenyl)-3-(pyridin-4-yl)pyrazol-l- yl]phenyl}piperidine-l-carboxylate (1.5 g, 2.920 mmol, 1 equiv) and TEA (0.89 g, 8.760 mmol, 3 equiv) in DCM (15 mL) was added propane- 1 -sulfonyl chloride (0.62 g, 4.380 mmol, 1.5 equiv) dropwise at 0 °C. The resulting mixture was stirred at room temperature for one hour. The reaction was quenched with water at 0 °C. The resulting mixture was concentrated under vacuum. To the above mixture was added THF (10 mL), ACN (10 mL), and Na2CO3 (619.8 mg, 5.847 mmol, 2 equiv) in H2O (10 mL) at room temperature. The resulting mixture was stirred overnight at 60 °C. The resulting mixture was extracted with CH2CI2. The combined organic layers were washed with water and dried over anhydrous ISfeSCU After filtration, the filtrate was concentrated under reduced pressure. The residue product was purified by reverse phase flash chromatography with MeCN:H2O (60:40) to afford tert-butyl 4-(4-{4-[2-fhioro-3- (propane- 1 -sulfonamido)phenyl]-3 -(pyridin-4-yl)pyrazol- 1 -yl }phenyl)piperidine- 1 - carboxylate (1.0 g, 55.25%) as a yellow solid. LCMS: C33H38FN5O4S requires: 619.3, found: m/z = 620.3 [M+H]+.
[000295] Step-5: Synthesis of A-(2-fluoro-3-H-[4-(Diperidin-4-yl)Dhenyl]-3- (Dyridin-4-yl)Dyrazol-4- Dropane-l-sulfonamide hydrochloride
A mixture of tert-butyl 4-(4-{4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-3-(pyridin-4- yl)pyrazol-l-yl}phenyl)piperidine-l-carboxylate (1 g, 1.614 mmol, 1 equiv) and HC1 (gas) in 1,4-di oxane (20 mL, 4 N) was stirred at room temperature overnight. The resulting mixture was concentrated under vacuum. This resulted in 7V-(2-fluoro-3-{ l-[4-(piperidin-4-yl)phenyl]- 3-(pyridin-4-yl)pyrazol-4-yl}phenyl)propane-l-sulfonamide hydrochloride (576.8 mg, crude) as a yellow solid. LCMS: C28H30FN5O2S requires: 519.2, found: m/z = 520.2 [M+H]+. 'HNMR (400 MHz, CD3OD) 5 8.81 - 8.74 (m, 2H), 8.68 (s, 1H), 8.26 - 8.21 (m, 2H), 8.03 - 7.96 (m, 2H), 7.65 - 7.49 (m, 3H), 7.45 - 7.32 (m, 2H), 3.61 - 3.52 (m, 2H), 3.26 - 3.12 (m, 4H), 3.11 - 3.01 (m, 1H), 2.18 - 2.12 (m, 2H), 2.09 - 1.95 (m, 2H), 1.93 - 1.84 (m, 2H), 1.07 - 1.03 (m, 3H).
[000296] Synthesis of A-(2-fluoro-3-H-[4-(DiDerazin-l-yl)phenyl]-3-(Dyridin-4- yl)Dyrazol-4-yl}Dhenyl)DroDane-l-sulfonamide
[000297] Step-1: Synthesis of tert-butyl 4-I4-[4-bromo-3-(pyridin-4-yl)pyrazol-l- yllphenyllpiperazine-l-carboxylate (2)
To a mixture of tert-butyl 4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl]piperazine-l -carboxylate (1 g, 2.57 mmol, 1 equiv) in pyridine (10 mL) was added 4-(4-bromo-lJ/-pyrazol-3-yl)pyridine (865 mg, 3.86 mmol, 1.5 equiv), Cu(OAc)2 (1.87 g, 5.15 mmol, 2 equiv), and molecular sieves (4A) (865 mg) at room temperature under an oxygen atmosphere. The resulting mixture was stirred overnight at 100 °C under the oxygen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CFLCL MeOH (10: 1) to afford tertbutyl 4-{4-[4-bromo-3-(pyridin-4-yl)pyrazol-l-yl]phenyl}piperazine-l-carboxylate (500 mg, 32.07%) as a brown oil. MS (ESI) cak’d for ^IMrNsCh) [M+H]+, 484.1; found, 484.1.
[000298] Step-2: Synthesis of tert-butyl 4-I4-[4-(3-amino-2-fluorophenyl)-3- (pyridin-4-yl)pyrazol-l-yl]phenvnpiperazine-l-carboxylate (3)
To a mixture of tert-butyl 4-{4-[4-bromo-3-(pyridin-4-yl)pyrazol-l-yl]phenyl}piperazine-l- carboxylate (2 g, 4.12 mmol, 1 equiv) in dioxane (20 mL) and H2O (4 mL) was added 2-fluoro- 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (1.96 g, 8.25 mmol, 2 equiv), PdAMPHOS (584 mg, 0.86 mmol, 0.2 equiv), and CsF (1.25 g, 8.25 mmol, 2 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred 2 h at 95 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (6: 1) to afford tert-butyl 4-{4-[4-(3-amino- 2-fluorophenyl)-3-(pyridin-4-yl)pyrazol-l-yl]phenyl}piperazine-l-carboxylate (1.8 g, 76.25%) as a yellow solid. MS (ESI) cak’d for (C29H31FN6O2) [M+H]+, 515.3; found, 515.1. [000299] Step-3: Synthesis of tert-butyl 4-(4-I4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-3-(pyridin-4-yl)pyrazol-l-vnphenyl)piperazine-l-carboxylate (4)
To a mixture of tert-butyl 4-{4-[4-(3-amino-2-fluorophenyl)-3-(pyridin-4-yl)pyrazol-l- yl]phenyl}piperazine-l-carboxylate (1.8 g, 3.49 mmol, 1 equiv) and TEA (1.06 g, 10.49 mmol, 3 equiv) in DCM (20 mL) was added propane- 1 -sulfonyl chloride (748 mg, 5.24 mmol, 1.5 equiv) at 0 °C. The resulting mixture was stirred one hour at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was dissolved in THF (10 mL), MeCN (10 mL), and H2O (10 mL). Then ISfeCCL (2 g, 19.25 mmol, 10 equiv) was added at room temperature. The resulting mixture was stirred overnight at 50 °C. The resulting mixture was extracted with DCM. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CEEChiMeOH (10: 1) to afford tert-butyl 4-(4-{4-[2-fhioro-3-(propane-l- sulfonamido)phenyl]-3-(pyridin-4-yl)pyrazol-l-yl}phenyl)piperazine-l -carboxylate (1 g, 58.55%) as a yellow solid. MS (ESI) cak’d for (C32H37FN6O4S) [M+H]+, 621.3; found, 621.2. [000300] Step-4: Synthesis of A-(2-fluoro-3-H-[4-(piperazin-l-yl)phenyl]-3- (pyridin-4-yl)pyrazol-4-vnphenyl)propane-l-sulfonamide
A mixture of tert-butyl 4-(4-{4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-3-(pyridin-4- yl)pyrazol-l-yl}phenyl)piperazine-l-carboxylate (1 g, 1.61 mmol, 1 equiv) in HC1 in 1,4- dioxane (20 mL, 4 M) was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with H2O (0.5% NILHCChfMeCN (7: 1) to afford 7V-(2-fluoro-3-{ l-[4- (piperazin-l-yl)phenyl]-3-(pyridin-4-yl)pyrazol-4-yl}phenyl)propane-l-sulfonamide (514.7 mg, 60.69%) as a white solid. MS (ESI) cak’d for (C27H29FN6O2S) [M+H]+, 521.2; found, 521.2. 'H NMR (400 MHz, DMSO-tL) 8 8.66 (s, 1H), 8.54 - 8.52 (m, 2H), 7.79 - 7.77 (m, 2H), 7.47 - 7.42 (m, 3H), 7.30 - 7.23 (m, 2H), 7.09 - 7.07 (m, 2H), 6.20 (s, 1H), 3.15 - 3.12 (m, 4H), 3.01 - 2.97 (m, 2H), 2.89 - 2.81 (m, 4H), 1.72 - 1.63 (m, 2H), 0.95 - 0.89 (m, 3H).
[000301 ] Synthesis of 7V-(3-(2-(l-(2-(2.,7-diazaspiro[3.5]nonan-7-yl)acetyl)piperidin- 4-yl)-5-(2-aminopyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide
[000302] Step-1: Synthesis of prop-2-en-l-yl A-(3-12-[l-(2-chloroacetyl)piperidin-4- yl]-5-(2-chloropyrimidin-4-yl)-l.,3-thiazol-4-yn-2-fluorophenyl)carbamate (2)
To a mixture of prop-2-en-l-yl A-{3-[5-(2-chloropyrimidin-4-yl)-2-(piperidin-4-yl)-l,3- thiazol-4-yl]-2-fluorophenyl}carbamate (1000 mg, 2.110 mmol, 1 equiv) and TEA (640.53 mg, 6.330 mmol, 3.0 equiv) in DCM (5 mL) was added chloroacetyl chloride (238.3 mg, 2.110 mmol, 1.0 equiv) at 0 °C. The resulting mixture was stirred for 2 h at room temperature. The reaction was quenched with water/ice at room temperature. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CFECE MeOH (8: 1) to afford prop- 2-en-l-yl A-(3-{2-[l-(2-chloroacetyl)piperidin-4-yl]-5-(2-chloropyrimidin-4-yl)-l,3-thiazol- 4-yl }-2-fluorophenyl)carbamate (800 mg, 68.88%) as a yellow solid. LCMS: C24H22CI2FN5O3S requires: 549.1, found: m/z = 550.1[M+H]+.
[000303] Step-2: Synthesis of tert-butyl 7-(2-]4-[5-(2-chloroDyrimidin-4-yl)-4-(2- fluoro-3-[[(prop-2-en-l-yloxy)carbonyl]amino}phenyl)-l.,3-thiazol-2-yl]piperidin-l-vn- 2-oxoethyl)-2,7-diazaspiro [3.5] nonane-2-carboxylate (4)
To a mixture of prop-2-en-l-yl A-(3-{2-[l-(2-chloroacetyl)piperidin-4-yl]-5-(2- chloropyrimidin-4-yl)-l,3-thiazol-4-yl}-2-fluorophenyl)carbamate (1.5 g, 2.725 mmol, 1 equiv) and tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (0.31 g, 1.363 mmol, 0.5 equiv) in DMSO (10 mL) was added DIEA (1.06 g, 8.175 mmol, 3 equiv) at room temperature. The resulting mixture was stirred at 80 °C overnight. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CEECh EtOAc 2: 1) to afford tert-butyl 7-(2-{4-[5-(2-chloropyrimidin- 4-yl)-4-(2-fluoro-3-{[(prop-2-en-l-yloxy)carbonyl]amino}phenyl)-l,3-thiazol-2-yl]piperidin- l-yl}-2-oxoethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (700 mg, 34.70%) as a yellow solid. LCMS: C36H43CIFN7O5S requires: 739.3, found: m/z = 740.3[M+H]+.
[000304] Step-3: Synthesis of tert-butyl 7-(2-[4-[4-(3-amino-2-fluorophenyl)-5-(2- chloropyrimidin-4-yl)-l,3-thiazol-2-yl]piperidin-l-vn-2-oxoethyl)-2,7- diazaspiro [3.5] nonane-2-carboxylate (5)
To a mixture of tert-butyl 7-(2-{4-[5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-3-{[(prop-2-en-l- yloxy)carbonyl]amino}phenyl)-l,3-thiazol-2-yl]piperidin-l-yl}-2-oxoethyl)-2,7- diazaspiro[3.5]nonane-2-carboxylate (1.2 g, 1.621 mmol, 1 equiv) and Pd PPlr^Ch (0.02 g, 0.032 mmol, 0.02 equiv) in DCM (15 mL) was added HO Ac (0.24 g, 4.053 mmol, 2.5 equiv) at room temperature under a nitrogen atmosphere. To the above mixture was added w-BusSnH (0.75 g, 2.594 mmol, 1.6 equiv) at 0 °C. The resulting mixture was stirred for an additional 30 min at room temperature. The resulting mixture was extracted with CH2Q2. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2C12:MeOH (92:8) to afford tert-butyl 7-(2-{4-[4-(3-amino-2- fluorophenyl)-5-(2-chloropyrimidin-4-yl)-l,3-thiazol-2-yl]piperidin-l-yl}-2-oxoethyl)-2,7- diazaspiro[3.5]nonane-2-carboxylate (570 mg, 53.59%) as a yellow solid. LCMS: C32H39CIFN7O3S requires: 655.3, found: m/z = 656.3 [M+H]+. [000305] Step-4: Synthesis of tert-butyl 7-(2-]4-[5-(2-chloroDyrimidin-4-yl)-4-[2- fluoro-3-(propane-l-sulfonamido)phenyl]-l.,3-thiazol-2-yl]piperidin-l-vn-2-oxoethyl)- 2,7-diazaspiro [3.5] nonane-2-carboxylate (6)
To a mixture of tert-butyl 7-(2-{4-[4-(3-amino-2-fluorophenyl)-5-(2-chloropyrimidin-4-yl)-
1.3-thiazol-2-yl]piperidin-l-yl}-2-oxoethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (1.1 g, 1.676 mmol, 1 equiv) and TEA (508.88 mg, 5.028 mmol, 3 equiv) in DCM (11 mL) was added propane- 1 -sulfonyl chloride (358.55 mg, 2.514 mmol, 1.5 equiv) at 0 °C. The resulting mixture was stirred for one hour at room temperature. The resulting mixture was concentrated under reduced pressure. To the above mixture was added THF (10 mL), ACN (10 mL), and ISfeCCL (0.36 g, 3.352 mmol, 2 equiv) in H2O (10 mL) at room temperature. The resulting mixture was stirred overnight at 50 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CFECh MeOH (10: 1) to afford tert-butyl 7-(2-{4-[5-(2-chloropyrimidin-4-yl)-4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-l,3-thiazol-2-yl]piperidin-l-yl}-2-oxoethyl)-2,7-diazaspiro[3.5]nonane- 2-carboxylate (980 mg, 76.69%) as a yellow solid. LCMS: C35H45CIFN7O5S2 requires: 761.3, found: m/z = 762.3 [M+H]+.
[000306] Step-5: Synthesis of tert-butyl 7-[2-[4-(5-[2-[(tert- butoxycarbonyl)amino]pyrimidin-4-vn-4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-
1.3-thiazol-2-yl)piperidin-l-yl]-2-oxoethvn-2,7-diazaspiro[3.5]nonane-2-carboxylate (7)
To a mixture of tert-butyl 7-(2-{4-[5-(2-chloropyrimidin-4-yl)-4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-l,3-thiazol-2-yl]piperidin-l-yl}-2-oxoethyl)-2,7-diazaspiro[3.5]nonane- 2-carboxylate (900 mg, 1.181 mmol, 1 equiv) and tert-butyl carbamate (691.49 mg, 5.905 mmol, 5 equiv) in 1,4-dioxane (10 mL) was added BrettPhos Pd G3 (100.87 mg, 0.111 mmol, 0.094 equiv) and CS2CO3 (769.29 mg, 2.362 mmol, 2 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 80 °C under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with CFECh EtOAc (1 : 1) to afford tert-butyl 7- {2-[4-(5-{2-[(tert-butoxycarbonyl)amino]pyrimidin-4-yl}-4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-l,3-thiazol-2-yl)piperidin-l-yl]-2-oxoethyl}-2,7-diazaspiro[3.5]nonane- 2-carboxylate (500 mg, 50.24%) as a light yellow solid. LCMS: C40H55FN8O7S2 requires: 842.4, found: m/z = 843.4[M+H]+. [000307] Step-6: Synthesis of Az-13-[5-(2-aminopyrimidin-4-yl)-2-[l-(2-12.,7- diazaspiro[3.5]nonan-7-vnacetyl)piperidin-4-yl]-l.,3-thiazol-4-yl]-2- fluoroDhenynpropane-l-sulfonamide hydrochloride
To tert-butyl 7-{2-[4-(5-{2-[(tert-butoxycarbonyl)amino]pyrimidin-4-yl}-4-[2-fluoro-3- (propane-l-sulfonamido)phenyl]-l,3-thiazol-2-yl)piperidin-l-yl]-2-oxoethyl}-2,7- diazaspiro[3.5]nonane-2-carboxylate (500 mg, 0.593 mmol, 1 equiv) was added HC1 (gas) in 1,4-di oxane (10 mL, 4 N) at room temperature. The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated under vacuum. This resulted in 7V-{3-[5-(2-aminopyrimidin-4-yl)-2-[l-(2-{2,7-diazaspiro[3.5]nonan-7-yl}acetyl)piperidin-4- yl]-l,3-thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide hydrochloride salt (501.4 mg, crude) as a yellow solid. LCMS: C30H39FN8O3S2 requires: 642.3, found: m/z = 643.2[M+H]+. 'HNMR (400 MHz, CD3OD) 5 8.10 (d, J= 6.8 Hz, 1H), 7.70 - 7.67 (m, 1H), 7.51 - 7.44 (m, 1H), 7.43 - 7.33 (m, 1H), 6.66 - 6.60 (m, 1H), 4.63 - 4.57 (m, 1H), 4.50 - 4.27 (m, 2H), 4.08 (s, 2H), 3.96 (s, 2H), 3.90 - 3.86 (m, 1H), 3.65 - 3.58 (m, 2H), 3.55 - 3.44 (m, 1H), 3.42 - 3.35 (m, 1H), 3.31 - 3.20 (m, 2H), 3.19 - 3.13 (m, 2H), 3.05 - 3.00 (m, 1H), 2.44 - 2.35 (m, 2H), 2.33 - 2.23 (m, 2H), 2.25 - 2.10 (m, 2H), 2.06 - 1.94 (m, 1H), 1.90 - 1.82 (m, 3H), 1.07 - 1.04 (m, 3H).
[000308] Synthesis of Az-12-fluoro-3-[2-(piperidin-4-yl)-5-(pyrimidin-4-yl)-l.,3- thiazol-4-yl]phenynpropane-l-sulfonamide hydrochloride salt
[000309] Step-1: Synthesis o butyl 4-14-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-5-(pyrimidin-4-yl)-l.,3-thiazol-2-vnpiperidine-l-carboxylate (2) To a mixture of tert-butyl 4-[5-(2-chloropyrimidin-4-yl)-4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-l,3-thiazol-2-yl]piperidine-l-carboxylate (700 mg, 1.174 mmol, 1 equiv) and NH4OAC (905.14 mg, 11.740 mmol, 10 equiv) in MeOH (10 mL) was added Pd/C (700 mg) at room temperature. The resulting mixture was stirred for 30 min at 40 °C. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluted with CH3CN H2O (1 : 1) to afford tert-butyl 4-{4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-5-(pyrimidin-4-yl)-l,3-thiazol-2- yl}piperidine-l-carboxylate (450 mg, 68.23%) as a yellow solid. LCMS: C26H32FN5O4S2 requires: 561.2, found: m/z = 562.2 [M+H]+.
[000310] Step-2: Synthesis of 7V-f2-fluoro-3-[2-(DiDeridin-4-yl)-5-(Dyrimidin-4-yl)-
1.3-thiazol-4-yl]DhenynDroDane-l-sulfonamide hydrochloride
A mixture of tert-butyl 4-{4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-5-(pyrimidin-4-yl)-
1.3-thiazol-2-yl}piperidine-l-carboxylate (450 mg, 0.801 mmol, 1 equiv) in HC1 (gas) in 1,4- dioxane (5 mL, 4 N) was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure. This resulted in A-{2-fluoro-3-[2-(piperidin-4-yl)-5- (pyrimidin-4-yl)-l,3-thiazol-4-yl]phenyl}propane-l-sulfonamide hydrochloride salt (300.1 mg, crude) as a yellow solid. LCMS: C21H24FN5O2S2 requires: 461.1, found: m/z = 462.1 [M+H]+. ‘HNMR (400 MHz, CD3OD) 5 9.30 - 9.28 (m, 1H), 8.76 - 8.74 (m, 1H), 7.71 - 7.67 (m, 1H), 7.50 - 7.38 (m, 3H), 3.60 - 3.55 (m, 3H), 3.27 - 3.22 (m, 2H), 3.16 - 3.12 (m, 2H), 2.48 - 2.43 (m, 2H), 2.20 - 2.14 (m, 2H), 1.89 - 1.83 (m, 2H), 1.06 - 1.03 (m, 3H).
[000311 ] Synthesis of A-f2-fluoro-3-[2-(Diperidin-4-yl)-5-(Dyridin-4-yl)-l.,3-thiazol- 4-yllDhenvnDropane-l-sulfonamide
[000312] Step-1: Synthesis of 2-bromo-l-(2-fluoro-3-nitrophenyl)ethanone (2)
To a mixture of l-(2-fluoro-3-nitrophenyl)ethanone (2 g, 10.92 mmol, 1 equiv) in EtOAc (20 mL) was added copper (II) bromide (4.88 g, 21.84 mmol, 2 equiv) at room temperature. The resulting mixture was stirred overnight at 75 °C. The precipitated solids were filtered out. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (6: 1) to afford 2-bromo-l-(2-fluoro-3- nitrophenyl)ethanone (2 g, 61.50%) as a yellow oil. LCMS: CsEEBrFNCE requires: 260.9, found: m/z = 262.0 [M+H]+.
[000313] Step-2: Synthesis of tert-butyl 4-[4-(2-fluoro-3-nitrophenyl)-l.,3-thiazol-2- yl]piperidine-l-carboxylate (4)
To a mixture of 2-bromo-l-(2-fluoro-3-nitrophenyl)ethanone (2 g, 7.63 mmol, 1 equiv) in DMF (20 mL) was added tert-butyl 4-carbamothioylpiperidine-l -carboxylate (2.05 g, 8.39 mmol, 1.1 equiv) at room temperature. The resulting mixture was stirred for 5 h at room temperature. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (5: 1) to afford tert-butyl 4-[4-(2-fluoro-3 -nitrophenyl)- 1, 3 -thiazol-2- yl]piperidine-l -carboxylate (2 g, 57.88%) as a yellow oil. LCMS: C19H22FN3O4S requires: 407.1, found: m/z = 408.1 [M+H]+. [000314] Step-3: Synthesis of tert-butyl 4-[5-bromo-4-(2-fluoro-3-nitrophenyl)-l.,3- thiazol-2-yl]piperidine-l-carboxylate (5)
To a mixture of tert-butyl 4-[4-(2-fluoro-3-nitrophenyl)-l,3-thiazol-2-yl]piperidine-l- carboxylate (2 g, 4.90 mmol, 1 equiv) in DMF (20 mL) was added NBS (960 mg, 5.39 mmol, 1.1 equiv) at room temperature. The resulting mixture was stirred overnight at room temperature. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous ISfeSCU After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (3: 1) to afford tert-butyl 4-[5-bromo-4-(2-fluoro-3- nitrophenyl)-l,3-thiazol-2-yl]piperidine-l-carboxylate (1.2 g, 45.24%) as a yellow oil. LCMS: CigEEiBrFNsCUS requires: 485.0, found: m/z = 486.1 [M+H]+.
[000315] Step-4: Synthesis of tert-butyl 4-[4-(3-amino-2-fluorophenyl)-5-bromo-l.,3- thiazol-2-vHpiperidine-l-carboxylate (6)
To a mixture of tert-butyl 4-[5-bromo-4-(2-fluoro-3-nitrophenyl)-l,3-thiazol-2-yl]piperidine- 1-carboxylate (1 g, 2.05 mmol, 1 equiv) in saturated aqueous NH4CI (10 mL) and MeOH (2 mL) was added Fe (114 mg, 2.05 mmol, 5 equiv) at room temperature. The resulting mixture was stirred for 2 h at 70 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CEEChiMeOH (10: 1) to afford tert-butyl 4-[4-(3-amino-2-fluorophenyl)-5-bromo-l,3-thiazol-2-yl]piperidine- 1-carboxylate (500 mg, 46.89%) as a yellow oil. LCMS: CigEEsBrFNsCLS requires: 455.0, found: m/z = 456.1 [M+H]+.
[000316] Step-5: Synthesis of tert-butyl 4-(5-bromo-4-(2-fluoro-3-
(propylsulfonamido)phenyl)thiazol-2-yl)piperidine-l-carboxylate (7)
To a mixture of tert-butyl 4-[4-(3-amino-2-fluorophenyl)-5-bromo-l,3-thiazol-2- yl]piperidine-l -carboxylate (1.2 g, 2.62 mmol, 1 equiv) in DCM (12 mL) was added TEA (798 mg, 7.88 mmol, 3 equiv) and propane- 1 -sulfonyl chloride (749 mg, 5.25 mmol, 2 equiv) at 0 °C. The resulting mixture was stirred for one hour at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was disolved in THF (5 mL), H2O (5 mL), and MeCN (5 mL). ISfeCCL (1.13 g, 10.68 mmol, 5 equiv) was added at room temperature. The resulting mixture was stirred overnight at 50 °C. The resulting mixture was concentrated under vacuum. The residue was extracted with DCM. The combined organic layers were washed with water and dried over anhydrous ISfeSCU After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with DCM:MeOH (10: 1) to afford tert-butyl 4-(5-bromo-4-(2-fluoro- 3-(propylsulfonamido)phenyl)thiazol-2-yl)piperidine-l-carboxylate_(l g, 56.88%) as a brown solid. LCMS: C22H29BrFN3O4S2 requires: 561.1, found: m/z = 562.1 [M+H]+.
[000317] Step-6: Synthesis of tert-butyl 4-]4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-5-(pyridin-4-yl)-l.,3-thiazol-2-vnpiperidine-l-carboxylate (9)
To a mixture of tert-butyl 4-{5-bromo-4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-l,3- thiazol-2-yl}piperidine-l-carboxylate (1 g, 1.77 mmol, 1 equiv) and pyridin-4-yl boronic acid (218 mg, 1.77 mmol, 1 equiv) in dioxane (10 mL) and H2O (1 mL) was added Pd(dppf)C12 (130 mg, 0.17 mmol, 0.1 equiv) and K2CO3 (491 mg, 3.55 mmol, 2 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 2 h at 80 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (3: 1) to afford tert-butyl 4-{4-[2-fluoro-3- (propane-l-sulfonamido)phenyl]-5-(pyridin-4-yl)-l,3-thiazol-2-yl}piperidine-l-carboxylate (500 mg, 40.13%) as a yellow solid. LCMS: C27H33FN4O4S2 requires: 560.2, found: m/z = 561.2 [M+H]+.
[000318] Step-7: Synthesis of A-]2-fluoro-3-[2-(piperidin-4-yl)-5-(pyridin-4-yl)-l.,3- thiazol-4-vHphenvnpropane-l-sulfonamide
A mixture of tert-butyl 4-{4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-5-(pyridin-4-yl)- l,3-thiazol-2-yl}piperidine-l-carboxylate (600 mg, 1.07 mmol, 1 equiv) in HCl/l,4-di oxane (5 mL, 4 M) was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product (500 mg) was purified by Prep-HPLC with the following conditions Column: XBridge Prep OBD C18 Column, 30*150 mm, 5pm; Mobile Phase A: water (10 mmol/L NH4HCO3); Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 20% B to 30% B in 10 min; Wave Length: 254 nm; Rn (min): 8.6 to afford N-{2- fluoro-3 -[2-(piperidin-4-yl)-5-(pyridin-4-yl)- 1 ,3 -thiazol-4-yl]phenyl (propane- 1 -sulfonamide (324.8 mg, 65.77%) as a white solid. LCMS: C22H25FN4O2S2 requires: 460.1, found: m/z = 461.1 [M+H]+. ‘H NMR (400 MHz, CD3OD) 5 8.45 - 8.44 (m, 2H), 7.61 - 7.57 (m, 1H), 7.35 - 7.23 (m, 4H), 3.29 - 3.19 (m, 3H), 2.95 - 2.91 (m, 2H), 2.86 - 2.79 (m, 2H), 2.21 - 2.18 (m, 2H), 1.86 - 1.62 (m, 4H), 0.98 - 0.94 (m, 3H).
[000319] Synthesis of 7V-]3-[5-(2-aminopyrimidin-4-yl)-2-[4-(piperidin-4-yl)phenyl]- l,3-thiazol-4-yl]-2-fluorophenvnpropane-l-sulfonamide
[000320] Step-1: Synthesis of tert-butyl 4-(4-carbamoylDhenyl)Diperidine-l- carboxylate (2)
To a mixture of 4-[l-(tert-butoxycarbonyl)piperidin-4-yl]benzoic acid (5 g, 16.37 mmol, 1 equiv) and NH4CI (4.37 g, 81.86 mmol, 5 equiv) in DMF (50 mL) was added HATU (9.33 g, 24.55 mmol, 1.5 equiv) and DIEA (6.34 g, 49.11 mmol, 3 equiv) at room temperature. The resulting mixture was stirred for one hour at room temperature. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The product was washed with EtOAc. The precipitated solids were collected by filtration to afford terLbutyl 4-(4-carbamoylphenyl)piperidine-l -carboxylate (4.8 g, 96.31%) as a white solid. LCMS: C17H24N2O3 requires: 304.2, found: m/z = 305.2 [M+H]+.
[000321 ] Step-2: Synthesis of te -butyl 4-(4-carbamothioylphenyl)piperidine-l- carboxylate (3)
To a mixture of tert-butyl 4-(4-carbamoylphenyl)piperidine-l -carboxylate (3 g, 9.85 mmol, 1 equiv) in THF (30 mL) were added Lawesson’ s Reagent (1.99 g, 4.92 mmol, 0.5 equiv) at room temperature. The resulting mixture was stirred overnight at 50 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with aqueous NaHCCh and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CEECh EtOAc (4: 1) to afford tert-butyl 4-(4-carbamothioylphenyl)piperidine-l -carboxylate (2.2 g, 69.66%) as a white solid. LCMS: C17H24N2O2S requires: 320.1, found: m/z = 321.2 [M+H]+.
[000322] Step-3: Synthesis of tert-butyl 4-]4-[5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-
3-f[(prop-2-en-l-yloxy)carbonyl]amino}phenyl)-l.,3-thiazol-2-yl]phenvnpiperidine-l- carboxylate (5)
To a mixture of prop-2-en-l-yl A-{3-[2-(2-chloropyrimidin-4-yl)acetyl]-2- fluorophenyl} carbamate (1.8 g, 5.14 mmol, 1 equiv) in DMA (20 mL) was added tert-butyl 4- (4-carbamothioylphenyl)piperidine-l -carboxylate (1.98 g, 6.17 mmol, 1.2 equiv) and NBS (1.83 g, 10.29 mmol, 2 equiv) at room temperature. The resulting mixture was stirred for 2 h at 60 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (5: 1) to afford tert-butyl 4-{4-[5-(2-chloropyrimidin-
4-yl)-4-(2-fluoro-3-{[(prop-2-en-l-yloxy)carbonyl]amino}phenyl)-l,3-thiazol-2- yl]phenyl}piperidine-l-carboxylate (1.8 g, 48.95%) as a yellow solid. LCMS: C33H33CIFN5O4S requires: 649.2, found: m/z = 650.2 [M+H]+.
[000323] Step-4: Synthesis of tert-butyl 4-]4-[4-(3-amino-2-fluorophenyl)-5-(2- chloropyrimidin-4-yl)- 1.,3-thiazol-2-yl] phenyl] piperidine- 1-carboxylate (6)
To a mixture of tert-butyl 4-{4-[5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-3-{[(prop-2-en-l- yloxy)carbonyl]amino}phenyl)-l,3-thiazol-2-yl]phenyl}piperidine-l-carboxylate (1.8 g, 2.76 mmol, 1 equiv) and HOAc (415 mg, 6.93 mmol, 2.5 equiv) in DCM (20 mL) was added n- BusSnH (1.29 g, 4.43 mmol, 1.6 equiv) and Pd(PPh3)2C12 (39 mg, 0.05 mmol, 0.02 equiv) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred for 30 min at room temperature. The reaction was quenched with saturated aqueous NaHCCL at 0 °C. The resulting mixture was extracted with CH2Q2. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford tert-butyl 4-{4-[4-(3-amino-2-fluorophenyl)-5-(2-chloropyrimidin-4-yl)-
1.3-thiazol-2-yl]phenyl}piperidine-l-carboxylate (1.5 g, crude) as a brown solid. LCMS: C29H29CIFN5O2S requires: 565.2, found: m/z = 566.2 [M+H]+.
[000324] Step-5: Synthesis of tert-butyl 4-(4-(5-(2-chloropyrimidin-4-yl)-4-(2-fluoro- 3-(propylsulfonamido)phenyl)thiazol-2-yl)phenyl)piperidine-l-carboxylate (7)
To a mixture of tert-butyl 4-{4-[4-(3-amino-2-fluorophenyl)-5-(2-chloropyrimidin-4-yl)-l,3- thiazol-2-yl]phenyl}piperidine-l-carboxylate (1.5 g, 2.65 mmol, 1 equiv) in DCM (15 mL) was added propane- 1 -sulfonyl chloride (755 mg, 5.30 mmol, 2 equiv) and TEA (804 mg, 7.95 mmol, 3 equiv) at 0 °C. The resulting mixture was stirred for one hour at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was dissolved in THF (5 mL), H2O (5 mL), and MeCN (5 mL). Na2COs (1.13 g, 10.68 mmol, 5 equiv) was added at room temperature. The resulting mixture was stirred overnight at 50 °C. The resulting mixture was concentrated under vacuum. The residue was extracted with DCM. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with DCM:MeOH (10: 1) to afford tert-butyl 4-(4-(5-(2- chloropyrimidin-4-yl)-4-(2-fluoro-3-(propylsulfonamido)phenyl)thiazol-2- yl)phenyl)piperidine-l -carboxylate (1.1 g, 73.77%) as a yellow solid. LCMS: C32H35CIFN5O4S2 requires: 671.2, found: m/z = 672.2 [M+H]+.
[000325] Step-6: Synthesis of tert-butyl 4-[4-(5-12-[(tert- butoxycarbonyl)amino]pyrimidin-4-vn-4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-
1.3-thiazol-2-yl)phenyl]piperidine-l-carboxylate (8)
To a mixture of tert-butyl 4-{4-[5-(2-chloropyrimidin-4-yl)-4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-l,3-thiazol-2-yl]phenyl}piperidine-l-carboxylate (600 mg, 0.89 mmol, 1 equiv) and tert-butyl carbamate (522.80 mg, 4.465 mmol, 5 equiv) in dioxane (6 mL) was added BrettPhos Pd G3 (81 mg, 0.089 mmol, 0.1 equiv) and CS2CO3 (581 mg, 1.78 mmol, 2 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 2 h at 80 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EtOAc (1 : 1) to afford tert-butyl 4-[4-(5-{2-[(tert-butoxycarbonyl)amino]pyrimidin-4-yl}-4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-l,3-thiazol-2-yl)phenyl]piperidine-l-carboxylate (400 mg, 53.57%) as a yellow solid. LCMS: C37H45FN6O6S2 requires: 752.2, found: m/z = 753.3 [M+H]+.
[000326] Step-7: Synthesis of 7V-f3-[5-(2-aminoDyrimidin-4-yl)-2-[4-(DiDeridin-4- Yl)phenyl]-l.,3-thiazol-4-yl]-2-fluoroDhenynDroDane-l-sulfonamide
A mixture of tert-butyl 4-[4-(5-{2-[(terZ-butoxycarbonyl)amino]pyrimidin-4-yl}-4-[2-fluoro- 3-(propane-l-sulfonamido)phenyl]-l,3-thiazol-2-yl)phenyl]piperidine-l -carboxylate (400 mg, 0.53 mmol, 1 equiv) in HCl/l,4-di oxane (5 mL, 4 M) was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 pm; Mobile Phase A: water (10 mmol/L NH4HCO3); Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 38% B in 8 min; Wave Length: 220/254 nm; Rti (min): 6.75 to afford A-{3-[5-(2-aminopyrimidin-4-yl)-2-[4-(piperidin-4-yl)phenyl]-l,3- thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide (223.7 mg, 70.01%) as a yellow solid. LCMS: C27H29FN6O2S2 requires: 552.2, found: m/z = 553.2 [M+H]+.
'H NMR (400 MHz, DMSO4) 8 8.15 - 8.06 (m, 1H), 7.98 - 7.93 (m, 2H), 7.56 - 7.52 (m, 1 H), 7.40 - 7.37 (m, 2H), 7.24 - 7.16 (m, 2H), 6.79 (s, 2H), 6.18 - 6.16 (m, 1H), 3.21 - 3.12 (m, 2H), 2.97 - 2.93 (m, 2H), 2.77 - 2.69 (m, 3H), 1.80 - 1.71 (m, 2H), 1.69 - 1.57 (m, 4H), 0.94 - 0.90 (m, 3H).
[000327] Synthesis of A-(2-fluoro-3-f5-[2-(methylamino)pyrimidin-4-yl]-2- (piperidin-4-yl)-l.,3-thiazol-4- DroDane-l-sulfonaniide hydrochloride salt [000328] Step-1: Synthesis of tert-butyl 4-]4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-5-[2-(methylamino)pyrimidin-4-yl]-l.,3-thiazol-2-vnpiperidine-l- carboxylate (2)
To a mixture of tert-butyl 4-[5-(2-chloropyrimidin-4-yl)-4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-l,3-thiazol-2-yl]piperidine-l-carboxylate (300 mg, 0.503 mmol, 1 equiv) and CH3NH2 HCI (101.9 mg, 1.509 mmol, 3 equiv) in DMSO (3 mL) was added DIEA (195.1 mg, 1.509 mmol, 3 equiv) at room temperature. The resulting mixture was stirred at 80 °C overnight. The residue was purified by reverse phase column chromatography eluted with CHsCbbEEO (1 : 1) to afford tert-butyl 4-{4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-5-[2- (methylamino)pyrimidin-4-yl]-l,3-thiazol-2-yl}piperidine-l-carboxylate (280 mg, 94.19%) as a light yellow solid. LCMS: C27H35FN6O4S2 requires: 590.2, found: m/z = 591.3. [M+H]+.
[000329] Step-2: Synthesis of A-(2-fluoro-3-]5-[2-(methylamino)pyrimidin-4-yl]-2- (piperidin-4-yl)-l.,3-thiazol-4-vnphenyl)propane-l-sulfonamide hydrochloride
To a mixture of tert-butyl 4-{4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-5-[2- (methylamino)pyrimidin-4-yl]-l,3-thiazol-2-yl}piperidine-l-carboxylate (280 mg, 0.474 mmol, 1 equiv) in DCM (3 mL) was added HC1 (gas) in 1,4-di oxane (3 mL, 4 N) at room temperature. The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure. This resulted in 7V-(2-fluoro-3-{5-[2- (m ethyl amino)pyrimidin-4-yl]-2-(piperidin-4-yl)- 1 ,3 -thiazol-4-yl }phenyl)propane- 1 - sulfonamide hydrochloride salt (174.0 mg, crude) as a yellow solid. LCMS: C22H27FN6O2S2 requires: 490.2, found: m/z = 491.2. [M+H]+.
'HNMR (400 MHz, CD3OD) 5 8.14 (s, 1H), 7.72 - 7.62 (m, 1H), 7.49 - 7.43 (m, 1H), 7.42 - 7.35 (m, 1H), 6.72 (s, 1H), 3.72 - 3.49 (m, 3H), 3.31 - 3.20 (m, 2H), 3.20 - 3.12 (m, 2H), 2.98 (s, 3H), 2.51 - 2.36 (m, 2H), 2.26 - 2.05 (m, 2H), 1.98 - 1.76 (m, 2H), 1.16 - 1.00 (m, 3H).
[000330] Synthesis of A-]2-fluoro-3-[5-(2-][ -l-hvdroxypropan-2- yl]amino}pyrimidin-4-yl)-2-(piperidin-4-yl)-l.,3-thiazol-4-yl]phenvnpropane-l- sulfonamide hydrochloride salt
[000331 ] Step-1: Synthesis of tert-butyl 4-14-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-5-(2-l -l-hvdroxypropan-2-yl]amino}pyrimidin-4-yl)-l.,3- thiazol-2-yl}piperidine-l-carboxylate (2)
To a mixture of tert-butyl 4-[5-(2-chloropyrimidin-4-yl)-4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-l,3-thiazol-2-yl]piperidine-l-carboxylate (300 mg, 0.503 mmol, 1 equiv) in EtOH (2 mL) was added (A)-(-)-2-amino-l -propanol (113 mg, 1.509 mmol, 3 equiv) at room temperature. The resulting mixture was stirred overnight at 70 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with FEO MeCN (3: 1) to afford tert-butyl 4-{4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-5-(2-{[(2A)-l-hydroxypropan-2-yl]amino}pyrimidin-4-yl)-l,3-thiazol- 2-yl (piperidine- 1 -carboxylate (210 mg, 62.45%) as a yellow solid. LCMS: C29H39FN6O5S2 requires: 634.2, found: m/z = 635.3 [M+H]+.
[000332] Step-2: Synthesis of A-12-fluoro-3-[5-(2-ll(21?)-l-hvdroxypropan-2- yl]amino}pyrimidin-4-yl)-2-(piperidin-4-yl)-l.,3-thiazol-4-yl]phenvnpropane-l- sulfonamide hydrochloride
A mixture of tert-butyl 4-{4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-5-(2-{[(2A)-l- hydroxypropan-2-yl]amino}pyrimidin-4-yl)-l,3-thiazol-2-yl}piperidine-l-carboxylate (210 mg, 0.331 mmol, 1 equiv) in HCl/l,4-di oxane (10 mL, 4 M) was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure to afford N-{2- fhioro-3-[5-(2-{[(2A)-l-hydroxypropan-2-yl]amino}pyrimidin-4-yl)-2-(piperidin-4-yl)-l,3- thiazol-4-yl]phenyl}propane-l-sulfonamide hydrochloride salt (150.4 mg, crude) as a yellow solid. LCMS: C24H31FN6O3S2 requires: 534.2, found: m/z = 535.2 [M+H]+. 'H NMR (400 MHz, CD3OD) 5 8.14 (s, 1H), 7.80 - 7.69 (m, 1H), 7.47 - 7.40 (m, 1H), 7.38 - 7.30 (m, 1H), 6.71 (s, 1H), 4.05 (s, 1H), 3.83 - 3.45 (m, 5H), 3.33 - 3.24 (m, 2H), 3.22 - 3.15 (m, 2H), 2.46 - 2.43 (m, 2H), 2.21 - 2.14 (m, 2H), 1.90 - 1.84 (m, 2H), 1.28 - 1.21 (m, 3H), 1.08 - 1.04 (m, 3H).
[000333] Synthesis of A-12-fluoro-3-[2-methyl-5-(2-l[4-(piperidin-4- yl)phenyl]amino}pyrimidin-4-yl)-l.,3-thiazol-4-yl]phenvnpropane-l-sulfonaniide hydrochloride salt
[000334] Step-1: Synthesis of prop-Z-en-l-yl 7V-13-[5-(2-chloropyrimidin-4-yl)-2- methyl-l.,3-thiazol-4-yl]-2-fluorophenyncarbamate (1)
To a mixture of prop-2-en-l-yl A-{3-[2-(2-chloropyrimidin-4-yl)acetyl]-2- fluorophenyl} carbamate (2 g, 5.718 mmol, 1 equiv) in DMA (10 mL) was added NBS (1.02 g, 5.731 mmol, 1 equiv) and the mixture was stirred for 15 min. Then, thioacetamide (516 mg, 6.862 mmol, 1.2 equiv) was added. The resulting mixture was stirred at 60 °C for 2 h. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 :2) to afford prop-2-en-l-yl N-{3-[5-(2-chloropyrimidin-4-yl)-2-methyl-l,3- thiazol-4-yl]-2-fluorophenyl}carbamate (1 g, 35.42%) as a yellow solid. LCMS: C18H14CIFN4O2S requires: 404.1, found: m/z = 405.1 [M+H]+.
[000335] Step-2: Synthesis of 3-[5-(2-chloropyrimidin-4-yl)-2-methyl-l.,3-thiazol-4- yl]-2-fluoroaniline (2)
To a mixture of prop-2-en-l-yl N-{3-[5-(2-chloropyrimidin-4-yl)-2-methyl-l,3-thiazol-4-yl]- 2-fluorophenyl} carbamate (1 g, 2.47 mmol, 1 equiv) in DCM (10 mL) was added HOAc (356 mg, 5.928 mmol, 2.4 equiv) and Pd(PPh3)2C12 (34.68 mg, 0.049 mmol, 0.02 equiv). Then, n- BusSnH (1.08 g, 3.705 mmol, 1.5 equiv) was added at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for one hour. The reaction was quenched with saturated aqueous NaHCCL at 0 °C. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 : 1) to afford 3-[5-(2-chloropyrimidin-4-yl)-2-methyl-l,3-thiazol-4-yl]-2-fluoroaniline (700 mg, 79.51%) as a yellow solid. LCMS: C14H10CIFN4S requires: 320.0, found: m/z = 321.0 [M+H]+.
[000336] Step-3: Synthesis of \-!3-|5-(2-cliloropyriiiiidiii-4-yl)-2-iiietliyl-1.3-thiazol- 4-yl]-2-fluorophenvnpropane-l-sulfonamide
To a mixture of 3-[5-(2-chloropyrimidin-4-yl)-2-methyl-l,3-thiazol-4-yl]-2-fluoroaniline (150 mg, 0.468 mmol, 1 equiv) and TEA (142 mg, 1.404 mmol, 3 equiv) in DCM (10 mL) was added propane- 1 -sulfonyl chloride (200 mg, 1.404 mmol, 3 equiv) at 0 °C. The resulting mixture was stirred at room temperature for one hour. The resulting mixture was concentrated under vacuum. To the above mixture was added THF (5 mL), ACN (5 mL), and Na2COs (743 mg, 7.02 mmol, 15 equiv) in H2O (5 mL). The resulting mixture was stirred at 50 °C overnight. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase flash chromatography eluted with ACbFEhO (1 : 1) to afford A-{3-[5-(2-chloropyrimidin- 4-yl)-2-methyl-l,3-thiazol-4-yl]-2-fhiorophenyl}propane-l-sulfonamide (113.4 mg, 56.63%) as a light yellow solid. LCMS: C17H16CIFN4O2S2 requires: 426.0, found: m/z = 427.0 [M+H]+. 'H NMR (400 MHz, CD3OD) 5 8.48 (d, J= 5.2 Hz, 1H), 7.76 - 7.63 (m, 1H), 7.50 - 7.30 (m, 2H), 7.15 - 7.02 (m, 1H), 3.19 - 3.07 (m, 2H), 2.81 (s, 3H), 1.93 - 1.74 (m, 2H), 1.13 - 0.94 (m, 3H).
[000337] Step-4: Synthesis of tert-butyl 4-]4-[(4-]4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-2-methyl-l.,3-thiazol-5-vnpyriniidin-2- yl)amino]phenvnpiperidine-l-carboxylate (4) To a mixture of A-{3-[5-(2-chloropyrimidin-4-yl)-2-methyl-l,3-thiazol-4-yl]-2- fluorophenyl} propane- 1 -sulfonamide (500 mg, 1.171 mmol, 1 equiv) and tert-butyl 4-(4- aminophenyl)piperidine-l -carboxylate (647 mg, 2.342 mmol, 2 equiv) in 1,4-dioxane (10 mL) was added CS2CO3 (763 mg, 2.342 mmol, 2 equiv) and BrettPhos Pd G3 (106 mg, 0.117 mmol, 0.1 equiv). The resulting mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 : 1) to afford tert-butyl 4-{4-[(4-{4-[2-fluoro- 3 -(propane- 1 -sulfonamido)phenyl]-2-methyl- 1 ,3-thiazol-5-yl}pyrimidin-2- yl)amino]phenyl (piperidine- 1 -carboxylate (500 mg, 57.62%) as a yellow solid. LCMS: C33H39FN6O4S2 requires: 666.3, found: m/z = 667.3 [M+H]+.
[000338] Step-5: Synthesis of A-]2-fluoro-3-[2-methyl-5-(2-][4-(Diperidin-4- yl)Dhenyl]amino}Dyrimidin-4-yl)-l.,3-thiazol-4-yl]DhenynDroDane-l-sulfonamide hydrochloride
To a mixture of tert-butyl 4-{4-[(4-{4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-2-methyl-
1.3-thiazol-5-yl(pyrimidin-2-yl)amino]phenyl(piperidine-l-carboxylate (1.0 g, 1.5 mmol, 1 equiv) in DCM (10 mL) was added HC1 (gas) in 1,4-dioxane (5 mL, 4 N) at 0 °C. The resulting mixture was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase flash chromatography eluted with ACbTEhO (1 : 1) to afford A-{2-fhioro-3-[2-methyl-5-(2-{[4-(piperidin-4- yl)phenyl]amino(pyrimidin-4-yl)-l,3-thiazol-4-yl]phenyl(propane-l-sulfonamide hydrochloride salt (561.3 mg, 61.12%) as a yellow solid. LCMS: C28H31FN6O2S2 requires: 566.2, found: m/z = 567.2 [M+H]+. 'H NMR (400 MHz, CD3COOD) 5 8.24 (d, J= 5.6 Hz, 1H), 7.82 - 7.70 (m, 1H), 7.68 - 7.59 (m, 2H), 7.56 - 7.46 (m, 1H), 7.44 - 7.34 (m, 1H), 7.32 - 7.20 (m, 2H), 6.62 (d, J= 5.6 Hz, 1H), 3.77 - 3.63 (m, 2H), 3.34 - 3.16 (m, 2H), 3.14 - 3.00 (m, 2H), 2.87 (s, 4H), 2.11 (s, 4H), 1.87 - 1.72 (m, 2H), 1.07 - 0.94 (m, 3H).
[000339] Synthesis of A-]3-[5-(2-aminoDyrimidin-4-yl)-2-[2-(Diperidin-4-yl)ethyl]-
1.3-thiazol-4-yl]-2-fluoroDhenvnDroDane-l-sulfonamide hydrochloride salt
[000340] Step-1: Synthesis of tert-butyl 4-(2-carbamoylethyl)piperidine-l- carboxylate (2)
To a mixture of 3-[l-(tert-butoxycarbonyl)piperidin-4-yl]propanoic acid (5.0 g, 19.430 mmol, 1 equiv), HATU (11.08 g, 29.145 mmol, 1.5 equiv), and NH4CI (5.19 g, 97.150 mmol, 5.0 equiv) in DMF (50 mL) was added DIEA (7.53 g, 58.290 mmol, 3.0 equiv) dropwise at room temperature. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (2: 1) to afford tert-butyl 4-(2-carbamoylethyl)piperidine-l -carboxylate (3.2 g, 64.25%) as a white solid. LCMS: C13H24N2O3 requires: 256.2, found: m/z = 257.2 [M+H]+.
[000341 ] Step-2: Synthesis of tert-butyl 4-(2-carbamothioylethyl)piperidine-l- carboxylate (3) To a mixture of tert-butyl 4-(2-carbamoylethyl)piperidine-l -carboxylate (3.0 g, 11.703 mmol, 1 equiv) in THF (30 mL) was added Lawesson’s Reagent (2.36 g, 5.851 mmol, 0.5 equiv). The resulting mixture was stirred for at 50 °C overnight. The reaction was quenched by the addition of saturated aqueous sodium hyposulfite at 0 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CFLCL MeOH (1 : 1) to afford tertbutyl 4-(2-carbamothioylethyl)piperidine-l -carboxylate (1.5 g, 47.05%) as a white solid. LCMS: C13H24N2O2S requires: 272.2, found: m/z = 273.2 [M+H]+.
[000342] Step-3: Synthesis of tert-butyl 4-f2-[5-(2-chloropyrimidin-4-yl)-4-(2-fluoro- 3-f[(prop-2-en-l-yloxy)carbonyl]amino}phenyl)-l.,3-thiazol-2-yl]ethvnpiperidine-l- carboxylate (5)
To a mixture of prop-2-en-l-yl A-{3-[2-(2-chloropyrimidin-4-yl)acetyl]-2- fluorophenyl] carbamate (1.92 g, 5.506 mmol, 1.00 equiv) in DMA (15 mL) was added NBS (980.06 mg, 5.506 mmol, 1.0 equiv) for 15 min at room temperature followed by the addition of tert-butyl 4-(2-carbamothioylethyl)piperidine-l-carboxylate (1.5g, 5.506 mmol, 1.00 equiv) at room temperature. The resulting mixture was stirred for 2 h at 60 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CEECh MeOH (6: 1) to afford tert-butyl 4-{2-[5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-3-{[(prop-2-en-l- yloxy)carbonyl]amino}phenyl)-l,3-thiazol-2-yl]ethyl}piperidine-l-carboxylate (1.2 g, 36.19%) as a white solid. LCMS: C29H33CIFN5O4S requires: 601.2, found: m/z = 602.2 [M+H]+.
[000343] Step-4: Synthesis of tert-butyl 4-f2-[4-(3-amino-2-fluorophenyl)-5-(2- chloropyrimidin-4-yl)-l.,3-thiazol-2-yl]ethvnpiperidine-l-carboxylate (6)
To a mixture of tert-butyl 4-{2-[5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-3-{[(prop-2-en-l- yloxy)carbonyl]amino}phenyl)-l,3-thiazol-2-yl]ethyl}piperidine-l-carboxylate (1.2 g, 1.993 mmol, 1 equiv) and HOAc (0.30 g, 4.982 mmol, 2.5 equiv) in DCM (12 mL) was added n- BusSnH (0.93 g, 3.189 mmol, 1.6 equiv) and Pd PPtr^Ch (27.98 mg, 0.040 mmol, 0.02 equiv) at room temperature. The resulting mixture was stirred for 0.5 h at room temperature under a nitrogen atmosphere. The resulting mixture was extracted with DCM. The combined organic layers were washed with water and dried over anhydrous ISfeSC After filtration, the filtrate was concentrated under reduced pressure to afford tert-butyl 4-{2-[4-(3-amino-2- fluorophenyl)-5-(2-chloropyrimidin-4-yl)-l,3-thiazol-2-yl]ethyl}piperidine-l-carboxylate (800 mg, crude) as a yellow oil. The crude product was used in the next step directly without further purification. LCMS: C25H29CIFN5O2S requires: 517.2, found: m/z = 518.2 [M+H]+.
[000344] Step-5: Synthesis of tert-butyl 4-f2-[5-(2-chloropyrimidin-4-yl)-4-[2-fluoro- 3-(propane-l-sulfonamido)phenyl]-l.,3-thiazol-2-yl]ethvnpiperidine-l-carboxylate (7)
To a mixture of tert-butyl 4-{2-[4-(3-amino-2-fluorophenyl)-5-(2-chloropyrimidin-4-yl)-l,3- thiazol-2-yl]ethyl]piperidine-l-carboxylate (800 mg, 1.544 mmol, 1 equiv) and TEA (468.80 mg, 4.632 mmol, 3.0 equiv) in DCM (10 mL) was added propane- 1 -sulfonyl chloride (440.42 mg, 3.088 mmol, 2.0 equiv) at room temperature. The resulting mixture was stirred for one hour at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was dissolved in THF (3 mL), ACN (3 mL), and H2O (3 mL). ISfeCCL (799.92 mg, 7.545 mmol, 6.89 equiv) was added at room temperature. The resulting mixture was stirred at 50 °C overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CFECh MeOH (10: 1) to afford tert-butyl 4-{2-[5-(2-chloropyrimidin-4-yl)-4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]- l,3-thiazol-2-yl]ethyl}piperidine-l-carboxylate (680 mg, 85.00%) as a yellow solid. LCMS: C28H35CIFN5O4S2 requires: 623.2, found: m/z = 624.2 [M+H]+.
[000345] Step-6: Synthesis of tert-butyl 4-f2-[5-(2-chloropyrimidin-4-yl)-4-(2-fluoro- 3-f[(prop-2-en-l-yloxy)carbonyl]amino}phenyl)-l.,3-thiazol-2-yl]ethvnpiperidine-l- carboxylate (8)
To a mixture of tert-butyl 4-{2-[5-(2-chloropyrimidin-4-yl)-4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-l,3-thiazol-2-yl]ethyl}piperidine-l-carboxylate (660 mg, 1.057 mmol, 1 equiv) and tert-butyl carbamate (619.34 mg, 5.285 mmol, 5.0 equiv) in 1,4-di oxane (7 mL) was added CS2CO3 (689.02 mg, 2.114 mmol, 2.0 equiv) and BrettPhos Pd G3 (95.85 mg, 0.106 mmol, 0.1 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 2 h at 80 °C under the nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CFECh MeOH (10: 1) to afford tert-butyl 4-[2-(5-{2-[(tert- butoxycarbonyl)amino]pyrimidin-4-yl}-4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-l,3- thiazol-2-yl)ethyl]piperidine-l -carboxylate (400 mg, 53.67%) as a white solid. LCMS: C33H45FN6O6S2 requires: 704.3, found: m/z = 705.3 [M+H]+. [000346] Step-7: Synthesis of \-!3-|5-(2-aiiiiiiopyriiiiidiii-4-yl)-2-|2-(piperidiii-4- yl)ethyl]-l.,3-thiazol-4-yl]-2-fluorophenvnpropane-l-sulfonaniide hydrochloride
To a mixture of tert-butyl 4-[2-(5-{2-[(tert-butoxycarbonyl)amino]pyrimidin-4-yl}-4-[2- fluoro-3 -(propane- 1 -sulfonamido)phenyl]- 1 ,3 -thiazol-2-yl)ethyl]piperidine- 1 -carboxylate (380 mg, 0.539 mmol, 1 equiv) in DCM (2 mL) was added HC1 (gas) in 1,4-dioxane (6 mL, 4 M). The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford TV- {3-[5-(2-aminopyrimidin-4-yl)-2-[2-(piperidin-4-yl)ethyl]-l,3-thiazol-4-yl]-2-fluorophenyl} propane- 1 -sulfonamide hydrochloride salt (205.9 mg, 67.55%) as a yellow solid. LCMS: C23H29FN6O2S2 requires: 504.2, found: m/z = 505.2 [M+H]+. 'H NMR (400 MHz, CD3OD) 5 8.00 (s, 1H), 7.62 - 7.58 (m, 1H), 7.39 - 7.19 (m, 1H), 6.58 - 6.47 (m, 1H), 3.82 - 3.42 (m, 1H), 3.36 - 3.25 (m, 2H), 3.14 - 2.98 (m, 4H), 2.94 - 2.86 (m, 2H), 2.03 - 1.90 (m, 2H), 1.82 - 1.65 (m, 5H), 1.48 - 1.31 (m, 2H), 0.97 - 0.93 (m, 3H).
[000347] Synthesis of Az-(3-]5-[2-(cvdoDroDylamino)Dyrimidin-4-yl]-2-(Diperidin-4- yl)-l.,3-thiazol-4-yl}-2-fluoroDhenyl)DroDane-l-sulfonaniide hydrochloride salt [000348] Step-1: Synthesis of tert-butyl 4-]5-[2-(cvclopropylamino)pyrimidin-4-yl]- 4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-l.,3-thiazol-2-vnpiperidine-l-carboxylate 01
To a mixture of tert-butyl 4-[5-(2-chloropyrimidin-4-yl)-4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-l,3-thiazol-2-yl]piperidine-l-carboxylate (500 mg, 0.83 mmol, 1 equiv) and DIEA (325 mg, 2.51 mmol, 3 equiv) in DMSO (5 mL) was added aminocyclopropane (143 mg, 2.51 mmol, 3 equiv) at room temperature. The resulting mixture was stirred overnight at 80 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous ISfeSCU After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with EhO:MeCN (1 : 1) to afford tert-butyl 4-{5-[2- (cy cl opropylamino)pyrimidin-4-yl]-4-[2-fluoro-3 -(propane- l-sulfonamido)phenyl]- 1,3- thiazol-2-yl}piperidine-l-carboxylate (400 mg, 75.78%) as a yellow solid. LCMS: C29H37FN6O4S2 requires: 616.2, found: m/z = 617.3 [M+H]+.
[000349] Step-2: Synthesis of 7V-(3-]5-[2-(cvclopropylamino)pyrimidin-4-yl]-2- (piperidin-4-yl)-l.,3-thiazol-4-vn-2-fluorophenyl)propane-l-sulfonaniide hydrochloride
To a mixture of tert-butyl 4-{5-[2-(cyclopropylamino)pyrimidin-4-yl]-4-[2-fluoro-3-(propane-
1-sulfonamido)phenyl]-l,3-thiazol-2-yl}piperidine-l-carboxylate (400 mg, 0.649 mmol, 1 equiv) in DCM (10 mL) was added HC1 in 1,4-dioxane (1 mL, 4 M) at room temperature. The resulting mixture was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure to afford A-(3-{5-[2-(cyclopropylamino)pyrimidin-4-yl]-
2-(piperidin-4-yl)-l,3-thiazol-4-yl}-2-fluorophenyl)propane-l -sulfonamide hydrochloride salt (213.6 mg, crude) as a yellow solid. LCMS: C24H29FN6O2S2 requires: 516.2, found: m/z = 517.2 [M+H]+. 'HNMR (400 MHz, CD3OD) 5 8.13 (d, J= 6.8 Hz, 1H), 7.67 - 7.65 (m, 1H), 7.45 - 7.43 (m, 1H), 7.38 - 7.36 (m, 1H), 6.66 (d, J= 6.8 Hz, 1H), 3.56 - 3.52 (m, 3H), 3.24 - 3.12 (m, 4H), 2.71 - 2.69 (m, 1H), 2.42 - 2.38 (m, 2H), 2.14 - 2.09 (m, 2H), 1.88 - 1.82 (m, 2H), 1.06 - 1.00 (m, 5H), 0.83 - 0.75 (m, 2H).
[000350] Synthesis of 7V-(2-fluoro-3-]5-[2-(isopropylamino)pyrimidin-4-yl]-2- (piperidin-4-yl)-l.,3-thiazol-4-vnphenyl)propane-l-sulfonaniide hydrochloride salt
[000351 ] Step-1: Synthesis of tert-butyl 4-14-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-5-[2-(isopropylamino)pyrimidin-4-yl]-l.,3-thiazol-2-vnpiperidine-
1-carboxylate (2)
To a mixture of tert-butyl 4-[5-(2-chloropyrimidin-4-yl)-4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-l,3-thiazol-2-yl]piperidine-l-carboxylate (500 mg, 0.839 mmol, 1 equiv) and isopropylamine (148.74 mg, 2.517 mmol, 3.0 equiv) in DMSO (5 mL) was added DIEA (325.22 mg, 2.517 mmol, 3.0 equiv) at room temperature. The resulting mixture was stirred at 80 °C overnight. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous ISfeSCU After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CFLCL MeOH (10: 1) to afford tert-butyl 4-{4-[2-fluoro-3- (propane-l-sulfonamido)phenyl]-5-[2-(isopropylamino)pyrimidin-4-yl]-l,3-thiazol-2- yl}piperidine-l-carboxylate (490 mg, 94.41%) as a yellow solid. LCMS: C29H39FN6O4S2 requires: 618.3, found: m/z = 619.1 [M+H]+.
[000352] Step-2: Synthesis of 7V-(2-fluoro-3-15-[2-(isopropylamino)pyrimidin-4-yl]- 2-(piperidin-4-yl)-l.,3-thiazol-4-vnphenyl)propane-l-sulfonaniide hydrochloride
A mixture of tert-butyl 4-{4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-5-[2- (isopropylamino)pyrimidin-4-yl]-l,3-thiazol-2-yl}piperidine-l-carboxylate (490 mg, 0.792 mmol, 1 equiv) in HC1 (gas)/l,4-di oxane (5 mL, 4 M) was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by C18 reverse phase flash chromatography with ACbhJbO (0.5% HC1) (1 : 1) to afford 7V-(2-fluoro-3-{5-[2-(isopropylamino)pyrimidin-4-yl]-2-(piperidin-4-yl)-l,3-thiazol-4- yl}phenyl)propane-l-sulfonamide hydrochloride salt (185.9 mg, 45.26%) as a yellow solid. LCMS: C24H31FN6O2S2 requires: 518.2, found: m/z = 519.2 [M+H]+.
'H NMR (300 MHz, CD3OD) 5 8.12 (d, J= 6.6 Hz, 1H), 7.70 - 768 (m, 1H), 7.52 - 7.35 (m, 2H), 6.69 (s, 1H), 4.01 (s, 1H), 3.64 - 3.52 (m, 3H), 3.30 - 3.25 (m, 2H), 3.20 - 3.08 (m, 2H), 2.47 - 2.43 (m, 2H), 2.28 - 2.08 (m, 2H), 1.96 - 1.79 (m, 2H), 1.37 - 1.23 (m, 6H), 1.10 - 1.02 (m, 3H).
[000353] Synthesis of \-!2-fluoro-3-|3-(pyridin-4-yl)-l//-pyr:izol-4- yl]phenvnpropane-l-sulfonamide
[000354] Step-1: Synthesis of 4-(4-bromo-l-fl2-
(trimethylsilyl)ethoxy] methvnpyrazol-3-yl)Dyridin (2)
To a mixture of 4-(4-bromo-U/-pyrazol-3-yl)pyridine (5 g, 22.315 mmol, 1 equiv) in THF (70 mL) was added NaH (1.07 g, 44.630 mmol, 2 equiv, 60% in mineral oil) at 0 °C. After the mixture was stirred for 30 min, SEM-C1 (5.58 g, 33.473 mmol, 1.5 equiv) was added at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous ISfeSCU After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CFLCL MeOH (10: 1) to afford 4-(4-bromo-l-{[2- (trimethylsilyl)ethoxy]methyl}pyrazol-3-yl)pyridine (6.8 g, 86.00%) as a yellow oil. MS (ESI) calc’d for (Ci4H2oBrN3OSi) [M+H]+, 354.1; found, 354.0.
[000355] Step-2: Synthesis of 2-fluoro-3-[3-(pyridin-4-yl)-l- [2-
(trimethylsilyl)ethoxy]methynDyrazol-4-yl]aniline (4)
To a mixture of 4-(4-bromo-l-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-3-yl)pyridine (5.0 g, 14.111 mmol, 1 equiv) and 2-fluoro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (4.01 g, 16.933 mmol, 1.2 equiv) in dioxane (50 mL) and H2O (10 mL) was added CS2CO3 (9.2 g, 28.222 mmol, 2 equiv) and Pd^ppfJCL CEECh (2.3 g, 2.822 mmol, 0.2 equiv). The resulting mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CEECkMeOH (10: 1) to afford 2-fluoro-3-[3-(pyridin-4- yl)-l-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-4-yl]aniline (4.2 g, 77.40%) as ayellow solid. MS (ESI) calc’d for (C2oH25FN4OSi) [M+H]+, 385.2; found, 385.2.
[000356] Step-3: Synthesis of \-!2-nuoro-3-|3-(pyridin-4-yl)-l-!|2-
(trimethylsilyl)ethoxy]methvnpyrazol-4-yl]phenvnpropane-l-sulfonamide (5)
To a mixture of 2-fluoro-3-[3-(pyridin-4-yl)-l-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-4- yl]aniline (4.2 g, 10.922 mmol, 1 equiv) and TEA (3.3 g, 32.766 mmol, 3 equiv) in DCM (50 mL) was added propane- 1 -sulfonyl chloride (3.1 g, 21.844 mmol, 2 equiv) at room temperature. The resulting mixture was stirred at room temperature for one hour. The resulting mixture was concentrated under reduced pressure. The crude product was dissolved in THF (12 mL), ACN (12 mL), and H2O (12 mL). Then ISfeCCL (3.7 g, 35.190 mmol, 6 equiv) was added at room temperature. The resulting mixture was stirred at 50 °C overnight. The bulk of the organic solvents were removed under reduced pressure. The resulting mixture was extracted with DCM. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CELCkMeOH (10: 1) to afford A-{2-fluoro-3- [3-(pyridin-4-yl)-l-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-4-yl]phenyl}propane-l- sulfonamide (2.5 g, 86.88%) as ayellow solid. MS (ESI) calc’d for (C23H3iFN4O3SSi) [M+H]+, 491.2; found, 491.2.
[000357] Step-4: Synthesis of !2-niioro-3-|3-(pyridin-4-yl)-l//-pyrazol-4- yllphenyllpropane-l-sulfonamide To a mixture of 7V-{2-fluoro-3-[3-(pyridin-4-yl)-l-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol- 4-yl]phenyl (propane- 1 -sulfonamide (2.5 g, 5.095 mmol, 1 equiv) in DCM (15 mL) was added TFA (15 mL). The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CFECkMeOH (10: 1) to afford 7V-{2-fluoro-3-[3- (pyridin-4-yl)-U/-pyrazol-4-yl]phenyl}propane-l-sulfonamide (1.55 g, 84.41%) as a yellow solid. MS (ESI) cak’d for (C17H17FN4O2S) [M+H]+, 361.1; found, 361.0.
[000358] Synthesis of 7V-(2-fluoro-3-I2- [4-(DiDerazin-l-yl)Dhenyl]-5-(pyridin-4-yl)- l,3-thiazol-4- DroDane-l-sulfonamide hydrochloride salt
[000359] Step-1: Synthesis of tert-butyl 4-I4-[4-(2-fluoro-3-nitrophenyl)-l.,3-thiazol-
2-yl]DhenynDiDerazine-l-carboxylate (4)
To a mixture of 2-bromo-l-(2-fluoro-3-nitrophenyl)ethanone (2 g, 7.633 mmol, 1 equiv) in DMF (20 mL) was added terLbutyl 4-(4-carbamothioylphenyl)piperazine-l -carboxylate (2.70 g, 8.396 mmol, 1.1 equiv) at room temperature. The resulting mixture was stirred at room temperature overnight. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous ISfeSCU. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (2: 1) to afford tert-butyl 4-{4-[4-(2-fluoro-3- nitrophenyl)-l,3-thiazol-2-yl]phenyl}piperazine-l-carboxylate (3.2 g, 86.52%) as a yellow solid. LCMS: C24H25FN4O4S requires: 484.2, found: m/z = 485.2 [M+H]+.
[000360] Step-2: Synthesis of tert-butyl 4-]4-[5-bromo-4-(2-fluoro-3-nitrophenyl)- l,3-thiazol-2-yl]phenvnpiperazine-l-carboxylate (5)
To a mixture of tert-butyl 4-{4-[4-(2-fluoro-3-nitrophenyl)-l,3-thiazol-2- yl]phenyl}piperazine-l-carboxylate (3 g, 6.191 mmol, 1 equiv) in DMF (30 mL) was added NBS (1.21 g, 6.810 mmol, 1.1 equiv) at room temperature. The resulting mixture was stirred at room temperature overnight. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by C18 reverse phase flash chromatography with ACbFEhO (1 : 1) to afford tert-butyl 4-{4-[5- bromo-4-(2-fluoro-3-nitrophenyl)-l,3-thiazol-2-yl]phenyl}piperazine-l -carboxylate (900 mg, 25.8%) as a yellow solid. LCMS: C24H24BrFN4O4S requires: 562.1, found: m/z = 563.1 [M+H]+.
[000361 ] Step-3: Synthesis of tert-butyl 4-]4-[4-(3-amino-2-fluorophenyl)-5-bromo- l,3-thiazol-2-yl]phenvnpiperazine-l-carboxylate (6)
To a mixture of tert-butyl 4-{4-[5-bromo-4-(2-fluoro-3-nitrophenyl)-l,3-thiazol-2- yl]phenyl}piperazine-l-carboxylate (900 mg, 1.588 mmol, 1 equiv) in saturated aqueous NH4CI (2 mL) and MeOH (8 mL) was added Fe (55.75 mg, 0.995 mmol, 0.6 equiv) in portions at room temperature. The resulting mixture was stirred for 2 h at 70 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by C18 reverse phase flash chromatography with ACbFEhO (1 : 1) to afford tert-butyl 4-{4-[4-(3-amino-2-fluorophenyl)- 5-bromo-l,3-thiazol-2-yl]phenyl}piperazine-l-carboxylate (800 mg, 94.44%) as a yellow solid. LCMS: C24H26BrFN4O2S requires: 532.1, found: m/z = 533.1 [M+H]+.
Step-4: Synthesis of tert-butyl 4-(4-]5-bromo-4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-l.,3-thiazol-2-vnphenyl)piperazine-l-carboxylate (7)
To a mixture of tert-butyl 4-{4-[4-(3-amino-2-fluorophenyl)-5-bromo-l,3-thiazol-2- yl]phenyl}piperazine-l-carboxylate (800 mg, 1.500 mmol, 1 equiv) and TEA (455.26 mg, 4.500 mmol, 3.0 equiv) in DCM (10 mL) was added propane- 1 -sulfonyl chloride (320.77 mg, 2.250 mmol, 1.5 equiv) in portions at 0 °C. The resulting mixture was stirred for one hour at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was dissolved in THF (3 mL), ACN (3 mL), and H2O (3 mL). ISfeCCL (953.67 mg, 9.000 mmol, 6 equiv) was added at room temperature. The resulting mixture was stirred at 50 °C overnight. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with DCM. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CFLCh MeOH (5: 1) to afford tert-butyl 4-(4-{5-bromo-4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-l, 3 -thiazol-2-yl}phenyl)piperazine-l -carboxylate (900 mg, 93.83%) as a yellow solid. LCMS: C2?H32BrFN4O4S2 requires: 638.1, found: m/z = 639.1 [M+H]+.
[000362] Step-5: Synthesis of tert-butyl 4-(4-]4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-5-(pyridin-4-yl)-l.,3-thiazol-2-vnphenyl)piperazine-l-carboxylate (81
To a mixture of tert-butyl 4-(4-{5-bromo-4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-l,3- thiazol-2-yl}phenyl)piperazine-l -carboxylate (900 mg, 1.407 mmol, 1 equiv) and pyridin-4- ylboronic acid (259.45 mg, 2.111 mmol, 1.5 equiv) in dioxane (10 mL) and H2O (1 mL) was added Pd(dppf)C12-CH2C12 (229.26 mg, 0.281 mmol, 0.2 equiv) in portions at room temperature. The resulting mixture was stirred for 2 h at 90 °C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with DCM:EtOAc (5: 1) to afford tert-butyl 4-(4-{4- [2-fluoro-3-(propane-l-sulfonamido)phenyl]-5-(pyridin-4-yl)-l,3-thiazol-2- yl}phenyl)piperazine-l-carboxylate (200 mg, 22.28%) as a yellow solid. LCMS: C32H36FN5O4S2 requires: 637.2, found: m/z = 638.2 [M+H]+.
[000363] Step-6: Synthesis of A-(2-fluoro-3-]2-[4-(piperazin-l-yl)phenyl]-5- (pyridin-4-yl)-l.,3-thiazol-4-vnphenyl)propane-l-sulfonamide hydrochloride
To a mixture of tert-butyl 4-(4-{4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-5-(pyridin-4- yl)-l,3-thiazol-2-yl}phenyl)piperazine-l-carboxylate (200 mg, 0.313 mmol, 1 equiv) in DCM (2 mL) was added HC1 (gas) in 1,4-di oxane (2 mL, 4M). The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.5% HC1), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford A-(2-fluoro-3-{2-[4-(piperazin-l- yl)phenyl]-5-(pyridin-4-yl)-l,3-thiazol-4-yl}phenyl)propane-l-sulfonamide hydrochloride salt (136.9 mg, 80.90%) as a yellow solid. LCMS: C27H28FN5O2S2 requires: 537.2, found: m/z = 538.2 [M+H]+.
'HNMR (400 MHz, CD3OD) 5 8.97 (d, J= 6.2 Hz, 2H), 8.56 (d, J= 6.2 Hz, 2H), 8.31 - 8.16 (m, 2H), 8.13 - 8.08 (m, 1H), 7.96 (d, J= 2.6 Hz, 1H), 7.65 - 7.52 (m, 2H), 7.28 -7.25 (m, 1H), 3.32 - 3.26 (m, 8H), 3.21 - 3.13 (m, 2H), 1.97 - 1.86 (m, 2H), 1.09 - 1.05 (m, 3H).
[000364] Synthesis of Az-13-[2-tert-butyl-5-(2-l[4-(Diperazin-l- yl)Dhenyl]amino}pyrimidin-4-yl)-l.,3-thiazol-4-yl]-2-fluoroDhenyl}DroDane-l- sulfonamide hydrochloride salt
[000365] Step-1: Synthesis of tert-butyl 4-14-[(4-12-tert-butyl-4-[2-fluoro-3-
(DroDane-l-sulfonamido)phenyl]-l.,3-thiazol-5-ynDyrimidin-2- vDaminolDhenynpiperazine-l-carboxylate (2) To a mixture of 7V-{3-[2-tert-butyl-5-(2-chloropyrimidin-4-yl)-l,3-thiazol-4-yl]-2- fluorophenyl} propane- 1 -sulfonamide (800 mg, 1.70 mmol, 1 equiv) in dioxane (10 mL) was added tert-butyl 4-(4-aminophenyl)piperazine-l -carboxylate (1.18 g, 4.265 mmol, 2.5 equiv), BrettPhosPdGs (154 mg, 0.17 mmol, 0.1 equiv), and CS2CO3 (1.11 g, 3.41 mmol, 2 equiv) at room temperature. The resulting mixture was stirred 2 h at 80 °C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with FhChMeCN (1 :8) to afford tert-butyl 4-{4-[(4-{2- tert-butyl-4-[2-fluoro-3 -(propane- 1 -sulfonamido)phenyl]- 1 ,3 -thiazol-5-yl }pyrimidin-2- yl)amino]phenyl}piperazine-l-carboxylate (500 mg, 39.23%) as a yellow solid. LCMS: C35H44FN7O4S2 requires: 709.3, found: m/z = 710.2 [M+H]+.
[000366] Step-2: Synthesis of \-!3-|2-tert-biityl-5-(2-!|4-(piperazin-l- yl)phenyl]amino}pyrimidin-4-yl)-l.,3-thiazol-4-yl]-2-fluorophenyl}propane-l- sulfonamide hydrochloride
A mixture of tert-butyl 4-{4-[(4-{2-tert-butyl-4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]- l,3-thiazol-5-yl}pyrimidin-2-yl)amino]phenyl}piperazine-l-carboxylate (500 mg, 0.70 mmol, 1 equiv) in HCl/l,4-di oxane (10 mL, 4 M) was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure to afford 7V-{3-[2-tert-butyl-5-(2- {[4-(piperazin-l-yl)phenyl]amino}pyrimidin-4-yl)-l,3-thiazol-4-yl]-2-fluorophenyl}propane- 1-sulfonamide hydrochloride salt (371.7 mg, crude) as a brown solid. LCMS: C30H36FN7O2S2 requires: 609.2, found: m/z = 610.2 [M+H]+.
1 H NMR (400 MHz, CD3OD) 5 8.11 (s, 1H), 7.62 - 7.45 (m, 2H), 7.36 - 7.32 (m, 3H), 7.14 - 7.12 (m, 2H), 6.78 (s, 1H), 3.59 - 3.41 (m, 8H), 3.09 - 3.06 (m, 2H), 1.84 - 1.79 (m, 2H), 1.52 (s, 9H), 1.07 - 1.03 (m, 3H).
[000367] Synthesis of A-(2-fluoro-3-H-[4-(Diperazine-l-carbonyl)Dhenyl]-3- (Dyridin-4-yl)Dyrazol-4- Dropane-l-sulfonamide hydrochloride salt
[000368] Step-1: Synthesis of tert-butyl 4-[4-(4,4.,5.,5-tetramethyl-l.,3.,2- dioxaborolan-2-yl)benzoyl]piperazine-l-carboxylate (3)
To a mixture of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoic acid (3.2 g, 12.886 mmol, 1.2 equiv) in DCM (20 mL) and DMF (2 mL) was added HOBT (1.74 g, 12.886 mmol, 1.2 equiv) and tert-butyl piperazine- 1 -carboxylate (2.0 g, 10.738 mmol, 1.00 equiv) at room temperature. To the above mixture was added EDCI (2.47 g, 12.886 mmol, 1.2 equiv) at room temperature. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was extracted with CH2Q2. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (2: 1) to afford tert-butyl 4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzoyl]piperazine-l -carboxylate (2.2 g, 49.21%) as a white solid. LCMS: C22H33BN2O5 requires: 416.2, found: m/z = 417.2 [M+H]+.
[000369] Step-2: Synthesis of tert-butyl 4-(4-14-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-3-(pyridin-4-yl)pyrazol-l-vnbenzoyl)piperazine-l-carboxylate (5)
To a stirred mixture of tert-butyl 4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzoyl]piperazine-l -carboxylate (1.50 g, 3.603 mmol, 1.5 equiv) and A-{2-fhioro-3-[3- (pyridin-4-yl)-177-pyrazol-4-yl]phenyl}propane-l-sulfonamide (0.58 g, 1.609 mmol, 0.67 equiv) in pyridine (15 mL) was added Cu(OAc)2 (0.87 g, 4.804 mmol, 2.0 equiv) and molecular sieves 4 A (0.58 g) at room temperature. The resulting mixture was stirred at 110 °C overnight under an oxygen atmosphere. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous ISfeSCU After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CFECb MeOH (10: 1) to afford tert-butyl 4-(4-{4-[2-fhioro-3- (propane- 1 -sulfonamido)phenyl]-3 -(pyridin-4-yl)pyrazol- 1 -yl }benzoyl)piperazine- 1 - carboxylate (400 mg, 25.67%) as a yellow solid. LCMS: C33H37FN6O5S requires: 648.3, found: m/z = 649.3 [M+H]+.
[000370] Step-3: Synthesis of A-(2-fluoro-3-H-[4-(Diperazine-l-carbonyl)Dhenyl]-3- (Dyridin-4-yl)Dyrazol-4-ynDhenyl)DroDane-l-sulfonamide hydrochloride
To a mixture of tert-butyl 4-(4-{4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-3-(pyridin-4- yl)pyrazol-l-yl}benzoyl)piperazine-l -carboxylate (400 mg, 0.617 mmol, 1 equiv) in DCM (2 mL) was added HC1 in 1,4-di oxane (5 mL, 4 M). The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in water (0.5% HC1), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford A-(2-fluoro-3-{ l-[4-(piperazine-l-carbonyl)phenyl]-3- (pyridin-4-yl)pyrazol-4-yl}phenyl)propane-l-sulfonamide hydrochloride salt (216.3 mg, 57.98%) as a white solid. LCMS: C28H29FN6O3S requires: 548.2, found: m/z = 549.3 [M+H]+. 'H NMR (400 MHz, DMSO-tL) 8 9.74 (s, 1H), 9.48 - 9.44 (m, 2H), 9.07 - 9.02 (m, 1H), 8.85
- 8.80 (m, 1H), 8.15 - 8.09 (m, 2H), 7.93 - 7.89 (m, 2H), 7.75 - 7.68 (m, 2H), 7.57 - 7.48 (m, 1H), 7.46 - 7.38 (m, 1H), 7.38 - 7.30 (m, 1H), 3.78 - 3.41 (m, 4H), 3.21 - 3.16 (m, 4H), 3.11
- 3.03 (m, 2H), 1.78 - 1.63 (m, 2H), 0.98 - 0.89 (m, 3H).
[000371 ] Synthesis of A-(2-fluoro-3-H-[4-(DiDeridin-4- phenyl]-3-(Dyridin-4- yl)Dyrazol-4- Dropane-l-sulfonaniide hydrochloride salt
[000372] Step-1: Synthesis o butyl 4-(4-bromophenoxy)piperidine-l- carboxylate (2)
To a mixture of NaH (238.47 mg, 9.93 mmol, 1 equiv) in NMP (20 mL) was added tert-butyl 4-hydroxypiperidine-l -carboxylate (2 g, 9.93 mmol, 1 equiv) at 0 °C. The resulting mixture was stirred one hour at 0 °C under a nitrogen atmosphere. To the above mixture was added 4- bromofluorobenzene (1.74 g, 9.93 mmol, 1 equiv) at 0 °C. The resulting mixture was stirred overnight at 120 °C under the nitrogen atmosphere. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (4: 1) to afford tert-butyl 4-(4-bromophenoxy)piperidine-l -carboxylate (1.3 g, 33.05%) as a white solid. LCMS: CieE BrNCh requires: 355.1, found: m/z = 356.1 [M+H]+.
[000373] Step-2: Synthesis of tert-butyl 4-[4-(4,4,5,5-tetramethyl-l,3.,2- dioxaborolan-2-yl)phenoxy] piperidine-l-carboxylate (3)
To a mixture of tert-butyl 4-(4-bromophenoxy)piperidine-l -carboxylate (1.3 g, 3.64 mmol, 1 equiv) in dioxane (10 mL) was added 4,4,5,5-tetramethyl-2-(tetramethyl-l,3,2-dioxaborolan- 2-yl)-l,3,2-dioxaborolane (1.85 g, 7.29 mmol, 2 equiv), KOAc (1.07 g, 10.94 mmol, 3 equiv), and Pd(dppf)C12 (1.34 g, 1.85 mmol, 0.5 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred 2 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (2: 1) to afford tert-butyl 4-[4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)phenoxy]piperidine-l-carboxylate (1 g, 61.15%) as a yellow solid. LCMS: C22H34BNO5 requires: 403.3, found: m/z = 404.2 [M+H]+.
[000374] Step-3: Synthesis of tert-butyl 4-(4-]4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-3-(pyridin-4-yl)pyrazol-l-vnphenoxy)piperidine-l-carboxylate (4)
To a mixture of tert-butyl 4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenoxy]piperidine-l -carboxylate (1 g, 2.47 mmol, 1 equiv) in pyridine (10 mL) was added A-{2-fluoro-3-[3-(pyridin-4-yl)-lJ/-pyrazol-4-yl]phenyl}propane-l-sulfonamide (893 mg, 2.47 mmol, 1 equiv), Cu(OAc)2 (900 mg, 4.95 mmol, 2 equiv), and molecular sieves 4A (893 mg) at room temperature. The resulting mixture was stirred at 110 °C overnight under an oxygen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions FhChMeCN (1 : 1) to afford tert-butyl 4-(4-{4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-3- (pyridin-4-yl)pyrazol-l-yl}phenoxy)piperidine-l-carboxylate (400 mg, 24.11%) as a white solid. LCMS: C33H38FN5O5S requires: 635.3, found: m/z = 636.2 [M+H]+.
[000375] Step-4: Synthesis of A-(2-fluoro-3-H-[4-(piperidin-4-yloxy)phenyl]-3- (pyridin-4-yl)pyrazol-4-vnphenyl)propane-l-sulfonamide hydrochloride
A mixture of tert-butyl 4-(4-{4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-3-(pyridin-4- yl)pyrazol-l-yl}phenoxy)piperidine-l-carboxylate (500 mg, 0.78 mmol, 1 equiv) in HCl/1,4- di oxane (10 mL, 4 M) was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure to afford A-(2-fluoro-3-{ l-[4-(piperidin-4-yloxy )phenyl]- 3-(pyridin-4-yl)pyrazol-4-yl}phenyl)propane-l-sulfonamide hydrochloride salt (341.3 mg, crude) as a yellow solid. LCMS: C28H30FN5O3S requires: 535.2, found: m/z = 536.2 [M+H]+. 'HNMR (400 MHz, CD3OD) 5 8.75 - 8.73 (m, 2H), 8.58 (s, 1H), 8.21 - 8.20 (m, 2H), 7.93 - 7.91 (m, 2H), 7.58 - 7.56 (m, 1H), 7.38 - 7.30 (m, 2H), 7.23 - 7.20 (m, 2H), 3.47 - 3.40 (m, 2H), 3.23 - 3.26 (m, 2H), 3.14 - 3.11 (m, 2H), 2.26 - 2.20 (m, 2H), 2.10 - 2.05 (m, 2H), 1.93 (s, 1H), 1.87 - 1.81 (m, 2H), 1.05 - 1.01 (m, 3H).
[000376] Synthesis of 7V-]2-fluoro-3-H-(piperidin-4-yl)-3-(pyridin-4-yl)pyrazol-4- vHphenvnpropane-l-sulfonamide hydrochloride salt
[000377] Step-1: Synthesis of tert-butyl 4-14-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-3-(pyridin-4-yl)pyrazol-l-vnpiperidine-l-carboxylate (3)
To a stirred mixture of 7V-{2-fluoro-3-[3-(pyridin-4-yl)-lJ/-pyrazol-4-yl]phenyl}propane-l- sulfonamide (400 mg, 1.110 mmol, 1 equiv) and tert-butyl 4-bromopiperidine-l -carboxylate (322.50 mg, 1.221 mmol, 1.1 equiv) in DMF (4 mL) was added CS2CO3 (723.22 mg, 2.220 mmol, 2.0 equiv) at room temperature. The resulting mixture was stirred at 100 °C overnight. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CEEChiMeOH (10: 1) to afford tert-butyl 4-{4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]- 3-(pyridin-4-yl)pyrazol-l-yl}piperidine-l-carboxylate (220 mg, 36.46%) as a yellow solid. LCMS: C27H34FN5O4S requires: 543.2, found: m/z = 544.2 [M+H]+.
[000378] Step-2: Synthesis of A-12-fluoro-3-[l-(piperidin-4-yl)-3-(pyridin-4- yl)pyrazol-4-yl]phenvnpropane-l-sulfonamide hydrochloride To a mixture of tert-butyl 4-{4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-3-(pyridin-4- yl)pyrazol-l-yl}piperidine-l-carboxylate (200 mg, 0.368 mmol, 1 equiv) in DCM (2 mL) was added HC1 (gas) in 1,4-di oxane (2 mL, 4 M). The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.5% HC1), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford 7V-{2-fluoro-3-[l-(piperidin-4-yl)-3-(pyridin-4-yl)pyrazol- 4-yl]phenyl (propane- 1 -sulfonamide hydrochloride salt (140 mg, 79.28%) as a yellow solid. LCMS: C22H26FN5O2S requires: 443.2, found: m/z = 444.1 [M+H]+.
‘H NMR (400 MHz, CD3OD) 5 8.78 - 8.67 (m, 2H), 8.19 - 8.11 (m, 3H), 7.63 - 7.52 (m, 1H), 7.39 - 7.29 (m, 2H), 4.85 - 4.79 (m, 1H), 3.73 - 3.62 (m, 2H), 3.39 - 3.36 (m, 1H), 3.35 - 3.29 (m, 1H), 3.21 - 3.11 (m, 2H), 2.55 - 2.22 (m, 4H), 1.91 - 1.79 (m, 2H), 1.10 - 0.95 (m, 3H).
[000379] Synthesis of N-12-fluoro-3-[3-(morDholin-4-yl)-l-(Diperidin-4-yl)Dyrazol- 4-yl]DhenynDroDane-l-sulfonamide; trifluoroacetic acid salt
[000380] Step-1: Synthesis of tert-butyl 4-(4-bromo-3-nitroDyrazol-l-yl)Diperidine-
1-carboxylate (2) To a mixture of 4-bromo-3-nitro-l/Z-pyrazole (2 g, 10.418 mmol, 1 equiv) in DMF (20 mL) was added tert-butyl 4-bromopiperidine-l -carboxylate (3.03 g, 11.460 mmol, 1.1 equiv) and CS2CO3 (3.39 g, 10.418 mmol, 1 equiv) at room temperature. The resulting mixture was stirred at 120 °C overnight. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (20:80) to afford tert-butyl 4-(4-bromo-3-nitropyrazol- l-yl)piperidine-l -carboxylate (3 g, 76.74%) as a yellow solid. LCMS: Ci3Hi9BrN4O4 requires: 374.1, found: m/z = 375.1 [M+H]+.
[000381 ] Step-2: Synthesis of tert-butyl 4-(3-amino-4-bromopyrazol-l-yl)piperidine- 1-carboxylate (3)
To a mixture of tert-butyl 4-(4-bromo-3-nitropyrazol-l-yl)piperidine-l-carboxylate (3 g, 7.995 mmol, 1 equiv) and Fe (22.32 mg, 0.400 mmol, 5 equiv) in MeOH (30 mL) was added saturated aqueous NH4CI (4 mL) at room temperature. The resulting mixture was stirred for 2 h at 70 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CFECh MeOH (10: 1) to afford tert-butyl 4-(3- amino-4-bromopyrazol-l-yl)piperidine-l -carboxylate (2.6 g, 94.19%) as ayellow solid. LCMS: Ci3H2iBrN4O2 requires: 344.1, found: m/z = 345.1 [M+H]+.
[000382] Step-3: Synthesis of tert-butyl 4-[4-bromo-3-(morpholin-4-yl)pyrazol-l- yllpiperidine-l-carboxylate (4)
To a mixture of tert-butyl 4-(3-amino-4-bromopyrazol-l-yl)piperidine-l -carboxylate (2.5 g, 7.241 mmol, 1 equiv) and DIEA (2.81 g, 21.723 mmol, 3 equiv) in DMF (25 mL) was added l-bromo-2-(2-bromoethoxy)ethane (2.02 g, 8.689 mmol, 1.2 equiv) at room temperature. The resulting mixture was stirred overnight at 120 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CEECh EtOAc (75:25) to afford tertbutyl 4-[4-bromo-3-(morpholin-4-yl)pyrazol-l-yl]piperidine-l -carboxylate (1.4 g, 46.55%) as a yellow oil. LCMS: C17H16CIFN4O2S2 requires: 414.1, found: m/z = 414.2 [M+H]+.
[000383] Step-4: Synthesis of tert-butyl 4-[4-(3-amino-2-fluorophenyl)-3-
(morpholin-4-yl)pyrazol-l-yl]piperidine-l-carboxylate (6) To a mixture of tert-butyl 4-[4-bromo-3-(morpholin-4-yl)pyrazol-l-yl]piperidine-l- carboxylate (1.4 g, 3.371 mmol, 1 equiv) and 2-fhioro-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)aniline (1.04 g, 4.382 mmol, 1.3 equiv) in dioxane (15 mL) and H2O (1.5 mL) was added Pd(dppf)C12-CH2C12 (274.59 mg, 0.337 mmol, 0.1 equiv) and K2CO3 (931.7 mg, 6.742 mmol, 2 equiv ) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 2 h at 90 °C under the nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with C^CL MeOH (10: 1) to afford tert-butyl 4-[4-(3-amino-2-fluorophenyl)-3- (morpholin-4-yl)pyrazol-l-yl]piperidine-l -carboxylate (1 g, 66.59%) as a dark yellow oil. LCMS: C23H32FN5O3 requires: 445.3, found: m/z = 446.2 [M+H]+.
[000384] Step-5: Synthesis of tert-butyl 4-]4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-3-(morpholin-4-yl)pyrazol-l-vnpiperidine-l-carboxylate (7)
To a mixture of tert-butyl 4-[4-(3-amino-2-fluorophenyl)-3-(morpholin-4-yl)pyrazol-l- yl]piperidine-l -carboxylate (1 g, 2.244 mmol, 1 equiv) and TEA (1.14 g, 11.220 mmol, 5 equiv) in DCM (10 mL) was added propane- 1 -sulfonyl chloride (384.07 mg, 2.693 mmol, 1.2 equiv) at 0 °C. The resulting mixture was stirred for one hour at room temperature. The resulting mixture was concentrated under vacuum. To the above mixture was added ISfeCCL (0.71 g, 6.732 mmol, 3 equiv) in THF (10 mL), MeCN (10 mL), and H2O (10 mL) at room temperature. The resulting mixture was stirred overnight at 50 °C. The resulting mixture was extracted with CH2Q2. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with C^CL MeOH (10: 1). The residue product was purified by reverse phase flash chromatography with MeCbkEEO (60:40) to afford terLbutyl 4- {4-[2-fluoro-3 -(propane- 1 -sulfonamido)phenyl]-3 -(morpholin-4-yl)pyrazol- 1 - yl}piperidine-l-carboxylate (600 mg, 48.46%) as a yellow solid. LCMS: C26H38FN5O5S requires: 551.3, found: m/z = 552.3 [M+H]+. 'H NMR (300 MHz, CD3OD) 5 7.75 (d, J= 2.4 Hz, 1H), 7.70 - 7.61 (m, 1H), 7.40 - 7.34 (m, 1H), 7.21 - 7.12 (m, 1H), 4.33 - 4.16 (m, 3H), 3.77 - 3.72 (m, 4H), 3.19 - 3.09 (m, 2H), 3.06 - 2.90 (m, 6H), 2.15 - 2.03 (m, 2H), 1.97 - 1.83 (m, 4H), 1.50 (s, 9H), 1.08 - 1.03 (m, 3H).
[000385] Step-6: Synthesis of A-]2-fluoro-3-[3-(morpholin-4-yl)-l-(piperidin-4- yl)pyrazol-4-yl]phenvnpropane-l-sulfonamide., trifluoroacetic acid
To a mixture of tert-butyl 4-{4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-3-(morpholin-4- yl)pyrazol-l-yl}piperidine-l-carboxylate (600 mg, 1.088 mmol, 1 equiv) in DCM (9 mL) was added TFA (3 mL) at room temperature. The resulting mixture was stirred for one hour at room temperature. The resulting mixture was concentrated under vacuum. This resulted in N-{2- fluoro-3-[3-(morpholin-4-yl)-l-(piperidin-4-yl)pyrazol-4-yl]phenyl}propane-l-sulfonamide, trifluoroacetic acid salt (232.0 mg, crude) as a yellow solid. LCMS: C21H30FN5O3S requires: 451.2, found: m/z = 452.1 [M+H]+.
'HNMR (300 MHz, CD3OD) 5 7.77 (d, J= 2.4 Hz, 1H), 7.69 - 7.63 (m, 1H), 7.40 - 7.35 (m, 1H), 7.19 - 7.14 (m, 1H), 4.51 - 4.38 (m, 1H), 3.77 - 3.72 (m, 4H), 3.62 - 3.56 (m, 2H), 3.31 - 3.10 (m, 4H), 3.02 - 2.99 (m, 4H), 2.32 - 2.27 (m, 4H), 1.91 - 1.84 (m, 2H), 1.08 - 1.03 (m, 3H).
[000386] Synthesis ol' \-!3-|5-(2-aiiiiiiopyriiiiidiii-4-yl)-2-|4-(piperaziii-l-yl)plieiiyl|- l,3-thiazol-4-yl]-2-fluorophenynpropane-l-sulfonamide hydrochloride salt [000387] Step-1: Synthesis of tert-butyl 4-}4-[5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-
3-}[(prop-2-en-l-yloxy)carbonyl]amino}phenyl)-l.,3-thiazol-2-yl]phenvnpiperazine-l- carboxylate (2)
To a mixture of prop-2-en-l-yl A-{3-[2-(2-chloropyrimidin-4-yl)acetyl]-2- fluorophenyl} carbamate (2 g, 5.71 mmol, 1 equiv) in DMA (20 mL) was added tert-butyl 4- (4-carbamothioylphenyl)piperazine-l -carboxylate (2.21 g, 6.86 mmol, 1.2 equiv) and NBS (508 mg, 2.85 mmol, 0.5 equiv) at 0 °C. The resulting mixture was stirred 2 h at 60 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EtOAc (1 : 1) to afford tert-butyl 4-{4-[5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-3-{[(prop-2- en-l-yloxy)carbonyl]amino}phenyl)-l,3-thiazol-2-yl]phenyl}piperazine-l-carboxylate (1.5 g, 36.26%) as a yellow green solid. LCMS: C32H32CIFN6O4S requires: 650.2, found: m/z = 651.1 [M+H]+.
[000388] Step-2: Synthesis of tert-butyl 4-}4-[4-(3-amino-2-fluorophenyl)-5-(2- chloropyrimidin-4-yl)- 1.,3-thiazol-2-yl] phenyl} piperazine- 1-carboxylate (3)
To a mixture of tert-butyl 4-{4-[5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-3-{[(prop-2-en-l- yloxy)carbonyl]amino}phenyl)-l,3-thiazol-2-yl]phenyl}piperazine-l-carboxylate (1.5 g, 2.30 mmol, 1 equiv), HO Ac (332 mg, 5.53 mmol, 2.4 equiv), and Pd(PPh3)2C12 (32 mg, 0.046 mmol, 0.02 equiv) in DCM (15 mL) was added w-BusSnH (1 g, 3.45 mmol, 1.5 equiv) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred for 30 min at room temperature. The reaction was quenched by the addition of saturated aqueous NaHCOs (10 mL) at 0 °C. The resulting mixture was extracted with DCM. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (2: 1) to afford tert-butyl 4-{4-[4-(3-amino-2-fluorophenyl)-5-(2-chloropyrimidin-
4-yl)-l,3-thiazol-2-yl]phenyl}piperazine-l-carboxylate (1.2 g, 83.59%) as a yellow solid. LCMS: C28H28CIFN6O2S requires: 566.2, found: m/z = 567.2 [M+H]+.
[000389] Step-3: Synthesis of tert-butyl 4-}4-[5-(2-chloropyrimidin-4-yl)-4-[2-fluoro- 3-(propane-l-snlfonamido)phenyl]-l.,3-thiazol-2-yl]phenyl}piperazine-l-carboxylate (4)
To a mixture of tert-butyl 4-{4-[4-(3-amino-2-fluorophenyl)-5-(2-chloropyrimidin-4-yl)-l,3- thiazol-2-yl]phenyl}piperazine-l-carboxylate (1.2 g, 2.11 mmol, 1 equiv) and TEA (642 mg, 6.34 mmol, 3 equiv) in DCM (10 mL) was added propane- 1 -sulfonyl chloride (452 mg, 3.17 mmol, 1.5 equiv) at 0 °C. The resulting mixture was stirred for one hour at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was dissolved in THF (10 mL), MeCN (10 mL), and H2O (10 mL). ISfeCCL (2 g, 19.25 mmol, 10 equiv) was added at room temperature. The resulting mixture was stirred overnight at 50 °C. The resulting mixture was concentrated under vacuum. The residue was extracted with DCM. The combined organic layers were washed with water and dried over anhydrous ISfeSC After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with DCM:MeOH (10: 1) to afford tert-butyl 4-{4-[5- (2-chloropyrimidin-4-yl)-4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-l,3-thiazol-2- yl]phenyl(piperazine-l-carboxylate (1 g, 69.46%) as a yellow-green solid. LCMS: C31H34CIFN6O4S2 requires: 672.2, found: m/z = 673.2 [M+H]+.
[000390] Step-4: Synthesis of tert-butyl 4-[4-(5-]2-[(tert- butoxycarbonyl)amino]pyrimidin-4-vn-4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-
1.3-thiazol-2-yl)phenyl]piperazine-l-carboxylate (5)
To a mixture of tert-butyl 4-{4-[5-(2-chloropyrimidin-4-yl)-4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-l, 3 -thiazol-2-yl]phenyl (piperazine- 1 -carboxylate (1 g, 1.48 mmol, 1 equiv) in dioxane (10 mL) was added tert-butyl carbamate (870 mg, 7.42 mmol, 5 equiv), CS2CO3 (967 mg, 2.97 mmol, 2 equiv), and BrettPhos Pd G3 (134 mg, 0.15 mmol, 0.1 equiv) at room temperature. The resulting mixture was stirred 2 h at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with LBOMeCN (1 :7) to afford tert-butyl 4-[4-(5-{2- [(tert-butoxycarbonyl)amino]pyrimidin-4-yl(-4-[2-fluoro-3 -(propane- 1 -sulfonamido)phenyl]-
1.3-thiazol-2-yl)phenyl]piperazine-l-carboxylate (500 mg, 42.42%) as a yellow solid. LCMS: C36H44FN7O6S2 requires: 753.3, found: m/z = 754.2 [M+H]+.
[000391 ] Step-5: Synthesis of A-]3-[5-(2-aminopyrimidin-4-yl)-2-[4-(piperazin-l- yl)phenyl]-l.,3-thiazol-4-yl]-2-fluorophenvnpropane-l-sulfonaniide hydrochloride
A mixture of tert-butyl 4-[4-(5-{2-[(tert-butoxycarbonyl)amino]pyrimidin-4-yl(-4-[2-fluoro- 3 -(propane- 1 -sulfonamido)phenyl]- 1 ,3 -thiazol-2-yl)phenyl]piperazine- 1 -carboxylate (500 mg, 0.663 mmol, 1 equiv) in HCl/l,4-di oxane (10 mL, 4 M) was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure to afford N-{3- [5-(2-aminopyrimidin-4-yl)-2-[4-(piperazin-l-yl)phenyl]-l,3-thiazol-4-yl]-2- fluorophenyl (propane- 1 -sulfonamide hydrochloride salt (383.5 mg, crude) as a red solid. LCMS: C26H28FN7O2S2 requires: 553.2, found: m/z = 554.2 [M+H]+. 'H NMR (400 MHz, CD3ODJ 5 8.02 - 7.99 (m, 3H), 7.73 - 7.69 (m, 1H), 7.52 - 7.48 (m, 1H), 7.41 - 7.37 (m, 1H), 7.16 - 7.14 (m, 2H), 6.58 - 6.56 (m, 1H), 3.67 - 3.57 (m, 4H), 3.40 - 3.38 (m, 4H), 3.17 - 3.14 (m, 2H), 1.89 - 1.83 (m, 2H), 1.06 - 1.02 (m, 3H).
[000392] Synthesis of 4-[4-(3-llethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-2- methyl-l.,3-thiazol-5-yl]-N-[5-(DiDerazin-l-yl)Dyridin-2-yl]Dyriniidin-2-aniine; trifluoroacetic acid salt
[000393] Step-1: Synthesis of G3-[5-(2-chloroDyrimidin-4-yl)-2-methyl-l.,3-thiazol-
4-yl]-2-fluoroDhenynsulfamoyl)(ethyl)methylamine (2)
To a stirred mixture of 3-[5-(2-chloropyrimidin-4-yl)-2-methyl-l,3-thiazol-4-yl]-2- fluoroaniline (2.62 g, 8.162 mmol, 0.78 equiv) and methylethylamine hydrochloride (1 g, 10.464 mmol, 1 equiv) in pyridine (30 mL) was added DMAP (256 mg, 2.093 mmol, 0.2 equiv). The resulting mixture was stirred at -30 °C for 10 min under a nitrogen atmosphere. To the above mixture was added sulfonyl chloride (1.77 g, 13.08 mmol, 1.25 equiv) at -30 °C under the nitrogen atmosphere. The resulting mixture was stirred at -30 °C for 20 min under the nitrogen atmosphere and then was stirred at room temperature for one hour under the nitrogen atmosphere. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (3:2) to afford ({3-[5-(2-chloropyrimidin-4-yl)-2- methyl-l,3-thiazol-4-yl]-2-fluorophenyl}sulfamoyl)(ethyl)methylamine (1.1 g, 79.82%) as a brown solid. LCMS: C17H17CIFN5O2S2 requires: 441.1, found: m/z = 442.2 [M+H]+.
[000394] Step-2: Synthesis of tert-butyl 4-[6-({4-[4-(3- llethyl(methyl)sulfamoyl]amino}-2-fluoroDhenyl)-2-methyl-l.,3-thiazol-5-yl]Dyrimidin- 2-vnamino)pyridin-3-yl]piperazine-l-carboxylate (3)
To a stirred mixture of ({3-[5-(2-chloropyrimidin-4-yl)-2-methyl-l,3-thiazol-4-yl]-2- fluorophenyl}sulfamoyl)(ethyl)methylamine (1.1 g, 2.489 mmol, 1 equiv) and tert-butyl 4-(6- aminopyridin-3-yl)piperazine-l -carboxylate (901 mg, 3.236 mmol, 1.3 equiv) in dioxane (10 mL) was added Brettphos Pd G3 (226 mg, 0.249 mmol, 0.1 equiv) and CS2CO3 (1.62 g, 4.978 mmol, 2 equiv). The resulting mixture was stirred at 80 °C for one hour under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 :4) to afford tert-butyl 4-[6-({4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-2-methyl-l,3-thiazol-5- yl]pyrimidin-2-yl}amino)pyridin-3-yl]piperazine-l-carboxylate (700 mg, 37.01%) as a yellow solid. LCMS: C31H38FN9O4S2 requires: 683.3, found: m/z = 684.4 [M+H]+.
[000395] Step-3: Synthesis of 4-[4-(3-llethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)-2-methyl-l.,3-thiazol-5-yl]-A-[5-(piperazin-l-yl)pyridin-2-yl]pyriniidin-2- amine; trifluoroacetic acid
To a stirred mixture of tert-butyl 4-[6-({4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)-2 -methyl- 1,3-thi azol-5-yl]pyrimidin-2-yl}amino)pyri din-3 -yl]piperazine-l - carboxylate (700 mg, 1.024 mmol, 1 equiv) in DCM (12 mL) was added TFA (4 mL) at 0 °C. The resulting mixture was stirred at room temperature for one hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography with ACbFFhO (1 :3) to afford 4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)-2 -methyl- l,3-thiazol-5-yl]-7V-[5-(piperazin-l-yl)pyri din-2 -yl]pyrimidin-2- amine; trifluoroacetic acid salt (520.4 mg, 71.04%) as an orange solid. LCMS: C26H30FN9O2S2 requires: 583.2, found: m/z = 584.2 [M+H]+.
1H NMR (400 MHz, CD3OD) 5 8.58 - 8.52 (m, 1H), 8.20 - 8.13 (m, 1H), 7.82 - 7.77 (m, 1H), 7.69 - 7.60 (m, 1H), 7.57 - 7.50 (m, 1H), 7.48 - 7.40 (m, 1H), 7.40 - 7.32 (m, 1H), 6.95 - 6.89 (m, 1H), 3.66 - 3.50 (m, 4H), 3.50 - 3.29 (m, 4H), 3.27 - 3.17 (m, 2H), 2.86 - 2.79 (m, 6H), 1.16 - 1.08 (m, 3H).
[000396] Synthesis of 4-[4-(3-flethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-2- methyl-l.,3-thiazol-5-yl]-Az-[5-(piperidin-4-yl)pyridin-2-yl]pyrimidin-2-amine; trifluoroacetic acid salt
[000397] Step-1: _ Synthesis o butyl 4-[6-(14-r4-(3- f[ethyl(methyl)sulfamoyl]amino}-2-fluoroDhenyl)-2-methyl-l.,3-thiazol-5-yl]Dyrimidin-
2-vnamino)pyridin-3-yl] piperidine-l-carboxylate (2) To a mixture of ({3-[5-(2-chloropyrimidin-4-yl)-2-methyl-l,3-thiazol-4-yl]-2- fluorophenyl}sulfamoyl)(ethyl)methylamine (300 mg, 0.679 mmol, 1 equiv) and tert-butyl 4- (6-aminopyridin-3-yl)piperidine-l-carboxylate (282 mg, 1.018 mmol, 1.5 equiv) in dioxane (10 mL) was added Brettphos Pd G3 (62 mg, 0.068 mmol, 0.1 equiv) and CS2CO3 (442 mg, 1.358 mmol, 2 equiv). The resulting mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 :4) to afford tert-butyl 4-[6-({4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-2-methyl-l,3-thiazol-5- yl]pyrimidin-2-yl}amino)pyri din-3 -yl]piperi dine- 1 -carboxylate (350 mg, 67.95%) as a brown solid. LCMS: C32H39FN8O4S2 requires: 682.3, found: m/z = 683.2 [M+H]+.
[000398] Step-2: Synthesis of 4-[4-(3-][ethyl(methyl)sulfamoyl]amino}-2- fluoroDhenyl)-2-methyl-l.,3-thiazol-5-yl]-7V-[5-(DiDeridin-4-yl)Dyridin-2-yl]Dyrimidin-2- amine; trifluoroacetic acid
To a mixture of tert-butyl 4-[6-({4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)- 2-methyl-l,3-thiazol-5-yl]pyrimidin-2-yl}amino)pyridin-3-yl]piperidine-l -carboxylate (340 mg, 0.498 mmol, 1 equiv) in DCM (6 mL) was added TFA (2 mL) at 0 °C under an air atmosphere. The resulting mixture was stirred at room temperature for one hour. The resulting mixture was concentrated under reduced pressure. This resulted in 4-[4-(3- {[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-2-methyl-l,3-thiazol-5-yl]-7V-[5- (piperidin-4-yl)pyridin-2-yl]pyrimidin-2-amine; trifluoroacetic acid salt (319.4 mg, 91.05%) as a brown solid. LCMS: C27H31FN8O2S2 requires: 582.2, found: m/z = 583.2 [M+H]+. JH NMR (400 MHz, DMSO-tL) 5 11.09 - 11.05 (m, 1H), 9.69 - 9.65 (m, 1H), 8.76 - 8.69 (m, 1H), 8.55 - 8.46 (m, 1H), 8.19 - 8.14 (m, 1H), 7.97 - 7.90 (m, 1H), 7.86 - 7.79 (m, 1H), 7.58
- 7.49 (m, 1H), 7.48 - 7.39 (m, 1H), 7.39 - 7.31 (m, 1H), 6.72 - 6.66 (m, 1H), 3.46 - 3.39 (m, 2H), 3.11 - 3.00 (m, 4H), 3.00 - 2.90 (m, 1H), 2.81 - 2.76 (m, 3H), 2.69 - 2.64 (m, 3H), 2.04
- 1.96 (m, 2H), 1.87 - 1.72 (m, 2H), 1.06 - 0.98 (m, 3H).
[000399] Synthesis of 4-[4-(3-flethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-2- methyl-l.,3-thiazol-5-yl]-A-[3-fluoro-4-(DiDerazin-l-yl)Dhenyl]Dyrimidin-2-amine; trifluoroacetic acid salt
[000400]
][ethyl(methyl)sulfamoyl]amino}-2-fluoroDhenyl)-2-methyl-l.,3-thiazol-5-yl]Dyrimidin-
2-ynamino)-2-fluoroDhenyl]DiDerazine-l-carboxylate (2)
To a stirred mixture of ({3-[5-(2-chloropyrimidin-4-yl)-2-methyl-l,3-thiazol-4-yl]-2- fluorophenyl]sulfamoyl)(ethyl)methylamine (450 mg, 1.018 mmol, 1 equiv) and tert-butyl 4- (4-amino-2-fluorophenyl)piperazine-l -carboxylate (451 mg, 1.527 mmol, 1.5 equiv) in dioxane (10 mL) was added Brettphos Pd G3 (92 mg, 0.102 mmol, 0.1 equiv) and CS2CO3 (664 mg, 2.036 mmol, 2 equiv). The resulting mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The residue was purified by Cl 8 reverse phase column chromatography with ACN:H2O (7:3) to afford tert-butyl 4-[4-({4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)-2 -methyl- 1,3-thi azol-5-yl]pyrimidin-2-yl}amino)-2-fluorophenyl]piperazine-l- carboxylate (400 mg, 50.45%) as a yellow solid. LCMS: C32H38F2N8O4S2 requires: 700.2, found: m/z = 701.2 [M+H]+.
[000401 ] Step-2: Synthesis of 4-[4-(3-flethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)-2-methyl-l.,3-thiazol-5-yl]-7V-[3-fluoro-4-(DiDerazin-l- yl)Dhenyl]pyrimidin-2-amine; trifluoroacetic acid To a stirred mixture of tert-butyl 4-[4-({4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)-2 -methyl- 1,3-thi azol-5-yl]pyrimidin-2-yl}amino)-2-fluorophenyl]piperazine-l- carboxylate (400 mg, 0.571 mmol, 1 equiv) in DCM (6 mL) was added TFA (2 mL) at 0 °C. The resulting mixture was stirred at room temperature for one hour. The resulting mixture was concentrated under reduced pressure. This resulted in 4-[4-(3- { [ethyl (methyl)sulfamoyl]amino}-2-fluorophenyl)-2-methyl-l,3-thiazol-5-yl]-7V-[3-fluoro-4- (piperazin-l-yl)phenyl]pyrimidin-2-amine; trifluoroacetic acid salt (345.9 mg, crude) as an orange solid. LCMS: C27H30F2N8O2S2 requires: 600.2, found: m/z = 601.1 [M+H]+.
1 H NMR (400 MHz, CD3OD) 5 8.29 - 8.23 (m, 1H), 7.71 - 7.60 (m, 2H), 7.37 - 7.27 (m, 3H), 7.09 - 7.00 (m, 1H), 6.52 - 6.46 (m, 1H), 3.45 - 3.38 (m, 4H), 3.33 - 3.14 (m, 4H), 3.27 - 3.12 (m, 2H), 2.82 - 2.76 (m, 6H), 1.13 - 1.05 (m, 3H).
[000402] Synthesis of 7V-]2-fluoro-3-[l-(4-formylDhenyl)-3-(Dyridin-4-yl)Dyrazol-4- yl]DhenynDroDane-l-sulfonamide
[000403] Step-1: Synthesis of N-!2-niioro-3-|3-(pyridin-4-yl)-l//-pyrazol-4- yl]phenvnpropane-l-sulfonamide (2)
To a mixture of 7V-{2-fluoro-3-[3-(pyridin-4-yl)-l-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol- 4-yl]phenyl (propane- 1 -sulfonamide (2.0 g, 4.076 mmol, 1 equiv) in DCM (15 mL) was added TFA (5 mL). The resulting mixture was stirred for one hour at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with C^CL MeOH (8: 1) to afford 7V-{2-fluoro-3-[3-(pyridin- 4-yl)-U/-pyrazol-4-yl]phenyl}propane-l-sulfonamide (1.0 g, 68.07%) as a yellow solid. LCMS: C17H17FN4O2S requires: 360.1, found: m/z = 361.1 [M+H]+.
[000404] Step-2: Synthesis of 7V-]2-fluoro-3-|l-(4-formylDhenyl)-3-(Dyridin-4- yl)Dyrazol-4-yl]DhenynDroDane-l-sulfonamide
To a mixture of A-{2-fluoro-3-[3-(pyridin-4-yl)-U/-pyrazol-4-yl]phenyl}propane-l- sulfonamide (500 mg, 1.387 mmol, 1 equiv) and 4-fluorobenzaldehyde (516.55 mg, 4.161 mmol, 3.0 equiv) in DMSO (1 mL) was added K2CO3 (958.67 mg, 6.935 mmol, 5.0 equiv) in portions at room temperature. The resulting mixture was stirred at 110 °C overnight. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous ISfeSCU After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol/L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford A-{2-fluoro-3-[l- (4-formylphenyl)-3-(pyridin-4-yl)pyrazol-4-yl]phenyl}propane-l-sulfonamide (297.3 mg, 46.13%) as a light yellow solid. LCMS: C24H21FN4O3S requires: 464.1, found: m/z = 465.1 [M+H]+. 'HNMR (400 MHz, CD3OD) 5 10.06 (s, 1H), 8.71 (s, 1H), 8.55 (d, J= 1.8 Hz, 2H), 8.23 - 8.19 (s, 2H), 8.12 (d, J= 8.6 Hz, 2H), 7.66 - 7.55 (m, 3H), 7.28 - 7.13 (m, 2H), 3.10 - 3.02 (m, 2H), 1.87 - 1.73 (m, 2H), 1.05 - 0.95 (m, 3H).
[000405] Synthesis of A-(2-fluoro-3-]l-[4-(4-formylDiperidin-l-yl)Dhenyl]-3- (Dyridin-4-yl)Dyrazol-4- Dropane-l-sulfonamide
[000406] Step-1: Synthesis of A-I3-[l-(4-bromophenyl)-3-(pyridin-4-yl)pyrazol-4- vH-2-fluorophenvnpropane-l-sulfonamide (2)
To a stirred mixture of 7V-{2-fluoro-3-[3-(pyridin-4-yl)-lJ/-pyrazol-4-yl]phenyl}propane-l- sulfonamide (3 g, 8.324 mmol, 1 equiv) and 2-(4-bromophenyl)-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (3.53 g, 12.486 mmol, 1.5 equiv) in pyridine (50 mL) was added Cu(OAc)2 (3.02 g, 16.648 mmol, 2 equiv) and molecular sieves (4A) (3 g). The resulting mixture was stirred at 100 °C overnight under an oxygen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 : 1) to afford N-{ 3 -[ 1 -(4-bromophenyl)-3-(pyridin-4- yl)pyrazol-4-yl]-2-fluorophenyl (propane- 1 -sulfonamide (2.4 g, 39.16%) as abrown semi-solid. LCMS: C23H2oBrFN402S requires: 514.1, found: m/z = 515.0 [M+H]+.
[000407] Step-2: Synthesis of A-[3-(l-I4-[4-(dimethoxymethyl)piperidin-l- yl]phenvn-3-(pyridin-4-yl)pyrazol-4-yl)-2-fluorophenyl]propane-l-sulfonamide (3)
To a stirred mixture of A-{3-[l-(4-bromophenyl)-3-(pyridin-4-yl)pyrazol-4-yl]-2- fluorophenyl (propane- 1 -sulfonamide (2.4 g, 4.657 mmol, 1 equiv) and 4- (dimethoxymethyl)piperidine (1.11 g, 6.986 mmol, 1.5 equiv) in DMSO (20 mL) was added L-proline (214 mg, 1.863 mmol, 0.4 equiv), K2CO3 (1.93 g, 13.971 mmol, 3 equiv), and Cui (177 mg, 0.931 mmol, 0.2 equiv). The resulting mixture was stirred at 100 °C overnight under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (4: 1) to afford A-[3-(l-{4-[4-(dimethoxymethyl)piperidin-l-yl]phenyl}-3-(pyridin-4-yl)pyrazol-4-yl)-2- fluorophenyl]propane-l -sulfonamide (700 mg, 22.79%) as a brown solid. LCMS: C31H36FN5O4S requires: 593.3, found: m/z = 594.2 [M+H]+.
[000408] Step-3: Synthesis of A-(2-fluoro-3-H-[4-(4-formylDiDeridin-l-yl)phenyl]-3- (Dyridin-4-yl)Dyrazol-4-ynDhenyl)DroDane-l-sulfonamide
To a stirred mixture of 7V-[3-(l-{4-[4-(dimethoxymethyl)piperidin-l-yl]phenyl}-3-(pyridin-4- yl)pyrazol-4-yl)-2-fluorophenyl]propane-l -sulfonamide (500 mg, 0.842 mmol, 1 equiv) in THF (5 mL) was added PPTS (423 mg, 1.684 mmol, 2 equiv). The resulting mixture was stirred at 70 °C overnight under a nitrogen atmosphere. The residue was purified by Cl 8 reverse phase column chromatography with ACbTEhO (1 : 1) to afford A-(2-fluoro-3-{ l-[4-(4- formylpiperidin-l-yl)phenyl]-3-(pyridin-4-yl)pyrazol-4-yl}phenyl)propane-l-sulfonamide (348.7 mg, 74.09%) as a light yellow solid. LCMS: C29H30FN5O3S requires: 547.2, found: m/z = 548.2 [M+H]+. 1 H NMR (400 MHz, DMSO-t/e) 8 9.70 - 9.64 (m, 2H), 8.72 - 8.68 (m, 1H), 8.64 - 8.56 (m, 2H), 7.82 - 7.75 (m, 2H), 7.56 - 7.43 (m, 3H), 7.39 - 7.25 (m, 2H), 7.16 - 7.08 (m, 2H), 3.75 - 3.66 (m, 2H), 3.07 - 2.99 (m, 2H), 2.98 - 2.87 (m, 2H), 2.56 - 2.51 (m, 1H), 2.01 - 1.92 (m, 2H), 1.76 - 1.55 (m, 4H), 0.96 - 0.88 (m, 3H).
[000409] Synthesis of 4-[4-(3-]|ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-2- (l)iperidiii-4-yl)-l .3-tlii:izol-5-yl|-\-isoi)roi)yli)yriiiiidiii-2-ainine: trifluoroacetic acid salt
[000410] Step-1: Synthesis of tert-butyl 4-[5-(2-chloroDyrimidin-4-yl)-4-(2-fluoro-3- 2-en-l-yloxy)carbonyl]amino}Dhenyl)-l.,3-thiazol-2-yl]DiDeridine-l-carboxylate (3)
A mixture of prop-2-en-l-yl 7V-{3-[2-(2-chloropyrimidin-4-yl)acetyl]-2- fluorophenyl} carbamate (4.29 g, 12.277 mmol, 1.0 equiv) and NBS (1.75 g, 9.822 mmol, 0.8 equiv) in DMA (15 mL) was stirred for 15 min at room temperature. To the above mixture was added tert-butyl 4-carbamothioylpiperidine-l -carboxylate (3.0 g, 12.277 mmol, 1 equiv) in portions at room temperature. The resulting mixture was stirred for an additional 2 h at room temperature. The reaction was quenched with water/ice at 0 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (4: 1) to afford tert-butyl 4-[5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-3-{[(prop-2-en-l- yloxy)carbonyl]amino}phenyl)-l,3-thiazol-2-yl]piperidine-l-carboxylate (3.4 g, 48.23%) as a yellow solid. LCMS: C27H29CIFN5O4S requires: 573.2, found: m/z = 574.2 [M+H]+. [00041 1] Step-2: Synthesis of te -butyl 4-[4-(3-amino-2-fluorophenyl)-5-(2- chloropyrimidin-4-yl)-l.,3-thiazol-2-yl]piperidine-l-carboxylate (4)
To a mixture of tert-butyl 4-[5-(2-chloropyrimidin-4-yl)-4-{3-[(ethoxycarbonyl)amino]-2- fluorophenyl}-l,3-thiazol-2-yl]piperidine-l-carboxylate (3.4 g, 6.049 mmol, 1 equiv) and Pd(PPh3)2Cl2 (84.92 mg, 0.121 mmol, 0.02 equiv) in DCM (35 mL) was added HO Ac (908.16 mg, 15.123 mmol, 2.5 equiv) dropwise at room temperature under a nitrogen atmosphere. To the above mixture was added w-BusSnH (2817.14 mg, 9.678 mmol, 1.6 equiv) dropwise at 0 °C. The resulting mixture was stirred for one hour at room temperature. The reaction was quenched with saturated aqueous sodium hyposulfite at 0 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2:MeOH (10: 1) to afford tert-butyl 4-[4-(3-amino-2-fluorophenyl)-5-(2-chloropyrimidin-4-yl)-l,3-thiazol-2- yl]piperidine-l -carboxylate (2.5 g, 84.34%) as a yellow solid. LCMS: C23H25C1FNSO2S requires: 489.1 found: m/z = 490.1 [M+H]+.
[000412] Step-3: Synthesis of tert-butyl 4-[5-(2-chloropyrimidin-4-yl)-4-(3- f|ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l.,3-thiazol-2-yl]piperidine-l- carboxylate (6)
To a stirred mixture of tert-butyl 4-[4-(3-amino-2-fluorophenyl)-5-(2-chloropyrimidin-4-yl)- l,3-thiazol-2-yl]piperidine-l-carboxylate (1.0 g, 2.041 mmol, 1 equiv) and A-ethyl-A- methyl sulfamoyl chloride (1.93 g, 12.246 mmol, 6.0 equiv, in situ) in DCM (10 mL) was added TEA (1.03 g, 10.205 mmol, 5.0 equiv) at room temperature. The resulting mixture was stirred for 3 h at 70 °C. The reaction was quenched with water/ice at 0 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2:EtOAc (2: 1) to afford tert-butyl 4-[5-(2-chloropyrimidin-4-yl)-4-(3-{ [ethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)-l,3-thiazol-2-yl]piperidine-l-carboxylate (500 mg, 40.09%) as a yellow solid. LCMS: C26H32C1FN6O4S2 requires: 610.2 found: m/z = 611.2 [M+H]+.
[000413] Step-4: Synthesis of tert-butyl 4-[4-(3-f[ethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)-5-[2-(isopropylamino)pyrimidin-4-yl]-l.,3-thiazol-2-yl]piperidine-l- carboxylate (7) To a mixture of tert-butyl 4-[5-(2-chloropyrimidin-4-yl)-4-(3- {[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3-thiazol-2-yl]piperidine-l-carboxylate (500 mg, 0.818 mmol, 1 equiv) and isopropylamine (145.08 mg, 2.454 mmol, 3.0 equiv) in DMSO (5 mL) was added DIEA (317.22 mg, 2.454 mmol, 3.0 equiv) dropwise at room temperature. The resulting mixture was stirred at 80 °C overnight. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous ISfeSCU After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CEEChiEtOAc (2: 1) to afford tert-butyl 4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-5-[2- (isopropylamino)pyrimidin-4-yl]-l,3-thiazol-2-yl]piperidine-l-carboxylate (350 mg, 67.50%) as a yellow solid. LCMS: C29H40FN7O4S2 requires: 633.3 found: m/z = 634.3 [M+H]+.
[000414] Step-5: Synthesis of 4-[4-(3-f[ethyl(methyl)sulfamoyl]amino}-2- fluoroDhenyl)-2-(DiDeridin-4-yl)-l.,3-thiazol-5-yl]-A-isoDroDylDyrimidin-2-amine; trifluoroacetic acid
To a mixture of tert-butyl 4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-5-[2- (isopropylamino)pyrimidin-4-yl]-l,3-thiazol-2-yl]piperidine-l-carboxylate (350 mg, 0.552 mmol, 1 equiv) in DCM (2 mL) was added TFA (2 mL). The resulting mixture was stirred at room temperature for one hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford 4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}- 2-fluorophenyl)-2-(piperidin-4-yl)-l,3-thiazol-5-yl]-7V-isopropylpyrimidin-2-amine; trifluoroacetic acid salt (339.6 mg, 94.94%) as a yellow solid. LCMS: C24H32FN7O2S2 requires: 533.2 found: m/z = 534.2 [M+H]+. 'H NMR (400 MHz, CD3OD) 5 8.07 (d, J= 6.2 Hz, 1H), 7.72 - 7.62 (m, 1H), 7.38 - 7.27 (m, 2H), 6.48 (s, 1H), 4.05 - 3.95 (m, 1H), 3.58 - 3.50 (m, 3H), 3.26 - 3.15 (m, 4H), 2.85 - 2.77 (m, 3H), 2.41 - 2.31 (m, 2H), 2.19 - 2.04 (m, 2H), 1.24 - 1.18 (m, 6H), 1.21 - 1.05 (m, 3H).
[000415] Synthesis of A-(2-fluoro-3-n-[6-(Diperazin-l-yl)Dyridin-3-yl]-3-(Dyridin-4- yl)Dyrazol-4-yl}Dhenyl)DroDane-l-sulfonamide; trifluoroacetic acid salt
[000416] Step-1: Synthesis of tert-butyl 4-(5-14-[2-fluoro-3-(proDane-l- sulfonamido)Dhenyl]-3-(Dyridin-4-yl)Dyrazol-l-vnDyridin-2-yl)Diperazine-l-carboxylate
(3)
To a mixture of 7V-{2-fluoro-3-[3-(pyridin-4-yl)-lJ/-pyrazol-4-yl]phenyl}propane-l- sulfonamide (600 mg, 1.665 mmol, 1 equiv) and tert-butyl 4-[5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridin-2-yl]piperazine-l-carboxylate (972.14 mg, 2.498 mmol, 1.5 equiv) in pyridine (4 mL) was added Cu(OAc)2 (604.76 mg, 3.330 mmol, 2.0 equiv) and molecular sieves 4 A (600 mg) at room temperature. The resulting mixture was stirred at 100 °C overnight under an oxygen atmosphere. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous ISfeSCU After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CthCb MeOH (10: 1) to afford tert-butyl 4-(5-{4-[2-fhioro-3- (propane- 1 -sulfonamido)phenyl]-3 -(pyridin-4-yl)pyrazol- 1 -yl }pyridin-2-yl)piperazine- 1 - carboxylate (440 mg, 42.51%) as a white solid. LCMS: C31H36FN7O4S requires: 621.3, found: m/z = 622.3 [M+H]+.
[000417] Step-2: Synthesis of A-(2-fluoro-3-fl-[6-(DiDerazin-l-yl)Dyridin-3-yl]-3- (Dyridin-4-yl)Dyrazol-4-ynDhenyl)DroDane-l-sulfonamide; trifluoroacetic acid
To a mixture of tert-butyl 4-(5-{4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-3-(pyridin-4- yl)pyrazol-l-yl}pyridin-2-yl)piperazine-l-carboxylate (440 mg, 0.708 mmol, 1 equiv) in DCM (3 mL) was added TFA (3 mL). The resulting mixture was stirred for one hour at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford A-(2-fhioro-3-{ l-[6-(piperazin-l-yl)pyridin-3-yl]-3-(pyridin-4- yl)pyrazol-4-yl}phenyl)propane-l-sulfonamide; trifluoroacetic acid salt (314.4 mg, 68.03%) as a yellow solid. LCMS: C26H28FN7O2S requires: 521.2, found: m/z = 522.1 [M+H]+. 'H NMR (400 MHz, CD3OD) 5 8.78 (s, 1H), 8.76 - 8.69 (m, 2H), 8.58 (s, 1H), 8.24 - 8.18 (m, 1H), 8.16 (d, J= 6.8 Hz, 2H), 7.62 - 7.56 (m, 1H), 7.43 - 7.28 (m, 2H), 7.12 (d, J= 9.2 Hz, 1H), 4.08 - 3.80 (m, 4H), 3.48 - 3.32 (m, 4H), 3.21 - 3.06 (m, 2H), 1.99 - 1.70 (m, 2H), 1.10 - 0.92 (m, 3H).
[000418 ] Synthesis of A-f3-[5-(2-aminoDyrimidin-4-yl)-2-[2-(Diperidin-4- yl)ethynyl]-l.,3-thiazol-4-yl]-2-fluoroDhenvnDroDane-l-sulfonaniide; trifluoroacetic acid salt
[000419] Step-1: Synthesis of prop-2-eii-l-yl \-!3-|2-:iiiiiiio-5-(2-chloropyriniidin-4- yl)-l.,3-thiazol-4-yl]-2-fluoroDhenyncarbamate (2)
To a mixture of prop-2-en-l-yl A-{3-[2-(2-chloropyrimidin-4-yl)acetyl]-2- fluorophenyl} carbamate (3 g, 8.578 mmol, 1 equiv) in DMA (30 mL) was added NBS (1.53 g, 8.578 mmol, 1 equiv) at 0 °C. The resulting mixture was stirred for 15 min at 0 °C. To the above mixture was added thiourea (0.78 g, 10.294 mmol, 1.2 equiv) at 0 °C. The resulting mixture was stirred for an additional 2 h at 60 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with DCM:EtOAc (1 : 1) to afford prop-2- en-l-yl A-{3-[2-amino-5-(2-chloropyrimidin-4-yl)-l,3-thiazol-4-yl]-2- fluorophenyl] carbamate (3.1 g, 89.05%) as a yellow solid. LCMS: C17H13CIFN5O2S requires: 405.1, found: m/z =406.0[M+H]+.
[000420] Step-2: Synthesis of prop-2-en-l-yl A-13-[2-bromo-5-(2-chloropyrimidin-4- yl)-l.,3-thiazol-4-yl]-2-fluorophenvncarbamate (3)
To a mixture of prop-2-en-l-yl A-{3-[2-amino-5-(2-chloropyrimidin-4-yl)-l,3-thiazol-4-yl]-2- fluorophenyl] carbamate (3 g, 7.392 mmol, 1 equiv) in MeCN (30 mL) was added CuBn (825.55 mg, 3.696 mmol, 0.5 equiv) and Z-BuONO (762.30 mg, 7.392 mmol, 1 equiv) at 0 °C. The resulting mixture was stirred for 3 h at 0 °C. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with CEEChiEtOAc (1 : 1) to afford prop-2-en-l-yl A-{3-[2-bromo-5-(2-chloropyrimidin-4-yl)-l,3- thiazol-4-yl]-2-fluorophenyl}carbamate (1.5 g, 43.20%) as an off-white solid. LCMS: Ci7HnBrClFN4O2S requires: 468.0, found: m/z = 469.0 [M+H]+.
[000421 ] Step-3: Synthesis of 3-[2-bromo-5-(2-chloropyrimidin-4-yl)-l.,3-thiazol-4- yl]-2-fluoroaniline (4)
To a mixture of prop-2-en-l-yl A-{3-[2-bromo-5-(2-chloropyrimidin-4-yl)-l,3-thiazol-4-yl]-
2-fluorophenyl} carbamate (1.2 g, 2.555 mmol, 1 equiv) and Pd(PPh3)2Ch (0.04 g, 0.051 mmol, 0.02 equiv) in DCM (10 mL) was added HOAc (0.40 g, 6.643 mmol, 2.6 equiv) and w-BusSnH (1.19 g, 4.088 mmol, 1.6 equiv) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred for 30 min at room temperature under nitrogen atmosphere. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaHCOs and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CEEChiMeOH (10: 1) to afford 3-[2-bromo-5-(2-chloropyrimidin-4-yl)-l,3-thiazol-4-yl]-2- fluoroaniline (603 mg, 61.20%) as a yellow solid. LCMS: CnHyBrClFN-tS requires: 383.9, found: m/z =385.0 [M+H]+.
[000422] Step-4: Synthesis of A-]3-[2-bromo-5-(2-chloropyrimidin-4-yl)-l.,3-thiazol- 4-yl]-2-fluorophenvnpropane-l-sulfonamide (6)
To a mixture of 3-[2-bromo-5-(2-chloropyrimidin-4-yl)-l,3-thiazol-4-yl]-2 -fluoroaniline (603 mg, 1.564 mmol, 1 equiv) and TEA (791.14 mg, 7.820 mmol, 5 equiv) in DCM (650 mL) was added propane- 1 -sulfonyl chloride (267.57 mg, 1.877 mmol, 1.2 equiv) at 0 °C. The resulting mixture was stirred for one hour at room temperature. The resulting mixture was concentrated under vacuum. To the above mixture was added Na2COs (497.18 mg, 4.692 mmol, 3 equiv) in THF (10 mL), MeCN (10 mL), and H2O (10 mL) at room temperature. The resulting mixture was stirred overnight at 50 °C. The resulting mixture was extracted with CH2CI2. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CEEChiMeOH (10: 1) to afford A-{3-[2-bromo-5-(2- chloropyrimidin-4-yl)- 1 ,3 -thiazol-4-yl]-2-fluorophenyl (propane- 1 -sulfonamide (701 mg, 91.16%) as a yellow solid. LCMS: CieHi3BrClFN4O2S2 requires: 489.9, found: m/z =491.0 [M+H]+.
[000423] Step-5: Synthesis of fert-butyl 4-]2-[5-(2-chloropyrimidin-4-yl)-4-[2-fluoro-
3-(propane-l-sulfonamido)phenyl]-l.,3-thiazol-2-yl]ethvnvnpiperidine-l-carboxylate (8) To a mixture of A-{3-[2-bromo-5-(2-chloropyrimidin-4-yl)-l,3-thiazol-4-yl]-2- fluorophenyl} propane- 1 -sulfonamide (710 mg, 1.444 mmol, 1 equiv) and tert-butyl 4- ethynylpiperidine-1 -carboxylate (453.24 mg, 2.166 mmol, 1.5 equiv) in THF (300 mL) was added TEA (100 mL), Pd(PPh3)4 (250.25 mg, 0.217 mmol, 0.15 equiv), and Cui (82.49 mg, 0.433 mmol, 0.3 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight under the nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CFLCL MeOH (10: 1) to afford tert-butyl 4-{2-[5-(2- chloropyrimidin-4-yl)-4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-l,3-thiazol-2- yl]ethynyl (piperidine- 1 -carboxylate (587 mg, 65.56%) as a yellow solid. LCMS: C28H31CIFN5O4S2 requires: 619.2, found: m/z =620.1 [M+H]+.
[000424] Step-6: Synthesis of tert-butyl 4-|2-(5-!2-|(tert- butoxycarbonyl)amino]pyrimidin-4-vn-4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]- l,3-thiazol-2-yl)ethvnyl]piperidine-l-carboxylate (9)
To a mixture of tert-butyl 4-{2-[5-(2-chloropyrimidin-4-yl)-4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-l,3-thiazol-2-yl]ethynyl}piperidine-l-carboxylate (587 mg, 0.947 mmol, 1 equiv) and tert-butyl carbamate (554.42 mg, 4.735 mmol, 5 equiv) in dioxane (15 mL) was added BrettPhos Pd G3 (85.80 mg, 0.095 mmol, 0.1 equiv) and CS2CO3 (616.79 mg, 1.894 mmol, 2 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 2 h at 80 °C under the nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CEECh MeOH (10: 1). The residue product was purified by reverse phase flash chromatography with MeCN/FEO (65:35) to afford tert-butyl 4-[2-(5-{2-[(tert- butoxycarbonyl)amino]pyrimidin-4-yl}-4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-l,3- thiazol-2-yl)ethynyl]piperidine-l -carboxylate (270 mg, 40.70%) as a yellow solid. LCMS: C33H41FN6O6S2 requires: 700.3, found: m/z =701.3 [M+H]+.
[000425] Step-7: Synthesis of N-I3-[5-(2-aminopyrimidin-4-yl)-2-[2-(piperidin-4- yl)ethvnyl]-l.,3-thiazol-4-yl]-2-fluorophenvnpropane-l-sulfonaniide; trifluoroacetic acid (10)
To a mixture of tert-butyl 4-[2-(5-{2-[(tert-butoxycarbonyl)amino]pyrimidin-4-yl}-4-[2- fluoro-3-(propane-l-sulfonamido)phenyl]-l,3-thiazol-2-yl)ethynyl]piperidine-l-carboxylate (270 mg, 0.385 mmol, 1 equiv) in DCM (6 mL) was added TFA (2 mL) at room temperature. The resulting mixture was stirred for one hour at room temperature. The resulting mixture was concentrated under vacuum. This resulted in 7V-{3-[5-(2-aminopyrimidin-4-yl)-2-[2- (piperidin-4-yl)ethynyl]- 1 ,3 -thiazol-4-yl]-2-fluorophenyl (propane- 1 -sulfonamide; trifluoroacetic acid (297.6 mg, crude) as a yellow solid. LCMS: C23H25FN6O2S2 requires: 500.2, found: m/z =501.0 [M+H]+. *H NMR (400 MHz, CD3OD) 5 8.11 (d, J = 5.6 Hz, 1H), 7.71 - 7.68 (m, 1H), 7.40 - 7.33 (m, 2H), 6.40 - 6.38 (m, 1H), 3.47 - 3.41 (m, 2H), 3.24 - 3.17 (m, 3H), 3.14 - 3.10 (m, 2H), 2.27 - 2.22 (m, 2H), 2.10 - 1.96 (m, 2H), 1.88 - 1.82 (m, 2H), 1.05 - 1.02 (m, 3H).
[000426] Synthesis of 7V-[3-(l-]3-azasDiro[5.5]undecan-9-vn-3-(Dyridin-4- yl)Dyrazol-4-yl)-2-fluoroDhenyl]DroDane-l-sulfonamide; trifluoroacetic acid salt azasDiro[5.5]undecane-3-carboxylate (2) To a mixture of tert-butyl 9-hydroxy-3-azaspiro[5.5]undecane-3-carboxylate (1.0 g, 3.712 mmol, 1 equiv) and TEA (563.47 mg, 5.568 mmol, 1.5 equiv) in DCM (5 mL) was added methanesulfonic anhydride (711.28 mg, 4.083 mmol, 1.1 equiv) dropwise at 0 °C. The resulting mixture was stirred for 3 h at room temperature. The reaction was quenched by the addition of H2O at 0 °C. The resulting mixture was extracted with CH2Q2. The combined organic layers were washed with water and dried over anhydrous ISfeSC After filtration, the filtrate was concentrated under reduced pressure to afford tert-butyl 9-(methanesulfonyloxy)-3- azaspiro[5.5 ]undecane-3 -carboxylate (1.15 g, crude) as a white solid.
[000428] Step-2: Synthesis of tert-butyl 9-]4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-3-(pyridin-4-yl)pyrazol-l-vn-3-azaspiro[5.5]undecane-3- carboxylate (4)
To a mixture of tert-butyl 9-(methanesulfonyloxy)-3-azaspiro[5.5 ]undecane-3 -carboxylate (2603.06 mg, 7.494 mmol, 6.0 equiv) and A-{2-fluoro-3-[3-(pyridin-4-yl)-lJ/-pyrazol-4- yl]phenyl}propane-l-sulfonamide (450 mg, 1.249 mmol, 1.00 equiv) in DMF (5 mL) was added K2CO3 (345.12 mg, 2.498 mmol, 2.0 equiv) at room temperature. The resulting mixture was stirred at 80 °C overnight. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous ISfeSC After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CFLCL MeOH (10: 1) to afford tert-butyl 9-{4-[2-fhioro-3- (propane- 1 -sulfonamido)phenyl]-3 -(pyridin-4-yl)pyrazol- 1 -yl } -3 -azaspiro[5.5]undecane-3 - carboxylate (221 mg, 28.93%) as a yellow solid. LCMS: C32H42FN5O4S requires: 611.3, found: m/z = 612.0 [M+H]+.
[000429] Step-3: Synthesis of 7V-[3-(l-]3-azaspiro[5.5]undecan-9-vn-3-(pyridin-4- yl)pyrazol-4-yl)-2-fluorophenyl]propane-l-sulfonamide; trifluoroacetic acid
To a stirred mixture of tert-butyl 9-{4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-3- (pyridin-4-yl)pyrazol-l-yl}-3-azaspiro[5.5]undecane-3-carboxylate (200 mg, 0.327 mmol, 1 equiv) in DCM (0.5 mL) was added TFA (0.5 mL) at room temperature. The resulting mixture was stirred for one hour at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CEECbFEhO (10: 1) to afford A-[3-(l-{3-azaspiro[5.5]undecan-9-yl}-3-(pyridin-4-yl)pyrazol- 4-yl)-2-fluorophenyl]propane-l -sulfonamide; trifluoroacetic acid salt (165.3 mg, 78.96%) as an off-white solid. LCMS: C27H34FN5O2S requires: 511.2, found: m/z = 512.2 [M+H]+. JH NMR (400 MHz, CD3OD) 5 8.68 - 8.60 (m, 2H), 8.08 - 7.92 (m, 3H), 7.62 - 7.58 (m, 1H), 7.49 - 7.45 (m, 1H), 7.41 - 7.35 (m, 1H), 3.97 - 3.91 (m, 1H), 3.25 - 3.11 (m, 4H), 3.08 -3.02 (m, 2H), 2.03 - 1.93 (m, 1H), 1.88 - 1.72 (m, 5H), 1.58 - 1.52(m, 4H), 1.43 - 1.30 (m, 3H), 1.27 - 1.23 (m, 1H), 1.08 - 1.02 (m, 3H).
[000430] Synthesis of 4-[4-(3-l[ethyl(methyl)sulfamoyl]amino}-2-fluoroDhenyl)-l.,3- thiazol-5-YH-7V-[5-(DiDerazin-l-yl)Dyridin-2-yl]Dyrimidin-2-amine; trifluoroacetic acid salt
[000431 ] Step-1: Synthesis of i)i op-2-eii-l-yl 5-(2-cliloi opyi iiiiidiii-4- yl)-l.,3-thiazol-4-yl]-2-fluoroDhenyncarbamate (2)
To a mixture of prop-2-en-l-yl A-{3-[2-(2-chloropyrimidin-4-yl)acetyl]-2- fluorophenyl} carbamate (5.0 g, 14.296 mmol, 1 equiv) and NBS (2.54 g, 14.296 mmol, 1.0 equiv) in DMA (40 mL) was stirred for 15 min at 0 °C. To the above mixture was added thiourea (1.31 g, 17.155 mmol, 1.2 equiv) in portions at 0 °C. The resulting mixture was stirred for an additional 2 h at room temperature. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CEEChiMeOEl (10: 1) to afford prop-2-en-l-yl A-{3-[2-amino-5-(2-chloropyrimidin-4-yl)-l,3-thiazol-4-yl]-2-fluorophenyl (carbamate (3.8 g, 65.50%) as a yellow solid. LCMS: C17H13CIFN5O2S requires: 405.1, found: m/z = 406.0 [M+H]+.
[00043 ] Step-2: Synthesis of prop-2-en-l-yl \-!3-|5-(2-chloropyrimidin-4-yl)-L3- thiazol-4-yl]-2-fluorophenyncarbamate (3)
To a mixture of prop-2-en-l-yl A-{3-[2-amino-5-(2-chloropyrimidin-4-yl)-l,3-thiazol-4-yl]-2- fluorophenyl} carbamate (3.0 g, 7.392 mmol, 1 equiv) in EtOAc (30.0 mL) was added tertbutyl nitrite (1.14 g, 11.088 mmol, 1.5 equiv) in portions at room temperature. The resulting mixture was stirred for 4 h at 50 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CTECh EtOAc (3: 1) to afford prop-2-en-l-yl A-{3-[5-(2-chloropyrimidin-4-yl)-l,3-thiazol-4- yl]-2-fluorophenyl}carbamate (1.5 g, 51.92%) as a yellow solid. LCMS: C17H12CIFN4O2S requires: 390.0, found: m/z = 391.0 [M+H]+.
[000433] Step-3: Synthesis of 3-[5-(2-chloropyrimidin-4-yl)-l.,3-thiazol-4-yl]-2- fluoroaniline (4)
To a mixture of prop-2-en-l-yl A-{3-[5-(2-chloropyrimidin-4-yl)-l,3-thiazol-4-yl]-2- fluorophenyl} carbamate (1.5 g, 3.838 mmol, 1 equiv) and HOAc (0.58 g, 9.595 mmol, 2.5 equiv) in DCM (15 mL) was added w-BusSnH (1.79 g, 6.141 mmol, 1.6 equiv) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred for one hour at room temperature under the nitrogen atmosphere. The reaction was quenched by the addition of sat. sodium hyposulfite at 0 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CFLCL MeOH (10: 1) to afford 3-[5-(2-chloropyrimidin-4-yl)- l,3-thiazol-4-yl]-2 -fluoroaniline (800 mg, 78.14%) as a yellow oil. LCMS: C13H8CIFN4S requires: 306.0, found: m/z = 307.1 [M+H]+.
[000434] Step-4: Synthesis of (]3-[5-(2-chloropyrimidin-4-yl)-l.,3-thiazol-4-yl]-2- fluorophenyBsulfamoyl) (ethyl)methylamine (5)
To a mixture of 3-[5-(2-chloropyrimidin-4-yl)-l,3-thiazol-4-yl]-2-fluoroaniline (800 mg, 2.608 mmol, 1 equiv) and TEA (1.32 g, 13.040 mmol, 5.0 equiv) in DCM (8 mL) was addedA-ethyl- A-m ethyl sulfamoyl chloride (2.46 g, 15.648 mmol, 6.0 equiv) at room temperature. The resulting mixture was stirred for 3 h at 70 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Ch:MeOH (10: 1) to afford ({3-[5-(2-chloropyrimidin-4-yl)-l,3-thiazol-4-yl]-2- fluorophenyl}sulfamoyl)(ethyl)methylamine (290 mg, 25.99%) as a yellow solid. LCMS: C16H15CIFN5O2S2 requires: 427.0, found: m/z = 428.0 [M+H]+.
[000435] Step-5: Synthesis of tert-butyl 4-[6-({4-[4-(3- (methyl)sulfamoyl]amino}-2-flnorophenyl)-l.,3-thiazol-5-yl]pyriniidin-2- vnamino)pyridin-3-yl]piperazine-l-carboxylate (6)
To a mixture of ({3-[5-(2-chloropyrimidin-4-yl)-l,3-thiazol-4-yl]-2-fluorophenyl} sulfamoyl)(ethyl)methylamine (290 mg, 0.678 mmol, 1 equiv) and tert-butyl 4-(6- aminopyridin-3-yl)piperazine-l -carboxylate (245.24 mg, 0.881 mmol, 1.3 equiv) in 1,4- dioxane (3 mL) was added CS2CO3 (441.63 mg, 1.356 mmol, 2.0 equiv) and BrettPhos Pd G3 (61.44 mg, 0.068 mmol, 0.1 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 2 h at 80 °C under the nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CffCh MeOH (8: 1) to afford tert-butyl 4-[6-({4-[4-(3- {[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3-thiazol-5-yl]pyrimidin-2- yl}amino)pyri din-3 -yl]piperazine-l -carboxylate (200 mg, 44.06%) as a yellow solid. LCMS: C30H36FN9O4S2 requires: 669.2, found: m/z = 670.2 [M+H]+.
[000436] Step-6: Synthesis of 4-[4-(3-f[ethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)-l.,3-thiazol-5-yl]-7V-[5-(piperazin-l-yl)pyridin-2-yl]pyriniidin-2-aniine; trifluoroacetic acid
To a mixture of tert-butyl 4-[6-({4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)- l,3-thiazol-5-yl]pyrimidin-2-yl}amino)pyridin-3-yl]piperazine-l-carboxylate (200 mg, 0.299 mmol, 1 equiv) in DCM (2 mL) was added TFA (2 mL) at room temperature. The resulting mixture was stirred for one hour at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford 4-[4-(3- {[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3-thiazol-5-yl]-A-[5-(piperazin-l- yl)pyridin-2-yl]pyrimidin-2-amine; trifluoroacetic acid salt (160.8 mg, 78.77%) as a yellow solid. LCMS: C25H28FN9O2S2 requires: 569.2, found: m/z = 570.2 [M+H]+. 'HNMR (400 MHz, CD3OD) 5 9.31 (s, 1H), 8.62 - 8.58 (m, 1H), 8.17 - 8.13 (m, 1H), 7.79 - 7.75 (m, 1H), 7.68 - 7.64 (m, 1H), 7.56 (s, 1H), 7.49 - 7.47 (m, 1H), 7.39 - 7.34 (m 1H), 7.01 (d, J= 5.6 Hz, 1H), 3.58 - 3.54 (m, 4H), 3.47 - 3.43 (m, 4H), 3.33 - 3.27 (m, 2H), 2.81 (s, 3H), 1.15 - 1.12 (m, 3H).
[000437] Synthesis of 13-[2-tert-butyl-5-(2-fl5-(Diperazin-l-yl)Dyridin-2- yl]amino}Dyrimidin-4-yl)-l.,3-thiazol-4-yl]-2-fluoroDhenynDroDane-l-sulfonamide; trifluoroacetic acid salt
[000438] Step-1: Synthesis of tert-butyl 4-16-[(4-12-tert-butyl-4-[2-fluoro-3-
(DroDane-l-sulfonamido)phenyl]-l.,3-thiazol-5-vnDyriniidin-2-yl)aniino]Dyridin-3- ynpiperazine-l-carboxylate (2)
To a stirred mixture of 7V-{3-[2-tert-butyl-5-(2-chloropyrimidin-4-yl)-l,3-thiazol-4-yl]-2- fluorophenyl} propane- 1 -sulfonamide (600 mg, 1.279 mmol, 1 equiv) and tert-butyl 4-(6- aminopyridin-3-yl)piperazine-l -carboxylate (534 mg, 1.918 mmol, 1.5 equiv) in dioxane (10 mL) was added Brettphos Pd G3 (116 mg, 0.128 mmol, 0.1 equiv) and CS2CO3 (834 mg, 2.558 mmol, 2 equiv). The resulting mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 :4) to afford tert-butyl 4-{6-[(4-{2- tert-butyl-4-[2-fluoro-3 -(propane- 1 -sulfonamido)phenyl]- 1 ,3 -thiazol-5-yl }pyrimidin-2- yl)amino]pyridin-3-yl}piperazine-l-carboxylate (620 mg, 61.35%) as a yellow solid. LCMS: C34H43FN8O4S2 requires: 710.3, found: m/z = 711.4 [M+H]+.
[000439] Step-2: Synthesis of V-!3-|2-tert-biityl-5-(2-!|5-(piperaziii-l-yl)pyridiii-2- yl]amino}pyrimidin-4-yl)-l.,3-thiazol-4-yl]-2-fluorophenvnpropane-l-sulfonaniide; trifluoroacetic acid
To a stirred mixture of tert-butyl 4-{6-[(4-{2-tert-butyl-4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]- 1 ,3 -thiazol-5-yl }pyrimidin-2-yl)amino]pyri din-3 -yl (piperazine- 1 - carboxylate (600 mg, 0.844 mmol, 1 equiv) in DCM (6 mL) was added TFA (3 mL) at 0 °C. The resulting mixture was stirred at room temperature for one hour. The resulting mixture was concentrated under reduced pressure. This resulted in 7V-{3-[2-tert-butyl-5-(2-{[5-(piperazin- l-yl)pyridin-2-yl]amino}pyrimidin-4-yl)-l,3-thiazol-4-yl]-2-fluorophenyl}propane-l- sulfonamide; trifluoroacetic acid salt (549.7 mg, crude) as a brown solid. LCMS: C29H35FN8O2S2 requires: 610.2, found: m/z = 611.2 [M+H]+. 'HNMR (400 MHz, DMSO-tL) 5 10.76 - 10.72 (m, 1H), 9.72 - 9.68 (m, 1H), 8.91 - 8.87 (m, 2H), 7.95 - 7.90 (m, 1H), 7.81
- 7.69 (m, 2H), 7.58 - 7.47 (m, 2H), 7.42 - 7.34 (m, 1H), 6.75 - 6.69 (m, 1H), 3.47 - 3.40 (m, 4H), 3.40 - 3.31 (m, 4H), 3.03 - 2.95 (m, 2H), 1.74 - 1.60 (m, 2H), 1.50 - 1.46 (m, 9H), 0.96
- 0.87 (m, 3H).
[000440] Synthesis of A-]2-fluoro-3-[2-methyl-5-(2-fl5-(Diperazin-l-yl)Dyridin-2- yl]amino}Dyrimidin-4-yl)-l.,3-thiazol-4-yl]Dhenyl}DroDane-l-sulfonaniide; trifluoroacetic acid salt
[000441 ] Step-1: Synthesis of 7V-13-[5-(2-chloropyrimidin-4-yl)-2-methyl-l.,3-thiazol-
4-yl]-2-fluorophenvnpropane-l-sulfonamide (2)
To a stirred mixture of 3-[5-(2-chloropyrimidin-4-yl)-2-methyl-l,3-thiazol-4-yl]-2- fluoroaniline (600 mg, 1.870 mmol, 1 equiv) and TEA (568 mg, 5.61 mmol, 3 equiv) in DCM (10 mL) was added propane- 1 -sulfonyl chloride (800 mg, 5.61 mmol, 3 equiv) at 0 °C. The resulting mixture was stirred at room temperature for one hour. The resulting mixture was concentrated under reduced pressure. To the above mixture was added THF (5 mL), MeCN (5 mL), and Na2COs (2.97 g, 28.05 mmol, 15 equiv) in H2O (5 mL). The resulting mixture was stirred at 50 °C overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (2:3) to afford A-{3-[5-(2-chl oropyrimidin-4-yl)-2-methyl-l,3-thiazol-4-yl]-2 -fluorophenyl (propane- 1- sulfonamide (550 mg, 61.99%) as a brown solid. LCMS: C17H16CIFN4O2S2 requires: 426.0, found: m/z = 427.0 [M+H]+.
[000442] Step-2: Synthesis of tert-butyl 4-16-[(4-14-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-2-methyl-l.,3-thiazol-5-vnpyriniidin-2-yl)aniino]pyridin-3- vBpiperazine-l-carboxylate (3)
To a stirred mixture of A-{3-[5-(2-chloropyrimidin-4-yl)-2-methyl-l,3-thiazol-4-yl]-2- fluorophenyl (propane- 1 -sulfonamide (550 mg, 1.288 mmol, 1 equiv) and tert-butyl 4-(6- aminopyridin-3-yl)piperazine-l -carboxylate (538 mg, 1.932 mmol, 1.5 equiv) in dioxane (10 mL) was added Brettphos Pd G3 (117 mg, 0.129 mmol, 0.1 equiv) and CS2CO3 (839.52 mg, 2.576 mmol, 2 equiv). The resulting mixture was stirred at 80 °C for one hour under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 :4) to afford tert-butyl 4-{6-[(4-{4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-2-methyl-l,3-thiazol-5- yl}pyrimidin-2-yl)amino]pyridin-3-yl}piperazine-l-carboxylate (600 mg, 66.15%) as a brown solid. LCMS: C31H37FN8O4S2 requires: 668.2, found: m/z = 669.2 [M+H]+.
[000443] Step-3: Synthesis of in \-!2-niioro-3-|2-iiiethyl-5-(2-!|5-(piper:izin-l- yl)pyridin-2-yl]amino}pyrimidin-4-yl)-l.,3-thiazol-4-yl]phenvnpropane-l-sulfonaniide; trifluoroacetic acid
To a stirred mixture of tert-butyl 4-{6-[(4-{4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-2- methyl-1, 3-thiazol-5-yl}pyrimi din-2 -yl)amino]pyri din-3 -yl (piperazine- 1 -carboxylate (300 mg, 0.449 mmol, 1 equiv) in DCM (8 mL) was added TFA (2 mL) at 0 °C. The resulting mixture was stirred at room temperature for one hour. The resulting mixture was concentrated under reduced pressure. This resulted in A-{2-fluoro-3-[2-methyl-5-(2-{[5-(piperazin-l- yl)pyridin-2-yl]amino}pyrimidin-4-yl)-l,3-thiazol-4-yl]phenyl}propane-l-sulfonamide; trifluoroacetic acid salt (225.1 mg, crude) as a brown solid. LCMS: C26H29FN8O2S2 requires: 568.2, found: m/z = 569.3 [M+H]+. 'HNMR (400 MHz, CD3OD) 5 8.60 - 8.54 (m, 1H), 8.23
- 8.16 (m, 1H), 7.81 - 7.76 (m, 1H), 7.68 - 7.59 (m, 1H), 7.56 - 7.47 (m, 2H), 7.43 - 7.35 (m, 1H), 7.00 - 6.94 (m, 1H), 3.56 - 3.51 (m, 4H), 3.50 - 3.42 (m, 4H), 3.13 - 3.05 (m, 2H), 2.86
- 2.79 (m, 3H), 1.92 - 1.76 (m, 2H), 1.07 - 0.96 (m, 3H).
[000444] Synthesis of 4-[2-tert-butyl-4-(3-flethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)-l.,3-thiazol-5-yl]-A-(5-]3.,8-diazabicvclo[3.2.1]octan-8-vnDyridin-2- yl)pyrimidin-2-amine; trifluoroacetic acid salt
[000445] Step-1: 1- 12-tert-butyl-5-(2-i thiazol-4-yl]-2-fluoroDhenynsulfamoyl)(ethyl)methylamine (3)
To a mixture of 3-[2-tert-butyl-5-(2-chloropyrimidin-4-yl)-l,3-thiazol-4-yl]-2-fluoroaniline (3.0 g, 8.268 mmol, 1 equiv) and DMAP (1.21 g, 9.922 mmol, 1.2 equiv) in pyridine (1.5 mL) was added A-ethyl-A-m ethyl sulfamoyl chloride (2.61 g, 16.536 mmol, 2.0 equiv) dropwise at room temperature. The resulting mixture was stirred overnight at 40 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with DCM:EtOAc (5: 1) to afford ({3-[2-tert-butyl-5-(2-chloropyrimidin-4-yl)-l,3-thiazol-4-yl]-2- fluorophenyl}sulfamoyl)(ethyl)methylamine (1.82 g, 45.48%) as a yellow solid. LCMS: C20H23CIFN5O2S2 requires: 483.1, found: m/z = 484.1 [M+H]+.
[000446] Step-2: Synthesis of tert-butyl 8-[6-(44-[2-tert-butyl-4-(3- llethyl sulfamoyl]amino}-2-fluorophenyl)-l.,3-thiazol-5-yl]pyrimidin-2- vnamino)pyridin-3-yl]-3.,8-diazabicvclo[3.2.1]octane-3-carboxylate (5)
To a mixture of ({3-[2-tert-butyl-5-(2-chloropyrimidin-4-yl)-l,3-thiazol-4-yl]-2- fluorophenyl}sulfamoyl)(ethyl)methylamine (700 mg, 1.446 mmol, 1 equiv) and tert-butyl 8- (6-aminopyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (572.30 mg, 1.880 mmol, 1.3 equiv) in 1,4-dioxane (6 mL) was added BrettPhos Pd G3 (131.10 mg, 0.145 mmol, 0.1 equiv) and CS2CO3 (942.43 mg, 2.892 mmol, 2.0 equiv) at room temperature. The resulting mixture was stirred for 2 h at 80 °C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CthCb MeOH (5: 1) to afford tert-butyl 8-[6-({4-[2-tert-butyl-4- (3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3-thiazol-5-yl]pyrimidin-2- yl}amino)pyridin-3-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (400 mg, 36.78%) as a yellow solid. LCMS: C36H46FN9O4S2 requires: 751.3, found: m/z = 752.3 [M+H]+.
[000447] Step-3: Synthesis of 4-[2-tert-butyl-4-(3-l[ethyl(methyl)sulfamoyl]amino}-
2-fluorophenyl)-l.,3-thiazol-5-yl]-7V-(5-13.,8-diazabicyclo[3.2.1]octan-8-ynDyridin-2- yl)pyrimidin-2-amine; trifluoroacetic acid
To a stirred mixture of tert-butyl 8-[6-({4-[2-tert-butyl-4-(3- {[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3-thiazol-5-yl]pyrimidin-2- yl}amino)pyridin-3-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (390 mg, 0.519 mmol, 1 equiv) in DCM (2 mL) was added TFA (2 mL) dropwise at 0 °C. The resulting mixture was stirred for one hour at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford 4-[2-tert-butyl-4-(3- {[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3-thiazol-5-yl]-A-(5-{3,8- diazabicyclo[3.2.1]octan-8-yl}pyridin-2-yl)pyrimidin-2-amine; trifluoroacetic acid salt (352.1 mg, 86.25%) as a yellow solid. LCMS: C31H38FN9O2S2 requires: 651.3, found: m/z = 652.3 [M+H]+. 'H NMR (300 MHz, CD3OD) 5 8.57 - 8.55 (m, 1H), 8.07 (d, J = 9.6 Hz, 1H), 7.72 (s, 1H), 7.62 (d, .7= 8.1 Hz, 1H), 7.52 - 7.48 (m, 2H), 7.42 - 7.31 (m, 1H), 6.96 (d, J = 4.8 Hz, 1H), 4.57 - 4.43 (m, 2H), 3.52 - 3.38 (m, 2H), 3.31 -3.18 (m, 4H), 2.85 - 2.79 (m, 3H), 2.41 - 2.23 (m, 2H), 2.21 - 2.11 (m, 2H), 1.62 - 1.48 (m, 9H), 1.20 - 1.08 (m, 3H).
[000448] Synthesis of 4-14-[4-(3-flethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-
3-(Dyrimidin-4-yl)Dyrazol-l-yl]DhenvnDiperazine; trifluoroacetic acid salt
[000449] Step-1: Synthesis of 4-(2//-pyr:izol-3-yl)pyriniidine (3)
To a mixture of 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2J/-pyrazole (3.05 g, 15.716 mmol, 1.2 equiv) and 4-chloropyrimidine (1.5 g, 13.097 mmol, 1.00 equiv) in 1,4-di oxane (20 mL) and H2O (2 mL) was added Na2COs (2.78 g, 26.194 mmol, 2.0 equiv) and Pd(dppf)C12 (958.32 mg, 1.310 mmol, 0.1 equiv) at room temperature. The resulting mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2C12:MeOH (5: 1) to afford 4-(2J/-pyrazol-3-yl)pyrimidine (790 mg, 41.27%) as a yellow solid. LCMS: C7H6N4 requires: 146.1, found: m/z = 147.1 [M+H]+.
[000450] Step-2: Synthesis of 4-(4-bi oiiio-2//-pyi azol-3-yl)pyi iiiiidine (4)
To a mixture of 4-(2J/-pyrazol-3-yl)pyrimidine (790 mg, 5.405 mmol, 1 equiv) in DMF (8 mL) was added NBS (1.06 g, 5.946 mmol, 1.1 equiv) in portions at 0 °C. The resulting mixture was stirred for one hour at room temperature. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CffCh MeOH (5: 1) to afford 4-(4-bromo-27/- pyrazol-3-yl)pyrimidine (710 mg, 58.37%) as a yellow solid. LCMS: CLHjBrN-t requires: 224.0, found: m/z = 225.0 [M+H]+.
[000451 ] Step-3: Synthesis of tert-butyl 4-I4-[4-bromo-3-(pyrimidin-4-yl)pyrazol-l- yl]phenvnpiperazine-l-carboxylate (6)
To a stirred mixture of 4-(4-bromo-2//-pyrazol-3-yl)pyrimidine (710 mg, 3.155 mmol, 1 equiv) and tert-butyl 4-(4-iodophenyl)piperazine-l -carboxylate (1.83 g, 4.732 mmol, 1.5 equiv) in DMSO (8 mL) was added L-proline (145.29 mg, 1.262 mmol, 0.4 equiv), K2CO3 (1.31 g, 9.47 mmol, 3.0 equiv), and Cui (120.17 mg, 0.631 mmol, 0.2 equiv) at room temperature. The resulting mixture was stirred for 2 h at 100 °C under a nitrogen atmosphere. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CEEChiMeOH (5: 1) to afford tert-butyl 4-{4-[4-bromo-3-(pyrimidin-4-yl)pyrazol-l- yl]phenyl}piperazine-l-carboxylate (310 mg, 20.24%) as a yellow solid. LCMS: C22H25BrNeO2 requires: 484.1, found: m/z = 485.1 [M+H]+.
[000452] Step-4: Synthesis of tert-butyl 4-I4-[4-(3-Ilethyl(methyl)sulfamoyl]amino}- 2-fluorophenyl)-3-(pyrimidin-4-yl)pyrazol-l-yl]phenyl}piperazine-l-carboxylate
To a mixture of tert-butyl 4-{4-[4-bromo-3-(pyrimidin-4-yl)pyrazol-l-yl]phenyl}piperazine- 1-carboxylate (310 mg, 0.639 mmol, 1 equiv) and 3-{[ethyl(methyl)sulfamoyl]amino}-2- fluorophenylboronic acid (176.33 mg, 0.639 mmol, 1.0 equiv) in 1,4-dioxane (3.0 mL) and H2O (0.3 mL) was added CsF (194.03 mg, 1.278 mmol, 2.0 equiv) and PdC12(AMPHOS)2 (90.45 mg, 0.128 mmol, 0.2 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 2 h at 90 °C under the nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with C^CHCHsOH (5: 1) to afford tert-butyl 4-{4-[4-(3- {[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-3-(pyrimidin-4-yl)pyrazol-l- yl]phenyl}piperazine-l-carboxylate (150 mg, 36.88%) as a pink solid. LCMS: C31H37FN8O4S requires: 636.3, found: m/z = 637.2 [M+H]+. 'H NMR (400 MHz, CD3OD) 5 9.06 (s, 1H), 8.68 (d, J= 5.2 Hz, 1H), 7.93 (s, 1H), 7.52 - 7.44 (m, 1H), 7.28 - 7.22 (m, 1H), 7.20 (d, J= 8.8 Hz, 2H), 7.18 - 7.10 (m, 2H), 7.00 (d, J = 8.9 Hz, 2H), 3.59 - 3.54 (m, 4H), 3.35 - 3.26 (m, 4H), 3.21 - 3.12 (m, 2H), 2.74 (s, 3H), 1.50 (s, 9H), 1.07 - 1.01 (m, 3H). [000453 ] Step-5: Synthesis of 4-f4-[4-(3-f[ethyl(methyl)sulfamoyl]amino}-2- fluoroDhenyl)-3-(Dyrimidin-4-yl)Dyrazol-l-yl]DhenynDiDerazine; trifluoroacetic acid
To a mixture of tert-butyl 4-{4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-3- (pyrimidin-4-yl)pyrazol-l-yl]phenyl}piperazine-l-carboxylate (150 mg, 0.236 mmol, 1 equiv) in DCM (3 mL) was added TFA (3 mL) at room temperature. The resulting mixture was stirred for one hour at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), 10% to 60% gradient in 10 min; detector, UV 254 nm to afford 4-{4-[4-(3- {[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-3-(pyrimidin-4-yl)pyrazol-l- yl]phenyl}piperazine; trifluoroacetic acid salt (130.8 mg, 85.34%) as a yellow solid. LCMS: C26H29FN8O2S requires: 536.2, found: m/z = 537.4 [M+H]+. 'H NMR (400 MHz, CD3OD) 5 9.02 - 8.97 (m, 1H), 8.81 - 8.75 (m, 1H), 8.43 (s, 1H), 8.01 - 7.95 (m, 1H), 7.92 - 7.84 (m, 2H), 7.60 - 7.51 (m, 1H), 7.31 - 7.23 (m, 1H), 7.26 - 7.15 (m, 3H), 3.56 - 3.49 (m, 4H), 3.48 - 3.40 (m, 4H), 3.26 - 3.16 (m, 2H), 2.81 (s, 3H), 1.15 - 1.07 (m, 3H).
[000454] Synthesis of 4-]4-[3-(3-flethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)- 4-(Dyridin-4-yl)Dyrazol-l-yl]Dhenyl}piDeridine; trifluoroacetic acid salt
fluorophenylpyrazole (2)
To a mixture of 3-bromo-UT-pyrazole (1.6 g, 10.886 mmol, 1.2 equiv) and 3- { [ethyl (methyl)sulfamoyl]amino}-2-fluorophenylboronic acid (2.5 g, 9.055 mmol, 1 equiv) in 1,4-dioxane (30 mL) was added CsF (2.75 g, 18.104 mmol, 2 equiv) in H2O (6 mL) and PdAMPHOS (1.28 g, 1.811 mmol, 0.2 equiv). The resulting mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1/2) to afford 3-{[ethyl(methyl)sulfamoyl]amino}-2-fhiorophenylpyrazole (1.9 g, 63.30%) as a yellow solid. LCMS: C12H15FN4O2S requires: 298.1, found: m/z = 299.1 [M+H]+.
[000456] Step-2: Synthesis of tert-butyl 4-I4-[3-(3-Ilethyl(methyl)sulfamoyl]amino}- 2-fluorophenyl)pyrazol-l-yl]phenvnpiperazine-l-carboxylate (3)
To a mixture of 3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenylpyrazole (800 mg, 2.682 mmol, 1 equiv) and tert-butyl 4-(4-iodophenyl)piperazine-l -carboxylate (1.56 g, 4.018 mmol, 1.50 equiv) in DMSO (20 mL) was added L-proline (123 mg, 1.073 mmol, 0.4 equiv), K2CO3 (1.11 g, 8.046 mmol, 3 equiv), and Cui (102 mg, 0.536 mmol, 0.2 equiv). The resulting mixture was stirred at 100 °C for three days under a nitrogen atmosphere. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous ISfeSCU After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 : 1) to afford tert-butyl 4-{4-[3-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)pyrazol-l- yl]phenyl}piperazine-l-carboxylate (630 mg, 37.85%) as a yellow solid. LCMS: C27H35FN6O4S requires: 558.2, found: m/z = 559.4 [M+H]+.
[000457] Step-3: Synthesis of tert-butyl 4-]4-[4-bromo-3-(3-
] (methyl)sulfamoyl]amino}-2-flnorophenyl)pyrazol-l-yl]phenvnpiperazine-l- carboxylate (4)
To a mixture of tert-butyl 4-{4-[3-(3-{[ethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)pyrazol-l-yl]phenyl}piperazine-l-carboxylate (620 mg, 1.11 mmol, 1 equiv) in DMF (5 mL) was added NBS (277 mg, 1.554 mmol, 1.4 equiv) at 0 °C. The resulting mixture was stirred at room temperature for one hour. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with saturated aqueous Na2S20s and dried over anhydrous ISfeSCU. After filtration, the filtrate was concentrated under reduced pressure. This resulted in tert-butyl 4-{4-[4-bromo-3-(3-{[ethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)pyrazol-l-yl]phenyl}piperazine-l-carboxylate (700 mg, 98.93%) as a yellow solid. LCMS: C27H34BrFNeO4S requires: 636.2, found: m/z = 637.4 [M+H]+.
[000458] Step-4: Synthesis of tert-butyl 4-]4-[3-(3-]|ethyl(methyl)sulfamoyl]amino}- 2-fluorophenyl)-4-(pyridin-4-yl)pyrazol-l-yl]phenvnpiperazine-l-carboxylate
To a mixture of tert-butyl 4-{4-[4-bromo-3-(3-{[ethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)pyrazol-l-yl]phenyl}piperazine-l-carboxylate (700 mg, 1.098 mmol, 1 equiv) and 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (450 mg, 2.196 mmol, 2 equiv) in DME (11 mL) was added CS2CO3 (715 mg, 2.196 mmol, 2 equiv) in H2O (1.3 mL) and Pd(dppf)C12CH2C12 (89 mg, 0.11 mmol, 0.1 equiv). The final reaction mixture was irradiated with microwave radiation at 100 °C for 30 min under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 : 1) to afford te/7-butyl 4-{4-[3-(3- { [ethyl (methyl)sulfamoyl]amino}-2-fluorophenyl)-4-(pyridin-4-yl)pyrazol-l- yl]phenyl}piperazine-l-carboxylate (420 mg, 57.16%) as a yellow solid. LCMS: C32H38FN7O4S requires: 635.3, found: m/z = 636.4 [M+H]+. 'H NMR (400 MHz, CD3OD) 5 8.68 - 8.62 (m, 2H), 8.35 - 8.30 (m, 1H), 7.91 - 7.80 (m, 5H), 7.57 - 7.49 (m, 1H), 7.34 (d, J = 8.7 Hz, 1H), 7.26 - 7.17 (m, 1H), 6.96 - 6.90 (m, 1H), 3.42 - 3.35 (m, 4H), 3.29 - 3.19 (m, 2H), 2.89 - 2.82 (m, 7H), 1.47 (s, 9H), 1.14 - 1.06 (m, 3H).
[000459] Step-5: Synthesis of 4-]4-[3-(3-][ethyl(methyl)sulfamoyl]amino}-2- flnorophenyl)-4-(pyridin-4-yl)pyrazol-l-yl]phenynpiperidine; trifluoroacetic acid To a mixture of tert-butyl 4-{4-[3-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-4- (pyridin-4-yl)pyrazol-l-yl]phenyl}piperazine-l-carboxylate (420 mg, 0.661 mmol, 1 equiv) in DCM (9 mL) was added TFA (3 mL) at 0 °C. The resulting mixture was stirred at 0 °C for one hour. The resulting mixture was concentrated under vacuum. This resulted in 4-{4-[3-(3- { [ethyl (methyl)sulfamoyl]amino}-2-fluorophenyl)-4-(pyridin-4-yl)pyrazol-l- yl]phenyl}piperidine; trifluoroacetic acid salt (411.2 mg, crude) as a yellow solid. LCMS: C27H30FN7O2S requires: 535.2, found: m/z = 536.2 [M+H]+. 'H NMR (400 MHz, CD3OD) 5 8.96 - 8.87 (m, 2H), 8.54 - 8.44 (m, 2H), 8.39 (d, J= 2.8 Hz, 1H), 8.10 - 8.01 (m, 2H), 7.89 - 7.79 (m, 1H), 7.58 - 7.46 (m, 2H), 7.25 - 7.12 (m, 1H), 7.01 - 6.89 (m, 1H), 3.36 - 3.28 (m, 6H), 3.20 - 3.11 (m, 4H), 2.82 (s, 3H), 1.12 - 1.04 (m, 3H).
[000460] General Procedure for Buchwald Coupling Followed by Deprotection [000461 ] Synthesis of Az-]3-[2-tert-butyl-5-(2-][4-(Diperazin-l- ylmethyl)Dhenyl]amino}pyrimidin-4-yl)-l.,3-thiazol-4-yl]-2-fluoroDhenyl}DroDane-l- sulfonamide
[000462] Step-1: tert-butyl 4-(4-((4-(2-(tert-butyl)-4-(2-fluoro-3-
(DroDylsulfonamido)Dhenyl)thiazol-5-yl)Dyrimidin-2-yl)amino)benzyl)DiDerazine-l- carboxylate
To a solution of 7V-{3-[2-terZ-butyl-5-(2-chloropyrimidin-4-yl)-l,3-thiazol-4-yl]-2- fluorophenyl} propane- 1 -sulfonamide (703 mg, 1.5 mmol) and tert-butyl 4-(4- aminobenzyl)piperazine-l -carboxylate (304 mg, 1.05 equiv) in dioxane (10.00 mL) was added sodium tert-butoxide (216 mg, 1.5 eq), Pd2(dba)s or tris(dibenzylideneacetone)dipalladium(0) (205 mg, 0.15 equiv), and 2'-(dicyclohexylphosphanyl)-7V,7V-dimethyl-[l,l'-biphenyl]-2- amine (DavePhos 177 mg, 0.3 mmol). Then the mixture was purged with nitrogen gas for 5 min, followed by irradiation in a microwave reactor at 120 °C for 2 h. The reaction mixture was filtered through a Celite plug and washed with ethyl acetate. Solvent was then removed by rotary evaporation. Silica gel column chromatography purification eluting with 0-70% EtOAc:DCM provided tert-butyl 4-(4-((4-(2-(tert-butyl)-4-(2-fluoro-3- (propylsulfonamido)phenyl)thiazol-5-yl)pyrimidin-2-yl)amino)benzyl)piperazine-l- carboxylate.
[000463] Step-2: \-!3- (pipei azin-l- ylmethyl)Dhenyl]amino}Dyrimidin-4-yl)-l.,3-thiazol-4-yl]-2-fluoroDhenyl}DroDane-l- sulfonamide
Tert-butyl 4-(4-((4-(2-(tert-butyl)-4-(2-fluoro-3-(propylsulfonamido)phenyl)thiazol-5- yl)pyrimidin-2-yl)amino)benzyl)piperazine-l -carboxylate was dissolved in DCM:TFA (4: 1 ratio, 0.1 M) at room temperature, followed by stirring for 3 h. The reaction mixture was concentrated, then triturated with ether, and used as-is (667 mg, 63% over two steps). LCMS: C31H38FN7O2S2 requires 623.3, found: m/z = 624.5 [M+H]+.
[000464] The following compounds were made using the above General Procedure for Buchwald Coupling Followed by Deprotection.
[000465] tert-butyl 4-[(4-{2-tert-butyl-4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]- l,3-thiazol-5-yl}pyrimidin-2-yl)amino]benzoate
LCMS: C31H36FN5O4S2 requires 625.2, found: m/z = 626.5 [M+H]+. [000466] 4-[(4-{2-ter/-butyl-4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-l,3-thiazol-
5-yl}pyrimidin-2-yl)amino]benzoic acid
LCMS: C27H28FN5O4S2 requires 569.2, found: m/z = 570.5 [M+H]+.
[000467] tert-butyl 4-{4-[(4-{2-tert-butyl-4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]- 1 ,3 -thiazol-5-yl }pyrimidin-2-yl)amino]-2-fluorophenyl } piperazine- 1 - carboxylate
LCMS: C35H43F2N7O4S2 requires 727.3, found: m/z = 728.5 [M+H]+.
[000468 ] N- { 3 - [2-/cr/-buty 1 -5 -(2- { [3 -fluoro-4-(piperazin- 1 -yl)phenyl] amino } pyrimidin-
4-yl)- 1 ,3 -thiazol-4-yl]-2-fluorophenyl [propane- 1 -sulfonamide
LCMS: C35H43F2N7O4S2 requires 627.2, found: m/z = 628.5 [M+H]+.
[000469] tert-butyl 4-[4-({4-[2-tert-butyl-4-(3-{ [ethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)-l,3-thiazol-5-yl]pyrimidin-2-yl}amino)-2-fluorophenyl]piperazine-l- carboxylate
LCMS: C35H44F2N8O4S2 requires 742.3, found: m/z = 743.7 [M+H]+.
[000470] 4-[2-tert-butyl-4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3- thiazol-5-yl]-7V-[3-fluoro-4-(piperazin-l-yl)phenyl]pyrimidin-2-amine
LCMS: C30H36F2N8O2S2 requires 642.2, found: m/z = 643.6 [M+H]+.
[000471] tert-butyl 4-(4-((4-(2-(tert-butyl)-4-(3-((7V-ethyl-7V-methylsulfamoyl)amino)-2- fluorophenyl)thiazol-5-yl)pyrimidin-2-yl)amino)-2-chlorophenyl)piperazine-l -carboxylate
LCMS: C35H44CIFN8O4S2 requires 758.3, found: m/z = 759.5 [M+H]+.
[000472] 4-[2-tert-butyl-4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3- thiazol-5-yl]-7V-[3-chloro-4-(piperazin-l-yl)phenyl]pyrimidin-2-amine.
LCMS: C30H36CIFN8O2S2 requires 658.2, found: m/z = 659.5 [M+H]+.
[000473] General Procedure for SnAr Coupling Followed by Deprotection (Version 1)
[000474] Synthesis of A- [3-(2-tert-butyl-5- !2- [(piperidin-4- ylmethyl)amino]pyrimidin-4-yn-l.,3-thiazol-4-yl)-2-fluorophenyl]propane-l- sulfonamide
[000475] Step-1: tert-butyl 4-(((4-(2-(tert-butyl)-4-(2-fluoro-3-
(propylsulfonamido)phenyl)thiazol-5-yl)pyrimidin-2-yl)amino)methyl)piperidine-l- carboxylate To a solution of A-{3-[2-tert-butyl-5-(2-chloropyrimidin-4-yl)-l,3-thiazol-4-yl]-2- fluorophenyl] propane- 1 -sulfonamide (850 mg, 1.81 mmol) and triethylamine (0.75 mL, 3 equiv) in dioxane (10 mL) and isopropanol (2.5 mL) was added tert-butyl 4- (aminomethyl)piperidine-l -carboxylate (505 mg, 1.3 equiv), and the solution was heated at 60 °C for 30 h. The reaction mixture was diluted with EtOAc (40 mL), and the resulting organic solution was washed with aqueous ammonium chloride, then brine, and dried with mag sulfate. Filtration and concentration of the organic solution provided the boc-protected intermediate tert-butyl 4-(((4-(2-(tert-butyl)-4-(2-fluoro-3-(propylsulfonamido)phenyl)thiazol-5- yl)pyrimidin-2-yl)amino)methyl)piperidine-l -carboxylate.
[000476] Step-2: \-|3-(2-tert-biityl-5-!2-|(pipei idiii-4-yliiietliyl) iiiiidin-4- yl}-l.,3-thiazol-4-yl)-2-fluorophenyl]propane-l-sulfonamide
The crude tert-butyl 4-(((4-(2-(tert-butyl)-4-(2-fluoro-3-(propylsulfonamido)phenyl)thiazol-5- yl)pyrimidin-2-yl)amino)methyl)piperidine-l -carboxylate was dissolved in DCM (10 mL) and TFA (3 mL). This reaction was stirred for 6 h, and was then concentrated onto silica. Silica gel column chromatography purification eluting with methanol: DCM (0-20%) provided 7V-[3-(2- tert-butyl-5-{2-[(piperidin-4-ylmethyl)amino]pyrimidin-4-yl}-l,3-thiazol-4-yl)-2- fluorophenyl]propane-l -sulfonamide (0.86g, 87% over two steps). LCMS: C26H35FN6O2S2 requires 546.2, found: m/z = 547.5 [M+H]+.
[000477] The following compounds were made using the above General Procedure for SnAr Coupling Followed by Deprotection (Version 1).
[000478] 7V-(3-{2-tert-butyl-5-[2-(pyrrolidin-3-ylamino)pyrimidin-4-yl]-l,3-thiazol-4- yl } -2-fluorophenyl)propane- 1 -sulfonamide
LCMS: C24H31FN6O2S2 requires 518.2, found: m/z = 519.5 [M+H]+.
[000479] [(4- { 2-tert-butyl-4- [2-fluoro-3 -(propane- 1 -sulfonamido)phenyl] - 1 , 3 -thiazol -5 - yl}pyrimidin-2-yl)amino]acetic acid
LCMS: C22H26FN5O4S2 requires 507.1, found: m/z = 506.5 [M-H]+.
[000480] 7V-(3-{2-tert-butyl-5-[2-(piperidin-4-ylamino)pyrimidin-4-yl]-l,3-thiazol-4- yl } -2-fluorophenyl)propane- 1 -sulfonamide
LCMS: C25H33FN6O2S2 requires 532.2, found: m/z = 533.5 [M+H]+.
[000481] 7V-{3-[2-tert-butyl-5-(2-{[2-methyl-2-(piperidin-4-yl)propyl]amino}pyrimidin-
4-yl)- 1 ,3 -thiazol-4-yl]-2-fluorophenyl [propane- 1 -sulfonamide
LCMS: C29H41FN6O2S2 requires 588.3, found: m/z = 589.7 [M-H]+.
[000482] 7V-{3-[5-(2-{[l,4-bipiperidin]-4-ylamino}pyrimidin-4-yl)-2-terLbutyl-l,3- thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide
LCMS: C30H42FN7O2S2 requires 615.3, found: m/z = 616.6 [M+H]+.
[000483] 7V-{3-[2-tert-butyl-5-(2-{[4-(piperazin-l-yl)cyclohexyl]amino}pyrimidin-4- yl)-l,3-thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide
LCMS: C30H42FN7O2S2 requires 615.3, found: m/z = 616.6 [M+H]+.
[000484] 7V-{3-[5-(2-{7-azaspiro[3.5]nonan-2-ylamino}pyrimidin-4-yl)-2-tert-butyl- l,3-thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide
LCMS: C28H37FN6O2S2 requires 572.2, found: m/z = 573.5 [M+H]+.
[000485] General Procedure for Nucleophilic Substitution Followed by Oxidation
[000486] Step-1: \-(3- H-tcrt-butvI-S-ll-t !l( lr.4r)-4-
(hydroxymethyl)cyclohexyl]methynamino)Dyrimidin-4-yl]-l.,3-thiazol-4-yn-2- fluorophenyl)propane-l-sulfonamide
To a solution of 7V-{3-[2-tert-butyl-5-(2-chloropyrimidin-4-yl)-l,3-thiazol-4-yl]-2- fluorophenyl} propane- 1 -sulfonamide (950 mg, 2.03 mmol) and triethylamine (0.83 mL, 3 equiv) in dioxane (15 mL) and isopropanol (5 mL) was added [(lr,4r)-4- (aminomethyl)cyclohexyl]methanol (571 mg, 1.1 equiv) and the solution was heated at 60 °C for 18 h. The reaction mixture was diluted with EtOAc (40 mL)and the combined organic solution was washed with aqueous ammonium chloride, brine, dried over magnesium sulfate, filtered, and concentrated to provide 7V-(3-{2-terLbutyl-5-[2-({[(lr,4r)-4- (hydroxymethyl)cyclohexyl]methyl}amino)pyrimidin-4-yl]-l,3-thiazol-4-yl}-2- fluorophenyl)propane-l -sulfonamide (0.8 g). LCMS: C28H37FN6O2S2 requires 575.2, found: m/z = 576.7 [M+H]+.
[000487] Step-2: \-(3- !2- butyl-5-|2-( !l( lr.4r)-4- formylcvclohexyl]methvnamino)pyrimidin-4-yl]-l.,3-thiazol-4-vn-2- fluorophenvDpropane-l-sulfonamide Crude 7V-(3-{2-tert-butyl-5-[2-({[(lr,4r)-4-
(hydroxymethyl)cyclohexyl]methyl}amino)pyrimidin-4-yl]-l,3-thiazol-4-yl}-2- fluorophenyl)propane-l -sulfonamide from the previous reaction was dissolved in DCM at rt and then DMP (0.66g, 1.1 equiv) was added in one portion. The reaction stirred for 2 h and then concentrated onto silica and purified by silica gel column chromatography (0-100% ethyl acetate in DCM) to provide 7V-(3-{2-tert-butyl-5-[2-({[(lr,4r)-4- formylcy cl ohexyl]methyl}amino)pyrimidin-4-yl]- 1,3-thi azol -4-yl }-2-fluorophenyl)propane- 1-sulfonamide (0.8g, 70% over two steps). LCMS: C28H37FN6O2S2 requires 573.2, found: m/z = 574.7 [M+H]+.
[000488] The following compounds were made using the above General Procedure for Nucleophilic Substitution Followed by Oxidation.
[000489] N- { 3-[2-tert-butyl-5-(2- { [(lr,4r)-4-
(hydroxymethyl)cyclohexyl]amino}pyrimidin-4-yl)-l,3-thiazol-4-yl]-2- fluorophenyl } propane- 1 -sulfonamide
LCMS: C27H36FN5O3S2 requires 561.2, found: m/z = 562.6 [M+H]+.
[000490] 7V-(3-(2-(tert-butyl)-5-(2-(((lr,4r)-4-formylcyclohexyl)amino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide
LCMS: C27H34FN5O3S2 requires 559.2, found: m/z = 560.5 [M+H]+.
[000491] General Procedure for Amide Coupling Followed by Deprotection
[000492] Synthesis of \-!3-|2-ter/,-biityl-5-(2-!|4-(piperazine-l- carbonyl)phenyl]amino}pyrimidin-4-yl)-l.,3-thiazol-4-yl]-2-fluorophenynpropane-l- sulfonamide
[000493] Step-1: tert-butyl 4-(4-((4-(2-(tert-butyl)-4-(2-fluoro-3-
(propylsnlfonamido)phenyl)thiazol-5-yl)pyrimidin-2-yl)amino)benzoyl)piperazine-l- carboxylate 4-((4-(2-(tert-butyl)-4-(2-fluoro-3-(propylsulfonamido)phenyl)thiazol-5-yl)pyrimidin-2- yl)amino)benzoic acid (0.5g, 0.887 mmol), and HATU (0.33g, 1 equiv) were dissolved in DMF (0.2 M) and DIEA (0.1 mL) followed by the addition of tert-butyl piperazine- 1 -carboxylate (0.16 g, 1 equiv). The reaction was stirred for 2 h, followed by partition between water and ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulfate, filtered, and concentrated. Crude tert-butyl 4-(4-((4-(2-(terZ-butyl)-4-(2-fluoro-3- (propylsulfonamido)phenyl)thiazol-5-yl)pyrimidin-2-yl)amino)benzoyl)piperazine-l- carboxylate was used in the next step without purification.
[000494] Step-2: A-]3-[2-tert-butyl-5-(2-][4-(Diperazine-l- carbonyl)Dhenyl]amino}Dyrimidin-4-yl)-l.,3-thiazol-4-yl]-2-fluoroDhenynDroDane-l- sulfonamide
Crude tert-butyl 4-(4-((4-(2-(tert-butyl)-4-(2-fluoro-3-(propylsulfonamido)phenyl)thiazol-5- yl)pyrimidin-2-yl)amino)benzoyl)piperazine-l -carboxylate was dissolved in DCM (10 mL) and TFA (2 mL) was added. The reaction was then stirred for 3 h and then concentrated onto silica gel. Silica gel column chromatography (0-20% methanol in DCM) provided 7V-{3-[2- tert-butyl-5-(2-{[4-(piperazine-l-carbonyl)phenyl]amino}pyrimidin-4-yl)-l,3-thiazol-4-yl]-2- fluorophenyl (propane- 1 -sulfonamide (0.2g, 36%). LCMS: C31H36FN7O3S2 requires 637.2, found: m/z = 638.5 [M+H]+.
[000495] General Procedure for Buchwald Coupling Followed by BOC Deprotection
[000496] Synthesis of 7V-(3-(2-(tert-butyl)-5-(2-((4-(Diperidin-4- yl)Dhenyl)amino)Dyrimidin-4-yl)thiazol-4-yl)-2-fluoroDhenyl)DroDane-l-sulfonamide
[000497] Step-1: tert-butyl 4-(4-((4-(2-(tert-butyl)-4-(2-fluoro-3-
(DroDylsulfonamido)Dhenyl)thiazol-5-yl)Dyrimidin-2-yl)amino)Dhenyl)DiDeridine-l- carboxylate
To a solution of 7V-{3-[2-tert-butyl-5-(2-chloropyrimidin-4-yl)-l,3-thiazol-4-yl]-2- fluorophenyl] propane- 1 -sulfonamide (600.00 mg, 1.2793 mmol) and tert-butyl 4-(4- aminophenyl)piperidine-l -carboxylate (530.38 mg, 1.9190 mmol) in dioxane (15.00 mL) was added sodium tert-butoxide (184.43 mg, 1.9190 mmol), Pd2(dba)s (117.15 mg, 0.1279 mmol), and Dave-Phos 2'-(dicyclohexylphosphanyl)-7V,7V-dimethyl-[l,r-biphenyl]-2-amine (503.49 mg, 1.2793 mmol). The mixture was purged with nitrogen gas for five minutes. The reaction mixture was then heated by microwave at 120 °C for two hours. Solvent was evaporated under reduced pressure. The crude product was loaded onto a Redi-Sep prepacked silica gel column eluting with 0-70% EtOAc in hexanes, followed by a second purification using a Redi-Sep prepacked silica gel column purification eluting with a gradient of 0-40% EtOAc in DCM to afford tert-butyl 4-{4-[(4-{2-tert-butyl-4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-l,3- thiazol-5-yl}pyrimidin-2-yl)amino]phenyl}piperidine-l-carboxylate (0.605 g, 66.71%). LCMS: C36H45FN6O4S2, requires: 708.29, found: m/z = 709.51 [M+H]+. *H NMR (500 MHz, DMSO-tC) 6 9.65 (s, 1H), 8.33 (d, J= 5.2 Hz, 1H), 7.56 (dd, J= 16.5, 8.0 Hz, 3H), 7.37 (t, J = 7.9 Hz, 1H), 7.13 (d, J= 8.4 Hz, 2H), 3.07 - 2.95 (m, 2H), 2.81 (s, 2H), 1.75 (d, J= 12.8 Hz, 2H), 1.66 (p, J= 7.5 Hz, 2H), 1.47 (s, 9H), 1.43 (s, 9H), 0.90 (t, J= 7.4 Hz, 3H).
[000498 ] Step-2: Az-(3-(2-(tert-butyl)-5-(2-((4-(Diperidin-4- yl)Dhenyl)amino)Dyrimidin-4-yl)thiazol-4-yl)-2-fluoroDhenyl)DroDane-l-sulfonamide
To a solution of tert-butyl 4-{4-[(4-{2-tert-butyl-4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]- 1 ,3 -thiazol-5-yl }pyrimidin-2-yl)amino]phenyl (piperidine- 1 -carboxylate (0.55g, 0.903mmol) in DCM (5 mL) was added 4 N HC1 in dioxane solution (5 mL). The solution was stirred for two hours. Solvent was removed under reduced pressure and the product was lyophilized to dryness to afford 7V-{3-[2-tert-butyl-5-(2-{[4-(piperidin-4- yl)phenyl]amino}pyrimidin-4-yl)-l,3-thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide (0.55 g, 94.6%) as an HC1 salt. LCMS: C31H37FN6O2S2, requires: 608.24, found: m/z = 609.47 [M+H]+.
[000499] The following compounds were made using the above General Procedure for Buchwald Coupling Followed by BOC Deprotection.
[000500] 4-[(4-{2-terCbutyl-4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-l,3-thiazol- 5-yl}pyrimidin-2-yl)amino]benzoic acid [M+H]+ 626.5, then 570.5.
[000501 ] N- { 3 - [2-tert-butyl-5 -(2- { [3 -fluoro-4-(piperazin- 1 -yl)phenyl] amino } pyrimidin-
4-yl)-l,3-thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide [M+H]+ 728.5, then 628.5.
[000502] 4-[2-tert-butyl-4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3- thiazol-5-yl]-7V-[3-fluoro-4-(piperazin-l-yl)phenyl]pyrimidin-2-amine [M+H]+ 743.7, then 643.6.
[000503] 4-[2-tert-butyl-4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3- thiazol-5-yl]-7V-[3-chloro-4-(piperazin-l-yl)phenyl]pyrimidin-2-amine [M+H]+ 759.5, then 659.5 (Boc deprotection).
[000504] The following scheme uses the above General Procedure for Buchwald Coupling Followed by BOC Deprotection.
[000505] Tert-butyl 4-[4-({4-[2-tert-butyl-4-(3-{ [ethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)-l,3-thiazol-5-yl]pyrimidin-2-yl}amino)phenyl]piperidine-l-carboxylate
LCMS: C36H46FN7O4S2, requires: 723.3, found: m/z = 724.5 [M+H]+.
[000506] 4-[2-tert-butyl-4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3- thiazol-5-yl]-7V-[4-(piperidin-4-yl)phenyl]pyrimidin-2-amine
LCMS: C31H38FN7O2S2, requires: 623.3, found: m/z = 624.4 [M+H]+. 'H NMR (500 MHz, DMSO-tC) 8 9.70 (s, 2H), 8.82 (s, 1H), 7.64 (d, J= 8.3 Hz, 2H), 7.56 (t, J= 7.7 Hz, 1H), 7.40 (t, J= 6.7 Hz, 1H), 7.35 (t, J= 7.9 Hz, 1H), 7.13 (d, J= 8.3 Hz, 2H), 3.75 - 3.65 (m, 6H), 3.49 (dd, J= 15.3, 4.9 Hz, 1H), 3.37 (d, J= 12.4 Hz, 2H), 3.08 (d, J= 7.2 Hz, 1H), 3.05 (d, J= 7.2 Hz, 1H), 2.99 (d, J= 12.1 Hz, 2H), 2.84 - 2.74 (m, 1H), 2.67 (s, 2H), 1.93 (d, J= 13.7 Hz, 2H), 1.81 (q, J= 13.1 Hz, 2H), 1.47 (s, 9H), 1.00 (t, J = 7.1 Hz, 3H).
[000507] The following scheme uses the above General Procedure for Buchwald Coupling Followed by BOC Deprotection.
[000508] Tert-butyl 4-[6-({4-[2-tert-butyl-4-(3-{ [ethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)-!, 3-thiazol-5-yl]pyrimidin-2-yl}amino)pyridin-3-yl]piperazine-l-carboxylate
LCMS: C34H44FN9O4S2 requires: 725.29, found: m/z = 726.52 [M+H]+.
[000509] 4-[6-({4-[2-terZ-butyl-4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)- l,3-thiazol-5-yl]pyrimidin-2-yl}amino)pyridin-3-yl]piperazine
LCMS: C29H36FN9O2S2 requires: 625.24, found: m/z = 626.44 [M+H]+. 'H NMR (500 MHz, DMSO-t/e) 8 10.92 (s, 1H), 9.68 (s, 1H), 9.17 (s, 2H), 8.50 (d, J = 5.4 Hz, 1H), 8.06 (s, 1H), 7.92 (s, 1H), 7.88 - 7.84 (m, 1H), 7.74 (d, J= 9.3 Hz, 1H), 7.54 (t, J= 7.9 Hz, 1H), 7.45 (t, J = 6.8 Hz, 1H), 7.36 (t, J= 7.9 Hz, 1H), 6.68 (d, J = 5.3 Hz, 1H), 5.16 (d, J= 7.4 Hz, 1H), 3.75 - 3.65 (m, 1H), 3.54 - 3.44 (m, 1H), 3.40 (t, J= 5.2 Hz, 4H), 3.07 (q, J= 7.1 Hz, 2H), 2.68 (s, 3H), 1.48 (s, 9H), 1.01 (t, J= 7.1 Hz, 3H). [000510] The following scheme uses the above General Procedure for Buchwald Coupling Followed by BOC Deprotection.
[000511] 7c/7-butyl 4-{6-[(4-{4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-2-methyl- l,3-thiazol-5-yl}pyrimidin-2-yl)amino]pyridin-3-yl}piperazine-l-carboxylate LCMS: C31H37FN8O4S2 requires: 668.23, found: m/z = 669.51 [M+H]+. 'H NMR (500 MHz, CDCI3) 8 8.31 (d, J= 5.2 Hz, 1H), 8.29 (s, 1H), 8.08 (d, J= 9.0 Hz, 1H), 8.03 (d, J= 2.9 Hz, 1H), 7.75 - 7.67 (m, 1H), 7.41 (td, J= 7.2, 6.5, 1.7 Hz, 1H), 7.35 - 7.29 (m, 2H), 6.83 (d, J = 17.4 Hz, 1H), 6.50 (d, J= 5.2 Hz, 1H), 3.63 (t, J= 5.1 Hz, 4H), 3.12 (t, J= 5.1 Hz, 4H), 3.04 (ddd, J= 9.4, 5.6, 1.4 Hz, 2H), 2.82 (d, J= 0.9 Hz, 3H), 1.84 (q, J= 7.8 Hz, 2H), 1.52 (s, 9H), 1.01 (td, J= 7.4, 1.4 Hz, 3H).
[000512] N- { 2-fluoro-3 - [2-methyl-5 -(2- { [5 -(piperazin- 1 -yl)pyridin-2- yl]amino}pyrimidin-4-yl)-l,3-thiazol-4-yl]phenyl}propane-l-sulfonamide
LCMS: C26H29FN8O2S2 requires: 568.18, found: m/z = 569.51 [M+H]+.
[000513] General Procedure for SnAr Coupling Followed by Deprotection (Version 2)
[000514] Synthesis of 7V-(3-(5-(2-((2-azaspiro [3.3] heptan-6-yl)amino)pyrimidin-4- yl)-2-(tert-butyl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide
[000515] Step-1: tert-butyl 6-((4-(2-(tert-butyl)-4-(2-fluoro-3-
(propylsulfonamido)phenyl)thiazol-5-yl)pyrimidin-2-yl)amino)-2-azaspiro[3.3]heptane- 2-carboxylate
To a solution of A-{3-[2-tert-butyl-5-(2-chloropyrimidin-4-yl)-l,3-thiazol-4-yl]-2- fluorophenyl} propane- 1 -sulfonamide (800.00 mg, 1.7058 mmol) and triethylamine (0.70 mL, 5.1174 mmol) in dioxane (2.50 mL) and isopropanol (2.50 mL) was added tert-butyl 6-amino- 2-azaspiro[3.3]heptane-2-carboxylate (543.19 mg, 2.5587 mmol). The reaction mixture was heated at 60 °C for sixty hours. The reaction mixture was then cooled down and diluted with EtOAc (40 mL). The organic solution was washed by 20% citric acid solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was loaded onto a Redi-Sep prepacked silica gel column eluting with a gradient of 15-90% EtOAc in hexanes, to provide terLbutyl 6-[(4-{2-terLbutyl-4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-l,3-thiazol-5-yl}pyrimidin-2-yl)amino]-2-azaspiro[3.3]heptane-2- carboxylate (0.86 g, 78.19%). LCMS: C31H41FN6O4S2 required: 644.26 found: m/z = 645.49 [M+H]+.
[000516] Step-2: A-(3-(5-(2-((2-azaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)-2- (tert-butyl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide To a solution of tert-butyl 6-[(4-{2-tert-butyl-4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]- l,3-thiazol-5-yl(pyrimidin-2-yl)amino]-2-azaspiro[3.3]heptane-2-carboxylate (860.00 mg, 1.3337 mmol) in hexafluoro-2-propanol (4 mL) was added TFA (0.5 mL) and the reaction was stirred for one hour at room temperature. The solution was concentrated in vacuo. The dried product was dissolved in DCM (30 mL), washed with sat. NaHCCL solution, and concentrated in vacuo. The product was lyophilized to provide A-{3-[5-(2-{2-azaspiro[3.3]heptan-6- ylamino(pyrimidin-4-yl)-2-tert-butyl-l, 3-thiazol-4-yl]-2-fluorophenyl (propane- 1- sulfonamide (0.661 g, 90.99%) as a yellow oil. LCMS: C26H33FN6O2S2, requires: 544.21, found: m/z = 545.34 [M+H]+.
[000517] The following scheme uses the above General Procedure for SnAr Coupling Followed by Deprotection (Version 2).
[000518] 7b/7-butyl (3R)-3-{ [(4-{ 2-tert-butyl-4-[2-fluoro-3-(propane-l - sulfonamido)phenyl]- 1 ,3 -thiazol-5-yl (pyrimidin-2-yl)amino]methyl (pyrrolidine- 1 - carboxylate
LCMS: C30H41FN6O4S2 requires: 632.26, found: m/z = 633.30 [M+H]+.
[000519] 7V-{3-[2-tert-butyl-5-(2-{[(35)-pyrrolidin-3-ylmethyl]amino}pyrimidin-4-yl)- l,3-thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide
LCMS: C25H33FN6O2S2, requires: 532.21, found: m/z = 533.69 [M+H]+.
[000520] The following scheme uses the above General Procedure for SnAr Coupling Followed by Deprotection (Version 2).
[000521 ] Tert-butyl (3S)-3 - { [(4- [ 2-/ert-buty 1 -4- [2-fl uoro-3 -(propane- 1 - sulfonamido)phenyl]- 1 ,3 -thiazol-5-yl }pyrimidin-2-yl)amino]methyl (pyrrolidine- 1 - carboxylate
LCMS: C30H41FN6O4S2 requires: 632.26, found: m/z = 633.86 [M+H]+.
[000522] 7V-{3-[2-tert-butyl-5-(2-{[(3T?)-pyrrolidin-3-ylmethyl]amino(pyrimidin-4-yl)- l,3-thiazol-4-yl]-2-fluorophenyl(propane-l-sulfonamide
LCMS: C25H33FN6O2S2, requires: 532.21, found: m/z = 533.76 [M+H]+.
[000523] The following scheme uses a modified General Procedure for Amide Coupling Followed by Deprotection.
[000524] Synthesis of V-(3-(2- hiityl)-5-(2-((2-(4-niioropiperidine-4-carhonyl)- 2-azaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-
1-sulfonamide
[000525] Step-1: tert-butyl 4-(6-((4-(2-(tert-butyl)-4-(2-fluoro-3-
(DroDylsulfonamido)Dhenyl)thiazol-5-yl)Dyrimidin-2-yl)amino)-2-azasDiro[3.3]heDtane- 2-carbonyl)-4-fluoroDiperidine-l-carboxylate
To a solution of l-(tert-butoxycarbonyl)-4-fluoropiperidine-4-carboxylic acid (23.15 mg, 0.0936 mmol) and [(dimethylamino)({[l,2,3]triazolo[4,5-Z>]pyridine-3- yloxy})methylidene]dimethylazanium; hexafluoro-lambda5-phosphanuide (35.60 mg, 0.0936 mmol) in DMF (0.4 mL) was added 7V,7V-diisopropylethylamine (40.34 mg, 0.3121 mmol) followed by the addition of 7V-{3-[5-(2-{2-azaspiro[3.3]heptan-6-ylamino}pyrimidin- 4-yl)-2-tert-butyl-l,3-thiazol-4-yl]-2-fluorophenyl }propane-l -sulfonamide (34.00 mg, 0.0624 mmol) in DMF (0.2 mL). The reaction was stirred at room temperature for twenty minutes. The reaction mixture was then diluted with EtOAc (20 mL). The organic solution was washed with water (0.5 mL) twice, dried over sodium sulfate, filtered, and concentrated in vacuo. The product was loaded onto a Redi-Sep prepacked silica gel column eluting with a gradient of 0- 10% DCM in MeOH to afford tert-butyl 4-{6-[(4-{2-tert-butyl-4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-l,3-thiazol-5-yl}pyrimidin-2-yl)amino]-2-azaspiro[3.3]heptane-2- carbonyl}-4-fluoropiperidine-l -carboxylate (0.046 g, 95.22%). LCMS: C37H49F2N7O5S2 requires: 773.32, found: m/z = 775.04.
[000526] Step-2: \-(3-(2-(ter/,-butyl)-5-(2-((2-(4-nuoropipcridinc-4-carbonyl)-2- azaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-flnorophenyl)propane-l- sulfonamide
Tert-butyl 4-{6-[(4-{2-tert-butyl-4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-l,3-thiazol-
5-yl}pyrimidin-2-yl)amino]-2-azaspiro[3.3]heptane-2-carbonyl}-4-fluoropiperidine-l- carboxylate (46.00 mg, 0.0594 mmol) was dissolved in DCM (2 mL) and 4 N HC1 in dioxane (0.30 mL, 1.1887 mmol) was added. The reaction was stirred for one hour and the solvent was removed in vacuo. 7V-(3-(2-(tert-butyl)-5-(2-((2-(4-fluoropiperidine-4-carbonyl)-2- azaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide was isolated without further purification. LCMS: C32H41F2N7O3S2 requires: 673.27, found: m/z = 674.84 [M+H]+.
[000527] General Procedure for Reductive Alkylation Followed by Deprotection
[000528] Synthesis ol' \-(3-(5-(2-aiiiiiiopyi iiiiidiii-4-yl)-2-(l-(azetidiii-3-yl)pipei idiii-
4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide
[000529] Step-1: tert-butyl 3-(4-(5-(2-aminopyrimidin-4-yl)-4-(2-fluoro-3-
(propylsulfonamido)phenyl)thiazol-2-yl)piperidin-l-yl)azetidine-l-carboxylate
To a solution of 7V-{3-[5-(2-aminopyrimidin-4-yl)-2-(piperidin-4-yl)-l,3-thiazol-4-yl]-2- fluorophenyl} propane- 1 -sulfonamide (130.00 mg, 0.2728 mmol) and tert-butyl 3- oxoazetidine-1 -carboxylate (46.70 mg, 0.2728 mmol) in DMSO (0.50 mL) and DCM (4.00 mL) was added triethylamine (37.81 pL, 27.60 mg, 0.2728 mmol) followed by sodium triacetoxyborohydride (173.43 mg, 0.8183 mmol) powder in portions. The reaction was stirred at room temperature for sixteen hours. The reaction was diluted with DCM (30 mL). The organic solution was washed with water (1 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was loaded onto a Redi-Sep prepacked silica gel column eluting with a gradient of 2-10% MeOH in DCM to provide tert-butyl 3-(4-(5-(2- aminopyrimidin-4-yl)-4-(2-fluoro-3-(propylsulfonamido)phenyl)thiazol-2-yl)piperidin-l- yl)azetidine-l -carboxylate (0.146 g, 84.72%). LCMS: C29H38FN7O4S2 requires 631.24, found m/z = 632.56 [M+H]+.
[000530] Step-2: 7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(azetidin-3-yl)piperidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide To a solution of tert-butyl 3-(4-(5-(2-aminopyrimidin-4-yl)-4-(2-fluoro-3- (propylsulfonamido)phenyl)thiazol-2-yl)piperidin-l-yl)azetidine-l -carboxylate (146.00 mg, 0.2311 mmol) in DCM (2 mL) was added hydrogen chloride (2.00 mL, 0.29 g, 8.0000 mmol) in dioxane (4 M) . The reaction was stirred for twenty minutes. Solvents were removed under reduced pressure to provide 7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(azetidin-3-yl)piperidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide without further purification. LCMS C24H30FN7O2S2 requires: 531.19; found: m/z = 532.44 [M+H]+.
[000531 ] General Procedure for Reductive Amination Followed by Deprotection
[000532] Synthesis of V-(2-niioro-3-( l-(4-(piperaziii-l-yliiietliyl)plieiiyl)-3-(pyridiii-
4-yl)-lZ/-pyrazol-4-yl)phenyl)propane-l-sulfonamide
[000533] Step-1 : tert-butyl 4-(4-(4-(2-fluoro-3-(DroDylsulfonamido)phenyl)-3-
(pyridiii-4-yl)-l//-pyrazol-l-yl)beiizyl)piperaziiie-l -carboxylate
To a solution of 7V-{2-fluoro-3-[l-(4-formylphenyl)-3-(pyridin-4-yl)pyrazol-4- yl]phenyl}propane-l-sulfonamide (101.20 mg, 0.2179 mmol) and tert-butyl piperazine-1- carboxylate (44.64 mg, 0.2396 mmol) in DCM (3.0 mL) was added acetic acid (0.05 mL) followed by the addition of sodium triacetoxyborohydride (138.52 mg, 0.6536 mmol). The reaction was stirred for thirty minutes; however, the starting material did not dissolve. Thus, MeOH (0.10 mL) was added and the starting material started to dissolve. The reaction was stirred for 2.5 hours. The crude product was diluted with DCM (30 mL), the solution was washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was loaded onto a Redi-Sep prepacked silica gel column eluting with a gradient of 20-100% EtOAc in DCM to afford /crt-butyl 4-[(4-{4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-3-(pyridin-4-yl)pyrazol-l-yl}phenyl)methyl]piperazine-l-carboxylate (0.121 g, 70.00%). LCMS:C33H39FN6O4S requires: 634.3, found: m/z = 635.7 [M+H]+.
[000534] Step-2: 7V-(2-fluoro-3-(l-(4-(DiDerazin-l-ylmethyl)Dhenyl)-3-(Dyridin-4- yl)-l//-pyrazol-4-yl)phenyl)propane-l -sulfonamide
To a solution of tert-butyl 4-[(4-{4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-3-(pyridin-4- yl)pyrazol-l-yl}phenyl)methyl]piperazine-l-carboxylate (121.00 mg, 0.1906 mmol) in DCM (4 mL) was added TFA (1 mL). The reaction was stirred for thirty minutes and then TFA and DCM were removed in vacuo. The crude product was loaded onto Redi-Sep prepacked C18 column (30 g) eluting with a gradient of 10-90% acetonitrile in water (with 0.01% TFA) to afford A-(2-fluoro-3-{ l-[4-(piperazin-l-ylmethyl)phenyl]-3-(pyridin-4-yl)pyrazol-4- yl}phenyl)propane-l-sulfonamide (0.1 g, 81.12%) as a TFA salt. LCMS: C28H31FN6O2S, requires: 534.22, found: m/z = 535.57 [M+H]+.
[000535] The following scheme uses another modified General Procedure for Amide Coupling Followed by Deprotection.
[000536] Synthesis of 7V-(3-(5-(2-aminoDyrimidin-4-yl)-2-(l-(Diperidine-4- carbonyl)DiDeridin-4-yl)thiazol-4-yl)-2-fluoroDhenyl)DroDane-l-sulfonamide
[000537] Step-1: tert-butyl 4-(4-(5-(2-aminopyrimidin-4-yl)-4-(2-fluoro-3-
(DroDylsulfonamido)Dhenyl)thiazol-2-yl)DiDeridine-l-carbonyl)DiDeridine-l-carboxylate
To a solution of l-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (81.78 mg, 0.3567 mmol) and [(dimethylamino)({[l,2,3]triazolo[4,5-Z>]pyridin-3- yloxy})methylidene]dimethylazanium; hexafluoro-lambda5-phosphanuide (135.63 mg, 0.3567 mmol) in DMF (1 mL) was added N, A-diisopropylethylamine (256.12 pL, 184.41 mg, 1.4268 mmol). After stirring the reaction for three minutes, the reaction mixture was added into 7V-{3-[5-(2-aminopyrimidin-4-yl)-2-(piperidin-4-yl)-l,3- thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide (170.00 mg, 0.3567 mmol) in DMF (0.5 mL) and the reaction mixture was stirred for twenty minutes. The crude product was diluted with EtOAc (10 mL), washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was loaded onto Redi-Sep prepacked silica gel column eluting with EtOAc in heptanes, to afford terLbutyl 4-{4-[5-(2-aminopyrimidin-4-yl)- 4-[2-fluoro-3 -(propane- 1 -sulfonamido)phenyl]- 1 ,3 -thiazol-2-yl]piperidine- 1 - carbonyl}piperidine-l-carboxylate (0.145 g, 38.41%). LCMS: C32H42FN7O5S2 requires: 687.3, found: m/z = 688.7 [M+H]+. [000538] Step-2: 7V-(3-(5-(2-aminoDyrimidin-4-yl)-2-(l-(Diperidine-4- carbonyl)DiDeridin-4-yl)thiazol-4-yl)-2-fluoroDhenyl)DroDane-l-sulfonamide
Tert-butyl 4-{4-[5-(2-aminopyrimidin-4-yl)-4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]- l,3-thiazol-2-yl]piperidine-l-carbonyl}piperidine-l-carboxylate (145.00 mg, 0.2108 mmol) was dissolved in 50% v/v TFA in DCM (4 mL) and the solution was stirred for thirty minutes. TFA and DCM were then removed in vacuo. The crude product was loaded onto Redi-Sep prepacked Cl 8 column (30 g) eluting with a gradient of 10-90% acetonitrile in water (0.01% TFA) to afford A-{3-[5-(2-aminopyrimidin-4-yl)-2-[l-(piperidine-4- carbonyl)piperidin-4-yl]- 1 ,3 -thiazol-4-yl]-2-fluorophenyl (propane- 1 -sulfonamide (0.1 g, 67.6%). LCMS: C27H34FN7O3S2, requires: 587.2, found: m/z = 588.6 [M+H]+. 'H NMR (500 MHz, DMSO-tC) 8 9.74 (s, 1H), 8.49 (d, J= 11.1 Hz, 1H), 8.26 (s, 1H), 8.09 (d, J= 5.3 Hz, 1H), 7.55 (t, J = 7.7 Hz, 1H), 7.40 (t, J = 7.0 Hz, 1H), 7.33 (t, J = 7.9 Hz, 1H), 6.84 (s, 2H), 6.12 (d, J = 5.2 Hz, 1H), 4.46 (d, J = 12.9 Hz, 1H), 4.08 (d, J= 13.5 Hz, 1H), 3.26 (dd, J = 35.6, 12.8 Hz, 4H), 3.06 (dd, J = 9.0, 6.3 Hz, 2H), 3.02 - 2.86 (m, 2H), 2.76 (d, J = 19.8 Hz, 2H), 2.15 (dd, J= 25.6, 12.8 Hz, 2H), 1.85 - 1.62 (m, 8H), 1.63 - 1.49 (m, 1H), 1.27 (q, J = 5.8, 4.7 Hz, 2H), 0.93 (t, J= 7.4 Hz, 3H).
[000539] Synthesis of -A-(5-chloro-2-fluoro-3-(l-(4-(3-methylDiDerazin-l- yl)plieiiyl)-3-(pyridiii-4-yl)-l//-pyrazol-4-yl)phenyl)propane-l -sulfonamide (12)
[000540] Step-1: Synthesis of tert-butyl d?)-4-(4-bromoDhenyl)-2-methylpiDerazine- 1-carboxylate (3)
[000541] To a stirred solution of compound 1 (4.5 g, 22.47 mmol, 1.0 equiv) and compound 2 (12.25 g, 56.2 mmol, 2.5 equiv) in toluene (300 mL) was added sodium tert- butoxide (6.48 g, 67.4 mmol. 3.0 equiv) and BINAP (0.700 g, 1.123 mmol, 0.05 equiv) at room temperature. The resulting mixture was purged with N2 for 10 min and then Pd2(dba)s (1.029 g, 1.123 mmol, 0.05 equiv) was added. The resulting mixture was purged with N2 for another 5 min and then heated at 60 °C for 16 h. The progress of the reaction was monitored by TLC (10% ethyl acetate:petroleum ether, Rf: ~0.8). The reaction mixture was then cooled to room temperature and filtered through a Celite pad and washed with ethyl acetate (100 mL). The filtrate was diluted with water (200 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layer was dried over sodium sulphate and concentrated under vacuum to afford a crude compound (17 g) as a brown liquid. The crude compound was purified via Isol era (silica gel: 230-400 mesh) using ethyl acetate:petroleum ether (5-10%) as eluent to afford compound 3 (6.5 g, 78%) as a pale yellow solid. [000542] Step-2: Synthesis of tert-butyl (l?)-2-methyl-4-(4-(4.,4.,5.,5-tetramethyl-l.,3.,2- dioxaborolan-2-yl)phenyl)piperazine-l-carboxylate (5)
[000543] To a solution of compound 3 (6.5 g, 18.30 mmol, 1.0 equiv) and compound 4 (6.97 g, 27.4 mmol, 1.5 equiv) in 1,4-dioxane (300 mL) was added potassium acetate (3.59 g, 36.6 mmol, 2.0 equiv) at room temperature. The resulting mixture was purged with N2 for 10 min and then PdC12(dppf) CH2C12 adduct (1.494 g, 1.830 mmol, 0.1 equiv) was added. The resulting mixture was purged with N2 for another 5 min and then heated at 100 °C for 16 h. The progress of the reaction was monitored by TLC (10% ethyl acetate:petroleum ether, Rf: ~0.6). The reaction mixture was then cooled to room temperature and filtered through a Celite pad and washed with ethyl acetate (100 mL). The filtrate was diluted with water (200 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layer was dried over sodium sulphate and concentrated under vacuum to afford a crude compound (14 g) as a brown liquid. The crude compound was purified via Isolera (silica gel: 230-400 mesh) using ethyl acetate:petroleum ether (5-7%) as eluent to afford compound 5 (7 g, 92%) as a pale yellow solid.
[000544] Step-3: Synthesis of tert-butyl (/?)-4-(4-(4-bronio-3-(pyridin-4-yl)-l//- pyrazol-l-yl)phenyl)-2-methylpiperazine-l-carboxylate (7)
[000545] To a mixture of compound 6 (1.5 g, 6.69 mmol, 1.0 equiv) and compound 5 (3.23 g, 8.03 mmol, 1.2 equiv) in pyridine (20 mL) was added molecular sieves, 4 A (0.731 g, 3.35 mmol, 0.5 equiv) and copper (II) acetate (1.824 g, 10.04 mmol, 1.5 equiv) at room temperature. The resulting mixture was then purged with O2 for 15 min and then heated at 100 °C for 16 h. The progress of the reaction was monitored by TLC (50% ethyl acetate: petroleum ether, Rf: -0.3) and LCMS. The reaction mixture was then cooled to room temperature, filtered through a Celite pad, and washed with ethyl acetate (100 mL). The filtrate was diluted with water (200 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layer was dried over sodium sulphate and concentrated under vacuum to afford a crude compound (10 g) as a brown liquid. The crude compound was purified via Isolera (silica gel: 230-400 mesh) using ethyl acetate:petroleum ether (10%) as eluent to afford compound 7 (1.7g, 47.6%) as a yellow gummy liquid.
[000546] Step-4: Synthesis of (3-broiiio-5-cliloro-2-niioroplienyl)propane- 1 - sulfonamide (10) [000547] To a stirred solution of compound 9 (1.0 g, 4.46 mmol, 1.0 equiv) in di chloromethane (30 mL) was added triethylamine (2.484 mL, 17.82 mmol, 4.0 equiv) and propane- 1 -sulfonyl chloride (1.003 mL, 8.91 mmol, 2.0 equiv) at 0 °C, and the resulting reaction mixture was then warmed and stirred at room temperature for 4 h. Upon completion of the reaction as confirmed by TLC (10% ethyl acetate:petroleum ether, Rf:~0.1) the reaction mixture was then concentrated under vacuum to give the crude product which was dissolved in acetonitrlie (30 mL). To this was added ISfeCCL (4.72 g, 44.6 mmol) in water (30 mL) and the reaction was heated at 80 °C for 2 h. Then the reaction mixture was concentrated under vacuum and the residue obtained was acidified with aq. citric acid solution. The solid obtained was filtered and dried to give the crude product which was purified via Isolera (silica gel, 230- 400 mesh) using ethyl acetate:petroleum ether (35-40%) as eluent. The pure fractions were concentrated under vacuum and the solid obtained was washed with petroleum ether (100 mL) and dried under vacuum to give compound 10 (1.0 g, 63.8%) as a white solid.
[000548] Step-5: Synthesis of Az-(5-chloro-2-fluoro-3-(4.,4.,5.,5-tetramethyl-l.,3.,2- dioxaborolan-2-yl)phenyl)propane-l-sulfonamide (11)
[000549] To a mixture of compound 10 (1.0 g, 3.02 mmol, 1.0 equiv) and compound 4 (1.152 g, 4.54 mmol, 1.5 equiv) in 1,4-dioxane (15 mL) was added potassium acetate (1.039 g, 10.59 mmol, 3.5 qeuiv) and PdC^dppff CLLCh (0.247 g, 0.302 mmol, 0.1 equiv). The resulting mixture was purged with nitrogen for 10 min and then stirred at 100 °C for 2 h. Upon completion of the reaction, as confirmed by LCMS, the reaction mixture was filtered through a Celite bed and washed with 1,4-dioxane (25 mL). The filtrate was concentrated under vacuum to afford crude compound 11. LCMS: m/z: 294 indicated the corresponding boronic acid of 11
[000550] Step-6: Synthesis of tert-butyl (l?)-4-(4-(4-(5-chloro-2-fluoro-3- (propylsulfoii:iiiiido)plieiiyl)-3-(pyridiii-4-yl)-l//-pyr:izol-l-yl)phenyl)-2- methylpiperazine-l-carboxylate (8)
[000551] To a stirred solution of compound 7 (1 g, 2.006 mmol, 1.0 equiv) and compound 11 (3 g, crude) in 1,4-dioxane (15 mL) and water (4 mL) was added CsF (0.610 g, 4.01 mmol, 2.0 equiv) and Pd(amphos)C12 (0.142 g, 0.201 mmol, 0.1 equiv) and the reaction mixture was purged with nitrogen for 10 min. The reaction was then heated at 100 °C for 2 h. Upon completion of reaction as confirmed by LCMS, the reaction mixture was filtered through a Celite bed and washed with 1,4-dioxane (20 mL). The filtrate was concentrated under vacuum and the residue was washed with water (100 mL) and extracted with ethyl acetate (100 mL). The combined organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum to provide the crude product which was purified via Isolera (silica gel, 230-400 mesh) using ethyl acetate: petroleum ether (30-35%) as eluent to afford compound 8 (0.480 g, 30%) as a yellow solid.
[000552] Step-7: Synthesis of (R)-N-(5-chloro-2-fluoro-3-(l-(4-(3-methylpiDerazin- l-yl)Dhenyl)-3-(Dyridin-4-yl)-lH-Dyrazol-4-yl)Dhenyl)DroDane-l-sulfonamide (12)
[000553] To stirred solution of compound 8 (0.480 g, 0.717 mmol, 1.0 equiv) in DCM (10 mL) was added DIPEA (0.260 mL, 1.435 mmol, 2.0 equiv) and TMS-OTf (0.195 mL, 1.076 mmol, 1.5 equiv) at 0 °C and the reaction was stirred at room temperature for 2 h. Upon completion of reaction as confirmed by LCMS, the reaction mixture was quenched with water (20 mL) and extracted with DCM (2 x 20 mL). The combined organic layer was dried over Na2SO4 and concentrated under vacuum provide the crude product which was purified by prep- HPLC (Column: X Bridge C8 150, Method: Formic acid: ACN , Rt: 10 min, Flow rate: 15 mL/min) to provide 12 (0.222 g, 51.6%, Formate salt) as a yellow solid. LCMS: m/z : 569.2 (M+H)+, Rt: 1.329 min, Area: 95.991%; Column: X-BRIDGE C8 (50 x 4.6mm) 3.5pm, Mobile phase: A: 0.1% TFA in H2O, B: ACN, Flow Rate: 2.0 mL/min. HPLC: Rt: 7.636 min, Area: 94.819 %, Column: Atlantis T3 (150 x 4.6) mm, 3pm, Mobile phase: A:0.1% TFA in water, Mobile phase: B: ACN, Flow: 1.2 mL/min. 'H NMR (400 MHz, DMSO-t/e): 8 8.78 (s, 1H), 8.57 (q, J= 1.60 Hz, 2H), 8.15 (s, 1H), 7.83 (d, J= 9.20 Hz, 2H), 7.43 - 7.50 (m, 4H), 7.18 (d, J= 9.20 Hz, 2H), 3.85 (q, J= 13.20 Hz, 2H), 3.40 - 3.33 (m, 3H), 3.14 - 3.06 (m, 3H), 2.94 (m, 1H), 2.74 - 2.68 (m, 1H), 1.69 - 1.63 (m, 2H), 1.26 (d, J= 6.40 Hz, 3H), 0.92 (t, J= 7.20 Hz, 3H).
[000554] Synthesis of -(5-chloro-2-fluoro-3-(l-(4-(3-methylDiDerazin-l- yl)pheiiyl)-3-(pyridiii-4-yl)-l//-pyrazol-4-yl)phenyl)propane-l -sulfonamide (12)
[000555] Step-1: Synthesis of tert-butyl 6S)-4-(4-bromoDhenyl)-2-methylDiperazine-
1-carboxylate (3)
[000556] To a stirred solution of compound 1 (3.5 g, 17.48 mmol, 1.0 equiv) and compound 2 (10.31 g, 43.7 mmol, 2.5 equiv) in toluene (300 mL) was added sodium tert- butoxide (5.04 g, 52.4 mmol. 3.0 equiv) and BINAP (0.544 g, 0.874 mmol, 0.05 equiv) at room temperature. The resulting mixture was purged with N2 for 10 min and then Pd2(dba)s (0.800 g, 0.874 mmol, 0.05 equiv) was added. The resulting mixture was then purged with N2 for another 5 min and the reaction was then heated at 60 °C for 16 h. The progress of the reaction was monitored by TLC (10% ethyl acetate:petroleum ether, Rf: ~0.8). The reaction mixture was then cooled to room temperature and filtered through a Celite pad and washed with ethyl acetate (100 mL). The filtrate was diluted with water (200 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layer was dried over sodium sulphate and concentrated under vacuum to afford a crude compound (15 g) as a brown liquid. The crude compound was purified via Isolera (silica gel: 230-400 mesh) using ethyl acetate:petroleum ether (5-10%) as eluent to afford compound 3 (6.2 g, 95%) as a pale yellow solid. [000557] Step-2: Synthesis of tert-butyl (S)-2-methyl-4-(4-(4.,4.,5.,5-tetramethyl-l.,3.,2- dioxaborolan-2-yl)phenyl)piperazine-l-carboxylate (5)
[000558] To a solution of compound 3 (7.7 g, 21.67 mmol, 1.0 equiv) and compound 4 (8.26 g, 32.5 mmol, 1.5 equiv) in 1,4-dioxane (300 mL) was added potassium acetate (4.25 g, 43.3 mmol, 2.0 equiv) at room temperature. The resulting mixture was purged with N2 for 10 min and then PdC12(dppf) CH2C12 adduct (1.770 g, 2.167 mmol, 0.1 equiv) was added. The resulting mixture was purged with N2 for another 5 min and the reaction was then heated at 100 °C for 16 h. The progress of the reaction was monitored by TLC (10% ethyl acetate:petroleum ether, Rf: ~0.6). The reaction mixture was then cooled to room temperature and filtered through a Celite pad and washed with ethyl acetate (100 mL). The filtrate was diluted with water (200 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layer was dried over sodium sulphate and concentrated under vacuum to afford a crude compound (16 g) as a brown liquid. The crude compound was purified via Isolera (silica gel: 230-400 mesh) using ethyl acetate:petroleum ether (5-7%) as eluent to afford compound 5 (8.7 g, 98%) as a pale yellow solid.
[000559] Step-3: Synthesis of tert-butyl (.S)-4-(4-(4-bronio-3-(pyridin-4-yl)-l//- pyrazol-l-yl)phenyl)-2-methylpiperazine-l-carboxylate (7)
[000560] To a mixture of compound 6 (2 g, 8.93 mmol, 1.0 equiv) and compound 5 (4.31 g, 10.71 mmol, 1.2 equiv) in pyridine (25 mL) was added molecular sieves, 4 A (0.974 g, 4.46 mmol, 0.5 equiv) and copper (II) acetate (2.432 g, 13.39 mmol, 1.5 equiv) at room temperature. The resulting mixture was purged with O2 for 15 min and then the reaction was heated at 100 °C for 16 h. The progress of the reaction was monitored by TLC (50% ethyl acetate: petroleum ether, Rf: -0.3) and LCMS. The reaction mixture was then cooled to room temperature and filtered through a Celite pad and washed with ethyl acetate (100 mL). The filtrate was diluted with water (200 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layer was dried over sodium sulphate and concentrated under vacuum to afford a crude compound (12 g) as a brown liquid. The crude compound was purified via Isolera (silica gel: 230-400 mesh) using ethyl acetate:petroleum ether (15-20%) as eluent to afford compound 7 (1.5 g, 32%) as a yellow gummy liquid.
[000561 ] Step-4: Synthesis of (3-broiiio-5-cliloro-2-niioroplienyl)propane- 1 - sulfonamide (10) [000562] To a stirred solution of compound 9 (0.8 g, 3.56 mmol, 1.0 equiv) in di chloromethane (30 mL) was added triethylamine (1.44 g, 14.26 mmol, 4.0 equiv) and propane- 1 -sulfonyl chloride (1.203 mL, 10.69 mmol, 3.0 equiv) at 0 °C and the resulting reaction mixture was stirred at room temperature for 4 h. Upon completion of the reaction as confirmed by TLC (10% ethyl acetate:petroleum ether, Rf:~0.1), the reaction mixture was then concentrated under vacuum to give the crude product which was dissolved in acetonitrlie (30 mL). Na2CC>3 (3.77 g, 35.6 mmol) in water (30 mL) was then added and the reaction was then heated at 80 °C for 2 h. Then the reaction mixture was concentrated under vacuum and the residue obtained was acidified with aq. citric acid solution. The solid obtained was filtered and dried to give the crude product which was purified via Isolera (silica gel, 230-400 mesh) using ethyl acetate: petroleum ether (35-40%) as eluent. The pure fractions were concentrated under vacuum and the solid obtained was washed with petroleum ether (25 mL) and dried under vacuum to give compound 10 (1.1 g, 91%) as a white solid.
[000563] Step-5: Synthesis of Az-(5-chloro-2-fluoro-3-(4.,4.,5.,5-tetramethyl-l.,3.,2- dioxaborolan-2-yl)phenyl)propane-l-sulfonamide (11)
[000564] To a mixture of compound 10 (1.1 g, 3.33 mmol, 1.0 equiv) and compound 4 (1.267 g, 4.99 mmol, 1.5 equiv) in 1,4-dioxane (15 mL) was added potassium acetate (1.14 g, 11.65 mmol, 3.5 equiv) and PdC^dppff CLLCh (0.272 g, 0.333 mmol, 0.1 equiv). The resulting mixture was purged with nitrogen for 10 min and then stirred at 100 °C for 2 h. Upon completion of the reaction, as confirmed by LCMS, the reaction mixture was filtered through a Celite bed and washed with 1,4-dioxane (25 mL). The filtrate was concentrated under vacuum to afford crude compound 11 (2.9 g, quant.). LCMS: m/z = 294 corresponds to the boronic acid derivative of 11.
[000565] Step-6: Synthesis of tert-butyl -4-(4-(4-(5-chloro-2-fluoro-3- (propylsulfoii:iiiiido)plieiiyl)-3-(pyridiii-4-yl)-l//-pyr:izol-l-yl)phenyl)-2- methylpiperazine-l-carboxylate (8)
[000566] To a stirred solution of compound 7 (1.1 g, 2.207 mmol, 1.0 equiv) and compound 11 (2.9 g, crude) in 1,4-dioxane (15 mL) and water (4 mL) was added CsF (0.670 g, 4.41 mmol, 2.0 equiv) and Pd(amphos)C12 (0.156 g, 0.221 mmol, 0.1 equiv) and the reaction mixture was purged with nitrogen for 10 min. The reaction was then heated at 100 °C for 2 h. Upon completion of the reaction, as confirmed by LCMS, the reaction mixture was then filtered through a Celite bed and washed with 1,4-dioxane (20 mL). The filtrate was concentrated under vacuum and the residue was washed with water (100 mL) and extracted with ethyl acetate (100 mL). The combined organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum to provide the crude product which was purified via Isol era (silica gel, 230-400 mesh) using ethyl acetate:petroleum ether (30-35%) as eluent to afford compound 8 (0.580 g, 31.8%) as a yellow solid.
[000567] Step-7: Synthesis of (.S)- V-(5-chloro-2-niioro-3-( l-(4-(3-iiiethylpiperazin-l- yl)pheiiyl)-3-(pyridiii-4-yl)-l//-pyr:izol-4-yl)phenyl)propane-l -sulfonamide (12)
[000568] To stirred solution of compound 8 (0.580 g, 0.867 mmol, 1.0 equiv) in DCM (10 mL) was added DIPEA (0.302 mL, 1.733 mmol, 2.0 equiv) and TMS-OTf (0.473 mL, 2.60 mmol, 3 equiv) at 0 °C and the reaction was then stirred at room temperature for 2 h. Upon completion of then reaction, as confirmed by LCMS, the reaction mixture was then quenched with water (20 mL) and extracted with DCM (2 x 20 mL). The combined organic layer was dried over Na2SO4 and concentrated under vacuum provide the crude which was purified by prep-HPLC (Column: Xselect C18 250 mm, Method: Formic acid (FA): ACN, Rt: 10 min, Flow rate: 15 mL/min) to provide 12 (0.156 g, 31.2%, formate salt) as a yellow solid. LCMS: Rt: 1.461 min, Area: 99.33%, m/z = 569.2 (M+H)+. Column: BEH C18 (50 x 2.1 mm) 1.7 pm; Mobile phase: A: 0.1% HCOOH in H2O, B: ACN; Flow Rate: 0.8 mL/min. HPLC: Rt: 7.653 min, Area: 99.93 %; Method Info: Column: Atlantis T3 (150 x 4.6 mm, 3pm; Mobile phase: A: 0.1% TFA in water; Mobile phase: B: ACN; Flow: 1.2 mL/min. JH NMR (400 MHz, DMSO-t/e): 8 9.00 (bs, 2H), 8.78 (s, 1H), 8.57 (q, J= 1.60 Hz, 2H), 7.83 (d, J= 9.20 Hz, 2H), 7.51 - 7.41 (m, 4H), 7.18 (d, J= 9.20 Hz, 2H), 3.88 - 3.79 (m, 2H), 3.39 - 3.33 (m, 2H), 3.13 - 3.05 (m, 3H), 2.96 - 2.93 (m, 1H), 2.73 - 2.68 (m, 1H), 1.69 - 1.63 (m, 2H), 1.26 (d, J = 6.80 Hz, 3H), 0.92 (t, J= 7.60 Hz, 3H).
[000569] Synthesis of d?)-7V-(5-chloro-2-fluoro-3-(l-(5-(DiDerazin-l-yl)pyridin-2-yl)- 3-(pyridin-4-yl)-l //-pyrazol-4-yl)phenyl)-3-fliioropyrrolidine- 1 -sulfonamide (11)
Synthesis of Common Intermediate 9
[000570] Step-1: Synthesis of -3-fluoroDyrrolidine-l-sulfonyl chloride (2)
[000571] To a solution of compound 1 (4.5 g, 35.8 mmol, 1.0 equiv) in DCM (90 mL) was added DIPEA (17.78 mL, 108 mmol, 3.0 equiv) and the solution was cooled to -70 °C. Sulfuryl dichloride (9.67 g, 71.7 mmol, 2.0 equiv) was then added and the reaction was stirred at -70 °C for one hour. The reaction was then warmed and stirred at room temperature for one hour. The progress of the reaction was monitored by TLC (20% ethyl acetate:petroleum ether, Rf: ~0.6, KMnO4 active). The reaction mixture was then quenched with water (200 mL), extracted with DCM (2 x 200 mL), and washed with 1.5 N HC1 (100 mL). The combined organic layer was dried over Na2SO4 and concentrated under vacuum at room temperature to afford compound 2 (5 g, 74.4%) as an off white solid. [000572] Step-2: Synthesis of (R)-N-(3-bromo-5-chloro-2-fluorophenyl)-3- fluoropyrrolidine-l-sulfonamide (4)
[000573] To a solution of compound 2 (3 g, 13.38 mmol, 1.0 equiv) in pyridine (4.5 mL) was added DMAP (0.327 g, 2.637 mmol, 0.2 equiv) followed by compound 3 (3.261 g, 17.37 mmol, 1.3 equiv) at 0 °C, and the resulting reaction mixture was then heated to 40 °C for 24 h. Upon completion of the reaction, as confirmed by LCMS, the reaction mixture was concentrated under vacuum to afford a crude compound (5 g) as a brown gum. The crude compound was purified via Isolera (silica gel: 230-400 mesh) using ethyl acetate:petroleum ether (10-12%) as eluent to afford compound 4 (1.7 g, 33.8%) as a yellow solid.
[000574] Step-3: Synthesis of ( /?)-V-(5-chloro-2-nuoro-3-(4.4.5.5-tetramet hyl- 1.3.2- dioxaborolan-2-yl)phenyl)-3-fluoropyrrolidine-l-sulfonamide (6)
[000575] To a solution of compound 4 (1 g, 2.66 mmol, 1.0 equiv) in 1,4-dioxane (30 mL) was added compound 5 (1.014 g, 3.99 mmol, 1.5 equiv) and potassium acetate (0.523 g, 5.32 mmol, 2.0 equiv) and the mixture was purged with nitrogen for 15 min. Then PdC12(dppf) DCM (0.195 g, 0.266 mmol, 0.1 equiv) was added and the reaction was heated to 90 °C for 4 h. The progress of the reaction was monitored by TLC (50% ethyl acetate:petroleum ether, Rf: ~0.4). The reaction mixture was then cooled to room temperature and filtered through a Celite pad and washed with ethyl acetate (100 mL). The filtrate was diluted with water (200 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layer was passed through silica gel (100-120 mesh), dried over ISfeSCL, and concentrated under vacuum to afford crude compound 6 (1.0 g, 89%) as a brown liquid.
[000576] Step-4: Synthesis of tert-butyl 4-(6-(4-broiiio-3-(pyridin-4-yl)-l//-pyrazol- l-yl)pyridin-3-yl)piperazine-l-carboxylate (9)
[000577] A mixture of compound 7 (0.5 g, 0.0022 mmol, 1.0 equiv) and 8 (0.75 g, 0.0022 mmol, 1.0 equiv) in DMSO (5 mL) was treated with cesium carbonate (1.45 g, 0.0044 mmol, 2.0 equiv), copper(I)oxide (0.032 g, 0.0002 mmol, 0.1 equiv), and 8-hydroxyquinoline (0.064 g, 0.0004 mmol, 0.2 equiv) at room temperature. The reaction mixture was purged with N2 for 10 min and then heated at 100 °C in a closed vial for 16 h. Similarly, five additional batches were peformed on 0.5 g scale.
[000578] All the batches were then cooled to room temperature, mixed together, and filtered through a Celite pad. The Celite pad was washed with ethyl acetate (100 mL). The filtrate was diluted with water (200 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layer was dried over Na2SO4 and concentrated under vacuum to afford a crude compound (6 g) as a brown liquid. The crude compound was purified via Isolera (silica gel: 230-400 mesh) using ethyl acetate:petroleum ether (30-35%) as eluent to afford compound 9 (3.0 g, 46%) as an off-white solid.
[000579] Step-5: Synthesis of tert-butyl (l?)-4-(6-(4-(5-chloro-2-fluoro-3-((3- niioropyrrolidiiie)-l-siilfoii:iiiiido)pheiiyl)-3-(pyridiii-4-yl)-l//-pyrazol-l-yl)pyridin-3- yl)piperazine-l-carboxylate (10)
[000580] To a mixture of compound 6 (1.0 g, 2.366 mmol, 1.0 equiv) and compound 9 (0.918 g, 1.892 mmol, 0.8 equiv) in 1,4-dioxane (24 mL) and H2O (6 mL) was added cesium fluoride (0.718 g, 4.732 mmol, 2.0 equiv) and Pd(amphos)C12 (0.168 g, 0.236 mmol, 0.1 equiv) at room temperature. The reaction mixture was purged with N2 for 10 min and then heated at 90 °C for 6 h. Upon completion of reaction, as confirmed by LCMS, the reaction mixture was filtered through a Celite pad and washed with ethyl acetate (50 mL). The filtrate was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was dried over Na2SO4 and concentrated under vacuum provide a crude which was purified by prep-HPLC (Column: SUNFIRE C18 250 x 30 mm, Method: TFA: ACN, Rt: 12 min, Flow rate: 15 mL/min) to provide compound 10 (0.6 g, 37.2%) as a yellow solid.
[000581] Step-6: Synthesis of (l?)-7V-(5-chloro-2-fluoro-3-(l-(5-(piperazin-l- yl)pyridin-2-yl)-3-(pyridin-4-yl)-lH-pyrazol-4-yl)phenyl)-3-fluoropyrrolidine-l- sulfonamide (11)
[000582] To a solution of compound 10 (0.6 g, 0.856 mmol, 1.0 equiv) in DCM (20 mL) was added trifluoroacetic acid (0.976 g, 8.56 mmol, 10 equiv) at 0 °C and the reaction was warmed and stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC (100% ethyl acetate, Rf: ~0.2). The reaction mixture was then concentrated under vacuum to give a brown gum, which was washed with petroleum ether (3 x 20 mL), dried under vacuum, and lyophilized to provide 11 (537 mg, 98%, TFA salt) as a yellow solid. LCMS: Rt: 1.261 min, Area: 96.8 %, m/z = 601.1 (M+H)+. Column: X-BRIDGE C8 (50 x 4.6 mm) 3.5 pm; Mobile phase: A: 0.1% TFA in H2O, B: ACN; Flow Rate: 2.0 mL/min. HPLC: Rt: 7.444 min, Area: 95.07 %; Method Info: Column: Atlantis T3 150 x 4.6 mm, 3 pm; Mobile phase: A:0.1% TFA in water; Mobile phase: B: ACN; Flow: 1.2 mL/min. 1HNMR (400 MHz, DMSO- d6): 10.10 (s, 1H), 8.85 (s, 3H), 8.71 (d, J= 6.40 Hz, 2H), 8.29 (d, J= 2.80 Hz, 1H), 7.99 (d, J = 9.20 Hz, 1H), 7.75 - 7.68 (m, 3H), 7.54 (q, J= 2.40 Hz, 1H), 7.43 (q, J= 2.40 Hz, 1H), 5.30 (d, J= 52.00 Hz, 2H), 3.51 (q, J= 8.00 Hz, 5H), 3.41 - 3.37 (m, 2H), 3.28 (t, J= 2.40 Hz, 4H), 2.17 - 1.99 (m, 2H). 19F NMR (400 MHz, DMSO-t/e): -74.32, -126.08, -174.86.
[000583] Synthesis of ethylmethyl[(5-chloro-2-fluoro-3-H-[5-(piperazin-l- yl)pyridiii-2-yl|-3-(pyridiii-4-yl)-l//-pyr:izol-4-yl!plieiiyl)
[000584] Step-1: Synthesis of ethylmethyl[(3-bromo-5-chloro-2- fluorophenyDsulfamoyllamine (3)
[000585] To a solution of compound 1 (1 g, 4.46 mmol, 1.0 equiv) in pyridine (1.5 mL) was added DMAP (0.109 g, 0.891 mmol, 0.2 equiv) followed by compound 2 (0.913 g, 17.37 mmol, 1.3 equiv) at 0 °C and the resulting reaction mixture was heated to 40 °C for 16 h. Upon completion of the reaction, as confirmed by LCMS, the reaction mixture was concentrated under vacuum to afford a crude compound (1.5 g) as a brown gum. The crude compound was purified via Isolera (silica gel: 230-400 mesh) using ethyl acetate:petroleum ether (7-10%) as eluent to afford compound 3 (0.85 g, 49.5%) as an off-white solid. [000586] Step-2: Synthesis of ethylmethylf[5-chloro-2-fluoro-3-(4.,4.,5.,5-tetramethyl- l,3.,2-dioxaborolan-2-yl)Dhenyl]sulfamoynamine (5)
[000587] To a solution of compound 3 (0.5 g, 1.447 mmol, 1.0 equiv) in 1,4-dioxane (10 mL) was added compound 4 (0.551 g, 2.17 mmol, 1.5 equiv) and potassium acetate (0.284 g, 2.89 mmol, 2.0 equiv) at room temperature. The resulting mixture was purged with N2 for 15 min. Then PdC12(dppf) DCM (0.117 g, 0.145 mmol, 0.1 equiv) was added and the reaction was heated to 90 °C for 3 h. The progress of the reaction was monitored by TLC (50% ethyl acetate:petroleum ether, Rf: ~0.2). The reaction mixture was then cooled to room temperature and filtered through a Celite pad and washed with ethyl acetate (50 mL). The combined organic layer was passed through silica gel (100-120 mesh), dried over Na2SO4, and concentrated under vacuum to afford crude compound 5 (1.0 g, quant.) as a brown solid.
[000588] Step-3: Synthesis o butyl 4-(6-(4-(5-chloro-3-((7V-ethyl-7V- iiietliylsiillaiiioyl):iiiiiiio)-2-niiorophenyl)-3-(pyridin-4-yl)-l //-pyrazol- 1 -yl)pyridin-3- yl)piperazine-l-carboxylate (6)
[000589] To a mixture of compound compound 5 (2.0 g, 5.28 mmol, 3.0 equiv) and tert- butyl 4-(6-(4-bromo-3-(pyridin-4-yl)-U/-pyrazol-l-yl)pyri din-3 -yl)piperazine-l -carboxylate (common intermediate 9, 0.85 g, 1.751 mmol, 1.0 equiv) and in 1,4-dioxane (30 mL) and water (7.5 mL) was added CsF (0.532 g, 3.5 mmol, 2.0 equiv) and Pd(Amphos)C12 (0.124 g, 0.175 mmol, 0.1 equiv) and the reaction mixture was purged with nitrogen for 10 min. The reaction was then heated at 90 °C for 6 h. Upon completion of reaction as confirmed by LCMS, the reaction mixture was filtered through a Celite pad and washed with ethyl acetate (100 mL). The filtrate was diluted with water (50 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layer was dried over Na2SO4 and concentrated under vacuum to provide a crude which was purified by prep-HPLC (Column: SUNFIRE C18 250 x 30 mm, Method: TFA: ACN, Rt: 12 min, Flow rate: 15 mL/min) to provide compound 6 (0.6 g, 51%) as a yellow solid.
[000590] Step-4: Synthesis of ethylmethyl[(5-chloro-2-fluoro-3-Il-[5-(piperazin-l- yl)pyridiii-2-yl|-3-(pyridiii-4-yl)-l//-pyr:izol-4-yllpheiiyl)siilf:iiiioyl|aniine (7)
[000591 ] To a solution of compound 6 (0.6 g, 0.8939 mmol, 1.0 equiv) in DCM (14 mL) was added trifluoroacetic acid (0.70 mL, 8.939 mmol, 10 equiv) at 0 °C and the reaction was warmed and stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC (100% ethyl acetate, Rf: -0.2). The reaction mixture was concentrated under vacuum to provide a crude product as a brown gum. The crude was washed with petroleum ether (3 x 20 mL) and dried under vacuum to afford a crude compound (0.6 g, 92%) by LCMS. The crude was purified by prep-HPLC (Column: SUNFIRE C18 250 x 30 mm, Method: TFA: ACN, Rt: 12 min, Flow rate: 15 mL/min) and then lyophilized to provide 7 (392 mg, 98%, TFA salt) as a pale yellow solid. LCMS: Rt: 1.306 min, Area: 99.6 %, m/z = 571.2 (M+H)+; Column: X- BRIDGE C8 (50 x 4.6 mm) 3.5 pm; Mobile phase: A: 0.1% TFA in H2O, B: ACN; Flow Rate: 2.0 mL/min. HPLC: Rt: 7.527 min, Area: 99.31 %; Method Info: Column: Atlantis T3 150 x 4.6 mm, 3 pm; Mobile phase: A: 0.1% TFA in water; Mobile phase: B: ACN; Flow: 1.2 mL/min. 'HNMR (400 MHz, DMSO-< 9.96 (s, 1H), 8.87 - 8.85 (m, 3H), 8.66 (d, J= 1.60 Hz, 2H), 8.28 (d, J= 3.20 Hz, 1H), 7.98 (d, J= 8.80 HZ, 1H), 7.73 (dd, J= 3.20, 9.00 Hz, 1H), 7.58 (d, J = 1.60 Hz, 2H), 7.47 (dd, J= 2.80, 6.40 Hz, 1H), 7.41 (dd, J= 2.80, 5.60 Hz, 1H), 3.32 - 3.50 (m, 4H), 3.30 (br s, 4H), 3.10 (q, J = 7.20 Hz, 2H), 2.69 (s, 3H), 1.03 (t, J = 7.20 Hz, 3H). 19F NMR (400 MHz, DMSO4): -74.08, -126.55.
[000592] Synthesis of /V-(5-chloro-3-(l-(4-(3.,3-diniethylpiperazin-l-yl)-2- niiorophenyl)-3-(pyridin-4-yl)- 1 //-pyrazol-4-yl)-2-niiorophenyl)pyrrolidine-l - sulfonamide TFA salt (7)
[000593] Step-1: Synthesis o butyl 4-(4-chloro-3-fluorophenyl)-2,2- dimethylpiperazine-l-carboxylate (2)
[000594] To a mixture of 4-bromo-l-chloro-2-fluorobenzene (3 g, 14.324 mmol, 1 equiv) and terr-butyl 2,2-dimethyLl-piperazinecarboxyiate (3.07 g, 14.324 mmol, 1 equiv) in toluene (60 mL) was added Pd2(dba)s (131 mg, 0.143 mmol, 0.01 equiv), BINAP (178 mg, 0.286 mmol, 0.02 equiv), and Z-BuONa (1.93 g, 20.054 mmol, 1.4 equiv). The resulting mixture was stirred at 60 °C overnight under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with petroleum ether (PE):EtOAc (4: 1) to afford tert-butyl 4-(4-chloro-3-fluorophenyl)-2,2- dimethylpiperazine-1 -carboxylate (2.3 g, 46.84%) as an off-white solid. LCMS: C17H24CIFN2O2 requires: 342.2, found: m/z = 343.3 [M+H]+.
[000595] Step-2: Synthesis of tert-butyl 4-[3-fluoro-4-(4.,4.,5.,5-tetramethyl-l.,3.,2- dioxaborolan-2-yl)phenyl]-2.,2-dimethylpiperazine-l-carboxylate (3)
[000596] To a mixture of tert-butyl 4-(4-chl oro-3 -fluorophenyl)-2,2-dimethylpiperazine- 1-carboxylate (2.1 g, 6.1253 mmol, 1 equiv) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (B2Pin2) (2.38 g, 9.188 mmol, 1.5 equiv) in methoxycyclopentane (30 mL) was added Pd2(dba)s (171 mg, 0.188 mmol, 0.03 equiv), X- Phos (176 mg, 0.376 mmol, 0.06 equiv), and KOAc (1.75 g, 18.375 mmol, 3 equiv). The resulting mixture was then stirred at 110 °C for 2.0 h under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (4: 1) to afford tert-butyl 4-[3-fluoro- 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]- 2,2-dimethylpiperazine-l- carboxylate (1.3 g, 48.86%) as a brown oil. LCMS: C23H36BFN2O4 requires: 434.3, found: m/z = 435.2 [M+H]+.
[000597] Step-3: Synthesis of tert-butyl 4-]4-[4-bromo-3-(pyridin-4-yl)pyrazol-l-yl]- 3-fluorophenyn-2.,2-dimethylpiperazine-l-carboxylate (4)
[000598] To a mixture of tert-butyl 4-[3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]- 2,2-dimethylpiperazine-l -carboxylate (1.3 g, 2.993 mmol, 1 equiv) and 4-(4-bromo-l//-pyrazol-3-yl)pyridine (1.006 g, 4.489 mmol, 1.5 equiv) in pyridine (20 mL) was added Cu(OAc)2 (1.09 g, 5.986 mmol, 2 equiv) and molecular sieves (4A) (1.4 g). The resulting mixture was stirred at 100°C overnight under an oxygen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CFLCL MeOH (20: 1) to afford tert-butyl 4-{4- [4-bromo-3-(pyridin-4-yl)pyrazol-l-yl]-3-fluorophenyl}-2,2-dimethylpiperazine-l- carboxylate (0.45 g, 28.35%) as a brown semi-solid. LCMS: C25H29BrFNsO2 requires: 529.1, found: m/z = 530.2 [M+H]+. [000599] Step-4: Synthesis of tert-butyl 4-[4-(4-]5-chloro-2-fluoro-3-[(pyrrolidine-l- snlfonyl)amino]phenvn-3-(pyridin-4-yl)pyrazol-l-yl)-3-flnorophenyl]-2.,2- dimethylpiperazine-l-carboxylate (6)
[000600] To a mixture of tert-butyl 4-{4-[4-bromo-3-(pyridin-4-yl)pyrazol-l-yl]-3- fluorophenyl}-2,2-dimethylpiperazine-l-carboxylate (450 mg, 0.8483 mmol, 1 equiv) and A- [5-chl oro-2 -fluoro-3-(4, 4,5, 5-tetramethyl- 1,3, 2-dioxaborolan-2-yl)phenyl]pyrrolidine-l- sulfonamide (1.03 g, 2.545 mmol, 3 equiv) in dioxane (10 mL) was added CsF (258 mg, 1.70 mmol, 2 equiv) in H2O (2 mL) and Pd(AMPHOS)2Ch (60 mg, 0.085 mmol, 0.1 equiv). The resulting mixture was then stirred at 90 °C for one hour under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 :2) to afford tert-butyl 4-[4-(4-{5- chloro-2-fluoro-3 -[(pyrrolidine- l-sulfonyl)amino]phenyl} -3 -(pyri din-4-yl)pyrazol- l-yl)-3- fluorophenyl]-2,2-dimethylpiperazine-l-carboxylate (170 mg, 27.52%) as an off-white solid. LCMS: C35H40CIF2N7O4S requires: 727.3, found: m/z = 728.3 [M+H]+.
[000601 ] Step-5: Synthesis of 7V-(5-chloro-3-(l-(4-(3.,3-diniethylpiperazin-l-yl)-2- fluorophenyl)-3-(pyridin-4-yl)-lH-pyrazol-4-yl)-2-fluorophenyl)pyrrolidine-l- sulfonamide TFA salt (7)
[000602] To a mixture of tert-butyl 4-[4-(4-{5-chloro-2-fluoro-3-[(pyrrolidine-l- sulfonyl)amino]phenyl}-3-(pyridin-4-yl)pyrazol-l-yl)-3-fluorophenyl]-2,2- dimethylpiperazine-1 -carboxylate (170 mg, 0.2334 mmol, 1 equiv) in DCM (6 mL) was added TFA (3 mL) at 0 °C. The resulting mixture was stirred at 0 °C for one hour. The resulting mixture was then concentrated under vacuum. The residue was purified by reverse phase flash chromatography eluted with ACbFEhO (1 : 1) to afford A-(5-chloro-3-{ l-[4-(3,3- dimethylpiperazin-l-yl)-2-fluorophenyl]-3-(pyridin-4-yl)pyrazol-4-yl}-2- fluorophenyl)pyrrolidine-l -sulfonamide trifluoroacetic acid (100.0 mg, 68.22%) as a yellow solid. LCMS: C30H32CIF2N7O2S requires: 627.2, found: m/z = 628.3 [M+H]+.
[000603] Synthesis of 7V-(3-(l-(4-(3.,3-diniethylpiperazin-l-yl)-2-fluorophenyl)-3- (pyridin-4-yl)-l//-pyr:izol-4-yl)-2.5-dinuorophenyl)pyrrolidine-l -sulfonamide TFA salt (6)
[000604] Step-1: Synthesis of tert-butyl 4-(4-chloro-3-fluorophenyl)-2,2- dimethylpiperazine-l-carboxylate (2)
[000605] To a mixture of 4-bromo-l-chloro-2-fluorobenzene (5 g, 23.873 mmol, 1 equiv) and tert-butyl 2,2-dimethylpiperazine-l -carboxylate (5.12 g, 23.873 mmol, 1 equiv) in toluene (50 mL) was added Pd2(dba)s (0.22 g, 0.239 mmol, 0.01 equiv), BINAP (0.30 g, 0.477 mmol, 0.02 equiv), and Z-BuONa (3.21 g, 33.422 mmol, 1.4 equiv). The resulting mixture was stirred at 60 °C overnight under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAC (9: 1) to afford tert-butyl 4-(4-chloro-3-fluorophenyl)-2,2-dimethylpiperazine- 1-carboxylate (7.8 g, 95.30%) as an orange solid. LCMS: C17H24CIFN2O2 requires: 342.2, found: m/z =343.3 [M+H]+.
[000606] Step-2: Synthesis of tert-butyl 4-[3-fluoro-4-(4.,4.,5.,5-tetramethyl-l.,3.,2- dioxaborolan-2-yl)phenyl]-2.,2-dimethylpiperazine-l-carboxylate (3)
[000607] To a mixture of tert-butyl 4-(4-chl oro-3 -fluorophenyl)-2,2-dimethylpiperazine-
1-carboxylate (7.8 g, 22.751 mmol, 1 equiv) and bis(pinacolato)diboron (B2?in2) (8.67 g, 34.127 mmol, 1.5 equiv) in methoxy cyclopentane (80 mL) was added Pd2(dba)s (0.63 g, 0.683 mmol, 0.03 equiv), XPhos (0.65 g, 1.365 mmol, 0.06 equiv), and AcOK (6.70 g, 68.253 mmol, 3 equiv). The resulting mixture was stirred at 110 °C overnight under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (9: 1) to afford tert-butyl 4-[3- fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]-2,2-dimethylpiperazine-l- carboxylate (9 g, 91.07%) as an orange solid. LCMS: C23H36BFN2O4 requires: 434.3, found: m/z =435.2 [M+H]+.
[000608] Step-3: Synthesis of tert-butyl 4-]4-[4-bromo-3-(pyridin-4-yl)pyrazol-l-yl]- 3-fluorophenyn-2.,2-dimethylpiperazine-l-carboxylate (4)
[000609] To a mixture of tert-butyl 4-[3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]-2,2-dimethylpiperazine-l -carboxylate (2 g, 4.604 mmol, 1 equiv) and 4-(4-bromo-l//-pyrazol-3-yl)pyridine (1.13 g, 5.064 mmol, 1.1 equiv) in pyridine (20 mL) was added Cu(OAc)2 (1.67 g, 9.208 mmol, 2 equiv) and molecular sieves (4A) (2 g). The resulting mixture was stirred at 60 °C overnight under an oxygen atmosphere. The resulting mixture was then diluted with water and extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous ISfeSCU After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 : 1) to afford tert-butyl 4-{4-[4-bromo-3-(pyridin-4- yl)pyrazol-l-yl]-3-fluorophenyl}-2,2-dimethylpiperazine-l-carboxylate (1 g, 40.94%) as a white solid. LCMS: C25H29BrFNsO2 requires: 529.2, found: m/z = 530.1 [M+H]+.
[000610] Step-4: Synthesis of tert-butyl 4-[4-(4-]2.,5-difluoro-3-[(pyrrolidine-l- sulfonyl)amino]phenvn-3-(pyridin-4-yl)pyrazol-l-yl)-3-fluorophenyl]-2.,2- dimethylpiperazine-l-carboxylate (5)
[00061 1] To a mixture of A-[2,5-difluoro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl]pyrrolidine-l -sulfonamide (586 mg, 1.508 mmol, 1 equiv) and tert-butyl 4-(4-(4- bromo-3-(pyridin-4-yl)-l//-pyrazol-l-yl)-3-fluorophenyl)-2,2-dimethylpiperazine-l- carboxylate (800 mg, 1.508 mmol, 1 equiv) in dioxane (10 mL) was added Pd(AMPHOS)2C12 (107 mg, 0.151 mmol, 0.1 equiv) and CsF (458 mg, 3.016 mmol, 2 equiv) in H2O (2 mL). The resulting mixture was stirred at 90 °C for one hour under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 : 1). The crude product was further purified by trituration with EtOAc to afford tert-butyl 4-[4-(4-{2,5-difluoro-3-[(pyrrolidine-l- sulfonyl)amino]phenyl}-3-(pyridin-4-yl)pyrazol-l-yl)-3-fluorophenyl]-2,2- dimethylpiperazine-1 -carboxylate (250 mg, 23.29%) as a white solid. LCMS: C35H40F3N7O4S requires: 711.3, found: m/z = 712.4 [M+H]+.
[000612] Step-5: Synthesis of A-(3-H-[4-(3.,3-dimethylDiDerazin-l-yl)-2- fluoroDhenyl]-3-(Dyridin-4-yl)Dyrazol-4-yn-2.,5-difluoroDhenyl)Dyrrolidine-l- sulfonamide TFA salt (6)
[000613] To a mixture of tert-butyl 4-[4-(4-{2,5-difhroro-3-[(pyrrolidine-l- sulfonyl)amino]phenyl}-3-(pyridin-4-yl)pyrazol-l-yl)-3-fluorophenyl]-2,2- dimethylpiperazine-1 -carboxylate (250 mg, 0.351 mmol, 1 equiv) in DCM (9 mL) was added TFA (3 mL) at 0 °C. The resulting mixture was stirred at room temperature for one hour. The resulting mixture was then concentrated under vacuum to afford A-(3-(l-(4-(3,3- dimethylpiperazin-l-yl)-2-fluorophenyl)-3-(pyridin-4-yl)-U/-pyrazol-4-yl)-2,5- difluorophenyl)pyrrolidine-l -sulfonamide trifluoroacetic acid salt (219 mg, crude) as a yellow solid. LCMS: C30H32F3N7O2S requires: 611.2, found: m/z = 612.4 [M+H]+. ' H NMR (400 MHz, Methanol-^) 8 8.78 - 8.70 (m, 2H), 8.40 - 8.35 (m, 1H), 8.12 - 8.05 (m, 2H), 7.88 - 7.79 (m, 1H), 7.45 - 7.36 (m, 1H), 7.14 - 7.01 (m, 3H), 3.60 - 3.53 (m, 2H), 3.48 - 3.44 (m, 2H), 3.42 (s, 2H), 3.33 - 3.30 (m, 3H), 1.96 - 1.84 (m, 5H), 1.53 (s, 6H).
[000614] Synthesis of 7V-(2.,5-difluoro-3-(l-(2-fluoro-4-(DiDerazin-l-yl)Dhenyl)-3-
(pyi idiii-4-yl)-l//-pyi azol-4-yl)plieiiyl)cvclopeiitaiiesiilfoiiainide TFA salt (5) [000615] Step-1: Synthesis of 7V-(3-brom 0-2,5- difluorophenyDcyclopentanesulfonamide (2)
[000616] To a mixture of NaH (1.08 g, 28.8454 mmol, 2 equiv, 60%) in THF (50 mL) was added 3 -bromo-2, 5 -difluoroaniline (3 g, 14.4227 mmol, 1 equiv). The resulting mixture was stirred for one hour at 0 °C under a nitrogen atmosphere. To the above mixture was added cyclopentanesulfonyl chloride (4.86 g, 28.845 mmol, 2 equiv) at 0 °C. The resulting mixture was then warmed and stirred at room temperature overnight under a nitrogen atmosphere. The reaction was then quenched by the addition of water at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:DCM (1 :3) to afford N-(3 -bromo-2, 5- difluorophenyl)cyclopentanesulfonamide (639 mg, 13.02%) as an off-white solid. LCMS: CnHi2BrF2NO2S requires: 340.0, found: m/z =341.1 [M-H]'.
[000617] Step-2: Synthesis of 7V-[2,5-difluoro-3-(4, 4, 5, 5-tetramethyl-l, 3,2- dioxaborolan-2-yl)phenyl] cyclopentanesulfonamide (3)
[000618] To a mixture of N-(3-bromo-2,5-difluorophenyl)cyclopentanesulfonamide (639 mg, 1.878 mmol, 1 equiv) and 4,4,5, 5-tetramethyl-2-(4, 4,5, 5-tetramethyl-l, 3, 2-dioxaborolan-
2-yl)-l,3,2-dioxaborolane (B2Pin2) (953 mg, 3.754 mmol, 2 equiv) in dioxane (10 mL) was added KO Ac (369 mg, 3.754 mmol, 2 equiv) and Pd(dppf)C12 (137 mg, 0.188 mmol, 0.1 equiv). The resulting mixture was stirred at 90 °C overnight under a nitrogen atmosphere. The resulting mixture was then filtered. The filtrate was concentrated under reduced pressure. This resulted in 7V-[2, 5-difluoro-3-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl)phenyl]cyclopentanesulfonamide (620 mg, crude) as a black oil. LCMS: C17H24BF2NO4S requires: 387.1, found: m/z =388.2 [M+H]+.
[000619] Step-3: Synthesis of tert-butyl 4-14-[4-(3-cvclopentanesulfonamido-2,5- difluorophenyl)-3-(pyridin-4-yl)pyrazol-l-yl]-3-fluorophenyl}piperazine-l-carboxylate (4)
[000620] To a mixture of tert-butyl 4-{4-[4-bromo-3-(pyridin-4-yl)pyrazol-l-yl]-3- fluorophenyl (piperazine- 1 -carboxylate (700 mg, 1.3933 mmol, 1 equiv) and 7V-[2,5-difluoro-
3-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)phenyl]cyclopentanesulfonamide (540 mg, 1.3933 mmol, 1 equiv) in dioxane (10 mL) was added Pd(AMPHOS)2C12 (98 mg, 0.139 mmol, 0.1 equiv) and CsF (424 mg, 2.79 mmol, 2 equiv) in H2O (2 mL). The resulting mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Q2: EtOAc (1 : 1) to afford tert-butyl 4-{4-[4-(3- cyclopentanesulfonamido-2,5-difluorophenyl)-3-(pyridin-4-yl)pyrazol-l-yl]-3- fluorophenyl (piperazine- 1 -carboxylate (192 mg, 20.29%) as an off-white solid. LCMS: C34H37F3N6O4S requires: 682.3, found: m/z =683.1 [M+H]+.
[000621 ] Step-4: Synthesis of A-(2,5-difluoro-3-ll-[2-fluoro-4-(piperazin-l- yl)phenyl]-3-(pyridin-4-yl)pyrazol-4-vnphenyl)cyclopentanesulfonamide trifluoroacetic acid salt (5)
[000622] A mixture of tert-butyl 4-{4-[4-(3-cyclopentanesulfonamido-2,5- difluorophenyl)-3 -(pyridin-4-yl)pyrazol- 1 -y 1 ] -3 -fluorophenyl } piperazine- 1 -carboxylate (192 mg, 0.281 mmol, 1 equiv) in TFA (5 mL) was stirred at 0 °C for one hour. The resulting mixture was concentrated under reduced pressure and then lyophilized. This resulted in 7V-(2,5-difluoro- 3-{ l-[2-fluoro-4-(piperazin-l-yl)phenyl]-3-(pyridin-4-yl)pyrazol-4- yl}phenyl)cyclopentanesulfonamide trifluoroacetic acid slat (161 mg, crude) as a yellow solid. LCMS: C29H29F3N6O2S requires: 582.2, found: m/z =583.3 [M+H]+.
[000623] Synthesis of 7V-(2,5-difluoro-3-(l-(2-fluoro-4-(piperazin-l-yl)phenyl)-3-
(pyi idiii-4-yl)-l//-pyi azol-4-yl)plieiiyl)cvcloliexaiiesiilfoiiainide TFA salt (5)
[000624] Step-1: Synthesis of 7V-(3-bromo-2,5- difluorophenyDcyclohexanesulfonamide (2) [000625] To a mixture of NaH (1.26 g, 33.653 mmol, 2 equiv, 60%) in THF (60 mL) was added 3-bromo-2,5-difluoroaniline (3.5 g, 16.826 mmol, 1 equiv). The resulting mixture was stirred for one hour at 0 °C under a nitrogen atmosphere. To the above mixture was added cyclohexanesulfonyl chloride (6.18 g, 33.653 mmol, 2 equiv) at 0 °C. The resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. The reaction was then quenched by the addition of water at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:DCM (1 :3) to afford A-(3-bromo-2,5-difluorophenyl)cyclohexanesulfonamide (1.02 g, 17.1%) as an off-white solid. LCMS: CnHuB^NCLS requires: 353.0, found: m/z =354.4 [M- H]-.
[000626] Step-2: Synthesis of \-|2.5-dinuoro-3-(4.4.5.5-tetraniethyl-1.3.2- dioxaborolan-2-yl)phenyl] cyclohexanesulfonamide (3)
[000627] To a mixture of A-(3-bromo-2,5-difluorophenyl)cyclohexanesulfonamide (800 mg, 1.878 mmol, 1 equiv) and 4,4,5, 5-tetramethyl-2-(4, 4,5, 5-tetramethyl-l, 3, 2-dioxaborolan- 2-yl)-l,3,2-dioxaborolane (953 mg, 3.754 mmol, 2 equiv) in dioxane (10 mL) was added KOAc (369 mg, 3.754 mmol, 2 equiv) and Pd(dppf)C12 (137 mg, 0.188 mmol, 0.1 equiv). The resulting mixture was stirred at 90 °C overnight under a nitrogen atmosphere. The resulting mixture was then filtered. The filtrate was concentrated under reduced pressure. This resulted in 7V-[2, 5-difluoro-3-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl)phenyl]cyclohexanesulfonamide (650 mg, crude) as a black oil. LCMS: C18H26BF2NO4S requires: 387.1, found: m/z =388.2 [M+H]+.
[000628] Step-3: Synthesis of tert-butyl 4-(4-(4-(3-(cvclohexanesulfonamido)-2.,5- difluorophenyl)-3-(pyridin-4-yl)-lH-pyrazol-l-yl)-3-fluorophenyl)piperazine-l- carboxylate (4)
[000629] To a mixture of tert-butyl 4-{4-[4-bromo-3-(pyridin-4-yl)pyrazol-l-yl]-3- fluorophenyl (piperazine- 1 -carboxylate (751 mg, 1.495 mmol, 1 equiv) and N-[2,5-difluoro-3- (4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)phenyl]cyclohexanesulfonamide (600 mg, 1.495 mmol, 1 equiv) in dioxane (10 mL) was added Pd(AMPHOS)2C12 (105 mg, 0.150 mmol, 0.1 equiv) and CsF (454 mg, 2.99 mmol, 2 equiv) in H2O (2 mL). The resulting mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CFLChiEtOAc (1 : 1) to afford tert-butyl 4-(4-(4-(3-(cyclohexanesulfonamido)-2,5- difluorophenyl)-3-(pyridin-4-yl)-177-pyrazol-l-yl)-3-fluorophenyl)piperazine-l -carboxylate (188 mg, 18%) as an off-white solid. LCMS: C35H39F3N6O4S requires: 696.3, found: m/z = 697.5 [M+H]+.
[000630] Step-4: Synthesis of A-(2,5-difluoro-3-ll-[2-fluoro-4-(piperazin-l- yl)phenyl]-3-(pyridin-4-yl)pyrazol-4-vnphenyl)cyclohexanesulfonamide trifluoroacetic acid salt (5)
[000631] A mixture of tert-butyl 4-(4-(4-(3-(cyclohexanesulfonamido)-2,5- difl uorophenyl)-3-(pyri di n-4-yl)- IT/-pyrazol - I -yl)-3 -fluorophenyl (piperazine-! -carboxylate (188 mg, 0.27 mmol, 1 equiv) in TFA (4 mL) was stirred at 0 °C for one hour. The resulting mixture was then concentrated under reduced pressure and then lyophilized. This resulted in 7V-(2,5-difluoro-3-{ l-[2-fluoro-4-(piperazin-l-yl)phenyl]-3-(pyridin-4-yl)pyrazol-4- yl}phenyl)cyclohexanesulfonamide trifluoroacetic acid salt (177 mg, crude) as a yellow solid. LCMS: C30H31F3N6O2S requires: 596.2, found: m/z = 597.2 [M+H]+.
[000632] Synthesis of A-(2,5-difluoro-3-(l-(3-fluoro-4-(piperazin-l-yl)phenyl)-3-
(pyi idiii-4-yl)-l//-pyi azol-4-yl)plieiiyl)cvclopeiitaiiesiilfoiiainide TFA salt (5)
[000633] Step-1: Synthesis of 7V-(3-bromo-2,5- difluorophenyDcyclopentanesulfonamide (2)
[000634] To a mixture of NaH (1.08 g, 28.8454 mmol, 2 equiv, 60%) in THF (50 mL) was added 3 -bromo-2, 5 -difluoroaniline (3 g, 14.4227 mmol, 1 equiv). The resulting mixture was stirred for one hour at 0 °C under a nitrogen atmosphere. To the above mixture was added cyclopentanesulfonyl chloride (4.86 g, 28.845 mmol, 2 equiv) at 0 °C. The resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. The reaction was then quenched by the addition of water at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:DCM (1 :3) to afford A-(3-bromo-2,5-difluorophenyl)cyclopentanesulfonamide (639 mg, 13.02%) as an off-white solid. LCMS: CnHnB^NCLS requires: 340.0, found: m/z =341.1 [M-H]-.
[000635] Step-2: Synthesis of AL[2.,5-difluoro-3-(4.,4.,5.,5-tetramethyl-l.,3.,2- dioxaborolan-2-yl)phenyl] cyclopentanesulfonamide (3)
[000636] To a mixture of A-(3-bromo-2,5-difluorophenyl)cyclopentanesulfonamide (639 mg, 1.878 mmol, 1 equiv) and 4,4,5, 5-tetramethyl-2-(4, 4,5, 5-tetramethyl-l, 3, 2-dioxaborolan- 2-yl)-l,3,2-dioxaborolane (B2Pin2) (953 mg, 3.754 mmol, 2 equiv) in dioxane (10 mL) was added KO Ac (369 mg, 3.754 mmol, 2 equiv) and Pd(dppf)C12 (137 mg, 0.188 mmol, 0.1 equiv). The resulting mixture was stirred at 90 °C overnight under a nitrogen atmosphere. The resulting mixture was then filtered. The filtrate was concentrated under reduced pressure. This resulted in 7V-[2, 5-difluoro-3-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl)phenyl]cyclopentanesulfonamide (620 mg, crude) as a black oil. LCMS: C17H24BF2NO4S requires: 387.1, found: m/z =388.2 [M+H]+.
[000637] Step-3: Synthesis of tert-butyl 4-]4-[4-(3-cvclopentanesulfonamido-2.,5- difluorophenyl)-3-(pyridin-4-yl)pyrazol-l-yl]-2-fluorophenyl}piperazine-l-carboxylate (4)
[000638] To a mixture of tert-butyl 4-{4-[4-bromo-3-(pyridin-4-yl)pyrazol-l-yl]-2- fluorophenyl (piperazine- 1 -carboxylate (800 mg, 1.593 mmol, 1 equiv) and /f-[2,5-difluoro-3- (4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)phenyl]cyclopentanesulfonamide (617 mg, 1.5933 mmol, 1 equiv) in dioxane (10 mL) was added Pd(AMPHOS)2C12 (112 mg, 0.159 mmol, 0.1 equiv) and CsF (486 mg, 3.186 mmol, 2 equiv) in H2O (2 mL). The resulting mixture was stirred at 90 °C for one hour under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CEEChiEtOAc (1 : 1) to afford terLbutyl 4-{4-[4-(3- cyclopentanesulfonamido-2,5-difluorophenyl)-3-(pyridin-4-yl)pyrazol-l-yl]-2- fluorophenyl (piperazine- l-carboxylate_(210 mg, 19.3%) as an off-white solid. LCMS: C34H37F3N6O4S requires: 682.3, found: m/z = 683.3 [M+H]+. [000639] Step-4: Synthesis of 7V-(2.,5-difluoro-3-ll-[3-fluoro-4-(piperazin-l- yl)phenyl]-3-(pyridin-4-yl)pyrazol-4-vnphenyl)cyclopentanesulfonamide trifluoroacetic acid salt (5)
[000640] A mixture of tert-butyl 4-{4-[4-(3-cyclopentanesulfonamido-2,5- difluorophenyl)-3 -(pyridin-4-yl)pyrazol- 1 -yl]-2-fluorophenyl (piperazine- 1 -carboxyl ate_(210 mg, 0.307 mmol, 1 equiv) in TFA (5 mL) was stirred at 0 °C for one hour. The resulting mixture was then concentrated under reduced pressure and then lyophilized. This resulted in N-(2,5- difluoro-3-{ l-[3-fluoro-4-(piperazin-l-yl)phenyl]-3-(pyridin-4-yl)pyrazol-4- yl}phenyl)cyclopentanesulfonamide trifluoroacetic acid salt (160 mg, crude) as a yellow solid. LCMS: C29H29F3N6O2S requires: 582.2, found: m/z = 583.3 [M+H]+.
[000641 ] Synthesis of 7V-(5-chloro-2-fluoro-3-(l-(3-fluoro-4-(piperazin-l-yl)phenyl)-
3-(pyridin-4-yl)-l//-pyr:izol-4-yl)phenyl)cvclopent:inesulfonainide TFA salt (3)
[000642] Step-1: Synthesis of tert-butyl 4-14-[4-(5-chloro-3- cvclopentanesulfonamido-2-fluorophenyl)-3-(pyridin-4-yl)pyrazol-l-yl]-2- fluorophenynpiperazine-l-carboxylate (2) [000643] To a mixture of tert-butyl 4-{4-[4-bromo-3-(pyridin-4-yl)pyrazol-l-yl]-2- fluorophenyl] piperazine- 1 -carboxylate (996 mg, 1.982 mmol, 1 equiv) and 7V-[5-chloro-2- fluoro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]cyclopentanesulfonamide (800 mg, 1.982 mmol, 1 equiv) in dioxane (10 mL) was added Pd(AMPHOS)2C12 (140 mg, 0.198 mmol, 0.1 equiv) and CsF (606 mg, 3.964 mmol, 2 equiv) in H2O (2 mL). The resulting mixture was stirred at 90 °C for one hour under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CFLCbiEtOAc (1 : 1) to afford tert-butyl 4-{4-[4-(5-chloro-3- cyclopentanesulfonamido-2-fluorophenyl)-3-(pyridin-4-yl)pyrazol-l-yl]-2- fluorophenyl (piperazine- 1 -carboxylate (350 mg, 25.3%) as an off-white solid. LCMS: C34H37CIF2N6O4S requires: 698.2, found: m/z = 699.3 [M+H]+.
[000644] Step-2: Synthesis of N-(5-chloro-2-fluoro-3-]l-[3-fluoro-4-(Diperazin-l- yl)Dhenyl]-3-(Dyridin-4-yl)Dyrazol-4-ynDhenyl)cycloDentanesulfonamide trifluoroacetic acid salt (3)
[000645] A mixture of tert-butyl 4-{4-[4-(5-chloro-3-cyclopentanesulfonamido-2- fluorophenyl)-3 -(pyridin-4-yl)pyrazol- 1 -yl]-2 -fluorophenyl (piperazine- 1 -carboxylate (350 mg, 0.5 mmol, 1 equiv) in TFA (5 mL) was stirred at 0 °C for one hour. The resulting mixture was then concentrated under reduced pressure and then lyophilized. This resulted in A-(5- chloro-2-fluoro-3-{ l-[3-fluoro-4-(piperazin-l-yl)phenyl]-3-(pyridin-4-yl)pyrazol-4- yl(phenyl)cyclopentanesulfonamide trifluoroacetic acid salt (276 mg, crude) as a yellow solid. LCMS : C29H29CIF2N6O2S requires: 598.2, found: m/z = 599.2 [M+H]+.
[000646] Synthesis of U?)-7V-(5-chloro-2-fluoro-3-(l-(2-fluoro-4-(3-methylDiDerazin- l-yl)phenyl)-3-(pyridin-4-yl)-l//-pyr:izol-4-yl)phenyl)cvclopentanesiilfonainide TFA salt (3)
[000647] Step-1: Synthesis of tert-butyl (21?)-4-14-[4-(5-chloro-3- cycloDentanesulfonamido-2-fluoroDhenyl)-3-(Dyridin-4-yl)Dyrazol-l-yl]-3- fluoroDhenyn-2-methylDiDerazine-l-carboxylate (2)
[000648] To a mixture of tert-butyl (27?)-4-{4-[4-bromo-3-(pyridin-4-yl)pyrazol-l-yl]-3- fluorophenyl }-2-m ethylpiperazine- 1 -carboxylate (1.0 g, 1.936 mmol, 1 equiv) and 7V-[5- chloro-2-fluoro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl]cyclopentanesulfonamide (782 mg, 1.936 mmol, 1 equiv) in dioxane (10 mL) was added Pd(AMPHOS)2Ch (136 mg, 0.194 mmol, 0.1 equiv) and CsF (592 mg, 3.872 mmol, 2 equiv) in H2O (2 mL). The resulting mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CFLChiEtOAc (1 : 1) to afford terLbutyl (2A)-4-{4-[4-(5-chloro-3-cyclopentanesulfonamido-2-fluorophenyl)-3-(pyridin-4- yl)pyrazol-l-yl]-3-fluorophenyl}-2-methylpiperazine-l-carboxylate (400 mg, 28.96%) as an off-white solid. LCMS: C35H39CIF2N6O4S requires: 712.2, found: m/z = 713.4 [M+H]+. [000649] Step-2: Synthesis of 7V-[5-chloro-2-fluoro-3-(l-]2-fluoro-4-[(31?)-3- methylDiDerazin-l-yl]Dhenvn-3-(Dyridin-4-yl)pyrazol-4- yl)Dhenyl]cvclopentanesulfonamide trifluoroacetic acid salt (3)
[000650] A mixture of tert-butyl (27?)-4-{4-[4-(5-chloro-3-cyclopentanesulfonamido-2- fluorophenyl)-3 -(pyridin-4-yl)pyrazol- 1 -y 1 ] -3 -fluorophenyl } -2-methylpiperazine- 1 - carboxylate (400 mg, 0.561 mmol, 1 equiv) in TFA (6 mL) was stirred at 0 °C for one hour. The resulting mixture was then concentrated under reduced pressure and then lyophilized. This resulted /'/-[5-chloro-2-fluoro-3-( l -[2-fluoro-4-[(3A>)-3-methylpiperazin- l -yl]phenyl }-3- (pyridin-4-yl)pyrazol-4-yl)phenyl]cyclopentanesulfonamide trifluoroacetic acid salt (321 mg, crude) as a yellow solid. LCMS: C30H31CIF3N6O2S requires: 612.2, found: m/z = 613.2 [M+H]+.
[000651 ] Synthesis of (2.5-diniioro-3-(l-(2-niioro-4-(3-niethylpiperazin-l- yl)phenyl)-3-(pyridin-4-yl)-l//-pyr:izol-4-yl)phenyl)cvclopentanesiilfonaniide TFA salt (3) [000652] Step-1: Synthesis of tert-butyl (21?)-4-f4-[4-(3-cvclopentanesulfonamido- 2,5-difluorophenyl)-3-(pyridin-4-yl)pyrazol-l-yl]-3-fluorophenvn-2-methylpiperazine-l- carboxylate (2)
[000653] To a mixture of tert-butyl (2A)-4-{4-[4-bromo-3-(pyridin-4-yl)pyrazol-l-yl]-3- fluorophenyl }-2-m ethylpiperazine- 1 -carboxylate (900mg, 1.743 mmol, 1 equiv) and A-[2,5- difluoro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]cyclopentanesulfonamide (675 mg, 1.743 mmol, 1 equiv) in dioxane (10 mL) was added Pd(AMPHOS)2Ch (122 mg, 0.174 mmol, 0.1 equiv) and CsF (533 mg, 3.486 mmol, 2 equiv) in H2O (2 mL). The resulting mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CFLCbiEtOAc (1 : 1) to afford tert-butyl (2/?)-4-[4-[4-(3- cyclopentanesulfonamido-2,5-difluorophenyl)-3-(pyridin-4-yl)pyrazol-l-yl]-3-fluorophenyl}- 2-methylpiperazine-l -carboxylate (208 mg, 17.13%) as an off-white solid. LCMS: C35H39F3N6O4S requires: 696.3, found: m/z = 697.7 [M+H]+.
[000654] Step-2: Synthesis of \-|2.5-dinuoro-3-(l-!2-nuoro-4-|(3/?)-3- methylpiperazin-l-yl]phenvn-3-(pyridin-4-yl)pyrazol-4- yl)phenyl]cvclopentanesulfonamide; trifluoroacetic acid salt (3)
[000655] A mixture of tert-butyl (2A)-4-{4-[4-(3-cyclopentanesulfonamido-2,5- difluorophenyl)-3-(pyridin-4-yl)pyrazol-l-yl]-3-fluorophenyl}-2-methylpiperazine-l- carboxylate (208 mg, 0.2985 mmol, 1 equiv) in TFA (4 mL) was stirred at 0 °C for one hour. The resulting mixture was then concentrated under reduced pressure and then lyophilized. This resulted 7V-[2, 5 -difluoro-3 -( 1 - { 2-fluoro-4- [(3 R)-3 -methylpiperazin- 1 -yl]phenyl } -3 -(pyridin-4- yl)pyrazol-4-yl)phenyl]cyclopentanesulfonamide trifluoroacetic acid salt (171 mg, crude) as a yellow solid. LCMS: C30H31F4N6O2S requires: 596.2, found: m/z = 597.4 [M+H]+.
[000656] Synthesis of 7V-(3-(l-(2.,6-difluoro-4-(piperazin-l-yl)phenyl)-3-(pyridin-4- yl)-l//-pyr:izol-4-yl)-2.5-dinuoropheiiyl)cvclopeiitaiiesulfonamide TFA salt (7)
[000657] Step-1: Synthesis of 4-[4-bromo-l-(2.,6-difluoro-4-nitrophenyl)pyrazol-3- yl] pyridine (2)
[000658] To a mixture of 4-(4-bromo-17/-pyrazol-3-yl)pyridine (29 g, 129.43 mmol, 1 equiv) in DMSO (200 mL) was added K2CO3 (27 g, 194.1 mmol, 1.5 equiv) and 1,2,3-trifluoro- 5 -nitrobenzene (27.5 g, 155.32 mmol, 1.2 equiv). The resulting mixture was stirred at room temperature for 6 h. The resulting mixture was then extracted with CH2Q2. The combined organic layers were washed with water and dried over anhydrous ISfeSCU After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (3: 1) to afford 4-[4-bromo-l-(2,6-difhioro-4- nitrophenyl)pyrazol-3-yl]pyridine (44 g, 89.2%) as a white solid. LCMS: CuEEB^lSkCh requires: 379.9, found: m/z = 380.9 [M+H]+.
[000659] Step-2: Synthesis of A-]3-[l-(2.,6-difluoro-4-nitrophenyl)-3-(pyridin-4- yl)pyrazol-4-yl]-2.,5-difluorophenvncvclopentanesulfonaniide (3)
[000660] To a mixture of 4-[4-bromo-l-(2,6-difluoro-4-nitrophenyl)pyrazol-3- yl]pyridine (9.0 g, 23.61 mmol, 1 equiv) and A-[5-chloro-2-fluoro-3-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)phenyl]pyrrolidine-l-sulfonamide (9.1 g, 23.61 mmol, 1 equiv) in dioxane (100 mL) was added Pd(AMPHOS)2C12 (1.63 g, 2.361 mmol, 0.1 equiv) and CsF (7.15 g, 47.22 mmol, 2 equiv) in H2O (20 mL). The resulting mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. The resulting mixture was then concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 : 1) to afford N- { 3 - [ 1 -(2, 6-difluoro-4-nitrophenyl)-3 -(pyridin-4-yl)pyrazol-4-yl] -2, 5 - difluorophenyl} cyclopentanesulfonamide (5.3 g, 40%) as a yellow solid. LCMS: C25H19F4N5O4S requires: 561.1, found: m/z = 562.1 [M+H]+.
[000661 ] Step-3: Synthesis of A-]3-[l-(4-amino-2.,6-difluorophenyl)-3-(pyridin-4- yl)pyrazol-4-yl]-2.,5-difluorophenvncvclopentanesulfonaniide (4)
[000662] A mixture of Fe (2.64 g, 47.2 mmol, 5 equiv) and NH4CI (49 mg, 0.944 mmol, 0.1 equiv) in AcOH (2 mL) and H2O (10 mL) was stirred at 80 °C for 5 min. To the above mixture was added 7V-{3-[l-(2,6-difluoro-4-nitrophenyl)-3-(pyridin-4-yl)pyrazol-4-yl]-2,5- difluorophenyl} cyclopentanesulfonamide (5.3 g, 9.439 mmol, 1 equiv) in EtOH (100 mL). The resulting mixture was stirred at 80 °C for 0.5 h. The resulting mixture was then concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 :4) to afford A-{3-[l-(4-amino-2,6-difluorophenyl)-3-(pyridin-4-yl)pyrazol-4- yl]-2,5-difhiorophenyl}cyclopentanesulfonamide (3.7 g, 73.7%) as a yellow solid. LCMS: C25H19F4N5O2S requires: 531.1, found: m/z = 532.2 [M+H]+.
[000663] Step-4: Synthesis of A-]3-[l-(2.,6-difluoro-4-iodophenyl)-3-(pyridin-4- yl)pyrazol-4-yl]-2.,5-difluorophenvncvclopentanesulfonaniide (5)
[000664] To a mixture of A-{3-[l-(4-amino-2,6-difluorophenyl)-3-(pyridin-4-yl)pyrazol-
4-yl]-2,5-difluorophenyl}cyclopentanesulfonamide (3.7 g, 6.961 mmol, 1 equiv) and TsOH (3.64 g, 20.88 mmol, 3 equiv) in ACN (30 mL) was added NaNCL (1.46 g, 20.88 mmol, 3 equiv) in H2O (3 mL) and KI (4.0 g, 17.40 mmol, 2.5 equiv) at 0 °C. The resulting mixture was stirred at 0 °C for 10 min and was then warmed to room temperature. The mixture was stirred for additional 30 min at room temperature. The mixture was then basified to pH = 8 with saturated aqueous ISfeCCL. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous ISfeSCU After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (3:2) to afford A-{3-[l-(2,6-difhroro-4-iodophenyl)-3- (pyridin-4-yl)pyrazol-4-yl]-2,5-difluorophenyl(cyclopentanesulfonamide (770 mg, 17.2%) as a brown solid. LCMS: C25H19F4IN4O2S requires: 642.0, found: m/z = 643.7 [M+H]+.
[000665] Step-5: Synthesis of tert-butyl 4-I4-[4-(3-cyclopentanesulfonamido-2.,5- difluorophenyl)-3-(pyridin-4-yl)pyrazol-l-yl]-3.,5-difluorophenvnpiperazine-l- carboxylate (6)
[000666] To a mixture of 7V-{3-[l-(2,6-difluoro-4-iodophenyl)-3-(pyridin-4-yl)pyrazol- 4-yl]-2,5-difluorophenyl(cyclopentanesulfonamide (770 mg, 1.199 mmol, 1 equiv) and tertbutyl piperazine- 1 -carboxylate (558 mg, 2.998 mmol, 2.5 equiv) in dioxane (10 mL) was added Pd-PEPPSLIHeptCl (116 mg, 0.12 mmol, 0.1 equiv) and CS2CO3 (976 mg, 2.998 mmol, 2.5 equiv). The resulting mixture was stirred at 90 °C for 4 h under a nitrogen atmosphere. The resulting mixture was then concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 :2) to afford tert-butyl 4-{4-[4-(3- cyclopentanesulfonamido-2,5-difluorophenyl)-3-(pyridin-4-yl)pyrazol-l-yl]-3,5- difluorophenyl (piperazine- 1 -carboxylate (320 mg, 38.1%) as a brown solid. LCMS: C34H36F4N6O4S requires: 700.2, found: m/z = 701.4 [M+H]+.
[000667] Step-6: Synthesis of A-(3-H-[2.,6-difluoro-4-(piperazin-l-yl)phenyl]-3- (pyridin-4-yl)pyrazol-4-vn-2.,5-difluorophenyl)cvclopentanesulfonamide trifluoroacetic acid salt (7)
[000668] A mixture of tert-butyl 4-{4-[4-(3-cyclopentanesulfonamido-2,5- difluorophenyl)-3 -(pyridin-4-yl)pyrazol- 1 -y 1 ] -3 , 5 -difluorophenyl (piperazine- 1 -carboxylate (320 mg, 0.457 mmol, 1 equiv) in TFA (5 mL) was stirred at 0 °C for one hour. The resulting mixture was then concentrated under vacuum. The product was lyophilized to afford N-(3-{ 1- [2,6-difluoro-4-(piperazin-l-yl)phenyl]-3-(pyridin-4-yl)pyrazol-4-yl(-2,5- difluorophenyl)cyclopentanesulfonamide trifluoroacetic acid salt (210 mg, crude) as a light yellow solid. LCMS: C29H28F4N6O4S requires: 600.2, found: m/z = 601.2 [M+H]+.
[000669] Synthesis of 7V-(5-chloro-3-(l-(2.,6-difluoro-4-(DiDerazin-l-yl)Dhenyl)-3-
(pyridin-4-yl)-l//-pyrazol-4-yl)-2-niiorophenyl)cvclopentanesulfonaniide TFA salt (7)
[000670] Step-1: Synthesis of 7V-(5-chloro-3-(l-(2.,6-difluoro-4-nitroDhenyl)-3-
(pyridin-4-yl)-l//-pyrazol-4-yl)-2-niiorophenyl)cvclopentanesulfonainide (3)
[000671 ] To a mixture of 4-[4-bromo-l-(2,6-difluoro-4-nitrophenyl)pyrazol-3- yl]pyridine (9.0 g, 23.61 mmol, 1 equiv) and 7V-[5-chloro-2-fluoro-3-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)phenyl]cyclopentanesulfonamide (9.53 g, 23.61 mmol, 1 equiv) in dioxane (100 mL) was added Pd(AMPHOS)2C12 (1.64 g, 2.361 mmol, 0.1 equiv) and CsF (7.2 g, 47.22 mmol, 2 equiv) in H2O (20 mL). The resulting mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 : 1) to afford 7V-(5-chloro-3-(l-(2,6-difluoro-4-nitrophenyl)-3-(pyridin-4-yl)-l//-pyrazol-4- yl)-2-fluorophenyl)cyclopentanesulfonamide_(6.1 g, 44.7%) as a yellow solid. LCMS: C25H19CIF3N5O4S requires: 577.1, found: m/z = 578.1 [M+H]+.
[000672] Step-2: Synthesis of A-I3-[l-(4-amino-2.,6-difluorophenyl)-3-(pyridin-4- yl)pyrazol-4-yl]-5-chloro-2-fluorophenvncvclopentanesulfonamide (4)
[000673] A mixture of Fe (2.94 g, 52.77 mmol, 5 equiv) and NH4CI (55 mg, 1.055 mmol, 0.1 equiv) in AcOH (2 mL) and H2O (10 mL) was stirred at 80 °C for 5 min. To the above mixture was added 7V-{5-chloro-3-[l-(2,6-difluoro-4-nitrophenyl)-3-(pyridin-4-yl)pyrazol-4- yl]-2-fluorophenyl}cyclopentanesulfonamide (6.1 g, 10.55 mmol, 1 equiv) in EtOH (100 mL). The resulting mixture was stirred at 80 °C for 0.5 h. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 :4) to afford N-{ 3 -[1 -(4-amino-2,6-difhiorophenyl)-
3-(pyridin-4-yl)pyrazol-4-yl]-5-chloro-2-fluorophenyl}cyclopentanesulfonamide (4.05 g, 70%) as a yellow solid. LCMS: C25H21CIF3N5O2S requires: 547.1, found: m/z = 548.2 [M+H]+.
[000674] Step-3: Synthesis of A-I5-chloro-3-[l-(2.,6-difluoro-4-iodophenyl)-3-
(pyridin-4-yl)pyrazol-4-yl]-2-fluorophenvnpyrrolidine-l-sulfonamide (5)
[000675] To a mixture of A-{3-[l-(4-amino-2,6-difluorophenyl)-3-(pyridin-4-yl)pyrazol-
4-yl]-5-chloro-2-fluorophenyl}cyclopentanesulfonamide (4.0 g, 7.3 mmol, 1 equiv) and TsOH (3.82 g, 21.9 mmol, 3 equiv) in ACN (30 mL) was added NaNCL (1.53 g, 21.9 mmol, 3 equiv) in H2O (3 mL) and KI (3.1 g, 18.25 mmol, 2.5 equiv) at 0 °C. The resulting mixture was stirred at 0 °C for 10 min and then the reaction was warmed to room temperature. The mixture was stirred for additional 30 min at room temperature. The mixture was basified to pH = 8 with saturated aqueous ISfeCCL. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous ISfeSCU After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (3:2) to afford A-{5-chloro-3-[l-(2,6-difluoro-4- iodophenyl)-3-(pyridin-4-yl)pyrazol-4-yl]-2-fluorophenyl}cyclopentanesulfonamide (982 mg, 20.4%) as a brown solid. LCMS: C25H19CIF3IN4O2S requires: 657.9, found: m/z = 658.9 [M+H]+.
[000676] Step-4: Synthesis of tert-butyl 4-I4-[4-(5-chloro-3- cvclopentanesulfonamido-2-fluorophenyl)-3-(pyridin-4-yl)pyrazol-l-yl]-3.,5- difluorophenyllpiperazine-l-carboxylate (6) [000677] To a mixture of A-{5-chloro-3-[l-(2,6-difluoro-4-iodophenyl)-3-(pyridin-4- yl)pyrazol-4-yl]-2-fluorophenyl}cyclopentanesulfonamide (982 mg, 1.49 mmol, 1 equiv) and tert-butyl piperazine- 1 -carboxylate (694 mg, 3.725 mmol, 2.5 equiv) in dioxane (10 mL) was added Pd-PEPPSI-IHeptCl (145 mg, 0.149 mmol, 0.1 equiv) and CS2CO3 (1.21 g, 3.725 mmol, 2.5 equiv). The resulting mixture was stirred at 90 °C for 4 h under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 :2) to afford tert-butyl 4-{4-[4-(5- chloro-3-cyclopentanesulfonamido-2-fluorophenyl)-3-(pyridin-4-yl)pyrazol-l-yl]-3,5- difluorophenyl (piperazine- 1 -carboxylate (451 mg, 42.2%) as a brown solid. LCMS: C34H36CIF3N6O4S requires: 716.2, found: m/z = 717.3 [M+H]+.
[000678] Step-5: Synthesis of A-(5-chloro-3-ll-[2.,6-difluoro-4-(DiDerazin-l- yl)Dhenyl]-3-(Dyridin-4-yl)Dyrazol-4-yn-2-fluoroDhenyl)cycloDentanesulfonamide TFA salt (7)
[000679] A mixture of afford tert-butyl 4-{4-[4-(5-chloro-3-cyclopentanesulfonamido-2- fluorophenyl)-3 -(pyridin-4-yl)pyrazol- 1 -y 1 ] -3 , 5 -difluorophenyl (piperazine- 1 -carboxylate (451 mg, 0.6288 mmol, 1 equiv) in TFA (5 mL) was stirred at 0 °C for one hour. The resulting mixture was then concentrated and lyophilized to afford A-(5-chloro-3-{ l-[2,6-difluoro-4- (piperazin-l-yl)phenyl]-3-(pyridin-4-yl)pyrazol-4-yl(-2- fluorophenyl)cyclopentanesulfonamide trifluoroacetic acid salt (310 mg, crude) as a light yellow solid. LCMS : C29H28CIF3N6O2S requires: 616.2; found: m/z = 617.2 [M+H]+.
[000680] Synthesis of ethylmethyl[(2-fluoro-3-ll-[3-fluoro-4-(Diperazin-l- yl)Dhenyl]-3-(Dyridin-4-yl)Dyrazol-4- sulfamoyl]amine TFA salt (6)
[000681 ] Step-1: Synthesis of tert-butyl 4-(4-chloro-2-fluorophenyl)piperazine-l- carboxylate (2)
[000682] To a mixture of l-bromo-4-chloro-2-fluorobenzene (3 g, 14.324 mmol, 1 equiv) and tert-butyl piperazine- 1 -carboxylate (2.67 g, 14.324 mmol, 1 equiv) in toluene (60 mL) was added Pd2(dba)s (131 mg, 0.143 mmol, 0.01 equiv), BINAP (178 mg, 0.286 mmol, 0.02 equiv), and Z-BuONa (1.93 g, 20.054 mmol, 1.4 equiv). The resulting mixture was stirred at 60 °C overnight under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (4: 1) to afford tert-butyl 4-(4-chloro-2-fluorophenyl)piperazine-l -carboxylate (2 g, 39.92%) as an off-white solid. LCMS: C15H20CIFN2O2 requires: 314.1, found: m/z = 315.1 [M+H]+.
[000683] Step-2: Synthesis of tert-butyl 4-[2-fluoro-4-(4.,4.,5.,5-tetramethyl-l.,3.,2- dioxaborolan-2-yl)phenyl] piperazine-l-carboxylate (3)
[000684] To a mixture of tert-butyl 4-(4-chloro-2-fluorophenyl)piperazine-l -carboxylate (2 g, 6.353 mmol, 1 equiv) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)-l,3,2-dioxaborolane (B2Pin2) (2.42 g, 9.529 mmol, 1.5 equiv) in methoxycyclopentane (30 mL) was added Pd2(dba)3 (175 mg, 0.191 mmol, 0.03 equiv), X-Phos (182 mg, 0.381 mmol, 0.06 equiv), and KO Ac (1.87 g, 19.059 mmol, 3 equiv). The resulting mixture was stirred at 110 °C for 2 h under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (4: 1) to afford tert-butyl 4-[2-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl]piperazine-l -carboxylate (2.5 g, 87.16%) as a brown oil. LCMS: C21H32BFN2O4 requires: 406.2, found: m/z = 407.2 [M+H]+.
[000685] Step-3: Synthesis of tert-butyl 4-14-[4-bromo-3-(pyridin-4-yl)pyrazol-l-yl]-
2-fluorophenvnpiperazine-l-carboxylate (4)
[000686] To a mixture of tert-butyl 4-[2-fluoro-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]piperazine-l -carboxylate (2.5 g, 6.153 mmol, 1 equiv) and 4-(4- bromo-17/-pyrazol-3-yl)pyridine (2.07 g, 9.229 mmol, 1.5 equiv) in pyridine (20 mL) was added Cu(OAc)2 (2.24 g, 12.306 mmol, 2 equiv) and molecular sieves (4A) (2.07 g). The resulting mixture was stirred at 100 °C overnight under an oxygen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CFLCL MeOH (20: 1) to afford tert-butyl 4-{4-[4-bromo-
3-(pyridin-4-yl)pyrazol-l-yl]-2-fluorophenyl}piperazine-l-carboxylate (2 g, 51.76%) as a brown semi-solid. LCMS: C23H25BrFNsO2 requires: 501.1, found: m/z = 502.1 [M+H]+.
[000687] Step-4: Synthesis of tert-butyl 4-]4-[4-(3-]|ethyl(methyl)sulfamoyl]amino}- 2-fluorophenyl)-3-(pyridin-4-yl)pyrazol-l-yl]-2-fluorophenvnpiperazine-l-carboxylate (5)
[000688] To a mixture of tert-butyl 4-{4-[4-bromo-3-(pyridin-4-yl)pyrazol-l-yl]-2- fluorophenyl (piperazine- 1 -carboxylate (1.5 g, 2.986 mmol, 1 equiv) and 3- { [ethyl (methyl)sulfamoyl]amino}-2-fluorophenylboronic acid (824 mg, 2.986 mmol, 1 equiv) in dioxane (10 mL) was added PdAMPHOS (423 mg, 0.597 mmol, 0.2 equiv) and CsF (907 mg, 5.972 mmol, 2 equiv) in H2O (2 mL). The resulting mixture was stirred at 90 °C for one hour under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by Cl 8 reverse phase column chromatography with ACN:H2O (2: 1) to afford tert-butyl 4-{4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)-3-(pyridin-4-yl)pyrazol-l-yl]-2-fluorophenyl}piperazine-l -carboxylate (500 mg, 24.33%) as an off-white solid. LCMS: C32H37F2N7O4S requires: 653.3, found: m/z = 654.3 [M+H]+. [000689] Step-5: Synthesis of ethylmethyl[(2-fluoro-3-]l-[3-fluoro-4-(Diperazin-l- yl)Dhenyl]-3-(Dyridin-4-yl)Dyrazol-4-ynDhenyl)sulfamoyl]amine trifluoroacetic acid salt (6)
[000690] To a mixture of tert-butyl 4-{4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)-3-(pyridin-4-yl)pyrazol-l-yl]-2-fluorophenyl}piperazine-l -carboxylate (500 mg, 0.903 mmol, 1 equiv) in DCM (9 mL) was added TFA (3 mL) at 0 °C. The resulting mixture was warmed and stirred at room temperature for one hour. The resulting mixture was then concentrated under reduced pressure. The product was then lyophilized under vacuum. This resulted in ethylmethyl[(2-fluoro-3-{ l-[3-fluoro-4-(piperazin-l-yl)phenyl]-3-(pyridin-4- yl)pyrazol-4-yl}phenyl)sulfamoyl]amine_trifluoroacetic acid salt (344.1 mg, crude) as a yellow solid. LCMS: C27H29F2N7O2S requires: 553.2, found: m/z = 554.2 [M+H]+. 1HNMR (400 MHz, CD3OD) 5 8.79 - 8.73 (m, 2H), 8.66 - 8.62 (m, 1H), 8.20 - 8.14 (m, 2H), 7.91 - 7.83 (m, 1H), 7.83 - 7.76 (m, 1H), 7.66 - 7.57 (m, 1H), 7.38 - 7.27 (m, 3H), 3.50 - 3.39 (m, 8H), 3.33 - 3.20 (m, 2H), 2.86 - 2.82 (m, 3H), 1.18 - 1.10 (m, 3H).
[000691 ] Synthesis of ethylmethyl[(2-fluoro-3-]l-[2-fluoro-4-(Diperazin-l- yl)Dhenyl]-3-(Dyridin-4-yl)Dyrazol-4- sulfamoyl]amine trifluoroacetic acid salt (6)
[000692] Step-1: Synthesis of tert-butyl 4-(4-chloro-3-fluorophenyl)piperazine-l- carboxylate (2)
[000693] To a mixture of 4-bromo-l-chloro-2-fluorobenzene (3 g, 14.324 mmol, 1 equiv) and tert-butyl piperazine- 1 -carboxylate (2.67 g, 14.324 mmol, 1 equiv) in toluene (60 mL) was added Pd2(dba)s (131 mg, 0.143 mmol, 0.01 equiv), BINAP (178 mg, 0.286 mmol, 0.02 equiv), and Z-BuONa (1.93 g, 20.054 mmol, 1.4 equiv). The resulting mixture was stirred at 60 °C overnight under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (4: 1) to afford tert-butyl 4-(4-chloro-3-fluorophenyl)piperazine-l-carboxylate (2 g, 39.92%) as an off-white solid. LCMS: C15H20CIFN2O2 requires: 314.1, found: m/z = 315.1 [M+H]+.
[000694] Step-2: Synthesis of tert-butyl 4-[3-fluoro-4-(4,4,5,5-tetramethyl-l,3.,2- dioxaborolan-2-yl)phenyl] piperazine-l-carboxylate (3)
[000695] To a mixture of tert-butyl 4-(4-chloro-3-fluorophenyl)piperazine-l -carboxylate (2 g, 6.353 mmol, 1 equiv) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)-l,3,2-dioxaborolane (B2Pin2) (2.42 g, 9.529 mmol, 1.5 equiv) in methoxycyclopentane (30 mL) was added Pd2(dba)3 (175 mg, 0.191 mmol, 0.03 equiv), X-Phos (182 mg, 0.381 mmol, 0.06 equiv) and KOAc (1.87 g, 19.059 mmol, 3 equiv). The resulting mixture was stirred at 110 °C for 2 h under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (4: 1) to afford tert-butyl 4-[3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl]piperazine-l -carboxylate (1.5 g, 46.49%) as a brown oil. LCMS: C21H32BFN2O4 requires: 406.2, found: m/z = 407.2 [M+H]+.
[000696] Step-3: Synthesis of tert-butyl 4-(4-(4-broiiio-3-(pyridin-4-yl)-l//-pyrazol-
1-yl)-3-fluorophenyl)piperazine-l-carboxylate (4)
[000697] To a mixture of tert-butyl 4-[3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]piperazine-l -carboxylate (1.5 g, 3.692 mmol, 1 equiv) and 4-(4- bromo-17/-pyrazol-3-yl)pyridine (1.24 g, 5.538 mmol, 1.5 equiv) in pyridine (20 mL) was added Cu(OAc)2 (1.34 g, 7.384 mmol, 2 equiv) and molecular sieves (4A) (1.5 g). The resulting mixture was stirred at 100 °C overnight under an oxygen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CFLCL MeOH (20: 1) to afford tert-butyl 4-(4-(4-bromo-3- (pyridin-4-yl)-lrt-pyrazol-l-yl)-3-fluorophenyl)piperazine-l-carboxylate (500 mg, 22.91%) as a brown semi-solid. LCMS: C23H25BrFNsO2 requires: 501.1, found: m/z = 502.1 [M+H]+.
[000698] Step-4: Synthesis of tert-butyl 4-14-[4-(3-llethyl(methyl)sulfamoyl]amino}-
2-fluorophenyl)-3-(pyridin-4-yl)pyrazol-l-yl]-3-fluorophenvnpiperazine-l-carboxylate
(5)
[000699] To a mixture of tert-butyl 4-(4-(4-bromo-3-(pyridin-4-yl)-17/-pyrazol-l-yl)-3- fluorophenyl)piperazine-l -carboxylate (500 mg, 0.995 mmol, 1 equiv) and 3- { [ethyl (methyl)sulfamoyl]amino}-2-fluorophenylboronic acid (275 mg, 0.995 mmol, 1 equiv) in dioxane (10 mL) was added PdAMPHOS (141 mg, 0.199 mmol, 0.2 equiv) and CsF (302.36 mg, 1.990 mmol, 2 equiv) in H2O (2 mL). The resulting mixture was stirred at 90 °C for 1 h under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 :2) to afford tert-butyl 4-{4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-3- (pyridin-4-yl)pyrazol-l-yl]-3-fluorophenyl}piperazine-l-carboxylate (450 mg, 55.33%) as a yellow solid. LCMS: C32H37F2N7O4S requires: 653.3, found: m/z = 654.3 [M+H]+.
[000700] Step-5: Synthesis of ethylmethyl[(2-fluoro-3-ll-[2-fluoro-4-(piperazin-l- yl)phenyl]-3-(pyridin-4-yl)pyrazol-4-vnphenyl)snlfamoyl]amine trifluoroacetic acid salt
(6) [000701] To a mixture of tert-butyl 4-{4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)-3 -(pyridin-4-yl)pyrazol- 1 -y 1 ] -3 -fluorophenyl } piperazine- 1 -carboxylate (400 mg, 0.612 mmol, 1 equiv) in DCM (3 mL) was added TFA (1 mL) at 0 °C. The resulting mixture was warmed and stirred at room temperature for one hour. The resulting mixture was then concentrated under reduced pressure. The residue was purified by Cl 8 reverse phase column chromatography with ACbTFhO (0.5% TFA) (1 :3) to afford ethylmethyl[(2-fluoro-3- { l-[2-fluoro-4-(piperazin-l-yl)phenyl]-3-(pyridin-4-yl)pyrazol-4-yl}phenyl)sulfamoyl]amine trifluoroacetic acid salt (317.6 mg, 77.28%) as a yellow solid. LCMS: C27H29F2N7O2S requires: 553.2, found: m/z = 554.3 [M+H]+. 'H NMR (400 MHz, DMSO-tL) 8 9.67 - 9.62 (m, 1H), 8.85 - 8.81 (m, 2H), 8.66 - 8.60 (m, 2H), 8.46 - 8.41 (m, 1H), 7.80 - 7.71 (m, 1H), 7.57 - 7.51 (m, 2H), 7.54 - 7.45 (m, 1H), 7.31 - 7.20 (m, 2H), 7.20 - 7.12 (m, 1H), 7.05 - 6.96 (m, 1H), 3.55 - 3.48 (m, 4H), 3.32 - 3.22 (m, 4H), 3.13 - 3.03 (m, 2H), 2.70 - 2.66 (m, 3H), 1.05 - 0.97 (m, 3H).
[000702] Synthesis of A-[2-fluoro-3-(l-]4- -2-methylDiDerazin-l-yl]Dhenyn-3- (Dyridin-4-yl)Dyrazol-4-yl)Dhenyl]DroDane-l-sulfonamide trifluoroacetic acid salt (8)
[000703] Step-1: Synthesis of tert-butyl (37?)-3-methyl-4-DhenylpiDerazine-l- carboxylate (2)
[000704] To a mixture of bromobenzene (2 g, 12.762 mmol, 1.2 equiv) and tert-butyl (37?)-3-methylpiperazine-l-carboxylate (2.13 g, 10.635 mmol, 1 equiv) in toluene (20 mL) was added [P(Z-Bu)3]BF4 (0.29 g, 0.851 mmol, 0.08 equiv), Pd(OAc)2 (0.07 g, 0.319 mmol, 0.03 equiv), and Z-BuONa (1.43 g, 14.889 mmol, 1.4 equiv). The resulting mixture was stirred at 110 °C overnight under a nitrogen atmosphere. The resulting mixture was then concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (3: 1) to afford tert-butyl (3A)-3-methyl-4-phenylpiperazine-l -carboxylate (2.5 g, 76.55%) as a yellow oil. LCMS: C16H24N2O2 requires: 276.2, found: m/z = 277.2 [M+H]+.
[000705] Step-2: Synthesis of tert-butyl -4-(4-bromophenyl)-3- methylpiperazine-l-carboxylate (3)
[000706] To a mixture of tert-butyl (3A)-3-methyl-4-phenylpiperazine-l -carboxylate (2.4 g, 8.684 mmol, 1 equiv) in CHCI3 (50 mL) was added tetrabutylammonium tribromide (4.19 g, 8.684 mmol, 1 equiv) at 0 °C. The resulting mixture was warmed and stirred at room temperature for 0.5 h. The resulting mixture was then extracted with CHCI3. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 : 1) to afford tert-butyl (3A)-4-(4-bromophenyl)-3-methylpiperazine- 1-carboxylate (2.5 g, 72.93%) as a light yellow oil. LCMS: CieEfaBr^CL requires: 354.1, found: m/z = 355.2 [M+H]+.
[000707] Step-3: Synthesis of tert-butyl (37?)-3-methyl-4-[4-(4.,4.,5.,5-tetramethyl- l,3.,2-dioxaborolan-2-yl)phenyl]piperazine-l-carboxylate (4)
[000708] To a mixture of tert-butyl (3 A)-4-(4-bromophenyl)-3 -methylpiperazine- 1- carboxylate (2.47 g, 6.952 mmol, 1 equiv) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (ELPi^) (5.3 g, 20.856 mmol, 3 equiv) in 1,4- dioxane (50 mL) was added Pd(dppf)C12 (0.57 g, 0.7 mmol, 0.1 equiv) and KOAc (1.36 g, 13.9 mmol, 2 equiv). The resulting mixture was stirred at 80 °C overnight under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (2: 1) to afford tertbutyl (3A)-3-methyl-4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]piperazine-l- carboxylate (2.5 g, 80.44%) as a white solid. LCMS: C22H35BN2O4 requires: 402.3, found: m/z = 403.2 [M+H]+.
[000709] Step-4: Synthesis of tert-butyl -4-14-[4-bromo-3-(pyridin-4-yl)pyrazol- l-yl]phenvn-3-methylpiperazine-l-carboxylate (5)
[000710] To a mixture of tert-butyl (3A)-3-methyl-4-[4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]piperazine-l -carboxylate (2.5 g, 6.214 mmol, 1 equiv) and 4-(4- bromo-17/-pyrazol-3-yl)pyridine (1.95 g, 8.7 mmol, 1.4 equiv) in pyridine (25 mL) was added CU(OAC)2 (2.26 g, 12.428 mmol, 2 equiv) and molecular sieves (4A) (2.5 g). The resulting mixture was stirred at 100 °C overnight under an oxygen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (3: 1) to afford tert-butyl (3/?)-4-[4-[4-bromo-3- (pyridin-4-yl)pyrazol-l-yl]phenyl} -3 -methylpiperazine- 1 -carboxylate (2 g, 58.12%) as a light yellow solid. LCMS: C24H28BrNsO2 requires: 497.1, found: m/z = 498.1 [M+H]+.
[00071 1 ] Step-5: Synthesis of tert-butyl (31?)-4-[4-(4-]2-fluoro-3-|7V-(propane-l- sulfonyl)-A-propane-l-sulfonamido]phenvn-3-(pyridin-4-yl)pyrazol-l-yl)phenyl]-3- methylpiperazine-l-carboxylate (6)
[000712] To a mixture of tert-butyl (3A)-4-{4-[4-bromo-3-(pyridin-4-yl)pyrazol-l- yl]phenyl} -3 -methylpiperazine- 1 -carboxylate (400 mg, 0.803 mmol, 1 equiv) and 2-fluoro-3- [A-(propane-l-sulfonyl)-A-propane-l-sulfonamido]phenylboronic acid (884 mg, 2.408 mmol, 3 equiv) in dioxane (10 mL) was added Pd(AMPHOS)2C12 (114 mg, 0.161 mmol, 0.2 equiv) and CsF (244 mg, 1.605 mmol, 2 equiv) in H2O (2 mL). The resulting mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 :2) to afford tert-butyl (3A)-4-[4-(4-{2-fluoro-3-[A-(propane-l-sulfonyl)-7V- propane- 1 -sulfonamido]phenyl } -3 -(pyridin-4-yl)pyrazol- 1 -yl)phenyl]-3 -methylpiperazine- 1 - carboxylate (400 mg, 53.82%) as a dark yellow solid. LCMS: C36H45FN6O6S2 requires: 740.3, found: m/z = 741.2 [M+H]+.
[000713] Step-6: Synthesis of tert-butyl -4-(4-]4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-3-(pyridin-4-yl)pyrazol-l-vnphenyl)-3-methylpiperazine-l- carboxylate (7)
[000714] To a mixture of tert-butyl (3A)-4-[4-(4-{2-fluoro-3-[7V-(propane-l -sulfonyl )-M propane- 1 -sulfonamido]phenyl } -3 -(pyridin-4-yl)pyrazol- 1 -yl)phenyl]-3 -methylpiperazine- 1 - carboxylate (400 mg, 0.54 mmol, 1 equiv) in THF (10 mL) and ACN (10 mL) was added Na2CC>3 (858 mg, 8.1 mmol, 15 equiv) in H2O (10 mL). The resulting mixture was stirred at 50 °C overnight. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (5: 1) to afford tert-butyl (3A)-4-(4-{4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-3-(pyridin-4-yl)pyrazol- l-yl}phenyl)-3 -methylpiperazine- 1 -carboxylate (310 mg, 78.79%) as a yellow solid. LCMS: C33H39FN6O4S requires: 634.3, found: m/z = 635.2 [M+H]+. [000715] Step-7: Synthesis of \-|2-niioro-3-(l-!4-|(2/?)-2-iiiethylpiper:izin-l- yl]phenvn-3-(pyridin-4-yl)pyrazol-4-yl)phenyl]propane-l-sulfonamide trifluoroacetic acid salt (8)
[000716] To a mixture of tert-butyl (37?)-4-(4-{4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-3-(pyridin-4-yl)pyrazol-l-yl}phenyl)-3-methylpiperazine-l-carboxylate (310 mg, 0.488 mmol, 1 equiv) in DCM (6 mL) was added TFA (2 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 2 h. The resulting mixture was then concentrated under reduced pressure and subjected to lyophilization. This resulted in 7V-[2-fluoro-3-(l-{4-[(27?)-2- methylpiperazin-l-yl]phenyl] -3 -(pyridin-4-yl)pyrazol-4-yl)phenyl]propane-l -sulfonamide trifluoroacetic acid salt (309.0 mg, crude) as a yellow solid. LCMS: C28H31FN6O2S requires: 534.2, found: m/z = 535.2 [M+H]+. 'HNMR (400 MHz, Methanol-^) 8 8.78 - 8.72 (m, 2H), 8.60 (s, 1H), 8.24 - 8.17 (m, 2H), 7.98 - 7.89 (m, 2H), 7.65 - 7.56 (m, 1H), 7.45 - 7.23 (m, 4H), 4.16 - 4.08 (m, 1H), 3.58 - 3.44 (m, 3H), 3.41 - 3.34 (m, 2H), 3.31 - 3.26 (m, 1H), 3.19 - 3.11 (m, 2H), 1.94 - 1.80 (m, 2H), 1.21 - 1.15 (m, 3H), 1.10 - 1.01 (m, 3H).
[000717] Synthesis of TV-H-fluoro- -methylDiDerazin-l-yllDhenvn-S- (Dyridin-4-yl)Dyrazol-4-yl)Dhenyl]Dropane-l-sulfonamide trifluoroacetic acid salt (8)
[000718] Step-1: Synthesis of tert-butyl (35l)-3-methyl-4-DhenylDiDerazine-l- carboxylate (2)
[000719] To a mixture of bromobenzene (2.8 g, 17.975 mmol, 1.2 equiv) and tert-butyl (35)-3 -methylpiperazine- 1 -carboxylate (3 g, 14.979 mmol, 1 equiv) in toluene (30 mL) was added [P(t-Bu)s]BF4 (348 mg, 1.198 mmol, 0.08 equiv), Pd(OAc)2 (101 mg, 0.449 mmol, 0.03 equiv), and t-BuOK (2 g, 20.971 mmol, 1.4 equiv). The resulting mixture was stirred at 110 °C overnight under a nitrogen atmosphere. The resulting mixture was then extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous ISfeSCU. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (3: 1) to afford tert-butyl (35)-3- methyl-4-phenylpiperazine-l -carboxylate (3.5 g, 84.54%) as an off-white oil. LCMS: C16H24N2O2 requires: 276.2, found: m/z = 277.2 [M+H]+.
[000720] Step-2: Synthesis of tert-butyl -4-(4-bromophenyl)-3- methylpiperazine-l-carboxylate (3)
[000721 ] To a mixture of tert-butyl (35)-3-methyl-4-phenylpiperazine-l -carboxylate (3.5 g, 12.664 mmol, 1 equiv) in CHCI3 (40 mL) was added tetrabutylammonium tribromide (6.1 g, 12.664 mmol, 1 equiv) at 0 °C. The resulting mixture was warmed and stirred at room temperature for 0.5 h. The resulting mixture was then extracted with CHCI3. The combined organic layers were washed with water and dried over anhydrous ISfeSCU. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (2: 1) to afford tert-butyl (35)-4-(4-bromophenyl)-3- m ethylpiperazine- 1 -carboxylate (4 g, 80.02%) as a white solid. LCMS: CieEfeBrlSbCh requires: 354.2, found: m/z = 355.2 [M+H]+.
[000722] Step-3: Synthesis of tert-butyl (35l)-3-methyl-4-[4-(4.,4.,5.,5-tetramethyl- l,3.,2-dioxaborolan-2-yl)phenyl]piperazine-l-carboxylate (4)
[000723] To a mixture of tert-butyl (35)-4-(4-bromophenyl)-3 -methylpiperazine- 1- carboxylate (4 g, 11.259 mmol, 1 equiv) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-l,3,2-dioxaborolane (ELPim) (8.6 g, 33.777 mmol, 3 equiv) in 1,4-dioxane (40 mL) was added Pd(dppf)C12 (917 mg, 1.126 mmol, 0.1 equiv) and KOAc (2.2 g, 22.518 mmol, 2 equiv). The resulting mixture was stirred at 80 °C overnight under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (2: 1) to afford tertbutyl (35)-3-methyl-4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]piperazine-l- carboxylate (4 g, 88.30%) as a white solid. LCMS: C22H35BN2O4 requires: 402.2, found: m/z = 403.2 [M+H]+.
[000724] Step-4: Synthesis of tert-butyl -4-]4-[4-bromo-3-(pyridin-4-yl)pyrazol- l-yl]phenvn-3-methylpiperazine-l-carboxylate (5) [000725] To a mixture of tert-butyl (35)-3-methyl-4-[4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]piperazine-l -carboxylate (4 g, 9.942 mmol, 1 equiv) and 4-(4- bromo-17/-pyrazol-3-yl)pyridine (3.1 g, 13.919 mmol, 1.4 equiv) in pyridine (40 mL) was added Cu(OAc)2 (3.6 g, 19.884 mmol, 2 equiv) and molecular sieves (4A) (3.1 g). The resulting mixture was stirred at 100 °C overnight under an oxygen atmosphere. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 : 1) to afford tert-butyl (3,S')-4-[4-[4-bromo-3- (pyridin-4-yl)pyrazol-l-yl]phenyl} -3 -methylpiperazine- 1 -carboxylate (2 g, 36.33%) as a light yellow oil. LCMS: C24H28BrNsO2 requires: 497.1, found: m/z = 498.1 [M+H]+.
[000726] Step-5: Synthesis of tert-butyl -4-[4-(4-]2-fluoro-3-[A-(propane-l- sulfonyl)-A-propane-l-sulfonamido]phenvn-3-(pyridin-4-yl)pyrazol-l-yl)phenyl]-3- methylpiperazine-l-carboxylate (6)
[000727] To a mixture of tert-butyl (35)-4-{4-[4-bromo-3-(pyridin-4-yl)pyrazol-l- yl]phenyl} -3 -methylpiperazine- 1 -carboxylate (500 mg, 1.003 mmol, 1 equiv) and 2-fluoro-3- [A-(propane-l-sulfonyl)-A-propane-l-sulfonamido]phenylboronic acid (1.5 g, 4.012 mmol, 4 equiv) in dioxane (10 mL) was added Pd(AMPHOS)2C12 (142 mg, 0.201 mmol, 0.2 equiv) and CsF (305 mg, 2.006 mmol, 2 equiv) in H2O (2 mL). The resulting mixture was stirred at 90 °C for one hour under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. This resulted in tert-butyl (35)-4-[4-(4-{2-fluoro-3-[A-(propane-l-sulfonyl)- A-propane-l-sulfonamido]phenyl}-3-(pyridin-4-yl)pyrazol-l-yl)phenyl]-3-methylpiperazine- 1-carboxylate (700 mg, crude) as a dark yellow solid. LCMS: C36H45FN6O6S2 requires: 740.2, found: m/z = 741.2 [M+H]+.
[000728] Step-6: Synthesis of tert-butyl -4-(4-]4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-3-(pyridin-4-yl)pyrazol-l-vnphenyl)-3-methylpiperazine-l- carboxylate (7)
[000729] To a mixture of tert-butyl (35)-4-[4-(4-{2-fluoro-3-[A-(propane-l-sulfonyl)-A- propane- 1 -sulfonamido]phenyl } -3 -(pyridin-4-yl)pyrazol- 1 -yl)phenyl]-3 -methylpiperazine- 1 - carboxylate (700 mg, 0.945 mmol, 1 equiv) was added THF (20 mL), ACN (20 mL), and Na2CC>3 (1.5 g, 14.175 mmol, 15 equiv) in H2O (20 mL). The resulting mixture was stirred at 50 °C overnight. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 : 1) to afford tert-butyl (35)-4-(4-{4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-3-(pyridin-4-yl)pyrazol- l-yl}phenyl)-3 -methylpiperazine- 1 -carboxylate (250 mg, 37.52%) as a yellow solid. LCMS: C33H39FN6O4S requires: 634.2, found: m/z = 635.2 [M+H]+.
[000730] Step-7: Synthesis of A^Z-fluoro-S-fl-M-lYZtSl-Z-methylDiDerazin-l- yl]Dhenyn-3-(Dyridin-4-yl)Dyrazol-4-yl)Dhenyl]DroDane-l-sulfonamide trifluoroacetic acid salt (8)
[000731 ] To a mixture of tert-butyl (35)-4-(4-{4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-3-(pyridin-4-yl)pyrazol-l-yl}phenyl)-3-methylpiperazine-l-carboxylate (240 mg, 0.378 mmol, 1 equiv) in DCM (6 mL) was added TFA (2 mL) at 0 °C. The resulting mixture was warmed and stirred at room temperature for one hour. The resulting mixture was concentrated under reduced pressure. This resulted in 7V-[2-fluoro-3-(l-{4-[(2y)-2- methylpiperazin-l-yl]phenyl} -3 -(pyridin-4-yl)pyrazol-4-yl)phenyl]propane-l -sulfonamide trifluoroacetic acid salt (215.5 mg, 87.51%) as a yellow solid. LCMS: C28H31FN6O2S requires: 534.2, found: m/z = 535.2 [M+H]+. 'HNMR (400 MHz, Methanol-^) 8 8.78 - 8.72 (m, 2H), 8.60 (s, 1H), 8.24 - 8.17 (m, 2H), 7.98 - 7.89 (m, 2H), 7.65 - 7.56 (m, 1H), 7.45 - 7.32 (m, 2H), 7.31 - 7.23 (m, 2H), 4.16 - 4.08 (m, 1H), 3.58 - 3.44 (m, 3H), 3.41 - 3.34 (m, 2H), 3.31 - 3.26 (m, 1H), 3.19 - 3.11 (m, 2H), 1.94 - 1.80 (m, 2H), 1.21 - 1.15 (m, 3H), 1.10 - 1.01 (m, 3H).
[000732] Synthesis of 7V-[2-fluoro-3-(l-]4 -methylDiDerazin-l-yl]Dhenvn-3- (Dyridin-4-yl)Dyrazol-4-yl)Dhenyl]Dropane-l-sulfonamide trifluoroacetic acid salt (7)
[000733] Step-1: Synthesis of tert-butyl -4-(4-bromophenyl)-2- methylpiperazine-l-carboxylate (2)
[000734] To a mixture of tert-butyl (27?)-2-m ethylpiperazine- 1 -carboxylate (5 g, 24.965 mmol, 1 equiv) and 1,4-dibromobenzene (14.72 g, 62.413 mmol, 2.5 equiv) in 1,4-dioxane (50 mL) was added Pd2(dba)s (1.14 g, 1.248 mmol, 0.05 equiv), BINAP (0.78 g, 1.248 mmol, 0.05 equiv), and CS2CO3 (12.2 g, 37.447 mmol, 1.5 equiv). The resulting mixture was stirred at 90 °C overnight under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography eluted with ACN:H2O (1 : 1) to afford tert-butyl (2A)-4-(4-bromophenyl)-2-methylpiperazine-l- carboxylate (4.97 g, 56%) as a white solid. LCMS: CieLfeBrl^Ch requires: 354.1, found: m/z = 355.2 [M+H]+.
[000735] Step-2: Synthesis of tert-butyl (27?)-2-methyl-4-[4-(4.,4.,5.,5-tetramethyl- l,3.,2-dioxaborolan-2-yl)phenyl]piperazine-l-carboxylate (3)
[000736] To a mixture of tert-butyl (2A)-4-(4-bromophenyl)-2-methylpiperazine-l- carboxylate (2 g, 5.629 mmol, 1 equiv) and B2Pin2 (4.29 g, 16.887 mmol, 3 equiv) in 1,4- dioxane (20 mL) was added Pd(dppf)C12 (412 mg, 0.563 mmol, 0.1 equiv) and KOAc (1.1 g, 11.258 mmol, 2 equiv). The resulting mixture was stirred at 80 °C overnight under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 : 1) to afford tert-butyl (2A)-2-methyl-4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]piperazine-l- carboxylate (2 g, 79.47%) as a white solid. LCMS: C22H35BN2O4 requires: 402.3, found: m/z = 403.2 [M+H]+.
[000737] Step-3: Synthesis of tert-butyl -4-14-[4-bromo-3-(pyridin-4-yl)pyrazol- l-yl]phenvn-2-methylpiperazine-l-carboxylate (4)
[000738] To a mixture of tert-butyl (2A)-2-methyl-4-[4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]piperazine-l -carboxylate (2 g, 4.971 mmol, 1 equiv) and 4-(4- bromo-17/-pyrazol-3-yl)pyridine (1.56 g, 6.959 mmol, 1.4 equiv) in pyridine (20 mL) was added Cu(OAc)2 (1.81 g, 9.942 mmol, 2 equiv) and molecular sieves (4A) (2 g). The resulting mixture was stirred at 100 °C overnight under an oxygen atmosphere. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography eluted with ACbTEhO (1 : 1) to afford tert-butyl (2A)-4-{4-[4-bromo-3-(pyridin-4-yl)pyrazol-l-yl]phenyl}-2- m ethylpiperazine- 1 -carboxylate (900 mg, 26.52%) as a yellow solid. LCMS: C24H28BrNsO2 requires: 497.1, found: m/z = 498.1 [M+H]+.
[000739] Step-4: Synthesis of tert-butyl (21?)-4-[4-(4-12-fluoro-3-|7V-(propane-l- sulfonyl)-A-propane-l-sulfonamido]phenvn-3-(pyridin-4-yl)pyrazol-l-yl)phenyl]-2- methylpiperazine-l-carboxylate (5)
[000740] To a mixture of tert-butyl (2A)-4-{4-[4-bromo-3-(pyridin-4-yl)pyrazol-l- yl]phenyl]-2-methylpiperazine-l -carboxylate (400 mg, 0.803 mmol, 1 equiv) and 2-fluoro-3- [A-(propane-l-sulfonyl)-A-propane-l-sulfonamido]phenylboronic acid (1179 mg, 3.21 mmol, 4 equiv) in dioxane (10 mL) was added Pd(AMPHOS)2C12 (114 mg, 0.161 mmol, 0.2 equiv) and CsF (2441 mg, 1.606 mmol, 2 equiv) in H2O (2 mL). The resulting mixture was stirred at 90° C for 2 h under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 :3) to afford tert-butyl (2A)-4-[4-(4-{2-fluoro-3-[A-(propane-l-sulfonyl)-7V- propane-l-sulfonamido]phenyl}-3-(pyridin-4-yl)pyrazol-l-yl)phenyl]-2-methylpiperazine-l- carboxylate (400 mg, 61.89%) as a yellow solid. LCMS: C36H45FN6O6S2 requires: 740.3, found: m/z = 741.2 [M+H]+.
[000741] Step-5: Synthesis of tert-butyl (21?)-4-(4-]4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-3-(pyridin-4-yl)pyrazol-l-vnphenyl)-2-methylpiperazine-l- carboxylate (6)
[000742] To a mixture of tert-butyl (2A)-4-[4-(4-{2-fluoro-3-[A-(propane-l-sulfonyl)-7V- propane-l-sulfonamido]phenyl}-3-(pyridin-4-yl)pyrazol-l-yl)phenyl]-2-methylpiperazine-l- carboxylate (400 mg, 0.54 mmol, 1 equiv) was added THF (10 mL), ACN (10 mL), and Na2CC>3 (858 mg, 8.1 mmol, 15 equiv) in H2O (10 mL). The resulting mixture was stirred at 50 °C overnight. The resulting mixture was then extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous ISfeSCU After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography eluted with ACbTEhO (1 : 1) to afford tert-butyl (2/?)-4-(4-{4-[2-fluoro-3- (propane-l-sulfonamido)phenyl]-3-(pyridin-4-yl)pyrazol-l-yl}phenyl)-2-methylpiperazine-l- carboxylate (220 mg, 57.78%) as a yellow solid. LCMS: C33H39FN6O4S requires: 634.3, found: m/z = 635.2 [M+H]+.
[000743] Step-6: Synthesis of 7V-[2-fluoro-3-(l-]4-[ -3-methylpiperazin-l- yl]phenvn-3-(pyridin-4-yl)pyrazol-4-yl)phenyl]propane-l-sulfonamide trifluoroacetic acid salt (7)
[000744] To a mixture of tert-butyl (2A)-4-(4-{4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-3-(pyridin-4-yl)pyrazol-l-yl}phenyl)-2-methylpiperazine-l-carboxylate (215 mg, 0.339 mmol, 1 equiv) in DCM (6 mL) was added TFA (2 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 2 h. The resulting mixture was then concentrated under reduced pressure and subjected to lyophilization. This resulted in A-[2-fluoro-3-(l-{4-[(3A)-3- methylpiperazin-l-yl]phenyl} -3 -(pyridin-4-yl)pyrazol-4-yl)phenyl]propane-l -sulfonamide trifluoroacetic acid salt (217.9 mg, crude) as a yellow solid. LCMS: C28H31FN6O2S requires: 534.2, found: m/z = 535.2 [M+H]+. 'HNMR (400 MHz, Methanol-^) 8 8.77 - 8.68 (m, 2H), 8.57 (s, 1H), 8.20 - 8.11 (m, 2H), 7.94 - 7.86 (m, 2H), 7.64 - 7.56 (m, 1H), 7.44 - 7.30 (m, 2H), 7.27 - 7.22 (m, 2H), 4.01 - 3.83 (m, 2H), 3.66 - 3.35 (m, 2H), 3.34 (s, 1H), 3.20 - 3.07 (m, 3H), 2.97 - 2.84 (m, 1H), 1.92 - 1.80 (m, 2H), 1.50 - 1.39 (m, 3H), 1.12 - 1.00 (m, 3H).
[000745] Synthesis of ethylmethyl[(2-fluoro-3-H-[6-(piperazin-l-yl)pyridin-3-yl]-3- (pyridin-4-yl)pyrazol-4-vnphenyl)snlfamoyl] amine trifluoroacetic acid salt (4)
[000746] Step-1: Synthesis of tert-butyl 4-]5-[4-bromo-3-(Dyridin-4-yl)pyrazol-l- yl]Dyridin-2-ynDiDerazine-l-carboxylate (2)
[000747] To a mixture of tert-butyl 4-[5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-2-yl]piperazine-l -carboxylate (2 g, 5.137 mmol, 1 equiv) and 4-(4-bromo-17T- pyrazol-3-yl)pyridine (1.7 g, 7.705 mmol, 1.5 equiv) in pyridine (20 mL) was added Cu(OAc)2 (1.87 g, 10.274 mmol, 2 equiv) and molecular sieves (4A) (1.7 g). The resulting mixture was stirred at 100 °C overnight under an oxygen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 : 1) to afford tert-butyl 4-{5-[4-bromo-3-(pyridin-4- yl)pyrazol-l-yl]pyri din-2 -yl (piperazine- 1 -carboxylate (1.5 g, 60.15%) as a yellow solid. LCMS: C22H25BrNeO2 requires: 484.1, found: m/z = 485.1 [M+H]+. [000748] Step-2: Synthesis of tert-butyl 4-f5-[4-(3-f[ethyl(methyl)sulfamoyl]amino}- 2-fluorophenyl)-3-(pyridin-4-yl)pyrazol-l-yl]pyridin-2-vnpiperazine-l-carboxylate (3)
[000749] To a mixture of tert-butyl 4-{5-[4-bromo-3-(pyridin-4-yl)pyrazol-l-yl]pyridin-
2-yl (piperazine- 1 -carboxylate (500 mg, 1.03 mmol, 1 equiv) and 3- { [ethyl (methyl)sulfamoyl]amino(-2-fluorophenylboronic acid (341 mg, 1.236 mmol, 1.2 equiv) in dioxane (5 mL) was added PdAMPHOS (73 mg, 0.103 mmol, 0.1 equiv) and CsF (313 mg, 2.06 mmol, 2 equiv) in H2O (1 mL). The resulting mixture was stirred at 90 °C for one hour under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography eluted with ACbTFhO (1 :2) to afford tert-butyl 4-{5-[4-(3-{[ethyl(methyl)sulfamoyl]amino(-2- fluorophenyl)-3 -(pyridin-4-yl)pyrazol- 1 -yl]pyri din-2 -yl (piperazine- 1 -carboxylate (300 mg, 41.16%) as a white solid. LCMS: C31H37FN8O4S requires: 636.3, found: m/z = 637.3 [M+H]+.
[000750] Step-3: Synthesis of ethylmethyl[(2-fluoro-3-H-[6-(piperazin-l-yl)pyridin-
3-yl]-3-(pyridin-4-yl)pyrazol-4-vnphenyl)sulfamoyl]amine trifluoroacetic acid salt (4)
[000751 ] To a mixture of tert-butyl 4-{5-[4-(3-{[ethyl(methyl)sulfamoyl]amino(-2- fluorophenyl)-3 -(pyridin-4-yl)pyrazol- 1 -yl]pyri din-2 -yl (piperazine- 1 -carboxylate (300 mg, 0.471 mmol, 1 equiv) in DCM (6 mL) was added TFA (2 mL) at 0 °C. The resulting mixture was stirred at room temperature for one hour. The resulting mixture was then concentrated under reduced pressure and subjected to lyophilization. This resulted in ethylmethyl [(2-fluoro- 3-{ l-[6-(piperazin-l-yl)pyridin-3-yl]-3-(pyridin-4-yl)pyrazol-4-yl(phenyl)sulfamoyl]amine trifluoroacetic acid salt (233.3 mg, crude) as a yellow solid. LCMS: C26H29FN8O2S requires: 536, found: m/z = 537 [M+H]+. 'HNMR (400 MHz, Methanol-^) 8 8.86 - 8.72 (m, 3H), 8.59 (s, 1H), 8.26 - 8.13 (m, 3H), 7.64 - 7.56 (m, 1H), 7.38 - 7.29 (m, 2H), 7.19 - 7.10 (m, 1H), 3.99 - 3.88 (m, 4H), 3.44 - 3.37 (m, 4H), 3.29 - 3.21 (m, 2H), 2.84 (s, 3H), 1.23 - 1.10 (m, 3H).
[000752] Synthesis of A-(2.,5-difluoro-3-H-[4-(piperazin-l-yl)phenyl]-3-(pyridin-4- yl)pyrazol-4-yl}phenyl)propane-l-sulfonamide trifluoroacetic acid salt (6)
[000753] Step-1: Synthesis of 3-bromo-2,5-difluoroaniline (2)
[000754] To a mixture of Fe (5.8 g, 105.045 mmol, 5 equiv) in AcOH (2 mL) and H2O (10 mL) was added NH4CI (112 mg, 2.101 mmol, 0.1 equiv). The resulting mixture was stirred at 80 °C for 5 min. To the above mixture was added l-bromo-2,5-difluoro-3-nitrobenzene (5 g, 21.009 mmol, 1 equiv) in EtOH (100 mL). The resulting mixture was stirred at 80 °C for 0.5 h. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (2: 1) to afford 3-bromo- 2, 5 -difluoroaniline (4 g, 82.38%) as an off-white oil. LCMS: CeELB^N requires: 207.2, found: m/z = 208.3 [M+H]+.
[000755] Step-2: Synthesis of A-(3-bromo-2.,5-difluorophenyl)propane-l- sulfonamide (3)
[000756] To a mixture of 3 -bromo-2, 5 -difluoroaniline (500 mg, 2.404 mmol, 1 equiv) and TEA (729 mg, 7.212 mmol, 3 equiv) in DCM (20 mL) was added propane- 1 -sulfonyl chloride (1.1 g, 7.212 mmol, 3 equiv) at 0 °C. The resulting mixture was stirred at room temperature for one hour. The resulting mixture was then concentrated under reduced pressure. To the above mixture was then added THF (50 mL), ACN (50 mL), and ISfeCCL (3.8 g, 36.060 mmol, 15 equiv) in H2O (50 mL). The resulting mixture was stirred at 50 °C overnight. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 : 1) to afford N-(3 -bromo-2, 5- difluorophenyl)propane-l -sulfonamide (700 mg, 83.43%) as a white solid. LCMS: C9HioBrF2N02S requires: 313.2, found: m/z = 314.3 [M+H]+.
[000757] Step-3: Synthesis of A-[2.,5-difluoro-3-(4.,4.,5.,5-tetramethyl-l.,3.,2- dioxaborolan-2-yl)phenyl] propane-l-sulfonamide (4)
[000758] To a mixture of A-(3-bromo-2,5-difluorophenyl)propane-l-sulfonamide (700 mg, 2.228 mmol, 1 equiv) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-
2-yl)-l,3,2-dioxaborolane (E^Pim) (1.1 g, 4.456 mmol, 2 equiv) in 1,4-dioxane (10 mL) was added Pd(dppf)C12 (181 mg, 0.223 mmol, 0.1 equiv) and KO Ac (437 mg, 4.456 mmol, 2 equiv). The resulting mixture was stirred at 90 °C overnight under a nitrogen atmosphere. After filtration, the filtrate was concentrated under reduced pressure. This resulted in A-[2,5-difluoro-
3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]propane-l-sulfonamide (700 mg, crude) as a black oil. LCMS: C15H22BF2NO4S requires: 361.2, found: m/z = 362.2 [M+H]+.
[000759] Step-4: Synthesis o butyl 4-(4-]4-[2.,5-difluoro-3-(propane-l- sulfonamido)phenyl]-3-(pyridin-4-yl)pyrazol-l-vnphenyl)piperazine-l-carboxylate (5)
[000760] To a mixture of A-[2,5-difluoro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl]propane-l -sulfonamide (700 mg, 1.938 mmol, 3 equiv) and terLbutyl 4-{4-[4- bromo-3-(pyridin-4-yl)pyrazol-l-yl]phenyl]piperazine-l-carboxylate (313 mg, 0.646 mmol, 1 equiv) in dioxane (10 mL) was added Pd(AMPHOS)2C12 (46 mg, 0.065 mmol, 0.1 equiv) and CsF (196 mg, 1.292 mmol, 2 equiv) in H2O (2 mL). The resulting mixture was stirred at 90 °C for one hour under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 : 1) to afford tert-butyl 4-(4-{4-[2,5-difluoro-3-(propane-l-sulfonamido)phenyl]- 3-(pyridin-4-yl)pyrazol-l-yl}phenyl)piperazine-l-carboxylate (200 mg, 43.61%) as a yellow solid. LCMS: C32H36F2N6O4S requires: 638.2, found: m/z = 639.2 [M+H]+.
[000761 ] Step-5: Synthesis of (2.5-diniioro-3-!l-|4-(piperaziii-l-yl)plieiiyl|-3-
(pyridin-4-yl)pyrazol-4-vnphenyl)propane-l-sulfonamide trifluoroacetic acid salt (6)
[000762] To a mixture of tert-butyl 4-(4-{4-[2,5-difluoro-3-(propane-l- sulfonamido)phenyl]-3-(pyridin-4-yl)pyrazol-l-yl}phenyl)piperazine-l -carboxylate (200 mg, 0.313 mmol, 1 equiv) in DCM (6 mL) was added TFA (2 mL) at 0 °C. The resulting mixture was stirred at room temperature for one hour. The resulting mixture was then concentrated under reduced pressure and subjected to lyophilization. This resulted in A-(2,5-difluoro-3-{ l- [4-(piperazin-l-yl)phenyl]-3-(pyridin-4-yl)pyrazol-4-yl}phenyl)propane-l -sulfonamide trifluoroacetic acid salt (196.1 mg, crude) as a yellow solid. LCMS: C27H28F2N6O2S requires: 538.2, found: m/z = 539.2 [M+H]+. 'HNMR (400 MHz, Methanol-^) 8 8.77 - 8.71 (m, 2H), 8.59 (s, 1H), 8.16 - 8.09 (m, 2H), 7.94 - 7.85 (m, 2H), 7.46 - 7.37 (m, 1H), 7.28 - 7.20 (m, 2H), 7.19 - 7.11 (m, 1H), 3.57 - 3.50 (m, 4H), 3.50 - 3.40 (m, 4H), 3.22 - 3.13 (m, 2H), 1.92 - 1.78 (m, 2H), 1.09 - 1.01 (m, 3H).
[000763] Synthesis of [(5-chloro-2-fluoro-3-H-[4-(Diperazin-l-yl)Dhenyl]-3- (Dyridin-4-yl)Dyrazol-4-vnDhenyl)sulfamoyl]-A-ethyl-A-niethylaniine trifluoroacetic acid salt (3)
[000764] Step-1: Synthesis of tert-butyl 4-14-[4-(5-chloro-3- llethyl(methyl)sulfamoyl]amino}-2-flnorophenyl)-3-(pyridin-4-yl)pyrazol-l- yllDhenynpiperazine-l-carboxylate (2)
[000765] To a mixture of tert-butyl 4-{4-[4-(3-amino-5-chloro-2-fluorophenyl)-3- (pyridin-4-yl)pyrazol-l-yl]phenyl}piperazine-l-carboxylate (400 mg, 0.729 mmol, 1 equiv) and 7V-ethyl-7V-methylsulfamoyl chloride (230 mg, 1.458 mmol, 2 equiv) in pyridine (1.6 mL) was added DMAP (107 mg, 0.875 mmol, 1.2 equiv). The resulting mixture was stirred at 40 °C overnight under a nitrogen atmosphere. The residue was purified via C 18 reverse phase column chromatography with ACN:EhO (4: 1). The residue was then purified by silica gel column chromatography eluted with PE:EtOAc (1 : 1) to afford tert-butyl 4-{4-[4-(5-chloro-3- {[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-3-(pyridin-4-yl)pyrazol-l- yl]phenyl}piperazine-l-carboxylate (100 mg, 18.43%) as a white solid. LCMS: C32H37CIFN7O4S requires: 669.2, found: m/z = 670.1 [M+H]+.
[000766] Step-2: Synthesis of [(5-chloro-2-fluoro-3-ll-[4-(piperazin-l-yl)phenyl]-3-
(pyridin-4-yl)pyrazol-4-vnphenyl)sulfamoyl]-A-ethyl-A-niethylaniine trifluoroacetic acid salt (3) [000767] To a mixture of tert-butyl 4-{4-[4-(5-chloro-3- {[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-3-(pyridin-4-yl)pyrazol-l- yl]phenyl}piperazine-l-carboxylate (100 mg, 0.149 mmol, 1 equiv) in DCM (3 mL) was added TFA (1 mL) at 0 °C. The resulting mixture was stirred at 0 °C for one hour. The resulting mixture was then concentrated under reduced pressure and subjected to lyophilization. This resulted in [(5-chloro-2-fluoro-3-{ l-[4-(piperazin-l-yl)phenyl]-3-(pyridin-4-yl)pyrazol-4- yl}phenyl)sulfamoyl]-7V-ethyl-7V-methylamine trifluoroacetic acid salt (81.8 mg, crude) as a yellow solid. LCMS: C27H29CIFN7O2S requires: 569.2, found: m/z = 570.3. [M+H]+. 'HNMR (400 MHz, Methanol-t/4) 8 8.76 - 8.70 (m, 2H), 8.60 - 8.56 (m, 1H), 8.09 - 8.03 (m, 2H), 7.94 - 7.85 (m, 2H), 7.63 - 7.56 (m, 1H), 7.38 - 7.32 (m, 1H), 7.28 - 7.19 (m, 2H), 3.57 - 3.50 (m, 4H), 3.47 - 3.40 (m, 4H), 3.32 - 3.22 (m, 2H), 2.86 - 2.82 (m, 3H), 1.20 - 1.12 (m, 3H).
[000768] Synthesis of Az-(5-chloro-2-fluoro-3-H-[2-fluoro-4-(DiDerazin-l-yl)Dhenyl]- 3-(Dyridin-4-yl)Dyrazol-4-ynDhenyl)Dyrrolidine-l-sulfonamide trifluoroacetic acid salt (3)
[000769] Step-1: Synthesis of tert-butyl 4-[4-(4-15-chloro-2-fluoro-3-[(pyrrolidine-l- sulfonyl)amino]Dhenyn-3-(Dyridin-4-yl)Dyrazol-l-yl)-3-fluoroDhenyl]DiDerazine-l- carboxylate (2)
[000770] To a mixture of tert-butyl 4-{4-[4-bromo-3-(pyridin-4-yl)pyrazol-l-yl]-3- fluorophenyl} piperazine- 1 -carboxylate (400 mg, 0.796 mmol, 1 equiv) and 7V-[5-chloro-2- fluoro-3-(4, 4, 5, 5 -tetramethyl- 1, 3, 2-dioxaborolan-2-yl)phenyl]pyrrolidine-l -sulfonamide (967 mg, 2.388 mmol, 3 equiv) in dioxane (10 mL) was added CsF (242 mg, 1.592 mmol, 2 equiv) in H2O (2 mL) and Pd(AMPHOS)2Ch (59 mg, 0.08 mmol, 0.1 equiv). The resulting mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. The resulting mixture was then concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 : 10) to afford tert-butyl 4-[4-(4-{5-chloro-2-fluoro-3-[(pyrrolidine-l- sulfonyl)amino]phenyl } -3 -(pyridin-4-yl)pyrazol- 1 -y l)-3 -fluorophenyl]piperazine- 1 - carboxylate (260 mg, 46.64%) as a brown solid. LCMS: C33H36CIF2N7O4S requires: 699.2, found: m/z = 700.2 [M+H]+. [000771] Step-2: Synthesis of (5-cliloro-2-niioro-3-!l-|2-nuoro-4-(piper:izin-l- yl)phenyl]-3-(pyridin-4-yl)pyrazol-4-vnphenyl)pyrrolidine-l-sulfonamide trifluoroacetic acid salt (3)
[000772] To a mixture of tert-butyl 4-[4-(4-{5-chloro-2-fhioro-3-[(pyrrolidine-l- sulfonyl)amino]phenyl } -3 -(pyridin-4-yl)pyrazol- 1 -y l)-3 -fluorophenyl]piperazine- 1 - carboxylate (210 mg, 0.300 mmol, 1 equiv) in DCM (9 mL) was added TFA (3 mL) at 0 °C. The resulting mixture was stirred at 0 °C for one hour. The resulting mixture was then concentrated under vacuum. The residue was purified by reverse phase flash chromatography eluted with ACbTFhO (1 : 1) to afford A-(5-chloro-2-fhioro-3-{ l-[2-fhioro-4-(piperazin-l- yl)phenyl]-3-(pyridin-4-yl)pyrazol-4-yl}phenyl)pyrrolidine-l-sulfonamide trifluoroacetic acid salt (137.6 mg, 61.48%) as a yellow solid. LCMS: C28H28CIF2N7O2S requires:599.2, found: m/z = 600.2 [M+H]+. 'H NMR (400 MHz, Methanol-^) 5 8.70 (s, 2H), 8.36 (s, 1H), 7.99 - 7.93 (m, 2H), 7.84 (s, 1H), 7.63 (s, 1H), 7.30 (s, 1H), 7.14 - 7.04 (m, 2H), 3.59 (s, 4H), 3.43 (s, 4H), 3.34 - 3.28 (m, 4H), 1.96 - 1.86 (m, 4H).
[000773] Synthesis of A-(5-chloro-2-fluoro-3-H-[5-(Diperazin-l-yl)Dyridin-2-yl]-3- (Dyridin-4-yl)Dyrazol-4- Dropane-l-sulfonamide trifluoroacetic acid salt (6)
[000774] Step-1: Synthesis of tert-butyl 4-(6-chloropyridin-3-yl)piperazine-l- carboxylate (2)
[000775] To a mixture of 5-bromo-2-chloropyridine (5 g, 25.982 mmol, 1 equiv) and tertbutyl piperazine- 1 -carboxylate (4.8 g, 25.982 mmol, 1 equiv) in toluene (150 mL) was added XantPhos (902 mg, 1.559 mmol, 0.06 equiv), Pd2(dba)s (476 mg, 0.520 mmol, 0.02 equiv), and Z-BuOK (3.8 g, 38.973 mmol, 1.5 equiv). The resulting mixture was stirred at 100 °C overnight under a nitrogen atmosphere. The resulting mixture was then extracted with EtOAc. The combined organic layers were washed with waterand dried over anhydrous ISfeSCU After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (3: 1) to afford tert-butyl 4-(6- chloropyridin-3-yl)piperazine-l -carboxylate (7 g, 81.43%) as a white solid. LCMS: C14H20CIN3O2 requires: 297.1, found: m/z = 298.2 [M+H]+.
[000776] Step-2: Synthesis of tert-butyl 4-[6-(4.,4.,5.,5-tetramethyl-l.,3.,2- dioxaborolan-2-yl)pyridin-3-yl] piperazin e-l-carboxylate (3) [000777] To a mixture of tert-butyl 4-(6-chloropyridin-3-yl)piperazine-l-carboxylate (2 g, 6.716 mmol, 1 equiv) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-l,3,2-dioxaborolane (B2Pin2) (1.9 g, 7.388 mmol, 1.1 equiv) in 1,4-dioxane (40 mL) was added Pd(OAc)2 (181 mg, 0.806 mmol, 0.12 equiv), XPhos (576 mg, 1.209 mmol, 0.18 equiv), and KO Ac (2 g, 20.148 mmol, 3 equiv). The resulting mixture was stirred at 90 °C overnight under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. After filtration, the filtrate was concentrated under reduced pressure. This resulted in tert-butyl 4-[6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-3-yl]piperazine-l- carboxylate (3 g, crude) as a black oil. LCMS: C20H32BN3O4 requires: 389.3, found: m/z = 390.2 [M+H]+.
[000778] Step-3: Synthesis of tert-butyl 4-]6-[4-bromo-3-(pyridin-4-yl)pyrazol-l- yl]pyridin-3-yl}piperazine-l-carboxylate (4)
[000779] To a mixture of tert-butyl 4-[6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-3-yl]piperazine-l -carboxylate (3 g, 7.706 mmol, 1 equiv) and 4-(4-bromo-lJ7- pyrazol-3-yl)pyridine (2.4 g, 10.801 mmol, 1.4 equiv) in pyridine (30 mL) was added CU(OAC)2 (2.8 g, 15.412 mmol, 2 equiv) and molecular sieves (4A) (2.4 g). The resulting mixture was stirred at 100 °C overnight under an oxygen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 : 1) to afford tert-butyl 4-{6-[4-bromo-3-(pyridin-4- yl)pyrazol-l-yl]pyri din-3 -yl (piperazine- 1 -carboxylate (230 mg, 5.23%) as a yellow solid. LCMS: C22H25BrNeO2 requires: 484.1, found: m/z = 485.1 [M+H]+.
[000780] Step-4: Synthesis of tert-butyl 4-(6-]4-[5-chloro-2-fluoro-3-(propane-l- sulfonamido)phenyl]-3-(pyridin-4-yl)pyrazol-l-vnpyridin-3-yl)piperazine-l-carboxylate (5)
[000781 ] To a mixture of tert-butyl 4-{6-[4-bromo-3-(pyridin-4-yl)pyrazol-l-yl]pyridin- 3 -yl (piperazine- 1 -carboxylate (220 mg, 0.453 mmol, 1 equiv) and 7V-[5-chloro-2-fluoro-3- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]propane-l-sulfonamide (514 mg, 1.359 mmol, 3 equiv) in dioxane (5 mL) was added Pd(AMPHOS)2C12 (32 mg, 0.045 mmol, 0.1 equiv) and CsF (138 mg, 0.906 mmol, 2 equiv) in H2O (1 mL). The resulting mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 : 1) to afford tert-butyl 4-(6-{4-[5-chloro-2-fluoro-3- (propane- 1 -sulfonamido)phenyl]-3 -(pyridin-4-yl)pyrazol- 1 -yl Jpyri din-3 -yl)piperazine- 1 - carboxylate (150 mg, 45.39%) as a white solid. LCMS: C31H35CIFN7O4S: 655.2, found: m/z =
656.2 [M+H]+.
[000782] Step-5: Synthesis of 7V-(5-chloro-2-fluoro-3-n-[5-(DiDerazin-l-yl)Dyridin- 2-yl]-3-(Dyridin-4-yl)Dyrazol-4-ynDhenyl)DroDane-l-sulfonamide trifluoroacetic acid salt (6)
[000783] To a mixture of tert-butyl 4-(6-{4-[5-chloro-2-fluoro-3-(propane-l- sulfonamido)phenyl]-3-(pyridin-4-yl)pyrazol-l-yl}pyridin-3-yl)piperazine-l-carboxylate
(145 mg, 0.221 mmol, 1 equiv) in DCM (6 mL) was added TFA (2 mL) at 0 °C. The resulting mixture was stirred at room temperature for one hour. The resulting mixture was then concentrated under reduced pressure and subjected to lyophilization. This resulted in 7V-(5- chloro-2-fluoro-3-{ l-[5-(piperazin-l-yl)pyridin-2-yl]-3-(pyridin-4-yl)pyrazol-4- yl}phenyl)propane-l-sulfonamide trifluoroacetic acid salt (125.4 mg, crude) as a yellow solid. LCMS: C26H27CIFN7O2S requires: 555.2, found: m/z = 556.2 [M+H]+. XH NMR (400 MHz, Methanol-t/4) 8 8.85 (s, 1H), 8.76 - 8.70 (m, 2H), 8.35 - 8.24 (m, 1H), 8.14 - 8.03 (m, 3H), 7.81 - 7.69 (m, 1H), 7.67 - 7.58 (m, 1H), 7.44 - 7.31 (m, 1H), 3.63 - 3.54 (m, 4H), 3.51 - 3.43 (m, 4H), 3.20 - 3.12 (m, 2H), 1.91 - 1.78 (m, 2H), 1.09 - 1.00 (m, 3H).
[000784] Synthesis of 7V-(5-chloro-2-fluoro-3-] 1 -|4-(piper:izin-l-yl)phenyl|-3- (Dyridin-4-yl)Dyrazol-4- Dyrrolidine-l-sulfonamide trifluoroacetic acid salt (6)
[000785] Step-1: Synthesis of 7V-(3-bromo-5-chloro-2-fluorophenyr)pyrrolidine-l- sulfonamide (2)
[000786] To a mixture of 3-bromo-5-chloro-2-fluoroaniline hydrochloride (2 g, 7.665 mmol, 1 equiv) and pyrrolidine- 1 -sulfonyl chloride (2.6 g, 15.33 mmol, 2 equiv) in pyridine (4 mL) was added DMAP (1.12 g, 9.198 mmol, 1.2 equiv). The resulting mixture was stirred at 40 °C overnight under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (3: 1) to afford A-(3-bromo-5-chloro-2-fluorophenyl)pyrrolidine-l- sulfonamide (2 g, 65.66%) as a yellow solid. LCMS: CioEhiBrCLENbCES requires: 355.9, found: m/z =357.1 [M+H]+.
[000787] Step-2: Synthesis of A-[5-chloro-2-fluoro-3-(4,4,5,5-tetramethyl-l,3.,2- dioxaborolan-2-yl)phenyl] pyrrolidine-l-sulfonamide (3)
[000788] To a mixture of A-(3-bromo-5-chloro-2-fluorophenyl)pyrrolidine-l- sulfonamide (2 g, 5.593 mmol, 1 equiv) and bis(pinacolato)diboron (B2Pin2) (2.84 g, 11.186 mmol, 2 equiv) in dioxane (30 mL) was added KO Ac (1.1 g, 11.186 mmol, 2 equiv) and Pd(dppf)C12 (0.41 g, 0.559 mmol, 0.1 equiv). The resulting mixture was stirred at 90 °C for 1 h under a nitrogen atmosphere. The resulting mixture was then filtered. The filtrate was concentrated under reduced pressure. This resulted in A-[5-chloro-2-fluoro-3-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]pyrrolidine-l-sulfonamide (2 g, crude) as a black oil. LCMS: C16H23BCIFN2O4S requires: 404.1, found: m/z = 405.2 [M+H]+.
[000789] Step-3: Synthesis of tert-butyl 4-[4-(4-]5-chloro-2-fluoro-3-[(pyrrolidine-l- snlfonyl)amino]phenvn-3-(pyridin-4-yl)pyrazol-l-yl)phenyl]piperazine-l-carboxylate
(5)
[000790] To a mixture of tert-butyl 4-{4-[4-bromo-3-(pyridin-4-yl)pyrazol-l- yl]phenyl}piperazine-l-carboxylate (800 mg, 1.652 mmol, 1 equiv) and A-[5-chloro-2-fhioro- 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]pyrrolidine-l-sulfonamide (2 g, 4.956 mmol, 3 equiv) in dioxane (20 mL) was added CsF (502 mg, 3.304 mmol, 2 equiv) in H2O (4 mL) and Pd(AMPHOS)2C12 (117 mg, 0.165 mmol, 0.1 equiv). The resulting mixture was stirred at 90 °C for 1 h under a nitrogen atmosphere. The resulting mixture was then concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 :2) to afford tert-butyl 4-[4-(4-{5-chloro-2-fluoro-3-[(pyrrolidine-l- sulfonyl)amino]phenyl } -3 -(pyridin-4-yl)pyrazol- 1 -yl)phenyl]piperazine- 1 -carboxylate (350 mg, 26.40%) as an off-white solid. LCMS: C33H37CIFN7O4S requires: 681.2, found: m/z = 682.2 [M+H]+.
[000791 ] Step-4: Synthesis of A-(5-chloro-2-fluoro-3-H-[4-(piperazin-l-yl)phenyl]-
3-(pyridin-4-yl)pyrazol-4-vnphenyl)pyrrolidine-l-sulfonamide trifluoroacetic acid salt
(6)
[000792] To a mixture of tert-butyl 4-[4-(4-{5-chloro-2-fluoro-3-[(pyrrolidine-l- sulfonyl)amino]phenyl] -3 -(pyridin-4-yl)pyrazol-l-yl)phenyl]piperazine-l -carboxylate (360 mg, 0.528 mmol, 1 equiv) in DCM (9 mL) was added TFA (3 mL) at 0 °C. The resulting mixture was stirred at 0 °C for one hour. The resulting mixture was then concentrated under vacuum. The residue was purified by reverse phase flash chromatography eluted with ACbkEhO (1 : 1) to afford A-(5-chloro-2-fluoro-3-{ l-[4-(piperazin-l-yl)phenyl]-3-(pyridin-4- yl)pyrazol-4-yl}phenyl)pyrrolidine-l-sulfonamide trifluoroacetic acid salt (161.0 mg, 61.45%) as a yellow solid. LCMS: C28H29CIFN7O2S requires: 581.2;, found: m/z = 582.2 [M+H]+. JH NMR (400 MHz, Methanol-^) 8 8.78 - 8.72 (m, 2H), 8.59 (s, 1H), 8.15 - 8.08 (m, 2H), 7.93 - 7.85 (m, 2H), 7.64 (s, 1H), 7.36 (s, 1H), 7.28 - 7.19 (m, 2H), 3.54 (s, 4H), 3.44 (s, 4H), 3.33 (s, 2H), 3.35 (s, 2H) 1.98 - 1.85 (m, 4H).
[000793] Synthesis of 7V-(5-chloro-2-fluoro-3-ll-[2-fluoro-4-(DiDerazin-l-yl)phenyl]- 3-(Dyridin-4-yl)Dyrazol-4-vnphenyl)methanesulfonamide trifluoroacetic acid salt (4)
[000794] Step-1 Synthesis of tert-butyl 4-(4-14-[5-chloro-2-fluoro-3- methanesulfonylmethanesulfonamido)Dhenyl]-3-(Dyridin-4-yl)Dyrazol-l-yn-3- fluoroDhenyl)Diperazine-l-carboxylate (2)
[000795] To a mixture of tert-butyl 4-{4-[4-(3-amino-5-chloro-2-fluorophenyl)-3- (pyridin-4-yl)pyrazol-l-yl]-3-fluorophenyl}piperazine-l-carboxylate (400 mg, 0.705 mmol, 1 equiv) and pyridine (837 mg, 10.575 mmol, 15 equiv) in DCM (10 mL) was added methanesulfonic anhydride (737 mg, 4.23 mmol, 6 equiv) at 0 °C. The resulting mixture was stirred at room temperature for one hour. The resulting mixture was then extracted with CH2Q2. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in tert-butyl 4-(4- { 4- [5 -chloro-2-fluoro-3 -(A-methanesulfonylmethanesulfonami do)phenyl] -3 -(pyridin-4- yl)pyrazol-l-yl}-3-fluorophenyl)piperazine-l-carboxylate (385 mg, crude) as a yellow solid. LCMS: C31H33CIF2N6O6S2 requires: 722.2, found: m/z = 723.2 [M+H]+.
[000796] Step-2 Synthesis of tert-butyl 4-14-[4-(5-chloro-2-fluoro-3- methanesulfonamidophenyl)-3-(pyridin-4-yl)pyrazol-l-yl]-3-fluorophenyl}piperazine-l- carboxylate (3)
[000797] To a mixture of tert-butyl 4-(4-{4-[5-chloro-2-fluoro-3-(7V- methanesulfonylmethanesulfonamido)phenyl]-3-(pyridin-4-yl)pyrazol-l-yl}-3- fluorophenyl)piperazine-l -carboxylate (375 mg, 0.519 mmol, 1 equiv) in THF (5 mL) and MeCN (5 mL) was added Na2CO3 (824 mg, 7.785 mmol, 15 equiv) in H2O (5 mL). The resulting mixture was stirred at 50 °C overnight. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (E4) to afford tert-butyl 4-{4-[4-(5-chloro-2-fluoro-3- methanesulfonamidophenyl)-3-(pyridin-4-yl)pyrazol-l-yl]-3-fluorophenyl}piperazine-l- carboxylate (250 mg, 74.74%) as an off-white solid. LCMS: C30H31CIF2N6O4S requires: 644.2, found: m/z = 645.2 [M+H]+.
[000798] Step-3 Synthesis of A-(5-chloro-2-fluoro-3-H-[2-fluoro-4-(piperazin-l- yl)phenyl]-3-(pyridin-4-yl)pyrazol-4-vnphenyl)methanesulfonamide trifluoroacetic acid salt (4)
[000799] To a mixture of tert-butyl 4-{4-[4-(5-chloro-2-fluoro-3- methanesulfonamidophenyl)-3-(pyridin-4-yl)pyrazol-l-yl]-3-fluorophenyl}piperazine-l- carboxylate (380 mg, 0.589 mmol, 1 equiv) in DCM (9 mL) was added TFA (3 mL) at 0 °C. The resulting mixture was stirred at room temperature for one hour. The resulting mixture was then concentrated under reduced pressure and subjected to lyophilization. This resulted in N- (5-chloro-2-fluoro-3-{ l-[2-fluoro-4-(piperazin-l-yl)phenyl]-3-(pyridin-4-yl)pyrazol-4- yl}phenyl)methanesulfonamide trifluoroacetic acid salt (390.8 mg, crude) as a yellow solid. LCMS: C25H23CIF2N6O2S requires: 544.1, found: m/z = 545.2 [M+H]+. 'H NMR (400 MHz, Methanol-^) 6 8.77 - 8.71 (m, 2H), 8.40 (s, 1H), 8.11 - 8.05 (m, 2H), 7.85 (s, 1H), 7.62 (s, 1H), 7.40 (s, 1H), 7.15 - 7.02 (m, 2H), 3.59 (s, 4H), 3.43 (s, 4H), 3.08 (s, 3H).
[000800] Synthesis of 7V-(5-chloro-2-fluoro-3-n-[5-(DiDerazin-l-yl)Dyridin-2-yl]-3- (Dyridin-4-yl)Dyrazol-4-ynDhenyl)Dyrrolidine-l-sulfonamide trifluoroacetic acid salt (3) [000801 ] Step-1: Synthesis of tert-butyl 4-[6-(4-f5-chloro-2-fluoro-3-[(pyrrolidine-l- sulfonyl)amino]phenvn-3-(pyridin-4-yl)pyrazol-l-yl)pyridin-3-yl]piperazine-l- carboxylate (2)
[000802] To a mixture of A-[5-chloro-2-fluoro-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]pyrrolidine-l -sulfonamide (1 g, 2.472 mmol, 3 equiv) and tert-butyl 4-{6-[4-bromo-3-(pyridin-4-yl)pyrazol-l-yl]pyridin-3-yl}piperazine-l-carboxylate (400 mg, 0.824 mmol, 1 equiv) in dioxane (10 mL) was added CsF (83.87 mg, 0.552 mmol, 0.67 equiv) in H2O (2 mL) and Pd(AMPHOS)2Ch (58.35 mg, 0.082 mmol, 0.1 equiv). The resulting mixture was stirred at 90 °C for 1 h under a nitrogen atmosphere. The resulting mixture was then concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 : 1) to afford tert-butyl 4-[6-(4-{5-chloro-2-fluoro-3- [(pyrrolidine-l-sulfonyl)amino]phenyl}-3-(pyridin-4-yl)pyrazol-l-yl)pyridin-3-yl]piperazine-
1 -carboxylate (600 mg, 35.52%) as a yellow solid. LCMS: C32H36CIFN8O4S requires: 682.2, found: m/z = 683.2 [M+H]+.
[000803] Step-2: Synthesis of A-(5-chloro-2-fluoro-3-H-[5-(piperazin-l-yl)pyridin-
2-yl]-3-(pyridin-4-yl)pyrazol-4-vnphenyl)pyrrolidine-l-sulfonamide trifluoroacetic acid salt (3)
[000804] To a mixture of tert-butyl 4-[6-(4-{5-chloro-2-fluoro-3-[(pyrrolidine-l- sulfonyl)amino]phenyl } -3 -(pyridin-4-yl)pyrazol-l-yl)pyri din-3 -yl]piperazine-l -carboxylate (590 mg, 0.864 mmol, 1 equiv) in DCM (9 mL) was added TFA (3 mL) at 0 °C. The resulting mixture was stirred at 0 °C for one hour. The resulting mixture was then concentrated under vacuum. The residue was purified by reverse phase flash chromatography eluted with ACbFEhO (1 : 1) to afford A-(5-chloro-2-fluoro-3-{ l-[5-(piperazin-l-yl)pyridin-2-yl]-3- (pyridin-4-yl)pyrazol-4-yl}phenyl)pyrrolidine-l-sulfonamide trifluoroacetic acid salt (509.1 mg, 84.06%) as a yellow solid. LCMS: C27H28CIFN8O2S requires: 582.1, found: m/z = 583.2 [M+H]+. 'HNMR (400 MHz, Methanol-^) 5 8.84 (s, 1H), 8.77 - 8.71 (m, 2H), 8.29 (s, 1H), 8.10 - 8.02 (m, 3H), 7.73 (s, 1H), 7.64 (s, 1H), 7.32 (s, 1H), 3.76 (s, 4H), 3.59 (s, 4H), 3.46 (s, 2H), 3.33 (s, 2H), 1.98 - 1.85 (m, 4H).
[000805] Synthesis of A-(2.,5-difluoro-3-H-[4-(piperazin-l-yl)phenyl]-3-(pyridin-4- yl)pyrazol-4-yl}phenyl)pyrrolidine-l-sulfonamide trifluoroacetic acid salt (5)
[000806] Step-1: Synthesis of 7V-(3-bromo-2.,5-difluorophenyl)pyrrolidine-l- sulfonamide (2)
[000807] To a mixture of 3-bromo-2,5-difluoroaniline (2.5 g, 12.019 mmol, 1 equiv) and pyrrolidine- 1 -sulfonyl chloride (4.08 g, 24.038 mmol, 2 equiv) in pyridine (4 mL) was added DMAP (1.76 g, 14.423 mmol, 1.2 equiv). The resulting mixture was stirred at 40 °C for 2 days under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (5: 1) to afford /'/-(3-bromo-2,5-difluorophenyl)pyrrolidine- l -sulfonamide (2.8 g, 54.63%) as a white solid. LCMS: CioHnBrF2N202S requires: 340.0, found: m/z = 341.1 [M+H]+.
[000808] Step-2: Synthesis of 7V-[2.,5-difluoro-3-(4.,4.,5.,5-tetramethyl-l.,3.,2- dioxaborolan-2-yl)phenyl] pyrrolidine-l-sulfonamide (3) [000809] To a mixture of 7V-(3-bromo-2,5-difluorophenyl)pyrrolidine-l-sulfonamide (500 mg, 1.466 mmol, 1 equiv) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-l,3,2-dioxaborolane (B2Pin2) (744 mg, 2.932 mmol, 2 equiv) in 1,4- dioxane (10 mL) was added Pd(dppf)C12 (120 mg, 0.147 mmol, 0.1 equiv) and KO Ac (288 mg, 2.932 mmol, 2 equiv). The resulting mixture was stirred at 90 °C overnight under a nitrogen atmosphere. The resulting mixture was then filtered. The filtrate was concentrated under reduced pressure. This resulted in A-[2,5-difhroro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)phenyl]pyrrolidine-l -sulfonamide (500 mg, 87.88%) as a black oil. LCMS: C16H23BF2N2O4S requires: 388.1, found: m/z = 389.2 [M+H]+.
[000810] Step-3: Synthesis of tert-butyl 4-[4-(4-(2.,5-difluoro-3-[(pyrrolidine-l- sulfonyl)amino]phenvn-3-(pyridin-4-yl)pyrazol-l-yl)phenyl]piperazine-l-carboxylate (4)
[000811] To a mixture of A-[2,5-difhroro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl]pyrrolidine-l -sulfonamide (500 mg, 1.29 mmol, 1 equiv) and tert-butyl 4-{4-[4- bromo-3-(pyridin-4-yl)pyrazol-l-yl]phenyl}piperazine-l-carboxylate (625 mg, 1.29 mmol, 1 equiv) in dioxane (10 mL) was added Pd(AMPHOS)2C12 (91 mg, 0.129 mmol, 0.1 equiv) and CsF (392 mg, 2.58 mmol, 2 equiv) in H2O (2 mL). The resulting mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (E4) to afford tert-butyl 4-[4-(4-{2,5-difluoro-3-[(pyrrolidine-l- sulfonyl)amino]phenyl } -3 -(pyridin-4-yl)pyrazol- 1 -yl)phenyl]piperazine- 1 -carboxylate (400 mg, 40.51%) as an off-white solid. LCMS: C33H37F2N7O4S requires: 665.3, found: m/z = 666.3 [M+H]+.
[000812] Step-4: Synthesis of A-(2.,5-difluoro-3-ll-[4-(piperazin-l-yl)phenyl]-3-
(pyridin-4-yl)pyrazol-4-vnphenyl)pyrrolidine-l-sulfonamide trifluoroacetic acid salt (5)
[000813] To a mixture of tert-butyl 4-[4-(4-{2,5-difhroro-3-[(pyrrolidine-l- sulfonyl)amino]phenyl } -3 -(pyridin-4-yl)pyrazol- 1 -yl)phenyl]piperazine- 1 -carboxylate (400 mg, 0.601 mmol, 1 equiv) in DCM (9 mL) was added TFA (3 mL) at 0 °C. The resulting mixture was stirred at room temperature for one hour. The resulting mixture was then concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography eluted with ACbkEhO (1 :4) to afford A-(2,5-difluoro-3-{ l-[4-(piperazin-l - yl)phenyl]-3-(pyridin-4-yl)pyrazol-4-yl}phenyl)pyrrolidine-l-sulfonamide trifluoroacetic acid salt (212.6 mg, 51.70%) as a yellow solid. LCMS: C28H29F2N7O2S requires: 565.2, found: m/z = 566.3 [M+H]+. 'HNMR (400 MHz, Methanol-^) 6 8.79 - 8.69 (m, 2H), 8.57 (s, 1H), 8.13 - 8.03 (m, 2H), 7.95 - 7.86 (m, 2H), 7.48 - 7.37 (m, 1H), 7.30 - 7.20 (m, 2H), 7.14 - 7.03 (m, 1H), 3.60 - 3.49 (m, 4H), 3.44 (m, 4H), 3.35 (m, 2H), 3.31 (m, 2H), 2.06 - 1.80 (m, 4H).
[000814] Synthesis of -Az-(5-chloro-2-fluoro-3-H-[4-(DiDerazin-l-yl)Dhenyl]-3- (Dyridin-4-yl)Dyrazol-4-ynDhenyl)-3-fluoroDyrrolidine-l-sulfonamide trifluoroacetic acid salt (6)
[000815] Step-1: Synthesis of (37?)-3-fluoropyrrolidine-l-sulfonyl chloride (2)
[000816] To a mixture of (3R)-3 -fluoropyrrolidine hydrochloride (20 g, 159.274 mmol, 1 equiv) in DCM (400 mL) was added TEA (67 mL, 477.822 mmol, 3 equiv). To the above mixture was then added sulfonyl chloride (26 mL, 318.548 mmol, 2 equiv) in DCM (100 mL) dropwise over 30 min at -30 °C. The resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. The resulting mixture was then diluted with HC1 (I N) (300 mL). The resulting mixture was extracted with DCM. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in (3R)-3 -fluoropyrrolidine- 1 -sulfonyl chloride (20 g, crude) as a dark yellow solid. LCMS: C4H7CIFNO2S requires: 187.0, found: 188.6.
[000817] Step-2: Synthesis of (37?)-7V-(3-bromo-5-chloro-2-fluorophenyl)-3- fluoropyrrolidine-l-sulfonamide (3)
[000818] To a mixture of 3-bromo-5-chloro-2 -fluoroaniline hydrochloride (5 g, 19.163 mmol, 1 equiv) and (3R)-3 -fluoropyrrolidine- 1 -sulfonyl chloride (7.19 g, 38.326 mmol, 2 equiv) in pyridine (8 mL) was added DMAP (2.81 g, 22.996 mmol, 1.2 equiv). The resulting mixture was stirred at 40 °C for 2 days under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (5: 1) to afford (3A)-A-(3-bromo-5-chloro-2- fluorophenyl)-3 -fluoropyrrolidine- 1 -sulfonamide (5 g, 57.66%) as a brown solid. LCMS: CioHioBrClF2N202S requires: 373.9, found: m/z = 373.1 [M-H]'.
[000819] Step-3: Synthesis o -[5-chloro-2-fluoro-3-(4.,4.,5.,5-tetramethyl-l.,3.,2- dioxaborolan-2-yl)phenyl]-3-fluoropyrrolidine-l-sulfonamide (4)
[000820] To a mixture of (3A)-A-(3-bromo-5-chloro-2-fluorophenyl)-3- fluoropyrrolidine-1 -sulfonamide (2 g, 5.325 mmol, 1 equiv) and 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (B2Pin2) (2.7 g, 10.632 mmol, 2 equiv) in 1,4-dioxane (20 mL) was added Pd(dppf)C12 (434 mg, 0.533 mmol, 0.1 equiv) and KO Ac (1.05 g, 10.65 mmol, 2 equiv). The resulting mixture was stirred at 90 °C overnight under a nitrogen atmosphere. The resulting mixture was then filtered. The filtrate was concentrated under reduced pressure. This resulted in (3A)-A-[5-chloro-2-fluoro-3-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]-3-fluoropyrrolidine-l-sulfonamide (2 g, crude) as a black oil. LCMS: C16H22BCIF2N2O4S requires: 422.1, found: m/z = 423.2 [M+H]+. [000821 ] Step-4: Synthesis of tert-butyl 4-]4-[4-(5-chloro-2-fluoro-3-H(31?)-3- fluoropyrrolidin-l-ylsulfonyl]amino}phenyl)-3-(pyridin-4-yl)pyrazol-l- yllDhenynpiperazine-l-carboxylate (5)
[000822] To a mixture of tert-butyl 4-{4-[4-bromo-3-(pyridin-4-yl)pyrazol-l- yl]phenyl}piperazine-l-carboxylate (2.4 g, 4.955 mmol, 1 equiv) and (3A)-7V-[5-chloro-2- fluoro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]-3-fluoropyrrolidine-l- sulfonamide (2.09 g, 4.955 mmol, 1 equiv) in dioxane (40 mL) was added Pd(AMPHOS)2C12 (0.35 g, 0.496 mmol, 0.1 equiv) and CsF (1.51 g, 9.91 mmol, 2 equiv) in H2O (8 mL). The resulting mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 :2) to afford tert-butyl 4-{4-[4-(5-chloro-2- fluoro-3-{[(37?)-3-fluoropyrrolidin-l-ylsulfonyl]amino}phenyl)-3-(pyridin-4-yl)pyrazol-l- yl]phenyl}piperazine-l-carboxylate (1.1 g, 26.95%) as a yellow solid. LCMS: C33H36CIF2N7O4S requires: 699.2, found: m/z = 700.3 [M+H]+.
[000823] Step-5: Synthesis of (37?)-7V-(5-chloro-2-fluoro-3-]l-[4-(Diperazin-l- yl)phenyl]-3-(pyridin-4-yl)pyrazol-4-vnphenyl)-3-fluoropyrrolidine-l-sulfonamide trifluoroacetic acid salt (6)
[000824] To a mixture of tert-butyl 4-{4-[4-(5-chloro-2-fhioro-3-{[(3A)-3- fluoropyrrolidin-l-ylsulfonyl]amino}phenyl)-3-(pyridin-4-yl)pyrazol-l- yl]phenyl}piperazine-l-carboxylate (1.1 g, 1.571 mmol, 1 equiv) was added TFA (10 mL) at 0 °C. The resulting mixture was stirred at 0 °C for one hour. The resulting mixture was then concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography eluted with ACbFEhO (1 :4) to afford (3A)-A-(5-chloro-2-fhioro-3-{ l-[4- (piperazin- 1 -yl)phenyl]-3 -(pyridin-4-yl)pyrazol-4-yl }phenyl)-3 -fluoropyrrolidine- 1 - sulfonamide trifluoroacetic acid salt (1.0020 g, 87.71%) as a yellow solid. LCMS: C28H28CIF2N7O2S requires: 599.2, found: m/z = 600.2 [M+H]+. 'HNMR (400 MHz, Methanol- tZ4) 5 8.74 - 8.67 (m, 2H), 8.54 (s, 1H), 8.04 - 7.96 (m, 2H), 7.92 - 7.84 (m, 2H), 7.72 - 7.64 (m, 1H), 7.37 - 7.31 (m, 1H), 7.28 - 7.19 (m, 2H), 5.28 (m, 1H), 3.66 - 3.49 (m, 7H), 3.49 - 3.38 (m, 5H), 2.33 - 1.98 (m, 2H).
[000825] Synthesis of (31?)-A-[5-chloro-2-fluoro-3-(l-]4-[(31?)-3-methylpiperazin-l- yl]phenvn-3-(pyridin-4-yl)pyrazol-4-yl)phenyl]-3-fluoropyrrolidine-l-sulfonamide trifluoroacetic acid salt (6)
p [000826] Step-1: Synthesis of tert-butyl -4-(4-bromophenyl)-2- methylpiperazine-l-carboxylate (2)
[000827] To a mixture of 4-bromoiodobenzene (10 g, 35.347 mmol, 1 equiv) and tertbutyl (2A)-2-methylpiperazine-l -carboxylate (8.5 g, 42.416 mmol, 1.2 equiv) in 1,4-dioxane (150 mL) was added Pd2(dba)s (1.6 g, 1.767 mmol, 0.05 equiv), Xantphos (2.1 g, 3.535 mmol, 0.1 equiv), and CS2CO3 (17.3 g, 53.020 mmol, 1.5 equiv). The resulting mixture was stirred at 90 °C overnight under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography eluted with PE:EtOAc (5: 1) to afford tert-butyl (2/?)-4-(4-bromophenyl)-2-methylpiperazine- l - carboxylate (3 g, 23.89%) as a brown solid. LCMS: CieEfeBr^CE requires: 354.0, found: m/z = 355.2 [M+H]+.
[000828] Step-2: Synthesis of tert-butyl -2-methyl-4-[4-(4.,4.,5.,5-tetramethyl- l,3.,2-dioxaborolan-2-yl)phenyl]piperazine-l-carboxylate (3):
[000829] To a mixture of tert-butyl (2A)-4-(4-bromophenyl)-2-methylpiperazine-l- carboxylate (3 g, 8.444 mmol, 1 equiv) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-l,3,2-dioxaborolane (E^Pim) (4.3 g, 16.888 mmol, 2 equiv) in 1,4-dioxane (35 mL) was added Pd(dppf)C12 (0.7 g, 0.844 mmol, 0.1 equiv) and KO Ac (1.7 g, 16.888 mmol, 2 equiv). The resulting mixture was stirred at 90 °C overnight under a nitrogen atmosphere. The resulting mixture was then filtered. The filtrate was concentrated under reduced pressure. This resulted in tert-butyl (2A)-2-methyl-4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl]piperazine-l -carboxylate (3 g, crude) as a brown solid. LCMS: C22H35BN2O4 requires: 402.2, found: m/z = 403.2 [M+H]+.
[000830] Step-3: Synthesis of tert-butyl -4-14-[4-bromo-3-(pyridin-4-yl)pyrazol- l-yl]phenvn-2-methylpiperazine-l-carboxylate (4)
[000831 ] To a mixture of tert-butyl (2A)-2-methyl-4-[4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]piperazine-l -carboxylate (3 g, 7.456 mmol, 1 equiv) and 4-(4- bromo-17/-pyrazol-3-yl)pyridine (2 g, 8.947 mmol, 1.2 equiv) in pyridine (40 mL) was added CU(OAC)2 (2.7 g, 14.912 mmol, 2 equiv) and molecular sieves (4A) (3 g). The resulting mixture was stirred at 100 °C overnight under an oxygen atmosphere. The resulting mixture was then extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (3 :2) to afford tert-butyl (2A)-4-{4-[4-bromo-3-(pyridin-4-yl)pyrazol-l-yl]phenyl}-2-methylpiperazine-l- carboxylate (900 mg, 21.80%) as an orange oil. LCMS: C24H28BrNsO2 requires: 497.1, found: m/z = 498.1 [M+H]+.
[000832] Step-4: Synthesis of tert-butyl (27?)-4-14-[4-(5-chloro-2-fluoro-3-H(31?)-3- fluoropyrrolidin-l-ylsulfonyl]amino}phenyl)-3-(pyridin-4-yl)pyrazol-l-yl]phenvn-2- methylpiperazine-l-carboxylate (5)
[000833] To a mixture of tert-butyl (2A)-4-{4-[4-bromo-3-(pyridin-4-yl)pyrazol-l- yl]phenyl}-2-methylpiperazine-l -carboxylate (900 mg, 1.806 mmol, 1 equiv) and (3R)-N-[5- chloro-2-fluoro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]-3-fluoropyrrolidine- 1-sulfonamide (763 mg, 1.806 mmol, 1 equiv) in dioxane (15 mL) was added Pd(AMPHOS)2C12 (128 mg, 0.181 mmol, 0.1 equiv) and CsF (549 mg, 3.612 mmol, 2 equiv) in H2O (3 mL). The resulting mixture was stirred at 90 °C for one hour under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CFBChiEtOAc (5: 1) to afford tert-butyl (2A)-4- { 4- [4-(5 -chloro-2-fluoro-3 - { [(3 A)-3 -fluoropyrrolidin- 1 - ylsulfonyl]amino}phenyl)-3-(pyridin-4-yl)pyrazol-l-yl]phenyl}-2-methylpiperazine-l- carboxylate (460 mg, 19.62%) as a brown solid. LCMS: C34H38CIF2N7O4S requires: 713.2, found: m/z = 714.2 [M+H]+.
[000834] Step-5: Synthesis of (31?)-A-[5-chloro-2-fluoro-3-(l-14-[(31?)-3- methylpiperazin-l-yl]phenvn-3-(pyridin-4-yl)pyrazol-4-yl)phenyl]-3-fluoropyrrolidine- 1-sulfonamide trifluoroacetic acid salt (6)
[000835] A mixture of tert-butyl (2A)-4-{4-[4-(5-chloro-2-fluoro-3-{[(3A)-3- fluoropyrrolidin-l-ylsulfonyl]amino}phenyl)-3-(pyridin-4-yl)pyrazol-l-yl]phenyl}-2- methylpiperazine- 1 -carboxylate (600 mg, 0.840 mmol, 1 equiv) in TFA (6 mL) was stirred at room temperature for one hour. The resulting mixture was then concentrated under reduced pressure. The crude product was purified by prep-HPLC with the following conditions: Column: Xcelect CSH F-pheny OBD Column 19 x 250 mm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 35% B to 50% B in 15 min; Wave Length: 254/220 nm to afford (3A)-A-[5-chloro-2-fluoro-3-(l-{4-[(3A)-3-methylpiperazin-l- yl]phenyl} -3 -(pyridin-4-yl)pyrazol-4-yl)phenyl]-3 -fluoropyrrolidine- 1-sulfonamide trifluoroacetic acid salt (136.2 mg, 20.04%) as a yellow solid. LCMS: C29H30CIF2N7O2S requires: 613.1, found: m/z = 614.2 [M+H]+. 'HNMR (400 MHz, Methanol-^) 8 8.73 - 8.67 (m, 2H), 8.57 - 8.52 (m, 1H), 8.05 - 7.99 (m, 2H), 7.93 - 7.85 (m, 2H), 7.71 - 7.64 (m, 1H), 7.37 - 7.31 (m, 1H), 7.27 - 7.20 (m, 2H), 5.37 - 5.18 (m, 1H), 3.99 - 3.86 (m, 2H), 3.68 - 3.34 (m, 4H), 3.38 - 3.33 (m, 3H), 3.14 - 3.06 (m, 1H), 2.95 - 2.84 (m, 1H), 2.30 - 2.03 (m, 2H), 1.48 - 1.42 (m, 3H).
[000836] Synthesis of (3/?)-\-|5-cliloro-2-niioro-3-(l-!5-|(3/?)-3-iiiethylpiper:izin-l- yl]pyridin-2-yl}-3-(pyridin-4-yl)pyrazol-4-yl)phenyri-3-fluoropyrrolidine-l-sulfonamide trifluoroacetic acid salt (5)
°C
[000837] Step-1: Synthesis of tert-butyl (21?)-4-(6-bromopyridin-3-yl)-2- methylpiperazine-l-carboxylate (2)
[000838] To a mixture of 2-bromo-5-iodopyridine (18.3 g, 64.410 mmol, 1.29 equiv) and tert-butyl (27?)-2-m ethylpiperazine- 1 -carboxylate (10 g, 49.930 mmol, 1 equiv) in toluene (200 mL) was added Z-BuONa (14.4 g, 149.790 mmol, 3 equiv), Xantphos (3.47 g, 5.992 mmol, 0.12 equiv), and Pd2(dba)s (2.3 g, 2.497 mmol, 0.05 equiv). The resulting mixture was stirred at 110 °C for 2 h under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (4: 1) to afford tert-butyl (27?)-4-(6-brom opyri din-3 -yl)-2-m ethylpiperazine- 1- carboxylate (11 g, 55.6%) as a yellow solid. LCMS: CisEfoBrNsCE requires: 355.0, found: m/z = 356.1 [M+H]+.
[000839] Step-2: Synthesis of tert-butyl -4-I6-[4-bromo-3-(pyridin-4-yl)pyrazol-
1-yl]pyridin-3-vn-2-methylpiperazine-l-carboxylate (3)
[000840] To a mixture of tert-butyl (27?)-4-(6-brom opyri din-3 -yl)-2-m ethylpiperazine- 1- carboxylate (6 g, 16.888 mmol, 1 equiv) and 4-(4-bromo-177-pyrazol-3-yl)pyridine (5.7 g, 25.332 mmol, 1.5 equiv) in DMF (80 mL) was added K2CO3 (7.0 g, 50.664 mmol, 3 equiv), TMEDA (0.79 g, 6.755 mmol, 0.4 equiv), and Cui (640 mg, 3.378 mmol, 0.2 equiv). The resulting mixture was stirred at 120 °C overnight under a nitrogen atmosphere. The resulting mixture was then extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 :3) to afford tert-butyl (2A)-4-{6-[4-bromo-3-(pyridin-4-yl)pyrazol-l-yl]pyridin-3-yl}-2- m ethylpiperazine- 1 -carboxylate (5 g, 53.35%) as a brown solid. LCMS: C23H27BrNeO2 requires: 498.1, found: m/z = 499.2 [M+H]+.
[000841 ] Step-3: Synthesis of tert-butyl (27?)-4-I6-[4-(5-chloro-2-fluoro-3-H(31?)-3- fluoropyrrolidin-l-ylsulfonyl]amino}phenyl)-3-(pyridin-4-yl)pyrazol-l-yl]pyridin-3-vB-
2-methylpiperazine-l-carboxylate (4):
[000842] To a mixture of tert-butyl (2A)-4-{6-[4-bromo-3-(pyridin-4-yl)pyrazol-l- yl]pyridin-3-yl}-2-methylpiperazine-l -carboxylate (1.2 g, 2.403 mmol, 1 equiv) and (3R)-N- [5-chl oro-2 -fluoro-3-(4, 4,5, 5-tetramethyl- 1,3, 2-di oxaborolan-2-yl)phenyl]-3- fluoropyrrolidine-1 -sulfonamide (3.1 g, 7.209 mmol, 3 equiv) in dioxane (15 mL) was added Pd(AMPHOS)2C12 (170 mg, 0.240 mmol, 0.1 equiv) and CsF (730 mg, 4.806 mmol, 2 equiv) in H2O (3 mL). The resulting mixture was stirred at 90 °C for 1 h under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (3: 1) to afford tert-butyl (2A)-4- {6-[4-(5-chloro-2-fluoro-3-{[(3A)-3-fluoropyrrolidin-l-ylsulfonyl]amino}phenyl)-3-(pyridin- 4-yl)pyrazol-l-yl]pyri din-3 -yl}-2-methylpiperazine-l -carboxylate (690 mg, 35.33%) as a yellow solid. LCMS: C33H37CIF2N8O4S requires: 714.2, found: m/z = 715.2 [M+H]+.
[000843] Step-4: Synthesis of (3/?)-.\-|5-chloro-2-nuoro-3-(l-!5-|(3/?)-3- methylDiDerazin-l-yl]Dyridin-2-yn-3-(Dyridin-4-yl)Dyrazol-4-yl)Dhenyl]-3- fluoropyrrolidine-l-sulfonamide trifluoroacetic acid salt (5)
[000844] A mixture of tert-butyl (2A)-4-{6-[4-(5-chloro-2-fluoro-3-{[(3A)-3- fluoropyrrolidin-l-ylsulfonyl]amino}phenyl)-3-(pyridin-4-yl)pyrazol-l-yl]pyridin-3-yl}-2- methylpiperazine- 1 -carboxylate (680 mg, 0.951 mmol, 1 equiv) in TFA (7 mL) was stirred at 0 °C for one hour. The resulting mixture was then concentrated under reduced pressure. The residue was purified by C18 reverse phase flash chromatography eluted with ACbFEhO (4: 1) to afford (3 R)-N- [5 -chloro-2-fluoro-3 -( 1 - { 5 - [(3 R)-3 -methylpiperazin- 1 -yl]pyridin-2-yl } -3 - (pyridin-4-yl)pyrazol-4-yl)phenyl]-3 -fluoropyrrolidine- 1 -sulfonamide trifluoroacetic acid salt (427.6 mg, 59.09%) as a yellow solid. LCMS: C28H29CIF2N8O2S requires: 614.1, found: m/z = 615.1 [M+H]+. 'HNMR (300 MHz, Methanol-^) 8 8.86 - 8.80 (m, 1H), 8.79 - 8.71 (m, 2H),
8.33 - 8.26 (m, 1H), 8.16 - 8.04 (m, 3H), 7.79 - 7.65 (m, 2H), 7.37 - 7.29 (m, 1H), 5.40 - 5.34 (m, 1H), 4.05 - 3.90 (m, 2H), 3.65 - 3.35 (m, 7H), 3.26 - 3.11 (m, 1H), 3.03 - 2.89 (m, 1H),
2.33 - 1.98 (m, 2H), 1.50 - 1.41 (m, 3H).
[000845] Synthesis of (3/?)-\-(5-cliloro-2-niioro-3-!l-|5-(i)ii)cr:izin-l-yl)pyridin-2- yl]-3-(Dyridin-4-yl)Dyrazol-4- -3-fluoroDyrrolidine-l-sulfonamide trifluoroacetic acid salt (3)
[000846] Step-1: Synthesis of tert-butyl 4-16-[4-(5-chloro-2-fluoro-3-H(31?)-3- fluoropyrrolidin-l-ylsulfonyl]amino}phenyl)-3-(pyridin-4-yl)pyrazol-l-yl]pyridin-3- yllpiperazine-l-carboxylate (2)
[000847] To a mixture of (3A)-A-[5-chloro-2-fluoro-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]-3-fluoropyrrolidine-l-sulfonamide (1.9 g, 4.495 mmol, 1 equiv) and tert-butyl 4- { 6- [4-bromo-3 -(pyridin-4-yl)pyrazol - 1 -yl]pyri din-3 -yl } piperazine- 1 - carboxylate (2.2 g, 4.495 mmol, 1 equiv) in dioxane (30 mL) was added CsF (1.37 g, 8.99 mmol, 2 equiv) in H2O (6 mL) and Pd(AMPHOS)2C12 (0.32 g, 0.449 mmol, 0.1 equiv). The resulting mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. The resulting mixture was then concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 :3) to afford tert-butyl 4-{6-[4-(5-chloro-2-fluoro-3- {[(3A)-3-fluoropyrrolidin-l-ylsulfonyl]amino}phenyl)-3-(pyridin-4-yl)pyrazol-l-yl]pyridin- 3 -yl (piperazine- 1 -carboxylate (1.5 g, 45.21%) as an off-white solid. LCMS: C32H35CIF2N8O4S requires: 700.2, found: m/z = 701.2 [M+H]+.
[000848] Step-2: Synthesis of (31?)-A-(5-chloro-2-fluoro-3-ll-[5-(piperazin-l- yl)pyridin-2-yl]-3-(pyridin-4-yl)pyrazol-4-vnphenyl)-3-fluoropyrrolidine-l-sulfonamide trifluoroacetic acid salt (3)
[000849] A mixture of tert-butyl 4-{6-[4-(5-chloro-2-fluoro-3-{[(3A)-3-fluoropyrrolidin- l-ylsulfonyl]amino}phenyl)-3-(pyridin-4-yl)pyrazol-l-yl]pyridin-3-yl}piperazine-l- carboxylate (1 g, 1.426 mmol, 1 equiv) in TFA (10 mL) was stirred at 0 °C for 2 h. The resulting mixture was then concentrated under vacuum. The residue was purified by reverse phase flash chromatography eluted with ACbTFhO (1 :4) to afford (3A)-A-(5-chloro-2-fluoro- 3-{ l-[5-(piperazin-l-yl)pyridin-2-yl]-3-(pyridin-4-yl)pyrazol-4-yl}phenyl)-3- fluoropyrrolidine-1 -sulfonamide trifluoroacetic acid salt (468.7 mg, 53.04%) as a yellow solid. LCMS: C27H27CIF2N8O2S requires: 600.2, found: m/z = 601.1 [M+H]+. *H NMR (400 MHz, Methanol-t/4) 8 8.81 (s, 1H), 8.76 - 8.68 (m, 2H), 8.31 - 8.25 (m, 1H), 8.13 - 8.06 (m, 3H), 7.76 - 7.63 (m, 2H), 7.35 - 7.27 (m, 1H), 5.39 - 5.17 (m, 1H), 3.65 - 3.48 (m, 7H), 3.47 - 3.37 (m, 5H), 2.31 - 1.94 (m, 2H).
[000850] Synthesis of \-|5-cliloro-2-niioro-3-(l-!4-|(3/?)-3-iiiethylpiper:izin-l- yl]phenvn-3-(pyridin-4-yl)pyrazol-4-yl)phenyl]pyrrolidine-l-sulfonamide trifluoroacetic acid salt (3)
[000851] Step-1: Synthesis of tert-butyl (21?)-4-[4-(4-]5-chloro-2-fluoro-3-
[(pyrrolidine-l-sulfonyl)amino]phenvn-3-(pyridin-4-yl)pyrazol-l-yl)phenyl]-2- methylpiperazine-l-carboxylate (2)
[000852] To a mixture of tert-butyl (27?)-4-{4-[4-bromo-3-(pyridin-4-yl)pyrazol-l- yl]phenyl}-2-methylpiperazine-l -carboxylate (500 mg, 1.003 mmol, 1 equiv) and 7V-[5-chloro- 2-fluoro-3-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)phenyl]pyrrolidine-l -sulfonamide (406 mg, 1.003 mmol, 1 equiv) in dioxane (15 mL) was added Pd(AMPHOS)2Ch (71 mg, 0.1 mmol, 0.1 equiv) and CsF (305 mg, 2.006 mmol, 2 equiv) in H2O (3 mL). The resulting mixture was stirred at 90 °C for one hour under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CFLCbiEtOAc (2: 1) to afford tert-butyl (2/?)-4-[4-(4-{ 5-chloro- 2-fluoro-3 -[(pyrrolidine- 1 -sulfonyl)amino]phenyl } -3 -(pyridin-4-yl)pyrazol- 1 -yl)phenyl]-2- m ethylpiperazine- 1 -carboxylate (300 mg, 30.07%) as a brown oil. LCMS: C34H39CIFN7O4S requires: 695.2, found: m/z = 696.2 [M+H]+.
[000853] Step-2: Synthesis of 7V-[5-chloro-2-fluoro-3-(l-]4-[(31?)-3-methylpiperazin- l-yl]phenvn-3-(pyridin-4-yl)pyrazol-4-yl)phenyl]pyrrolidine-l-sulfonamide trifluoroacetic acid salt (3) [000854] A mixture of tert-butyl (2A)-4-[4-(4-{5-chloro-2-fluoro-3-[(pyrrolidine-l- sulfonyl)amino]phenyl } -3 -(pyridin-4-yl)pyrazol- 1 -yl)phenyl]-2-methylpiperazine- 1 - carboxylate (280 mg, 0.402 mmol, 1 equiv) in TFA (3 mL) was stirred at 0 °C for one hour. The resulting mixture was then concentrated under reduced pressure. The crude product was purified by prep-HPLC with the following conditions: Column: Xselect CSH C18 OBD Column 30 x 150mm 5 pm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 5% B in 2 min, 10% B to 25% B in 15 min; Wave Length: 254/220 nm to afford A-[5-chloro-2-fluoro-3-(l-{4-[(3A)-3-methylpiperazin-l- yl]phenyl } -3 -(pyridin-4-yl)pyrazol-4-yl)phenyl]pyrrolidine-l -sulfonamide trifluoroacetic acid salt (188.8 mg, 22.73%) as a yellow solid. LCMS: C29H31CIFN7O2S requires: 595.1, found: m/z = 596.2 [M+H]+. 'H NMR (300 MHz, Methanol-^) 5 8.80 - 8.72 (m, 2H), 8.63 - 8.57 (m, 1H), 8.19 - 8.11 (m, 2H), 7.94 - 7.85 (m, 2H), 7.69 - 7.59 (m, 1H), 7.41 - 7.32 (m, 1H), 7.29 - 7.19 (m, 2H), 4.00 - 3.86 (m, 2H), 3.61 - 3.51 (m, 2H), 3.50 - 3.43 (m, 2H), 3.43 - 3.28 (m, 3H), 3.21 - 3.02 (m, 1H), 2.97 - 2.84 (m, 1H), 1.99 - 1.84 (m, 4H), 1.57 - 1.41 (m, 3H).
[000855] Synthesis of 7V-[5-chloro-2-fluoro-3-(l-]5 -methylDiDerazin-l- yl]Dyridin-2-yl}-3-(Dyridin-4-yl)Dyrazol-4-yl)DhenyriDyrrolidine-l-sulfonamide trifluoroacetic acid salt (3)
[(pyrrolidine-l-sulfonyl)amino]phenvn-3-(pyridin-4-yl)pyrazol-l-yl)pyridin-3-yl]-2- methylpiperazine-l-carboxylate (2)
[000857] To a mixture of tert-butyl (27?)-4-{6-[4-bromo-3-(pyridin-4-yl)pyrazol-l- yl]pyridin-3-yl}-2-methylpiperazine-l -carboxylate (700 mg, 1.402 mmol, 1 equiv) and 7V-[5- chloro-2-fluoro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]pyrrolidine-l- sulfonamide (567 mg, 1.402 mmol, 1 equiv) in dioxane (20 mL) was added Pd(AMPHOS)2C12 (99 mg, 0.140 mmol, 0.1 equiv) and CsF (430 mg, 2.804 mmol, 2 equiv) in H2O (4 mL). The resulting mixture was stirred at 90 °C for one hour under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CFLCbiEtOAc (2: 1) to afford tert-butyl (2/?)-4-[6-(4-[ 5- chloro-2-fluoro-3 -[(pyrrolidine- l-sulfonyl)amino]phenyl} -3 -(pyridin-4-yl)pyrazol-l- yl)pyridin-3-yl]-2-methylpiperazine-l-carboxylate (400 mg, 34.79%) as a brown solid. LCMS: C33H38CIFN8O4S requires: 696.2, found: m/z = 697.2 [M+H]+.
[000858] Step-2: Synthesis of 7V-[5-chloro-2-fluoro-3-(l-15-[ -3-methylpiperazin- l-yl]pyridin-2-vn-3-(pyridin-4-yl)pyrazol-4-yl)phenyl]pyrrolidine-l-sulfonamide trifluoroacetic acid salt (3) [000859] A mixture of tert-butyl (2A)-4-[6-(4-{5-chloro-2-fluoro-3-[(pyrrolidine-l- sulfonyl)amino]phenyl}-3-(pyridin-4-yl)pyrazol-l-yl)pyridin-3-yl]-2-methylpiperazine-l- carboxylate (390 mg, 0.559 mmol, 1 equiv) in TFA (4 mL) was stirred at room temperature for 2 h. The resulting mixture was then concentrated under reduced pressure. The crude product was purified by prep-HPLC with the following conditions: Column: XBridge Prep Phenyl OBD Columnl9 x 250 mm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 23% B to 33% B in 10 min; Wave Length: 254/297 nm to afford A-[5-chloro-2-fluoro-3-(l-{5-[(3A)-3-methylpiperazin-l-yl]pyridin-2-yl}-3-(pyri din-4- yl)pyrazol-4-yl)phenyl]pyrrolidine-l -sulfonamide trifluoroacetic acid salt (246.8 mg, 60.49%) as a yellow solid. LCMS: C28H30CIFN8O2S requires: 596.1, found: m/z = 597.2 [M+H]+. JH NMR (300 MHz, Methanol-^) 5 8.88 - 8.82 (m, 1H), 8.81 - 8.73 (m, 2H), 8.33 - 8.27 (m, 1H), 8.16 - 8.06 (m, 3H), 7.80 - 7.70 (m, 1H), 7.69 - 7.60 (m, 1H), 7.38 - 7.29 (m, 1H), 4.05 - 3.90 (m, 2H), 3.59 - 3.53 (m, 2H), 3.46 - 3.35 (m, 3H), 3.34 - 3.28 (m, 2H), 3.26 - 3.09 (m, 1H), 3.03 - 2.89 (m, 1H), 1.99 - 1.86 (m, 4H), 1.56 - 1.42 (m, 3H).
[000860] Synthesis of A-(5-chloro-2-fluoro-3-H-[4-(DiDerazin-l-yl)Dhenyl]-3-
(Dyridin-4-yl)Dyrazol-4-ynDhenyl)cycloDentanesulfonamide trifluoroacetic acid salt (5)
[000861 ] Step-1: Synthesis of \-(3-bronio-5-chloro-2- fluorophenyDcyclopentanesulfonamide (2)
[000862] To a mixture of NaH (1 g, 26.730 mmol, 2 equiv, 60%) in THF (50 mL) was added 3-bromo-5-chloro-2-fluoroaniline (3 g, 13.365 mmol, 1 equiv). The resulting mixture was then stirred for one hour at 0 °C under a nitrogen atmosphere. To the above mixture was then added cyclopentanesulfonyl chloride (4.5 g, 26.730 mmol, 2 equiv) at 0 °C. The resulting mixture was then stirred at room temperature overnight under a nitrogen atmosphere. The reaction was then quenched by the addition of water at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:DCM (1 :3) to afford 7V-(3-bromo-5-chloro-2- fluorophenyl)cyclopentanesulfonamide (630 mg, 11.90%) as an off-white solid. LCMS: CiiHnBrCIFNChSrequires: 354.9, found: m/z = 354.1 [M-H]'.
[000863] Step-2: Synthesis of Az-[5-chloro-2-fluoro-3-(4.,4.,5.,5-tetramethyl-l.,3.,2- dioxaborolan-2-yl)phenyl] cyclopentanesulfonamide (3)
[000864] To a mixture of 7V-(3-bromo-5-chloro-2- fluorophenyl)cyclopentanesulfonamide (630 mg, 1.767 mmol, 1 equiv) and 4, 4, 5, 5- tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (B2?in2) (897 mg, 3.534 mmol, 2 equiv) in dioxane (10 mL) was added KO Ac (347 mg, 3.534 mmol, 2 equiv) and Pd(dppf)C12 (129.26 mg, 0.177 mmol, 0.1 equiv). The resulting mixture was stirred at 90 °C overnight under a nitrogen atmosphere. The resulting mixture was then filtered. The filtrate was concentrated under reduced pressure. This resulted in A-[5-chloro-2-fluoro-3- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]cyclopentanesulfonamide (600 mg, crude) as a black oil. LCMS: C17H24BCIFNO4S requires: 403.1, found: m/z = 404.2 [M+H]+.
[000865] Step-3: Synthesis of tert-butyl 4-(4-(4-(5-chloro-3-
(cvclopentanesulfonamido)-2-fluorophenyl)-3-(pyridin-4-yl)-lH-pyrazol-l- yl)phenyl)piperazine-l-carboxylate (4)
[000866] To a mixture of A-[5-chloro-2-fluoro-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]cyclopentanesulfonamide (600 mg, 1.486 mmol, 1 equiv) and tertbutyl 4-{4-[4-bromo-3-(pyridin-4-yl)pyrazol-l-yl]phenyl}piperazine-l-carboxylate (720 mg, 1.486 mmol, 1 equiv) in dioxane (10 mL) was added Pd(AMPHOS)2C12 (105 mg, 0.149 mmol, 0.1 equiv) and CsF (452 mg, 2.972 mmol, 2 equiv) in H2O (2 mL). The resulting mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CFBChiEtOAc (1 : 1) to afford tert-butyl 4-{4-[4-(5-chloro-3- cyclopentanesulfonamido-2-fluorophenyl)-3-(pyridin-4-yl)pyrazol-l-yl]phenyl}piperazine-l- carboxylate (200 mg, 17.78%) as an off-white solid. LCMS: C34H38CIFN6O4S requires: 680.2, found: m/z = 681.1 [M+H]+.
[000867] Step-4: Synthesis of A-(5-chloro-2-fluoro-3-ll-[4-(piperazin-l-yl)phenyl]-
3-(pyridin-4-yl)pyrazol-4-vnphenyl)cyclopentanesulfonamide trifluoroacetic acid salt (5)
[000868] A mixture of tert-butyl 4-{4-[4-(5-chloro-3-cyclopentanesulfonamido-2- fluorophenyl)-3-(pyridin-4-yl)pyrazol-l-yl]phenyl (piperazine- 1 -carboxylate (200 mg, 0.294 mmol, 1 equiv) in TFA (2 mL) was stirred at 0 °C for one hour. The resulting mixture was then concentrated under reduced pressure and lyophilized. This resulted in 7V-(5-chloro-2-fluoro-3- { l-[4-(piperazin-l-yl)phenyl]-3-(pyridin-4-yl)pyrazol-4-yl}phenyl)cyclopentanesulfonamide trifluoroacetic acid salt (126.1 mg, crude) as a yellow solid. LCMS: C29H30CIFN6O2S requires: 580.1, found: m/z = 581.2 [M+H]+. 'HNMR (400 MHz, Methanol-^) 8 8.78 - 8.72 (m, 2H), 8.62 - 8.58 (m, 1H), 8.17 - 8.11 (m, 2H), 7.94 - 7.86 (m, 2H), 7.71 - 7.63 (m, 1H), 7.46 - 7.39 (m, 1H), 7.28 - 7.20 (m, 2H), 3.72 - 3.59 (m, 1H), 3.58 - 3.50 (m, 4H), 3.47 - 3.40 (m, 4H), 2.09 - 1.91 (m, 4H), 1.83 - 1.78 (m, 2H), 1.69 - 1.65 (m, 2H).
[000869] Synthesis of rac-(21?)-7V-(5-chloro-2-fluoro-3-n-[4-(DiDerazin-l-yl)Dhenyl]- 3-(Dyridin-4-yl)Dyrazol-4-ynDhenyl)butane-2-sulfonamide trifluoroacetic acid salt (5)
[000870] Step-1: Synthesis of 7V-(3-bromo-5-chloro-2-fluorophenyr)butane-2- sulfonamide (2)
[000871] To a mixture of NaH (891 mg, 22.276 mmol, 2 equiv, 60%) in DMF (50 mL) was added 3-bromo-5-chloro-2-fluoroaniline (2.5 g, 11.138 mmol, 1 equiv). The resulting mixture was stirred at 0 °C for one hour under a nitrogen atmosphere. To the above mixture was added butane-2-sulfonyl chloride (3.5 g, 22.276 mmol, 2 equiv) at 0 °C. The resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. The reaction was then quenched with water at 0 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PEiCEECh (1 : 1) to afford A-(3-bromo-5-chloro- 2-fluorophenyl)butane-2-sulfonamide (650 mg, 15.24%) as a brown semi-solid. LCMS: CioHnBrClFNCES Srequires: 342.9, found: m/z = 342.0 [M-H]'.
[000872] Step-2: Synthesis of 7V-[5-chloro-2-fluoro-3-(4.,4.,5.,5-tetramethyl-l.,3.,2- dioxaborolan-2-yl)phenyl] butane-2-sulfonamide (3)
[000873] To a mixture of A-(3-bromo-5-chloro-2-fluorophenyl)butane-2-sulfonamide
(650 mg, 1.886 mmol, 1 equiv) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-l,3,2-dioxaborolane (B2Pin2) (958 mg, 3.772 mmol, 2 equiv) in dioxane (10 mL) was added Pd(dppf)C12 (138 mg, 0.189 mmol, 0.1 equiv) and KOAc (370 mg, 3.772 mmol, 2 equiv). The resulting mixture was stirred at 90 °C overnight under a nitrogen atmosphere. The resulting mixture was then filtered. The filtrate was concentrated under reduced pressure. This resulted in A-[5-chloro-2-fluoro-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]butane-2-sulfonamide (650 mg, crude) as a black oil. LCMS: C16H24BCIFNO4S requires: 391.1, found: m/z = 392.2 [M+H]+.
[000874] Step-3: Synthesis of tert-butyl 4-(4-]4-[3-(butane-2-sulfonamido)-5-chloro- 2-fluorophenyl]-3-(pyridin-4-yl)pyrazol-l-vnphenyl)piperazine-l-carboxylate (4)
[000875] To a mixture of A-[5-chloro-2-fluoro-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]butane-2-sulfonamide (650 mg, 1.659 mmol, 1 equiv) and tert-butyl 4-{4-[4-bromo-3-(pyridin-4-yl)pyrazol-l-yl]phenyl}piperazine-l-carboxylate (804 mg, 1.659 mmol, 1 equiv) in dioxane (10 mL) was added Pd(AMPHOS)2C12 (118 mg, 0.166 mmol, 0.1 equiv) and CsF (504 mg, 3.318 mmol, 2 equiv) in H2O (2 mL). The resulting mixture was stirred at 90 °C for one hour under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CthChiEtOAc (1 : 1) to afford tert-butyl 4-(4-{4-[3-(butane-2- sulfonamido)-5-chloro-2-fluorophenyl]-3 -(pyridin-4-yl)pyrazol- 1 -yl }phenyl)piperazine- 1 - carboxylate (250 mg, 20.94%) as an off-white solid. LCMS: C33H38CIFN6O4S requires: 668.2, found: m/z = 669.1 [M+H]+.
[000876] Step-4: Synthesis of rac-(21?)-7V-(5-chloro-2-fluoro-3-fl-[4-(DiDerazin-l- yl)Dhenyl]-3-(Dyridin-4-yl)Dyrazol-4-ynDhenyl)butane-2-sulfonamide trifluoroacetic acid salt (5)
[000877] A mixture of tert-butyl 4-(4-{4-[3-(butane-2-sulfonamido)-5-chloro-2- fluorophenyl]-3-(pyridin-4-yl)pyrazol-l-yl}phenyl)piperazine-l -carboxylate (250 mg, 0.374 mmol, 1 equiv) in TFA (3 mL) was stirred at 0 °C for one hour. The resulting mixture was then concentrated under reduced pressure and lyophilized. This resulted in rac-(2A)-A-(5-chloro-2- fluoro-3 - { 1 - [4-(piperazin- 1 -yl)phenyl]-3 -(pyridin-4-yl)pyrazol -4-yl } phenyl)butane-2- sulfonamide trifluoroacetic acid salt (151.9 mg, crude) as a yellow solid. LCMS: C28H30CIFN6O2S requires: 568.1, found: m/z = 569.2 [M+H]+. 'HNMR (400 MHz, Methanol- d4) 8 8.79 - 8.73 (m, 2H), 8.63 - 8.58 (m, 1H), 8.18 - 8.11 (m, 2H), 7.94 - 7.86 (m, 2H), 7.70
- 7.63 (m, 1H), 7.45 - 7.38 (m, 1H), 7.28 - 7.20 (m, 2H), 3.57 - 3.50 (m, 4H), 3.50 - 3.40 (m, 4H), 3.17 - 3.05 (m, 1H), 2.13 - 1.98 (m, 1H), 1.68 - 1.52 (m, 1H), 1.40 - 1.31 (m, 3H), 1.07
- 0.99 (m, 3H).
[000878] Synthesis of A-(5-chloro-2-fluoro-3-H-[4-(Diperazin-l-yl)Dhenyl]-3- (Dyridin-4-yl)Dyrazol-4- -3-fluoroazetidine-l-sulfonamide trifluoroacetic acid salt (6)
[000879] Step-1: Synthesis of 3-fluoroazetidine-l-sulfonyl chloride (2)
[000880] To a mixture of sulfonyl chloride (9.0 g, 67.240 mmol, 2.5 equiv) in ACN (60 mL) was added 3 -fluoroazetidine hydrochloride (3 g, 26.896 mmol, 1 equiv) and TEA (7.2 g, 71.274 mmol, 2.65 equiv) at 0 °C. The resulting mixture was stirred at 50 °C for 30 min. The resulting mixture was then filtered. The filtrate was concentrated under reduced pressure. This resulted in 3-fluoroazetidine-l-sulfonyl chloride (3 g, crude) as an off-white solid. LCMS: C3H5CIFNO2S requires: 172.9, found: m/z = 173.8 [M+H]+.
[000881] Step-2: Synthesis of /V-(3-bromo-5-chloro-2-fluorophenyl)-3- fluoroazetidine-l-sulfonamide (3)
[000882] To a mixture of NaH (400 mg, 16.706 mmol, 2 equiv) in THF (100 mL) was added 3-bromo-5-chloro-2-fluoroaniline (1.9 g, 8.353 mmol, 1 equiv) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 30 min under a nitrogen atmosphere. To the above mixture was added 3-fluoroazetidine-l-sulfonyl chloride (2.9 g, 16.706 mmol, 2 equiv) at 0 °C under a nitrogen atmosphere. The resulting mixture was then stirred at 50 °C overnight under a nitrogen atmosphere. The reaction was then quenched with saturated aqueous NH4CI at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (3 : 1) to afford N-(3- bromo-5-chloro-2-fluorophenyl)-3-fluoroazetidine-l-sulfonamide (500 mg, 13.24%) as a brown solid. LCMS: CgHsBrC^lSbCLS requires: 359.9, found: m/z = 358.9 [M-H]'.
[000883] Step-3: Synthesis of 7V-[5-chloro-2-fluoro-3-(4.,4.,5.,5-tetramethyl-l.,3.,2- dioxaborolan-2-yl)phenyl]-3-fluoroazetidine-l-sulfonamide (4)
[000884] To a mixture of A-(3-brorno-5-chloro-2-fluorophenyl)-3-fluoroazetidine-l- sulfonamide (450 mg, 1.245 mmol, 1 equiv) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (B2Pin2) (632 mg, 2.490 mmol, 2 equiv) in dioxane (10 mL) was added KOAc (244 mg, 2.490 mmol, 2 equiv) and Pd(dppf)C12 (101 mg, 0.125 mmol, 0.1 equiv). The resulting mixture was stirred at 90 °C overnight under a nitrogen atmosphere. The resulting mixture was then filtered. The filtrate was concentrated under reduced pressure. This resulted in A-[5-chloro-2-fluoro-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]-3-fluoroazetidine-l-sulfonamide (450 mg, crude) as a black oil. LCMS: C15H20BCIF2N2O4S requires: 408.1, found: m/z = 409.2 [M+H]+. [000885] Step-4: Synthesis of tert-butyl 4-[4-(4-]5-chloro-2-fluoro-3-[(3- flnoroazetidin-l-ylsnlfonyl)amino]phenvn-3-(pyridin-4-yl)pyrazol-l- yl)phenyl]piperazine-l-carboxylate (5)
[000886] To a mixture of A-[5-chloro-2-fluoro-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]-3-fluoroazetidine-l-sulfonamide (450 mg, 1.101 mmol, 3 equiv) and tert-butyl 4-{4-[4-bromo-3-(pyridin-4-yl)pyrazol-l-yl]phenyl}piperazine-l -carboxylate (178 mg, 0.367 mmol, 1 equiv) in dioxane (5 mL) was added CsF (112 mg, 0.734 mmol, 2 equiv) in H2O (1 mL) and Pd(AMPHOS)2C12 (26 mg, 0.037 mmol, 0.1 equiv). The resulting mixture was stirred at 90 °C for one hour under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CFLCbiEtOAc (3:2) to afford tert-butyl 4-[4-(4-{5-chloro-2- fluoro-3-[(3-fluoroazetidin-l-ylsulfonyl)amino]phenyl}-3-(pyridin-4-yl)pyrazol-l- yl)phenyl]piperazine-l -carboxylate (380 mg, 90.52%) as a black solid. LCMS: C32H34CIF2N7O4S requires: 685.2, found: m/z = 686.2 [M+H]+.
[000887] Step-5: Synthesis of A-(5-chloro-2-fluoro-3-H-[4-(piperazin-l-yl)phenyl]- 3-(pyridin-4-yl)pyrazol-4-vnphenyl)-3-fluoroazetidine-l-sulfonamide trifluoroacetic acid salt (6)
[000888] A mixture of tert-butyl 4-[4-(4-{5-chloro-2-fluoro-3-[(3-fluoroazetidin-l- ylsulfonyl)amino]phenyl } -3 -(pyridin-4-yl)pyrazol- 1 -yl)phenyl]piperazine- 1 -carboxylate (380 mg, 0.554 mmol, 1 equiv) in TFA (4 mL) was stirred at 0 °C for one hour. The resulting mixture was then concentrated under reduced pressure. The crude product was purified by prep-HPLC with the following conditions: Column: XSelect CSH Fluoro Phenyl 30 x 150 mm, 5 pm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 40% B in 12min; Wave Length: 254/220 nm to afford A-(5-chloro-2-fhioro-3-{ l-[4- (piperazin-l-yl)phenyl]-3-(pyridin-4-yl)pyrazol-4-yl}phenyl)-3-fluoroazetidine-l- sulfonamide trifluoroacetic acid salt (220.8 mg, 21.01%) as a yellow solid. LCMS: C27H26CIF2N7O2S requires: 585.2;, found: m/z = 586.1 [M+H]+. 'H NMR (400 MHz, Methanol-^) 8 8.74 - 8.68 (m, 2H), 8.59 - 8.54 (m, 1H), 8.05 - 7.99 (m, 2H), 7.94 - 7.84 (m, 2H), 7.68 - 7.61 (m, 1H), 7.42 - 7.35 (m, 1H), 7.27 - 7.19 (m, 2H), 5.40 - 5.30 (m, 1H), 4.24 - 4.11 (m, 2H), 4.08 - 3.94 (m, 2H), 3.57 - 3.50 (m, 4H), 3.50 - 3.40 (m, 4H).
[000889] Synthesis of ethylmethyl[(2.,5-difluoro-3-H-[4-(piperazin-l-yl)phenyl]-3- (pyridin-4-yl)pyrazol-4-vnphenyl)snlfamoyl] amine trifluoroacetic acid salt (5) [000890] Step-1: Synthesis of [(3-bromo-2.,5- difluoroDhenyl)sulfamoyl](ethyl)methylamine (2)
[000891] To a mixture of 3 -bromo-2, 5 -difluoroaniline (1.5 g, 7.211 mmol, 1 equiv) and A-ethyl-A-methylsulfamoyl chloride (2.84 g, 18.027 mmol, 2.5 equiv) in pyridine (2 mL) was added DMAP (1.06 g, 8.653 mmol, 1.2 equiv). The resulting mixture was stirred at 40 °C overnight under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE: EtOAc (5: 1) to afford [(3-bromo-2,5-difluorophenyl)sulfamoyl](ethyl)methylamine (1.4 g, 58.98%) as a brown yellow solid. LCMS: CgHnB^lShCLS requires: 328.0, found: m/z = 329.1 [M+H]+.
[000892] Step-2: Synthesis of ethylmethyll[2.,5-difluoro-3-(4.,4.,5.,5-tetramethyl-l.,3.,2- dioxaborolan-2-yl)phenyl]sulfamovn amine (3)
[000893] To a mixture of [(3-bromo-2,5-difluorophenyl)sulfamoyl](ethyl)methylamine
(700 mg, 2.127 mmol, 1 equiv) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-l,3,2-dioxaborolane (E^Pim) (1.08 g, 4.254 mmol, 2 equiv) in 1,4-dioxane (10 mL) was added Pd(dppf)C12 (156 mg, 0.213 mmol, 0.1 equiv) and KOAc (417 mg, 4.254 mmol, 2 equiv). The resulting mixture was stirred at 90 °C overnight under a nitrogen atmosphere. The resulting mixture was then filtered. The filtrate was concentrated under reduced pressure. This resulted in ethylmethyl{[2,5-difluoro-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl] sulfamoyl} amine (700 mg, crude) as a black oil. LCMS: C15H23BF2N2O4S requires: 376.1, found: m/z = 377.2 [M+H]+.
[000894] Step-3: Synthesis of tert-butyl 4-]4-[4-(3-][ethyl(methyl)sulfamoyl]amino}- 2,5-difluorophenyl)-3-(pyridin-4-yl)pyrazol-l-yl]phenyl}piperazine-l-carboxylate (4)
[000895] To a mixture of ethylmethyl{[2,5-difluoro-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl] sulfamoyl }amine_(649 mg, 1.724 mmol, 1 equiv) and tert-butyl 4- {4-[4-bromo-3-(pyridin-4-yl)pyrazol-l-yl]phenyl}piperazine-l-carboxylate (835 mg, 1.724 mmol, 1 equiv) in dioxane (25 mL) was added CsF (524 mg, 3.448 mmol, 2 equiv) in H2O (5 mL) and Pd(AMPHOS)2C12 (122 mg, 0.172 mmol, 0.1 equiv). The resulting mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. The resulting mixture was then concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with DCM:EtOAc (2:3) to afford tert-butyl 4-{4-[4-(3- {[ethyl(methyl)sulfamoyl]amino}-2,5-difluorophenyl)-3-(pyridin-4-yl)pyrazol-l- yl]phenyl}piperazine-l-carboxylate (0.55 g, 48.81%) as a yellow solid. LCMS: C32H37F2N7O4S requires: 653.3, found: m/z = 654.3 [M+H]+.
[000896] Step-4: Synthesis of ethylmethyl[(2.,5-difluoro-3-]l-[4-(DiDerazin-l- yl)Dhenyl]-3-(Dyridin-4-yl)Dyrazol-4-ynDhenyl)sulfamoyl]amine trifluoroacetic acid salt (5)
[000897] A mixture of tert-butyl 4-{4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2,5- difluorophenyl)-3-(pyridin-4-yl)pyrazol-l-yl]phenyl}piperazine-l-carboxylate (0.55 g, 0.841 mmol, 1 equiv) in TFA (5 mL) was stirred at 0 °C for one hour. The resulting mixture was then concentrated under reduced pressure and lyophilized. This resulted in ethylmethyl [(2,5 - difluoro-3-{ l-[4-(piperazin-l-yl)phenyl]-3-(pyridin-4-yl)pyrazol-4- yl}phenyl)sulfamoyl]amine trifluoroacetic acid salt (301.9 mg, crude) as a yellow solid. LCMS: C27H29F2N7O2S requires: 553.2, found: m/z = 554.2 [M+H]+. 'H NMR (400 MHz, Methanol-t/4) 8 8.79 - 8.73 (m, 2H), 8.62 - 8.57 (m, 1H), 8.18 - 8.12 (m, 2H), 7.95 - 7.86 (m, 2H), 7.42 - 7.32 (m, 1H), 7.28 - 7.20 (m, 2H), 7.14 - 7.05 (m, 1H), 3.57 - 3.50 (m, 4H), 3.47 - 3.40 (m, 4H), 3.33 - 3.23 (m, 2H), 2.87 - 2.83 (m, 3H), 1.20 - 1.11 (m, 3H)
[000898] Synthesis of ethylmethyl[(5-chloro-2-fluoro-3-H-[5-(Diperazin-l- yl)Dyridin-2-yl]-3-(Dyridin-4-yl)Dyrazol-4- sulfamoyl]amine trifluoroacetic acid salt (3)
[000899] Step-1: Synthesis of tert-butyl 4-]6-[4-(5-chloro-3- f|ethyl(methyl)sulfamoyl]amino}-2-flnorophenyl)-3-(pyridin-4-yl)pyrazol-l-yl]pyridin- 3-vnpiperazine-l-carboxylate (2)
[000900] To a mixture of ethylmethyl{[5-chloro-2-fluoro-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl] sulfamoyl} amine (1 g, 2.547 mmol, 1 equiv) and tert-butyl 4-{6-[4- bromo-3-(pyridin-4-yl)pyrazol-l-yl]pyri din-3 -yl} piperazine- 1 -carboxylate (1.2 g, 2.547 mmol, 1 equiv) in dioxane (20 mL) was added Pd(AMphos)2C12 (180 mg, 0.255 mmol, 0.1 equiv) and CsF (774 mg, 5.094 mmol, 2 equiv) in H2O (4 mL). The resulting mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CFLChiEtOAc (1 : 1) to afford tert-butyl 4-{6-[4-(5-chloro-3- {[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-3-(pyridin-4-yl)pyrazol-l-yl]pyridin-3- yl (piperazine- 1 -carboxylate (500 mg, 23.40%) as a brown semi-solid. LCMS: C31H36CIFN8O4S requires: 670.2, found: m/z = 671.3 [M+H]+.
[000901 ] Step-2: Synthesis of ethylmethyl[(5-chloro-2-fluoro-3-]l-[5-(piperazin-l- yl)pyridin-2-yl]-3-(pyridin-4-yl)pyrazol-4-vnphenyl)sulfamoyl]amine trifluoroacetic acid salt (3) [000902] A mixture of tert-butyl 4-{6-[4-(5-chloro-3-{[ethyl(methyl)sulfamoyl]amino}- 2-fluorophenyl)-3-(pyridin-4-yl)pyrazol-l-yl]pyridin-3-yl}piperazine-l-carboxylate (500 mg, 0.745 mmol, 1 equiv) in TFA (5 mL) was stirred for one hour at 0 °C. The resulting mixture was then concentrated under reduced pressure. The crude product was purified by prep-HPLC with the following conditions: Column: XBridge Prep Phenyl OBD Columnl9 x 250 mm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: MeOH; Flow rate: 25 mL/min; Gradient: 40% B to 55% B in 10 min; Wave Length: 254/220 nm to afford ethylmethyl [(5- chloro-2-fluoro-3-{ l-[5-(piperazin-l-yl)pyridin-2-yl]-3-(pyridin-4-yl)pyrazol-4- yl}phenyl)sulfamoyl]amine_trifluoroacetic acid salt (222.9 mg, 43.50%) as a yellow solid. LCMS: C26H28CIFN8O2S requires: 570.1, found: m/z = 571.2 [M+H]+. 'H NMR (400 MHz, Methanol-t/4) 8 8.88 - 8.84 (m, 1H), 8.81 - 8.75 (m, 2H), 8.33 - 8.27 (m, 1H), 8.21 - 8.07 (m, 3H), 7.77 - 7.70 (m, 1H), 7.64 - 7.57 (m, 1H), 7.37 - 7.31 (m, 1H), 3.67 - 3.56 (m, 4H), 3.50 - 3.42 (m, 4H), 3.33 - 3.23 (m, 2H), 2.87 - 2.83 (m, 3H), 1.21 - 1.12 (m, 3H).
[000903] Synthesis of -A-(5-chloro-2-fluoro-3-H-[2-fluoro-4-(DiDerazin-l- yl)Dhenyl]-3-(Dyridin-4-yl)Dyrazol-4-ynDhenyl)-3-fluoroDyrrolidine-l-sulfonamide trifluoroacetic acid salt (3)
[000904] Step-1: Synthesis of tert-butyl 4-]4-[4-(5-chloro-2-fluoro-3-H(31?)-3- fluoroDyrrolidin-l-ylsulfonyl]amino}Dhenyl)-3-(Dyridin-4-yl)Dyrazol-l-yl]-3- fluoroDhenynpiperazine-l-carboxylate (2)
[000905] To a mixture of tert-butyl 4-{4-[4-bromo-3-(pyridin-4-yl)pyrazol-l-yl]-3- fluorophenyl] piperazine- 1 -carboxylate (1.5 g, 2.986 mmol, 1 equiv) and (37?)-7V-[5-chloro-2- fluoro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]-3-fluoropyrrolidine-l- sulfonamide (1.3 g, 2.986 mmol, 1 equiv) in dioxane (20 mL) was added Pd(AMPHOS)2C12 (211 mg, 0.299 mmol, 0.1 equiv) and CsF (907 mg, 5.972 mmol, 2 equiv) in H2O (4 mL). The resulting mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CFLChiEtOAc (1 : 1) to afford tert-butyl 4-{4-[4-(5- chloro-2-fluoro-3-{[(3A)-3-fluoropyrrolidin-l-ylsulfonyl]amino}phenyl)-3-(pyri din-4- yl)pyrazol-l-yl]-3-fluorophenyl}piperazine-l-carboxylate (900 mg, 31.48%) as a brown semisolid. LCMS: C33H35CIF3N7O4S requires: 717.2, found: m/z = 718.3 [M+H]+. [000906] Step-2: Synthesis o -(5-chloro-2-fluoro-3-fl-[2-fluoro-4-(DiDerazin- l-yl)Dhenyl]-3-(Dyridin-4-yl)Dyrazol-4-ynDhenyl)-3-fluoroDyrrolidine-l-sulfonamide trifluoroacetic acid (3)
[000907] A mixture of tert-butyl 4-{4-[4-(5-chloro-2-fluoro-3-{[(3A)-3-fluoropyrrolidin- l-ylsulfonyl]amino}phenyl)-3-(pyridin-4-yl)pyrazol-l-yl]-3-fluorophenyl}piperazine-l- carboxylate (900 mg, 1.253 mmol, 1 equiv) in TFA (5 mL) was stirred at 0 °C for one hour. The resulting mixture was then concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography with the following conditions: Column: Xselect CSH C18 OBD Column 30 x 150mm, 5 pm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 5% B in 2 min, 10% B to 35% B in 15 min; Wave Length: 254/220 nm to afford (3A)-7V-(5-chloro-2-fluoro-3-{ l-[2- fluoro-4-(piperazin- 1 -yl)phenyl]-3 -(pyridin-4-yl)pyrazol-4-yl }phenyl)-3 -fluoropyrrolidine- 1 - sulfonamide trifluoroacetic acid salt (485.3 mg, 51.84%) as a yellow solid. LCMS: C28H27CIF3N7O2S requires: 617.1, found: m/z = 618.1 [M+H]+. 1HNMR (300 MHz, Methanol- tZ4) 6 8.77 - 8.69 (m, 2H), 8.39 - 8.32 (m, 1H), 8.11 - 8.00 (m, 2H), 7.90 - 7.78 (m, 1H), 7.73 - 7.64 (m, 1H), 7.36 - 7.27 (m, 1H), 7.15 - 7.00 (m, 2H), 5.48 - 5.06 (m, 1H), 3.68 - 3.49 (m, 6H), 3.53 - 3.38 (m, 6H), 2.41 - 1.96 (m, 2H).
[000908 ] Synthesis of A-(5-chloro-2-fluoro-3-]l-[2-fluoro-4-(Diperazin-l-yl)Dhenyl]-
3-(Dyridin-4-yl)Dyrazol-4- -3-fluoroazetidine-l-sulfonamide trifluoroacetic acid salt (3)
[000909] Step-1: Synthesis of tert-butyl 4-[4-(4-]5-chloro-2-fluoro-3-[(3- fluoroazetidin-l-ylsulfonyl)amino]phenvn-3-(pyridin-4-yl)pyrazol-l-yl)-3- fluorophenyl] piperazine-l-carboxylate (2)
[000910] To a mixture of tert-butyl 4-{4-[4-bromo-3-(pyridin-4-yl)pyrazol-l-yl]-3- fluorophenyl} piperazine- 1 -carboxylate (830 mg, 1.652 mmol, 1 equiv) in dioxane (10 mL) was added A-[5-chloro-2-fluoro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]-3- fluoroazetidine- 1 -sulfonamide (2.1 g, 4.956 mmol, 3 equiv), CsF (502 mg, 3.304 mmol, 2 equiv) in H2O (2 mL), and Pd(AMPHOS)2C12 (117 mg, 0.165 mmol, 0.1 equiv) at room temperature. The resulting mixture was stirred at 90 °C for one hour under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 :2) to afford tertbutyl 4-[4-(4-{5-chloro-2-fluoro-3-[(3-fluoroazetidin-l-ylsulfonyl)amino]phenyl}-3-(pyridin- 4-yl)pyraz°l-l-yl)-3-fluorophenyl]piperazine-l -carboxylate (550 mg, 41.60%) as a yellow solid. LCMS: C32H33CIF3N7O4S requires: 703.2, found: m/z = 704.2 [M+H]+.
[00091 1 ] Step-2: Synthesis of V-(5-cliloro-2-niioro-3-!l-|2-niioro-4-(piperazin-l- yl)phenyl]-3-(pyridin-4-yl)pyrazol-4-vnphenyl)-3-fluoroazetidine-l-sulfonamide trifluoroacetic acid salt (3)
[000912] A mixture of tert-butyl 4-[4-(4-{5-chloro-2-fhioro-3-[(3-fhioroazetidin-l- ylsulfonyl)amino]phenyl } -3 -(pyridin-4-yl)pyrazol- 1 -y l)-3 -fluorophenyl]piperazine- 1 - carboxylate (500 mg, 0.710 mmol, 1 equiv) in TFA (5 mL) was stirred at 0 °C for one hour. The resulting mixture was then concentrated under reduced pressure. The crude product was purified by prep-HPLC with the following conditions: Column: XSelect CSH Fluoro Phenyl 30 x 150 mm, 5 pm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 40% B in 12min; Wave Length: 254/220 nm to afford N-(5- chloro-2-fluoro-3-{ l-[2-fluoro-4-(piperazin-l-yl)phenyl]-3-(pyridin-4-yl)pyrazol-4- yl}phenyl)-3-fluoroazetidine-l-sulfonamide trifluoroacetic acid salt (264.2 mg, 50.88%) as a yellow solid. LCMS: C27H25CIF3N7O2S requires: 603.1;, found: m/z = 604.2 [M+H]+. 'H NMR (300 MHz, Methanol-t/4) 8 8.81 - 8.72 (m, 2H), 8.41 - 8.37 (m, 1H), 8.10 - 8.05 (m, 2H), 7.90 - 7.79 (m, 1H), 7.69 - 7.63 (m, 1H), 7.40 - 7.33 (m, 1H), 7.14 - 7.01 (m, 2H), 5.42 - 5.14 (m, 1H), 4.25 - 4.10 (m, 2H), 4.09 - 3.91 (m, 2H), 3.67 - 3.54 (m, 4H), 3.48 - 3.38 (m, 4H). [000913 ] Synthesis of (5-cliloro-2-niioro-3-!l-|3-niioro-4-(piperazin-l- yl)phenyl]-3-(pyridin-4-yl)pyrazol-4-vnphenyl)-3-fluoropyrrolidine-l-sulfonamide trifluoroacetic acid salt (3)
[000914] Step-1: Synthesis of tert-butyl 4-14-[4-(5-chloro-2-fluoro-3-fl(31?)-3- fluoroDyrrolidin-l-ylsulfonyl]amino}Dhenyl)-3-(Dyridin-4-yl)pyrazol-l-yl]-2- fluoroDhenynDiperazine-l-carboxylate (2)
[000915] To a mixture of tert-butyl 4-{4-[4-bromo-3-(pyridin-4-yl)pyrazol-l-yl]-2- fluorophenyl] piperazine- 1 -carboxylate (900 mg, 1.791 mmol, 1 equiv) and (37?)-7V-[5-chloro- 2-fluoro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]-3-fluoropyrrolidine-l- sulfonamide (757 mg, 1.791 mmol, 1 equiv) in dioxane (10 mL) was added CsF (544 mg, 3.582 mmol, 2 equiv) and Pd(AMPHOS)2C12 (127 mg, 0.179 mmol, 0.1 equiv) in H2O (2 mL). The resulting mixture was stirred at 90 °C for one hour under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 : 1) to afford tert-butyl 4-{4-[4-(5-chloro-2- fluoro-3-{[(3R)-3-fluoropyrrolidin-l-ylsulfonyl]amino}phenyl)-3-(pyridin-4-yl)pyrazol-l- yl]-2-fhiorophenyl (piperazine- 1 -carboxylate (660 mg, 51.30%) as a white solid. LCMS: C33H35CIF3N7O4S requires: 717.2, found: m/z = 718.3 [M+H]+.
[000916] Step-2: Synthesis o -(5-chloro-2-fluoro-3-H-[3-fluoro-4-(DiDerazin- l-yl)Dhenyl]-3-(Dyridin-4-yl)Dyrazol-4-ynDhenyl)-3-fluoroDyrrolidine-l-sulfonamide trifluoroacetic acid salt (3)
[000917] A mixture of tert-butyl 4-{4-[4-(5-chloro-2-fluoro-3-{[(3A)-3-fluoropyrrolidin- l-ylsulfonyl]amino}phenyl)-3-(pyridin-4-yl)pyrazol-l-yl]-2-fluorophenyl}piperazine-l- carboxylate (660 mg, 0.919 mmol, 1 equiv) in TFA (5 mL) was stirred at 0 °C for one hour. The resulting mixture was concentrated under reduced pressure. The crude product was purified by prep-HPLC with the following conditions: Column: XSelect CSH Prep C18 OBD Column, 30 x 150 mm, 5 pm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 40% B in 12 min; Wave Length: 254/220 nm to provide (3A)-7V-(5-chloro-2-fluoro-3-{ l-[3-fluoro-4-(piperazin-l-yl)phenyl]-3-(pyridin-4- yl)pyrazol-4-yl}phenyl)-3-fluoropyrrolidine-l-sulfonamide trifluoroacetic acid salt (295.8 mg, 40.13%) as a yellow solid. LCMS: C28H27CIF3N7O2S requires: 617.2, found: m/z = 618.2 [M+H]+. 'H NMR (300 MHz, Methanol-^) 8 8.83 - 8.68 (m, 2H), 8.64 (s, 1H), 8.18 - 8.05 (m, 2H), 7.90 - 7.74 (m, 2H), 7.74 - 7.65 (m, 1H), 7.41 - 7.26 (m, 2H), 5.41 - 5.14 (m, 1H), 3.63 - 3.38 (m, 12H), 2.33 - 1.93 (m, 2H).
[000918] Synthesis of A-[5-(difluoromethyl)-2-fluoro-3-H-[2-fluoro-4-(Diperazin-l- yl)Dhenyl]-3-(Dyridin-4-yl)Dyrazol-4-vnDhenyl]Dyrrolidine-l-sulfonamide trifluoroacetic acid salt ( (5) [000919] Step-1: Synthesis of 7V-[3-bromo-5-(difluoromethyl)-2- fluoroDhenyl]Dyrrolidine-l-sulfonamide (2)
[000920] To a mixture of 3-bromo-5-(difluoromethyl)-2 -fluoroaniline (1.8 g, 7.499 mmol, 1 equiv) and pyrrolidine- 1 -sulfonyl chloride (2.3 g, 13.498 mmol, 1.8 equiv) in pyridine (3 mL) was added DMAP (1.1 g, 8.999 mmol, 1.2 equiv). The resulting mixture was stirred at 40 °C overnight under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 : 1) to afford /'/-[3-bromo-5-(difluoromethyl)-2-fluorophenyl]pyrrolidine- l - sulfonamide (1 g, 26.44%) as a yellow solid. LCMS: CnHnBrFs^CLS requires: 371.9, found: m/z = 373.0 [M+H]+.
[000921 ] Step-2: Synthesis of Az-[5-(difluoromethyl)-2-fluoro-3-(4.,4.,5.,5-tetramethyl- l,3.,2-dioxaborolan-2-yl)phenyl]pyrrolidine-l-sulfonaniide (3)
[000922] To a mixture of A-[3-bromo-5-(difluoromethyl)-2-fluorophenyl]pyrrolidine-l- sulfonamide (900 mg, 2.412 mmol, 1 equiv) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (B2Pin2) (1225 mg, 4.824 mmol, 2 equiv) in dioxane (10 mL) was added KOAc (473 mg, 4.824 mmol, 2 equiv) and Pd(dppf)C12 (197 mg, 0.241 mmol, 0.1 equiv). The resulting mixture was stirred at 90 °C overnight under a nitrogen atmosphere. The resulting mixture was then filtered. The resulting mixture was concentrated under reduced pressure to afford A-[5-(difluoromethyl)-2-fluoro-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]pyrrolidine-l -sulfonamide (900 mg, crude) as a black oil. LCMS: CnHi2BrF3N2O2S requires: 420.2;, found: m/z = 421.1 [M+H]+.
[000923] Step-3: Synthesis o butyl 4-(4-]4-[5-(difluoromethyl)-2-fluoro-3- [(pyrrolidine-l-sulfonyl)amino]phenyl]-3-(pyridin-4-yl)pyrazol-l-vn-3- fluorophenyl)piperazine-l-carboxylate (4)
[000924] To a mixture of A-[5-(difluoromethyl)-2-fluoro-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]pyrrolidine-l -sulfonamide (2.3 g, 5.572 mmol, 2.8 equiv) and tert- butyl 4-{4-[4-bromo-3-(pyridin-4-yl)pyrazol-l-yl]-3-fluorophenyl}piperazine-l-carboxylate (1 g, 1.990 mmol, 1 equiv) in 1,4-dioxane (40 mL) was added CsF (605 mg, 3.980 mmol, 2 equiv) in H2O (8 mL) and Pd(AMPHOS)2C12 (141 mg, 0.199 mmol, 0.1 equiv). The resulting mixture was stirred at 90 °C for one hour under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 : 1) to afford terLbutyl 4-(4-{ 4- [5 -(difluoromethyl)- 2-fluoro-3 - [(pyrrolidine- 1 -sulfonyl)amino]phenyl ]-3 -(pyridin-4-yl)pyrazol - 1 -y 1 } -3 - fluorophenyl)piperazine-l -carboxylate (560 mg, 39.31%) as a yellow solid. LCMS: C34H37F4N7O4S requires: 715.3, found: m/z = 716.1 [M+H]+.
[000925] Step-4: Synthesis of \-|5-(diniioroiiiethyl)-2-nuoro-3-!l-|2-nuoro-4- (DiDerazin-l-yl)Dhenyl]-3-(Dyridin-4-yl)Dyrazol-4-ynDhenyl]Dyrrolidine-l-sulfonamide trifluoroacetic acid salt (5)
[000926] A mixture of tert-butyl 4-(4-{4-[5-(difluoromethyl)-2-fluoro-3-[(pyrrolidine-l- sulfonyl)amino]phenyl]-3-(pyridin-4-yl)pyrazol-l-yl}-3-fluorophenyl)piperazine-l- carboxylate (470 mg, 0.657 mmol, 1 equiv) in TFA (7 mL) was stirred at room temperature for 2 h. The resulting mixture was then concentrated under reduced pressure. The crude product was purified by prep-HPLC with the following conditions: Column: Xcelect CSH F-pheny OBD Column 19 x 250 mm, 5 pm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: MeOH; Flow rate: 25 mL/min; Gradient: 28% B to 43% B in 30 min; Wave Length: 254/220 nmto provide A-[5-(difluoromethyl)-2-fluoro-3-{ l-[2-fluoro-4-(piperazin-l-yl)phenyl]-3- (pyridin-4-yl)pyrazol-4-yl}phenyl]pyrrolidine-l-sulfonamide trifluoroacetic acid salt (293.2 mg, 61.19%) as a yellow solid. LCMS: C29H29F4N7O2S requires: 615.2, found: m/z = 616.2 [M+H]+. 'H NMR (300 MHz, Methanol-^) 8 8.70 - 8.63 (m, 2H), 8.38 - 8.34 (m, 1H), 7.93 - 7.77 (m, 4H), 7.49 - 7.41 (m, 1H), 7.13 - 6.99 (m, 2H), 6.85 - 6.62 (m, 1H), 3.63 - 3.55 (m, 4H), 3.48 - 3.40 (m, 4H), 3.34 (s, 4H), 1.93 - 1.84 (m, 4H).
[000927] Synthesis of A-(5-chloro-2-fluoro-3-H-[3-fluoro-4-(Diperazin-l-yl)Dhenyl]-
3-(Dyridin-4-yl)Dyrazol-4- Dyrrolidine-l-sulfonamide trifluoroacetic acid salt (3)
[000928] Step-1: Synthesis of tert-butyl 4-[4-(4-]5-chloro-2-fluoro-3-[(pyrrolidine-l- sulfonyl)amino]phenvn-3-(pyridin-4-yl)pyrazol-l-yl)-2-fluorophenyl]piperazine-l- carboxylate (2)
[000929] To a mixture of tert-butyl 4-{4-[4-bromo-3-(pyridin-4-yl)pyrazol-l-yl]-2- fluorophenyl} piperazine- 1 -carboxylate (1 g, 1.990 mmol, 1 equiv) and A-[5-chloro-2-fluoro- 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]pyrrolidine-l -sulfonamide (805 mg, 1.990 mmol, 1 equiv) in dioxane (10 mL) was added CsF (604 mg, 3.980 mmol, 2 equiv) and Pd(AMPHOS)2C12 (141 mg, 0.199 mmol, 0.1 equiv) in H2O (2 mL). The resulting mixture was stirred at 90 °C for one hour under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CFLCL MeOH (1 : 1) to afford tert-butyl 4-[4-(4-{5-chloro-2- fluoro-3 -[(pyrrolidine- l-sulfonyl)amino]phenyl} -3 -(pyridin-4-yl)pyrazol- 1 -yl)-2- fluorophenyl]piperazine-l -carboxylate (700 mg, 40.18%) as a white solid. LCMS: C33H36CIF2N7O4S requires: 699.2, found: m/z = 700.2 [M+H]+.
[000930] Step-2: Synthesis of V-(5-cliloro-2-niioro-3-!l-|3-niioro-4-(piperazin-l- yl)phenyl]-3-(pyridin-4-yl)pyrazol-4-vnphenyl)pyrrolidine-l-sulfonamide trifluoroacetic acid salt (3)
[000931] A mixture of tert-butyl 4-[4-(4-{5-chloro-2-fluoro-3-[(pyrrolidine-l- sulfonyl)amino]phenyl } -3 -(pyridin-4-yl)pyrazol- 1 -yl)-2-fluorophenyl]piperazine- 1 - carboxylate (700 mg, 1.000 mmol, 1 equiv) in TFA (7 mL) was stirred at 0 °C for one hour. The resulting mixture was then concentrated under reduced pressure. The crude product was purified by prep-HPLC with the following conditions: Column: XSelect CSH Prep C18 OBD Column, 19 x 250 mm, 5 pm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: MeOH; Flow rate: 25 mL/min; Gradient: 35% B to 50% B in 11 min; Wave Length: 254/220 nm to provide A-(5-chloro-2-fluoro-3-{ l-[3-fluoro-4-(piperazin-l-yl)phenyl]-3-(pyridin-4- yl)pyrazol-4-yl}phenyl)pyrrolidine-l-sulfonamide trifluoroacetic acid salt (381.0 mg, 52.94%) as a yellow solid. LCMS: C28H28CIF2N7O2S requires: 599.2, found: m/z = 600.2 [M+H]+. JH NMR (300 MHz, Methanol-^) 8 8.80 - 8.70 (m, 2H), 8.66 (s, 1H), 8.13 - 8.04 (m, 2H), 7.88 - 7.73 (m, 2H), 7.68 - 7.61 (m, 1H), 7.41 - 7.24 (m, 2H), 3.53 - 3.39 (m, 8H), 3.36 - 3.34 (m, 2H), 3.32 - 3.29 (m, 2H), 2.02 - 1.63 (m, 4H). [000932] Synthesis of AL(5-chloro-3-fl-[2.,6-difluoro-4-(piperazin-l-yl)phenyl]-3-
(pyridin-4-yl)pyrazol-4-yl}-2-fluorophenyl)pyrrolidine-l-sulfonamide trifluoroacetic acid salt (7)
[000933 ] Step-1: Synthesis of 4-[4-bromo-l-(2.,6-difluoro-4-nitrophenyl)pyrazol-3- yl] pyridine (2)
[000934] To a mixture of 4-(4-bromo-17/-pyrazol-3-yl)pyridine (5.8 g, 25.886 mmol, 1 equiv) in DMSO (50 mL) was added K2CO3 (5.4 g, 38.829 mmol, 1.5 equiv) and 1,2,3- trifluoro-5-nitrobenzene (5.5 g, 31.063 mmol, 1.2 equiv). The resulting mixture was stirred at room temperature for 5 h. The resulting mixture was then extracted with CH2Q2. The combined organic layers were washed with water and dried over anhydrous ISfeSCU After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (3: 1) to afford 4-[4-bromo-l-(2,6-difluoro-4- nitrophenyl)pyrazol-3-yl]pyridine (9 g, 82.10%) as a white solid. LCMS: CuEEB^lSkCh requires: 379.9, found: m/z = 380.9 [M+H]+.
[000935] Step-2: Synthesis of \-!5-chloro-3-|l-(2.6-dinuoro-4-nitrophenyl)-3-
(pyridin-4-yl)pyrazol-4-yl]-2-fluorophenvnpyrrolidine-l-sulfonamide (3)
[000936] To a mixture of 4-[4-bromo-l-(2,6-difluoro-4-nitrophenyl)pyrazol-3- yl]pyridine (8.8 g, 23.089 mmol, 1 equiv) and A-[5-chloro-2-fluoro-3-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)phenyl]pyrrolidine-l-sulfonamide (9.3 g, 23.089 mmol, 1 equiv) in dioxane (100 mL) was added Pd(AMPHOS)2C12 (1.6 g, 2.309 mmol, 0.1 equiv) and CsF (7.0 g, 46.178 mmol, 2 equiv) in H2O (20 mL). The resulting mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. The resulting mixture was then concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 : 1) to afford N- { 5 -chi oro-3 - [ 1 -(2, 6-difluoro-4-nitrophenyl)-3 -(pyridin-4-yl)pyrazol-4-yl] -2- fhiorophenyl}pyrrolidine-l-sulfonamide (5.65 g, 33.81%) as a yellow solid. LCMS: C24H18CIF3N6O4S requires: 578.1, found: m/z = 579.1 [M+H]+.
[000937] Step-3: Synthesis of A-]3-[l-(4-amino-2.,6-difluorophenyl)-3-(pyridin-4- yl)pyrazol-4-yl]-5-chloro-2-fluorophenvnpyrrolidine-l-sulfonamide (4)
[000938] A mixture of Fe (2.7 g, 48.365 mmol, 5 equiv) and NH4CI (50 mg, 0.967 mmol, 0.1 equiv) in AcOH (2 mL) and H2O (10 mL) was stirred at 80 °C for 5 min. To the above mixture was added 7V-{5-chloro-3-[l-(2,6-difluoro-4-nitrophenyl)-3-(pyridin-4-yl)pyrazol-4- yl]-2-fluorophenyl}pyrrolidine-l-sulfonamide (5.6 g, 9.673 mmol, 1 equiv) in EtOH (100 mL). The resulting mixture was stirred at 80 °C for 0.5 h. The resulting mixture was then concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 :4) to afford A-{3-[l-(4-amino-2,6-difluorophenyl)-3-(pyridin-4- yl)pyrazol-4-yl]-5-chloro-2-fluorophenyl}pyrrolidine-l -sulfonamide (4.33 g, 65.24%) as a yellow solid. LCMS: C24H20CIF3N6O2S requires: 548.1, found: m/z = 549.2 [M+H]+.
[000939] Step-4: Synthesis of A-I5-chloro-3-[l-(2.,6-difluoro-4-iodophenyl)-3- (pyridin-4-yl)pyrazol-4-yl]-2-fluorophenvnpyrrolidine-l-sulfonamide (5)
[000940] To a mixture of 7V-{3-[l-(4-amino-2,6-difluorophenyl)-3-(pyridin-4-yl)pyrazol- 4-yl]-5-chloro-2-fluorophenyl (pyrrolidine- 1 -sulfonamide (3.7 g, 6.685 mmol, 1 equiv) and TsOH (3.5 g, 20.055 mmol, 3 equiv) in ACN (30 mL) was added NaNCL (1.4 g, 20.055 mmol, 3 equiv) in H2O (3 mL) and KI (2.8 g, 16.712 mmol, 2.5 equiv) at 0 °C. The resulting mixture was stirred at 0 °C for 10 min and then was warmed to room temperature. The mixture was stirred at room temperature for an additional 30 min. The mixture was then basified to pH = 8 with saturated aqueous ISfeCCh. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous ISfeSCU After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE: EtOAc (3:2) to afford A-{5-chloro-3-[l-(2, 6- difluoro-4-iodophenyl)-3 -(pyridin-4-yl)pyrazol-4-yl]-2-fluorophenyl (pyrrolidine- 1 - sulfonamide (850 mg, 15.42%) as a brown solid. LCMS: C24H18CIF3IN5O2S requires: 658.9, found: m/z = 659.9 [M+H]+.
[000941 ] Step-5: Synthesis of tert-butyl 4-[4-(4-I5-chloro-2-fluoro-3-[(pyrrolidine-l- sulfonyl)amino]phenvn-3-(pyridin-4-yl)pyrazol-l-yl)-3.,5-difluorophenyl]piperazine-l- carboxylate (6)
[000942] To a mixture of 7V-{5-chloro-3-[l-(2,6-difluoro-4-iodophenyl)-3-(pyridin-4- yl)pyrazol-4-yl]-2-fluorophenyl (pyrrolidine- 1 -sulfonamide (700 mg, 1.061 mmol, 1 equiv) and tert-butyl piperazine- 1 -carboxylate (494 mg, 2.652 mmol, 2.5 equiv) in dioxane (10 mL) was added Pd-PEPPSLIHeptCl (103 mg, 0.106 mmol, 0.1 equiv) and CS2CO3 (864 mg, 2.652 mmol, 2.5 equiv). The resulting mixture was stirred at 90 °C for 4 h under a nitrogen atmosphere. The resulting mixture was then concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 :2) to afford tert-butyl 4-[4-(4-{5-chloro-2-fluoro-3-[(pyrrolidine-l-sulfonyl)amino]phenyl(-3-(pyri din-4- yl)pyrazol-l-yl)-3,5-difluorophenyl]piperazine-l-carboxylate (430 mg, 44.02%) as a brown solid. LCMS: C33H35CIF3N7O4S requires: 717.2, found: m/z = 718.4 [M+H]+. [000943 ] Step-6: Synthesis of \-(5-chloro-3-!l-|2.6-diniioro-4-(piper:izin-l- yl)phenyl]-3-(pyridin-4-yl)pyrazol-4-vn-2-fluorophenyl)pyrrolidine-l-sulfonamide trifluoroacetic acid salt (7)
[000944] A mixture of tert-butyl 4-[4-(4-{5-chloro-2-fluoro-3-[(pyrrolidine-l- sulfonyl)amino]phenyl } -3 -(pyridin-4-yl)pyrazol- 1 -yl)-3 ,5-difluorophenyl]piperazine- 1 - carboxylate (430 mg, 0.599 mmol, 1 equiv) in TFA (5 mL) was stirred at 0 °C for one hour. The resulting mixture was then concentrated under vacuum. The crude product was purified by prep-HPLC with the following conditions: Column: XSelect CSH Prep C18 OBD Column, 30 x 150 mm, 5 pm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 50% B in 12 min; Wave Length: 254/220 nm to afford A-(5 -chi Oros' { 1 -[2,6-difluoro-4-(piperazin- 1 -yl)phenyl]-3 -(pyridin-4-yl)pyrazol-4-yl } -2- fluorophenyl)pyrrolidine-l -sulfonamide trifluoroacetic acid salt (163.9 mg, 37.09%) as a light yellow solid. LCMS: C28H27CIF3 requires: 617.2, found: m/z = 618.2 [M+H]+. 'H NMR (400 MHz, Methanol-^) 8 8.75 - 8.69 (m, 2H), 8.28 - 8.24 (m, 1H), 8.00 - 7.94 (m, 2H), 7.67 - 7.60 (m, 1H), 7.33 - 7.27 (m, 1H), 6.99 - 6.90 (m, 2H), 3.68 - 3.61 (m, 4H), 3.45 - 3.38 (m, 4H), 3.34 - 3.28 (m, 4H), 1.96 - 1.85 (m, 4H).
[000945] Synthesis of A-(5-chloro-3-H-[2.,5-difluoro-4-(DiDerazin-l-yl)Dhenyl]-3-
(Dyridin-4-yl)Dyrazol-4-vn-2-fluoroDhenyl)Dyrrolidine-l-sulfonamide trifluoroacetic acid salt (5)
[000946] Step-1: Synthesis of tert-butyl 4-(4-bromo-2.,5-difluoroDhenyl)DiDerazine- 1-carboxylate (2)
[000947] To a mixture of l-bromo-2,5-difluoro-4-iodobenzene (14.5 g, 45.471 mmol, 1 equiv) and tert-butyl piperazine- 1 -carboxylate (10.6 g, 56.839 mmol, 1.25 equiv) in toluene (150 mL) was added Z-BuONa (8.7 g, 90.942 mmol, 2 equiv), BINAP (5.7 g, 9.094 mmol, 0.2 equiv), and Pd2(dba)s (4.2 g, 4.547 mmol, 0.1 equiv). The resulting mixture was stirred at 60 °C overnight under a nitrogen atmosphere. The resulting mixture was then concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (4: 1) to afford tert-butyl 4-(4-bromo-2,5-difluorophenyl)piperazine-l-carboxylate (11 g, 51.30%) as a light yellow solid. LCMS: CisHi9BrF2N2O2 requires: 376.0, found: m/z = 377.1 [M+H]+. [000948] Step-2: Synthesis of tert-butyl 4-I4-[4-bromo-3-(pyridin-4-yl)pyrazol-l-yl]- 2,5-difluorophenvnpiperazine-l-carboxylate (3)
[000949] To a mixture of tert-butyl 4-(4-bromo-2,5-difluorophenyl)piperazine-l- carboxylate (11 g, 29.160 mmol, 1 equiv) and 4-(4-bromo-l//-pyrazol-3-yl)pyridine (7.2 g, 32.076 mmol, 1.1 equiv) in DMF (150 mL) was added K2CO3 (12.1 g, 87.480 mmol, 3 equiv), Cui (1.1 g, 5.832 mmol, 0.2 equiv), and TMEDA (1.4 g, 11.664 mmol, 0.4 equiv). The resulting mixture was stirred at 120 °C for two days under a nitrogen atmosphere. The resulting mixture was then extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 : 1). The residue was purified by trituration with EtOAc. This resulted in tert-butyl 4-{4-[4- bromo-3-(pyridin-4-yl)pyrazol-l-yl]-2,5-difluorophenyl}piperazine-l-carboxylate (900 mg, 5.34%) as a brown solid. LCMS: C23H24BrF2NsO2 requires: 519.1, found: m/z = 520.3 [M+H]+.
[000950] Step-3: Synthesis of tert-butyl 4-[4-(4-I5-chloro-2-fluoro-3-[(pyrrolidine-l- sulfonyl)amino]phenvn-3-(pyridin-4-yl)pyrazol-l-yl)-2.,5-difluorophenyl]piperazine-l- carboxylate (4)
[000951] To a mixture of tert-butyl 4-{4-[4-bromo-3-(pyridin-4-yl)pyrazol-l-yl]-2,5- difluorophenyl (piperazine- 1 -carboxylate (900 mg, 1.730 mmol, 1 equiv) and A-[5-chloro-2- fluoro-3-(4, 4, 5, 5 -tetramethyl- 1, 3, 2-dioxaborolan-2-yl)phenyl]pyrrolidine-l -sulfonamide (700 mg, 1.730 mmol, 1 equiv) in dioxane (10 mL) was added Pd(AMPHOS)2C12 (245 mg, 0.346 mmol, 0.2 equiv) and CsF (525 mg, 3.460 mmol, 2 equiv) in H2O (2 mL). The resulting mixture was stirred at 90 °C for 1 h under a nitrogen atmosphere. The resulting mixture was then concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (2:3). The residue was then purified by trituration with EtOAc. This resulted in tert-butyl 4-[4-(4-{5-chloro-2-fluoro-3-[(pyrrolidine-l-sulfonyl)amino]phenyl}-3- (pyridin-4-yl)pyrazol-l-yl)-2,5-difluorophenyl]piperazine-l-carboxylate (550 mg, 42.07%) as a white solid. LCMS: C33H35CIF3N7O4S requires: 717.2, found: m/z = 718.3 [M+H]+.
[000952] Step-4: Synthesis of 7V-(5-chloro-3-Il-[2.,5-difluoro-4-(piperazin-l- yl)phenyl]-3-(pyridin-4-yl)pyrazol-4-vn-2-fluorophenyl)pyrrolidine-l-sulfonamide trifluoroacetic acid salt (5)
[000953] A mixture of tert-butyl 4-[4-(4-{5-chloro-2-fluoro-3-[(pyrrolidine-l- sulfonyl)amino]phenyl } -3 -(pyridin-4-yl)pyrazol- 1 -yl)-2,5-difluorophenyl]piperazine- 1 - carboxylate (550 mg, 0.766 mmol, 1 equiv) in TFA (6 mL) was stirred at 0 °C for one hour. The resulting mixture was then concentrated under vacuum and lyophilized. This resulted in A-(5-chloro-3-{ l-[2,5-difluoro-4-(piperazin-l-yl)phenyl]-3-(pyridin-4-yl)pyrazol-4-yl}-2- fluorophenyl)pyrrolidine-l -sulfonamide trifluoroacetic acid salt (345.2 mg, crude) as a yellow solid. LCMS: C28H27CIF3N7O2S requires: 617.1, found: m/z = 618.2 [M+H]+. 'H NMR (400 MHz, Methanol-^) 8 8.82 - 8.75 (m, 2H), 8.51 - 8.46 (m, 1H), 8.17 - 8.10 (m, 2H), 7.90 - 7.81 (m, 1H), 7.68 - 7.61 (m, 1H), 7.37 - 7.31 (m, 1H), 7.29 - 7.18 (m, 1H), 3.50 - 3.44 (m, 8H), 3.38 - 3.29 (m, 4H), 1.97 - 1.86 (m, 4H).
[000954] Synthesis of 7V-(5-chloro-2-fluoro-3-n-[5-(DiDerazin-l-yl)Dyrimidin-2-yl]- 3-(Dyridin-4-yl)Dyrazol-4-ynDhenyl)Dyrrolidine-l-sulfonamide trifluoroacetic acid salt
[000955] Step-1: Synthesis of tert-butyl 4-(2-methoxyDyrimidin-5-yl)Diperazine-l- carboxylate (2)
[000956] To a mixture of 5-bromo-2-methoxypyrimidine (7.5 g, 39.680 mmol, 1 equiv) and tert-butyl piperazine- 1 -carboxylate (7.39 g, 39.680 mmol, 1 equiv) in toluene (30 mL) was added BINAP (0.49 g, 0.794 mmol, 0.02 equiv), Z-BuONa (7.63 g, 79.360 mmol, 2 equiv), and Pd2(dba)s (0.47 g, 0.518 mmol, 0.01 equiv). The resulting mixture was stirred at 80 °C overnight under a nitrogen atmosphere. The resulting mixture was then concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 : 1) to afford tert-butyl 4-(2-methoxypyrimidin-5-yl)piperazine-l -carboxylate (4.3 g, 25.36%) as a yellow solid. LCMS: C14H22N4O3 requires: 294.2, found: m/z = 295.2 [M+H]+.
[000957] Step-2: Synthesis of tert-butyl 4-(2-hvdroxypyrimidin-5-yl)piperazine-l- carboxylate (3)
[000958] To a mixture of tert-butyl 4-(2-methoxypyrimidin-5-yl)piperazine-l- carboxylate (3.21 g, 10.905 mmol, 1 equiv) in Z-BuOH (30 mL) was added KOH (0.86 g, 15.267 mmol, 1.4 equiv). The resulting mixture was stirred at 70 °C overnight. The mixture was then neutralized to pH = 7 with aqueous HC1 (2 M). The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with CH2C12:MeOH (10: 1) to afford tert-butyl 4-(2-hydroxypyrimidin-5-yl)piperazine- 1-carboxylate (2.61 g, 85.38%) as a yellow solid. LCMS: C13H20N4O3 requires: 280.2, found: m/z = 281.2 [M+H]+.
[000959] Step-3: Synthesis of tert-butyl 4-[2-
(trifluoromethanesulfonyloxy)pyrimidin-5-yl]piperazine-l-carboxylate (4)
[000960] To a mixture of tert-butyl 4-(2-hydroxypyrimidin-5-yl)piperazine-l- carboxylate (2.41 g, 8.597 mmol, 1 equiv) in DCM (7 mL) was added TEA (2.61 g, 25.791 mmol, 3 equiv) and Tf2O (4.85 g, 17.194 mmol, 2 equiv) at 0 °C. The resulting mixture was then warmed and stirred at room temperature for 2 h under a nitrogen atmosphere. The resulting mixture was then concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (3: 1) to afford tert-butyl 4-[2- (trifluoromethanesulfonyloxy)pyrimidin-5-yl]piperazine-l-carboxylate (1.4159 g, 37.94%) as a light brown solid. LCMS: C14H19F3N4O5S requires: 412.1, found: m/z = 413.1 [M+H]+.
[000961 ] Step-4: Synthesis of tert-butyl 4-]2-[4-bromo-3-(pyridin-4-yl)pyrazol-l- yl]pyrimidin-5-vnpiperazine-l-carboxylate (5)
[000962] To a mixture of tert-butyl 4-[2-(trifluoromethanesulfonyloxy)pyrimidin-5- yl]piperazine-l -carboxylate (3 g, 7.275 mmol, 1 equiv) and 4-(4-bromo-U/-pyrazol-3- yl)pyridine (2.5 g, 10.913 mmol, 1.5 equiv) in DMF (40 mL) was added K2CO3 (3.0 g, 21.825 mmol, 3 equiv), Cui (277 mg, 1.455 mmol, 0.2 equiv), and TMEDA (338 mg, 2.910 mmol, 0.4 equiv). The resulting mixture was stirred at 90 °C for one hour under a nitrogen atmosphere. The resulting mixture was then extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous ISfeSCU. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with EtOAc:MeOH (19: 1). The residue was then purified by trituration with EtOAc. This resulted in tert-butyl 4-{2-[4-bromo-3-(pyridin-4-yl)pyrazol-l-yl]pyrimidin- 5-yl}piperazine-l-carboxylate (900 mg, 22.89%) as a brown solid. LCMS: C2iH24BrN?O2 requires: 485.1, found: m/z = 486.3 [M+H]+.
[000963] Step-5: Synthesis of tert-butyl 4-[2-(4-f5-chloro-2-fluoro-3-[(pyrrolidine-l- sulfonyl)amino]phenvn-3-(pyridin-4-yl)pyrazol-l-yl)pyrimidin-5-yl]piperazine-l- carboxylate (6)
[000964] To a mixture of tert-butyl 4-{2-[4-bromo-3-(pyridin-4-yl)pyrazol-l- yl]pyrimidin-5-yl (piperazine- 1 -carboxylate (900 mg, 1.850 mmol, 1 equiv) and A-[5-chloro- 2-fluoro-3-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)phenyl]pyrrolidine-l -sulfonamide (749 mg, 1.850 mmol, 1 equiv) in dioxane (10 mL) was added Pd(AMPHOS)2C12 (131 mg, 0.185 mmol, 0.1 equiv) and CsF (562 mg, 3.700 mmol, 2 equiv) in H2O (2 mL). The resulting mixture was stirred at 90 °C for one hour under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with EtOAc:MeOH (9: 1). The residue was then purified by trituration with EtOAc. This resulted in tert-butyl 4-[2-(4-{5-chloro-2-fluoro-3-[(pyrrolidine-l- sulfonyl)amino]phenyl ( -3 -(pyridin-4-yl)pyrazol- 1 -yl)pyrimidin-5-yl]piperazine- 1 - carboxylate (700 mg, 44.23%) as abrown semi-solid. LCMS: C31H35CIFN9O4S requires: 683.2, found: m/z = 684.3 [M+H]+.
[000965] Step-6: Synthesis of A-(5-chloro-2-fluoro-3-fl-[5-(piperazin-l- yl)pyrimidin-2-yl]-3-(pyridin-4-yl)pyrazol-4-vnphenyl)pyrrolidine-l-sulfonamide trifluoroacetic acid salt (7)
[000966] A mixture of tert-butyl 4-[2-(4-{5-chloro-2-fluoro-3-[(pyrrolidine-l- sulfonyl)amino]phenyl ( -3 -(pyridin-4-yl)pyrazol- 1 -yl)pyrimidin-5-yl]piperazine- 1 - carboxylate (700 mg, 1.023 mmol, 1 equiv) in TFA (7 mL) was stirred at 0 °C for 2 h. The resulting mixture was then concentrated under vacuum. The crude product was purified by prep-HPLC with the following conditions: Column: XSelect CSH Prep C18 OBD Column, 19 x 250 mm, 5 pm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: MeOH; Flow rate: 25 mL/min; Gradient: 33% B to 48% B in 10 min; Wave Length: 254/220 nm to afford 7V-(5- chloro-2-fluoro-3-{ l-[5-(piperazin-l-yl)pyrimidin-2-yl]-3-(pyridin-4-yl)pyrazol-4- yl(phenyl)pyrrolidine-l-sulfonamide trifluoroacetic acid salt (342.5 mg, 46.67%) as a yellow solid. LCMS: C26H27CIFN9O2S requires: 583.2, found: m/z = 584.1 [M+H]+. 'H NMR (300 MHz, Methanol-t/4) 8 8.98 - 8.91 (m, 1H), 8.84 - 8.76 (m, 2H), 8.75 - 8.65 (m, 2H), 8.22 - 8.14 (m, 2H), 7.69 - 7.60 (m, 1H), 7.40 - 7.30 (m, 1H), 3.73 - 3.64 (m, 4H), 3.53 - 3.43 (m, 4H), 3.38 - 3.28 (m, 4H), 1.97 - 1.86 (m, 4H).
[000967] Synthesis of lS-ldifluoromethvD-Z-fluoro-S-H-M-lDiDerazin-l- yl)Dhenyl]-3-(Dyridin-4-yl)Dyrazol-4-vnDhenyl]Dyrrolidine-l-sulfonamide trifluoroacetic acid salt (3) [000968] Step-1: Synthesis of te -butyl 4-(4-]4-[5-(difluoromethyl)-2-fluoro-3- [(pyrrolidine-l-sulfonyl)amino]phenyl]-3-(pyridin-4-yl)pyrazol-l-vnphenyl)piperazine-
1-carboxylate (2)
[000969] To a mixture of tert-butyl 4-{4-[4-bromo-3-(pyridin-4-yl)pyrazol-l- yl]phenyl}piperazine-l-carboxylate (1.2 g, 2.477 mmol, 1 equiv) and A-[5-(difluoromethyl)-
2-fluoro-3-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)phenyl]pyrrolidine-l -sulfonamide (1.04 g, 2.477 mmol, 1 equiv) in dioxane (40 mL) was added Pd(AMPHOS)2C12 (175 mg, 0.248 mmol, 0.1 equiv) and CsF (753 mg, 4.954 mmol, 2 equiv) in H2O (8 mL). The resulting mixture was stirred at 90 °C for 1.5 h under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with DCM:EtOAc (1 : 1) to afford tert-butyl 4-(4-{4-[5- (difluoromethyl)-2-fluoro-3-[(pyrrolidine-l-sulfonyl)amino]phenyl]-3-(pyridin-4-yl)pyrazol- l-yl}phenyl)piperazine-l -carboxylate (450 mg, 20.83%) as an off-white solid. LCMS: C34H38F3N7O4S requires: 697.3, found: m/z = 698.3 [M+H]+.
[000970] Step-2: Synthesis of V-|5-(dinuoroinethyl)-2-nuoro-3-!l-|4-(piperazin-l- yl)phenyl]-3-(pyridin-4-yl)pyrazol-4-vnphenyl]pyrrolidine-l-sulfonamide trifluoroacetic acid salt (3)
[000971] A mixture of tert-butyl 4-(4-{4-[5-(difluoromethyl)-2-fluoro-3-[(pyrrolidine-l- sulfonyl)amino]phenyl]-3-(pyridin-4-yl)pyrazol-l-yl}phenyl)piperazine-l -carboxylate (440 mg, 0.631 mmol, 1 equiv) in TFA (3 mL) was stirred at 0 °C for one hour. The resulting mixture was then concentrated under reduced pressure. The crude product was purified by prep-HPLC with the following conditions: Column: XSelect CSH Prep C18 OBD Column, 30 x 150 mm, 5 pm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 40% B in 12 min; Wave Length: 254/220 nm to afford 7V-[5- (difluoromethyl)-2-fluoro-3-{ l-[4-(piperazin-l-yl)phenyl]-3-(pyridin-4-yl)pyrazol-4- yl}phenyl]pyrrolidine-l-sulfonamide trifluoroacetic acid salt (304.1 mg, 67.56%) as a yellow solid. LCMS: C29H30F3N7O2S requires: 597.2, found: m/z = 598.2 [M+H]+. ' H NMR (400 MHz, Methanol-t/4) 6 8.83 - 8.70 (m, 2H), 8.62 (s, 1H), 8.21 - 8.07 (m, 2H), 7.98 - 7.87 (m, 2H), 7.86 - 7.76 (m, 1H), 7.60 - 7.49 (m, 1H), 7.35 - 7.19 (m, 2H), 7.06 - 6.66 (m, 1H), 3.60 - 3.50 (m, 4H), 3.49 - 3.40 (m, 4H), 3.36 - 3.28 (m, 4H), 2.02 - 1.82 (m, 4H). [000972] Synthesis of \-(5-chIoro-3-!l-|4-(1.4-diazep:in-l-yl)-2-fluoroi)henyl|-3-
(pyridin-4-yl)pyrazol-4-yl}-2-fluorophenyl)pyrrolidine-l~sulfonamide trifluoroacetic acid salt (6)
Step-1
[000973 ] Step-1: Synthesis of tert-butyl 4-(4-chloro-3-fluorophenyl)-l,4-diazeDane- 1-carboxylate (2)
[000974] To a mixture of 4-bromo-l -chi oro-2 -fluorobenzene (21 g, 100.267 mmol, 1 equiv) and tert-butyl 1,4-diazepane-l -carboxylate (25.10 g, 125.334 mmol, 1.25 equiv) in toluene (200 mL) was added BINAP (12.49 g, 20.053 mmol, 0.2 equiv), Z-BuONa (19.27 g, 200.534 mmol, 2 equiv), and Pd2(dba)s (9.18 g, 10.027 mmol, 0.1 equiv). The resulting mixture was stirred at 60 °C overnight under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (5: 1) to afford tert-butyl 4-(4-chloro-3-fluorophenyl)- 1,4-diazepane-l -carboxylate (30 g, 90.99%) as a brown oil. LCMS: C16H22CIFN2O2 requires: 328.1, found: m/z = 329.3 [M+H]+.
[000975] Step-2: Synthesis of tert-butyl 4-[3-fluoro-4-(4.,4.,5.,5-tetramethyl-l.,3.,2- dioxaborolan-2-yl)phenyl]-l.,4-diazepane-l-carboxylate (3)
[000976] To a mixture of tert-butyl 4-(4-chloro-3-fluorophenyl)-l,4-diazepane-l- carboxylate (27 g, 82.114 mmol, 1 equiv) and bis(pinacolato)diboron (B2Pin2) (31.28 g, 123.171 mmol, 1.5 equiv) in methoxycyclopentane (300 mL) was added AcOK (24.18 g, 246.342 mmol, 3 equiv), XPhos (2.35 g, 4.927 mmol, 0.06 equiv), and Pd2(dba)s (2.26 g, 2.463 mmol, 0.03 equiv). The resulting mixture was stirred at 110 °C for 3 h under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (3: 1) to afford tertbutyl 4-[3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]-l,4-diazepane-l- carboxylate (12 g, 34.77%) as a white solid. LCMS: C22H34BFN2O4 requires: 420.3, found: m/z = 421.1 [M+H]+.
[000977] Step-3: Synthesis of tert-butyl 4-]4-[4-bromo-3-(pyridin-4-yl)pyrazol-l-yl]-
3-fluorophenyn-l.,4-diazepane-l-carboxylate (4)
[000978] To a mixture of tert-butyl 4-[3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]-l,4-diazepane-l-carboxylate (12 g, 28.549 mmol, 1 equiv) and 4- (4-bromo-177-pyrazol-3-yl)pyridine (7.04 g, 31.404 mmol, 1.1 equiv) in pyridine (120 mL) was added Cu(OAc)2 (10.37 g, 57.098 mmol, 2 equiv) and molecular sieves (4A) (12 g). The resulting mixture was stirred at 100 °C overnight under an oxygen atmosphere. The resulting mixture was then extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous ISfeSC After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 :3) to afford tert-butyl 4-{4-[4-bromo-3-(pyridin-4-yl)pyrazol-l-yl]-3-fluorophenyl}-l,4- diazepane-1 -carboxylate (3 g, 20.35%) as a white solid. LCMS: C24H27BrFNsO2 requires: 515.1, found: m/z = 516.3 [M+H]+.
[000979] Step-4: Synthesis of tert-butyl 4-[4-(4-]5-chloro-2-fluoro-3-[(pyrrolidine-l- sulfonyl)amino]phenvn-3-(pyridin-4-yl)pyrazol-l-yl)-3-fluorophenyl]-l.,4-diazepane-l- carboxylate (5) [000980] To a mixture of tert-butyl 4-{4-[4-bromo-3-(pyridin-4-yl)pyrazol-l-yl]-3- fluorophenyl}-l,4-diazepane-l -carboxylate (1 g, 1.936 mmol, 1 equiv) and 7V-[5-chloro-2- fluoro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]pyrrolidine-l-sulfonamide
(0.78 g, 1.936 mmol, 1 equiv) in dioxane (10 mL) was added CsF (0.59 g, 3.872 mmol, 2 equiv) and Pd(AMPHOS)2Ch (0.14 g, 0.194 mmol, 0.1 equiv) in H2O (2 mL). The resulting mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 :4) to afford tert-butyl 4-[4-(4-{5-chloro-2-fluoro-3- [(pyrrolidine- 1 -sulfonyl)amino]phenyl } -3 -(pyridin-4-yl)pyrazol- 1 -y l)-3 -fluorophenyl]- 1 ,4- diazepane-1 -carboxylate (700 mg, 50.61%) as a grey solid. LCMS: C34H38CIF2N7O4S requires: 713.2, found: m/z = 714.3 [M+H]+.
[000981 ] Step-5: Synthesis of 7V-(5-chloro-3-H-[4-(l.,4-diazeDan-l-yr)-2- fluoroDhenyl]-3-(Dyridin-4-yl)Dyrazol-4-yn-2-fluoroDhenyl)Dyrrolidine-l-sulfonamide trifluoroacetic acid salt (6)
[000982] A mixture of tert-butyl 4-[4-(4-{5-chloro-2-fluoro-3-[(pyrrolidine-l- sulfonyl)amino]phenyl } -3 -(pyridin-4-yl)pyrazol- 1 -y l)-3 -fluorophenyl]- 1 ,4-diazepane- 1 - carboxylate (700 mg, 0.980 mmol, 1 equiv) in TFA (10 mL) was stirred at 0 °C for one hour. The resulting mixture was then concentrated under reduced pressure. The crude product was purified by prep-HPLC with the following conditions: Column: XSelect CSH Prep C18 OBD Column, 30 x 150 mm, 5 pm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 40% B in 12 min; Wave Length: 254/220 nm to afford A-(5-chloro-3-{ l-[4-(l,4-diazepan-l-yl)-2-fluorophenyl]-3-(pyridin-4-yl)pyrazol-4- yl}-2-fluorophenyl)pyrrolidine-l -sulfonamide trifluoroacetic acid salt (347.2 mg, 48.65%) as a yellow solid. LCMS: C29H30CIF2N7O2S requires: 613.2, found: m/z = 614.3 [M+H]+. JH NMR (300 MHz, Methanol-^) 8 8.79 - 8.70 (m, 2H), 8.35 - 8.28 (m, 1H), 8.13 - 8.04 (m, 2H), 7.82 - 7.69 (m, 1H), 7.67 - 7.58 (m, 1H), 7.37 - 7.28 (m, 1H), 6.93 - 6.79 (m, 2H), 3.95 - 3.85 (m, 2H), 3.75 - 3.65 (m, 2H), 3.51 - 3.42 (m, 2H), 3.38 - 3.33 (m, 4H), 3.33 - 3.29 (m, 2H), 2.33 - 2.19 (m, 2H), 1.98 - 1.84 (m, 4H).
[000983] Synthesis of A-(5-chloro-2-fluoro-3-H-[6-(Diperazin-l-yl)Dyridin-3-yl]-3- (Dyridin-4-yl)Dyrazol-4- Dyrrolidine-l-sulfonamide trifluoroacetic acid salt (3)
[000984] Step-1: Synthesis of tert-butyl 4-[5-(4-15-chloro-2-fluoro-3-[(pyrrolidine-l- sulfonyl)amino]Dhenyn-3-(Dyridin-4-yl)Dyrazol-l-yl)Dyridin-2-yl]DiDerazine-l- carboxylate (2)
[000985] To a mixture of tert-butyl 4-{5-[4-bromo-3-(pyridin-4-yl)pyrazol-l-yl]pyridin- 2-yl (piperazine- 1 -carboxylate (1.2 g, 2.472 mmol, 1 equiv) and 7V-[5-chloro-2-fluoro-3- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]pyrrolidine-l-sulfonamide (1 g, 2.472 mmol, 1 equiv) in dioxane (40 mL) was added Pd(AMPHOS)2C12 (0.18 g, 0.247 mmol, 0.1 equiv) and CsF (0.75 g, 4.944 mmol, 2 equiv) in H2O (8 mL). The resulting mixture was stirred at 90 °C for 1.5 h under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with DCM:EtOAc (1 : 1) to afford tert-butyl 4-[5-(4-{5-chloro-2-fluoro-3-[(pyrrolidine-l- sulfonyl)amino]phenyl} -3 -(pyridin-4-yl)pyrazol-l-yl)pyri din-2 -yl]piperazine-l -carboxylate (700 mg, 33.15%) as an off-white solid. LCMS: C32H36CIFN8O4S requires: 682.2, found: m/z = 683.2 [M+H]+.
[000986] Step-2: Synthesis of 7V-(5-chloro-2-fluoro-3-n-[6-(DiDerazin-l-yl)Dyridin- 3-yl]-3-(Dyridin-4-yl)Dyrazol-4-ynDhenyl)Dyrrolidine-l-sulfonamide trifluoroacetic acid salt (3)
[000987] A mixture of tert-butyl 4-[5-(4-{5-chloro-2-fhioro-3-[(pyrrolidine-l- sulfonyl)amino]phenyl } -3 -(pyridin-4-yl)pyrazol-l-yl)pyri din-2 -yl]piperazine-l -carboxylate (690 mg, 1.01 mmol, 1 equiv) in TFA (5 mL) was stirred at 0 °C for one hour. The resulting mixture was then concentrated under reduced pressure. The crude product was purified by prep-HPLC with the following conditions: Column: XSelect CSH Prep C18 OBD Column, 30 x 150 mm, 5 pm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 40% B in 12 min; Wave Length: 254/220 nm to afford A-(5 -chi oro- 2-fluoro-3 - { 1 -[6-(piperazin- 1 -yl)pyri din-3 -y 1 ] -3 -(pyridin-4-yl)pyrazol-4- yl}phenyl)pyrrolidine-l-sulfonamide trifluoroacetic acid salt (462.3 mg, 64.42%) as a yellow solid. LCMS: C27H28CIFN8O2S requires: 582.2, found: m/z = 583.3 [M+H]+. 'H NMR (400 MHz, Methanol-t/4) 8 8.86 - 8.72 (m, 3H), 8.61 (s, 1H), 8.24 - 8.18 (m, 1H), 8.17 - 8.11 (m, 2H), 7.70 - 7.61 (m, 1H), 7.42 - 7.33 (m, 1H), 7.13 (m, 1H), 4.05 - 3.86 (m, 4H), 3.42 - 3.36 (m, 4H), 3.35 - 3.30 (m, 4H), 2.00 - 1.84 (m, 4H).
[000988] Synthesis of A-(2.,5-difluoro-3-H-[5-(DiDerazin-l-yl)Dyrimidin-2-yl]-3- (Dyridin-4-yl)Dyrazol-4- Dyrrolidine-l-sulfonamide trifluoroacetic acid salt (3)
[000989] Step-1: Synthesis of tert-butyl 4-[2-(4-12,5-difluoro-3-[(pyrrolidine-l- sulfonyl)amino]phenvn-3-(pyridin-4-yl)pyrazol-l-yl)pyrimidin-5-yl]piperazine-l- carboxylate (2)
[000990] To a mixture of tert-butyl 4-{2-[4-bromo-3-(pyridin-4-yl)pyrazol-l- yl]pyrimidin-5-yl (piperazine- 1 -carboxylate (900 mg, 1.850 mmol, 1 equiv) and V-[2,5- difluoro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]pyrrolidine-l-sulfonamide (718 mg, 1.850 mmol, 1 equiv) in dioxane (10 mL) was added Pd(AMphos)2C12 (131 mg, 0.185 mmol, 0.1 equiv) and CsF (562 mg, 3.700 mmol, 2 equiv) in H2O (2 mL). The resulting mixture was stirred at 90 °C for one hour under a nitrogen atmosphere. The resulting mixture was then concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with EtOAc:MeOH (9: 1) to afford tert-butyl 4-[2-(4-{2,5-difluoro-3-[(pyrrolidine-l- sulfonyl)amino]phenyl } -3 -(pyridin-4-yl)pyrazol- 1 -yl)pyrimidin-5-yl]piperazine- 1 - carboxylate (700 mg, 45.32%) as a brown solid. LCMS: C31H35F2N9O4S requires: 667.2, found: m/z = 668.3 [M+H]+.
[000991 ] Step-2: Synthesis of A-(2,5-difluoro-3-ll-[5-(piperazin-l-yl)pyrimidin-2- yl]-3-(pyridin-4-yl)pyrazol-4-vnphenyl)pyrrolidine-l-sulfonamide trifluoroacetic acid salt (3)
[000992] A mixture of tert-butyl 4-[2-(4-{2,5-difhioro-3-[(pyrrolidine-l- sulfonyl)amino]phenyl } -3 -(pyridin-4-yl)pyrazol- 1 -yl)pyrimidin-5-yl]piperazine- 1 - carboxylate (700 mg, 1.048 mmol, 1 equiv) in TFA (7 mL) was stirred at 0 °C for one hour. The resulting mixture was then concentrated under vacuum. The crude product was purified by prep-HPLC with the following conditions: Column: XSelect CSH Prep C18 OBD Column, 19 x 250 mm, 5 pm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: MeOH; Flow rate: 25 mL/min; Gradient: 30% B to 45% B in 10 min; Wave Length: 254/220 nm to afford N-(2,5- difluoro-3-{ l-[5-(piperazin-l-yl)pyrimidin-2-yl]-3-(pyridin-4-yl)pyrazol-4- yl}phenyl)pyrrolidine-l-sulfonamide trifluoroacetic acid salt (320.0 mg, 44.24%) as a yellow solid. LCMS: C26H27F2N9O2S requires: 567.2, found: m/z = 568.2 [M+H]+. 'H NMR (400 MHz, Methanol-t/4) 8 8.97 - 8.92 (m, 1H), 8.84 - 8.78 (m, 2H), 8.71 - 8.66 (m, 2H), 8.23 - 8.17 (m, 2H), 7.47 - 7.38 (m, 1H), 7.13 - 7.04 (m, 1H), 3.72 - 3.65 (m, 4H), 3.51 - 3.44 (m, 4H), 3.40 - 3.35 (m, 4H), 1.96 - 1.85 (m, 4H).
[000993] Synthesis of A-(2.,5-difluoro-3-H-[2-fluoro-4-(DiDerazin-l-yl)Dhenyl]-3- (Dyridin-4-yl)Dyrazol-4-ynDhenyl)Dyrrolidine-l-sulfonamide trifluoroacetic acid salt (3)
[000994] Step-1: Synthesis of tert-butyl 4-[4-(4-]2.,5-difluoro-3-[(pyrrolidine-l- sulfonyl)amino]phenvn-3-(pyridin-4-yl)pyrazol-l-yl)-3-fluorophenyl]piperazine-l- carboxylate (2)
[000995] To a mixture of tert-butyl 4-{4-[4-bromo-3-(pyridin-4-yl)pyrazol-l-yl]-3- fluorophenyl} piperazine- 1 -carboxylate (900 mg, 1.791 mmol, 1 equiv) and TV- [2,5 -difluoro-3- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]pyrrolidine-l-sulfonamide (695 mg, 1.791 mmol, 1 equiv) in dioxane (10 mL) was added CsF (544 mg, 3.582 mmol, 2 equiv) and Pd(AMPHOS)2C12 (126 mg, 0.179 mmol, 0.1 equiv) in H2O (2 mL). The resulting mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 :3) to afford tert-butyl 4-[4-(4-{2,5-difluoro-3- [(pyrrolidine- 1 -sulfonyl)amino]phenyl } -3 -(pyridin-4-yl)pyrazol- 1 -y l)-3 - fluorophenyl]piperazine-l -carboxylate (600 mg, 48.98%) as a yellow solid. LCMS: C33H36F3N7O4S requires: 683.2, found: m/z = 684.3 [M+H]+.
[000996] Step-2: Synthesis of Az-(2,5-difluoro-3-]l-[2-fluoro-4-(piperazin-l- yl)phenyl]-3-(pyridin-4-yl)pyrazol-4-vnphenyl)pyrrolidine-l-sulfonamide trifluoroacetic acid salt (3) [000997] A mixture of tert-butyl 4-[4-(4-{2,5-difhioro-3-[(pyrrolidine-l- sulfonyl)amino]phenyl } -3 -(pyridin-4-yl)pyrazol- 1 -y l)-3 -fluorophenyl]piperazine- 1 - carboxylate (600 mg, 0.878 mmol, 1 equiv) in TFA (6 mL) was stirred at 0 °C for one hour. The resulting mixture was then concentrated under reduced pressure. The crude product was purified by prep-HPLC with the following conditions: Column: XSelect CSH Prep C18 OBD Column, 19 x 250 mm, 5 pm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: MeOH; Flow rate: 25 mL/min; Gradient: 30% B to 45% B in 12 min; Wave Length: 254/220 nm to afford 7V-(2,5-difluoro-3-{ l-[2-fluoro-4-(piperazin-l-yl)phenyl]-3-(pyridin-4-yl)pyrazol-4- yl}phenyl)pyrrolidine-l-sulfonamide trifluoroacetic acid salt (284.0 mg, 46.39%) as a yellow solid. LCMS: C28H28F3N7O2S requires: 583.2, found: m/z = 584.1 [M+H]+. 'H NMR (300 MHz, Methanol-t/4) 8 8.80 - 8.72 (m, 2H), 8.41 - 8.34 (m, 1H), 8.16 - 8.08 (m, 2H), 7.90 - 7.78 (m, 1H), 7.47 - 7.35 (m, 1H), 7.14 - 7.01 (m, 3H), 3.65 - 3.55 (m, 4H), 3.47 - 3.38 (m, 4H), 3.38 - 3.33 (m, 4H), 1.98 - 1.84 (m, 4H).
[000998] Synthesis of A-[5-chloro-3-(l-]4- -3.,5-dimethylDiDerazin-l-yl]-2- fluoroDhenyn-3-(Dyridin-4-yl)Dyrazol-4-yl)-2-fluoroDhenyl]Dyrrolidine-l-sulfonamide; trifluoroacetic acid (6)
[000999] Step-1: Synthesis of tert-butyl (21?.,61?)-4-(4-chloro-3-fluorophenyl)-2.,6- dimethylpiperazine-l-carboxylate (2) [0001000] To a mixture of 4-bromo-l-chloro-2-fluorobenzene (4.9 g, 23.331 mmol, 1 equiv) and tert-butyl (2R, 6/?)-2,6-dimethylpiperazine- l -carboxylate (5 g, 23.331 mmol, 1 equiv) in toluene (60 mL) was added Pd2(dba)s (214 mg, 0.233 mmol, 0.01 equiv), Z-BuONa (3.4 g, 32.663 mmol, 1.4 equiv), and BINAP (291 mg, 0.467 mmol, 0.02 equiv). The resulting mixture was stirred at 60 °C overnight under a nitrogen atmosphere. The resulting mixture was then concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (10: 1) to afford tert-butyl (2R, 6/?)-4-(4-chl oro-3 - fluorophenyl)-2,6-dimethylpiperazine-l-carboxylate (5 g, 56.26%) as a brown solid. LCMS: C17H24CIFN2O2 requires: 342.1, found: m/z = 343.2 [M+H]+.
[0001001 ] Step-2: Synthesis of tert-butyl -4-[3-fluoro-4-(4.,4.,5.,5-tetramethyl- l,3.,2-dioxaborolan-2-yl)phenyl]-2.,6-dimethylpiperazine-l-carboxylate (3)
[0001002] To a mixture of tert-butyl (27?,67?)-4-(4-chloro-3-fluorophenyl)-2,6- dimethylpiperazine-1 -carboxylate (5 g, 14.584 mmol, 1 equiv) and 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (B2Pin2) (5.6 g, 21.876 mmol, 1.5 equiv) in methoxy cyclopentane (70 mL) was added Pd2(dba)s (401 mg, 0.438 mmol, 0.03 equiv), KOAc (4.3 g, 43.752 mmol, 3 equiv), and XPhos (417 mg, 0.875 mmol, 0.06 equiv). The resulting mixture was stirred at 110 °C for 3 h under a nitrogen atmosphere. The resulting mixture was then concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (9: 1) to afford tert-butyl (2/?,6/?)-4-[3-tluoro- 4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)phenyl]-2,6-dimethylpiperazine-l -carboxylate (5 g, 71.04%) as a brown solid. LCMS: C23H36BFN2O4 requires: 434.3, found: m/z = 435.3 [M+H]+.
[0001003 ] Step-3: Synthesis of tert-butyl (21?.,61?)-4-I4-[4-bromo-3-(pyridin-4- yl)pyrazol-l-yl]-3-fluorophenvn-2.,6-dimethylpiperazine-l-carboxylate (4)
[0001004] To a mixture of tert-butyl (2R, 6/?)-4-[3-fluoro-4-(4, 4, 5, 5-tetramethyl-l, 3,2- dioxaborolan-2-yl)phenyl]-2,6-dimethylpiperazine-l-carboxylate (3.5 g, 8.058 mmol, 1 equiv) and 4-(4-bromo-lJ/-pyrazol-3-yl)pyridine (2 g, 8.864 mmol, 1.1 equiv) in pyridine (40 mL) was added Cu(OAc)2 (2.9 g, 16.116 mmol, 2 equiv) and molecular sieves type 4A (3.5 g). The resulting mixture was stirred at 60 °C overnight under an oxygen atmosphere. The resulting mixture was then extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 : 1) to afford tert-butyl (2/?,6/?)-4-[4-[4-bromo-3-(pyridin-4-yl)pyrazol- l -yl]-3- fluorophenyl}-2,6-dimethylpiperazine-l-carboxylate (1.5 g, 31.58%) as an off-white solid. LCMS: C25H29BrFN5O2 requires: 529.2, found: m/z = 530.4 [M+H]+.
[0001005] Step-4: Synthesis of tert-butyl (21?.,61?)-4-[4-(4-]5-chloro-2-fluoro-3- [(pyrrolidine-l-sulfonyl)amino]phenvn-3-(pyridin-4-yl)pyrazol-l-yl)-3-fluorophenyl]- 2,6-dimethylpiperazine-l-carboxylate (5)
[0001006] To a mixture of tert-butyl (2A,6A)-4-{4-[4-bromo-3-(pyridin-4-yl)pyrazol-l- yl]-3-fluorophenyl}-2,6-dimethylpiperazine-l-carboxylate (500 mg, 0.943 mmol, 1 equiv) and 7V-[5-chl oro-2 -fluoro-3-(4, 4,5, 5-tetramethyl- 1,3, 2-dioxaborolan-2-yl)phenyl]pyrrolidine-l- sulfonamide (382 mg, 0.943 mmol, 1 equiv) in dioxane (10 mL) was added Pd(AMPHOS)2C12 (67 mg, 0.094 mmol, 0.1 equiv) and CsF (286 mg, 1.886 mmol, 2 equiv) in H2O (2 mL). The resulting mixture was stirred at 90 °C for one hour under a nitrogen atmosphere. The resulting mixture was then concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 :2). The residue was then purified by trituration with EtOAc. This resulted in tert-butyl (2A,6A)-4-[4-(4-{5-chloro-2-fluoro-3-[(pyrrolidine-l- sulfonyl)amino]phenyl}-3-(pyridin-4-yl)pyrazol-l-yl)-3-fluorophenyl]-2,6- dimethylpiperazine-1 -carboxylate (190 mg, 26.29%) as a white solid. LCMS: C35H40CIF2N7O4S requires: 727.2, found: m/z = 728.3 [M+H]+.
[0001007] Step-5: Synthesis of V-|5-chloro-3-(l-!4-|(3/?.5/?)-3.5-diinethylpiperazin-l- yl]-2-fluorophenvn-3-(pyridin-4-yl)pyrazol-4-yl)-2-fluorophenyl]pyrrolidine-l- sulfonamide trifluoroacetic acid salt (6)
[0001008] A mixture of tert-butyl (2A,6A)-4-[4-(4-{5-chloro-2-fluoro-3-[(pyrrolidine-l- sulfonyl)amino]phenyl}-3-(pyridin-4-yl)pyrazol-l-yl)-3-fluorophenyl]-2,6- dimethylpiperazine-1 -carboxylate (190 mg, 0.261 mmol, 1 equiv) in TFA (2 mL) was stirred at 0 °C for one hour. The resulting mixture was concentrated under vacuum and lyophilized. Thi s resulted in TV- [ 5 -chi oro-3 -( 1 - { 4-[(3 R, 5R)-3 , 5 -dimethylpiperazin- 1 -yl] -2-fluorophenyl } -3 - (pyridin-4-yl)pyrazol-4-yl)-2-fluorophenyl]pyrrolidine-l -sulfonamide trifluoroacetic acid salt (133.3 mg, crude) as a yellow solid. LCMS: C30H32CIF2N7O2S requires: 627.2, found: m/z = 628.2 [M+H]+. 'HNMR (400 MHz, Methanol-^) 8 8.80 - 8.71 (m, 2H), 8.41 - 8.32 (m, 1H), 8.15 - 8.09 (m, 2H), 7.87 - 7.78 (m, 1H), 7.67 - 7.60 (m, 1H), 7.37 - 7.30 (m, 1H), 7.13 - 7.00 (m, 2H), 3.90 - 3.78 (m, 2H), 3.70 - 3.61 (m, 2H), 3.41 - 3.33 (m, 3H), 3.33 - 3.28 (m, 3H), 1.96 - 1.85 (m, 4H), 1.52 - 1.46 (m, 6H). [0001009] Synthesis _ of _ \-|5-chloro-2-nuoro-3-(l-!2-nuoro-4-|(2.V)-2- methylDiDerazin-l-yl]Dhenvn-3-(Dyridin-4-yl)Dyrazol-4-yl)Dhenyl]Dyrrolidine-l- sulfonamide trifluoroacetic acid salt (6)
tep-
[0001010] Step-1: Synthesis of tert-butyl (35l)-4-(4-chloro-3-fluorophenyl)-3- methylpiperazine-l-carboxylate (2) [0001011] To a mixture of 4-bromo-l-chloro-2-fluorobenzene (8 g, 38.197 mmol, 1 equiv) and tert-butyl (35)-3-methylpiperazine-l-carboxylate (7.7 g, 38.197 mmol, 1 equiv) in toluene (100 mL) was added Pd2(dba)s (350 mg, 0.382 mmol, 0.01 equiv), Z-BuONa (5.1 g, 53.476 mmol, 1.4 equiv), and BINAP (476 mg, 0.764 mmol, 0.02 equiv). The resulting mixture was stirred at 60 °C overnight under a nitrogen atmosphere. The resulting mixture was then concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (5: 1) to afford tert-butyl (35)-4-(4-chloro-3-fluorophenyl)-3- m ethylpiperazine- 1 -carboxylate (8 g, 37.82%) as a yellow oil. LCMS: C16H22CIFN2O2 requires: 328.1, found: m/z = 329.2 [M+H]+.
[0001012] Step-2: Synthesis of tert-butyl (3 l)-4-[3-fluoro-4-(4.,4.,5.,5-tetramethyl-l.,3.,2- dioxaborolan-2-yl)phenyl]-3-methylpiperazine-l-carboxylate (3)
[0001013] To a mixture of tert-butyl (35)-4-(4-chloro-3-fluorophenyl)-3- m ethylpiperazine- 1 -carboxylate (5 g, 15.206 mmol, 1 equiv) and 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (B2Pin2) (5.8 g, 22.809 mmol, 1.5 equiv) in methoxy cyclopentane (70 mL) was added Pd2(dba)s (418 mg, 0.456 mmol, 0.03 equiv), KOAc (4.5 g, 45.618 mmol, 3 equiv), and XPhos (435 mg, 0.912 mmol, 0.06 equiv). The resulting mixture was stirred at 110 °C for 3 h under a nitrogen atmosphere. The resulting mixture was then concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (9: 1) to afford tert-butyl (35)-4-[3-fhioro-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]-3-methylpiperazine-l-carboxylate (5 g, 70.40%) as a brown solid. LCMS: C22H34BFN2O4 requires: 420.2, found: m/z = 421.3 [M+H]+.
[0001 14] Step-3: Synthesis of tert-butyl (3S)-4-14-[4-bromo-3-(pyridin-4-yl)pyrazol- l-yl]-3-fluorophenvn-3-methylpiperazine-l-carboxylate (4):
[0001015] To a mixture of tert-butyl (35)-4-[3-fhioro-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]-3-methylpiperazine-l-carboxylate (2.5 g, 5.948 mmol, 1 equiv) and 4-(4-bromo-lJ/-pyrazol-3-yl)pyridine (1.5 g, 6.543 mmol, 1.1 equiv) in pyridine (30 mL) was added Cu(OAc)2 (2.2 g, 11.896 mmol, 2 equiv) and molecular sieves type 4A (2.5 g). The resulting mixture was stirred at 60 °C overnight under an oxygen atmosphere. The resulting mixture was then extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 : 1). The residue was then purified by trituration with EtOAc. This resulted in tert-butyl (35)- 4-{4-[4-bromo-3-(pyridin-4-yl)pyrazol-l-yl]-3-fluorophenyl}-3-methylpiperazine-l- carboxylate (1 g, 29.30%) as an off-white semi-solid. LCMS: C24H27BrFNsO2 requires: 515.1, found: m/z = 516.3 [M+H]+.
[0001016] Step-4: Synthesis of tert-butyl (3S)-4-[4-(4-]5-chloro-2-fluoro-3- [(pyrrolidine-l-sulfonyl)amino]phenvn-3-(pyridin-4-yl)pyrazol-l-yl)-3-fluorophenyl]-3- methylpiperazine-l-carboxylate (5):
[0001017] To a mixture of tert-butyl (35)-4-{4-[4-bromo-3-(pyridin-4-yl)pyrazol-l-yl]-3- fluorophenyl] -3 -methylpiperazine- 1 -carboxylate (500 mg, 0.968 mmol, 1 equiv) and 7V-[5- chloro-2-fluoro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]pyrrolidine-l- sulfonamide (392 mg, 0.968 mmol, 1 equiv) in dioxane (10 mL) was added Pd(AMPHOS)2C12 (69 mg, 0.097 mmol, 0.1 equiv) and CsF (294 mg, 1.936 mmol, 2 equiv) in H2O (2 mL). The resulting mixture was stirred at 90 °C for one hour under a nitrogen atmosphere. The resulting mixture was then concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 :2). The residue was purified by trituration with EtOAc. This resulted in tert-butyl (35)-4-[4-(4-{5-chloro-2-fhroro-3-[(pyrrolidine-l- sulfonyl)amino]phenyl } -3 -(pyridin-4-yl)pyrazol-l-yl)-3-fluorophenyl]-3 -methylpiperazine- 1- carboxylate (200 mg, 27.48%) as a white solid. LCMS: C34H38CIF2N7O4S requires: 713.2, found: m/z = 714.3 [M+H]+.
[0001018] Step-5: Synthesis of A-[5-chloro-2-fluoro-3-(l-12-fluoro-4-[ -2- methylpiperazin-l-yl]phenvn-3-(pyridin-4-yl)pyrazol-4-yl)phenyl]pyrrolidine-l- sulfonamide trifluoroacetic acid salt (6)
[0001019] A mixture of tert-butyl (35)-4-[4-(4-{5-chloro-2-fluoro-3-[(pyrrolidine-l- sulfonyl)amino]phenyl } -3 -(pyridin-4-yl)pyrazol-l-yl)-3-fluorophenyl]-3 -methylpiperazine- 1- carboxylate (200 mg, 0.280 mmol, 1 equiv) in TFA (2 mL) was stirred at 0 °C for one hour. The resulting mixture was then concentrated under vacuum and lyophilized. This resulted in A-[5-chloro-2-fluoro-3-(l-{2-fluoro-4-[(2A)-2-methylpiperazin-l-yl]phenyl}-3-(pyridin-4- yl)pyrazol-4-yl)phenyl]pyrrolidine-l -sulfonamide trifluoroacetic acid salt (144.3 mg, crude) as a yellow solid. LCMS: C29H30CIF2N7O2S requires: 613.1, found: m/z = 614.2 [M+H]+. JH NMR (400 MHz, Methanol-^) 8 8.78 - 8.72 (m, 2H), 8.41 - 8.36 (m, 1H), 8.11 - 8.04 (m, 2H), 7.89 - 7.80 (m, 1H), 7.67 - 7.29 (m, 2H), 7.12 - 7.00 (m, 2H), 4.39 - 4.31 (m, 1H), 3.75 - 3.66 (m, 1H), 3.54 - 3.34 (m, 4H), 3.34 - 3.33 (m, 3H), 3.33 - 3.24 (m, 2H), 1.96 - 1.85 (m, 4H), 1.36 - 1.23 (m, 3H). [0001020] Synthesis of N- f5-chloro-2-fluoro-3-(l-]2-fluoro-4-[(21?)-2- methylDiDerazin-l-yl]Dhenvn-3-(Dyridin-4-yl)Dyrazol-4-yl)Dhenyl]Dyrrolidine-l- sulfonamide trifluoroacetic acid salt (6)
[0001021 ] Step-1: Synthesis of te -butyl (37?)-4-(4-chloro-3-fluorophenyl)-3- methylpiperazine-l-carboxylate (2)
[0001022] To a mixture of 4-bromo-l-chloro-2-fluorobenzene (8 g, 38.197 mmol, 1 equiv) and tert-butyl (3R)-3 -methylpiperazine- 1 -carboxylate (7.65 g, 38.197 mmol, 1 equiv) in toluene (80 mL) was added BINAP (0.48 g, 0.764 mmol, 0.02 equiv), Z-BuONa (5.14 g, 53.476 mmol, 1.4 equiv), and Pd2(dba)s (0.35 g, 0.382 mmol, 0.01 equiv). The resulting mixture was stirred at 60 °C overnight under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (4: 1) to afford tert-butyl (3/?)-4-(4-chl oro-3 - fluorophenyl)-3 -methylpiperazine- 1 -carboxylate (6 g, 47.77%) as a yellow oil. LCMS: C16H22CIFN2O2 requires: 328.1, found: m/z = 329.0 [M+H]+.
[0001023] Step-2: Synthesis of tert-butyl (31?)-4-[3-fluoro-4-(4.,4.,5.,5-tetramethyl-l.,3.,2- dioxaborolan-2-yl)phenyl]-3-methylpiperazine-l-carboxylate (3)
[0001024] To a mixture of tert-butyl (37?)-4-(4-chloro-3-fluorophenyl)-3- m ethylpiperazine- 1 -carboxylate (6 g, 18.248 mmol, 1 equiv) and 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (B2Pin2) (6.95 g, 27.372 mmol, 1.5 equiv) in methoxycyclopentane (60 mL) was added AcOK (5.37 g, 54.744 mmol, 3 equiv), XPhos (0.52 g, 1.095 mmol, 0.06 equiv), andPd2(dba)s (0.5 g, 0.547 mmol, 0.03 equiv). The resulting mixture was stirred at 110 °C for 3 h under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (8: 1) to afford tert-butyl (3 ’)-4-[3-fluoro-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]-3-methylpiperazine-l-carboxylate (6 g, 78.23%) as a yellow solid. LCMS: C22H34BFN2O4 requires: 420.3, found: m/z = 421.1 [M+H]+.
[0001025] Step-3: Synthesis of tert-butyl -4-I4-[4-bromo-3-(pyridin-4-yl)pyrazol- l-yl]-3-fluorophenvn-3-methylpiperazine-l-carboxylate (4)
[0001026] To a mixture of tert-butyl (3/?)-4-[3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]-3-methylpiperazine-l-carboxylate (3 g, 7.137 mmol, 1 equiv) and 4-(4-bromo-lJ/-pyrazol-3-yl)pyridine (1.76 g, 7.851 mmol, 1.1 equiv) in pyridine (30 mL) was added Cu(OAc)2 (2.59 g, 14.274 mmol, 2 equiv) and molecular sieves (4A) (3 g). The resulting mixture was stirred at 60 °C overnight under an oxygen atmosphere. The resulting mixture was then extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 : 1) to afford tert-butyl (37?)-4- {4-[4-bromo-3 -(pyridin-4-yl)pyrazol- 1 -y 1 ] -3 -fluorophenyl }-3 - methylpiperazine- 1 -carboxylate (2 g, 54.26%) as a white solid. LCMS: C24H27BrFNsO2 requires: 515.1, found: m/z = 516.1 [M+H]+.
[0001027] Step-4: Synthesis of tert-butyl -4-[4-(4-]5-chloro-2-fluoro-3- [(pyrrolidine-l-sulfonyl)amino]phenvn-3-(pyridin-4-yl)pyrazol-l-yl)-3-fluorophenyl]-3- methylpiperazine-l-carboxylate (5)
[0001028] To a stirred solution of tert-butyl (37?)-4-{4-[4-bromo-3-(pyridin-4-yl)pyrazol- l-yl]-3-fluorophenyl}-3-methylpiperazine-l-carboxylate (500 mg, 0.968 mmol, 1 equiv) and 7V-[5-chl oro-2 -fluoro-3-(4, 4,5, 5-tetramethyl- 1,3, 2-dioxaborolan-2-yl)phenyl]pyrrolidine-l- sulfonamide (391 mg, 0.968 mmol, 1 equiv) in dioxane (5 mL) was added Pd(AMPHOS)2C12 (68 mg, 0.097 mmol, 0.1 equiv) and CsF (294 mg, 1.936 mmol, 2 equiv) in FEO (1 mL). The resulting mixture was stirred at 90 °C for one hour under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 :4) to afford tert-butyl (37?)-4-[4-(4-{5- chloro-2-fluoro-3 -[(pyrrolidine- l-sulfonyl)amino]phenyl] -3 -(pyridin-4-yl)pyrazol- l-yl)-3- fluorophenyl]-3 -methylpiperazine- 1 -carboxylate (450 mg, 65.07%) as a white solid. LCMS: C34H38CIF2N7O4S requires: 713.2, found: m/z = 714.0 [M+H]+.
[0001029] Step-5: Synthesis of .\-|5-chloro-2-fluoro-3-(l-!2-nuoro-4-|(2/ )-2- methylpiperazin-l-yl]phenvn-3-(pyridin-4-yl)pyrazol-4-yl)phenyl]pyrrolidine-l- sulfonamide trifluoroacetic acid salt (6)
[0001030] A mixture of tert-butyl (3A)-4-[4-(4-{5-chloro-2-fluoro-3-[(pyrrolidine-l- sulfonyl)amino]phenyl } -3 -(pyridin-4-yl)pyrazol-l-yl)-3-fluorophenyl]-3 -methylpiperazine- 1- carboxylate (450 mg, 0.630 mmol, 1 equiv) in TFA (5 mL) was stirred at 0 °C for one hour. The resulting mixture was then concentrated under reduced pressure. The crude product was purified by prep-HPLC with the following conditions: Column: Xcelect CSH F-pheny OBD Column 19 x 250 mm, 5 pm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: MeOH; Flow rate: 25 mL/min; Gradient: 30% B to 45% B in 12 min; Wave Length: 254/220 nm to afford TV- [ 5 -chloro-2-fluoro-3 -( 1 - { 2-fluoro-4- [(2/?)-2-m ethyl pi perazi n- 1 -yl]phenyl } -3 -
(pyridin-4-yl)pyrazol-4-yl)phenyl]pyrrolidine-l -sulfonamide trifluoroacetic acid salt (149.4 mg, 32.57%) as a yellow solid. LCMS: C29H30CIF2N7O2S requires: 613.2, found: m/z = 614.3 [M+H]+. 1 H NMR (400 MHz, Methanol-^) 8 8.78 - 8.69 (m, 2H), 8.41 - 8.36 (m, 1H), 8.11 - 8.01 (m, 2H), 7.89 - 7.80 (m, 1H), 7.67 - 7.60 (m, 1H), 7.36 - 7.29 (m, 1H), 7.12 - 7.01 (m, 2H), 4.39 - 4.30 (m, 1H), 3.75 - 3.65 (m, 1H), 3.54 - 3.44 (m, 2H), 3.43 - 3.38 (m, 2H), 3.37 - 3.34 (m, 2H), 3.33 (s, 2H), 3.32 (s, 1H), 1.98 - 1.84 (m, 4H), 1.33 - 1.20 (m, 3H).
[0001031] Synthesis of -3.,5-dimethylDiDerazin-l-yl]-2- fluoroDhenyn-3-(Dyridin-4-yl)Dyrazol-4-yl)-2.,5-difluoroDhenyl]Dyrrolidine-l- sulfonamide trifluoroacetic acid salt (3) [0001032] Step-1: Synthesis of tert-butyl -[4-(4-f2.,5-difluoro-3- [(pyrrolidine-l-sulfonyl)amino]phenvn-3-(pyridin-4-yl)pyrazol-l-yl)-3-fluorophenyl]- 2,6-dimethylpiperazine-l-carboxylate (2)
[0001033] To a mixture of tert-butyl (2A,6A)-4-{4-[4-bromo-3-(pyridin-4-yl)pyrazol-l- yl]-3-fluorophenyl]-2,6-dimethylpiperazine-l-carboxylate (500 mg, 0.943 mmol, 1 equiv) and 7V-[2,5-difluoro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]pyrrolidine-l- sulfonamide (366 mg, 0.943 mmol, 1 equiv) in dioxane (7.5 mL) was added Pd(AMPHOS)2C12 (67 mg, 0.094 mmol, 0.1 equiv) and CsF (286 mg, 1.886 mmol, 2 equiv) in H2O (1.5 mL). The resulting mixture was stirred at 90 °C for one hour under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 :2) to afford tert-butyl (2/?,6/?)-4-[4-(4- { 2,5- difluoro-3 -[(pyrrolidine- 1 -sulfonyl)amino]phenyl } -3 -(pyridin-4-yl)pyrazol- 1 -y l)-3 - fluorophenyl]-2,6-dimethylpiperazine-l-carboxylate (300 mg, 42.48%) as a white solid. LCMS : C35H40F3N7O4S requires: 711.3, found: m/z = 712.3 [M+H]+.
[0001034] Step-2: Synthesis of V-|3-(l-!4- -3.5-diinethylpiperazin-l-yl|-2- fluorophenvn-3-(pyridin-4-yl)pyrazol-4-yl)-2.,5-difluorophenyl]pyrrolidine-l- sulfonamide trifluoroacetic acid salt (3)
[0001035] A mixture of tert-butyl (2A,6A)-4-[4-(4-{2,5-difluoro-3-[(pyrrolidine-l- sulfonyl)amino]phenyl}-3-(pyridin-4-yl)pyrazol-l-yl)-3-fluorophenyl]-2,6- dimethylpiperazine-1 -carboxylate (30 mg, 0.042 mmol, 1 equiv) in TFA (1 mL) was stirred at 0 °C for one hour. The resulting mixture was concentrated under vacuum and lyophilized. This resulted in A-[3-(l-{4-[(3A,5A)-3,5-dimethylpiperazin-l-yl]-2-fhiorophenyl}-3-(pyridin-4- yl)pyrazol-4-yl)-2,5-difluorophenyl]pyrrolidine-l-sulfonamide trifluoroacetic acid salt (16 mg, crude) as a yellow solid. LCMS: C30H32F3N7O2S requires: 611.2, found: m/z = 612.3 [M+H]+. 'HNMR (400 MHz, Methanol-^) 8 8.83 - 8.72 (m, 2H), 8.42 - 8.34 (m, 1H), 8.18 - 8.09 (m, 2H), 7.90 - 7.78 (m, 1H), 7.50 - 7.36 (m, 1H), 7.15 - 7.00 (m, 3H), 3.92 - 3.76 (m, 2H), 3.71 - 3.59 (m, 2H), 3.41 - 3.34 (m, 2H), 3.33 - 3.28 (m, 4H), 2.00 - 1.80 (m, 4H), 1.59 - 1.42 (m, 6H).
[0001036] Synthesis of 7V-(3-H- difluoro-4-(piperazin-l-yl)phenyl]-3-(pyridin-4- yl)pyrazol-4- 2.,5-difluorophenyl)pyrrolidine-l-sulfonamide trifluoroacetic acid salt (6)
[0001037] Step-1: Synthesis of tert-butyl 4-(4-bromo-2.,3-difluorophenyl)piperazine- 1-carboxylate (2)
[0001038] To a mixture of l,4-dibromo-2,3-difluorobenzene (8 g, 29.424 mmol, 1 equiv) and tert-butyl piperazine- 1 -carboxylate (6.03 g, 32.366 mmol, 1.1 equiv) in toluene (150 mL) was added BINAP (1.1 g, 1.765 mmol, 0.06 equiv), Z-BuONa (3.39 g, 35.309 mmol, 1.2 equiv), and Pd2(dba)s (1.62 g, 1.769 mmol, 0.06 equiv). The resulting mixture was stirred at 85 °C overnight under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (3: 1) to afford tert-butyl 4-(4-bromo-2,3-difluorophenyl)piperazine-l -carboxylate (8 g, 72.07%) as an orange solid. LCMS: CisHi9BrF2N2O2 requires: 376.1, found: m/z = 377.0 [M+H]+.
[0001039] Step-2: Synthesis of tert-butyl 4-[2,3-difluoro-4-(4.,4.,5.,5-tetramethyl-l.,3.,2- dioxaborolan-2-yl)phenyl] piperazine-l-carboxylate (3)
[0001040] To a mixture of tert-butyl 4-(4-bromo-2,3-difluorophenyl)piperazine-l- carboxylate (6 g, 15.905 mmol, 1 equiv) and 4,4,5,5-tetramethyl-2-(tetramethyl-l,3,2- dioxaborolan-2-yl)-l,3,2-dioxaborolane (B2Pin2) (8.08 g, 31.810 mmol, 2 equiv) in 1,4- dioxane (100 mL) was added AcOK (3.12 g, 31.810 mmol, 2 equiv) and Pd(dppf)C12 (1.3 g, 1.591 mmol, 0.1 equiv). The resulting mixture was stirred at 90 °C overnight under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (4: 1) to afford tertbutyl 4-[2,3-difluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]piperazine-l- carboxylate (5.6 g, 82.98%) as an orange solid. LCMS: C21H31BF2N2O4 requires: 424.2, found: m/z = 425.3 [M+H]+.
[0001041] Step-3: Synthesis of tert-butyl 4-I4-[4-bromo-3-(pyridin-4-yl)pyrazol-l-yl]- 2,3-difluorophenvnpiperazine-l-carboxylate (4)
[0001042] To a mixture of tert-butyl 4-[2,3-difluoro-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]piperazine-l -carboxylate (5.6 g, 13.198 mmol, 1 equiv) and 4-(4- bromo-17/-pyrazol-3-yl)pyridine (3.25 g, 14.518 mmol, 1.1 equiv) in pyridine (50 mL) was added Cu(OAc)2 (4.79 g, 26.396 mmol, 2 equiv) and molecular sieves (4A) (5.6 g). The resulting mixture was stirred at 60 °C overnight under an oxygen atmosphere. The resulting mixture was then extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 : 1) to afford tert-butyl 4-{4-[4-bromo-3-(pyridin-4-yl)pyrazol-l-yl]-2,3- difluorophenyl (piperazine- 1 -carboxylate (700 mg, 10.19%) as a white solid. LCMS: C23H24BrF2NsO2 requires: 519.1, found: m/z = 520.1 [M+H]+.
[0001043 ] Step-4: Synthesis of tert-butyl 4-[4-(4-12.,5-difluoro-3-[(pyrrolidine-l- sulfonyl)amino]phenvn-3-(pyridin-4-yl)pyrazol-l-yl)-2.,3-difluorophenyl]piperazine-l- carboxylate (5)
[0001044] To a mixture of tert-butyl 4-{4-[4-bromo-3-(pyridin-4-yl)pyrazol-l-yl]-2,3- difluorophenyl (piperazine- 1 -carboxylate (600 mg, 1.153 mmol, 1 equiv) and A-[2,5-difluoro- 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]pyrrolidine-l -sulfonamide (447 mg, 1.153 mmol, 1 equiv) in dioxane (5 mL) was added Pd(AMPHOS)2C12 (81 mg, 0.115 mmol, 0.1 equiv) and CsF (350 mg, 2.306 mmol, 2 equiv) in FEO (1 mL). The resulting mixture was stirred at 90 °C for one hour under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (2:3). The residue was then purified by trituration with EtOAc. This resulted in tert-butyl 4-[4-(4-{2,5-difluoro-3-[(pyrrolidine-l- sulfonyl)amino]phenyl(-3-(pyridin-4-yl)pyrazol-l-yl)-2,3-difluorophenyl]piperazine-l- carboxylate (400 mg, 49.44%) as a white solid. LCMS: C33H35F4N7O4S requires: 701.2, found: m/z = 702.3 [M+H]+.
[0001045] Step-5: Synthesis of A-(3-H-[2.,3-difluoro-4-(piperazin-l-yl)phenyl]-3- (pyridin-4-yl)pyrazol-4-vn-2.,5-difluorophenyl)pyrrolidine-l-sulfonamide trifluoroacetic acid salt (6)
[0001046] A mixture of tert-butyl 4-[4-(4-{2,5-difluoro-3-[(pyrrolidine-l- sulfonyl)amino]phenyl(-3-(pyridin-4-yl)pyrazol-l-yl)-2,3-difluorophenyl]piperazine-l- carboxylate (400 mg, 0.570 mmol, 1 equiv) in TFA (4 mL) was stirred at 0 °C for hone hour. The resulting mixture was then concentrated under vacuum and lyophilized. This resulted in N-(3 - { 1 - [2, 3 -difluoro-4-(piperazin- 1 -yl)phenyl] -3 -(pyridin-4-yl)pyrazol-4-yl (-2,5- difluorophenyl)pyrrolidine-l -sulfonamide trifluoroacetic acid salt (376.6 mg, crude) as a yellow solid. LCMS: C28H27F4N7O2S requires: 601.2, found: m/z = 602.3 [M+H]+. 'H NMR (400 MHz, Methanol-t/4) 8 8.89 - 8.77 (m, 2H), 8.51 - 8.46 (m, 1H), 8.21 - 8.14 (m, 2H), 7.79 - 7.70 (m, 1H), 7.47 - 7.37 (m, 1H), 7.19 - 7.05 (m, 2H), 3.52 - 3.43 (m, 8H), 3.37 - 3.35 (m, 1H), 3.34 - 3.33 (m, 3H), 1.98 - 1.86 (m, 4H). [0001047] Synthesis of \-|2.5-diniioro-3-(l-!4-|(3/?)-3-nietliylpiperazin-l- 3-(pyridin-4-yl)pyrazol-4-yl)phenyl]pyrrolidine-l-sulfonamide trifluoroacetic acid salt (3)
[0001048] Step-1: Synthesis of tert-butyl (21?)-4-[4-(4-]2.,5-difluoro-3-[(Dyrrolidine-l- sulfonyl)amino]Dhenyn-3-(Dyridin-4-yl)Dyrazol-l-yl)Dhenyl]-2-methylDiDerazine-l- carboxylate (2)
[0001049] To a mixture of tert-butyl (27?)-4-{4-[4-bromo-3-(pyridin-4-yl)pyrazol-l- yl]phenyl}-2-methylpiperazine-l -carboxylate (80 mg, 0.161 mmol, 1 equiv) and 7V-[2,5- difluoro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]pyrrolidine-l-sulfonamide (62 mg, 0.161 mmol, 1 equiv) in dioxane (1 mL) was added Pd(AMPHOS)2C12 (11 mg, 0.016 mmol, 0.1 equiv) and CsF (49 mg, 0.322 mmol, 2 equiv) in H2O (0.2 mL). The resulting mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. The resulting mixture was then concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (2:3). The residue was then purified by trituration with EtOAc. This resulted in tert-butyl (2A)-4-[4-(4-{2,5-difluoro-3-[(pyrrolidine-l- sulfonyl)amino]phenyl } -3 -(pyridin-4-yl)pyrazol- 1 -yl)phenyl]-2-methylpiperazine- 1 - carboxylate (20 mg, 17.41%) as an off-white solid. LCMS: C34H39F2N7O4S requires: 679.2, found: m/z = 680.4 [M+H]+.
[0001050] Step-2: Synthesis of V-|2.5-diniioro-3-( l-!4-|(3/?)-3-iiietliylpiperaziii-l- yl]Dhenyn-3-(Dyridin-4-yl)Dyrazol-4-yl)Dhenyl]Dyrrolidine-l-sulfonamide trifluoroacetic acid salt (3)
[0001051] A mixture of tert-butyl (2A)-4-[4-(4-{2,5-difhroro-3-[(pyrrolidine-l- sulfonyl)amino]phenyl } -3 -(pyridin-4-yl)pyrazol- 1 -yl)phenyl]-2-methylpiperazine- 1 - carboxylate (20 mg, 0.029 mmol, 1 equiv) in TFA (1 mL) was stirred at 0 °C for one hour. The resulting mixture was then concentrated under vacuum and lyophilized. This resulted in N- [2,5-difhioro-3-(l-{4-[(3A)-3-methylpiperazin-l-yl]phenyl}-3-(pyridin-4-yl)pyrazol-4- yl)phenyl]pyrrolidine-l -sulfonamide trifluoroacetic acid salt (11 mg, crude) as a yellow solid. LCMS: C29H31F2N7O2S requires: 579.2, found: m/z = 580.3 [M+H]+. 'H NMR (400 MHz, Methanol-t/4) 8 8.81 - 8.75 (m, 2H), 8.62 - 8.58 (m, 1H), 8.23 - 8.16 (m, 2H), 7.94 - 7.86 (m, 2H), 7.46 - 7.37 (m, 1H), 7.29 - 7.20 (m, 2H), 7.14 - 7.06 (m, 1H), 4.00 - 3.86 (m, 2H), 3.63 - 3.50 (m, 2H), 3.41 - 3.29 (m, 5H), 3.19 - 3.07 (m, 1H), 2.96 - 2.85 (m, 1H), 1.98 - 1.85 (m, 4H), 1.48 - 1.42 (m, 3H).
[0001052] Synthesis of 7V-[2.,5-difluoro-3-(l-12-fluoro-4- -methylDiDerazin-l- yl]Dhenvn-3-(Dyridin-4-yl)Dyrazol-4-yl)Dhenyl]Dyrrolidine-l-sulfonamide trifluoroacetic acid salt (6)
Step-1 [0001053] Step-1: Synthesis of te -butyl (27?)-4-(4-chloro-3-fluorophenyl)-2- methylpiperazine-l-carboxylate (2)
[0001054] To a mixture of 4-bromo-l-chloro-2-fluorobenzene (8 g, 38.197 mmol, 1 equiv) and tert-butyl (27?)-2-methylpiperazine-l -carboxylate (7.65 g, 38.196 mmol, 1 equiv) in toluene (80 mL) was added BINAP (0.48 g, 0.764 mmol, 0.02 equiv), Z-BuONa (5.14 g, 53.476 mmol, 1.4 equiv), and Pd2(dba)s (0.35 g, 0.382 mmol, 0.01 equiv). The resulting mixture was stirred at 60 °C overnight under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 : 1) to afford tert-butyl (2/?)-4-(4-chl oro-3 - fluorophenyl)-2-methylpiperazine-l -carboxylate (10 g, 79.62%) as a white solid. LCMS: C16H22CIFN2O2 requires: 328.1, found: m/z = 329.0 [M+H]+.
[0001055] Step-2: Synthesis of tert-butyl (21?)-4-[3-fluoro-4-(4.,4.,5.,5-tetramethyl-l.,3.,2- dioxaborolan-2-yl)phenyl]-2-methylpiperazine-l-carboxylate (3)
[0001056] To a mixture of tert-butyl (27?)-4-(4-chloro-3-fluorophenyl)-2- m ethylpiperazine- 1 -carboxylate (10 g, 30.413 mmol, 1 equiv) and 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (B2Pin2) (11.58 g, 45.620 mmol, 1.5 equiv) in methoxycyclopentane (100 mL) was added XPhos (0.87 g, 1.825 mmol, 0.06 equiv), AcOK (8.95 g, 91.239 mmol, 3 equiv), and Pd2(dba)s (0.84 g, 0.912 mmol, 0.03 equiv). The resulting mixture was stirred at 110 °C overnight under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (9: 1) to afford tert-butyl (2/?)-4-[3- fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]-2-methylpiperazine-l- carboxylate (12 g, 93.87%) as a brown oil. LCMS: C22H34BFN2O4 requires: 420.3, found: m/z = 421.1 [M+H]+.
[0001057] Step-3: Synthesis of tert-butyl -4-I4-[4-bromo-3-(pyridin-4-yl)pyrazol- l-yl]-3-fluorophenvn-2-methylpiperazine-l-carboxylate (4)
[0001058] To a mixture of tert-butyl (2/?)-4-[3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]-2-methylpiperazine-l-carboxylate (5 g, 11.895 mmol, 1 equiv) and 4-(4-bromo-lJ/-pyrazol-3-yl)pyridine (2.93 g, 13.085 mmol, 1.1 equiv) in pyridine (50 mL) was added Cu(OAc)2 (4.32 g, 23.790 mmol, 2 equiv) and molecular sieves (4A) (5 g). The resulting mixture was stirred at 60 °C overnight under an oxygen atmosphere. The resulting mixture was then extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (1 : 1) to afford tert-butyl (2A)-4-{4-[4-bromo-3-(pyridin-4-yl)pyrazol-l-yl]-3-fluorophenyl}- 2-methylpiperazine-l -carboxylate (2.1 g, 34.19%) as a white solid. LCMS: C24H27BrFNsO2 requires: 515.1, found: m/z = 516.1 [M+H]+.
[0001059] Step-4: Synthesis of tert-butyl (21?)-4-[4-(4-12.,5-difluoro-3-[(pyrrolidine-l- sulfonyl)amino]phenvn-3-(pyridin-4-yl)pyrazol-l-yl)-3-fluorophenyl]-2- methylpiperazine-l-carboxylate (5)
[0001060] To a mixture of tert-butyl (2A)-4-{4-[4-bromo-3-(pyridin-4-yl)pyrazol-l-yl]-3- fluorophenyl }-2-m ethylpiperazine- 1 -carboxylate (55 mg, 0.107 mmol, 1 equiv) and A- [2, 5- difluoro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]pyrrolidine-l-sulfonamide
(41 mg, 0.107 mmol, 1 equiv) in dioxane (1 mL) was added CsF (32 mg, 0.214 mmol, 2 equiv) and Pd(AMPHOS)2C12 (8 mg, 0.011 mmol, 0.1 equiv) in FEO (0.2 mL). The resulting mixture was stirred at 90 °C for one hour under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EtOAc (2:3) to afford tert-butyl (2A)-4-[4-(4-{2,5-difhroro-3- [(pyrrolidine-l-sulfonyl)amino]phenyl}-3-(pyridin-4-yl)pyrazol-l-yl)-3-fluorophenyl]-2- m ethylpiperazine- 1 -carboxylate (20 mg, 26.91%) as a yellow oil. LCMS: C34H38F3N7O4S requires: 697.3, found: m/z = 698.4 [M+H]+.
[0001061 ] Step-5: Synthesis of \-|2.5-dinuoro-3-(l-!2-nuoro-4-|(3/ )-3- methylpiperazin-l-yl]phenvn-3-(pyridin-4-yl)pyrazol-4-yl)phenyl]pyrrolidine-l- sulfonamide trifluoroacetic acid salt (6)
[0001062] A mixture of tert-butyl (2A)-4-[4-(4-{2,5-difluoro-3-[(pyrrolidine-l- sulfonyl)amino]phenyl}-3-(pyridin-4-yl)pyrazol-l-yl)-3-fluorophenyl]-2-methylpiperazine-l- carboxylate (20 mg, 0.029 mmol, 1 equiv) in TFA (1 mL) was stirred at 0 °C for one hour. The resulting mixture was then concentrated under vacuum and lyophilized. This resulted in N- [2,5-difluoro-3 -( 1 -{2-fluoro-4-[(3A)-3 -methylpiperazin- 1 -yl]phenyl } -3 -(pyridin-4- yl)pyrazol-4-yl)phenyl]pyrrolidine-l -sulfonamide trifluoroacetic acid (14 mg, crude) as a yellow solid. LCMS: C29H30F3N7O2S requires: 597.2, found: m/z = 598.3 [M+H]+. ' H NMR (400 MHz, Methanol-^) 8 8.83 - 8.72 (m, 2H), 8.43 - 8.34 (m, 1H), 8.19 - 8.09 (m, 2H), 7.93 - 7.78 (m, 1H), 7.49 - 7.38 (m, 1H), 7.19 - 7.00 (m, 3H), 4.09 - 3.90 (m, 2H), 3.64 - 3.49 (m, 2H), 3.40 - 3.34 (m, 3H), 3.32 - 3.29 (m, 2H), 3.25 - 3.11 (m, 1H), 3.03 - 2.87 (m, 1H), 2.00 - 1.84 (m, 4H), 1.53 - 1.39 (m, 3H).
[0001063] Synthesis of i-4-((6-((l?5)-2,6-dioxopiperidin-3-vl)-3,4- dihydroisoquinolin-2(LH)-yl)methyl)cyclohexane-l-carboxylic acid
[0001064] Step-1: Synthesis of tert-butyl (lr,4r)-4-formylcvclohexane-l-carboxylate
To a solution of tert-butyl (lr,4r)-4-(hydroxymethyl)cyclohexane-l-carboxylate (300.00 mg, 1.3999 mmol) in DMSO (1 mL) was added triethylamine (1.97 mL, 1416.57 mg, 13.9987 mmol) followed by the addition of sulfur trioxide pyridine complex (1.11 g, 6.9994 mmol) in DMSO (2 mL). The reaction mixture was stirred for 16 h. Additional sulfur tri oxide pyridine complex (0.56 g, 3.5mmol) in DMSO (0.5 mL) and tri ethylamine (0.985 mL, 7 mmol) was added after 16 h. The reaction was complete as indicated by TLC. z-PrOH (0.5 mL) was added to the reaction mixture. After stirring for three hours, the reaction mixture was concentrated under reduced pressure. The crude material was used in the next step without purification.
[0001065] Step-2: tert-butyl (ll?.,4r)-4-((6-((l?ty)-2.,6-dioxopiperidin-3-yl)-3.,4- dihvdroisoquinolin-2(lH)-yl)methyl)cvclohexane-l-carboxylate
To a solution of rac-(3A)-3-(l,2,3,4-tetrahydroisoquinolin-6-yl)piperidine-2,6-dione (100.00 mg, 0.4093 mmol) and tert-butyl (lr,4r)-4-formylcyclohexane-l-carboxylate (86.90 mg, 0.4093 mmol) in 2 ml DMSO (2 mL) was added triethylamine ( 57.5 pL, 0.41 mmol) and sodium triacetoxyborohydride (0.26 g, 1.2280 mmol) and the reaction mixture was stirred for thirty minutes. EtOAc (30 mL) was added and the organic solution was washed with water and brine, dried over sodium sulfate, filtered, and concentrated. The crude product was loaded onto a Redi-Sep prepacked silica gel column eluting with MeOH in DCM (0-10%), to provide tert-butyl _ (lAAr)-4-((6-07?M-2,6-dioxopiperidin-3-yl)-3,4-dihvdroisoquinolin-2 - yl)methyl)cyclohexane-l -carboxylate (0.18 g, 99.81%). LCMS C26H36N2O4 requires: 440.3, found: m/z = 441.7 [M+H]+.
[0001066] Step-3: (l/?.4r)-4-((6-((/?.S)-2.6-dioxopiperidin-3-yl)-3.4- dihvdroisoquinolin-2(lH)-yl)methyl)cvclohexane-l-carboxylic acid
To a solution of tert-butyl (17?,4r)-4-((6-((7?5)-2,6-dioxopiperidin-3-yl)-3,4- dihydroisoquinolin-2(177)-yl)methyl)cyclohexane-l -carboxylate (180.00 mg, 0.4085 mmol) in DCM (3 mL) was added trifluoroacetic acid (1.5 mL) and the reaction was stirred for one hour. TFA and DCM were evaporated under reduced pressure and the crude product was pumped to dryness to afford (17?,4r)-4-((6-((7?y)-2,6-dioxopiperidin-3-yl)-3,4-dihydroisoquinolin-2(lJ7)- yl)methyl)cyclohexane-l -carboxylic acid in quantitative yield. LCMS C22H28N2O4 requires: 384.2, found m/z = 385.6 [M+H]+.
[0001067] Synthesis of rac-(l?)-l-(l-(5-(2.,6-dioxopiperidin-3-yl)pyridin-2- yl)piperidine-4-carbonyl)-4-methylpiperidine-4-carboxylic acid
[0001068] Step-1: rac-tert-butyl -(l-(5-(2.,6-dioxopiperidin-3-yl)pyridin-2- yl)piperidine-4-carbonyl)-4-methylpiperidine-4-carboxylate
To a solution of rac-(/?)-l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carboxylic acid (214.00 mg, 0.6743 mmol) and [(dimethylamino)({[l,2,3]triazolo[4,5-Z>]pyridin-3- yloxy})methylidene]dimethylazanium; hexafluoro-lambda5-phosphanuide (282.05 mg, 0.7418 mmol) in DMF (2 mL) was added A,A-diisopropylethylamine (435.79 mg, 3.3717 mmol). Then tert-butyl 4-methylpiperidine-4-carboxylate (147.83 mg, 0.7418 mmol) in DMF (1 mL) was added. After stirring for one hour, the crude product was dissolved in ethyl acetate (40 mL) and the solution was then washed with water and brine, dried over sodium sulfate, filtered, and concentrated. The crude product was loaded onto a Redi-Sep prepacked silica gel column eluting with MeOH in DCM (0-6%) to afford rac-tert-butyl (A)-l-(l-(5-(2,6- dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)-4-methylpiperidine-4-carboxylate (0.236 g, 70.19%). LCMS: C27H38N4O5 requires: 498.6, found: m/z = 499.6 [M+H]+.
[0001069] Step-2: rac-(l?)-l-(l-(5-(2.,6-dioxoDiDeridin-3-yl)Dyridin-2-yl)DiDeridine-4- carbonyl)-4-methylDiDeridine-4-carboxylic acid rac-tert-butyl (A)-l-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)-4- methylpiperidine-4-carboxylate (0.236 g, 0.4733mmol) was dissolved in DCM (4 mL) and then trifluoroacetic acid (2 mL) was added. The solution was stirred for three hours. TFA and DCM were evaporated under reduced pressure. The crude product was loaded onto a Redi-Sep prepacked HP Cl 8 (30 grams) column eluting with acetonitrile in water (5%-80%) to afford rac-(A)-l-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)-4- methylpiperidine-4-carboxylic acid (0.132 g, 44.23%). LCMS: C23H30N4O5 required: 442.5, found: m/z = 443.6 [M+H]+.
[0001070] Synthesis of rac-(l?)-l-(2-(l-(5-(2.,6-dioxoDiDeridin-3-yl)Dyridin-2- yl)DiDeridin-4-yl)acetyl)-4-methylpiDeridine-4-carboxylic acid [0001071 ] Step-1: rac-tert-butyl (l?)-l-(2-(l-(5-(2.,6-dioxopiperidin-3-yl)pyridin-2- yl)piperidin-4-yl)acetyl)-4-methylpiperidine-4-carboxylate
To a solution of rac-(A)-2-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)acetic acid (200.90 mg, 0.6063 mmol) and [(dimethylamino)({[l,2,3]triazolo[4,5-Z>]pyridine-3- yloxy})methylidene]dimethylazanium; hexafluoro-lambda5-phosphanuide (253.58 mg, 0.6669 mmol) in DMF (2 mL) was added 7V,7V-diisopropylethylamine (391.79 mg, 3.0313 mmol). Then tert-butyl 4-methylpiperidine-4-carboxylate (122.03 mg, 0.6123 mmol) in DMF (1 mL) was added. After stirring for one hour, the crude product was dissolved in ethyl acetate, washed with water and brine, dried over ISfeSCU, filtered, and concentrated. The crude product was loaded onto a Redi-Sep prepacked silica gel column eluting with MeOH in DCM (0-6%) to afford the desired product which was contaminated with tert-butyl 4-methylpiperidine-4- carboxylate. The crude product was dissolved in DCM, washed with NH4CI solution three times, dried over ISfeSCh, filtered, and concentrated. The product was used in the next step without purification. rac-tert-butyl (A)-l-(2-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2- yl)piperidin-4-yl)acetyl)-4-methylpiperidine-4-carboxylate (0.26g, 83.65%). LCMS: C28H40N4O5 requires: 512.3, found: m/z = 513.3 [M+H]+.
[0001072] Step-2: rac-(l?)-l-(2-(l-(5-(2.,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-
4-yl)acetyl)-4-methylpiperidine-4-carboxylic acid rac-tert-butyl (A)-l-(2-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)acetyl)-4- methylpiperidine-4-carboxylate (260.00 mg, 0.5072 mmol) was dissolved in DCM (3 mL) and trifluoroacetic acid (2 mL) was added. The solution was then stirred for three hours. TFA and DCM were evaporated under reduced pressure. The crude product was loaded onto a Redi-Sep prepacked HP Cl 8 (30 grams) column eluting with acetonitrile in water (0%-60%) to afford rac-(A)-l-(2-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)acetyl)-4- methylpiperidine-4-carboxylic acid (0.19 g, 82.06%) as white solid. LCMS: C24H32N4O5 required: 456.2, found: m/z = 457.3 [M+H]+.
[0001073] Synthesis of rac-(l?)-l-(5-(2.,6-dioxopiperidin-3-yl)pyridin-2-yl)-4- methylpiperidine-4-carboxylic acid
[0001074] Step-1 : rac-tert-butyl (l?)-l-(5-(2.,6-dioxopiperidin-3-yl)pyridin-2-yl)-4- methylpiperidine-4-carboxylate
A mixture of rac-(A)-3-(6-fluoropyri din-3 -yl)piperidine-2, 6-dione (200.00 mg, 0.9607 mmol), tert-butyl 4-methylpiperidine-4-carboxylate hydrochloride (452.95 mg, 1.9213 mmol), and A,A-diisopropylethylamine (671.14 pL, 496.65 mg, 3.8426 mmol) in DMSO (2.00 mL) was heated at 120 °C for sixteen hours. The crude product was then cooled down and water (5 mL) was added. The solution was then extracted with EtOAc twice. The organic solution was dried over sodium sulfate, filtered, and concentrated. The crude product was loaded onto a Redi-Sep prepacked silica gel column eluting with EtOAc:heptane (10-100%) to provide rac-tert-butyl (A)-l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)-4-methylpiperidine-4- carboxylate (0.3 g, 80.59%). LCMS: C21H29N3O4 required: 387.2, found: m/z = 388.5 [M+H]+.
[0001075] Step-2: rac-(l?)-l-(5-(2.,6-dioxopiperidin-3-yl)pyridin-2-yl)-4- methylpiDeridine-4-carboxylic acid rac-tert-butyl (A)-l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)-4-methylpiperidine-4- carboxylate (300.00 mg, 0.7742 mmol) was dissolved in DCM (2 mL) and then TFA (2 mL) was added. The reaction was then stirred for three hours. TFA and DCM were evaporated. The crude product was loaded onto a Redi-Sep prepacked HP C18 (30 grams) column eluting with acetonitrile: water (0-90%) to afford rac-(A)-l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)-4- methylpiperidine-4-carboxylic acid (0.21 g, 81.85%) as white solid. LCMS C17H21N3O4 requires: 331.2, found: m/z = 332.4 [M+H]+.
[0001076] Synthesis of rac-(l?)-2-(5-(2.,6-dioxopiperidin-3-yl)pyridin-2-yl)-2- azaspiro[3.3]heptane-6-carbaldehyde
[0001077] Step-1 : rac-H?)-3-(6-(6-(hvdroxymethyl)-2-azaspiro [3.3] heptan-2- yl)pyridin-3-yl)piperidine-2, 6-dione
A mixture of rac-(A)-3-(6-fluoropyri din-3 -yl)piperidine-2, 6-dione (250.00 mg, 1.2008 mmol), (2-azaspiro[3.3]heptan-6-yl)methanol (413.57 mg, 1.2008 mmol), and N,N- diisopropylethylamine (1.05 mL, 776.01 mg, 6.0041 mmol) in DMSO (2.00 mL) was heated at 120 °C for sixteen hours. The reaction mixture was lyophilized to remove DMSO. The crude product was loaded onto a Redi-Sep prepacked silica gel column eluting with MeOH in DCM (3-20%) to provide rac-(A)-3-(6-(6-(hydroxymethyl)-2-azaspiro[3.3]heptan-2- yl)pyri din-3 -yl)piperidine-2, 6-dione (0.12 g, 31.69%). LCMS: C17H21N3O3 required: 315.2, found: m/z = 316.5 [M+H]+. 'HNMR (500 MHz, CDCI3) 8 8.14 - 7.86 (m, 2H), 6.30 (d, J = 8.6 Hz, 1H), 4.06 (d, J= 9.8 Hz, 2H), 3.96 (d, J= 7.4 Hz, 2H), 3.65 (dq, J= 15.8, 8.8, 7.0 Hz, 4H), 3.52 (s, 2H), 2.80 (dt, J = 17.7, 4.8 Hz, 1H), 2.74 - 2.58 (m, 2H), 2.52 - 2.12 (m, 7H), 2.11 - 1.99 (m, 3H), 1.56 - 1.31 (m, 3H).
[0001078] Step-2: rac-(l?)-2-(5-(2.,6-dioxopiperidin-3-yl)pyridin-2-yl)-2- azaspiro[3.3]heptane-6-carbaldehyde rac- (R)-3-{6-[6-(hydroxymethyl)-2-azaspiro[3.3]heptan-2-yl]pyridin-3-yl}piperidine-2,6- dione (45.00 mg, 0.1427 mmol) was dissolved in DMSO (0.5 mL) and then triethylamine (0.40 mL, 0.29 g, 2.8538 mmol) and sulfur trioxide pyridine complex (227.10 mg, 1.4269 mmol) were added. After stirring for 30 min, TLC showed no more starting material left. The solution was dissolved in DCM (30 mL). The solution was washed with water and brine, dried over sodium sulfate, filtered, and concentrated. The crude product was used in the next step without purification. LCMS: C17H19N3O3, requires: 313.36, found m/z = 314.33 [M+H]+.
[0001079] Synthesis of 3-(4-(2.,6-diazaspiro [3.3] heptan-2-yl)phenyl)piperidine-2,6- dione
[0001080] Step-1 : tert-butyl 6-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-2,6- diazaspiro [3.3] heptane-2-carboxylate
To a 20 mLvial was added 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (500.00 mg, 1.1202 mmol), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (244.31 mg, 1.2322 mmol), 1,3- bis[2,6-bis(pentan-3-yl)phenyl]-2H-imidazole, 3 -chloropyridine, palladium chloride (44.46 mg, 0.0560 mmol), and cesium carbonate (1094.96 mg, 3.3606 mmol). Dioxane (4.00 mL) was then added and the mixture was purged with nitrogen gas for three minutes. Then the suspension was heated at 100 °C for sixteen hours. The crude reaction was diluted with EtOAc, washed with water twice, dried over Na2SO4, filtered, and concentrated. The crude product was loaded onto a Redi-Sep prepacked silica gel column (40g column) eluting with EtOAc:hexane (0-70%) to provide tert-butyl 6-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-2,6- diazaspiro[3.3]heptane-2-carboxylate (0.443 g, 70.15%). LCMS: C35H37N3O4, requires: 563.70, found: m/z = 564.52 [M+H]+.
[0001081] Step-2: tert-butyl 6-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,6- diazaspiro [3.3] heptane-2-carboxylate
To a mixture of tert-butyl 6-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-2,6- diazaspiro[3.3]heptane-2-carboxylate (443.00 mg, 0.7859 mmol) and palladium on carbon (150.00 mg) in THF (10.00 mL) was added isopropanol (3.00 mL) and the reaction mixture was stirred under a hydrogen balloon for 24 h. Pd/C solids were then filtered and the filtrate was washed with 10% MeOH in DCM and concentrated. The crude product was loaded onto a Redi-Sep prepacked silica gel column eluting with EtOAc in hexanes (70-100%) to afford terLbutyl 6-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (0.22 g, 72.62%). LCMS: C21H27N3O4, requires: 385.2, found m/z = 386.4 [M+H]+.
[00 1082] Step-3: 3-(4-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl)piperidine-2, 6-dione
To a solution of tert-butyl 6-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,6-diazaspiro[3.3]heptane- 2-carboxylate (150.00 mg, 0.3881 mmol) in DCM (2.00 mL) was added trifluoroacetic acid (2 mL). After stirring for one hour, TFA and DCM were evaporated. The product was lyophilized to dryness to provide 3-(4-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl)piperidine-2,6-dione in quantitative yield. LCMS C16H19N3O2 requires: 285.1, found: m/z = 286.3 [M+H]+.
[0001083] Synthesis of 3-16-12, 6-diazaspiro[3.3]heptan-2-vnpyridin-3-yl)piperidine- 2, 6-dione synthesis
[0001084] Step-1: Synthesis of tert-butyl 6-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)-
2,6-diazaspiro [3.3] heptane-2-carboxylate
To a solution of 3 -(6-fluoropyri din-3 -yl)piperidine-2, 6-dione (250.00 mg, 1.2008 mmol) and tert-butyl 2, 6-diazaspiro[3.3]heptane-2-carboxylate (238.08 mg, 1.2008 mmol) in DMSO (2.00 mL), was added A,A-diisopropylethylamine (0.85 mL, 0.62 g, 4.8033 mmol) and the solution was heated at 120 °C for four hours. The crude product was lyophilized to remove DMSO. The resulting crude oil was loaded onto a Redi-Sep prepacked silica gel column eluting with 0-10% MeOH in EtOAc to afford tert-butyl 6-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)- 2,6-diazaspiro[3.3]heptane-2-carboxylate (0.15 g, 32.32%). LCMS: C21H29N3O4 required: 386.2, found: m/z = 386.5 [M+H]+.
[0001085] Step-2: Synthesis of 3-(6-[2,6-diazaspiro[3.3]heptan-2-vnpyridin-3- yl)piperidine-2, 6-dione
To a solution of tert-butyl 6-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)-2,6- diazaspiro[3.3]heptane-2-carboxylate (150.00 mg, 0.3881 mmol) in DCM (2.00 mL)was added trifluoroacetic acid (2 mL) and the resulting mixture was stirred for one hour. Solvent was removed under reduced pressure, and the product was lyophilized to afford 3 -(6- {2,6- diazaspiro[3.3]heptan-2-yl}pyridin-3-yl)piperidine-2, 6-dione as a TFA salt in quantitative yield. LCMS: C15H18N4O2 required: 286.1, found: m/z = 286.3 [M+H]+.
[0001086] Amide Bond Formation Between the Hook Amines and the Harness Acids
[0001087] FluidX barcoded tubes containing harness acid stocks in NMP (0.1 M, eq = 10 pmol) were retrieved from the Hamilton Storage Q20 unit and placed onto the deck of a 1.3m Hamilton Robotics Vantage. The hook amines were dissolved in NMP (0.1 M) containing DIEA (0.15 M, 1.5 equiv) in V-bottom 20 mL vials and placed into vial racks onto the deck. Transfers of 100 pL from the harness acid stocks into corresponding wells of 96 deep well plates were performed, followed by addition of each of DIEA (0.15 M, 1.5 equiv) and HATU (0.1 M, 1 equiv) cocktails from 60 mL troughs. The plates were shaken ten minutes at 600 rpm for activation. Transfers of 100 pL from the hook stocks into corresponding wells of the same plates were performed and then the plates were sealed and shaken overnight at 600 rpm for amide bond formation. Finally, these plates were submitted for RP-HPLC purification.
[0001088] Reductive Amination Between the Hook Amines and the Hamess Aldehydes
[0001089] FluidX barcoded tubes containing harness aldehyde stocks in NMP (0.1 M, eq = 10 pmol) were retrieved from the Hamilton Storage Q20 unit and placed onto the deck of a 1.3m Hamilton Robotics Vantage. The hook amines were dissolved in dry NMP (0.1 M) containing DIEA (0.2 M, 2 equiv) and AcOH (0.2 equiv, 0.02 M) in V-bottom 20 mL vials and placed into vial racks onto the deck. Transfers of 100 pL from the harness stocks into corresponding wells of 96 deep well plates were performed, followed by transfers of 100 pL from the hook stocks into corresponding wells of the same 96 deep well plates. The plates were then shaken ninety minutes at 600 rpm for Schiff base formation. Additional plates dry -loaded with polymer-supported BH3CN (20 mg, 4 equiv) in each well were placed on the deck and the reactions were transferred into these corresponding plates using the 96 pipettor head. The plates were then sealed and shaken overnight at 600 rpm for the reductive amination to occur. The plates were then unsealed, and the reaction mixture was separated from the polymer-supported BH3CN by decantation followed by washing cycles with fresh solvent from 60 mL troughs to recover only the liquid phase into new plates. Finally, these plates were submitted for RP- HPLC purification.
[0001090] Synthesis of l-(4-(2.6-dioxoDiDeridin-3-yl)-2-fluoroDhenyl)DiDeridine-4- carbaldehyde (HA-3)
[0001091 ] Step-1: Synthesis of (l-(4-bromo-2-fluorophenyl)piperidin-4-yl)methanol
[0001092] To a solution of 4-bromo-2-fluoro-iodobenzene (42.1 g, 365 mmol, 1.10 equiv) and piperidin-4-ylmethanol (100 g, 332 mmol, 1.00 equiv) in DMSO (1000 mL) was added L- proline (17.4 g, 132 mmol, 0.400 equiv), K2CO3 (91.8 g, 664 mmol, 2.00 equiv) and Cui (12.6 g, 66.4 mmol, 0.200 equiv) under a nitrogen atmosphere. The reaction was stirred at 90 °C for 12 h. The reaction mixture was then cooled to 20 °C and poured into saturated NH4CI solution (1000 mL). The product was extracted with ethyl acetate (1000 mL x 3) and the combined organic layers were washed with brine (1000 mL), dried over Na2SC>4, filtered, and concentrated. The residue was purified by column chromatography (SiCh, petroleum etherethyl acetate = 10: 1 to 0: 1, Rf = 0.55). The desired product (10.7 g, 35.6 mmol, 10.7% yield) was obtained as a yellow solid. LCMS: m/z = 290.0 (M+H)+.
[0001093] Step-2: Synthesis of (l-(4-(2,6-bis(benzyloxy)Dyridin-3-yl)-2- fluorophenyl)piperidin-4-yl)methanol
[0001094] To a solution of (l-(4-bromo-2-fluorophenyl)piperidin-4-yl)methanol (11.6 g, 38.6 mmol, 1.00 equiv), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridine (17.7 g, 42.4 mmol, 1.10 equiv), K2CO3 (16.0 g, 115 mmol, 3.00 equiv) in dioxane (116 mL) and H2O (23 mL) was added Pd(dppf C12-CH2C12 (3.15 g, 3.86 mmol, 0.100 equiv) under a nitrogen atmosphere. Then the reaction mixture was stirred at 110 °C for 12 h. The mixture was then cooled to 25 °C. Then the reaction mixture was poured into H2O (300 mL) and was extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, and concentrated. The crude product was purified by MPLC (SiO2, petroleum etherethyl acetate = 100: 1 to 5: 1), Rf = 0.5 (petroleum etherethyl acetate = 1 : 1). (l-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-2-fluorophenyl)piperidin-4-yl)methanol (10.7 g, 20.5 mmol, 53.2% yield) was obtained as a light yellow solid. LCMS: m/z = 499.4 (M+H)+.
[0001095] Step-3: Synthesis of 3-(3-fluoro-4-(4-(hvdroxymethyl)piperidin-l- yl)phenyl)piperidine-2.,6-dione
[0001096] To a solution of (l-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-2- fluorophenyl)piperidin-4-yl)methanol (11.6 g, 23.2 mmol, 1.00 equiv) in THF (120 mL) and EtOH (120 mL) was added AcOH (4.19 g, 69.8 mmol, 3.99 mL, 3.00 equiv), Pd/C (2.90 g, 10% purity) and Pd(OH)2/C (3.01 g, 4.29 mmol, 20% purity) under a nitrogen atmosphere. The suspension was degassed under vacuum and purged with EL several times. The mixture was stirred under EE (50 psi) at 80 °C for 12 h. The reaction was then cooled to 20 °C and filtered. The filtrate was concentrated. The desired product (8.40 g, crude) was obtained as a yellow solid and used in the next step without further purification. LCMS: m/z = 321.2 (M+H)+.
[0001097] Step-4: Synthesis of l-(4-(2,6-dioxopiperidin-3-yl)-2- fluorophenyl)piperidine-4-carbaldehvde
[0001098] To a solution of 3-(3-fluoro-4-(4-(hydroxymethyl)piperidin-l- yl)phenyl)piperidine-2, 6-dione (8.40 g, 26.2 mmol, 1.00 equiv) in DMSO (90.0 mL) was added DMP (22.2 g, 52.4 mmol, 16.2 mL, 2.00 equiv) in portions. The reaction was stirred at 25 °C for 12 h. The pH of the reaction mixture then was adjusted to pH = 10 with saturated aqueous Na2CC>3 and the aqueous layer was extracted with ethyl acetate (400 mL x 4). The combined organic layers were washed with Na2S20s solution (500 mL x 2) and brine (1000 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was triturated with ethyl acetate (100 mL) at 25 °C for 12 h. l-(4-(2,6-dioxopiperi din-3 -yl)-2- fluorophenyl)piperidine-4-carbaldehyde (2.50 g, 7.60 mmol, 28.9% yield) was obtained as a yellow solid. LCMS: m/z = 317.1 (M-H)+. 'HNMR (400 MHz, DMSO ) 8 10.8 (s, 1H), 9.64 (s, 1H), 7.06 - 6.90 (s, 3H), 3.83 - 3.76 (m, 1H), 3.29 - 3.24 (m, 2H), 2.76 (t, J= 10.0 Hz, 2H), 2.69 - 2.60 (m, 1H), 2.48 - 2.41 (m, 2H), 2.24 - 2.13 (m, 1H), 2.04 - 1.91 (m, 3H), 1.71 - 1.58 (m, 2H).
[0001099] Synthesis of l-(4-(2,6-dioxopiperidin-3-yl)-3-fluorophenyl)piperidine-4- carbaldehyde (HA-4)
[0001 100] HA-4 was synthesized following the same procedure as HA-3 except substituting 4-bromo-2-fluoro-l-iodobenzene with l-bromo-2-fluoro-4-iodobenzene in Step 1 to give l-(4-(2,6-dioxopiperidin-3-yl)-3-fluorophenyl)piperidine-4-carbaldehyde. LCMS: m/z = 317.1 (M-H)+. 'H NMR (400 MHz, DMSO-A) 5 10.79 (s, 1H), 9.62 (s, 1H), 7.07 (t, 8.8
Hz, 1H), 6.77 - 6.69 (m, 2H), 3.91 - 3.84 (m, 1H), 3.67 - 3.59 (m, 2H), 2.91 -2.81 (m, 2H), 2.76 - 2.65 (m, 1H), 2.56 - 2.52 (m, 1H), 2.49 - 2.45 (m, 1H), 2.20 -2.07 (m, 1H), 1.97 -1.86 (m, 3H), 1.61 - 1.49 (m, 2H).
[0001101] Synthesis of l-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperidine-
4-carbaldehyde (HA-5)
[00 1 102] Step 1: Synthesis of l-(4-bromo-3,5-difluorophenyl)-4-
(dimethoxymethyl)piperidine
[0001103] 2-bromo-l,3-difluoro-5-iodobenzene (56.3 g, 176 mmol, 1.00 equiv), 4- (dimethoxymethyl)piperidine (30.9 g, 194 mmol, 1.10 equiv), L-proline (8.13 g, 70.6 mmol, 0.40 equiv), CS2CO3 (115 g, 353 mmol, 2.00 equiv), and Cui (6.72 g, 35.3 mmol, 0.20 equiv) was stirred in DMSO (350 mL) at 20 °C and purged with N2 three times. The mixture was then stirred at 85 °C for 16 h under a nitrogen atmosphere. LCMS showed 60.5% of the desired mass (Rt = 0.715 min) was detected. TLC (Petroleum ether:Ethyl acetate = 10: 1) showed that 2-bromo-l,3-difluoro-5-iodobenzene (Rf = 0.8) was consumed and a major spot (Rf = 0.3) was detected. The reaction was then added to water (800 mL) and extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with brine (1.00 L x 1), dried over ISfeSCU, filtered, and concentrated. The residue was purified by column chromatography (SiCL, Ethyl acetate:Petroleum ether = 0: 1 to 1 :20; Ethyl acetate :Petroleum ether = 1 : 10, Rf = 0.3). Then the combined fractions were concentrated under vacuum. l-(4-bromo-3,5-difluorophenyl)-4- (dimethoxymethyl)piperidine (30.0 g, 84.1 mmol, 48.5% yield, 98.2% purity) was obtained as a light-yellow solid. LCMS: m/z = 350.2 (M+H)+. 'H NMR (400 MHz, CDC13) d 6.47 (d, J= 10.0 Hz, 2H), 4.07 (d, J= 6.8 Hz, 1H), 3.74 - 3.62 (m, 2H), 3.38 (s, 6H), 2.84 -2.68 (m, 2H), 1.89 - 1.77 (m, 3H), 1.52 -1.30 (m, 2H).
[0001 104] Step 2: Synthesis of 2,6-bis(benzyloxy)-3-(4-(4-
(dimethoxymethyl)piperidin-l-yl)-2.,6-difluorophenyl)pyridine
[0001105] l-(4-bromo-3,5-difluorophenyl)-4-(dimethoxymethyl)piperidine (20.0 g, 57.1 mmol, 1.00 equiv), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridine (30.9 g, 74.2 mmol, 1.30 equiv), K2CO3 (23.6 g, 171 mmol, 3.00 equiv), and Pd(dppf)C12-DCM(2.51 g, 3.43 mmol, 0.06 equiv) was added to dioxane (200 mL) and H2O (40 mL) at 20 °C and purged with nitrogen three times. The mixture was then stirred at 100 °C for 16 h under a nitrogen atmosphere. LCMS showed 67.7% of the desired mass (Rt = 0.796 min) was detected. TLC (Petroleum ether:Ethyl acetate = 10: 1) showed that l-(4-bromo-3,5- difluorophenyl)-4-(dimethoxymethyl)piperidine (Rf = 0.3) was consumed and a major spot (Rf = 0.25) was detected. The reaction was then added to water (1.00 L) and extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with brine (1.00 L x 1), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, Ethyl acetate :Petroleum ether = 0: 1 to 1 :20; Ethyl acetate:Petroleum ether = 1 : 10, Rf = 0.3). Then the fractions were concentrated under vacuum. 2,6-bis(benzyloxy)-3-(4-(4- (dimethoxymethyl)piperi din- l-yl)-2,6-difluorophenyl)pyri dine (20.0 g, 34.0 mmol, 59.6% yield, 95.5% purity) was obtained as a yellow solid. LCMS: m/z = 561.3 (M+H)+. 'H NMR (400 MHz, CDCI3) d 7.56 - 7.29 (m, 11H), 6.50 - 6.44 (m, 3H), 5.39 - 5.32 (m, 4H), 4.09 (d, J = 7.0 Hz, 1H), 3.75 - 3.71 (m, 2H), 3.39 (s, 6H), 2.79 - 2.73 (m, 2H), 1.93 -1.72 (m, 3H), 1.56 (s, 2H).
[0001 106] Step 3: Synthesis of 3-(4-(4-(dimethoxymethyl)piperidin-l-yl)-2.,6- difluorophenyl)piperidine-2.,6-dione [0001 107] To a solution of 2,6-bis(benzyloxy)-3-(4-(4-(dimethoxymethyl)piperidin-l-yl)- 2,6-difluorophenyl)pyridine (5.00 g, 8.92 mmol, 1.00 equiv) in THF (50.0 mL) was added Pd/C (1.50 g, 1.41 mmol, 10% purity) and Pd(OH)2/C (1.50 g, 3.20 mmol, 30% purity) under a nitrogen atmosphere. The suspension was degassed and purged with H2 three times. The mixture was then stirred under H2 (50 psi) at 25 °C for 12 h. LCMS showed that the desired peak (Rt = 0.568 min) was detected and the starting material was consumed completely. The mixture was then filtered and concentrated. 3-(4-(4-(dimethoxymethyl)piperidin-l-yl)-2,6- difluorophenyl)piperidine-2, 6-dione (2.40 g, 6.28 mmol, 70.3% yield) was obtained as an off- white solid. LCMS: m/z = 383.2 (M+H)+. *H NMR (400 MHz, CDCI3) d 8.04 (s, 1H), 6.42 (d, J = 12.1 Hz, 2H), 4.07 (d, J= 6.6 Hz, 1H), 4.01 - 3.88 (m, 1H), 3.69 (br d, J= 12.6 Hz, 2H), 3.38 (s, 6H), 2.88 - 2.61 (m, 4H), 2.41 - 2.24 (m, 1H), 2.21 - 2.06 (m, 1H), 1.92 - 1.77 (m, 3H), 1.52 - 1.31 (m, 2H).
[0001 108] Step 4: Synthesis of l-(4- dioxoDiDeridin-3-yl)-3.,5- difluoroDhenyl)DiDeridine-4-carbaldehyde
[0001 109] To a solution of 3-(4-(4-(dimethoxymethyl)piperidin-l-yl)-2,6- difluorophenyl)piperidine-2, 6-dione (20.0 g, 52.3 mmol, 1.00 equiv) in THF (460 mL) was added HC1 (2 N, 465 mL, 17.8 equiv) dropwise slowly. The reaction solution was then stirred at 70 °C for one hour. LCMS showed 100% of the desired mass (Rt = 0.535 min) was detected. The reaction mixture was then treated with saturated NaHCCL solution until pH = 7, extracted with methyl tetrahydrofuran (500 mL x 3), dried over Na2SO4, filtered, and concentrated to provide a crude product. The crude was triturated with MTBE (30.0 mL) at 25 °C for 30 min. l-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperidine-4-carbaldehyde (15.4 g, 42.9 mmol, 84.2% yield, 96.2% purity) was obtained as a white solid. LCMS: m/z = 337.2 (M+H)+. ’HNMR (400 MHz, DMSO ) d 10.88 (s, 1H), 9.62 (s, 1H), 6.64 (d, J= 12.6 Hz, 2H), 4.10 - 4.00 (m, 1H), 3.73 - 3.62 (m, 2H), 2.99 - 2.87 (m, 2H), 2.85 - 2.72 (m, 1H), 2.61 - 2.50 (m, 2H), 2.19 - 2.05 (m, 1H), 2.01 - 1.83 (m, 3H), 1.62 - 1.46 (m, 2H).
[0001110] Synthesis of !-(4-(2.,6-dioxoDiDeridin-3-yl)-2.,5-difluoroDhenyl)DiDeridine-
4-carbaldehyde (HA-6)
[0001111] Step 1: Synthesis of l-(4-bromo-2.,5-difluorophenyl)-4-
(dimethoxymethyl)piperidine
[0001112] To a solution of l-bromo-2,5-difluoro-4-iodobenzene (30.0 g, 94.1 mmol, 1.00 equiv), 4-(dimethoxymethyl)piperidine (18.0 g, 113 mmol, 1.20 equiv), Xantphos (10.9 g, 18.8 mmol, 0.200 equiv), and Z-BuOK (13.7 g, 122 mmol, 1.30 equiv) in toluene (210 mL) was added Pd2(dba)s (8.61 g, 9.41 mmol, 0.100 equiv) under N2. The reaction was then stirred at 100 °C for 12 h. The mixture was then diluted with H2O (500 mL) and extracted with EtOAc (500 mL x 2). The combined organic layer was washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by column chromatography (SiCL, Petroleum ether: Ethyl acetate = 0: 1 to 10:1; Petroleum ether :Ethyl acetate = 81, Rf = 0.4) and concentrated to provide l-(4-bromo-2,5-difluorophenyl)-4- (dimethoxymethyl)piperidine (15.3 g, 40.3 mmol, 42.8% yield, 92.2% purity) as a yellow oil. LCMS: m/z = 352.0 (M+H)+. 'H NMR (400 MHz, CDCI3) d 7.18 (dd, J = 6.4, 11.6 Hz, 1H), 6.71 (dd, J= 7.6, 10.4 Hz, 1H), 4.10 (d, J= 7.2 Hz, 1H), 3.46 (d, J= 11.6 Hz, 2H), 3.38 (s, 6H), 2.62 (dt, J= 2.0, 12.0 Hz, 2H), 1.85 (br d, J= 13.2 Hz, 2H), 1.81 - 1.69 (m, 1H), 1.57 - 1.43 (m, 2H).
[0001113] Step 2: Synthesis of 2,6-bis(benzyloxy)-3-(4-(4-
(dimethoxymethyl)piperidin-l-yl)-2.,5-difluorophenyl)pyridine
[0001 1 14] To a solution of l-(4-bromo-2,5-difhrorophenyl)-4- (dimethoxymethyl)piperidine (15.3 g, 40.3 mmol, 1.00 equiv) in dioxane (300 mL) and H2O (60.0 mL) was added 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridine (23.8 g, 52.4 mmol, 1.30 equiv), CS2CO3 (32.8 g, 101 mmol, 2.50 equiv), and Pd(dppf)C12'CH2C12 (1.64 g, 2.01 mmol, 0.05 equiv) at 25 °C under N2. The reaction mixture was then stirred at 100 °C for 12 h. The mixture was then poured into H2O (100 mL) and extracted with EtOAc (50.0 mL x 3). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by MPLC (SiCL, Petroleum ether: Ethyl acetate = 1 :0 to 10: 1; Petroleum ether:Ethyl acetate = 5: 1, Rf = 0.4) and concentrated to provide 2,6-bis(benzyloxy)-3-(4-(4- (dimethoxymethyl)piperidin-l-yl)-2,5-difluorophenyl)pyridine (21.5 g, 37.0 mmol, 91.9% yield, 96.5% purity) as a yellow oil. LCMS: m/z = 561.3 (M+H)+. JH NMR (400 MHz, CDCI3) d 7.54 (dd, J= 1.2, 8.0 Hz, 1H), 7.45 - 7.41 (m, 2H), 7.40 - 7.28 (m, 8H), 7.09 (dd, J = 7.2, 13.2 Hz, 1H), 6.78 - 6.65 (m, 1H), 6.46 (d, J= 8.0 Hz, 1H), 5.41 (s, 2H), 5.36 (s, 2H), 4.12 (d, J= 7.2 Hz, 1H), 3.54 (d, J = 12.0 Hz, 2H), 3.40 (s, 6H), 2.66 (br t, J= 11.6 Hz, 2H), 2.06 (s, 1H), 1.87 (br d, J= 12.8 Hz, 2H), 1.81 -1.73 (m, 1H), 1.58 - 1.47 (m, 2H).
[0001115] Step 3: Synthesis of 3-(4-(4-(dimethoxymethyl)piperidin-l-yl)-2.,5- difluorophenyl)piperidine-2.,6-dione
[0001 1 16] To a solution of 2,6-bis(benzyloxy)-3-(4-(4-(dimethoxymethyl)piperidin-l-yl)- 2,5-difluorophenyl)pyridine (21.5 g, 37.0 mmol, 1.00 equiv) in THF (360 mL) was added Pd/C (6.45 g, 10% purity) and Pd(OH)2/C (6.45 g, 20% purity) under N2. The suspension was then degassed and purged with H2 three times. The mixture was then stirred under H2 (50 psi) at 25 °C for 12 h. LCMS showed the starting material was consumed and desired mass (Rt = 0.745 min) was formed. The mixture was then filtered through celite and the filtrate was concentrated under reduced pressure. The crude was triturated with MTBE (100 mL) at 25 °C for 0.5 h, filtered, and the cake was dried under reduced pressure to provide 3-(4-(4- (dimethoxymethyl)piperidin-l-yl)-2,5-difluorophenyl)piperidine-2, 6-dione (14.0 g, 36.6 mmol, 98.9% yield, 100% purity) as a white solid. LCMS: m/z = 383.1 (M+H)+. 'H NMR (400 MHz, CDCI3) d 8.20 - 8.01 (m, 1H), 6.82 (dd, J= 6.8, 12.4 Hz, 1H), 6.69 (dd, J = 7.2, 11.6 Hz, 1H), 4.10 (d, J = 7.2 Hz, 1H), 3.81 (dd, = 5.6, 11.2 Hz, 1H), 3.49 (br d, J = 11.2 Hz, 2H), 3.38 (s, 6H), 2.86 - 2.75 (m, 1H), 2.74 - 2.56 (m, 3H), 2.33 - 2.13 (m, 2H), 1.84 (br d, J = 13.2 Hz, 2H), 1.77 - 1.71 (m, 1H), 1.58 - 1.43 (m, 2H).
[0001 117] Step 4: Synthesis of l-(4- dioxopiperidin-3-yl)-2.,5- difluorophenyl)piperidine-4-carbaldehvde
[0001 1 18] To a solution of 3-(4-(4-(dimethoxymethyl)piperidin-l-yl)-2,5- difluorophenyl)piperidine-2, 6-dione (10.0 g, 26.2 mmol, 1.00 equiv) in THF (250 mL) was added HC1 (2 N, 233 mL, 17.8 equiv). The reaction solution was then stirred at 70 °C for one hour. The reaction mixture was then cooled to 25 °C and saturated NaHCCf solution was added until pH = 7. The mixture was then extratcted with EtOAc (300 mL x 3) and the combined organic layer was washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated to provide l-(4-(2,6-dioxopiperidin-3-yl)-2,5-difluorophenyl)piperidine-4-carbaldehyde (7.68 g, 22.8 mmol, 87.1% yield, 99.7% purity) as an off-white solid. LCMS: m/z = 337.1 (M+H)+. 'H NMR (400 MHz, CDC13) d 9.72 (s, 1H), 8.12 (br s, 1H), 6.84 (dd, J= 6.8, 12.4 Hz, 1H), 6.68 (dd, J = 7.2, 11.6 Hz, 1H), 3.82 (dd, J = 5.6, 11.2 Hz, 1H), 3.48 - 3.34 (m, 2H), 2.92 - 2.75 (m, 3H), 2.74 - 2.61 (m, 1H), 2.49 - 2.36 (m, 1H), 2.33 - 2.14 (m, 2H), 2.10 - 2.00 (m, 2H), 1.94 - 1.78 (m, 2H).
[0001 1 19] Synthesis of l-(4-(2.,6-dioxopiperidin-3-yl)-2.,3-difluorophenyl)piperidine-
4-carbaldehyde (HA-7)
[0001120] Step 1: of l-(4-bromo-2,3-di 1-4-
(dimethoxymethyl)piperidine
[0001121] l-Bromo-2,3-difluoro-4-iodobenzene (20.0 g, 62.7 mmol, 1.00 equiv), 4- (dimethoxymethyl)piperidine (10.9 g, 68.9 mmol, 1.10 equiv), BINAP (1.56 g, 2.51 mmol, 0.04 equiv), Z-BuONa (12.0 g, 125 mmol, 2.00 equiv), and Pd2(dba)s (1.15 g, 1.25 mmol, 0.02 equiv) was added to toluene (200 mL) at 20 °C and the mixture was purged with N2 three times. The mixture was then stirred at 100 °C for 16 h. The mixture was then concentrated directly via vacuum. The residue was purified by column chromatography (SiCL, Ethyl acetate:Petroleum ether = 0: 1 to 1 :20; Ethyl acetate:Petroleum ether = 1 : 10, Rf = 0.30). Then the fractions were concentrated under vacuum. l-(4-bromo-2,3-difluorophenyl)-4- (dimethoxymethyl)piperidine (14.0 g, 31.5 mmol, 50.3% yield, 79.0% purity) was obtained as a yellow solid. LCMS: m/z = 350.1 (M+H)+. 'H NMR (400 MHz, CDCI3) d 7.21 - 7.12 (m, 1H), 6.67 - 6.55 (m, 1H), 4.10 (d, J= 7.1 Hz, 1H), 3.46 (br d, J= 12.0 Hz, 2H), 3.38 (s, 6H), 2.73 - 2.60 (td, 2H), 1.85 (br d, J= 13.9 Hz, 2H), 1.56 - 1.43 (m, 2H), 1.26 (t, 1H).
[0001122] Step 2: Synthesis of 2,6-bis(benzyloxy)-3-(4-(4-
(dimethoxymethyl)piperidin-l-yl)-2.,3-difluorophenyl)pyridine
[0001 123] l-(4-bromo-2,3-difluorophenyl)-4-(dimethoxymethyl)piperidine (13.0 g, 29.7 mmol, 1.00 equiv), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridine (16.1 g, 38.6 mmol, 1.30 equiv), CS2CO3 (24.1 g, 74.2 mmol, 2.50 equiv), and Pd(dppf)C12'CH2C12 (1.21 g, 1.48 mmol, 0.05 equiv) was added into dioxane (260 mL) and H2O (52.0 mL) at 20 °C and the mixture was purged with N2 three times. The mixture was then stirred at 100 °C for 16 h under a nitrogen atmosphere. The residue was then added to water (200 mL) and extracted with ethyl acetate (60.0 mL x 3). The combined organic layers were washed with brine (100 mL x 1), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiCh, Ethyl acetate:Petroleum ether = 0: 1 to 1 :20; Ethyl acetate:Petroleum ether = 1 : 10, Rf = 0.25). Then the fractions were concentrated under vacuum. 2,6-bis(benzyloxy)-3-(4-(4-(dimethoxymethyl)piperidin-l-yl)-2,3- difhiorophenyl)pyridine (8.80 g, 13.8 mmol, 46.5% yield, 88.0% purity) was obtained as a yellow solid. LCMS: m/z = 561.3 (M+H)+. 'H NMR (400 MHz, CDCI3) d 7.56 - 7.29 (m, 11H), 7.10 - 6.95 (m, 1H), 6.46 (d, J= 8.1 Hz, 1H), 5.46 - 5.23 (m, 4H), 4.12 (d, J= 7.2 Hz, 1H), 3.54 (br d, J= 11.9 Hz, 2H), 3.40 (s, 6H), 2.71 (t, J= 11.4 Hz, 2H), 1.87 (br d, J= 12.8 Hz, 2H), 1.81 - 1.71 (m, 1H), 1.64 - 1.48 (m, 3H).
[0001 124] Step 3: Synthesis of 3-(4-(4-(dimethoxymethyl)piperidin-l-yl)-2.,3- difluorophenyl)piperidine-2.,6-dione
[0001125] To a solution of 2,6-bis(benzyloxy)-3-(4-(4-(dimethoxymethyl)piperidin-l-yl)- 2,3-difluorophenyl)pyridine (43.0 g, 76.7 mmol, 1.00 equiv) in THF (430 mL) was added Pd/C (12.9 g, 12.1 mmol, 10% purity) and Pd(OH)2/C (12.9 g, 27.5 mmol, 30% purity) under a nitrogen atmosphere. The suspension was then degassed and purged with H2 three times. The mixture was then stirred under H2 (50 psi) at 25 °C for 6 h. The mixture was then filtered and concentrated. The crude was triturated with MTBE (20.0 mL) at 25 °C for 30 min, filtered, and the cake was dried under reduced pressure to provide 3-(4-(4-(dimethoxymethyl)piperidin-l- yl)-2,3-difluorophenyl)piperidine-2, 6-dione (8.00 g, 20.9 mmol, 88.8% yield) as a white solid. LCMS: m/z = 383.1 (M+H)+. 'H NMR (400 MHz, DMSO-tL) d 10.92 (s, 1H), 7.18 - 6.69 (m, 2H), 4.16 (d, J= 6.5 Hz, 1H), 4.11 - 4.00 (m, 1H), 3.47 - 3.38 (m, 3H), 3.32 (s, 6H), 2.85 - 2.64 (m, 3H), 2.30 - 2.13 (m, 1H), 2.10 - 1.95 (m, 1H), 1.84 - 1.68 (m, 3H), 1.52 - 1.35 (m, 2H).
[0001126] Step 4: Synthesis of l-(4- dioxoDiDeridin-3-yl)-2.,3- difluoroDhenyl)DiDeridine-4-carbaldehyde
[0001 127] To a solution of 3-(4-(4-(dimethoxymethyl)piperidin-l-yl)-2,3- difluorophenyl)piperidine-2, 6-dione (4.00 g, 10.4 mmol, 1.00 equiv) in THF (93.0 mL) was added HC1 (2.00 N, 93.1 mL, 17.8 equiv) dropwise slowly. After addition, the reaction solution was then stirred at 70 °C for one hour. The reaction mixture was then treated with saturated NaHCCh solution until pH = 7, extracted with EtOAc (30.0 mL x 3), dried over Na2SO4, filtered, and concentrated to provide crude material. The crude was triturated with EtOAc (10.0 mL) at 25 °C for 30 min. l-(4-(2,6-dioxopiperidin-3-yl)-2,3-difluorophenyl)piperidine-4- carbaldehyde (2.00 g, 5.86 mmol, 56.0% yield, 98.4% purity) was obtained as a white solid. LCMS: m/z = 337.2 (M+H)+. 'HNMR (400 MHz, DMSO-tL) d 10.88 (s, 1H), 9.64 (s, 1H), 6.99 (br t, J = 7.5 Hz, 1H), 6.82 (br t, J= 7.9 Hz, 1H), 4.12 - 3.94 (m, 1H), 3.35 - 3.26 (m, 2H), 2.88 - 2.67 (m, 3H), 2.55 (br d, J= 3.1 Hz, 1H), 2.49 - 2.43 (m, 1H), 2.26 - 2.09 (m, 1H), 2.05 - 1.88 (m, 3H), 1.73 - 1.56 (m, 2H).
[0001128] Synthesis of l-(5-(2,4-dioxotetrahvdroDyrimidin-l(2H)-yl) 679 yridine-2- yl)Diperidine-4-carbaldehvde (HA-8)
[0001129] Step-1: Synthesis of (l-(5-nitropyridin-2-yl)piperidin-4-yl)methanol
[0001130] A mixture of 2-fluoro-4-nitropyridine (20 g, 0.140 mol, 1 equiv), piperidin-4- ylmethanol (24.318 g, 0.211 mol, 1.5 equiv), and DIPEA (27.29 mL, 0.211 mol, 1.5 equiv) in anhydrous DMSO (50 mL, 2.82 M) was stirred at 90 °C overnight. Then the reaction mixture was poured into ice water. The resulting precipitate was filtered and purified by flash chromatography (DCM:MeOH = 9: 1) to provide [l-(5-nitropyridin-2-yl)piperidin-4- yl]methanol (33.37 g, 47% yield) as a yellow solid. LCMS: m/z = 237.7 (M+H)+. JH NMR (300 MHz, CDC13) 5 9.05 (d, J= 2.8 Hz, 1H), 8.20 (dd, J= 9.6, 2.8 Hz, 1H), 6.60 (d, J= 9.6 Hz, 1H), 4.59 (d, J= 13.4 Hz, 2H), 3.57 (d, J= 5.9 Hz, 2H), 3.11 - 2.95 (m, 2H), 1.98 - 1.84 (m, 3H), 1.31 (tdd, J= 14.3, 11.8, 4.2 Hz, 2H).
[0001 131] Step-2: Synthesis of (l-(5-aminopyridin-2-yl)piperidin-4-yl)methanol
[0001132] [l-(5-nitropyridin-2-yl)piperidin-4-yl]methanol (15.5 g, 0.065 mol, 1 equiv) was dissolved in a mixture of EtOH:MeOH (1 : 1) (250 mL, 0.26 M), degassed, and charged with Pd/C (50% wet, 2.32 g, 15% weight). The reaction mixture was then evacuated and backfilled with H2 (balloon, 1 atm) and left to stir overnight. The reaction was then filtered through a celite pad and concentrated to provide [l-(5-aminopyridin-2-yl)piperidin-4- yl]methanol (5.85 g, 45% yield) as a pale yellow oil, which was used in the next step without additional purification. LCMS: m/z = 208.25 (M+H)+. 'HNMR (300 MHz, DMSO-tL) 8 7.59 (dd, J= 2.9, 0.7 Hz, 1H), 6.89 (dd, J= 8.8, 2.9 Hz, 1H), 6.61 (dd, J= 8.9, 0.8 Hz, 1H), 4.56 -
4.39 (m, 3H), 4.02 - 3.89 (m, 2H), 3.26 (dd, J= 6.3, 5.3 Hz, 2H), 2.60 - 2.52 (m, 2H), 1.76 - 1.62 (m, 2H), 1.49 (s, 1H), 1.12 (dd, J= 12.2, 4.0 Hz, 2H).
[0001 133] Step-3: Synthesis of 3-((6-(4-(hvdroxymethyl)piperidin-l-yl)pyridin-3- yl)aiiiiiio)pi opanoic acid
[0001134] A pressure vessel was charged with [l-(5-aminopyridin-2-yl)piperidin-4-yl] methanol (5.8g, 27.9 mmol, 1 equiv) and acrylic acid (1.9 mL, 27.9 mmol, 1 equiv) dissolved in 1,4- dioxane (58 mL, 0.5 M). The reaction mixture was then stirred at 90 °C. After 16 h, 25% of the starting amine was still present. Additional acrylic acid (0.25 equiv) was added and the reaction mixture was stirred at 90 °C for another 16 h. Then the mixture was concentrated, the obtained residue was diluted with EtOAc and refluxed, and the solution was then decanted. The residue (black gum) was redissolved in MeOH and concentrated to yield 3-({6-[4- (hydroxymethyl)piperidin-l-yl]pyridin-3-yl}amino)propanoic acid (6.4 g, 78% yield). LCMS: m/z = 280.25 (M+H)+; 278.0(M-H)+. 'H NMR (300 MHz, DMSO-tL) 6 7.59 (d, J= 2.9 Hz, 1H), 6.93 (dd, J= 8.9, 3.0 Hz, 1H), 6.68 (d, J = 8.9 Hz, 1H), 4.00 (dt, J = 12.8, 3.3 Hz, 2H),
3.39 (t, J = 7.1 Hz, 1H), 3.26 (d, J = 6.3 Hz, 3H), 2.63 - 2.53 (m, 2H), 2.47 - 2.29 (m, 3H), 1.67 (s, 2H), 1.13 (dd, J= 12.2, 4.0 Hz, 2H).
[0001 135] Step-4 and Step-5: Synthesis of (l-(5-(2.,4-dioxotetrahvdropyriniidin- yl)pyridin-2-yl)piperidin-4-yl)methyl _ acetate _ and _ l-(6-(4-
(hvdroxyniethyl)piperidin-l-yl)pyridin-3-yl)dihvdropyriniidine-2.4( l//.3//)-dione
[0001136] 3-({6-[4-(hydroxymethyl)piperidin-l-yl]pyridin-3-yl}amino)propanoic acid (6.4 g, 21.76 mmol, 1.0 equiv), and urea (2.614 g, 43.53 mmol, 2.0 equiv) were dissolved in glacial acetic acid (64 mL, 10 vol) and left to stir at 90 °C for 48 h. The reaction mixture was then concentrated and the obtained residue was dissolved in EtOH (100 mL), followed by the addition of H2SO4 (0.012 mL, 0.022 mmol, 0.01 equiv) and the mixture was stirred at room temperature for 48 h. The reaction mixture pH was adjusted to 10-11 with KHSO4, concentrated, and purified by silica gel chromatography (DCM:MeOH = 9: 1). The obtained material was further triturated with DCM to provide l-{6-[4-(hydroxymethyl)piperidin-l- yl]pyridin-3-yl]-l,3-diazinane-2, 4-dione (1.28 g, 18% yield). LCMS: m/z = 305.05 (M+H)+. 'H NMR (300 MHz, DMSO-tL) 6 10.34 (s, 1H), 8.04 (d, J= 2.7 Hz, 1H), 7.47 (dd, J= 9.0, 2.8 Hz, 1H), 6.84 (d, J= 9.1 Hz, 1H), 4.47 (t, J= 5.3 Hz, 1H), 4.29 (d, J= 13.0 Hz, 2H), 3.70 (t, J = 6.7 Hz, 2H), 3.27 (t, J= 5.7 Hz, 2H), 2.83 - 2.65 (m, 4H), 1.77 - 1.54 (m, 3H), 1.18 - 1.03 (m, 2H).
[0001137] Step-6: Synthesis of l-(5-(2.,4-dioxotetrahvdropyriniidin-l -yl)pyridin-
2-yl)piperidine-4-carbaldehyde
[0001 138] To a solution of l-{6-[4-(hydroxymethyl)piperidin-l-yl]pyridin-3-yl}-l,3- diazinane-2,4- dione (0.715 g, 2.3 mmol, 1 equiv) dissolved in anhydrous DCM (0.3 M) was added Dess-Martin periodinane (1.073 g, 2.53 mmol, 1.1 equiv) in anhydrous DCM (0.15 M) dropwise at 0 °C. The reaction mixture was then warmed and left to stir at room temperature for one hour. The reaction was monitored by TLC and LCMS. The reaction mixture was then diluted with sat. aq. Na2S20s and the organic layer was separated and washed with sat. aq. NaHCCh. The aqueous layers were combined and back-extracted several times with DCM. The combined organic phase was dried over Na2SO4 and concentrated to provide l-[5-(2,4-dioxo- l,3-diazinan-l-yl)pyridin-2-yl]piperidine-4-carbaldehyde (0.56 g, yield 77%) as a beige solid. The product tends to form a stable hydrate. LCMS: ESI(+) m/z = = 305.11 [M+H]+. 'H NMR (300 MHz, DMSO d6) 5 10.35 (s, 1H), 9.63 (d, J= 0.9 Hz, 1H), 8.08 - 8.03 (m, 1H), 7.50 (dd, J = 9.0, 2.8 Hz, 1H), 6.88 (d, J= 9.1 Hz, 1H), 4.13 (dt, J= 13.2, 4.1 Hz, 2H), 3.70 (t, J= 6.7 Hz, 2H), 3.11 - 2.99 (m, 2H), 2.71 (d, J= 6.7 Hz, 2H), 2.66 - 2.55 (m, 1H), 1.90 (dd, J= 13.3, 3.9 Hz, 2H), 1.55 - 1.42 (m, 2H).
[0001 139] SFC Separation of Harnesses
[0001140] -(4-(2.,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbaldehvde and 6S)-l-(4-(2.,6- dioxopiperidin-3-yl)phenyl)piperidine-4-carbaldehvde (HA-XX, peak 1 and HA-XX, peak 2)
[0001 141] Racemic l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbaldehyde was purified by prep-SFC (column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 pm); mobile phase: [Neu-IPA]; B%: 65%-65%, 4.5; 650 min) to give peak 1 (13.64 g, 45.41 mmol, 48.7% yield) as yellow solid and crude peak 2. Crude peak 2 was purified by prep-SFC (column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 pm); mobile phase: [IPA-ACN]; B%: 65%- 65%, 4; 580 min) to give peak 2 (8.13 g, 27.07 mmol, 29.04% yield) as an off-white solid.
[0001 142] HA-XX (peak 1 ) :
[0001 143] LCMS: m/z = 299.1 (M-H)'.
[0001 144] SFC: ee% = 98.3% under 220 nm.
[0001 145] 'H NMR: (400 MHz, DMSO-A) 5 10.78 (s, 1H), 9.63 (s,lH), 7.04 (d, J= 8.4 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 3.75 - 3.68 (m, 1H), 3.62 - 3.52 (m, 2H), 2.86 - 2.75 (m, 2H), 2.68 - 2.57 (m, 1H), 2.49 - 2.40 (m, 2H), 2.18 - 2.08 (m, 1H), 2.05 - 1.88 (m, 3H), 1.64 - 1.51 (m, 2H).
[0001 146] HA-XX (peak 2):
[0001 147] LCMS : m/z = 299.1 (M-H).
[0001 148] SFC: ee% = 100% under 220 nm.
[0001 149] 'H NMR (400 MHz, DMSO-tL) 8 10.75 (s, 1H), 9.63 (s, 1H), 7.07 - 7.01 (m, 2H), 6.89 (d, J = 8.8 Hz, 2H), 3.75 - 3.68 (m, 1H), 3.61 - 3.53 (m, 2H), 2.85 - 2.75 (m, 2H), 2.68 - 2.58 (m, 1H),2.49 - 2.42 (m, 2H), 2.19 - 2.07 (m, 1H), 2.05 - 1.87 (m, 3H), 1.64 - 1.51 (m, 2H).
[0001150] H?)-l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbaldehvde and 6S)-l-(5-(2,6- dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbaldehvde (HA-XX, peak 1 and HA-XX, peak 2)
[0001 151] Racemic l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbaldehyde was purified by SFC (column: REGIS (s,s) WHELK-01 (250 mm x 50 mm, 10 pm); mobile phase: [IPA-ACN]; B%: 60%-60%, B2.7; 300 min) and concentrated under vacuum to provide a residue. The residue was triturated with ethyl acetate (60.0 mL) at 20 °C for 2 h, filtered, and the filter cake was concentrated under vacuum to provide HA-XX, peak 1 (17.79 g, 58.3 mmol, 40.5% yield) and HA-XX, peak 2, HA-33 (16.05 g, 52.6 mmol, 36.5% yield) as white solids.
[0001152] HA-XX (peak 1):
[0001153] LCMS: m/z = 320.0 (M+19)+.
[0001 154] 1 H NMR (400 MHz, DMSO-t/e) 6 10.79 (s, 1H), 9.61 (s, 1H), 7.94 (d, J= 2.4
Hz, 1H), 7.38 (dd, J= 2.4, 8.8 Hz, 1H), 6.82 (d, J= 8.8 Hz, 1H), 4.13 - 4.08 (m, 2H), 3.73 -
3.70 (m, 1H), 3.04 - 2.97 (m, 2H), 2.67 - 2.53 (m, 3H), 2.22 - 2.12 (m, 1H), 2.00 - 1.93 (m,
1H), 1.90 - 1.85 (m, 2H), 1.49 - 1.45 (m, 2H).
[0001155] SFC: 100% ee under 220 nm.
[0001156] HA-XX (peak 2):
[0001157] LCMS: m/z = 320.0 (M+19)+.
[0001 158] 'H NMR (400 MHz, DMSO-t/e) d 10.79 (s, 1H), 9.61 (s, 1H), 7.94 (d, J = 2.4 Hz, 1H), 7.38 (dd, J= 2.4, 8.8 Hz, 1H), 6.82 (d, J= 8.8 Hz, 1H), 4.13 - 4.09 (m, 2H), 3.74 -
3.70 (m, 1H), 3.04 - 2.97 (m, 2H), 2.67 - 2.53 (m, 3H), 2.22 - 2.12 (m, IH), 2.00 - 1.93 (m,
1H), 1.90 - 1.85 (m, 2H), 1.49 - 1.46 (m, 2H).
[0001159] SFC: 100% ee under 220 nm.
[0001160] General Procedures for Synthesis of Final Exemplary Chimeric Targeting Molecules (CTMs)
[0001 161] Reductive Amination Example
[0001 162] Synthesis of rac-A-[3-(2-fert-butyl-5-12-[(4-H-[(l-14-[(31?)-2.,6- dioxopiperidin-3-yl]phenvnpiperidin-4-yl)methyl]piperidin-4- vnphenyl)amino]pyrimidin-4-vn-l.,3-thiazol-4-yl)-2-fluorophenyl]propane-l- sulfonamide
[0001 163] A-{3-[2-tert-butyl-5-(2-{ [4-(piperidin-4-yl)phenyl]amino}pyrimidin-4-yl)- l,3-thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide (93 mg, 0.153 mmol) and rac-l-{4- [(3A)-2,6-dioxopiperidin-3-yl]phenyl}piperidine-4-carbaldehyde (57 mg, 1.25 equiv) were combined in DCE (0.1 M) and DIEA (0.08 mL, 3 equiv) and the reaction mixture was stirred for fifteen minutes, followed by the addition of STAB (89 mg, 2.75 equiv). The reaction was then stirred for 4 h, followed by concentration by rotary evaporator. The reaction was then diluted with DMF (0.5 mL), filtered through a syringe filter, and purified by HPLC to provide the desired product (32 mg, 22%). LCMS: C48H57FN8O4S2 requires: 892.4, found: m/z = 893.3 [M+H]+.
[0001 164] Amide Coupling Examples
[0001 165] Synthesis of rac- -2.6- dioxopiperidin-3-yl]-l.,3-dioxoisoindol-5-ynoxy)acetyl]piperidin-4- ynphenyl)amino]pyrimidin-4-yn-l.,3-thiazol-4-yl)-2-fluorophenyl]propane-l- sulfonamide [0001 166] N- { 3-[2-tert-butyl-5-(2- { [4-(piperidin-4-yl)phenyl]amino}pyrimidin-4-yl)- l,3-thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide (20 mg, 0.033 mmol), rac-({2-[(37?)- 2,6-dioxopiperidin-3-yl]-l,3-dioxoisoindol-5-yl}oxy)acetic acid (12 mg, 1.1 equiv) and HATU (13 mg, 1.1 equiv) in DMF (0.2 M) and DIEA (0.023 mL, 4 equiv) was stirred at rt for 4 h, followed by filtration by syringe filter and purification by HPLC to provide the desired product (13 mg, 39%). LCMS: C46H47FN8O8S2 requires: 922.3, found: m/z = 923.5 [M+H]+.
[0001167] Synthesis of rac-\-!3- -2.6-dioxopiperidin-3- yl]pyridin-2-vnpiperidin-4-yl)acetyl]piperazine-l-carbonvnphenyl)-3-(pyridin-4- yl)pyrazol-4-yl]-2-fluorophenvnpropane-l-sulfonamide
[0001168] 7V-(2-fluoro-3-{ l-[4-(piperazine-l-carbonyl)phenyl]-3-(pyridin-4-yl)pyrazol- 4-yl}phenyl)propane-l -sulfonamide (20 mg, 0.0336 mmol), rac-(l-{5-[(37?)-2,6- dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)acetic acid (12 mg, 1.1 equiv), and HATU (13 mg, 1.1 equiv) in DMF (0.2 M) and DIEA (0.023 mL, 4 equiv) was stirred at rt for 4 h. Filtration by syringe filter and purification by HPLC provided the desired product (23 mg, 66%). LCMS: C45H48FN9O6S requires: 861.3, found: m/z = 862.2 [M+H]+.
[0001 169] Synthesis of rac-\-|3-(l-!l-| l-(l-!5-|(3/?)-2.6-dioxopiperidin-3-yl|pyridin-
2-vnpiperidine-4-carbonyl)piperidine-4-carbonyl]piperidin-4-vn-3-(pyridin-4- yl)pyrazol-4-yl)-2-fluorophenyl]propane-l-sulfonamide [0001 170] A-{2-fluoro-3-[l-(piperidin-4-yl)-3-(pyridin-4-yl)pyrazol-4- yl]phenyl(propane-l-sulfonamide (10 mg, 0.023 mmol), rac-l-(l-{5-[(37?)-2,6- dioxopiperidin-3-yl]pyridin-2-yl}piperidine-4-carbonyl)piperidine-4-carboxylic acid (10 mg, 1.03 equiv), and HATU (9 mg, 1.05 equiv) in DMF (0.1 M) and DIEA (0.02 mL, 5 equiv) was stirred at rt for 4 h. Filtration by syringe filter and purification by HPLC provided the desired product (5.4 mg, 27%). LCMS: C44H52FN9O6S requires: 853.4, found: m/z = 854.7 [M+H]+.
[0001171] A-{3-[l-(4-{4-[(l-{5-[(35)-2,6-dioxopiperidin-3-yl]pyridin-2-yl(piperidin-4- yl)methyl]piperazin-l-yl(phenyl)-3-(pyridin-4-yl)-U7-pyrazol-4-yl]-2- fluorophenyl (propane- 1 -sulfonamide (1)
LCMS: C43H48FN9O4S requires: 805.4, found: m/z = 806.2 [M+H]+.
[0001 172] A-{3-[l-(4-{4-[(l-{5-[(3A)-2,6-dioxopiperidin-3-yl]pyridin-2-yl(piperidin-4- yl)methyl]piperazin-l-yl(phenyl)-3-(pyridin-4-yl)-U7-pyrazol-4-yl]-2- fluorophenyl (propane- 1 -sulfonamide (2)
'H NMR (500 MHz, DMSO-ok) 5 10.88 (s, 1H), 9.69 (s, 1H), 9.50 (s, 1H), 8.77 (s, 1H), 8.65 (d, J= 5.4 Hz, 2H), 7.94 (d, J= 2.4 Hz, 1H), 7.87 (d, J= 8.8 Hz, 2H), 7.63 (d, J= 5.7 Hz, 3H), 7.49 (td, J = 7.7, 1.9 Hz, 1H), 7.40 - 7.34 (m, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.25 - 7.17 (m, 2H), 4.28 (d, J= 13.0 Hz, 2H), 3.94 (d, J= 10.9 Hz, 3H), 3.89 - 3.79 (m, 1H), 3.25 - 3.10 (m, 6H), 3.09 - 2.94 (m, 4H), 2.75 - 2.60 (m, 1H), 2.32 - 2.13 (m, 2H), 2.03 - 1.92 (m, 1H), 1.88 (d, J= 12.9 Hz, 2H), 1.75 - 1.60 (m, 2H), 1.28 (d, J= 11.4 Hz, 1H), 0.92 (t, J= 7.4 Hz, 3H).
LCMS: C43H48FN9O4S requires: 805.4, found: m/z = 806.3 [M+H]+.
[0001173] rac-A-{3-[l-(6-{4-[(l-{5-[(3A)-2,6-dioxopiperidin-3-yl]pyridin-2- yl(piperidin-4-yl)methyl]piperazin-l-yl(pyridin-3-yl)-3-(pyridin-4-yl)-U7-pyrazol-4-yl]-2- fluorophenyl (propane- 1 -sulfonamide (3)
LCMS: C42H47FN10O4S requires: 806.3, found: m/z = 807.2 [M+H]+.
[0001174] A-{3-[l-(6-{4-[(l-{4-[(35)-2,6-dioxopiperidin-3-yl]phenyl(piperidin-4- yl)methyl]piperazin-l-yl(pyridin-3-yl)-3-(pyridin-4-yl)-U7-pyrazol-4-yl]-2- fluorophenyl (propane- 1 -sulfonamide (4)
LCMS: C43H48FN9O4S requires: 805.4, found: m/z = 806.2 [M+H]+. [0001 175] rac-7V-{3-[l-(4-{[l-(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2- yl Jpiperidine-4-carbonyl)piperidin-4-yl]oxy Jphenyl)-3-(pyridin-4-yl)- l//-pyrazol-4-yl]-2- fluorophenyl } propane- 1 -sulfonamide (5)
LCMS: C44H47FN8O6S requires: 834.3, found: m/z = 835.2 [M+H]+.
[0001176] rac-7V-{3-[l-(l-{l-[(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2- yl}piperidin-4-yl)methyl]piperidine-4-carbonyl}piperidin-4-yl)-3-(pyridin-4-yl)-lZ7-pyrazol- 4-yl]-2-fluorophenyl}propane-l-sulfonamide (6)
LCMS: C44H54FN9O5S requires: 839.4, found: m/z = 840.3 [M+H]+.
[0001177] rac-7V-[3-(l-{l-[l-(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2- yl}piperidine-4-carbonyl)piperidine-4-carbonyl]piperidin-4-yl}-3-(pyridin-4-yl)-177-pyrazol- 4-yl)-2-fluorophenyl]propane- 1 -sulfonamide (7)
LCMS: C44H52FN9O6S requires: 853.4, found: m/z = 854.7 [M+H]+.
[0001178] rac-7V-[3-(l-{l-[l-(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2- yl}piperidine-4-carbonyl)-4-methylpiperidine-4-carbonyl]piperidin-4-yl}-3-(pyridin-4-yl)- lH-pyrazol-4-yl)-2-fluorophenyl]propane-l-sulfonamide (8)
LCMS: C45H54FN9O6S requires: 867.4, found: m/z = 868.2 [M+H]+.
[0001179] rac-7V-[3-(l-{l-[l-(l-{4-[(37?)-2,6-dioxopiperidin-3-yl]phenyl}piperidine-4- carbonyl)piperidine-4-carbonyl]piperidin-4-yl}-3-(pyridin-4-yl)-U7-pyrazol-4-yl)-2- fluorophenyl]propane-l -sulfonamide (9)
LCMS: C45H53FN8O6S requires: 852.4, found: m/z = 853.2 [M+H]+.
[0001180] 7V-{3-[l-(4-{4-[(l-{4-[(35)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4- yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4-yl)-177-pyrazol-4-yl]-2- fluorophenyl } propane- 1 -sulfonamide (10)
JH NMR (500 MHz, DMSO-ok) 5 10.78 (s, 1H), 9.68 (s, 1H), 8.71 (s, 1H), 8.55 (d, J = 5.2 Hz, 2H), 7.83 (s, 2H), 7.45 (dd, J= 16.5, 6.4 Hz, 3H), 7.32 (dt, J= 26.2, 7.4 Hz, 2H), 7.24 - 7.00 (m, 4H), 6.92 (d, J = 8.2 Hz, 2H), 3.73 (dd, J = 11.1, 5.0 Hz, 1H), 3.21 (s, 6H), 3.02 (dd, J = 9.1, 6.3 Hz, 2H), 2.65 (t, J= 15.4 Hz, 3H), 2.32 - 2.07 (m, 1H), 2.02 (dd, J= 13.0, 5.6 Hz, 1H), 1.85 (d, J= 12.4 Hz, 2H), 1.69 (q, J= 7.6 Hz, 2H), 0.92 (t, J= 7.4 Hz, 3H).
LCMS: C44H49FN8O4S requires: 804.4, found: m/z = 805.7 [M+H]+.
[0001181] 7V-{3-[l-(4-{4-[(l-{4-[(3/?)-2,6-dioxopiperidin-3-yl]phenyl(piperidin-4- yl)methyl]piperazine-l-carbonyl}phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl]-2- fluorophenyl ( propane- 1 -sulfonamide (11)
LCMS: C45H49FN8O5S requires: 832.4, found: m/z = 833.2 [M+H]+.
[0001182] 7V-{3-[l-(4-{4-[(l-{4-[(35)-2,6-dioxopiperidin-3-yl]phenyl(piperidin-4- yl)methyl]piperazine-l-carbonyl}phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl]-2- fluorophenyl (propane- 1 -sulfonamide (12)
LCMS: C45H49FN8O5S requires: 832.4, found: m/z = 833.3 [M+H]+.
[0001183] rac-7V-{3-[l-(4-{4-[2-(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2- yl(piperidin-4-yl)acetyl]piperazine-l-carbonyl(phenyl)-3-(pyridin-4-yl)-lZ7-pyrazol-4-yl]-2- fluorophenyl (propane- 1 -sulfonamide (13)
LCMS: C45H48FN9O6S requires: 861.3, found: m/z = 862.2 [M+H]+.
[0001 184] rac-7V-[3-(l-{4-[4-(l-{4-[(3/?)-2,6-dioxopiperidin-3-yl]phenyl(piperidine-4- carbonyl)piperazine-l-carbonyl]phenyl(-3-(pyridin-4-yl)-U7-pyrazol-4-yl)-2- fluoropheny 1 ] prop ane- 1 - sulfonami de ( 14)
LCMS: C45H47FN8O6S requires: 846.3, found: m/z = 847.2 [M+H]+.
[0001185] 7V-{3-[l-(4-{l-[(l-{4-[(35)-2,6-dioxopiperidin-3-yl]phenyl(piperidin-4- yl)methyl]piperidin-4-yl]phenyl)-3-(pyridin-4-yl)-lJH-pyrazol-4-yl]-2-fluorophenyl]propane- 1 -sulfonamide (15)
LCMS: C45H5OFN704S requires: 803.4, found: m/z = 804.2 [M+H]+. [0001 186] 7V-{3-[l-(4-{4-[(l-{4-[(37?)-2,6-dioxopiperidin-3-yl]phenyl(piperidin-4- yl)methyl]piperazin- l -yl Jphenyl)-3-(pyridin-4-yl)- IT/-pyrazol-4-yl]-2- fluorophenyl ( propane- 1 -sulfonamide (16)
'HNMR (500 MHz, DMSO-ok) 5 10.78 (s, 1H), 9.69 (s, 1H), 8.69 (d, J= 3.0 Hz, 1H), 8.57 - 8.52 (m, 2H), 8.15 (s, 1H), 7.79 (d, J= 8.7 Hz, 2H), 7.50 - 7.44 (m, 1H), 7.47 - 7.41 (m, 2H), 7.37 - 7.31 (m, 1H), 7.29 (t, J = 7.8 Hz, 1H), 7.13 - 7.08 (m, 2H), 7.05 (d, J = 8.2 Hz, 2H), 6.90 (d, J = 8.3 Hz, 2H), 5.77 (s, 1H), 3.73 (dd, J= 10.9, 4.9 Hz, 1H), 3.68 (d, J = 11.8 Hz, 2H), 3.24 (d, J= 4.8 Hz, 3H), 3.02 (dd, J = 8.7, 6.6 Hz, 2H), 2.67 (d, J= 11.7 Hz, 2H), 2.25 (d, J= 7.1 Hz, 2H), 2.18 - 2.07 (m, 1H), 2.02 (dt, J= 13.3, 4.9 Hz, 1H), 1.83 (d, J= 12.5 Hz, 2H), 1.74 - 1.64 (m, 3H), 1.30 - 1.19 (m, 2H), 0.91 (t, J= 7.4 Hz, 3H).
LCMS: C44H49FN8O4S requires: 804.4, found: m/z = 805.2 [M+H]+.
[0001 187] rac-7V-{3-[l-(4-{4-[(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2-yl(-4- methylpiperidin-4-yl)methyl]piperazin-l-yl(phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl]-2- fluorophenyl (propane- 1 -sulfonamide (17)
LCMS: C44H50FN9O4S requires: 819.4, found: m/z = 820.2 [M+H]+.
[0001188] rac-7V-{3-[l-(4-{4-[(l-{4-[(37?)-2,6-dioxopiperidin-3-yl]-2- fluorophenyl(piperidin-4-yl)methyl]piperazin-l-yl(phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4- yl]-2-fluorophenyl (propane- 1 -sulfonamide (18)
'H NMR (500 MHz, DMSO-ok) 5 10.83 (s, 1H), 9.70 (s, 1H), 9.43 (s, 1H), 8.80 (s, 1H), 8.69 (d, J= 5.6 Hz, 2H), 7.89 (d, J= 8.7 Hz, 2H), 7.69 (d, J= 5.5 Hz, 2H), 7.50 (td, J= 7.7, 1.9 Hz, 1H), 7.41 - 7.36 (m, 1H), 7.32 (t, J = 7.8 Hz, 1H), 7.22 (d, J= 8.8 Hz, 2H), 7.08 - 6.95 (m, 3H), 3.95 (d, J= 11.6 Hz, 2H), 3.82 (dd, J= 11.8, 4.9 Hz, 1H), 3.73 - 3.62 (m, 2H), 3.40 (d, J = 11.5 Hz, 2H), 3.30 - 3.11 (m, 6H), 3.10 - 3.01 (m, 2H), 2.78 - 2.60 (m, 3H), 2.21 (dd, J = 12.4, 4.2 Hz, 1H), 2.06 - 1.95 (m, 2H), 1.95 - 1.84 (m, 2H), 1.70 (q, J = 7.6 Hz, 2H), 1.56 - 1.36 (m, 2H), 0.93 (t, J= 7.4 Hz, 3H).
LCMS: C44H48F2N8O4S requires: 822.3, found: m/z = 823.2 [M+H]+.
[0001 189] rac-7V-{3-[l-(4-{4-[(l-{4-[(37?)-2,6-dioxopiperidin-3-yl]-3- fluorophenyl(piperidin-4-yl)methyl]piperazin-l-yl(phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4- yl]-2-fluorophenyl (propane- 1 -sulfonamide (19) LCMS: C44H48F2N8O4S requires: 822.4, found: m/z = 823.2 [M+H]+.
[0001 190] rac-7V-{3-[l-(4-{4-[(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2- yl Jpiperidin-4-yl)methyl]piperazin- l -yl Jphenyl)-3-(pyridin-4-yl)- l//-pyrazol-4-yl]-2- fluorophenyl (propane- 1 -sulfonamide (20)
'H NMR (500 MHz, DMSO-t/e) 8 10.90 (s, 1H), 9.70 (s, 1H), 9.53 (s, 1H), 8.80 (s, 1H), 8.68 (d, J= 5.4 Hz, 2H), 7.95 (d, J= 2.3 Hz, 1H), 7.89 (d, J= 8.6 Hz, 2H), 7.67 (d, J= 5.5 Hz, 3H), 7.55 - 7.46 (m, 1H), 7.35 (dt, J= 29.6, 7.5 Hz, 2H), 7.22 (d, J= 8.7 Hz, 2H), 7.16 (s, 1H), 4.28 (d, J= 13.1 Hz, 2H), 3.95 (d, J= 11.1 Hz, 2H), 3.86 (dd, J= 12.6, 4.9 Hz, 1H), 3.67 (d, J = 10.4 Hz, 2H), 3.31 - 3.10 (m, 6H), 3.11 - 2.94 (m, 3H), 2.77 - 2.63 (m, 1H), 2.25 (ddd, J = 19.8, 14.4, 7.6 Hz, 2H), 1.98 (dq, J= 13.1, 4.8, 4.3 Hz, 1H), 1.89 (d, J= 12.8 Hz, 2H), 1.70 (q, J= 7.6 Hz, 2H), 1.30 (q, J= 12.9, 12.3 Hz, 2H), 0.93 (t, J= 7.4 Hz, 3H).
LCMS: C43H48FN9O4S requires: 805.4, found: m/z = 806.2 [M+H]+.
[0001 191] rac-7V-{3-[l-(4-{4-[(l-{4-[(37?)-2,6-dioxopiperidin-3-yl]phenyl(piperidin-4- yl)methyl]piperazin-l-yl(phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl]-2- fluorophenyl (propane- 1 -sulfonamide (21)
LCMS: C44H49FN8O4S requires: 804.4, found: m/z = 805.2 [M+H]+.
[0001192] rac-7V-{3-[l-(4-{ l-[(l-{4-[(37?)-2,6-dioxopiperidin-3-yl]-2- fluorophenyl(piperidin-4-yl)methyl]piperidin-4-yl(phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4- yl]-2-fluorophenyl (propane- 1 -sulfonamide (22)
LCMS: C45H49F2N7O4S requires: 821.4, found: m/z = 822.2 [M+H]+.
[0001193] rac-7V-{3-[l-(4-{ l-[(l-{4-[(37?)-2,6-dioxopiperidin-3-yl]-3- fluorophenyl(piperidin-4-yl)methyl]piperidin-4-yl(phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4- yl]-2-fluorophenyl (propane- 1 -sulfonamide (23)
LCMS: C45H49F2N7O4S requires: 821.4, found: m/z = 822.2 [M+H]+.
[0001 194] rac-7V-{ 3 -[ 1 -(4- { 1 -[( 1 -{ 5 -[(37?)-2,6-dioxopiperi din-3 -yl]pyridin-2- yl(piperidin-4-yl)methyl]piperidin-4-yl(phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl]-2- fluorophenyl (propane- 1 -sulfonamide (24) LCMS: C44H49FN8O4S requires: 804.4, found: m/z = 805.2 [M+H]+.
[0001 195] rac-7V-{3-[l-(4-{ l-[(l-{4-[(3/?)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4- yl)methyl]piperidin-4-yl [phenyl)-3-(pyridin-4-yl)- l//-pyrazol-4-yl]-2-fluorophenyl [propane- 1 -sulfonamide (25)
LCMS: C45H5OFN704S requires: 803.4, found: m/z = 804.3 [M+H]+.
[0001196] rac-7V-[3-(l-{4-[4-(l-{4-[(37?)-2,6-dioxopiperidin-3-yl]phenyl}piperidine-4- carbonyl)piperazin-l-yl]phenyl}-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2-fluorophenyl]propane-
1 -sulfonamide (26)
LCMS: C44H47FN8O5S requires: 818.3, found: m/z = 819.2 [M+H]+.
[0001 197] (3/?)-3-{6-[4-({4-[6-({4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)-2 -methyl- 1 ,3 -thiazol-5-yl]pyrimidin-2-yl } amino)pyri din-3 -yl]piperazin- 1 - yl }methyl)piperidin- 1 -yl]pyri din-3 -yl }piperidine-2, 6-dione (27)
LCMS: C42H49FN12O4S2 requires: 868.3, found: m/z = 869.2 [M+H]+.
[0001 198] rac-(3/?)-3-[2-(2-{4-[4-({4-[2-tert-butyl-4-(3-
{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3-thiazol-5-yl]pyrimidin-2-yl}amino)-2- fluorophenyl]piperazin-l-yl}-2-oxoethyl)-l,2,3,4-tetrahydroisoquinolin-6-yl]piperidine-2,6- dione (28)
LCMS: C46H52F2N10O5S2 requires: 926.4, found: m/z = 927.2 [M+H]+.
[0001199] (3/?)-3-{6-[4-({4-[6-({4-[2-terLbutyl-4-(3-{[ethyl(methyl)sulfamoyl]amino}-
2-fluorophenyl)-l,3-thiazol-5-yl]pyrimidin-2-yl}amino)pyridin-3-yl]piperazin-l- yl }methyl)piperidin- 1 -yl]pyri din-3 -yl }piperidine-2, 6-dione (29)
‘H NMR (500 MHz, DMSO-t/e) 8 10.81 (s, 1H), 9.70 (s, 1H), 9.56 (s, 1H), 8.35 (d, J = 5.2 Hz, 1H), 7.99 (d, J= 2.9 Hz, 1H), 7.95 (d, J= 2.4 Hz, 1H), 7.83 (d, J= 9.0 Hz, 1H), 7.55 (t, J= 7.8 Hz, 1H), 7.44 - 7.25 (m, 4H), 6.80 (d, J = 8.8 Hz, 1H), 6.44 (d, J = 5.2 Hz, 1H), 4.28 (d, J = 12.7 Hz, 2H), 3.73 (dd, J= 12.2, 4.9 Hz, 1H), 3.14 (s, 4H), 3.06 (q, J= 7.1 Hz, 2H), 2.80 (t, J = 12.4 Hz, 2H), 2.75 - 2.61 (m, 5H), 2.40 - 2.34 (m, 1H), 2.31 - 2.12 (m, 3H), 2.05 - 1.92 (m, 1H), 1.80 (d, J= 12.7 Hz, 3H), 1.48 (s, 10H), 1.25 (s, 2H), 1.19 - 1.05 (m, 2H), 1.00 (t, J= 7.1 Hz, 3H).
LCMS: C45H55FN12O4S2 requires: 910.4, found: m/z = 911.2 [M+H]+.
[0001200] rac-(37?)-3-{6-[6-({4-[6-({4-[2-tert-butyl-4-(3-
{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3-thiazol-5-yl]pyrimidin-2- yl}amino)pyridin-3-yl]piperazin-l-yl}methyl)-2-azaspiro[3.3]heptan-2-yl]pyridin-3- yl}piperidine-2, 6-dione (30)
LCMS: C46H55FN12O4S2 requires: 922.4, found: m/z = 923.2 [M+H]+.
[0001201] rac-7V-[3-(5-{2-[(4-{4-[(l-{4-[(37?)-2,6-dioxopiperidin-3-yl]phenyl}-4- fluoropiperidin-4-yl)methyl]piperazin-l-yl}phenyl)amino]pyrimidin-4-yl}-2-methyl-l,3- thiazol-4-yl)-2-fluorophenyl]propane-l -sulfonamide (31)
LCMS: C44H49F2N9O4S2 requires: 869.3, found: m/z = 870.3 [M+H]+.
[0001202] rac-7V-[3-(5-{2-[(4-{4-[(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}-4- methylpiperidin-4-yl)methyl]piperazin- 1 -yl }phenyl)amino]pyrimidin-4-yl } -2-m ethyl- 1,3- thiazol-4-yl)-2-fluorophenyl]propane-l -sulfonamide (32)
LCMS: C44H5IFNIO04S2 requires: 866.4, found: m/z = 867.3 [M+H]+.
[0001203] rac-(35)-3-{4-[4-({4-[6-({4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)-2 -methyl- 1 ,3 -thiazol-5-yl]pyrimidin-2-yl } amino)pyri din-3 -yl]piperazin- 1 - yl}methyl)-4-fluoropiperidin-l-yl]phenyl}piperidine-2, 6-dione (33)
LCMS: C43H49F2N11O4S2 requires: 885.3, found: m/z = 886.2 [M+H]+.
[0001204] rac-(35)-3-{6-[4-({4-[6-({4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)-2 -methyl- 1 ,3 -thiazol-5-yl]pyrimidin-2-yl } amino)pyri din-3 -yl]piperazin- 1 - yl }methyl)-4-methylpiperidin- 1 -yl]pyri din-3 -yl }piperidine-2, 6-dione (34)
LCMS: C43H51FN12O4S2 requires: 882.4, found: m/z = 883.2 [M+H]+. [0001205] rac-N-[3-(2-tert-butyl-5-{2-[(4-{l-[(l-{5-[(37?)-2,6-dioxopiperidin-3- yl]pyridin-2-yl }piperidin-4-yl)methyl]piperidin-4-yl }phenyl)amino]pyrimidin-4-yl } - 1 ,3 - thiazol-4-yl)-2-fluorophenyl]propane-l -sulfonamide (35)
LCMS: C47H56FN9O4S2 requires: 893.4, found: m/z = 894.2 [M+H]+.
[0001206] rac-(3S)-3 -[4-(4- { 4-[6-({ 4-[2-terLbutyl-4-(3 -
{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3-thiazol-5-yl]pyrimidin-2- yl}amino)pyridin-3-yl]piperazine-l-carbonyl}piperidin-l-yl)phenyl]piperidine-2, 6-dione (36)
LCMS: C46H54FNIIO5S2 requires: 923.4, found: m/z = 924.2 [M+H]+.
[0001207] rac-/V-(3-{2-terLbutyl-5-[2-({4-[l-(l-{4-[(3/?)-2,6-dioxopiperidin-3- yl]phenyl}piperidine-4-carbonyl)piperidin-4-yl]phenyl}amino)pyrimidin-4-yl]-l,3-thiazol-4- yl } -2-fluorophenyl)propane- 1 -sulfonamide (37)
LCMS: C48H55FN8O5S2 requires: 906.4, found: m/z = 907.2 [M+H]+.
[0001208] rac-/V-(3-{2-terLbutyl-5-[2-({4-[4-(l-{4-[(3/?)-2,6-dioxopiperidin-3- yl]phenyl}piperidine-4-carbonyl)piperazin-l-yl]phenyl}amino)pyrimidin-4-yl]-l,3-thiazol-4- yl } -2-fluorophenyl)propane- 1 -sulfonamide (38)
LCMS: C47H54FN9O5S2 requires: 907.4, found: m/z = 908.7 [M+H]+.
[0001209] rac-(3/?)-3-{6-[4-(2-{4-[6-({4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)-2 -methyl- 1 ,3 -thiazol-5-yl]pyrimidin-2-yl } amino)pyri din-3 -yl]piperazin- 1 -y 1 } - 2-oxoethyl)piperidin-l-yl]pyridin-3-yl}piperidine-2, 6-dione (39)
LCMS: C43H49FN12O5S2 requires: 896.3, found: m/z = 897.2 [M+H]+.
[0001210] rac-(35)-3-[6-(4-{4-[6-({4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)-2 -methyl- 1,3-thi azol-5-yl]pyrimidin-2-yl}amino)pyri din-3 -yl]piperazine-l - carbonyl}piperidin-l-yl)pyridin-3-yl]piperidine-2, 6-dione (40)
LCMS: C43H47FN12O5S2 requires: 882.3, found: m/z = 883.2 [M+H]+. [0001211] (3/?)-3-{4-[4-({4-[6-({4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)-2 -methyl- 1 ,3 -thiazol-5-yl]pyrimidin-2-yl } amino)pyri din-3 -yl]piperazin- 1 - yl}methyl)piperidin-l-yl]phenyl}piperidine-2, 6-dione (41)
LCMS: C43H5OFNII04S2 requires: 867.3, found: m/z = 868.2 [M+H]+.
[0001212] rac-(35)-3-[6-(4-{4-[6-({4-[2-terLbutyl-4-(3-
{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3-thiazol-5-yl]pyrimidin-2- yl}amino)pyri din-3 -yl]piperazine-l -carbonyl }-4-methylpiperi din- l-yl)pyri din-3 - yl]piperidine-2, 6-dione (42)
LCMS: C46H55FN12O5S2 requires: 938.4, found: m/z = 939.0 [M+H]+.
[0001213] rac-(35)-3-{6-[4-({4-[6-({4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)-2 -methyl- 1 ,3 -thiazol-5-yl]pyrimidin-2-yl } amino)pyri din-3 -yl]piperazin- 1 - yl }methyl)piperidin- 1 -yl]pyri din-3 -yl }piperidine-2, 6-dione (43)
LCMS: C42H49FN12O4S2 requires: 868.3, found: m/z = 868.3 [M+H]+.
[0001214] rac-7V-{3-[5-(2-{[4-(l-{2-[l-(4-{[(3/?)-2,6-dioxopiperidin-3- yl]amino}phenyl)piperidin-4-yl]acetyl}piperidin-4-yl)phenyl]amino}pyrimidin-4-yl)-2- methyl- 1 ,3 -thi azol -4-yl] -2-fluorophenyl (propane- 1 -sulfonamide (44)
LCMS: C46H52FN9O5S2 requires: 893.4, found: m/z = 894.4 [M+H]+.
[0001215] rac-/V-[3-(2-terLbutyl-5-{2-[(4-{4-[(l-{5-[(3/?)-2,6-dioxopiperidin-3- yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l-yl}-3-fluorophenyl)amino]pyrimidin-4- yl}-l,3-thiazol-4-yl)-2-fluorophenyl]propane-l -sulfonamide (45)
LCMS: C46H54F2N10O4S2 requires: 912.4, found: m/z = 913.6 [M+H]+.
[0001216] rac-/V-{3-[2-terLbutyl-5-(2-{[4-(4-{2-[l-(4-{[(3/?)-2,6-dioxopiperidin-3- yl]amino}phenyl)piperidin-4-yl]acetyl}piperazin-l-yl)-3-fluorophenyl]amino}pyrimidin-4- yl)-l,3-thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide (46)
LCMS: C48H56F2NIO05S2 requires: 954.4, found: m/z = 955.2 [M+H]+. [0001217] rac-/V-[3-(2-terLbutyl-5-{2-[(4-{4-[(l-{5-[(3/?)-2,6-dioxopiperidin-3- yl]pyridin-2-yl }piperidin-4-yl)methyl]piperazin- 1 -yl }phenyl)amino]pyrimidin-4-yl } - 1 ,3 - thiazol-4-yl)-2-fluorophenyl]propane-l -sulfonamide (47)
'H NMR (500 MHz, DMSO-ok) 5 10.88 (s, 1H), 9.73 (s, 1H), 9.55 (s, 1H), 9.32 (s, 1H), 8.30 (d, J= 5.2 Hz, 1H), 7.95 (s, 1H), 7.55 (d, J= 8.3 Hz, 3H), 7.47 (t, J= 6.9 Hz, 1H), 7.37 (t, J= 7.9 Hz, 1H), 7.09 (s, 1H), 6.94 (d, J= 8.7 Hz, 2H), 6.40 (d, J= 5.1 Hz, 1H), 4.29 (d, J= 13.1 Hz, 2H), 3.83 (s, 2H), 3.73 (d, J = 12.7 Hz, 2H), 3.64 (d, J = 11.7 Hz, 2H), 3.27 - 3.09 (m, 3H), 3.09 - 2.94 (m, 5H), 2.77 - 2.62 (m, 2H), 2.32 - 2.12 (m, 2H), 1.99 (dt, J= 11.5, 5.6 Hz, 1H), 1.88 (d, J= 12.5 Hz, 2H), 1.68 (p, J = 7.6 Hz, 2H), 1.37 - 1.21 (m, 3H), 0.91 (t, J= 7.4 Hz, 3H).
LCMS: C46H55FNIO04S2 requires: 894.4, found: m/z = 895.2 [M+H]+.
[0001218] rac-7V-[3-(2-terZ-butyl-5-{2-[(4-{4-[2-(l-{5-[(37?)-2,6-dioxopiperidin-3- yl]pyridin-2-yl}piperidin-4-yl)acetyl]piperazin-l-yl}-3-fluorophenyl)amino]pyrimidin-4-yl}- 1 ,3 -thiazol-4-yl)-2-fluorophenyl]propane- 1 -sulfonamide (48)
LCMS: C47H54F2N10O5S2 requires: 940.4, found: m/z = 941.3 [M+H]+.
[0001219] rac-/V-(3-(2-(terLbutyl)-5-(2-((4-(4-((R)-l-(5-((R)-2,6-dioxopiperidin-3- yl)pyridin-2-yl)pyrrolidine-3-carbonyl)piperazin-l-yl)-3-fluorophenyl)amino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide (49)
LCMS: C45H50F2N10O5S2 requires: 912.3, found: m/z = 913.6 [M+H]+.
[0001220] 7V-[3-(2-terLbutyl-5-{2-[(3-fluoro-4-{4-[(lr,4r)-4-({5-[(3/?5)-2,6- dioxopiperidin-3-yl]pyridin-2-yl}oxy)cyclohexanecarbonyl]piperazin-l- yl}phenyl)amino]pyrimidin-4-yl}-l,3-thiazol-4-yl)-2-fluorophenyl]propane-l-sulfonamide (50)
LCMS: C47H53F2N9O6S2 requires: 941.4, found: m/z = 942.1 [M+H]+.
[0001221] rac-/V-(3-{2-terLbutyl-5-[2-({4-[4-(2-{6-[(3/?)-2,6-dioxopiperidin-3-yl]- l,2,3,4-tetrahydroisoquinolin-2-yl}acetyl)piperazin-l-yl]-3-fluorophenyl}amino)pyrimidin-4- yl]-l,3-thiazol-4-yl}-2-fluorophenyl)propane-l -sulfonamide (51) LCMS: C46H51F2N9O5S2 requires: 911.3, found: m/z = 912.2 [M+H]+.
[0001222] rac-/V-{3-[2-terLbutyl-5-(2-{[4-(4-{2-[l-(4-{[(37?)-2,6-dioxopiperidin-3- yl]amino}-2-fluorophenyl)-4-hydroxypiperidin-4-yl]acetyl}piperazin-l-yl)-3- fluorophenyl]amino}pyrimidin-4-yl)-l, 3-thi azol -4-yl]-2-fluorophenyl (propane- 1- sulfonamide (52)
LCMS: C48H55F3NIO06S2 requires: 988.4, found: m/z = 989.2 [M+H]+.
[0001223] rac-(35)-3-[6-(3-{4-[6-({4-[2-terLbutyl-4-(3-
{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3-thiazol-5-yl]pyrimidin-2- yl}amino)pyri din-3 -yl]piperazine-l -carbonyl }azeti din- l-yl)pyri din-3 -yl]piperidine-2, 6-dione (53)
LCMS: C43H49FN12O5S2 requires: 896.3, found: m/z = 897.2 [M+H]+.
[0001224] rac-7V-[3-(5-{2-[(4-{ l-[(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2- yl}piperidin-4-yl)methyl]piperidin-4-yl}phenyl)amino]pyrimidin-4-yl}-2-methyl-l,3-thiazol- 4-yl)-2-fluorophenyl]propane- 1 -sulfonamide (54)
LCMS: C44H50FN9O4S2 requires: 851.3, found: m/z = 852.2 [M+H]+.
[0001225] rac-7V-(3-{5-[2-({4-[l-(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2- yl}piperidine-4-carbonyl)piperidin-4-yl]phenyl}amino)pyrimidin-4-yl]-2-methyl-l,3-thiazol- 4-yl}-2-fluorophenyl)propane-l -sulfonamide (55)
LCMS: C44H48FN9O5S2 requires: 865.3, found: m/z = 866.2 [M+H]+.
[0001226] rac-(37?)-3-[6-(4-{4-[6-({4-[2-tert-butyl-4-(3-
{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3-thiazol-5-yl]pyrimidin-2- yl}amino)pyridin-3-yl]piperazine-l-carbonyl}piperidin-l-yl)pyridin-3-yl]piperidine-2,6- dione (56)
LCMS: C45H53FN12O5S2 requires: 924.4, found: m/z = 925.7 [M+H]+. [0001227] rac-7V-(3-{2-terZ-butyl-5-[2-({4-[4-(l-{5-[(37?)-2,6-dioxopiperidin-3- yl]pyridin-2-yl}piperidine-4-carbonyl)piperazin-l-yl]-3-fluorophenyl}amino)pyrimidin-4- yl]-l,3-thiazol-4-yl}-2-fluorophenyl)propane-l -sulfonamide (57)
LCMS: C46H52F2N10O5S2 requires: 926.4, found: m/z = 927.2 [M+H]+.
[0001228] 7V-[3-(2-terLbutyl-5-{2-[(4-{4-[(l-{4-[(35)-2,6-dioxopiperidin-3- yl]phenyl }piperidin-4-yl)methyl]piperazin- 1 -yl }phenyl)amino]pyrimidin-4-yl } - 1 ,3 -thiazol-4- yl)-2-fluorophenyl]propane-l -sulfonamide (58)
'HNMR (500 MHz, DMSO-tL) 8 10.78 (s, 1H), 9.46 (s, 1H), 8.28 (d, J= 5.2 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.47 (dd, J= 23.0, 7.7 Hz, 3H), 7.36 (t, J= 7.9 Hz, 1H), 7.04 (d, J= 8.2 Hz, 2H), 6.88 (dd, J= 18.3, 8.5 Hz, 4H), 6.35 (d, J= 5.1 Hz, 1H), 3.79 - 3.62 (m, 3H), 3.08 (t, J= 4.9 Hz, 4H), 3.01 (t, J= 7.7 Hz, 2H), 2.72 - 2.58 (m, 4H), 2.24 (d, J= 7.2 Hz, 2H), 2.20 - 2.08 (m, 1H), 2.02 (dt, J= 13.4, 5.1 Hz, 1H), 1.82 (d, J = 12.7 Hz, 2H), 1.69 (dt, J= 15.2, 7.4 Hz, 3H), 1.30 - 1.17 (m, 2H), 0.91 (t, J= 7.4 Hz, 3H).
LCMS: C47H56FN9O4S2 requires: 893.4, found: m/z = 894.4 [M+H]+.
[0001229] 7V-[3-(2-terLbutyl-5-{2-[(4-{4-[(l-{4-[(3/?)-2,6-dioxopiperidin-3- yl]phenyl }piperidin-4-yl)methyl]piperazin- 1 -yl }phenyl)amino]pyrimidin-4-yl } - 1 ,3 -thiazol-4- yl)-2-fluorophenyl]propane-l -sulfonamide (59)
'HNMR (500 MHz, DMSO-tL) 6 10.80 (s, 1H), 9.73 (s, 1H), 9.56 (s, 1H), 9.34 (s, 1H), 8.30 (d, J= 5.2 Hz, 1H), 7.55 (d, J= 8.3 Hz, 3H), 7.47 (t, J= 7.0 Hz, 1H), 7.37 (t, J= 7.9 Hz, 1H), 7.17 - 7.05 (m, 2H), 7.05 - 6.84 (m, 4H), 6.40 (d, J= 5.1 Hz, 1H), 3.90 - 3.69 (m, 6H), 3.64 (d, J= 11.5 Hz, 2H), 3.18 (q, J= 8.9, 6.8 Hz, 4H), 3.10 - 2.95 (m, 4H), 2.80 (s, 2H), 2.65 (td, J= 11.9, 5.5 Hz, 1H), 2.22 - 1.96 (m, 3H), 1.89 (d, J= 12.3 Hz, 2H), 1.67 (q, J= 7.5 Hz, 2H), 1.48 (s, 9H), 1.38 (t, J = 15.5 Hz, 1H), 1.27 (q, J= 5.8, 4.7 Hz, 1H), 0.91 (t, J= 7.4 Hz, 3H).
LCMS: C47H56FN9O4S2 requires: 893.4, found: m/z = 894.2 [M+H]+.
[0001230] 7V-[3-(5-{2-[(5-{4-[(l-{4-[(3/?)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4- yl)methyl]piperazin- 1 -yl }pyridin-2-yl)amino]pyrimidin-4-yl } -2-m ethyl- 1 ,3 -thiazol-4-yl)-2- fluorophenyl]propane-l -sulfonamide (60)
LCMS: C43H49FN10O4S2 requires: 852.3, found: m/z = 853.2 [M+H]+. [0001231] 7V-[3-(5-{2-[(5-{4-[(l-{4-[(35)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4- yl)methyl]piperazin- 1 -yl }pyridin-2-yl)amino]pyrimidin-4-yl } -2-m ethyl- 1 ,3 -thiazol-4-yl)-2- fluoropheny 1 ] prop ane- 1 - sulfonami de (61 )
LCMS: C43H49FN10O4S2 requires: 852.3, found: m/z = 853.2 [M+H]+
[0001232] rac-7V-[3-(5-{2-[(5-{4-[(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2- yl}piperidin-4-yl)methyl]piperazin-l-yl}pyridin-2-yl)amino]pyrimidin-4-yl}-2-methyl-l,3- thiazol-4-yl)-2-fluorophenyl]propane-l -sulfonamide (62)
LCMS: C42H48FN11O4S2 requires: 853.3, found: m/z = 854.2 [M+H]+.
[0001233] 7V-[3-(5-{2-[(4-{l-[(l-{4-[(3/?)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4- yl)methyl]piperidin-4-yl}phenyl)amino]pyrimidin-4-yl}-2-methyl-l,3-thiazol-4-yl)-2- fluoropheny 1] prop ane- 1 -sulfonamide (63)
LCMS: C45H5IFN8O4S2 requires: 850.3, found: m/z = 851.2 [M+H]+.
[0001234] 7V-[3-(5-{2-[(4-{l-[(l-{4-[(35)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4- yl)methyl]piperidin-4-yl}phenyl)amino]pyrimidin-4-yl}-2-methyl-l,3-thiazol-4-yl)-2- fluoropheny 1] prop ane- 1 -sulfonamide (64)
LCMS: C45H5IFN8O4S2 requires: 850.3, found: m/z = 851.2 [M+H]+.
[0001235] rac-/V-(3-{2-terLbutyl-5-[2-({4-[4-(l-{4-[(3/?)-2,6-dioxopiperidin-3- yl]phenyl}piperidine-4-carbonyl)piperazin-l-yl]-3-fluorophenyl}amino)pyrimidin-4-yl]-l,3- thiazol-4-yl } -2-fluorophenyl)propane- 1 -sulfonamide (65)
LCMS: C47H53F2N9O5S2 requires: 925.4, found: m/z = 926.2 [M+H]+.
[0001236] 5-(4-{[4-({4-[(4-{2-terLbutyl-4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]- l,3-thiazol-5-yl}pyrimidin-2-yl)amino]-l/Z-pyrazol-l-yl}methyl)piperidin-l- yl]methyl}piperidin-l-yl)-7V-[(3/?)-2,6-dioxopiperidin-3-yl]pyridine-2-carboxamide (66)
LCMS: C46H57FN12O5S2 requires: 940.4, found: m/z = 941.2 [M+H]+. [0001237] 5-{4-[(4-{4-[(4-{2-terLbutyl-4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]- l,3-thiazol-5-yl}pyrimidin-2-yl)amino]-17/-pyrazol-l-yl}piperidin-l-yl)methyl]piperidin-l- yl}-7V-[(37?)-2,6-dioxopiperidin-3-yl]pyridine-2-carboxamide (67)
LCMS: C45H55FNi2O5S2 requires: 926.4, found: m/z = 927.3 [M+H]+.
[0001238] rac-/V-{3-[2-terLbutyl-5-(2-{[3-({l-[(l-{5-[(37?)-2,6-dioxopiperidin-3- yl]pyridin-2-yl}-4-methylpiperidin-4-yl)methyl]piperidin-4-yl}oxy)phenyl]amino}pyrimidin- 4-yl)- 1 ,3 -thiazol-4-yl]-2-fluorophenyl [propane- 1 -sulfonamide (68)
LCMS: C48H58FN9O5S2 requires: 923.4, found: m/z = 924.3 [M+H]+.
[0001239] 7V-(3-{2-terLbutyl-5-[2-({3-[(l-{2-[(35)-l-{5-[(37?5)-2,6-dioxopiperidin-3- yl]pyridin-2-yl}pyrrolidin-3-yl]ethyl}piperidin-4-yl)oxy]phenyl}amino)pyrimidin-4-yl]-l,3- thiazol-4-yl } -2-fluorophenyl)propane- 1 -sulfonamide (69)
LCMS: C47H56FN9O5S2 requires: 909.4, found: m/z = 910.6 [M+H]+.
[0001240] 7V-(3-{2-terLbutyl-5-[2-({3-[(l-{2-[(3/?)-l-{5-[(37?5)-2,6-dioxopiperidin-3- yl]pyridin-2-yl}pyrrolidin-3-yl]ethyl}piperidin-4-yl)oxy]phenyl}amino)pyrimidin-4-yl]-l,3- thiazol-4-yl } -2-fluorophenyl)propane- 1 -sulfonamide (70)
LCMS: C47H56FN9O5S2 requires: 909.4, found: m/z = 910.3 [M+H]+.
[0001241] rac-/V-{3-[2-terLbutyl-5-(2-{[3-({l-[(l-{2-[(37?)-2,6-dioxopiperidin-3-yl]-l- oxo-l,2-dihydroisoquinolin-6-yl}piperidin-4-yl)methyl]piperidin-4- yl}oxy)phenyl]amino}pyrimidin-4-yl)-l,3-thiazol-4-yl]-2-fluorophenyl}propane-l- sulfonamide (71)
LCMS: C5IH58FN9O6S2 requires: 975.4, found: m/z = 976.5 [M+H]+.
[0001242] N-(3 -(2-(terCbutyl)-5-(2-((3 -(( 1 -((( 1R, 4r)-4-(4-((R5)-2, 6-dioxopiperi din-3 - yl)phenoxy)cyclohexyl)methyl)piperidin-4-yl)oxy)phenyl)amino)pyrimidin-4-yl)thiazol-4- yl)-2-fluorophenyl)propane-l -sulfonamide (72)
LCMS: C49H58FN7O6S2 requires: 923.4, found: m/z = 924.2 [M+H]+. [0001243] rac-7V-[3-(2-terZ-butyl-5-{2-[(3-{ l-[(l-{5-[(37?)-2,6-dioxopiperidin-3- yl]pyridin-2-yl}-4-methylpiperidin-4-yl)methyl]piperidin-4-yl}phenyl)amino]pyrimidin-4- yl}-l,3-thiazol-4-yl)-2-fluorophenyl]propane-l -sulfonamide (73)
LCMS: C48H58FN9O4S2 requires: 907.4, found: m/z = 908.9 [M+H]+.
[0001244] 7V-{3-[2-tert-butyl-5-(2-{[3-(l-{2-[(35)-l-{5-[(37?5)-2,6-dioxopiperidin-3- yl]pyridin-2-yl}pyrrolidin-3-yl]ethyl}piperidin-4-yl)phenyl]amino}pyrimidin-4-yl)-l,3- thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide (74)
LCMS: C47H56FN9O4S2 requires: 893.4, found: m/z = 894.2 [M+H]+.
[0001245] 7V-{3-[2-terLbutyl-5-(2-{[3-(l-{2-[(3/?)-l-{5-[(3/?5)-2,6-dioxopiperidin-3- yl]pyridin-2-yl}pyrrolidin-3-yl]ethyl}piperidin-4-yl)phenyl]amino}pyrimidin-4-yl)-l,3- thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide (75)
LCMS: C47H56FN9O4S2 requires: 893.4, found: m/z = 894.2 [M+H]+.
[0001246] rac-/V-[3-(2-terLbutyl-5-{2-[(3-{ l-[(l-{2-[(3/?)-2,6-dioxopiperidin-3-yl]-l- oxo-l,2-dihydroisoquinolin-6-yl}piperidin-4-yl)methyl]piperidin-4- yl}phenyl)amino]pyrimidin-4-yl}-l,3-thiazol-4-yl)-2-fluorophenyl]propane-l-sulfonamide (76)
LCMS: C51H58FN9O4S2 requires: 959.4, found: m/z = 960.3 [M+H]+.
[0001247] 7V-{3-[2-terLbutyl-5-(2-{[l-(l-{2-[(35)-l-{5-[(3/?5)-2,6-dioxopiperidin-3- yl]pyridin-2-yl}pyrrolidin-3-yl]ethyl}piperidin-4-yl)-l/7-pyrazol-4-yl]amino}pyrimidin-4- yl)-l,3-thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide (77)
LCMS: C44H54FN11O4S2 requires: 883.4, found: m/z = 884.3 [M+H]+.
[0001248] N- { 3 - [2-te/7-butyl-5 -(2- { [ 1 -( 1 - { 2- [(3/?)- 1 - { 5 - [(3/?5)-2, 6-dioxopiperi din-3 - yl]pyridin-2-yl}pyrrolidin-3-yl]ethyl}piperidin-4-yl)-l/7-pyrazol-4-yl]amino}pyrimidin-4- yl)-l,3-thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide (78)
LCMS: C44H54FN11O4S2 requires: 883.4, found: m/z = 884.6 [M+H]+. [0001249] rac-5 - { 4- [(4- { 4- [(4- { 2-terLbutyl-4- [2-fluoro-3 -(propane- 1 - sulfonamido)phenyl]- 1 ,3 -thiazol-5-yl }pyrimidin-2-yl)amino]- 1 //-pyrazol - 1 -yl Jpiperidin- 1 - yl)methyl]piperidin-l-yl}-7V-[(37?)-2,6-dioxopiperidin-3-yl]pyridine-2-carboxamide (79)
LCMS: C45H55FNi2O5S2 requires: 926.4, found: m/z = 927.2 [M+H]+.
[0001250] rac-7V-[3-(2-terZ-butyl-5-{2-[(l-{l-[(l-{2-[(37?)-2,6-dioxopiperidin-3-yl]-l- oxo- 1 ,2-dihydroisoquinolin-6-yl }piperidin-4-yl)methyl]piperidin-4-yl } - l/Z-pyrazol-4- yl)amino]pyrimidin-4-yl}-l,3-thiazol-4-yl)-2-fluorophenyl]propane-l-sulfonamide (80)
LCMS: C48H56FNIIO5S2 requires: 949.4, found: m/z = 950.3 [M+H]+.
[0001251] 7V-(3-{2-terLbutyl-5-[2-({l-[(l-{2-[(3/?)-l-{5-[(37?5)-2,6-dioxopiperidin-3- yl]pyridin-2-yl}pyrrolidin-3-yl]ethyl}piperidin-4-yl)methyl]-l/7-pyrazol-4- yl}amino)pyrimidin-4-yl]-l,3-thiazol-4-yl}-2-fluorophenyl)propane-l -sulfonamide (81)
LCMS: C45H56FNIIO4S2 requires: 897.4, found: m/z = 898.2 [M+H]+.
[0001252] rac-5 -(4-{ [4-({4-[(4- {2-terLbutyl-4-[2-fluoro-3 -(propane- 1 - sulfonamido)phenyl]- 1 ,3 -thiazol-5-yl }pyrimidin-2-yl)amino]- 1 //-pyrazol - 1 - yl}methyl)piperidin-l-yl]methyl}piperidin-l-yl)-7V-[(37?)-2,6-dioxopiperidin-3-yl]pyridine-2- carboxamide (82)
LCMS: C46H57FN12O5S2 requires: 940.4, found: m/z = 941.3 [M+H]+.
[0001253] rac-/V-{3-[2-terLbutyl-5-(2-{[l-({l-[(l-{2-[(37?)-2,6-dioxopiperidin-3-yl]-l- oxo- l,2-dihydroisoquinolin-6-yl}piperidin-4-yl)methyl]piperidin-4-yl (methyl)- 1/7-pyrazol- 4-yl]amino}pyrimidin-4-yl)-l,3-thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide (83)
LCMS: C49H58FNIIO5S2 requires: 963.4, found: m/z = 964.2 [M+H]+.
[0001254] 7V-(3-{2-terLbutyl-5-[2-({l-[(l-{[(lr,4r)-4-{4-[(37?5)-2,6-dioxopiperidin-3- yl]phenoxy}cyclohexyl]methyl}piperidin-4-yl)methyl]-l/7-pyrazol-4-yl}amino)pyrimidin-4- yl]-l,3-thiazol-4-yl}-2-fluorophenyl)propane-l -sulfonamide (84)
LCMS: C47H58FN9O5S2 requires: 911.4, found: m/z = 912.2 [M+H]+. [0001255] rac-/V-(3-{2-terLbutyl-5-[2-({2-[(l-{2-[(3/?)-2,6-dioxopiperidin-3-yl]-l-oxo- l,2-dihydroisoquinolin-6-yl}piperidin-4-yl)methyl]-l,2,3,4-tetrahydroisoquinolin-6- yl}amino)pyrimidin-4-yl]-l,3-thiazol-4-yl}-2-fluorophenyl)propane-l -sulfonamide (85)
LCMS: C49H54FN9O5S2 requires: 931.4, found: m/z = 932.3 [M+H]+.
[0001256] (25,4/?)- 1 - [(25)-2- [5 -(4- { 4 - [ (4 - { 2-/c77-buty 1 -4- [2-fluoro-3 -(propane- 1 - sulfonamido)phenyl]-l,3-thiazol-5-yl}pyrimidin-2-yl)amino]phenyl}piperidin-l-yl)-5- oxopentanamido]-3,3-dimethylbutanoyl]-4-hydroxy-7V-[(15)-l-[4-(4-methyl-l,3-thiazol-5- yl)phenyl]ethyl]pyrrolidine-2-carboxamide (86)
LCMS: C59H73FN10O7S3 requires: 1148.5, found: m/z = 1149.3 [M+H]+.
[0001257] 7V-[3-(2-terLbutyl-5-{2-[(4-{4-[(l-{4-[(3/?)-2,6-dioxopiperidin-3- yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}-3-fluorophenyl)amino]pyrimidin-4-yl}-l,3- thiazol-4-yl)-2-fluorophenyl]propane-l -sulfonamide (87)
LCMS: C47H55F2N9O4S2 requires: 911.4, found: m/z = 912.6 [M+H]+.
[0001258] 7V-[3-(2-terLbutyl-5-{2-[(4-{4-[(l-{4-[(35)-2,6-dioxopiperidin-3- yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}-3-fluorophenyl)amino]pyrimidin-4-yl}-l,3- thiazol-4-yl)-2-fluorophenyl]propane-l -sulfonamide (88)
LCMS: C47H55F2N9O4S2 requires: 911.4, found: m/z = 912.3 [M+H]+.
[0001259] 7V-[3-(2-terLbutyl-5-{2-[(4-{l-[(l-{4-[(3/?)-2,6-dioxopiperidin-3- yl]phenyl}piperidin-4-yl)methyl]piperidin-4-yl}phenyl)amino]pyrimidin-4-yl}-l,3-thiazol-4- yl)-2-fluorophenyl]propane-l -sulfonamide (89)
LCMS: C48H57FN8O4S2 requires: 892.4, found: m/z = 893.2 [M+H]+.
[0001260] 7V-[3-(2-terLbutyl-5-{2-[(4-{l-[(l-{4-[(35)-2,6-dioxopiperidin-3- yl]phenyl}piperidin-4-yl)methyl]piperidin-4-yl}phenyl)amino]pyrimidin-4-yl}-l,3-thiazol-4- yl)-2-fluorophenyl]propane-l -sulfonamide (90)
LCMS: C48H57FN8O4S2 requires: 892.4, found: m/z = 893.2 [M+H]+. [0001261] 7V-(3-{2-tert-butyl-5-[2-({3-[(l-{2-[(37?)-l-{4-[(37?5)-2,6-dioxopiperidin-3- yl]phenyl}pyrrolidin-3-yl]acetyl}piperidin-4-yl)oxy]phenyl}amino)pyrimidin-4-yl]-l,3- thiazol-4-yl } -2-fluorophenyl)propane- 1 -sulfonamide (91)
LCMS: C48H55FN8O6S2 requires: 922.4, found: m/z = 923.3 [M+H]+.
[0001262] 7V-(3-{2-tert-butyl-5-[2-({3-[(l-{2-[(35)-l-{4-[(37?5)-2,6-dioxopiperidin-3- yl]phenyl}pyrrolidin-3-yl]acetyl}piperidin-4-yl)oxy]phenyl}amino)pyrimidin-4-yl]-l,3- thiazol-4-yl } -2-fluorophenyl)propane- 1 -sulfonamide (92)
LCMS: C48H55FN8O6S2 requires: 922.4, found: m/z = 923.2 [M+H]+.
[0001263] rac-/V-{3-[2-terLbutyl-5-(2-{[3-({ l-[2-(4-{4-[(3/?)-2,6-dioxopiperidin-3- yl]pyridin-2-yl (piperazin- 1 -yl)acetyl]piperidin-4-yl ( oxy)phenyl]amino(pyrimidin-4-yl)- 1,3- thiazol-4-yl]-2-fluorophenyl(propane-l-sulfonamide (93)
LCMS: C47H55FNIO06S2 requires: 938.4, found: m/z = 939.5 [M+H]+.
[0001264] 7V-{3-[2-terLbutyl-5-(2-{[3-({ l-[(3/?)-l-{5-[(3/?5)-2,6-dioxopiperidin-3- yl]pyridin-2-yl(pyrrolidine-3-carbonyl]piperidin-4-yl(oxy)phenyl]amino(pyrimidin-4-yl)-
1.3-thiazol-4-yl]-2-fluorophenyl(propane-l-sulfonamide (94)
LCMS: C46H52FN9O6S2 requires: 909.3, found: m/z = 910.2 [M+H]+.
[0001265] rac-5 -[4-(4- { 3 - [(4- { 2-terLbutyl-4-[2-fluoro-3 -(propane- 1 - sulfonamido)phenyl]- 1 ,3 -thiazol-5-yl (pyrimidin-2-yl)amino]phenoxy (piperidine- 1 - carbonyl)piperidin-l-yl]-7V-[(3/?)-2,6-dioxopiperidin-3-yl]pyridine-2-carboxamide (95)
LCMS: C48H55FNIO07S2 requires: 966.4, found: m/z = 967.2 [M+H]+.
[0001266] rac-/V-(3-{2-terLbutyl-5-[2-({3-[(l-{2-[4-(4-{[(3/?)-2,6-dioxopiperidin-3- yl]amino(phenyl)piperidin-l-yl]acetyl(piperidin-4-yl)oxy]phenyl(amino)pyrimidin-4-yl]-
1.3-thiazol-4-yl(-2-fluorophenyl)propane-l-sulfonamide (96)
LCMS: C49H58FN9O6S2 requires: 951.4, found: m/z = 952.2 [M+H]+. [0001267] 7V-{3-[2-terLbutyl-5-(2-{[3-({ l-[(lr,4r)-4-({5-[(37?5)-2,6-dioxopiperidin-3- yl]pyridin-2-yl}oxy)cyclohexanecarbonyl]piperidin-4-yl}oxy)phenyl]amino}pyrimidin-4-yl)- l,3-thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide (97)
LCMS: C48H55FN8O7S2 requires: 938.4, found: m/z = 939.2 [M+H]+.
[0001268] 7V-{3-[2-tert-butyl-5-(2-{[3-({ l-[(lr,4r)-4-{4-[(37?5)-2,6-dioxopiperidin-3- yl]phenoxy}cyclohexanecarbonyl]piperidin-4-yl}oxy)phenyl]amino}pyrimidin-4-yl)-l,3- thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide (98)
LCMS: C49H56FN7O7S2 requires: 937.4, found: m/z = 955.6 [M+NH4]+.
[0001269] rac-/V-[3-(2-terLbutyl-5-{2-[(3-{[l-(l-{3-[(37?)-2,6-dioxopiperidin-3- yl]phenyl}piperidine-4-carbonyl)piperidin-4-yl]oxy}phenyl)amino]pyrimidin-4-yl}-l,3- thiazol-4-yl)-2-fluorophenyl]propane-l -sulfonamide (99)
LCMS: C48H55FN8O6S2 requires: 922.4, found: m/z = 923.7 [M+H]+.
[0001270] rac-/V-[3-(2-terLbutyl-5-{2-[(3-{[l-(l-{4-[(37?)-2,6-dioxopiperidin-3- yl]pyridin-2-yl}piperidine-4-carbonyl)piperidin-4-yl]oxy}phenyl)amino]pyrimidin-4-yl}-l,3- thiazol-4-yl)-2-fluorophenyl]propane-l -sulfonamide (100)
LCMS: C47H54FN9O6S2 requires: 923.4, found: m/z = 924.3 [M+H]+.
[0001271] rac-/V-[3-(2-terLbutyl-5-{2-[(3-{[l-(2-{6-[(37?)-2,6-dioxopiperidin-3-yl]- l,2,3,4-tetrahydroisoquinolin-2-yl}acetyl)piperidin-4-yl]oxy}phenyl)amino]pyrimidin-4-yl}- l,3-thiazol-4-yl)-2-fluorophenyl]propane-l-sulfonamide (101)
LCMS: C47H53FN8O6S2 requires: 908.4, found: m/z = 909.0 [M+H]+.
[0001272] 7V-[3-(2-terLbutyl-5-{2-[(3-{ l-[(37?)-l-{5-[(37?5)-2,6-dioxopiperidin-3- yl]pyridin-2-yl}pyrrolidine-3-carbonyl]piperidin-4-yl}phenyl)amino]pyrimidin-4-yl}-l,3- thiazol-4-yl)-2-fluorophenyl]propane-l -sulfonamide (102)
LCMS: C46H52FN9O5S2 requires: 893.4, found: m/z = 894.2 [M+H]+. [0001273] rac-/V-{3-[2-terLbutyl-5-(2-{[3-(l-{2-[4-(4-{[(37?)-2,6-dioxopiperidin-3- yl]amino}phenyl)piperidin-l-yl]acetyl}piperidin-4-yl)phenyl]amino}pyrimidin-4-yl)-l,3- thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide (103)
LCMS: C49H58FN9O5S2 requires: 935.4, found: m/z = 936.2 [M+H]+.
[0001274] rac-7V-(3-{2-terZ-butyl-5-[2-({3-[l-(2-{6-[(37?)-2,6-dioxopiperidin-3-yl]- l,2,3,4-tetrahydroisoquinolin-2-yl}acetyl)piperidin-4-yl]phenyl}amino)pyrimidin-4-yl]-l,3- thiazol-4-yl } -2-fluorophenyl)propane- 1 -sulfonamide (104)
LCMS: C47H53FN8O5S2 requires: 892.4, found: m/z = 893.2 [M+H]+.
[0001275] 2V-{3-[2-tert-butyl-5-(2-{[l-(l-{2-[(3S)-l-{4-[(37?S)-2,6-dioxopiperidin-3- yl]phenyl}pyrrolidin-3-yl]acetyl}piperidin-4-yl)-lH-pyrazol-4-yl]amino}pyrimidin-4-yl)- l,3-thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide (105)
LCMS: C45H53FNIO05S2 requires: 896.4, found: m/z = 897.0 [M+H]+.
[0001276] 7V-[3-(2-terLbutyl-5-{2-[(l-{ l-[(37?)-l-{5-[(37?5)-2,6-dioxopiperidin-3- yl]pyridin-2-yl}pyrrolidine-3-carbonyl]piperidin-4-yl}-l/7-pyrazol-4-yl)amino]pyrimidin-4- yl}-l,3-thiazol-4-yl)-2-fluorophenyl]propane-l -sulfonamide (106)
LCMS: C43H50FN11O5S2 requires: 883.3, found: m/z = 884.3 [M+H]+.
[0001277] rac-5-[4-(4-{4-[(4-{2-terLbutyl-4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]- 1 ,3 -thiazol-5-yl }pyrimidin-2-yl)amino]- 1/7-pyrazol- 1 -yl (piperidine- 1 - carbonyl)piperidin-l-yl]-7V-[(37?)-2,6-dioxopiperidin-3-yl]pyridine-2-carboxamide (107)
LCMS: C45H53FN12O6S2 requires: 940.4, found: m/z = 941.3 [M+H]+.
[0001278] rac-/V-{3-[2-terLbutyl-5-(2-{[l-(l-{2-[4-(4-{[(37?)-2,6-dioxopiperidin-3- yl]amino}phenyl)piperidin-l-yl]acetyl}piperidin-4-yl)-177-pyrazol-4-yl]amino}pyrimidin-4- yl)-l,3-thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide (108)
LCMS: C46H56FNnO5S2 requires: 925.4, found: m/z = 926.1 [M+H]+. [0001279] 7V-[3-(2-terLbutyl-5-{2-[(l-{l-[(lr,4r)-4-({5-[(37?5)-2,6-dioxopiperidin-3- yl]pyridin-2-yl }oxy)cyclohexanecarbonyl]piperidin-4-yl J- l //-pyrazol -4-yl Jami no]pyri midi n- 4-yl}-l,3-thiazol-4-yl)-2-fluorophenyl]propane-l-sulfonamide (109)
LCMS: C45H53FNnO6S2 requires: 912.4, found: m/z = 913.2 [M+H]+.
[0001280] 7V-[3-(2-terLbutyl-5-{2-[(l-{l-[(lr,4r)-4-{4-[(37?5)-2,6-dioxopiperidin-3- yl]phenoxy}cyclohexanecarbonyl]piperidin-4-yl}-177-pyrazol-4-yl)amino]pyrimidin-4-yl}- 1 ,3 -thiazol-4-yl)-2-fluorophenyl]propane- 1 -sulfonamide (110)
LCMS: C46H54FN9O6S2 requires: 911.4, found: m/z = 912.2 [M+H]+.
[0001281] 7V-(3-{2-terLbutyl-5-[2-({l-[(l-{2-[(3/?)-l-{4-[(37?5)-2,6-dioxopiperidin-3- yl]phenyl}pyrrolidin-3-yl]acetyl}piperidin-4-yl)methyl]-177-pyrazol-4-yl}amino)pyrimidin- 4-yl]- 1 ,3 -thiazol-4-yl } -2-fluorophenyl)propane- 1 -sulfonamide (111)
LCMS: C46H55FNIO05S2 requires: 910.4, found: m/z = 911.4 [M+H]+.
[0001282] 7V-(3-{2-terLbutyl-5-[2-({ l-[(l-{2-[(35)-l-{4-[(37?5)-2,6-dioxopiperidin-3- yl]phenyl}pyrrolidin-3-yl]acetyl}piperidin-4-yl)methyl]-177-pyrazol-4-yl}amino)pyrimidin- 4-yl]- 1 ,3 -thiazol-4-yl } -2-fluorophenyl)propane- 1 -sulfonamide (112)
LCMS: C46H55FNIO05S2 requires: 910.4, found: m/z = 911.4 [M+H]+.
[0001283] rac-/V-{3-[2-terLbutyl-5-(2-{[l-({l-[2-(4-{4-[(37?)-2,6-dioxopiperidin-3- yl]pyridin-2-yl (piperazin- 1 -yl)acetyl]piperidin-4-yl (methyl)- U7-pyrazol-4- yl]amino(pyrimidin-4-yl)-l,3-thiazol-4-yl]-2-fluorophenyl(propane-l-sulfonamide (113)
LCMS: C45H55FNi2O5S2 requires: 926.4, found: m/z = 927.2 [M+H]+.
[0001284] 7V-{3-[2-terLbutyl-5-(2-{[l-({l-[(3/?)-l-{5-[(37?5)-2,6-dioxopiperidin-3- yl]pyridin-2-yl(pyrrolidine-3-carbonyl]piperidin-4-yl(methyl)-l/7-pyrazol-4- yl]amino(pyrimidin-4-yl)-l,3-thiazol-4-yl]-2-fluorophenyl(propane-l-sulfonamide (114)
LCMS: C44H52FN11O5S2 requires: 897.4, found: m/z = 898.4 [M+H]+.
[0001285] rac-5 - { 4- [4-( { 4- [(4- { 2-terLbutyl-4- [2-fluoro-3 -(propane- 1 - sulfonamido)phenyl]- 1 ,3 -thiazol-5-yl }pyrimidin-2-yl)amino]- 1/7-pyrazol- 1 - yl }methyl)piperidine- 1 -carbonyl]piperidin- 1 -yl } -7V-[(37?)-2,6-dioxopiperidin-3 -yl]pyridine-2- carb oxami de (115)
LCMS: C46H55FNi2O6S2 requires: 954.4, found: m/z = 955.3 [M+H]+.
[0001286] rac-7V-(3-{2-terZ-butyl-5-[2-({l-[(l-{2-[4-(4-{[(37?)-2,6-dioxopiperidin-3- yl]amino}phenyl)piperidin-l-yl]acetyl}piperidin-4-yl)methyl]-177-pyrazol-4- yl}amino)pyrimidin-4-yl]-l,3-thiazol-4-yl}-2-fluorophenyl)propane-l -sulfonamide (116)
LCMS: C47H58FNIIO5S2 requires: 939.4, found: m/z = 940.5 [M+H]+.
[0001287] 7V-{3-[2-terLbutyl-5-(2-{[l-({l-[(lr,4r)-4-({5-[(37?5)-2,6-dioxopiperidin-3- yl]pyridin-2-yl}oxy)cyclohexanecarbonyl]piperidin-4-yl}methyl)-177-pyrazol-4- yl]amino}pyrimidin-4-yl)-l,3-thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide (117)
LCMS: C46H55FNIO06S2 requires: 926.4, found: m/z = 927.2 [M+H]+.
[0001288] 7V-{3-[2-terLbutyl-5-(2-{[l-({l-[(lr,4r)-4-{4-[(37?5)-2,6-dioxopiperidin-3- yl]phenoxy}cyclohexanecarbonyl]piperidin-4-yl}methyl)-177-pyrazol-4-yl]amino}pyrimidin- 4-yl)- 1 ,3 -thi azol -4-yl]-2-fluorophenyl (propane- 1 -sulfonamide (118)
LCMS: C47H56FN9O6S2 requires: 925.4, found: m/z = 926.2 [M+H]+.
[0001289] rac-/V-[3-(2-terLbutyl-5-{2-[(l-{[l-(2-{6-[(37?)-2,6-dioxopiperidin-3-yl]- l,2,3,4-tetrahydroisoquinolin-2-yl}acetyl)piperidin-4-yl]methyl}-177-pyrazol-4- yl)amino]pyrimidin-4-yl } - 1 ,3 -thiazol-4-yl)-2-fluorophenyl]propane- 1 -sulfonamide (119)
LCMS: C45H53FNIO05S2 requires: 896.4, found: m/z = 897.5 [M+H]+.
[0001290] rac-/V-(3-{2-terLbutyl-5-[2-({2-[2-(4-{4-[(37?)-2,6-dioxopiperidin-3- yl]pyridin-2-yl}piperazin-l-yl)acetyl]-l,2,3,4-tetrahydroisoquinolin-6-yl}amino)pyrimidin-4- yl]-l,3-thiazol-4-yl}-2-fluorophenyl)propane-l -sulfonamide (120)
LCMS: C45H51FN10O5S2 requires: 894.3, found: m/z = 895.2 [M+H]+.
[0001291] 7V-(3-{2-terLbutyl-5-[2-({2-[(3/?)-l-{5-[(37?5)-2,6-dioxopiperidin-3- yl]pyridin-2-yl}pyrrolidine-3-carbonyl]-l,2,3,4-tetrahydroisoquinolin-6-yl}amino)pyrimidin- 4-yl]- 1 ,3 -thi azol -4 -yl } -2-fluorophenyl)propane- 1 -sulfonamide (121)
LCMS: C44H48FN9O5S2 requires: 865.3, found: m/z = 866.3 [M+H]+.
[0001292] rac-5-(4-{6-[(4-{2-terLbutyl-4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]- l,3-thiazol-5-yl}pyrimidin-2-yl)amino]-l,2,3,4-tetrahydroisoquinoline-2-carbonyl}piperidin- l-yl)-7V-[(37?)-2,6-dioxopiperidin-3-yl]pyridine-2-carboxamide (122) LCMS: C46H5IFNIO06S2 requires: 922.3, found: m/z = 923.1 [M+H]+.
[0001293] rac-7V-[3-(2-terZ-butyl-5-{2-[(2-{2-[4-(4-{[(37?)-2,6-dioxopiperidin-3- yl]amino}phenyl)piperidin-l-yl]acetyl}-l,2,3,4-tetrahydroisoquinolin-6-yl)amino]pyrimidin- 4-yl}-l,3-thiazol-4-yl)-2-fluorophenyl]propane-l-sulfonamide (123)
LCMS: C47H54FN9O5S2 requires: 907.4, found: m/z = 908.2 [M+H]+.
[0001294] Rac-(35)-3-(2-{[(lr,4r)-4-{4-[6-({4-[2-Zert-butyl-4-(3-
{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3-thiazol-5-yl]pyrimidin-2- yl }amino)pyri din-3 -yl]piperazine-l -carbonyl }cy cl ohexyl]methyl}- 1,2, 3,4- tetrahydroisoquinolin-7-yl)piperidine-2, 6-dione (124)
LCMS: C51H62FN11O5S2 requires: 991.4, found: m/z = 992.3 [M+H]+.
[0001295] Rac-(3S)-3-(2-{[(lr,4r)-4-{4-[6-({4-[2-Zert-butyl-4-(3-
{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3-thiazol-5-yl]pyrimidin-2- yl }amino)pyri din-3 -yl]piperazine-l -carbonyl }cy cl ohexyl]methyl}- 1,2, 3,4- tetrahydroisoquinolin-6-yl)piperidine-2, 6-dione (125)
LCMS: C51H62FN11O5S2 requires: 991.4, found: m/z = 992.2 [M+H]+.
[0001296] rac-(3S)-3-{6-[4-({4-[6-({4-[2-terLbutyl-4-(3-
{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3-thiazol-5-yl]pyrimidin-2- yl } amino)pyri din-3 -yl]piperazin- 1 -yl }methyl)piperidin- 1 -yl]pyri din-3 -yl }piperidine-2,6- dione (126)
'H NMR (500 MHz, CD3CN) 5 10.30 (s, 1H), 8.82 (s, 1H), 8.50 (d, J= 5.4 Hz, 1H), 7.95 (d, J= 2.3 Hz, 1H), 7.91 (dd, J= 9.7, 2.9 Hz, 1H), 7.80 (dd, J= 9.6, 2.3 Hz, 1H), 7.69 (d, J= 9.6 Hz, 1H), 7.63 - 7.55 (m, 2H), 7.49 (dd, J= 14.5, 7.6 Hz, 2H), 7.37 (t, J= 7.9 Hz, 1H), 7.19 (d, J= 9.5 Hz, 1H), 4.22 (d, J= 13.7 Hz, 2H), 3.83 (dd, J= 12.7, 5.1 Hz, 1H), 3.24 (t, J= 12.8 Hz, 2H), 3.17 (q, J= 7.1 Hz, 2H), 3.08 (d, J= 6.8 Hz, 2H), 2.76 (s, 3H), 2.74 - 2.69 (m, 2H), 2.40 - 2.09 (m, 2H), 2.09 - 2.02 (m, 2H), 1.54 (s, 9H), 1.50 - 1.40 (m, 2H), 1.09 (t, J= 7.1 Hz, 3H).
LCMS: C45H55FN12O4S2 requires: 910.4, found: m/z = 911.2 [M+H]+. [0001297] (35)-3-{4-[4-({4-[6-({4-[2-tert-butyl-4-(3-{[ethyl(methyl)sulfamoyl]amino}-
2-fluorophenyl)-l,3-thiazol-5-yl]pyrimidin-2-yl}amino)pyridin-3-yl]piperazin-l- yl}methyl)piperidin-l-yl]phenyl}piperidine-2, 6-dione (127)
'H NMR (500 MHz, DMSO ) 8 10.79 (s, 1H), 9.69 (s, 1H), 9.32 (s, 1H), 8.41 (s, 1H), 8.03 (s, 1H), 7.84 (s, 1H), 7.55 (t, J= 8.0 Hz, 1H), 7.48 - 7.26 (m, 2H), 7.09 (d, J= 7.7 Hz, 2H), 6.97 (s, 2H), 6.54 (s, 1H), 3.81 (d, J = 12.6 Hz, 2H), 3.77 - 3.62 (m, 2H), 3.29 - 2.99 (m, 6H), 2.73 (d, J= 28.4 Hz, 2H), 2.66 (d, J= 12.9 Hz, 4H), 2.15 (d, J = 11.0 Hz, 1H), 2.11 - 1.97 (m, 1H), 1.88 (d, J= 12.8 Hz, 2H), 1.48 (s, 8H), 1.38 (d, J= 11.6 Hz, 2H), 1.00 (t, J = 7.1 Hz, 3H).
LCMS: C46H56FNHO4S2 requires: 909.4, found: m/z = 910.3 [M+H]+.
[0001298] (37?)-3-{4-[4-({4-[6-({4-[2-terZ-butyl-4-(3-{[ethyl(methyl)sulfamoyl]amino}-
2-fluorophenyl)-l,3-thiazol-5-yl]pyrimidin-2-yl}amino)pyridin-3-yl]piperazin-l- yl}methyl)piperidin-l-yl]phenyl}piperidine-2, 6-dione (128)
LCMS: C46H56FNHO4S2 requires: 909.4, found: m/z = 910.2 [M+H]+.
[0001299] rac-/V-(3-{2-terLbutyl-5-[2-({7-[(l-{2-[(3/?)-2,6-dioxopiperidin-3-yl]-l-oxo-
1.2-dihydroisoquinolin-6-yl}piperidin-4-yl)methyl]-7-azaspiro[3.5]nonan-2- yl}amino)pyrimidin-4-yl]-l,3-thiazol-4-yl}-2-fluorophenyl)propane-l -sulfonamide (129)
LCMS: C48H58FN9O5S2 requires: 923.4, found: m/z = 924.2 [M+H]+.
[0001300] 7V-[3-(2-terLbutyl-5-{2-[(7-{[(lr,4r)-4-{4-[(3/?5)-2,6-dioxopiperidin-3- yl]phenoxy}cyclohexyl]methyl}-7-azaspiro[3.5]nonan-2-yl)amino]pyrimidin-4-yl}-l,3- thiazol-4-yl)-2-fluorophenyl]propane-l -sulfonamide (130)
LCMS: C46H58FN7O5S2 requires: 871.4, found: m/z = 872.3 [M+H]+.
[0001301] rac-/V-[3-(2-terLbutyl-5-{2-[(7-{2-[4-(4-{[(3/?)-2,6-dioxopiperidin-3- yl]amino}phenyl)piperidin-l-yl]acetyl}-7-azaspiro[3.5]nonan-2-yl)amino]pyrimidin-4-yl}-
1.3-thiazol-4-yl)-2-fluorophenyl]propane-l-sulfonamide (131)
LCMS: C46H58FN9O5S2 requires: 899.4, found: m/z = 900.3 [M+H]+. [0001302] rac-/V-(3-{2-terLbutyl-5-[2-({7-[2-(4-{2-[(37?)-2,6-dioxopiperidin-3-yl]-l,3- dioxo-2,3-dihydro- IT/-isoindol-5-yl Jpiperazin-l -yl)acetyl]-7-azaspiro[3.5]nonan-2- yl}amino)pyrimidin-4-yl]-l,3-thiazol-4-yl}-2-fluorophenyl)propane-l -sulfonamide (132)
LCMS: C47H55FNIO07S2 requires: 954.4, found: m/z = 955.4 [M+H]+.
[0001303] 7V-(3-{2-tert-butyl-5-[2-({7-[(l-{4-[(37?)-2,6-dioxopiperidin-3- yl]phenyl}piperidin-4-yl)methyl]-7-azaspiro[3.5]nonan-2-yl}amino)pyrimidin-4-yl]-l,3- thiazol-4-yl } -2-fluorophenyl)propane- 1 -sulfonamide (133)
LCMS: C45H57FN8O4S2 requires: 856.4, found: m/z = 857.3 [M+H]+.
[0001304] 7V-{3-[2-terLbutyl-5-(2-{[(ls,4s)-4-{4-[(l-{5-[(37?5)-2,6-dioxopiperidin-3- yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l-yl}cyclohexyl]amino}pyrimidin-4-yl)-l,3- thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide (134)
LCMS: C46H61FN10O4S2 requires: 900.4, found: m/z = 901.8 [M+H]+.
[0001305] 7V-{3-[2-terLbutyl-5-(2-{[(lr,4r)-4-{4-[(l-{5-[(37?5)-2,6-dioxopiperidin-3- yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l-yl}cyclohexyl]amino}pyrimidin-4-yl)-l,3- thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide (135)
LCMS: C46H61FN10O4S2 requires: 900.4, found: m/z = 901.4 [M+H]+.
[0001306] rac-7V-(3-{2-terCbutyl-5-[2-({r-[(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-
2-yl }piperidin-4-yl)methyl]-[ 1 ,4' -bipiperi din] -4-yl } amino)pyrimidin-4-yl]- 1 ,3 -thiazol-4-yl } - 2-fluorophenyl)propane- 1 -sulfonamide (136)
LCMS: C46H61FN10O4S2 requires: 900.4, found: m/z = 901.5 [M+H]+.
[0001307] 7V-{3-[2-terLbutyl-5-(2-{[(lr,4r)-4-[4-(l-{5-[(37?5')-2,6-dioxopiperidin-3- yl]pyridin-2-yl}piperidine-4-carbonyl)piperazin-l-yl]cyclohexyl]amino}pyrimidin-4-yl)-l,3- thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide (137)
LCMS: C46H59FNIO05S2 requires: 914.4, found: m/z = 915.4 [M+H]+. [0001308] /f-[3-[2-/c77-butyl-5-(2-[ [( l.s,4.s)-4-[4-( l -[ 5-[(3/C>')-2,6-dioxopiperidin-3- yl]pyridin-2-yl}piperidine-4-carbonyl)piperazin-l-yl]cyclohexyl]amino}pyrimidin-4-yl)-l,3- thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide (138)
LCMS: C46H59FNIO05S2 requires: 914.4, found: m/z = 915.3 [M+H]+.
[0001309] 7V-{3-[2-tert-butyl-5-(2-{[(lr,4r)-4-({4-[(l-{4-[(35)-2,6-dioxopiperidin-3- yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}methyl)cyclohexyl]amino}pyrimidin-4-yl)-
I,3-thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide (139)
LCMS: C48H64FN9O4S2 requires: 913.5, found: m/z = 914.4 [M+H]+.
[0001310] rac-/V-[3-(2-terLbutyl-5-{2-[(2-{[l-(l-{4-[(37?)-2,6-dioxopiperidin-3- yl]phenyl}piperidine-4-carbonyl)piperidin-4-yl]methyl}-2-azaspiro[3.3]heptan-6- yl)amino]pyrimidin-4-yl}-l,3-thiazol-4-yl)-2-fluorophenyl]propane-l-sulfonamide (140)
LCMS: C49H62FN9O5S2 requires: 939.4, found: m/z = 940.3 [M+H]+.
[0001311] rac-/V-[3-(2-terLbutyl-5-{2-[(2-{ l-[(l-{4-[(37?)-2,6-dioxopiperidin-3- yl]phenyl}piperidin-4-yl)methyl]-4-fluoropiperidine-4-carbonyl}-2-azaspiro[3.3]heptan-6- yl)amino]pyrimidin-4-yl}-l,3-thiazol-4-yl)-2-fluorophenyl]propane-l-sulfonamide (141)
LCMS: C49H61F2N9O5S2 requires: 957.4, found: m/z = 958.2 [M+H]+.
[0001312] rac-7V-{3-[2-terLbutyl-5-(2-{[2-({ l-[(l-{4-[(3/?)-2,6-dioxopiperidin-3- yl]phenyl}piperidin-4-yl)methyl]piperidin-4-yl}methyl)-2-azaspiro[3.3]heptan-6- yl]amino}pyrimidin-4-yl)-l,3-thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide (142)
XH NMR (500 MHz, DMSO4) 8 10.79 (s, 1H), 9.76 (d, J= 34.2 Hz, 2H), 8.94 (s, 1H), 8.15 (s, 1H), 7.63 - 7.49 (m, 2H), 7.41 (t, J= 7.0 Hz, 1H), 7.34 (t, J= 7.8 Hz, 1H), 7.09 (d, J= 8.2 Hz, 2H), 6.96 (d, J= 8.2 Hz, 2H), 6.23 (d, J= 90.8 Hz, 1H), 4.40 - 4.03 (m, 3H), 3.57 (d, J=
I I.9 Hz, 2H), 3.23 (s, 2H), 3.16 - 2.97 (m, 6H), 2.89 (d, J= 11.9 Hz, 2H), 2.82 - 2.57 (m, 3H), 2.24 (d, J= 20.9 Hz, 1H), 2.21 - 2.12 (m, 1H), 2.08 (s, 6H), 2.01 (dq, J= 14.9, 6.2, 5.5 Hz, 2H), 1.85 (t, J= 17.8 Hz, 6H), 1.69 (p, J= 7.5 Hz, 2H), 1.45 (s, 11H), 1.40 - 1.29 (m, 2H), 0.91 (t, .7= 7.4 Hz, 3H).
LCMS: C49H64FN9O4S2 requires: 925.5, found: m/z = 926.3 [M+H]+. [0001313] 5 -(4- { [(37?)-3 - { [(4- { 2-terLbutyl-4- [2-fluoro-3 -(propane- 1 - sulfonamido)phenyl]- 1 ,3 -thiazol-5-yl }pyrimidin-2-yl)amino]methyl Jpyrrolidin- 1 - yl]methyl}piperidin-l-yl)-7V-[(3y)-2,6-dioxopiperidin-3-yl]pyridine-2-carboxamide (143)
LCMS: C42H53FN10O5S2 requires: 860.4, found: m/z = 861.2 [M+H]+.
[0001314] 7V-[3-(2-terZ-butyl-5-{2-[(2-{l-[(l-{4-[(37?)-2,6-dioxopiperidin-3- yl]phenyl}piperidin-4-yl)methyl]piperidin-4-yl}-2-methylpropyl)amino]pyrimidin-4-yl}-l,3- thiazol-4-yl)-2-fluorophenyl]propane-l -sulfonamide (144)
LCMS: C46H61FN8O4S2 requires: 872.4, found: m/z = 873.3 [M+H]+.
[0001315] 7V-[3-(2-terLbutyl-5-{2-[({l-[(l-{4-[(37?)-2,6-dioxopiperidin-3- yl]phenyl}piperidin-4-yl)methyl]piperidin-4-yl}methyl)amino]pyrimidin-4-yl}-l,3-thiazol-4- yl)-2-fluorophenyl]propane-l -sulfonamide (145)
LCMS: C43H55FN8O4S2 requires: 830.4, found: m/z = 831.2 [M+H]+.
[0001316] 5-{4-[(4-{l-[(4-{2-terLbutyl-4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]- l,3-thiazol-5-yl}pyrimidin-2-yl)amino]-2-methylpropan-2-yl}piperidin-l- yl)methyl]piperidin-l-yl}-7V-[(35)-2,6-dioxopiperidin-3-yl]pyridine-2-carboxamide (146)
LCMS: C46H61FN10O5S2 requires: 916.4, found: m/z = 917.3 [M+H]+.
[0001317] 5-{4-[(4-{[(4-{2-terLbutyl-4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]- 1 ,3 -thiazol-5-yl }pyrimidin-2-yl)amino]methyl Jpiperidin- 1 -yl)methyl]piperidin- 1 -yl } -N- [(35)-2,6-dioxopiperidin-3-yl]pyridine-2-carboxamide (147)
LCMS: C43H55FNIO05S2 requires: 874.4, found: m/z = 875.2 [M+H]+.
[0001318] rac-/V-[3-(2-terLbutyl-5-{2-[(2-{2-[4-(3-{2-[(37?)-2,6-dioxopiperidin-3-yl]-
1 ,3 -di oxo-2, 3 -dihydro- 1 Z7-isoindol-4-yl }propyl)piperazin- 1 -yl]acetyl } -2- azaspiro[3.3]heptan-6-yl)amino]pyrimidin-4-yl}-l,3-thiazol-4-yl)-2-fluorophenyl]propane-l- sulfonamide (148)
LCMS: C48H57FN10O7S2 requires: 968.4, found: m/z = 969.2 [M+H]+. [0001319] rac-/V-[3-(2-terLbutyl-5-{2-[(4-{l-[2-(4-{2-[(37?)-2,6-dioxopiperidin-3-yl]-
1.3-dioxo-2,3-dihydro- IT/-isoindol-5-yl Jpiperazin- l-yl)acetyl]piperidin-4- yl}phenyl)amino]pyrimidin-4-yl}-l,3-thiazol-4-yl)-2-fluorophenyl]propane-l-sulfonamide (149)
LCMS: C50H55FN10O7S2 requires: 990.4, found: m/z = 991.2 [M+H]+.
[0001320] rac-/V-{3-[2-terLbutyl-5-(2-{[2-(6-{2-[(37?)-2,6-dioxopiperidin-3-yl]-3-oxo-
2.3-dihydro-17/-isoindol-5-yl}hexanoyl)-2-azaspiro[3.3]heptan-6-yl]amino}pyrimidin-4-yl)-
1.3-thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide (150)
LCMS: C45H53FN8O6S2 requires: 884.4, found: m/z = 885.2 [M+H]+.
[0001321] rac-/V-(3-{2-terLbutyl-5-[2-({4-[l-(6-{2-[(37?)-2,6-dioxopiperidin-3-yl]-3- oxo-2, 3-dihy dro- l/Z-isoindol-5-yl }hexanoyl)piperi din-4-yl]phenyl }amino)pyrimidin-4-yl]-
1.3-thiazol-4-yl}-2-fluorophenyl)propane-l-sulfonamide (151)
LCMS: C5OH57FN806S2 requires: 948.4, found: m/z = 885.2 [M+H]+.
[0001322] rac-/V-(3-{2-terLbutyl-5-[2-({2-[2-(2-{2-[(37?)-2,6-dioxopiperidin-3-yl]-l,3- dioxo-2,3-dihydro-l/Z-isoindol-5-yl}-2,7-diazaspiro[3.5]nonan-7-yl)acetyl]-2- azaspiro[3.3 ]heptan-6-yl } amino)pyrimidin-4-yl]- 1 ,3 -thi azol -4-yl } -2-fluorophenyl)propane- 1 - sulfonamide (152)
LCMS: C48H55FNIO07S2 requires: 966.4, found: m/z = 967.2 [M+H]+.
[0001323] rac-/V-[3-(2-terLbutyl-5-{2-[(4-{l-[2-(2-{2-[(37?)-2,6-dioxopiperidin-3-yl]-
1.3-dioxo-2,3-dihydro-17/-isoindol-5-yl}-2,7-diazaspiro[3.5]nonan-7-yl)acetyl]piperidin-4- yl}phenyl)amino]pyrimidin-4-yl}-l,3-thiazol-4-yl)-2-fluorophenyl]propane-l-sulfonamide (153)
LCMS: C53H59FN10O7S2 requires: 1030.4, found: m/z = 1031.2 [M+H]+.
[0001324] rac-/V-(3-{2-terLbutyl-5-[2-({2-[l-(l-{2-[(37?)-2,6-dioxopiperidin-3-yl]-l,3- dioxo-2,3-dihydro-17/-isoindol-5-yl}piperidin-4-yl)azetidine-3-carbonyl]-2- azaspiro[3.3 ]heptan-6-yl } amino)pyrimidin-4-yl]- 1 ,3 -thi azol -4-yl } -2-fluorophenyl)propane- 1 - sulfonamide (154)
LCMS: C48H55FNIO07S2 requires: 966.4, found: m/z = 967.2 [M+H]+.
[0001325] rac-/V-(3-{2-terLbutyl-5-[2-({4-[l-(l-{2-[(37?)-2,6-dioxopiperidin-3-yl]-l,3- dioxo-2,3-dihydro-17/-isoindol-5-yl}piperidine-4-carbonyl)piperidin-4- yl]phenyl}amino)pyrimidin-4-yl]-l, 3 -thiazol-4-yl}-2-fluorophenyl)propane-l -sulfonamide
(155)
LCMS: C50H54FN9O7S2 requires: 975.4, found: m/z = 976.2 [M+H]+.
[0001326] rac-/V-(3-{2-terLbutyl-5-[2-({4-[l-(l-{5-[(37?)-2,6-dioxopiperidin-3- yl]pyridin-2-yl}piperidine-4-carbonyl)piperidin-4-yl]phenyl}amino)pyrimidin-4-yl]-l,3- thiazol-4-yl } -2-fluorophenyl)propane- 1 -sulfonamide (156)
LCMS: C47H54FN9O5S2 requires: 907.4, found: m/z = 930.2 [M+Na]+.
[0001327] rac-/V-(3-{2-terLbutyl-5-[2-({2-[2-(r-{2-[(37?)-2,6-dioxopiperidin-3-yl]-l,3- dioxo-2,3-dihydro-17/-isoindol-5-yl}-[l,4'-bipiperidin]-4-yl)acetyl]-2-azaspiro[3.3]heptan-6- yl}amino)pyrimidin-4-yl]-l,3-thiazol-4-yl}-2-fluorophenyl)propane-l -sulfonamide (157)
[0001328] rac-/V-[3-(2-terLbutyl-5-{2-[(4-{l-[2-(r-{2-[(37?)-2,6-dioxopiperidin-3-yl]- l,3-dioxo-2,3-dihydro-17/-isoindol-5-yl}-[l,4'-bipiperidin]-4-yl)acetyl]piperidin-4- yl}phenyl)amino]pyrimidin-4-yl}-l,3-thiazol-4-yl)-2-fluorophenyl]propane-l-sulfonamide
(158)
LCMS: C56H65FN10O7S2 requires: 1072.4, found: m/z = 537.1 [M/2+H]+.
[0001329] rac-/V-(3-{2-terLbutyl-5-[2-({4-[l-(l-{5-[(37?)-2,6-dioxopiperidin-3- yl]pyridin-2-yl}azetidine-3-carbonyl)piperidin-4-yl]phenyl}amino)pyrimidin-4-yl]-l,3- thiazol-4-yl } -2-fluorophenyl)propane- 1 -sulfonamide (159)
LCMS: C45H50FN9O5S2 requires: 879.3, found: m/z = 880.2 [M+H]+.
[0001330] rac-/V-{3-[2-terLbutyl-5-(2-{[2-(l-{l-[(37?)-2,6-dioxopiperidin-3-yl]-3- methyl-2-oxo-2,3-dihydro-17/-l,3-benzodiazol-4-yl}piperidine-4-carbonyl)-2- azaspiro[3.3]heptan-6-yl]amino}pyrimidin-4-yl)-l,3-thiazol-4-yl]-2-fluorophenyl}propane-l- sulfonamide (160)
LCMS: C45H53FNIO06S2 requires: 912.4, found: m/z = 913.2 [M+H]+.
[0001331] rac-7V-(3-{2-terZ-butyl-5-[2-({4-[l-(l-{l-[(37?)-2,6-dioxopiperidin-3-yl]-3- methyl-2-oxo-2, 3-dihy dro-1/7-1, 3-benzodiazol -4-yl }piperidine-4-carbonyl)piperi din-4- yl]phenyl}amino)pyrimidin-4-yl]-l, 3 -thiazol-4-yl}-2-fluorophenyl)propane-l -sulfonamide
(161)
LCMS: C5OH57FNIO06S2 requires: 976.4, found: m/z = 977.3 [M+H]+.
[0001332] 7V-{3-[2-tert-butyl-5-(2-{[4-(l-{2-[(35)-l-{l-[(3/?5)-2,6-dioxopiperidin-3-yl]-
3-methyl-2-oxo-2, 3-dihy dro- 1/7-1, 3-benzodiazol-5-yl}pyrrolidin-3-yl]acetyl}piperi din-4- yl)phenyl]amino}pyrimidin-4-yl)-l,3-thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide
(162)
LCMS: C5OH57FNIO06S2 requires: 976.4, found: m/z = 977.2 [M+H]+.
[0001333] rac-/V-(3-{2-terLbutyl-5-[2-({4-[l-(l-{4-[(3/?)-2,6-dioxopiperidin-3- yl]pyridin-2-yl}piperidine-4-carbonyl)piperidin-4-yl]phenyl}amino)pyrimidin-4-yl]-l,3- thiazol-4-yl } -2-fluorophenyl)propane- 1 -sulfonamide (163)
[0001334] 7V-[3-(2-terLbutyl-5-{2-[(4-{l-[(3/?)-l-{5-[(3/?5)-2,6-dioxopiperidin-3- yl]pyridin-2-yl}pyrrolidine-3-carbonyl]piperidin-4-yl}phenyl)amino]pyrimidin-4-yl}-l,3- thiazol-4-yl)-2-fluorophenyl]propane-l -sulfonamide (164)
LCMS: C46H52FN9O5S2 requires: 893.2, found: m/z = 894.2 [M+H]+.
[0001335] 7V-{3-[2-terLbutyl-5-(2-{[4-(l-{2-[(3/?)-l-{4-[(3/?5)-2,6-dioxopiperidin-3- yl]phenyl}pyrrolidin-3-yl]acetyl}piperidin-4-yl)phenyl]amino}pyrimidin-4-yl)-l,3-thiazol-4- yl]-2-fluorophenyl}propane-l -sulfonamide (165)
LCMS: C48H55FN8O5S2 requires: 906.4, found: m/z = 907.2 [M+H]+. [0001336] 7V-{3-[2-terLbutyl-5-(2-{[4-(l-{2-[(35)-l-{4-[(37?5)-2,6-dioxopiperidin-3- yl]phenyl}pyrrolidin-3-yl]acetyl}piperidin-4-yl)phenyl]amino}pyrimidin-4-yl)-l,3-thiazol-4- yl]-2-fluorophenyl (propane- 1 -sulfonamide (166)
LCMS: C48H57FN8O5S2 requires: 906.4, found: m/z = 907.3 [M+H]+.
[0001337] rac-7V-[3-(2-terZ-butyl-5-{2-[(4-{ l-[(l-{4-[(37?)-2,6-dioxopiperidin-3- yl]phenyl}piperidin-4-yl)methyl]piperidin-4-yl}phenyl)amino]pyrimidin-4-yl}-l,3-thiazol-4- yl)-2-fluorophenyl]propane-l -sulfonamide (167)
LCMS: C48H57FN8O4S2 requires: 892.4, found: m/z = 893.3 [M+H]+.
[0001338] 7V-{3-[2-terLbutyl-5-(2-{[4-(l-{[(lr,4r)-4-({5-[(37?5)-2,6-dioxopiperidin-3- yl]pyridin-2-yl}oxy)cyclohexyl]methyl}piperidin-4-yl)phenyl]amino}pyrimidin-4-yl)-l,3- thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide (168)
LCMS: C48H57FN8O5S2 requires: 908.4, found: m/z = 909.3 [M+H]+.
[0001339] rac-5 - { 4- [(4- { 4- [(4- { 2-terLbutyl-4- [2-fluoro-3 -(propane- 1 - sulfonamido)phenyl]- 1 ,3 -thiazol-5-yl }pyrimidin-2-yl)amino]phenyl (piperidin- 1 - yl)methyl]piperidin-l-yl}-7V-[(37?)-2,6-dioxopiperidin-3-yl]pyridine-2-carboxamide (169)
LCMS: C48H57FNIO05S2 requires: 936.4, found: m/z = 937.3 [M+H]+.
[0001340] rac-4-[4-({6-[(4-{2-terLbutyl-4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]- l,3-thiazol-5-yl}pyrimidin-2-yl)amino]-2-azaspiro[3.3]heptan-2-yl}methyl)piperidin-l-yl]- 7V-[(37?)-2,6-dioxopiperidin-3-yl]benzamide (170)
LCMS: C44H54FN9O5S2 requires: 871.4, found: m/z = 872.3 [M+H]+.
[0001341 ] rac-4- { 4- [(4- { 4- [(4- { 2-terLbutyl-4- [2-fluoro-3 -(propane- 1 - sulfonamido)phenyl]- 1 ,3 -thiazol-5-yl }pyrimidin-2-yl)amino]phenyl (piperidin- 1 - yl)methyl]piperidin-l-yl}-7V-[(37?)-2,6-dioxopiperidin-3-yl]benzamide (171)
LCMS: C49H58FN9O5S2 requires: 935.4, found: m/z = 936.3 [M+H]+. [0001342] 7V-[3-(2-terZ-butyl-5-{2-[(2-{2-[(35)-l-{5-[(37?y)-2,6-dioxopiperidin-3- yl]pyridin-2-yl}pyrrolidin-3-yl]ethyl}-2-azaspiro[3.3]heptan-6-yl)amino]pyrimidin-4-yl}- l,3-thiazol-4-yl)-2-fluorophenyl]propane-l-sulfonamide (172)
LCMS: C42H52FN9O4S2 requires: 829.4, found: m/z = 830.3 [M+H]+.
[0001343] 7V-{3-[2-tert-butyl-5-(2-{[4-(l-{2-[(35)-l-{5-[(37?5)-2,6-dioxopiperidin-3- yl]pyridin-2-yl}pyrrolidin-3-yl]ethyl}piperidin-4-yl)phenyl]amino}pyrimidin-4-yl)-l,3- thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide (173)
LCMS: C47H56FN9O4S2 requires: 893.4, found: m/z = 894.4 [M+H]+.
[0001344] rac-/V-[3-(2-terLbutyl-5-{2-[(4-{ l-[2-(4-{4-[(3/?)-2,6-dioxopiperidin-3- yl]pyridin-2-yl } piperazin- 1 -yl)acetyl]piperidin-4-yl }phenyl)amino]pyrimidin-4-yl } - 1 ,3 - thiazol-4-yl)-2-fluorophenyl]propane-l -sulfonamide (174)
LCMS: C47H55FNIO05S2 requires: 922.4, found: m/z = 923.4 [M+H]+.
[0001345] rac-/V-{3-[2-terLbutyl-5-(2-{[4-(l-{l-[(l-{5-[(3/?)-2,6-dioxopiperidin-3- yl]pyridin-2-yl}piperidin-4-yl)methyl]piperidine-4-carbonyl}piperidin-4- yl)phenyl]amino}pyrimidin-4-yl)-l,3-thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide (175)
LCMS: C53H65FN10O5S2 requires: 1004.5, found: m/z = 1005.4 [M+H]+.
[0001346] rac-/V-[3-(2-terLbutyl-5-{2-[(4-{l-[2-({2-[(3/?)-2,6-dioxopiperidin-3-yl]-l,3- dioxo-2,3-dihydro-17/-isoindol-5-yl}oxy)acetyl]piperidin-4-yl}phenyl)amino]pyrimidin-4- yl}-l,3-thiazol-4-yl)-2-fluorophenyl]propane-l -sulfonamide (176)
LCMS: C46H47FN8O8S2 requires: 922.3, found: m/z = 923.5 [M+H]+.
[0001347] rac-/V-[3-(2-terLbutyl-5-{2-[(4-{ l-[(l-{5-[(3/?)-2,6-dioxopiperidin-3- yl]pyri din-3 -yl }piperidin-4-yl)methyl]piperidin-4-yl }phenyl)amino]pyrimidin-4-yl } - 1 ,3 - thiazol-4-yl)-2-fluorophenyl]propane-l -sulfonamide (177)
‘HNMR (500 MHz, DMSO-t/6) 8 10.87 (s, 1H), 9.67 (s, 1H), 9.15 (s, 2H), 8.34 (d, J= 5.3 Hz, 1H), 8.21 (d, J= 2.7 Hz, 1H), 7.85 (s, 1H), 7.67 - 7.52 (m, 3H), 7.47 (t, J= 7.0 Hz, 1H), 7.38 (t, J= 7.9 Hz, 1H), 7.22 (s, 1H), 7.15 (d, J= 8.1 Hz, 2H), 6.43 (d, J= 5.1 Hz, 1H), 3.93 - 3.72 (m, 3H), 3.68 - 3.55 (m, 5H), 3.18 (d, J = 4.7 Hz, 2H), 3.12 (q, J = 7.4 Hz, 6H), 2.99 (t, J= 7.7 Hz, 2H), 2.83 - 2.63 (m, 4H), 2.31 (qd, J= 12.7, 4.3 Hz, 2H), 2.02 (dq, J= 8.5, 5.8, 4.5 Hz, 2H), 1.67 (h, J= 7.5 Hz, 2H), 1.48 (s, 9H), 1.29 (d, J= 6.8 Hz, 36H), 0.98 - 0.82 (m, 4H).
[0001348] rac-7V-[3-(2-{ l-[l-(l-{4-[(37?)-2,6-dioxopiperidin-3-yl]phenyl}piperidine-4- carbonyl)-4-methylpiperidine-4-carbonyl]piperidin-4-yl}-5-(pyrimidin-4-yl)-l,3-thiazol-4- yl)-2-fluorophenyl]propane-l -sulfonamide (178)
LCMS: C45H53FN8O6S2 requires: 884.4, found: m/z = 885.2 [M+H]+.
[0001349] rac-7V-[3-(2-{ l-[l-(l-{4-[(37?)-2,6-dioxopiperidin-3-yl]phenyl}piperidine-4- carbonyl)-4-methylpiperidine-4-carbonyl]piperidin-4-yl}-5-{2-[(propan-2- yl)amino]pyrimidin-4-yl}-l,3-thiazol-4-yl)-2-fluorophenyl]propane-l-sulfonamide (179)
'H NMR (500 MHz, DMSO4) 8 9.72 (s, 1H), 8.11 (d, J = 5.2 Hz, 1H), 7.53 (t, J = 7.6 Hz, 1H), 7.37 (d, J= 7.1 Hz, 1H), 7.31 (t, J= 7.9 Hz, 1H), 7.13 (d, J= 7.9 Hz, 1H), 7.05 (s, 2H), 6.90 (s, 2H), 6.11 (s, 1H), 4.36 (s, 2H), 3.67 (s, 4H), 3.13 (s, 1H), 3.07 - 3.00 (m, 2H), 2.75 (s, 3H), 2.48 (s, 6H), 2.14 (d, J= 13.9 Hz, 4H), 2.00 (s, 2H), 1.70 (d, J= 7.7 Hz, 1H), 1.68 (s, 3H), 1.63 (s, 3H), 1.46 (s, 1H), 1.39 (s, 1H), 1.27 (s, 3H), 1.11 (d, J= 6.6 Hz, 6H), 0.91 (t, J= 7.4 Hz, 3H). LCMS: C48H60FN9O6S2 requires: 941.4, found: m/z = 942.2 [M+H]+.
[0001350] 7V-[3-(2-{ l-[l-(l-{5-[(37?5)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidine-4- carbonyl)piperidine-4-carbonyl]piperidin-4-yl}-5-(2-{[(27?)-l-hydroxypropan-2- yl]amino}pyrimidin-4-yl)-l,3-thiazol-4-yl)-2-fluorophenyl]propane-l-sulfonamide (180)
LCMS: C46H57FN10O7S2 requires: 944.4, found: m/z = 945.3 [M+H]+.
[0001351] rac-7V-[3-(2-{ l-[l-(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2- yl}piperidine-4-carbonyl)-4-methylpiperidine-4-carbonyl]piperidin-4-yl}-5-(pyrimidin-4-yl)- l,3-thiazol-4-yl)-2-fluorophenyl]propane-l-sulfonamide (181)
LCMS: C44H52FN9O6S2 requires: 885.3, found: m/z = 886.6 [M+H]+.
[0001352] rac-7V-[3-(2-{ l-[l-(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2- yl}piperidine-4-carbonyl)-4-methylpiperidine-4-carbonyl]piperidin-4-yl}-5-(pyridin-4-yl)- l,3-thiazol-4-yl)-2-fluorophenyl]propane-l-sulfonamide (182)
LCMS: C45H53FN8O6S2 requires: 884.4, found: m/z = 855.3 [M+H]+. [0001353] rac-(35)-3-{6-[4-(4-{4-[4-(3-{[ethyl(methyl)sulfamoyl]amino(-2- fluorophenyl)-5-{2-[(propan-2-yl)amino]pyrimidin-4-yl}-l,3-thiazol-2-yl]piperidine-l- carbonyl(piperidine-l-carbonyl)piperidin-l-yl]pyridin-3-yl(piperidine-2, 6-dione (183)
LCMS: C46H58FNIIO6S2 requires: 943.4, found: m/z = 944.2 [M+H]+.
[0001354] rac-7V-(3-{2-[l-(l-{2-[l-(4-{[(37?)-2,6-dioxopiperidin-3- yl]amino(phenyl)piperidin-4-yl]acetyl(piperidine-4-carbonyl)piperidin-4-yl]-5-(pyrimidin-4- yl)-l,3-thiazol-4-yl(-2-fluorophenyl)propane-l -sulfonamide (184)
LCMS: C45H54FN9O6S2 requires: 899.4, found: m/z = 900.3 [M+H]+.
[0001355] rac-7V-{3-[5-(2-aminopyrimidin-4-yl)-2-[4-(l-{2-[l-(4-{[(37?)-2,6- dioxopiperidin-3-yl]amino(phenyl)piperidin-4-yl]acetyl(piperidin-4-yl)phenyl]-l,3-thiazol- 4-yl]-2-fluorophenyl(propane-l-sulfonamide (185)
LCMS: C45H5OFN905S2 requires: 879.3, found: m/z = 880.1 [M+H]+.
[0001356] 7V-{3-[5-(2-aminopyrimidin-4-yl)-2-(4-{4-[(l-{4-[(35)-2,6-dioxopiperidin-3- yl]phenyl(piperidin-4-yl)methyl]piperazin-l-yl(phenyl)-l,3-thiazol-4-yl]-2- fluorophenyl (propane- 1 -sulfonamide (186)
‘H NMR (500 MHz, DMSO4) 8 10.80 (s, 1H), 9.79 (s, 1H), 9.43 (s, 1H), 8.11 (d, J= 5.3 Hz, 1H), 7.92 (d, J= 8.4 Hz, 2H), 7.59 (t, J= 7.6 Hz, 1H), 7.48 (t, J= 7.1 Hz, 1H), 7.38 (t, J= 7.9 Hz, 1H), 7.16 (d, J= 8.7 Hz, 2H), 7.10 (d, J= 8.1 Hz, 2H), 6.95 (d, J= 39.3 Hz, 4H), 6.13 (d, J = 5.3 Hz, 1H), 4.04 (d, J = 12.0 Hz, 3H), 3.83 - 3.58 (m, 6H), 3.29 - 3.13 (m, 6H), 3.13 - 3.04 (m, 2H), 2.79 (s, 2H), 2.66 (tt, J= 12.1, 5.2 Hz, 1H), 2.22 - 1.97 (m, 2H), 1.88 (d, J = 12.6 Hz, 2H), 1.72 (q, J = 7.6 Hz, 2H), 1.39 (d, J = 12.7 Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H). LCMS: C43H48FN9O4S2 requires: 837.3, found: m/z = 838.3 [M+H]+.
[0001357] rac-7V-{3-[5-(2-aminopyrimidin-4-yl)-2-(4-{4-[(l-{5-[(37?)-2,6- dioxopiperidin-3-yl]pyridin-2-yl(piperidin-4-yl)methyl]piperazin-l-yl(phenyl)-l,3-thiazol-4- yl]-2-fluorophenyl (propane- 1 -sulfonamide (187)
‘H NMR (500 MHz, DMSO-t/e) 6 10.87 (s, 1H), 9.79 (s, 1H), 9.44 (s, 1H), 8.10 (d, J= 5.2 Hz, 1H), 7.98 - 7.85 (m, 3H), 7.59 (t, J= 7.7 Hz, 1H), 7.48 (t, J= 7.0 Hz, 1H), 7.38 (t, J= 7.9 Hz, 1H), 7.16 (d, J= 8.5 Hz, 2H), 6.85 (s, 2H), 6.12 (d, J = 5.2 Hz, 1H), 4.29 (d, J= 12.8 Hz, 2H), 4.04 (d, J= 12.3 Hz, 2H), 3.65 (d, J= 11.2 Hz, 3H), 3.30 - 3.05 (m, 7H), 2.98 (s, 3H), 2.77 - 2.61 (m, 2H), 2.37 (s, 1H), 2.33 - 2.12 (m, 2H), 2.04 - 1.93 (m, 1H), 1.87 (d, J= 12.7 Hz, 2H),
- TLO - 1.72 (q, J = 7.6 Hz, 2H), 1.27 (d, J = 13.4 Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H). LCMS: C42H47FN10O4S2 requires: 838.3, found: m/z = 839.1 [M+H]+.
[0001358] rac-7V-{3-[5-(2-aminopyrimidin-4-yl)-2-{4-[4-(l-{5-[(37?)-2,6-dioxopiperidin-
3-yl]pyridin-2-yl(piperidine-4-carbonyl)piperazin-l-yl]phenyl(-l,3-thiazol-4-yl]-2- fluorophenyl ( propane- 1 -sulfonamide (188)
LCMS: C42H45FN10O5S2 requires: 852.3, found: m/z = 853.5 [M+H]+.
[0001359] rac-7V-{3-[5-(2-aminopyrimidin-4-yl)-2-(4-{4-[2-(l-{5-[(3/?)-2,6- dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)acetyl]piperazin-l-yl}phenyl)-l,3-thiazol-4- yl]-2-fluorophenyl (propane- 1 -sulfonamide (189)
LCMS: C43H47FN10O5S2 requires: 866.3, found: m/z = 867.2 [M+H]+. rac-7V-{3-[5-(2-aminopyrimidin-4-yl)-2-{4-[4-(l-{4-[(37?)-2,6-dioxopiperi din-3- yl]phenyl(piperidine-4-carbonyl)piperazin-l-yl]phenyl(-l,3-thiazol-4-yl]-2- fluorophenyl (propane- 1 -sulfonamide (190)
LCMS: C43H46FN9O5S2 requires: 851.3, found: m/z = 852.1 [M+H]+.
[0001360] 7V-{3-[5-(2-aminopyrimidin-4-yl)-2-(4-{4-[(l-{4-[(37?)-2,6-dioxopiperidin-3- yl]phenyl(piperidin-4-yl)methyl]piperazin-l-yl(phenyl)-l,3-thiazol-4-yl]-2- fluoropheny 1 ( propane- 1 - sulfonami de ( 191 )
'H NMR (500 MHz, DMSO ) 8 10.78 (s, 1H), 9.78 (s, 1H), 8.08 (d, J= 5.2 Hz, 1H), 7.85 (s, 2H), 7.58 (t, J= 7.8 Hz, 1H), 7.53 - 7.43 (m, 1H), 7.37 (t, J= 7.8 Hz, 1H), 7.05 (d, J= 8.1 Hz, 4H), 6.91 (d, J= 7.7 Hz, 2H), 6.78 (s, 2H), 6.10 (d, J= 5.2 Hz, 1H), 3.84 - 3.61 (m, 4H), 3.13 - 3.03 (m, 2H), 2.84 - 2.61 (m, 1H), 2.33 - 1.96 (m, 4H), 1.83 (d, J= 12.4 Hz, 2H), 1.72 (h, J = 7.5 Hz, 3H), 1.25 (s, 2H), 0.94 (t, J = 7.4 Hz, 3H). LCMS: C43H48FN9O4S2 requires: 837.3, found: m/z = 838.4 [M+H]+.
[0001361] 7V-{3-[5-(2-aminopyrimidin-4-yl)-2-(4-{l-[(l-{4-[(35)-2,6-dioxopiperidin-3- yl]phenyl(piperidin-4-yl)methyl]piperidin-4-yl(phenyl)-l,3-thiazol-4-yl]-2- fluorophenyl (propane- 1 -sulfonamide (192)
LCMS: C44H49FN8O4S2 requires: 836.3, found: m/z = 837.3 [M+H]+.
[0001362] rac-7V-{3-[5-(2-aminopyrimidin-4-yl)-2-{l-[l-(l-{5-[(3/?)-2,6-dioxopiperidin-
3-yl]pyridin-2-yl(-4-methylpiperidine-4-carbonyl)piperidine-4-carbonyl]piperidin-4-yl(-l,3- thiazol-4-yl]-2-fluorophenyl(propane-l-sulfonamide (193) 'H NMR (500 MHz, DMSO-t/e) 6 10.87 (s, 1H), 9.74 (s, 1H), 8.09 (d, J= 5.2 Hz, 1H), 7.90 (s, 1H), 7.62 - 7.50 (m, 1H), 7.45 - 7.37 (m, 1H), 7.33 (t, J= 7.9 Hz, 1H), 6.80 (s, 2H), 6.11 (d, .7= 5.2 Hz, 1H), 4.47 (d, J= 12.6 Hz, 1H), 4.30 (d, J= 12.8 Hz, 2H), 4.11 (d, J= 13.4 Hz, 1H), 3.79 (d, J= 41.1 Hz, 3H), 3.12 - 3.02 (m, 2H), 2.95 (d, J= 31.3 Hz, 1H), 2.82 - 2.62 (m, 2H), 2.34 - 2.06 (m, 6H), 2.02 - 1.93 (m, 1H), 1.70 (h, J= 6.9, 6.2 Hz, 5H), 1.58 (d, J= 11.8 Hz, 3H), 1.46 (d, J= 12.2 Hz, 2H), 1.28 (s, 3H), 0.93 (t, J= 7.4 Hz, 3H). LCMS: C44H53FN10O6S2 requires: 900.4, found: m/z = 901.2 [M+H]+.
[0001363] rac-7V-{3-[5-(2-aminopyrimidin-4-yl)-2-(l-{ l-[2-(l-{5-[(37?)-2,6- dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)acetyl]-4-methylpiperidine-4- carbonyl}piperidin-4-yl)-l,3-thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide (194)
‘H NMR (500 MHz, DMSO-7) 8 10.93 (s, 1H), 9.75 (s, 1H), 8.09 (d, J= 5.3 Hz, 1H), 7.87 (s, 1H), 7.55 (t, J = 7.5 Hz, 1H), 7.40 (t, J= 7.1 Hz, 1H), 7.33 (t, J = 7.8 Hz, 1H), 6.87 (s, 2H), 6.12 (d, J= 5.3 Hz, 1H), 4.36 (d, J= 13.0 Hz, 2H), 4.17 (d, J= 13.2 Hz, 3H), 3.46 - 3.27 (m, 2H), 3.22 - 2.95 (m, 7H), 2.75 - 2.62 (m, 2H), 2.28 (t, J= 6.3 Hz, 3H), 2.15 (d, J = 12.3 Hz, 2H), 2.11 - 1.93 (m, 3H), 1.81 (d, J= 12.7 Hz, 2H), 1.75 - 1.54 (m, 4H), 1.42 (d, J= 12.8 Hz, 2H), 1.26 (d, J = 12.5 Hz, 6H), 0.93 (t, J = 7.4 Hz, 3H). LCMS: C45H55FNIO06S2 requires: 914.4, found: m/z = 915.2 [M+H]+.
[0001364] rac-7V-{3-[5-(2-aminopyrimidin-4-yl)-2-(l-{ l-[(l-{ l-[(3/?)-2,6- dioxopiperi din-3-yl]-3-m ethyl -2-oxo-2,3-dihydro- 1/7-1, 3-benzodiazol-4-yl}piperi din-4- yl)methyl]piperidine-4-carbonyl }piperidin-4-yl)- 1 ,3 -thi azol -4-yl]-2-fluorophenyl (propane- 1 - sulfonamide (195)
LCMS: C46H56FNIIO6S2 requires: 941.4, found: m/z = 942.2 [M+H]+.
[0001365] rac-7V-{3-[5-(2-aminopyrimidin-4-yl)-2-{ l-[l-(l-{4-[(3/?)-2,6-dioxopiperidin-
3-yl]phenyl}piperidine-4-carbonyl)-4-methylpiperidine-4-carbonyl]piperidin-4-yl}-l,3- thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide (196)
'HNMR (500 MHz, DMSO-t/e) 6 10.78 (s, 1H), 9.74 (s, 1H), 8.18 - 7.96 (m, 1H), 7.55 (t, J= 7.6 Hz, 1H), 7.41 (t, J= 7.0 Hz, 1H), 7.33 (t, J= 7.9 Hz, 1H), 7.06 (s, 2H), 6.91 (s, 2H), 6.79 (s, 2H), 6.10 (d, J= 5.2 Hz, 1H), 4.37 (s, 2H), 3.69 (s, 3H), 3.20 - 2.95 (m, 3H), 2.85 - 2.59 (m, 5H), 2.23 - 2.07 (m, 4H), 2.02 (dd, J= 13.3, 5.3 Hz, 2H), 1.78 - 1.56 (m, 7H), 1.43 (d, J = 33.5 Hz, 1H), 1.28 (s, 3H), 0.93 (t, J= 7.4 Hz, 3H). LCMS: C45H54FN9O6S2 requires: 899.4, found: m/z = 900.3 [M+H]+. [0001366] rac-7V-{3-[5-(2-aminopyrimidin-4-yl)-2-{ l-[l-(l-{5-[(37?)-2,6-dioxopiperidin-
3-yl]pyridin-2-yl}piperidine-4-carbonyl)-4-methylpiperidine-4-carbonyl]piperidin-4-yl}-l,3- thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide (197)
‘H NMR (500 MHz, DMSO-t/e) 8 10.93 (s, 1H), 9.75 (s, 1H), 8.09 (d, J= 5.3 Hz, 1H), 7.89 (d, J= 2.2 Hz, 1H), 7.82 (s, 1H), 7.56 (t, J= 7.7 Hz, 1H), 7.41 (t, J= 7.4 Hz, 1H), 7.34 (t, J= 7.9 Hz, 1H), 6.89 (s, 2H), 6.12 (d, J= 5.3 Hz, 1H), 4.38 (d, J= 12.8 Hz, 2H), 4.19 (s, 3H), 3.90 (d, J= 12.0 Hz, 2H), 3.76 (s, 12H), 3.71 (s, 1H), 3.21 - 3.11 (m, 2H), 3.06 (t, J= 7.7 Hz, 2H), 2.73
- 2.65 (m, 1H), 2.28 (d, J= 12.1 Hz, 1H), 2.16 (d, J= 12.4 Hz, 2H), 2.05 - 1.96 (m, 2H), 1.78
- 1.68 (m, 3H), 1.65 - 1.60 (m, 5H), 1.29 (s, 3H), 0.93 (t, J = 7.5 Hz, 3H). LCMS: C44H53FN10O6S2 requires: 900.4, found: m/z = 901.2 [M+H]+.
[0001367] rac-7V-(3-{5-[2-(cyclopropylamino)pyrimidin-4-yl]-2-{ l-[l-(l-{5-[(37?)-2,6- dioxopiperidin-3-yl]pyridin-2-yl}piperidine-4-carbonyl)piperidine-4-carbonyl]piperidin-4- yl } - 1 ,3 -thi azol -4-yl } -2-fluorophenyl)propane- 1 -sulfonamide (198)
[0001368] rac-7V-[3-(2-{ l-[l-(l-{4-[(37?)-2,6-dioxopiperidin-3-yl]phenyl}piperidine-4- carbonyl)piperidine-4-carbonyl]piperidin-4-yl}-5-(pyrimidin-4-yl)-l,3-thiazol-4-yl)-2- fluoropheny 1 ] prop ane- 1 - sulfonami de ( 199)
‘H NMR (500 MHz, DMSO-t/e) 6 10.81 (d, J= 8.1 Hz, 1H), 9.74 (s, 1H), 9.16 (s, 1H), 8.68 (d, J= 5.5 Hz, 1H), 7.58 (t, .7= 7.7 Hz, 1H), 7.47 (t, J= 6.9 Hz, 1H), 7.36 (t, J= 7.9 Hz, 1H), 7.31
- 7.04 (m, 6H), 4.45 (dd, J = 35.7, 12.9 Hz, 2H), 4.14 (d, J= 13.4 Hz, 1H), 4.03 (d, J = 13.1 Hz, 1H), 3.88 - 3.63 (m, 3H), 3.28 - 3.11 (m, 1H), 3.06 (dd, J= 9.1, 6.2 Hz, 2H), 3.04 - 2.58 (m, 4H), 2.26 - 2.11 (m, 1H), 2.06 - 1.95 (m, 1H), 1.90 - 1.64 (m, 10H), 1.46 - 1.28 (m, 1H), 0.93 (t, J= 7.4 Hz, 3H). LCMS: C44H5IFN8O6S2 requires: 870.3, found: m/z = 871.2 [M+H]+.
[0001369] 7V-[3-(2-{ l-[l-(l-{4-[(35)-2,6-dioxopiperidin-3-yl]phenyl}piperidine-4- carbonyl)piperidine-4-carbonyl]piperidin-4-yl}-5-(pyridin-4-yl)-l,3-thiazol-4-yl)-2- fluoropheny 1] prop ane- 1 -sulfonamide (200)
‘HNMR (500 MHz, DMSO-t/e) 6 10.82 (s, 1H), 9.65 (s, 1H), 8.58 (d, J= 5.4 Hz, 2H), 7.51 (t, J = 7.7 Hz, 1H), 7.43 (t, J= 6.9 Hz, 1H), 7.32 (d, J = 13 Hz, 3H), 7.17 (s, 7H), 4.45 (dd, J = 36.2, 12.9 Hz, 2H), 4.14 (d, J= 13.4 Hz, 1H), 4.03 (d, J= 13.3 Hz, 1H), 3.80 (s, 1H), 3.69 (d, J = 11.8 Hz, 2H), 3.29 - 3.08 (m, 1H), 3.06 - 2.84 (m, 3H), 2.78 (t, J= 12.1 Hz, 1H), 2.73 - 2.59 (m, 2H), 2.27 - 2.11 (m, 3H), 2.03 (dt, J= 13.1, 4.9 Hz, 1H), 1.91 - 1.46 (m, 11H), 1.36 (s, 1H), 0.90 (t, J= 7.4 Hz, 3H). LCMS: C45H52FN7O6S2 requires: 869.3, found: m/z = 870.3 [M+H]+. [0001370] rac-7V-{3-[5-(2-aminopyrimidin-4-yl)-2-{4-[l-(l-{5-[(37?)-2,6-dioxopiperidin-
3-yl]pyridin-2-yl}piperidine-4-carbonyl)piperidin-4-yl]phenyl}-l,3-thiazol-4-yl]-2- fluorophenyl } propane- 1 -sulfonamide (201)
LCMS: C43H46FN9O5S2 requires: 851.3, found: m/z = 852.4 [M+H]+.
[0001371] rac-7V-{3-[5-(2-aminopyrimidin-4-yl)-2-[l-({l-[2-(l-{5-[(37?)-2,6- dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)acetyl]piperidin-4-yl}methyl)piperidin-4-yl]- l,3-thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide (202)
LCMS: C44H55FNIO05S2 requires: 886.4, found: m/z = 887.2 [M+H]+.
[0001372] rac-7V-{3-[5-(2-aminopyrimidin-4-yl)-2-(l-{l-[2-(l-{5-[(37?)-2,6- dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)acetyl]piperidine-4-carbonyl}piperidin-4-yl)- l,3-thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide (203)
LCMS: C44H53FNIO06S2 requires: 900.4, found: m/z = 901.2 [M+H]+.
[0001373] 7V-{3-[2-(l-{l-[(l-{4-[(37?)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4- yl)methyl]piperidine-4-carbonyl}piperidin-4-yl)-5-[2-(methylamino)pyrimidin-4-yl]-l,3- thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide (204)
LCMS: C45H56FN9O5S2 requires: 885.4, found: m/z = 886.2 [M+H]+.
[0001374] rac-7V-{3-[5-(2-aminopyrimidin-4-yl)-2-(2-{l-[l-(l-{5-[(3/?)-2,6- dioxopiperidin-3-yl]pyridin-2-yl}piperidine-4-carbonyl)piperidine-4-carbonyl]piperidin-4- yl}ethyl)-l,3-thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide (205)
LCMS: C45H55FNIO06S2 requires: 914.4, found: m/z = 915.2 [M+H]+.
[0001375] rac-7V-[3-(2-{l-[l-(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2- yl}piperidine-4-carbonyl)piperidine-4-carbonyl]piperidin-4-yl}-5-{2-[(propan-2- yl)amino]pyrimidin-4-yl}-l,3-thiazol-4-yl)-2-fluorophenyl]propane-l-sulfonamide (206)
LCMS: C46H57FNIO06S2 requires: 928.4, found: m/z = 929.2 [M+H]+.
[0001376] rac-7V-{3-[5-(2-aminopyrimidin-4-yl)-2-(4-{l-[2-(l-{5-[(37?)-2,6- dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)acetyl]piperidin-4-yl}phenyl)-l,3-thiazol-4- yl]-2-fluorophenyl (propane- 1 -sulfonamide (207)
LCMS: C44H48FN9O5S2 requires: 865.3, found: m/z = 866.1 [M+H]+. [0001377] rac-7V-{3-[5-(2-aminopyrimidin-4-yl)-2-(4-{l-[(l-{5-[(37?)-2,6- dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperidin-4-yl}phenyl)-l,3-thiazol-4- yl]-2-fluorophenyl (propane- 1 -sulfonamide (208)
LCMS: C43H48FN9O4S2 requires: 837.3, found: m/z = 838.2 [M+H]+.
[0001378] rac-(35)-3-{6-[4-(4-{4-[5-(2-aminopyrimidin-4-yl)-4-(3-
{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3-thiazol-2-yl]piperidine-l- carbonyl}piperidine-l-carbonyl)piperidin-l-yl]pyridin-3-yl}piperidine-2, 6-dione (209)
LCMS: C43H52FN11O6S2 requires: 901.4, found: m/z = 902.2 [M+H]+.
[0001379] rac-7V-[3-(2-{l-[l-(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2- yl}piperidine-4-carbonyl)piperidine-4-carbonyl]piperidin-4-yl}-5-(pyridin-4-yl)-l,3-thiazol- 4-yl)-2-fluorophenyl]propane-l -sulfonamide (210)
LCMS: C44H51FN8O6S2 requires: 870.3, found: m/z = 871.2 [M+H]+.
[0001380] rac-7V-{3-[2-(l-{l-[(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2- yl}piperidin-4-yl)methyl]piperidine-4-carbonyl}piperidin-4-yl)-5-(pyridin-4-yl)-l,3-thiazol- 4-yl]-2-fluorophenyl}propane-l-sulfonamide (211)
LCMS: C44H53FN8O5S2 requires: 856.4, found: m/z = 857.3 [M+H]+.
[0001381 ] rac-7V-[3-(2-{l-[l-(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2- yl}piperidine-4-carbonyl)piperidine-4-carbonyl]piperidin-4-yl}-5-[2-
(methylamino)pyrimidin-4-yl]-l,3-thiazol-4-yl)-2-fluorophenyl]propane-l -sulfonamide (212)
LCMS: C44H53FN10O6S2 requires: 900.4, found: m/z = 901.2 [M+H]+.
[0001382] rac-7V-{3-[5-(2-aminopyrimidin-4-yl)-2-(l-{[l-(l-{5-[(37?)-2,6- dioxopiperidin-3-yl]pyridin-2-yl}piperidine-4-carbonyl)piperidin-4-yl]methyl}piperidin-4- yl)-l,3-thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide (213)
LCMS: C43H53FN10O5S2 requires: 872.4, found: m/z = 873.2 [M+H]+.
[0001383] rac-7V-{3-[5-(2-aminopyrimidin-4-yl)-2-[l-(l-{2-[l-(4-{[(3/?)-2,6- dioxopiperidin-3-yl]amino}-2-fluorophenyl)-4-hydroxypiperidin-4-yl]acetyl}azetidin-3- yl)piperidin-4-yl]-l,3-thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide (214)
LCMS: C42H50F2N10O6S2 requires: 892.3, found: m/z = 893.2 [M+H]+. [0001384] rac-7V-{3-[5-(2-aminopyrimidin-4-yl)-2-(l-{ l-[2-(l-{4-[(3/?)-2,6- dioxopiperidin-3-yl]phenyl}piperidin-4-yl)acetyl]azetidin-3-yl}piperidin-4-yl)-l,3-thiazol-4- yl] -2-fluorophenyl } propane- 1 -sulfonamide (215)
LCMS: C42H50FN9O5S2 requires: 843.3, found: m/z = 844.2 [M+H]+.
[0001385] rac-7V-{3-[5-(2-aminopyrimidin-4-yl)-2-{ l-[l-(l-{4-[(37?)-2,6-dioxopiperidin- 3-yl]phenyl}piperidine-4-carbonyl)piperidine-4-carbonyl]piperidin-4-yl}-l,3-thiazol-4-yl]-2- fluorophenyl } propane- 1 -sulfonamide (216)
LCMS: C44H52FN9O6S2 requires: 885.3, found: m/z = 886.4 [M+H]+.
[0001386] rac-7V-{3-[2-(l-{l-[(l-{5-[(3/?)-2,6-dioxopiperidin-3-yl]pyridin-2- yl}piperidin-4-yl)methyl]piperidine-4-carbonyl}piperidin-4-yl)-5-[2-
(methylamino)pyrimidin-4-yl]-l,3-thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide (217)
LCMS: C44H55FNIO05S2 requires: 886.4, found: m/z = 887.4 [M+H]+.
[0001387] rac-7V-{3-[5-(2-aminopyrimidin-4-yl)-2-(l-{ 1 -[(1 - { 5-[(37?)-2,6- dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperidine-4-carbonyl}-4- methylpiperidin-4-yl)-l,3-thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide (218)
LCMS: C44H55FNIO05S2 requires: 886.4, found: m/z = 887.2 [M+H]+.
[0001388] rac-7V-[3-(2-{l-[2-(2-{2-[(3/?)-2,6-dioxopiperidin-3-yl]-l,3-dioxo-2,3-dihydro-
17/-isoindol-5-yl}-2,7-diazaspiro[3.5]nonan-7-yl)acetyl]piperidin-4-yl}-5-[2-
(methylamino)pyrimidin-4-yl]-l,3-thiazol-4-yl)-2-fluorophenyl]propane-l -sulfonamide (219)
LCMS: C44H49FN10O7S2 requires: 912.3, found: m/z = 913.2 [M+H]+.
[0001389] rac-7V-[3-(2-{l-[l-(l-{5-[(3/?)-2,6-dioxopiperidin-3-yl]pyridin-2- yl}piperidine-4-carbonyl)piperidine-4-carbonyl]piperidin-4-yl}-5-(pyrimidin-4-yl)-l,3- thiazol-4-yl)-2-fluorophenyl]propane-l -sulfonamide (220)
LCMS: C43H50FN9O6S2 requires: 871.3, found: m/z = 872.2 [M+H]+.
[0001390] rac-7V-{3-[2-(l-{l-[(l-{5-[(3/?)-2,6-dioxopiperidin-3-yl]pyridin-2- yl}piperidin-4-yl)methyl]piperidine-4-carbonyl}piperidin-4-yl)-5-(pyrimidin-4-yl)-l,3- thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide (221)
LCMS: C43H52FN9O5S2 requires: 857.4, found: m/z = 858.2 [M+H]+. [0001391] 7V-{3-[5-(2-aminopyrimidin-4-yl)-2-{l-[(lr,4r)-4-({6-[(3AS)-2,6- dioxopiperidin-3-yl]-l,2,3,4-tetrahydroisoquinolin-2- yl }methyl)cyclohexanecarbonyl]piperidin-4-yl } - 1 ,3 -thiazol-4-yl]-2-fluorophenyl (propane- 1 - sulfonamide (222)
LCMS: C43H5IFN8O5S2 requires: 842.3, found: m/z = 843.6 [M+H]+.
[0001392] 7V-{3-[5-(2-aminopyrimidin-4-yl)-2-[l-({ l-[(lr,4r)-4-{3-[(37?5)-2,6- dioxopiperidin-3-yl]phenoxy(cyclohexanecarbonyl]piperidin-4-yl(methyl)piperidin-4-yl]- l,3-thiazol-4-yl]-2-fluorophenyl(propane-l-sulfonamide (223)
LCMS: C45H55FN8O6S2 requires: 886.4, found: m/z = 887.3 [M+H]+.
[0001393] 7V-{3-[5-(2-aminopyrimidin-4-yl)-2-[l-({l-[(lr,4r)-4-{4-[(37?5)-2,6- dioxopiperidin-3-yl]phenoxy(cyclohexanecarbonyl]piperidin-4-yl(methyl)piperidin-4-yl]- l,3-thiazol-4-yl]-2-fluorophenyl(propane-l-sulfonamide (224)
LCMS: C45H55FN8O6S2 requires: 886.4, found: m/z = 887.3 [M+H]+.
[0001394] 7V-{3-[5-(2-aminopyrimidin-4-yl)-2-{l-[(l-{[(lr,4r)-4-{4-[(37?5)-2,6- dioxopiperidin-3-yl]phenoxy(cyclohexyl]methyl(piperidin-4-yl)methyl]piperidin-4-yl(-l,3- thiazol-4-yl]-2-fluorophenyl(propane-l-sulfonamide (225)
LCMS: C45H57FN8O5S2 requires: 872.4, found: m/z = 873.3 [M+H]+.
[0001395] rac-7V-{3-[5-(2-aminopyrimidin-4-yl)-2-(l-{[l-(2-{6-[(37?)-2,6- dioxopiperidin-3-yl]-l,2,3,4-tetrahydroisoquinolin-2-yl(acetyl)piperidin-4- yl]methyl(piperidin-4-yl)-l,3-thiazol-4-yl]-2-fluorophenyl(propane-l-sulfonamide (226)
LCMS: C43H52FN9O5S2 requires: 857.4, found: m/z = 858.2 [M+H]+.
[0001396] rac-7V-{3-[5-(2-aminopyrimidin-4-yl)-2-(l-{l-[(l-{4-[(37?)-2,6- dioxopiperidin-3-yl]phenyl(piperidin-4-yl)methyl]piperidine-4-carbonyl(-4-methylpiperidin- 4-yl)- 1 ,3 -thi azol -4-yl]-2-fluorophenyl (propane- 1 -sulfonamide (227)
LCMS: C45H56FN9O5S2 requires: 885.4, found: m/z = 886.2 [M+H]+.
[0001397] rac-7V-{3-[5-(2-aminopyrimidin-4-yl)-2-(l-{ l-[(l-{4-[(37?)-2,6- dioxopiperidin-3-yl]phenyl(piperidin-4-yl)methyl]piperidine-4-carbonyl(piperidin-4-yl)-l,3- thiazol-4-yl]-2-fluorophenyl(propane-l-sulfonamide (228)
LCMS: C44H54FN9O5S2 requires: 871.4, found: m/z = 872.2 [M+H]+. [0001398] rac-7V-{3-[5-(2-aminopyrimidin-4-yl)-2-(3-{2-[4-(3-{2-[(37?)-2,6- dioxopiperi din-3 -y 1] - 1 ,3 -dioxo-2,3 -dihydro- 1 Z7-isoindol-4-yl (propyl)piperazin- 1 -yl]acetyl ( - 3-azaspiro[5.5]undecan-9-yl)-l,3-thiazol-4-yl]-2-fluorophenyl(propane-l-sulfonamide (229)
LCMS: C48H57FN10O7S2 requires: 968.4, found: m/z = 969.2 [M+H]+.
[0001399] rac-7V-{3-[5-(2-aminopyrimidin-4-yl)-2-{2-[2-(4-{2-[(37?)-2,6-dioxopiperidin-
3-yl]-l,3-dioxo-2,3-dihydro-17/-isoindol-5-yl(piperazin-l-yl)acetyl]-2-azaspiro[3.5]nonan-7- yl ( - 1 ,3 -thi azol -4-yl] -2-fluorophenyl (propane- 1 -sulfonamide (230)
LCMS: C43H47FN10O7S2 requires: 898.3, found: m/z = 899.1 [M+H]+.
[0001400] rac-7V-{3-[5-(2-aminopyrimidin-4-yl)-2-{3-[2-(4-{2-[(37?)-2,6-dioxopiperidin-
3-yl]-l,3-dioxo-2,3-dihydro-17/-isoindol-5-yl(piperazin-l-yl)acetyl]-3-azaspiro[5.5]undecan- 9-yl(-l,3-thiazol-4-yl]-2-fluorophenyl(propane-l-sulfonamide (231)
LCMS: C45H5IFNIO07S2 requires: 926.3, found: m/z = 927.2 [M+H]+.
[0001401] rac-7V-{3-[5-(2-aminopyrimidin-4-yl)-2-{ l-[2-(4-{2-[(3/?)-2,6-dioxopiperidin-
3-yl]-l,3-dioxo-2,3-dihydro-17/-isoindol-5-yl(piperazin-l-yl)acetyl]-4-methylpiperidin-4- yl ( - 1 ,3 -thi azol -4-yl] -2-fluorophenyl (propane- 1 -sulfonamide (232)
LCMS: C41H45FN10O7S2 requires: 872.3, found: m/z = 873.1 [M+H]+.
[0001402] rac-7V-{3-[5-(2-aminopyrimidin-4-yl)-2-{ l-[2-(4-{2-[(3/?)-2,6-dioxopiperidin-
3-yl]-l,3-dioxo-2,3-dihydro-17/-isoindol-5-yl(piperazin-l-yl)acetyl]piperidin-4-yl(-l,3- thiazol-4-yl]-2-fluorophenyl(propane-l-sulfonamide (233)
LCMS: C40H43FN10O7S2 requires: 858.3, found: m/z = 859.1 [M+H]+.
[0001403] rac-7V-{3-[5-(2-aminopyrimidin-4-yl)-2-[2-(6-{2-[(37?)-2,6-dioxopiperidin-3- yl]-3-oxo-2,3-dihydro-17/-isoindol-5-yl(hexanoyl)-2-azaspiro[3.5]nonan-7-yl]-l,3-thiazol-4- yl]-2-fluorophenyl (propane- 1 -sulfonamide (234)
LCMS: C43H49FN8O6S2 requires: 856.3, found: m/z = 857.1 [M+H]+.
[0001404] rac-7V-{3-[5-(2-aminopyrimidin-4-yl)-2-[3-(6-{2-[(37?)-2,6-dioxopiperidin-3- yl]-3-oxo-2,3-dihydro-17/-isoindol-5-yl(hexanoyl)-3-azaspiro[5.5]undecan-9-yl]-l,3-thiazol-
4-yl]-2-fluorophenyl(propane-l-sulfonamide (235)
LCMS: C45H53FN8O6S2 requires: 884.4, found: m/z = 885.2 [M+H]+. [0001405] rac-7V-{3-[5-(2-aminopyrimidin-4-yl)-2-{2-[2-(2-{2-[(37?)-2,6-dioxopiperidin-
3-yl]- l,3-dioxo-2,3-dihydro- l//-isoindol-5-yl J-2,7-diazaspiro[3.5]nonan-7-yl)acetyl]-2- azaspiro[3.5 ]nonan-7-yl ( - 1 ,3 -thiazol-4-yl]-2-fluorophenyl [propane- 1 -sulfonamide (236)
LCMS: C46H5IFNIO07S2 requires: 937.3, found: m/z = 939.2 [M+H]+.
[0001406] rac-7V-{3-[5-(2-aminopyrimidin-4-yl)-2-{3-[2-(2-{2-[(37?)-2,6-dioxopiperidin-
3-yl]-l,3-dioxo-2,3-dihydro-U/-isoindol-5-yl(-2,7-diazaspiro[3.5]nonan-7-yl)acetyl]-3- azaspiro[5.5]undecan-9-yl(-l,3-thiazol-4-yl]-2-fluorophenyl(propane-l-sulfonamide (237)
LCMS: C48H55FNIO07S2 requires: 966.4, found: m/z = 967.2 [M+H]+.
[0001407] rac-7V-{3-[5-(2-aminopyrimidin-4-yl)-2-{l-[2-(2-{2-[(3/?)-2,6-dioxopiperidin-
3-yl]-l,3-dioxo-2,3-dihydro-U/-isoindol-5-yl(-2,7-diazaspiro[3.5]nonan-7-yl)acetyl]-4- methylpiperidin-4-yl ( - 1 ,3 -thi azol -4-yl]-2-fluorophenyl (propane- 1 -sulfonamide (238)
LCMS: C44H49FNIO07S2 requires: 912.3, found: m/z = 913.1 [M+H]+.
[0001408] rac-7V-{3-[5-(2-aminopyrimidin-4-yl)-2-{l-[2-(2-{2-[(3/?)-2,6-dioxopiperidin-
3-yl]-l,3-dioxo-2,3-dihydro-U/-isoindol-5-yl(-2,7-diazaspiro[3.5]nonan-7- yl)acetyl]piperidin-4-yl(-l,3-thiazol-4-yl]-2-fluorophenyl(propane-l-sulfonamide (239)
‘HNMR (500 MHz, DMSO-rL) 5 11.08 (s, 1H), 9.74 (s, 1H), 9.55 (s, 1H), 8.10 (d, J= 5.2 Hz, 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.56 (td, J = 7.8, 1.9 Hz, 1H), 7.43 - 7.37 (m, 1H), 7.34 (t, J = 7.8 Hz, 1H), 6.94 - 6.74 (m, 3H), 6.68 (dd, J= 8.4, 2.2 Hz, 1H), 6.12 (d, J= 5.2 Hz, 1H), 5.07 (dd, J= 12.7, 5.5 Hz, 1H), 4.51 - 4.25 (m, 3H), 3.44 (tt, J= 7.3, 3.6 Hz, 3H), 3.28 (t, J= 12.5 Hz, 1H), 3.17 - 3.00 (m, 3H), 3.00 - 2.80 (m, 2H), 2.67 - 2.56 (m, 2H), 2.27 - 2.11 (m, 4H), 2.11 - 1.97 (m, 2H), 1.91 - 1.76 (m, 1H), 1.80 - 1.57 (m, 3H), 0.93 (t, J= 7.4 Hz, 3H). LCMS: C43H47FNIOO?S2 requires: 898.3, found: m/z = 900.0 [M+H]+.
[0001409] rac-7V-{3-[5-(2-aminopyrimidin-4-yl)-2-(2-{l-[2-(2-{2-[(3/?)-2,6- dioxopiperidin-3-yl]-l,3-dioxo-2,3-dihydro-U/-isoindol-5-yl(-2,7-diazaspiro[3.5]nonan-7- yl)acetyl]piperidin-4-yl ( propan-2-yl)- 1 ,3 -thi azol-4-yl]-2-fluorophenyl (propane- 1 - sulfonamide (240)
LCMS: C46H53FNIO07S2 requires: 940.4, found: m/z = 941.2 [M+H]+.
[0001410] rac-7V-{3-[5-(2-aminopyrimidin-4-yl)-2-{2-[l-(l-{2-[(3/?)-2,6-dioxopiperidin-
3-yl]-l,3-dioxo-2,3-dihydro-U/-isoindol-5-yl(piperidin-4-yl)azetidine-3-carbonyl]-2- azaspiro[3.5 ]nonan-7-yl ( - 1 ,3 -thi azol -4-yl]-2-fluorophenyl (propane- 1 -sulfonamide (241) LCMS: C46H5IFNIO07S2 requires: 938.3, found: m/z = 939.0 [M+H]+.
[0001411] rac-7V-{3-[5-(2-aminopyrimidin-4-yl)-2-{l-[l-(l-{2-[(37?)-2,6-dioxopiperidin-
3-yl]-l,3-dioxo-2,3-dihydro-17/-isoindol-5-yl(piperidin-4-yl)azetidine-3-carbonyl]piperidin-
4-yl(-l,3-thiazol-4-yl]-2-fluorophenyl(propane-l-sulfonamide (242)
LCMS: C43H47FN10O7S2 requires: 898.3, found: m/z = 899.1 [M+H]+.
[0001412] rac-7V-{3-[5-(2-aminopyrimidin-4-yl)-2-(2-{l-[l-(l-{2-[(37?)-2,6- dioxopiperidin-3-yl]-l,3-dioxo-2,3-dihydro-l/Z-isoindol-5-yl}piperidin-4-yl)azetidine-3- carbonyl]piperidin-4-yl ( propan-2-yl)- 1 ,3 -thi azol-4-yl]-2-fluorophenyl (propane- 1 - sulfonamide (243)
LCMS: C46H53FN10O7S2 requires: 940.4, found: m/z = 941.2 [M+H]+.
[0001413] rac-7V-{ 3 -[5-(2-aminopyrimidin-4-yl)-2-[2-( 1 - {2-[(37?)-2,6-dioxopiperi din-3 - yl]-l,3-dioxo-2,3-dihydro-17/-isoindol-5-yl(piperidine-4-carbonyl)-2-azaspiro[3.5]nonan-7- yl]-l,3-thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide (244)
LCMS: C43H46FN9O7S2 requires: 883.3, found: m/z = 884.2 [M+H]+.
[0001414] rac-7V-{3-[5-(2-aminopyrimidin-4-yl)-2-[3-(l-{2-[(37?)-2,6-dioxopiperidin-3- yl]-l,3-dioxo-2,3-dihydro-l//-isoindol-5-yl(piperidine-4-carbonyl)-3-azaspiro[5.5]undecan- 9-yl]- 1 ,3 -thi azol -4-yl]-2-fluorophenyl (propane- 1 -sulfonamide (245)
LCMS: C45H50FN9O7S2 requires: 911.3, found: m/z = 912.2 [M+H]+.
[0001415] rac-7V-{3-[5-(2-aminopyrimidin-4-yl)-2-[3-(l-{5-[(37?)-2,6-dioxopiperidin-3- yl]pyridin-2-yl(piperidine-4-carbonyl)-3-azaspiro[5.5]undecan-9-yl]-l,3-thiazol-4-yl]-2- fluorophenyl (propane- 1 -sulfonamide (246)
LCMS: C42H50FN9O5S2 requires: 843.3, found: m/z = 422.6 [M/2]+.
[0001416] rac-7V-{3-[5-(2-aminopyrimidin-4-yl)-2-{2-[2-(r-{2-[(3/?)-2,6-dioxopiperidin-
3 -yl]- 1 ,3 -di oxo-2, 3 -dihydro- lZf-isoindol-5-yl ( -[ 1 ,4'-bipiperidin]-4-yl)acetyl]-2- azaspiro[3.5 ]nonan-7-yl ( - 1 ,3 -thi azol -4-yl]-2-fluorophenyl (propane- 1 -sulfonamide (247)
LCMS: C49H57FN10O7S2 requires: 980.4, found: m/z = 981.6 [M+H]+.
[0001417] rac-7V-{3-[5-(2-aminopyrimidin-4-yl)-2-{3-[2-(r-{2-[(37?)-2,6-dioxopiperidin-
3-yl]-l,3-dioxo-2,3-dihydro-17/-isoindol-5-yl(-[l,4'-bipiperidin]-4-yl)acetyl]-3- azaspiro[5.5]undecan-9-yl(-l,3-thiazol-4-yl]-2-fhrorophenyl(propane-l-sulfonamide (248) LCMS: C51H61FN10O7S2 requires: 1008.4, found: m/z = 1009.2 [M+H]+.
[0001418] rac-7V-{3-[5-(2-aminopyrimidin-4-yl)-2-{l-[2-(r-{2-[(37?)-2,6-dioxopiperidin-
3 -y 1 ] - 1 ,3 -di oxo-2, 3 -dihydro- lZf-isoindol-5-yl ( -[ 1 ,4'-bipiperidin]-4-yl)acetyl]-4- methylpiperidin-4-yl ( - 1 ,3 -thiazol-4-yl]-2-fluorophenyl (propane- 1 -sulfonamide (249)
LCMS: C47H55FNIO07S2 requires: 954.4, found: m/z = 955.2 [M+H]+.
[0001419] rac-7V-{3-[5-(2-aminopyrimidin-4-yl)-2-{l-[2-(r-{2-[(3/?)-2,6-dioxopiperidin-
3-yl]-l,3-dioxo-2,3-dihydro-U/-isoindol-5-yl(-[l,4'-bipiperidin]-4-yl)acetyl]piperidin-4-yl(- l,3-thiazol-4-yl]-2-fluorophenyl(propane-l-sulfonamide (250)
LCMS: C46H53FN10O7S2 requires: 940.4, found: m/z = 941.2 [M+H]+.
[0001420] rac-7V-{ 3 -[5-(2-aminopyrimidin-4-yl)-2-[3 -( 1 - { 1 -[(37?)-2,6-dioxopiperi din-3 - yl]-3-methyl-2-oxo-2,3-dihydro-lZZ-l,3-benzodiazol-4-yl}piperidine-4-carbonyl)-3- azaspiro[5.5 ]undecan-9-yl]- 1 ,3 -thi azol -4-yl]-2-fluorophenyl (propane- 1 -sulfonamide (251)
LCMS: C45H53FNIO06S2 requires: 912.4, found: m/z = 913.3 [M+H]+.
[0001421] rac-5 -(4-{ 9-[5-(2-aminopyrimidin-4-yl)-4-[2-fluoro-3 -(propane- 1 - sulfonamido)phenyl]- 1 ,3 -thiazol-2-yl]-3 -azaspiro[5.5]undecane-3 -carbonyl (piperi din- 1 -yl)- N-[(3R)-2, 6-dioxopiperi din-3 -yl]pyridine-2-carboxamide (252)
LCMS: C43H51FNIO06S2 requires: 886.3, found: m/z = 887.2 [M+H]+.
[0001422] 7V-{3-[5-(2-aminopyrimidin-4-yl)-2-(3-{2-[(3/?)-l-{4-[(37?5')-2,6- dioxopiperidin-3-yl]phenyl(pyrrolidin-3-yl]acetyl(-3-azaspiro[5.5]undecan-9-yl)-l,3-thiazol-
4-yl]-2-fluorophenyl(propane-l-sulfonamide (253)
LCMS: C43H51FN8O5S2 requires: 842.3, found: m/z = 843.2 [M+H]+.
[0001423] rac-7V-{3-[5-(2-aminopyrimidin-4-yl)-2-{l-[l-(l-{5-[(3/?)-2,6-dioxopiperidin-
3-yl]pyridin-2-yl(piperidine-4-carbonyl)piperidine-4-carbonyl]piperidin-4-yl(-l,3-thiazol-4- yl]-2-fluorophenyl (propane- 1 -sulfonamide (254)
‘HNMR (500 MHz, DMSO-t/e) 8 10.81 (s, 1H), 9.74 (s, 1H), 8.08 (d, J= 5.2 Hz, 1H), 7.96 (d, J= 2.4 Hz, 1H), 7.59 - 7.49 (m, 1H), 7.46 - 7.36 (m, 2H), 7.33 (t, J= 7.9 Hz, 1H), 6.88 - 6.72 (m, 3H), 6.11 (d, J= 5.2 Hz, 1H), 4.43 (dd, J= 39.3, 12.8 Hz, 2H), 4.28 (d, J= 12.6 Hz, 2H), 4.08 (dd, J= 36.0, 13.4 Hz, 2H), 3.74 (dd, J= 12.2, 4.9 Hz, 1H), 3.29 - 3.19 (m, 1H), 3.14 (t, J = 12.6 Hz, 1H), 3.09 - 3.02 (m, 2H), 3.02 - 2.83 (m, 4H), 2.82 - 2.59 (m, 3H), 2.37 (d, J = 3.0 Hz, 1H), 2.27 - 2.07 (m, 3H), 2.06 - 1.91 (m, 1H), 1.70 (td, J= 16.4, 15.6, 8.1 Hz, 7H), 1.51 (d, J = 32.9 Hz, 1H), 1.35 (s, 1H), 0.93 (t, J = 7.4 Hz, 3H). LCMS: C43H5IFNIO06S2 requires: 886.3, found: m/z = 887.2 [M+H]+.
[0001424] 4-({4-[5-(2-aminopyrimidin-4-yl)-4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]- 1 ,3 -thiazol-2-yl]piperidin- 1 -yl (methyl)-7V-[(37?)-2,6-dioxopiperi din-3 - yl]benzamide (255)
LCMS: C34H37FN8O5S2 requires: 720.2, found: m/z = 721.2 [M+H]+.
[0001425] rac-7V-{3-[5-(2-aminopyrimidin-4-yl)-2-{3-[(l-{4-[(3/?)-2,6-dioxopiperidin-3- yl]phenyl}piperidin-4-yl)methyl]-3-azaspiro[5.5]undecan-9-yl}-l,3-thiazol-4-yl]-2- fluorophenyl (propane- 1 -sulfonamide (256)
LCMS: C43H53FN8O4S2 requires: 828.4, found: m/z = 829.3 [M+H]+.
[0001426] 7V-{3-[5-(2-aminopyrimidin-4-yl)-2-(3-{[(lr,4r)-4-({5-[(37?5)-2,6- dioxopiperidin-3-yl]pyridin-2-yl}oxy)cyclohexyl]methyl}-3-azaspiro[5.5]undecan-9-yl)-l,3- thiazol-4-yl]-2-fluorophenyl}propane-l-sulfonamide (257)
LCMS: C43H53FN8O5S2 requires: 844.3, found: m/z = 845.3 [M+H]+.
[0001427] rac-7V-{3-[5-(2-aminopyrimidin-4-yl)-2-{3-[(l-{2-[(3/?)-2,6-dioxopiperidin-3- yl]-l-oxo-2,3-dihydro-U/-isoindol-5-yl}piperidin-4-yl)methyl]-3-azaspiro[5.5]undecan-9- yl } - 1 ,3 -thi azol -4-yl] -2-fluorophenyl (propane- 1 -sulfonamide (258)
LCMS: C45H54FN9O5S2 requires: 883.4, found: m/z = 845.3 [M+H]+.
[0001428] 7V-{3-[5-(2-aminopyrimidin-4-yl)-2-(3-{2-[(35)-l-{5-[(37?5)-2,6- dioxopiperidin-3-yl]pyridin-2-yl(pyrrolidin-3-yl]ethyl]-3-azaspiro[5.5]undecan-9-yl)-l,3- thiazol-4-yl]-2-fluorophenyl(propane-l-sulfonamide (259)
LCMS: C42H52FN9O4S2 requires: 829.4, found: m/z = 830.3 [M+H]+.
[0001429] rac-7V-{3-[5-(2-aminopyrimidin-4-yl)-2-{3-[(l-{5-[(3/?)-2,6-dioxopiperidin-3- yl]pyridin-2-yl (piperidin-4-yl)methyl]-3 -azaspiro[5.5]undecan-9-yl (-1,3 -thiazol-4-yl]-2- fluorophenyl (propane- 1 -sulfonamide (260)
LCMS: C42H52FN9O4S2 requires: 829.4, found: m/z = 830.5 [M+H]+.
[0001430] rac-7V-{3-[5-(2-aminopyrimidin-4-yl)-2-(l-{l-[(l-{5-[(37?)-2,6- dioxopiperidin-3-yl]pyridin-2-yl(piperidin-4-yl)methyl]piperidine-4-carbonyl]piperidin-4- yl)-l,3-thiazol-4-yl]-2-fluorophenyl(propane-l-sulfonamide (261) LCMS : C43H53FN10O5S2 requires: 872.4, found: m/z = 873.7 [M+H]+.
[0001431] rac-2-[(37?)-2,6-dioxopiperidin-3-yl]-5-(3-{[3-(4-{4-[(lZ)-l-(hydroxyimino)-
2,3 -dihydro- l/7-inden-5-yl]-3 -(pyridin-4-yl)- I //-pyrazol - 1 -yl }phenyl)azetidin- 1 - yl]methyl } azetidin- 1 -yl)-2, 3 -dihydro- 1/7-isoindole- 1 ,3 -di one (262)
[0001432] (R)-7V-(5-chloro-3-(l-(4-(4-((l-(5-(2,4-dioxotetrahydropyrimidin-l(2J7)- yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-l-yl)phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4- yl)-2-fluorophenyl)-3 -fluoropyrrolidine- 1 -sulfonamide (263)
LCMS : C43H46CIF2N11O4S requires: 885.3, found: m/z = 886.2 [M+H]+.
[0001433] (R)-7V-(5-chloro-3-(l-(4-(4-((l-(5-((/?)-2,6-dioxopiperidin-3-yl)pyridin-2- yl)piperidin-4-yl)methyl)piperazin-l-yl)phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2- fluorophenyl)-3 -fluoropyrrolidine- 1 -sulfonamide (264)
LCMS : C44H47CIF2N10O4S requires: 884.3, found: m/z = 885.2 [M+H]+.
[0001434] rac-(R)-7V-(5-chl oro-3 -( 1 -(4-(4-(( 1 -(5-(2,6-dioxopiperi din-3 -yl)pyridin-2- yl)piperidin-4-yl)methyl)piperazin-l-yl)phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2- fluorophenyl)pyrrolidine- 1 -sulfonamide (265)
'HNMR (500 MHz, DMSO) 5 10.83 (s, 1H), 9.94 (s, 1H), 8.79 (s, 1H), 8.64 - 8.53 (m, 2H), 7.96 (d, J= 2.5 Hz, 1H), 7.85 (d, J= 8.8 Hz, 2H), 7.53 (dd, J= 6.4, 2.7 Hz, 1H), 7.48 - 7.38 (m, 4H), 7.20 (d, J= 8.7 Hz, 2H), 6.90 (s, 1H), 4.31 (d, J= 12.9 Hz, 2H), 3.91 (d, J= 12.5 Hz, 2H), 3.76 (dd, J= 12.1, 4.8 Hz, 1H), 3.64 (d, J= 11.5 Hz, 2H), 3.20 - 3.07 (m, 8H), 2.89 (t, J= 12.6 Hz, 2H), 2.70 (ddt, J= 17.4, 12.4, 5.6 Hz, 1H), 2.54 (d, J= 4.2 Hz, 1H), 2.20 (tt, J = 12.5, 6.4 Hz, 2H), 2.03 - 1.94 (m, 1H), 1.89 (d, J= 12.6 Hz, 2H), 1.78 - 1.67 (m, 4H), 1.25 (d, J= 11.7 Hz, 2H).
LCMS: C44H48CIFN10O4S requires: 866.3, found: m/z = 867.3 [M+H]+.
[0001435] rac-(R)-7V-(5-chl oro-3 -( 1 -(4-(4-(( 1 -(5-(2,6-dioxopiperi din-3 -yl)pyridin-2- yl)piperidin-4-yl)methyl)piperazin-l-yl)-2-fluorophenyl)-3-(pyridin-4-yl)-lZ7-pyrazol-4-yl)- 2-fluorophenyl)pyrrolidine-l -sulfonamide (266)
'H NMR (500 MHz, DMSO) 5 10.73 (s, 1H), 9.86 (s, 1H), 8.51 - 8.47 (m, 2H), 8.37 (d, J= 2.0 Hz, 1H), 7.87 (d, J= 2.5 Hz, 1H), 7.60 (t, J= 9.0 Hz, 1H), 7.44 (dd, J= 6.4, 2.7 Hz, 1H), 7.36 - 7.25 (m, 4H), 6.98 (d, J= 14.3 Hz, 1H), 6.88 (d, J= 9.1 Hz, 1H), 6.73 (d, J= 8.9 Hz, 1H), 4.20 (d, J= 12.8 Hz, 2H), 3.66 (dd, J= 12.1, 4.9 Hz, 1H), 3.27 (s, 10H), 3.11 - 3.04 (m, 4H), 2.73 (t, J = 12.4 Hz, 2H), 2.61 (td, J= 12.2, 6.2 Hz, 1H), 2.46 (t, J= 4.1 Hz, 1H), 2.11 (td, J= 12.5, 8.3 Hz, 1H), 1.90 (dq, J= 13.4, 4.7 Hz, 1H), 1.73 (d, J= 12.9 Hz, 2H), 1.70 - 1.62 (m, 4H), 1.05 (d, J= 12.5 Hz, 2H).
[0001436] rac- (R)-7V-(3-(l-(4-(4-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)methyl)piperazin-l-yl)phenyl)-3-(pyridin-4-yl)-l//-pyrazol-4-yl)-2,5- difluorophenyl)pyrrolidine- 1 -sulfonamide (267)
LCMS: C44H48F2N10O4S requires: 850.4, found: m/z = 851.3 [M+H]+.
[0001437] 7V-(5-chloro-3-(l-(4-( (R)-4-((l-(5-((7?5)-2,6-dioxopiperidin-3-yl)pyridin-2- yl)piperidin-4-yl)methyl)-3-methylpiperazin-l-yl)phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)- 2-fluorophenyl)pyrrolidine-l -sulfonamide (268)
LCMS: C45H50CIFN10O4S requires: 880.3, found: m/z = 881.2 [M+H]+.
[0001438] (R)-7V-(3-(l-(4-(4-((l-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidin-4- yl)methyl)piperazin-l-yl)-2-fluorophenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2,5- difluorophenyl)cyclopentanesulfonamide (269)
LCMS C46H48F4N8O4S requires: 884.4, found: m/z = 885.2 [M+H]+.
[0001439] rac-(R)-7V-(3-(l-(4-(4-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)methyl)piperazin-l-yl)-3-fluorophenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2,5- difluorophenyl)cyclopentanesulfonamide (270)
LCMS C45H48F3N9O4S requires: 867.4, found: m/z = 868.2 [M+H]+.
[0001440] rac-(R)-7V-(5-chloro-3-(l-(4-(4-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2- yl)piperidin-4-yl)methyl)piperazin-l-yl)-3-fluorophenyl)-3-(pyridin-4-yl)-lZ7-pyrazol-4-yl)- 2-fluorophenyl)cyclopentanesulfonamide (271)
LCMS C45H48CIF2N9O4S requires: 883.3 found m/z = 884.6 [M+H]+.
[0001441 ] (R)-N-(5 -chi oro-3 -( 1 -(4-(4-(( 1 -(4-(2, 6-dioxopiperi din-3 -yl)-2- fluorophenyl)piperidin-4-yl)methyl)piperazin- 1 -y 1 ) -3 -fluorophenyl)-3 -(pyri din-4-yl)- 1H- pyrazol-4-yl)-2-fluorophenyl)cyclopentanesulfonamide (272)
LCMS C46H48CIF3N8O4S requires: 900.3, found m/z = 901.3 [M+H]+.
[0001442] (R)-7V-(5-chloro-3-(l-(4-(4-((l-(4-(2,6-dioxopiperidin-3-yl)-2- fluorophenyl)piperidin-4-yl)m ethyl)- 1,4-diazepan-l -yl)-2-fluorophenyl)-3 -(pyri din-4-yl)- 1H- pyrazol-4-yl)-2-fluorophenyl)pyrrolidine- 1 -sulfonamide (273) LCMS C46H49CIF3N9O4S requires: 915.3, found m/z = 916.5 [M+H]+.
[0001443] (7?)-7V-(3-(l-(4-(4-((l-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidin-4- yl)methyl)- 1 ,4-diazepan- 1 -yl)-2-fluorophenyl)-3 -(pyridin-4-yl)- l/7-pyrazol-4-yl)-2, 5- difluorophenyl)pyrrolidine-l -sulfonamide (274)
LCMS C46H49F4N9O4S requires: 899.4, found: m/z = 900.7 [M+H]+.
[0001444] 7V-[5-chloro-3-(l-{4-[(3/?)-4-[(l-{4-[(3/?)-2,6-dioxopiperidin-3- yl]phenyl}piperidin-4-yl)methyl]-3-methylpiperazin-l-yl]phenyl}-3-(pyridin-4-yl)-177- pyrazol-4-yl)-2-fluorophenyl]propane-l -sulfonamide (275)
LCMS: C45H50CIFN8O4S requires: 852.3, found: m/z = 853.2 [M+H]+.
[0001445] 7V-[5-chloro-3-(l-{4-[(3/?)-4-[(l-{5-[(3/?5)-2,6-dioxopiperidin-3-yl]pyridin-2- yl}piperidin-4-yl)methyl]-3-methylpiperazin-l-yl]phenyl}-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)- 2-fluorophenyl]propane-l -sulfonamide (276)
LCMS: C44H49CIFN9O4S requires: 853.3, found: m/z = 854.2 [M+H]+.
[0001446] N- [5 -chi oro-3 -( 1 -{4-[(37?)-4-({ 1 -[4-(2,4-dioxo- 1 ,3 -diazinan- 1 - yl)phenyl]piperidin-4-yl}methyl)-3-methylpiperazin-l-yl]phenyl}-3-(pyridin-4-yl)-177- pyrazol-4-yl)-2-fluorophenyl]propane-l -sulfonamide (277)
LCMS: C44H49CIFN9O4S requires: 853.3, found: m/z = 854.2 [M+H]+.
[0001447] 7V-[5-chloro-3-(l-{4-[(35')-4-[(l-{4-[(3.R)-2,6-dioxopiperidin-3- yl]phenyl}piperidin-4-yl)methyl]-3-methylpiperazin-l-yl]phenyl}-3-(pyridin-4-yl)-177- pyrazol-4-yl)-2-fluorophenyl]propane-l -sulfonamide (278)
LCMS: C45H50CIFN8O4S requires: 852.3, found: m/z = 853.3 [M+H]+.
[0001448] 7V-[5-chloro-3-(l-{4-[(35)-4-[(l-{5-[(3.R5)-2,6-dioxopiperidin-3-yl]pyridin-2- yl}piperidin-4-yl)methyl]-3-methylpiperazin-l-yl]phenyl}-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)- 2-fluorophenyl]propane-l -sulfonamide (279)
LCMS: C44H49CIFN9O4S requires: 853.3, found: m/z = 854.3 [M+H]+.
[0001449] 7V-[5-chloro-3-(l-{4-[(3y)-4-({ l-[4-(2,4-dioxo-l,3-diazinan-l- yl)phenyl]piperidin-4-yl}methyl)-3-methylpiperazin-l-yl]phenyl}-3-(pyridin-4-yl)-177- pyrazol-4-yl)-2-fluorophenyl]propane- 1 -sulfonamide (280)
LCMS: C44H49CIFN9O4S requires: 853.3, found: m/z = 854.3 [M+H]+. [0001450] 7V-{5-chloro-3-[l-(4-{4-[(l-{4-[(37?)-2,6-dioxopiperidin-3- yl]phenyl Jpiperidin-4-yl)methyl]piperazin- l -yl J-2-fluorophenyl)-3-(pyridin-4-yl)- IT/- pyrazol-4-yl]-2-fluorophenyl}pyrrolidine-l-sulfonamide (281)
'H NMR (500 MHz, DMSO-ok) 5 10.78 (s, 1H), 9.94 (s, 1H), 8.59 - 8.55 (m, 2H), 8.45 (s, 1H), 7.67 (s, 1H), 7.52 (dd, J= 6.5, 2.7 Hz, 1H), 7.44 - 7.39 (m, 2H), 7.36 (dd, J= 5.7, 2.7 Hz, 1H), 7.05 (d, J= 8.2 Hz, 3H), 6.91 (d, J= 8.3 Hz, 3H), 3.77 - 3.66 (m, 4H), 3.24 (s, 2H), 3.19 - 3.12 (m, 4H), 2.24 (s, 1H), 2.14 (d, J= 11.1 Hz, 1H), 2.02 (dd, J= 13.5, 5.2 Hz, 1H), 1.83 (d, J= 12.7 Hz, 2H), 1.77 - 1.71 (m, 4H), 1.25 (s, 2H).
[0001451 ] 7V-{5-chloro-3-[l-(4-{4-[(l-{4-[(37?)-2,6-dioxopiperidin-3- yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4-yl)-l//-pyrazol-4-yl]-2- fluorophenyl}pyrrolidine-l-sulfonamide (282)
LCMS: C45H49CIFN9O4S requires: 865.3, found: m/z = 866.2 [M+H]+.
[0001452] 7V-[5-chloro-3-(l-{4-[4-({l-[4-(2,4-dioxo-l,3-diazinan-l-yl)phenyl]piperidin- 4-yl}methyl)piperazin-l-yl]phenyl}-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2- fluorophenyl]pyrrolidine- 1 -sulfonamide (283)
LCMS: C44H48CIFN10O4S requires: 866.3, found: m/z = 867.3 [M+H]+.
[0001453] rac-7V-{ 5-chl oro-3 -[ 1 -(4-{4-[(l -{4-[(37?)-2,6-di ox opiperi din-3 -yl]phenyl }-4- fluoropiperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl]-2- fluorophenyl}pyrrolidine-l-sulfonamide (284)
LCMS: C45H48CIF2N9O4S requires: 883.3, found: m/z = 884.3 [M+H]+.
[0001454] 7V-{5-chloro-3-[l-(4-{4-[(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2- yl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl]-2- fluorophenyl}pyrrolidine-l-sulfonamide (285)
LCMS: C44H48CIFN10O4S requires: 866.3, found: m/z = 867.4 [M+H]+.
[0001455] 7V-{5-chloro-3-[l-(5-{4-[(l-{4-[(37?)-2,6-dioxopiperidin-3- yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}pyridin-2-yl)-3-(pyridin-4-yl)-l/7-pyrazol-4- yl]-2-fluorophenyl}pyrrolidine-l-sulfonamide (286)
LCMS: C44H48CIFN10O4S requires: 866.3, found: m/z = 867.2 [M+H]+. [0001456] 7V-[5-chloro-3-(l-{5-[4-({l-[4-(2,4-dioxo-l,3-diazinan-l-yl)phenyl]piperidin-
4-yl Jmethyl)piperazin- l-yl]pyridin-2-yl J-3-(pyridin-4-yl)- l//-pyrazol-4-yl)-2- fluorophenyl]pyrrolidine- 1 -sulfonamide (287)
LCMS: C43H47CIFN11O4S requires: 867.3, found: m/z = 868.2 [M+H]+.
[0001457] rac-7V-{5-chloro-3-[l-(5-{4-[(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2- yl}piperidin-4-yl)methyl]piperazin-l-yl}pyridin-2-yl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl]-2- fluorophenyl}pyrrolidine-l-sulfonamide (288)
LCMS: C43H47CIFN11O4S requires: 867.3, found: m/z = 868.3 [M+H]+.
[0001458] N-(3 -( 1 -(4-((/?)-4-(( 1 -(5-((R5)-2,6-dioxopiperi din-3 -yl)pyri din-2 -yl)piperidin-
4-yl)methyl)-3-methylpiperazin-l-yl)-2-fluorophenyl)-3-(pyridin-4-yl)-lH-pyrazol-4-yl)-2,5- difluorophenyl)pyrrolidine- 1 -sulfonamide (289)
LCMS: C45H49F3N10O4S requires: 882.4, found: m/z = 883.3 [M+H]+.
[0001459] 7V-{5-chloro-3-[l-(5-{4-[(l-{5-[(3/?)-2,6-dioxopiperidin-3-yl]pyridin-2- yl}piperidin-4-yl)methyl]piperazin-l-yl}pyridin-2-yl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl]-2- fluorophenyl}pyrrolidine-l-sulfonamide (290)
LCMS: C43H47CIFN11O4S requires: 867.3, found: m/z = 868.3 [M+H]+.
[0001460] (3/?)-7V-{5-chloro-3-[l-(4-{4-[(l-{4-[(3/?)-2,6-dioxopiperidin-3- yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl]-2- fluorophenyl} -3 -fluoropyrrolidine- 1 -sulfonamide (291)
LCMS: C45H48CIF2N9O4S requires: 883.3, found: m/z = 884.2 [M+H]+.
[0001461] (3/?)-7V-[5-chloro-3-(l-{4-[4-({l-[4-(2,4-dioxo-l,3-diazinan-l- yl)phenyl]piperidin-4-yl}methyl)piperazin-l-yl]phenyl}-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2- fluorophenyl]-3-fluoropyrrolidine-l-sulfonamide (292)
LCMS: C44H47CIF2N10O4S requires: 884.3, found: m/z = 885.3 [M+H]+.
[0001462] (3/?)-7V-{5-chloro-3-[l-(4-{4-[(l-{5-[(3/?)-2,6-dioxopiperidin-3-yl]pyridin-2- yl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl]-2- fluorophenyl } -3 -fluoropyrrolidine- 1 -sulfonamide (293)
LCMS: C44H47CIF2N10O4S requires: 884.3, found: m/z = 885.4 [M+H]+. [0001463] (37?)-7V-{5-chloro-3-[l-(5-{4-[(l-{4-[(37?)-2,6-dioxopiperidin-3- yl ]phenyl } pi peri di n-4-yl )methyl ]piperazi n- 1 -yl } pyri di n-2-yl )-3 -(pyri di n-4-yl )- l //-pyrazol -4- yl]-2-fluorophenyl } -3 -fluoropyrrolidine- 1 -sulfonamide (294)
LCMS: C44H47CIF2N10O4S requires: 884.3, found: m/z = 885.2 [M+H]+.
[0001464] (37?)-7V-[5-chl oro-3 -(1 - { 5-[4-({ 1 -[4-(2,4-dioxo- 1 ,3 -diazinan- 1 - yl)phenyl]piperidin-4-yl}methyl)piperazin-l-yl]pyridin-2-yl}-3-(pyridin-4-yl)-l/7-pyrazol-4- yl)-2-fluorophenyl]-3-fluoropyrrolidine-l-sulfonamide (295)
LCMS: C43H46CIF2N11O4S requires: 885.3, found: m/z = 886.3 [M+H]+.
[0001465] (3/?)-7V-{5-chloro-3-[l-(5-{4-[(l-{5-[(3/?5)-2,6-dioxopiperidin-3-yl]pyridin-2- yl}piperidin-4-yl)methyl]piperazin-l-yl}pyridin-2-yl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl]-2- fluorophenyl } -3 -fluoropyrrolidine- 1 -sulfonamide (296)
LCMS: C43H46CIF2N11O4S requires: 885.3, found: m/z = 886.2 [M+H]+.
[0001466] (3/?)-7V-{5-chloro-3-[l-(5-{4-[(l-{5-[(3/?)-2,6-dioxopiperidin-3-yl]pyridin-2- yl}piperidin-4-yl)methyl]piperazin-l-yl}pyridin-2-yl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl]-2- fluorophenyl } -3 -fluoropyrrolidine- 1 -sulfonamide (297)
LCMS: C43H46CIF2N11O4S requires: 885.3, found: m/z = 886.4 [M+H]+. 'H NMR (500 MHz, DMSO-de) 5 10.81 (s, 2H), 10.07 (s, 1H), 8.77 (s, 2H), 8.61 - 8.56 (m, 4H), 8.20 (d, 7 = 2.9 Hz, 2H), 7.94 (d, J= 2.5 Hz, 2H), 7.91 (d, J= 9.0 Hz, 2H), 7.65 (dd, J= 9.2, 2.9 Hz, 2H), 7.52 (dd, J= 6.5, 2.7 Hz, 2H), 7.48 - 7.43 (m, 4H), 7.36 (td, J= 7.8, 6.7, 2.7 Hz, 4H), 6.80 (d, J=
8.9 Hz, 2H), 5.34 (s, 1H), 5.24 (t, J = 3.5 Hz, 1H), 4.27 (d, J= 12.7 Hz, 4H), 3.73 (dd, J= 12.2,
4.9 Hz, 2H), 3.48 - 3.34 (m, 9H), 3.32 - 3.22 (m, 15H), 2.80 (t, J= 12.2 Hz, 4H), 2.68 (ddd, J= 17.1, 12.2, 5.2 Hz, 3H), 2.57 (s, 6H), 2.54 (d, 7= 4.1 Hz, 6H), 2.25 (d, J= 6.6 Hz, 3H), 2.23 - 2.04 (m, 6H), 1.98 (ddt, 7= 13.6, 9.0, 4.1 Hz, 3H), 1.80 (d, 7= 13.2 Hz, 5H), 1.10 (dd, 7 = 19.0, 7.4 Hz, 4H).
[0001467] (3/?)-7V-{5-chloro-3-[l-(5-{4-[(7-{4-[(3/?5)-2,6-dioxopiperidin-3-yl]phenyl}-
7-azaspiro[3.5]nonan-2-yl)methyl]piperazin-l-yl}pyridin-2-yl)-3-(pyridin-4-yl)-l/7-pyrazol- 4-yl]-2-fluorophenyl} -3 -fluoropyrrolidine- 1 -sulfonamide (298)
LCMS: C47H51CIF2N10O4S requires: 924.3, found: m/z = 925.2 [M+H]+. [0001468] 7V-{3-[l-(4-{4-[(l-{4-[(37?)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4- yl)methyl]piperazin- l-yl Jphenyl)-3-(pyridin-4-yl)-l//-pyrazol-4-yl]-2,5- difluorophenyl (pyrrolidine- 1 -sulfonamide (299)
LCMS: C45H49F2N9O4S requires: 849.4, found: m/z = 850.2 [M+H]+.
[0001469] 7V-[3 -( 1 - { 4 - [4-( { 1 -[4-(2,4-dioxo- 1 ,3 -diazinan- 1 -yl)phenyl]piperidin-4- yl ( methyl)piperazin- 1 -yl]phenyl ( -3 -(pyridin-4-yl)- 177-pyrazol-4-yl)-2, 5 - difluorophenyl]pyrrolidine- 1 -sulfonamide (300)
LCMS: C44H48F2N10O4S requires: 850.4, found: m/z = 851.3 [M+H]+.
[0001470] 7V-{3-[l-(4-{4-[(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2-yl(piperidin-4- yl)methyl]piperazin-l-yl(phenyl)-3-(pyridin-4-yl)-177-pyrazol-4-yl]-2,5- difluorophenyl (pyrrolidine- 1 -sulfonamide (301)
LCMS: C44H48F2N10O4S requires: 850.4, found: m/z = 851.4 [M+H]+.
[0001471] (3/?)-7V-{3-[l-(5-{4-[(l-{4-[(37?)-2,6-dioxopiperidin-3-yl]phenyl(piperidin-4- yl)methyl]piperazin-l-yl(pyridin-2-yl)-3-(pyridin-4-yl)-177-pyrazol-4-yl]-2,5- difluorophenyl} -3 -fluoropyrrolidine- 1 -sulfonamide (302)
LCMS: C44H47F3N10O4S requires: 868.3, found: m/z = 869.3 [M+H]+.
[0001472] (37?)-7V-[3-(l-{5-[4-({l-[4-(2,4-dioxo-l,3-diazinan-l-yl)phenyl]piperidin-4- yl(methyl)piperazin-l-yl]pyridin-2-yl(-3-(pyridin-4-yl)-177-pyrazol-4-yl)-2,5- difluorophenyl]-3-fluoropyrrolidine-l-sulfonamide (303)
LCMS: C43H46F3N11O4S requires: 869.3, found: m/z = 870.3 [M+H]+.
[0001473] (37?)-7V-{3-[l-(5-{4-[(l-{5-[(3R5)-2,6-dioxopiperidin-3-yl]pyridin-2- yl(piperidin-4-yl)methyl]piperazin-l-yl(pyridin-2-yl)-3-(pyridin-4-yl)-177-pyrazol-4-yl]-2,5- difluorophenyl} -3 -fluoropyrrolidine- 1 -sulfonamide (304)
LCMS: C43H46F3N11O4S requires: 869.3, found: m/z = 870.3 [M+H]+.
[0001474] (3/?)-7V-{3-[l-(5-{4-[(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2- yl(piperidin-4-yl)methyl]piperazin-l-yl(pyridin-2-yl)-3-(pyridin-4-yl)-177-pyrazol-4-yl]-2,5- difluorophenyl} -3 -fluoropyrrolidine- 1 -sulfonamide (305)
LCMS: C43H46F3N11O4S requires: 869.3, found: m/z = 870.4 [M+H]+. 'H NMR (500 MHz, DMSO-rL) 8 10.81 (s, 2H), 10.08 (s, 1H), 8.75 (s, 2H), 8.61 - 8.56 (m, 4H), 8.20 (d, J= 2.9 Hz, 2H), 7.94 (d, J= 2.5 Hz, 2H), 7.91 (d, J= 9.0 Hz, 2H), 7.65 (dd, J= 9.1, 2.9 Hz, 2H), 7.48 - 7.43 (m, 4H), 7.40 - 7.28 (m, 4H), 7.14 (d, J= 10.1 Hz, 2H), 6.80 (d, J= 8.9 Hz, 2H), 5.34 (s, 1H), 5.24 (t, J= 3.6 Hz, 1H), 4.27 (d, J= 12.7 Hz, 4H), 3.73 (dd, J= 12.1, 4.9 Hz, 2H), 3.48
- 3.34 (m, 8H), 3.32 - 3.23 (m, 13H), 2.79 (t, J= 12.3 Hz, 4H), 2.68 (ddd, J= 17.6, 12.4, 5.4 Hz, 3H), 2.55 (q, J= 7.7, 6.2 Hz, 11H), 2.24 (d, J= 6.7 Hz, 3H), 2.22 - 2.03 (m, 6H), 1.97 (dt, J= 13.5, 4.5 Hz, 3H), 1.80 (d, J= 13.2 Hz, 5H), 1.10 (td, J= 10.8, 5.8 Hz, 4H).
[0001475] (37?)-3-(4-{4-[(4-{4-[4-(5-chloro-3-{[ethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)-3 -(pyridin-4-yl)- 17/-py razol - 1 -yl]phenyl } piperazin- 1 -yl)methyl]piperidin- 1 - yl}phenyl)piperidine-2, 6-dione (306)
LCMS: C44H49CIFN9O4S requires: 853.3, found: m/z = 854.3 [M+H]+.
[0001476] l-(4-{4-[(4-{4-[4-(5-chloro-3-{[ethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)-3 -(pyridin-4-yl)- 17/-py razol - 1 -yl]phenyl Jpiperazin- 1 -yl)methyl]piperidin- 1 - yl}phenyl)-l,3-diazinane-2, 4-dione (307)
LCMS: C43H48CIFN10O4S requires: 854.3, found: m/z = 855.2 [M+H]+.
[0001477] rac-(37?)-3-(6-{4-[(4-{4-[4-(5-chloro-3-{[ethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)-3 -(pyridin-4-yl)- 17/-py razol - 1 -yl]phenyl Jpiperazin- 1 -yl)methyl]piperidin- 1 - yl}pyridin-3-yl)piperidine-2, 6-dione (308)
LCMS: C43H48CIFN10O4S requires: 854.3, found: m/z = 855.3 [M+H]+.
[0001478] (37?)-3-(6-{4-[(4-{4-[4-(5-chloro-3-{[ethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)-3 -(pyridin-4-yl)- 17/-py razol - 1 -yl]phenyl Jpiperazin- 1 -yl)methyl]piperidin- 1 - yl}pyridin-3-yl)piperidine-2, 6-dione (309)
LCMS: C43H48CIFN10O4S requires: 854.3, found: m/z = 855.4 [M+H]+. *H NMR (500 MHz, DMSO-tL) 8 10.81 (s, 2H), 9.94 (s, 1H), 8.75 (s, 2H), 8.59 - 8.54 (m, 4H), 7.95 (d, J= 2.6 Hz, 2H), 7.79 (d, J= 9.0 Hz, 4H), 7.49 - 7.34 (m, 11H), 7.11 (d, J = 8.8 Hz, 4H), 6.80 (d, J= 8.9 Hz, 2H), 4.28 (d, J= 12.8 Hz, 4H), 3.73 (dd, J= 12.1, 4.9 Hz, 3H), 3.24 (s, 4H), 3.09 (q, J= 7.1 Hz, 5H), 2.80 (t, J= 12.3 Hz, 5H), 2.68 (s, 8H), 2.53 (s, 9H), 2.25 (s, 1H), 2.17 (td, J= 12.5, 4.3 Hz, 3H), 2.00 (s, 1H), 1.80 (d, J= 13.1 Hz, 5H), 1.13 (s, 2H), 1.12 - 1.02 (m, 8H), 1.01 (s, 2H).
[0001479] (37?)-3-(4-{4-[(4-{6-[4-(5-chloro-3-{[ethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)-3 -(pyridin-4-yl)- 17/-py razol - 1 -yl]pyri din-3 -yl } piperazin- 1 - yl)methyl]piperidin-l-yl}phenyl)piperidine-2, 6-dione (310) LCMS: C43H48CIFN10O4S requires: 854.3, found: m/z = 855.2 [M+H]+.
[0001480] l-(4-{4-[(4-{6-[4-(5-chloro-3-{[ethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)-3 -(pyridin-4-yl)- 17/-py razol - 1 -yl]pyri din-3 -yl } piperazin- 1 - yl)methyl]piperidin-l-yl}phenyl)-l,3-diazinane-2, 4-dione (311)
LCMS: C42H47CIFN11O4S requires: 855.3, found: m/z = 856.3 [M+H]+.
[0001481] rac-(37?)-3-(6-{4-[(4-{6-[4-(5-chloro-3-{[ethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)-3 -(pyridin-4-yl)- 17/-py razol - 1 -yl]pyri din-3 -yl } piperazin- 1 - yl)methyl]piperidin-l-yl}pyridin-3-yl)piperidine-2, 6-dione (312)
LCMS: C42H47CIFN11O4S requires: 855.3, found: m/z = 856.2 [M+H]+.
[0001482] l-(6-{4-[(4-{6-[4-(5-chloro-3-{[ethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)-3 -(pyridin-4-yl)- 17/-py razol - 1 -yl]pyri din-3 -yl } piperazin- 1 - yl)methyl]piperidin-l-yl}pyridin-3-yl)-l,3-diazinane-2, 4-dione (313)
LCMS: C41H46CIFN12O4S requires: 856.3, found: m/z = 857.4 [M+H]+.
[0001483] (37?)-3-(6-{4-[(4-{6-[4-(5-chloro-3-{[ethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)-3 -(pyridin-4-yl)- 17/-py razol - 1 -yl]pyri din-3 -yl } piperazin- 1 - yl)methyl]piperidin-l-yl}pyridin-3-yl)piperidine-2, 6-dione (314)
LCMS: C42H47CIFN11O4S requires: 855.3, found: m/z = 856.4 [M+H]+. *H NMR (500 MHz, DMSO-tL) 8 10.81 (s, 1H), 8.79 (s, 1H), 8.61 - 8.56 (m, 2H), 8.20 (d, J= 2.9 Hz, 1H), 7.94 (d, J= 2.6 Hz, 1H), 7.91 (d, J= 9.0 Hz, 1H), 7.64 (dd, J= 9.2, 2.8 Hz, 1H), 7.49 - 7.43 (m, 3H), 7.37 (dq, J= 5.7, 2.5 Hz, 2H), 6.80 (d, J= 8.9 Hz, 1H), 4.27 (d, J= 12.7 Hz, 2H), 3.73 (dd, J= 12.1, 4.9 Hz, 1H), 3.28 (d, J= 5.9 Hz, 4H), 3.09 (q, J= 7.1 Hz, 2H), 2.79 (t, J= 11.8 Hz, 2H), 2.68 (s, 4H), 2.55 (d, J= 12.7 Hz, 4H), 2.24 (d, J= 6.7 Hz, 2H), 2.17 (td, J= 12.5, 4.3 Hz, 1H), 1.98 (dq, J= 8.3, 4.4 Hz, 1H), 1.80 (d, J= 13.1 Hz, 2H), 1.10 (td, J= 10.7, 5.7 Hz, 2H), 1.02 (t, J= 7.1 Hz, 3H).
[0001484] (37?)-7V-[5-chloro-3-(l-{4-[(37?)-4-({ l-[4-(2,4-dioxo-l,3-diazinan-l- yl)phenyl]piperidin-4-yl}methyl)-3-methylpiperazin-l-yl]phenyl}-3-(pyridin-4-yl)-U7- pyrazol-4-yl)-2-fluorophenyl]-3-fluoropyrrolidine-l-sulfonamide (315)
LCMS: C45H49CIF2N10O4S requires: 898.3, found: m/z = 899.2 [M+H]+. [0001485] 7V-[5-chl oro-3 -(l-{4-[(37?)-4-[(l-{4-[(37?)-2,6-dioxopiperidin-3- yl]phenyl }piperidin-4-yl)methyl]-3-methylpiperazin-l -yl]phenyl }-3-(pyridin-4-yl)-lJ7- pyrazol-4-yl)-2-fluorophenyl]pyrrolidine-l -sulfonamide (316)
LCMS: C46H5IC1FN9O4S requires: 879.3, found: m/z = 880.3 [M+H]+.
[0001486] (37?)-7V-[5-chloro-3-(l-{4-[(37?)-4-[(l-{4-[(37?)-2,6-dioxopiperidin-3- yl]phenyl}piperidin-4-yl)methyl]-3-methylpiperazin-l-yl]phenyl}-3-(pyridin-4-yl)-U7- pyrazol-4-yl)-2-fluorophenyl]-3-fluoropyrrolidine-l-sulfonamide (317)
LCMS: C46H50ClF2N9O4S requires: 897.3, found: m/z = 898.2 [M+H]+.
[0001487] (37?)-7V-[5-chloro-3-(l-{4-[(3/?)-4-[(l-{5-[(37?5)-2,6-dioxopiperidin-3- yl]pyridin-2-yl }piperidin-4-yl)methyl]-3 -methylpiperazin- 1 -yl]phenyl } -3 -(pyridin-4-yl)- 1H- pyrazol-4-yl)-2-fluorophenyl]-3-fluoropyrrolidine-l-sulfonamide (318)
LCMS: C45H49CIF2N10O4S requires: 898.3, found: m/z = 899.2 [M+H]+.
[0001488] N- [5 -chi oro-3 -( 1 -{4-[(37?)-4-({ 1 -[4-(2,4-dioxo- 1 ,3 -diazinan- 1 - yl)phenyl]piperidin-4-yl}methyl)-3 -methylpiperazin- l-yl]phenyl} -3 -(pyridin-4-yl)- 1H- pyrazol-4-yl)-2-fluorophenyl]pyrrolidine-l -sulfonamide (319)
LCMS: C45H50CIFN10O4S requires: 880.3, found: m/z = 881.3 [M+H]+.
[0001489] (37?)-7V-[5-chloro-3-(l-{5-[(3/?)-4-[(l-{4-[(37?)-2,6-dioxopiperidin-3- yl]phenyl}piperidin-4-yl)methyl]-3-methylpiperazin-l-yl]pyridin-2-yl}-3-(pyridin-4-yl)-l/7- pyrazol-4-yl)-2-fluorophenyl]-3-fluoropyrrolidine-l-sulfonamide (320)
'H NMR (500 MHz, DMSO-t/e) 8 10.77 (s, 1H), 10.08 (s, 1H), 8.77 (s, 1H), 8.61 - 8.56 (m, 2H), 8.21 (s, 1H), 7.91 (d, J= 8.9 Hz, 1H), 7.65 (s, 1H), 7.52 (dd, J= 6.4, 2.6 Hz, 1H), 7.48 - 7.43 (m, 2H), 7.37 (s, 1H), 7.04 (d, J= 8.5 Hz, 2H), 6.90 (d, J= 8.4 Hz, 2H), 5.34 (s, 1H), 5.24 (s, 1H), 3.72 (dd, 7= 11.1, 5.0 Hz, 1H), 3.68 (s, 2H), 3.58 (s, 2H), 3.46 (s, 1H), 3.45 - 3.37 (m, 1H), 3.40 - 3.35 (m, 1H), 3.30 - 3.23 (m, 1H), 2.99 (s, 2H), 2.68 (s, 3H), 2.16 - 2.10 (m, 1H), 2.05 - 1.99 (m, 1H), 1.91 (d, J= 13.7 Hz, 1H), 1.73 (s, 1H), 1.24 (s, 3H), 1.10 (s, 3H).
[0001490] (37?)-7V-[5-chloro-3-(l-{5-[(3/?)-4-[(l-{5-[(37?5)-2,6-dioxopiperidin-3- yl]pyridin-2-yl}piperidin-4-yl)methyl]-3-methylpiperazin-l-yl]pyridin-2-yl}-3-(pyridin-4- yl)-lJH-pyrazol-4-yl)-2-fluorophenyl]-3-fluoropyrrolidine-l-sulfonamide (321)
LCMS: C44H48CIF2N11O4S requires: 899.3, found: m/z = 900.2 [M+H]+. [0001491] (37?)-7V-[5-chloro-3-(l-{5-[(37?)-4-({ l-[4-(2,4-dioxo-l,3-diazinan-l- yl)phenyl]piperidin-4-yl Jmethyl)-3-methylpiperazin- l -yl]pyridin-2-yl J-3-(pyridin-4-yl)- IT/- pyrazol-4-yl)-2-fluorophenyl]-3-fluoropyrrolidine-l-sulfonamide (322)
LCMS: C44H48CIF2N11O4S requires: 899.3, found: m/z = 900.3 [M+H]+.
[0001492] 7V-[5-chloro-3-(l-{5-[(37?)-4-[(l-{5-[(37?5)-2,6-dioxopiperidin-3-yl]pyridin-2- yl}piperidin-4-yl)methyl]-3-methylpiperazin-l-yl]pyridin-2-yl}-3-(pyridin-4-yl)-l/7-pyrazol- 4-yl)-2-fluorophenyl]pyrrolidine-l -sulfonamide (323)
LCMS: C44H49CIFN11O4S requires: 881.3, found: m/z = 882.4 [M+H]+. *H NMR (500 MHz, DMSO-tL) 8 10.82 (s, 1H), 9.94 (s, 1H), 8.81 (s, 1H), 8.59 (d, J= 5.3 Hz, 2H), 8.31 (s, 1H), 7.96 (s, 2H), 7.75 (s, 1H), 7.52 (dd, J= 6.5, 2.7 Hz, 1H), 7.48 - 7.43 (m, 2H), 7.40 (dd, J= 5.7, 2.7 Hz, 1H), 6.84 (s, 1H), 4.33 (s, 2H), 4.02 (s, 1H), 3.74 (dd, J= 12.0, 4.9 Hz, 1H), 3.58 (s, OH), 3.48 (s, 1H), 3.20 (s, 2H), 3.18 - 3.12 (m, 2H), 3.00 (s, 2H), 2.84 (s, 2H), 2.18 (dd, J= 14.0, 9.9 Hz, 1H), 2.01 - 1.94 (m, 1H), 1.91 (s, 1H), 1.77 - 1.71 (m, 3H), 1.39 (s, 2H), 1.25 (s, 3H), 1.08 (s, 1H).
[0001493] N- [5 -chi oro-3 -( 1 - { 5 - [(37?)-4-( { 1 -[4-(2,4-dioxo- 1 ,3 -diazinan- 1 - yl)phenyl]piperidin-4-yl}methyl)-3-methylpiperazin-l-yl]pyridin-2-yl}-3-(pyridin-4-yl)-l/7- pyrazol-4-yl)-2-fluorophenyl]pyrrolidine- 1 -sulfonamide (324)
LCMS: C44H49CIFN11O4S requires: 881.3, found: m/z = 882.4 [M+H]+.
[0001494] 7V-[5-chloro-3-(l-{5-[(3/?)-4-[(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2- yl}piperidin-4-yl)methyl]-3-methylpiperazin-l-yl]pyridin-2-yl}-3-(pyridin-4-yl)-l/7-pyrazol- 4-yl)-2-fluorophenyl]pyrrolidine-l -sulfonamide (325)
LCMS: C44H49CIFN11O4S requires: 881.3, found: m/z = 882.3 [M+H]+.
[0001495] 7V-[5-chloro-3-(l-{5-[(3/?)-4-[(l-{4-[(37?)-2,6-dioxopiperidin-3- yl]phenyl}piperidin-4-yl)methyl]-3-methylpiperazin-l-yl]pyridin-2-yl}-3-(pyridin-4-yl)-l/7- pyrazol-4-yl)-2-fluorophenyl]pyrrolidine- 1 -sulfonamide (326)
LCMS: C45H50CIFN10O4S requires: 880.3, found: m/z = 881.3 [M+H]+. *H NMR (500 MHz, DMSO-tL) 6 10.77 (s, 1H), 9.94 (s, 1H), 8.78 (s, 1H), 8.61 - 8.56 (m, 2H), 8.20 (s, 1H), 7.91 (d, J= 9.0 Hz, 1H), 7.65 (d, J= 9.2 Hz, 1H), 7.52 (dd, J= 6.5, 2.7 Hz, 1H), 7.47 - 7.42 (m, 2H), 7.41 - 7.37 (m, 1H), 7.04 (d, J= 8.6 Hz, 2H), 6.90 (d, J= 8.5 Hz, 2H), 3.76 - 3.65 (m, 3H), 3.58 (s, 2H), 3.34 (dd, J= 10.8, 6.2 Hz, 5H), 3.18 - 3.12 (m, 2H), 2.98 (s, 2H), 2.69 (d, J = 13.1 Hz, 2H), 2.64 - 2.58 (m, OH), 2.31 (s, 1H), 2.08 (s, 1H), 2.02 (s, 2H), 1.91 (d, J= 12.9 Hz, 1H), 1.77 - 1.70 (m, 4H), 1.26 (d, J= 13.7 Hz, 1H), 1.20 (s, 1H), 1.09 (s, 2H).
[0001496] (7?5)-7V-(5-chloro-3-(l-(4-(4-((l-(5-( (R)-2,6-dioxopiperidin-3-yl)pyridin-2- yl)piperidin-4-yl)methyl)piperazin-l-yl)phenyl)-3-(pyridin-4-yl)-l//-pyrazol-4-yl)-2- fluorophenyl)butane-2-sulfonamide (327)
LCMS: C44H49CIFN9O4S requires: 853.3, found: m/z = 854.4 [M+H]+.
[0001497] rac-(27?)-7V-[5-chloro-3-(l-{4-[4-({l-[4-(2,4-dioxo-l,3-diazinan-l- yl)phenyl]piperidin-4-yl}methyl)piperazin-l-yl]phenyl}-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2- fluorophenyl]butane-2-sulfonamide (328)
LCMS: C44H49CIFN9O4S requires: 853.3, found: m/z = 854.3 [M+H]+.
[0001498] rac-(R)-7V-(5-chl oro-3 -( 1 -(4-(4-(( 1 -(5-((5)-2,6-di ox opiperi din-3 -yl)pyridin-2- yl)piperidin-4-yl)methyl)piperazin-l-yl)phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2- fluorophenyl)butane-2-sulfonamide (329)
LCMS: C44H49CIFN9O4S requires: 853.3, found: m/z = 854.3 [M+H]+.
[0001499] (27?5)-7V-{5-chloro-3-[l-(4-{4-[(l-{4-[(3/?)-2,6-dioxopiperidin-3- yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl]-2- fluorophenyl }butane-2-sulfonamide (330)
LCMS: C45H5OC1FN804S requires: 852.3, found: m/z = 853.4 [M+H]+.
[0001500] 7V-{5-chloro-3-[l-(4-{4-[(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2- yl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl]-2- fluorophenyl] -3 -fluoroazetidine- 1 -sulfonamide (331)
LCMS: C43H45CIF2N10O4S requires: 870.3, found: m/z = 871.2 [M+H]+.
[0001501] rac-7V-{5-chloro-3-[l-(4-{4-[(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2- yl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl]-2- fluorophenyl } -3 -fluoroazetidine- 1 -sulfonamide (332)
LCMS: C43H45CIF2N10O4S requires: 870.3, found: m/z = 871.2 [M+H]+.
[0001502] 7V-{5-chloro-3-[l-(4-{4-[(l-{4-[(37?)-2,6-dioxopiperidin-3- yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl]-2- fluorophenyl } -3 -fluoroazetidine- 1 -sulfonamide (333) LCMS: C44H46CIF2N9O4S requires: 869.3, found: m/z = 870.2 [M+H]+.
[0001503] (37?)-7V-{5-chloro-3-[l-(4-{4-[(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2- yl}piperidin-4-yl)methyl]piperazin-l-yl}-2-fluorophenyl)-3-(pyridin-4-yl)-lZ7-pyrazol-4-yl]- 2-fluorophenyl } -3 -fluoropyrrolidine- 1 -sulfonamide (334)
LCMS : C44H46CIF3N10O4S requires: 902.3, found: m/z = 903.2 [M+H]+.
[0001504] (37?)-7V-{5-chloro-3-[l-(4-{4-[(l-{5-[(37?5)-2,6-dioxopiperidin-3-yl]pyridin-2- yl}piperidin-4-yl)methyl]piperazin-l-yl}-2-fluorophenyl)-3-(pyridin-4-yl)-lZ7-pyrazol-4-yl]- 2-fluorophenyl } -3 -fluoropyrrolidine- 1 -sulfonamide (335)
LCMS: C44H46CIF3N10O4S requires: 902.3, found: m/z = 903.2 [M+H]+.
[0001505] (37?)-7V-{5-chloro-3-[l-(4-{4-[(l-{4-[(37?)-2,6-dioxopiperidin-3- yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}-2-fluorophenyl)-3-(pyridin-4-yl)-l^- pyrazol-4-yl]-2-fluorophenyl } -3 -fluoropyrrolidine- 1 -sulfonamide (336)
LCMS : C45H47CIF3N9O4S requires: 901.3, found: m/z = 902.3 [M+H]+.
[0001506] rac-7V-{5-chloro-3-[l-(4-{4-[(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2- yl}piperidin-4-yl)methyl]piperazin-l-yl}-2-fluorophenyl)-3-(pyridin-4-yl)-lZ7-pyrazol-4-yl]- 2-fluorophenyl } -3 -fluoroazetidine- 1 -sulfonamide (337)
LCMS: C43H44CIF3N10O4S requires: 888.3, found: m/z = 889.2 [M+H]+. 'H NMR (500 MHz, DMSO-tL) 8 12.74 (s, 1H), 10.81 (s, 1H), 8.60 - 8.55 (m, 2H), 8.46 (d, J= 2.0 Hz, 1H), 8.14 (s, 1H), 7.95 (d, J= 2.5 Hz, 1H), 7.68 (t, J= 9.0 Hz, 1H), 7.50 (dd, J= 6.4, 2.7 Hz, 1H), 7.45 - 7.40 (m, 2H), 7.40 - 7.35 (m, 2H), 7.07 (d, J= 14.9 Hz, 1H), 6.95 (d, J= 9.3 Hz, 1H), 6.81 (d, J= 8.8 Hz, 1H), 5.35 (dd, J= 6.9, 3.1 Hz, OH), 5.23 (td, J= 6.1, 3.1 Hz, OH), 4.28 (d, J= 12.8 Hz, 2H), 4.06 (ddd, J= 19.7, 10.4, 6.1 Hz, 2H), 3.89 (ddd, J= 24.5, 10.7, 3.8 Hz, 2H), 3.73 (dd, J= 12.1, 4.9 Hz, 1H), 2.81 (t, J= 12.4 Hz, 2H), 2.74 - 2.65 (m, 1H), 2.24 - 2.13 (m, 1H), 2.01 - 1.94 (m, 1H), 1.88 (s, 1H), 1.80 (d, J= 12.9 Hz, 2H), 1.13 (d, J= 12.2 Hz, 2H).
[0001507] 7V-{5-chloro-3-[l-(4-{4-[(l-{4-[(37?)-2,6-dioxopiperidin-3- yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}-2-fluorophenyl)-3-(pyridin-4-yl)-lZ7- pyrazol-4-yl]-2-fluorophenyl } -3 -fluoroazetidine- 1 -sulfonamide (338)
LCMS: C44H45CIF3N9O4S requires: 887.3, found: m/z = 888.2 [M+H]+. ‘H NMR (500 MHz, DMSO-tL) 6 10.77 (s, 1H), 10.23 (s, 1H), 8.60 - 8.55 (m, 2H), 8.45 (d, J= 2.0 Hz, 1H), 7.67 (t, J= 9.1 Hz, 1H), 7.50 (dd, J= 6.4, 2.7 Hz, 1H), 7.45 - 7.40 (m, 2H), 7.35 (s, 1H), 7.09 - 7.02 (m, 3H), 6.95 (d, J= 9.1 Hz, 1H), 6.90 (d, J= 8.8 Hz, 2H), 5.34 (td, J= 6.1, 3.1 Hz, OH), 5.23 (ddd, J= 9.9, 6.0, 3.9 Hz, 1H), 4.06 (ddd, J= 19.5, 10.0, 6.0 Hz, 2H), 3.88 (ddd, J= 24.5, 10.5, 3.8 Hz, 2H), 3.76 - 3.65 (m, 3H), 3.35 (s, 2H), 2.68 (d, J= 12.2 Hz, 2H), 2.64 - 2.58 (m, 1H), 2.50 - 2.42 (m, 1H), 2.33 (s, 2H), 2.19 - 2.06 (m, 1H), 2.05 - 1.98 (m, 1H), 1.82 (d, J= 12.7 Hz, 2H), 1.25 (q, J= 11.4 Hz, 2H).
[0001508] 7V-[5-chloro-3-(l-{4-[4-({ l-[4-(2,4-dioxo-l,3-diazinan-l-yl)phenyl]piperidin- 4-yl(methyl)piperazin-l-yl]-2-fluorophenyl)-3-(pyridin-4-yl)-lZ7-pyrazol-4-yl)-2- fluorophenyl]-3 -fluoroazetidine- 1 -sulfonamide (339)
LCMS: C43H44CIF3N10O4S requires: 888.3, found: m/z = 889.1 [M+H]+. 'H NMR (500 MHz, DMSO-tL) 8 10.26 (s, 1H), 8.60 - 8.55 (m, 2H), 8.45 (d, J= 2.0 Hz, 1H), 7.67 (t, J= 9.1 Hz, 1H), 7.50 (dd, J= 6.4, 2.7 Hz, 1H), 7.45 - 7.40 (m, 2H), 7.35 (s, 1H), 7.17 - 7.12 (m, 2H), 7.05 (d, J= 14.9 Hz, 1H), 6.97 - 6.91 (m, 2H), 5.38 - 5.31 (m, OH), 5.22 (dd, J= 7.0, 3.1 Hz, 1H), 4.11 - 4.00 (m, 2H), 3.88 (ddd, J= 24.7, 10.4, 3.8 Hz, 2H), 3.73 - 3.67 (m, 4H), 3.35 (s, 1H), 2.69 (h, J= 5.0 Hz, 4H), 2.59 (s, 4H), 2.32 (s, 3H), 1.83 (d, J= 12.9 Hz, 2H), 1.76 (s, 1H), 1.30 - 1.22 (m, 2H).
[0001509] 7V-{3-[l-(4-{4-[(l-{4-[(3/?)-2,6-dioxopiperidin-3-yl]phenyl(piperidin-4- yl)methyl ]piperazin- 1 -yl ( -2-fluorophenyl)-3 -(py ridin-4-yl)- 17/-py razol -4-y 1 ] -2, 5 - difluorophenyl (pyrrolidine- 1 -sulfonamide (340)
LCMS: C45H48F3N9O4S requires: 867.4, found: m/z = 868.2 [M+H]+.
[0001510] rac-7V-{3-[l-(4-{4-[(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2- yl(piperidin-4-yl)methyl]piperazin-l-yl(-2-fluorophenyl)-3-(pyridin-4-yl)-lZ7-pyrazol-4-yl]-
2.5-difluorophenyl}pyrrolidine-l-sulfonamide (341)
LCMS: C44H47F3N10O4S requires: 868.3, found: m/z = 869.2 [M+H]+.
[0001511] 7V-{3-[l-(5-{4-[(l-{4-[(3/?)-2,6-dioxopiperidin-3-yl]phenyl(piperidin-4- yl)methyl]piperazin-l-yl}pyrimidin-2-yl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl]-2,5- difluorophenyl (pyrrolidine- 1 -sulfonamide (342)
LCMS: C43H47F2N11O4S requires: 851.4, found: m/z = 852.3 [M+H]+.
[0001512] rac-7V-{3-[l-(5-{4-[(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2- yl(piperidin-4-yl)methyl]piperazin-l-yl(pyrimidin-2-yl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl]-
2.5-difluorophenyl(pyrrolidine-l-sulfonamide (343) LCMS: C42H46F2N12O4S requires: 852.3, found: m/z = 853.2 [M+H]+.
[0001513] 7V-{5-chloro-3-[l-(4-{4-[(l-{4-[(37?)-2,6-dioxopiperidin-3-yl]-3- fluorophenyl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4- yl]-2-fluorophenyl}pyrrolidine-l-sulfonamide (344)
'H NMR (500 MHz, DMSO4) 8 10.73 (s, 1H), 9.86 (s, 1H), 8.65 (s, 1H), 8.51 - 8.46 (m, 2H), 7.73 - 7.68 (m, 2H), 7.46 - 7.41 (m, 1H), 7.38 - 7.33 (m, 2H), 7.04 (s, 1H), 7.03 - 6.96 (m, 2H), 6.64 (d, J= 10.0 Hz, 2H), 3.81 (dd, J= 12.4, 5.0 Hz, 1H), 3.65 (d, J= 12.3 Hz, 2H), 3.15 (s, 5H), 3.06 (s, 5H), 2.63 (t, J= 12.1 Hz, 3H), 2.16 (d, J= 7.0 Hz, 2H), 2.07 (dd, J= 13.0, 4.2 Hz, 1H), 1.91 - 1.85 (m, 1H), 1.73 (d, J= 13.6 Hz, 2H), 1.69 - 1.63 (m, 4H), 1.18 - 1.10 (m, 3H).
[0001514] rac-7V-{5-chloro-3-[l-(4-{4-[(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2- yl}piperidin-4-yl)methyl]-l,4-diazepan-l-yl}-2-fluorophenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4- yl]-2-fluorophenyl}pyrrolidine-l-sulfonamide (345)
LCMS: C45H49CIF2N10O4S requires: 898.3, found: m/z = 899.2 [M+H]+. XH NMR (500 MHz, DMSO-tL) 6 10.81 (s, 1H), 9.93 (s, 1H), 8.59 - 8.54 (m, 2H), 8.40 (d, J= 1.9 Hz, 1H), 8.14 (s, 1H), 7.94 (s, 1H), 7.63 (s, 1H), 7.51 (dd, J = 6.4, 2.7 Hz, 1H), 7.43 - 7.38 (m, 2H), 7.35 (dd, J= 5.7, 2.7 Hz, 1H), 6.82 (s, 3H), 6.74 (s, 1H), 4.29 (s, 2H), 3.73 (d, J= 10.1 Hz, 1H), 3.53 (s, 2H), 3.18 - 3.12 (m, 5H), 2.80 (s, 3H), 2.72 - 2.64 (m, 1H), 2.18 (d, J= 10.5 Hz, 2H), 2.01 - 1.94 (m, 1H), 1.77 - 1.71 (m, 4H).
[0001515] 7V-{5-chloro-3-[l-(4-{4-[(l-{4-[(3/?)-2,6-dioxopiperidin-3- yl]phenyl}piperidin-4-yl)methyl]-l,4-diazepan-l-yl}-2-fluorophenyl)-3-(pyridin-4-yl)-lZ7- pyrazol-4-yl]-2-fluorophenyl}pyrrolidine-l-sulfonamide (346)
LCMS: C46H50ClF2N9O4S requires: 897.3, found: m/z = 898.2 [M+H]+. *H NMR (500 MHz, DMSO-tL) 6 10.77 (s, 1H), 9.93 (s, 1H), 8.63 - 8.49 (m, 2H), 8.39 (d, J= 1.9 Hz, 1H), 8.14 (s, OH), 7.59 (s, 1H), 7.51 (dd, J= 6.5, 2.7 Hz, 1H), 7.42 - 7.39 (m, 2H), 7.34 (dd, J= 5.5, 2.7 Hz, 1H), 7.00 (d, J= 8.2 Hz, 2H), 6.87 (d, J= 8.3 Hz, 2H), 6.78 (s, 2H), 6.70 (s, 1H), 3.77 - 3.58 (m, 6H), 3.53 (s, 2H), 3.19 - 3.09 (m, 4H), 2.69 - 2.56 (m, 4H), 2.39 - 2.34 (m, 1H), 2.18 - 2.05 (m, 1H), 2.00 (dd, J= 13.2, 5.0 Hz, 1H), 1.89 (s, 2H), 1.80 - 1.67 (m, 4H), 1.21 (d, J= 28.0 Hz, 2H). [0001516] rac-/V- { 5-chl oro-3 -[1 -(4- { 4-[(l - { 4-[(37?)-2,6-di oxopiperi din-3 -yl]-2- fluorophenyl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4- yl]-2-fluorophenyl}pyrrolidined -sulfonamide (347)
LCMS: C45H48CIF2N9O4S requires: 883.3, found: m/z = 884.2 [M+H]+. *H NMR (500 MHz, DMSO-tL) 8 10.82 (s, 1H), 9.94 (s, 1H), 8.75 (s, 1H), 8.57 (d, J= 5.2 Hz, 2H), 7.80 (s, 2H), 7.52 (dd, J= 6.4, 2.7 Hz, 1H), 7.46 - 7.36 (m, 2H), 7.11 (s, 1H), 6.99 (d, 7= 22.1 Hz, 3H), 3.80 (d, J= 9.1 Hz, 1H), 3.23 (s, 3H), 3.18 - 3.10 (m, 1H), 2.74 - 2.59 (m, 4H), 2.39 - 2.34 (m, 1H), 2.20 (d, 7= 8.7 Hz, OH), 2.01 (s, 1H), 1.85 (s, 2H), 1.79 - 1.65 (m, 3H), 1.30 (m, 3H).
[0001517] rac-7V-{5-chloro-3-[l-(4-{4-[(l-{4-[(37?)-2,6-dioxopiperidin-3-yl]-3- fluorophenyl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4- yl]-2-fluorophenyl}pyrrolidine-l-sulfonamide (348)
LCMS: C45H48CIF2N9O4S requires: 883.3, found: m/z = 884.2 [M+H]+. *H NMR (500 MHz, DMSO-tL) 6 10.81 (s, 1H), 9.93 (s, 1H), 8.74 (s, 1H), 8.59 - 8.54 (m, 2H), 7.79 (d, J= 8.6 Hz, 2H), 7.52 (dd, J= 6.5, 2.7 Hz, 1H), 7.46 - 7.38 (m, 3H), 7.14 - 7.04 (m, 3H), 6.72 (d, J= 10.6 Hz, 2H), 3.88 (dd, 7= 12.4, 5.1 Hz, 1H), 3.73 (d, 7= 12.3 Hz, 2H), 3.37 (s, 1H), 3.34 (s, 3H), 3.36 - 3.27 (m, 1H), 3.22 (s, 3H), 3.18 - 3.12 (m, 2H), 2.72 (t, 7= 12.4 Hz, 3H), 2.24 (s, 2H), 2.15 (dd, 7 = 12.7, 4.2 Hz, 1H), 1.99 - 1.93 (m, 1H), 1.81 (d, 7= 13.0 Hz, 2H), 1.77 - 1.71 (m, 4H), 1.22 (s, 3H).
[0001518] 7V-[5-(difluoromethyl)-3-[l-(4-{4-[(l-{4-[(3/?)-2,6-dioxopiperidin-3- yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl]-2- fluorophenyl]pyrrolidine- 1 -sulfonamide (349)
LCMS: C46H50F3N9O4S requires: 881.4, found: m/z = 882.3 [M+H]+. 'H NMR (500 MHz, DMSO-tL) 5 10.78 (s, 1H), 9.91 (s, 1H), 8.76 (s, 1H), 8.58 - 8.53 (m, 2H), 7.81 (s, 2H), 7.71 (d, 7= 6.7 Hz, 1H), 7.51 (d, 7= 5.9 Hz, 1H), 7.43 - 7.38 (m, 2H), 7.10 (s, 1H), 7.05 (d, 7= 8.2 Hz, 2H), 6.90 (d, 7 = 8.2 Hz, 2H), 3.73 (dd, 7= 11.0, 4.9 Hz, 1H), 3.25 - 3.19 (m, 5H), 3.19 - 3.13 (m, 5H), 2.66 (s, 2H), 2.48 (s, 2H), 2.24 (s, 1H), 2.13 (d, 7= 9.4 Hz, 1H), 2.05 - 1.98 (m, 1H), 1.83 (d, 7= 12.7 Hz, 2H), 1.77 - 1.70 (m, 4H), 1.25 (s, 3H).
[0001519] rac-7V-[5-(difluoromethyl)-3-[l-(4-{4-[(l-{5-[(3/?)-2,6-dioxopiperidin-3- yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4- yl]-2-fluorophenyl]pyrrolidine-l -sulfonamide (350) LCMS: C45H49F3N10O4S requires: 882.4, found: m/z = 883.3 [M+H]+. 'H NMR (500 MHz, DMSO-tL) 8 10.82 (s, 1H), 9.91 (s, 1H), 9.26 (s, 1H), 8.79 (s, 1H), 8.58 - 8.53 (m, 2H), 8.14 (s, 1H), 7.96 (d, J= 2.5 Hz, 1H), 7.85 (s, 2H), 7.72 (dd, J= 7.0, 2.1 Hz, 1H), 7.54 - 7.48 (m, 1H), 7.44 - 7.36 (m, 3H), 7.18 (s, 2H), 7.11 (s, OH), 6.84 (d, J= 9.0 Hz, 1H), 4.30 (d, J= 12.7 Hz, 2H), 3.93 (s, 1H), 3.74 (dd, J= 12.1, 4.9 Hz, 1H), 3.65 (s, 1H), 3.21 (s, 5H), 3.19 - 3.13 (m, 4H), 2.84 (s, 2H), 2.69 (td, J= 12.2, 6.2 Hz, 1H), 2.54 (d, J= 3.8 Hz, OH), 2.19 (qd, J= 12.7, 4.4 Hz, 1H), 2.01 - 1.94 (m, 1H), 1.82 (d, J= 12.7 Hz, 2H), 1.78 - 1.69 (m, 4H), 1.20 (s, 3H).
[0001520] 7V-{5-chloro-3-[l-(6-{4-[(l-{4-[(37?)-2,6-dioxopiperidin-3- yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}pyridin-3-yl)-3-(pyridin-4-yl)-l/7-pyrazol-4- yl]-2-fluorophenyl}pyrrolidine-l-sulfonamide (351)
LCMS: C44H48CIFN10O4S requires: 866.3, found: m/z = 867.2 [M+H]+.
[0001521] rac-7V-{5-chloro-3-[l-(6-{4-[(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2- yl}piperidin-4-yl)methyl]piperazin-l-yl}pyridin-3-yl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl]-2- fluorophenyl}pyrrolidine-l-sulfonamide (352)
LCMS: C43H47CIFN11O4S requires: 867.3, found: m/z = 868.3 [M+H]+.
[0001522] 7V-{5-chloro-3-[l-(4-{4-[(l-{4-[(37?)-2,6-dioxopiperidin-3- yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}-2,5-difluorophenyl)-3-(pyridin-4-yl)-l/7- pyrazol-4-yl]-2-fluorophenyl}pyrrolidine-l-sulfonamide (353)
LCMS: C45H47CIF3N9O4S requires: 901.3, found: m/z = 902.2 [M+H]+.
[0001523] rac-7V-{5-chloro-3-[l-(4-{4-[(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2- yl}piperidin-4-yl)methyl]piperazin-l-yl}-2,5-difluorophenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4- yl]-2-fluorophenyl}pyrrolidine-l-sulfonamide (354)
LCMS: C44H46CIF3N10O4S requires: 902.3, found: m/z = 903.2 [M+H]+.
[0001524] 7V-[5-chl oro-3 -(1 -{4-[4-({ 1 -[5-(2,4-di oxo- 1,3-diazinan-l -yl)pyri din-2 - yl]piperidin-4-yl }methyl)piperazin- 1 -yl]phenyl } -3 -(pyridin-4-yl)- l/7-pyrazol-4-yl)-2- fluorophenyl]pyrrolidine- 1 -sulfonamide (355)
LCMS: C43H47CIFN11O4S requires: 867.3, found: m/z = 868.2 [M+H]+. [0001525] 7V-[5-(difluoromethyl)-3-(l-{4-[4-({l-[4-(2,4-dioxo-l,3-diazinan-l- yl)phenyl]piperidin-4-yl } methyl)piperazin- 1 -yl]-2-fluorophenyl } -3 -(pyridin-4-yl)- 1H- pyrazol-4-yl)-2-fluorophenyl]pyrrolidine- 1 -sulfonamide (356)
LCMS: C45H48F4N10O4S requires: 900.4, found: m/z = 901.2 [M+H]+.
[0001526] rac-7V-[5-(difluoromethyl)-3-[l-(4-{4-[(l-{5-[(37?)-2,6-dioxopiperidin-3- yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l-yl}-2-fluorophenyl)-3-(pyridin-4-yl)-l/7- pyrazol-4-yl]-2-fluorophenyl]pyrrolidine-l -sulfonamide (357)
LCMS: C45H48F4N10O4S requires: 900.4, found: m/z = 901.3 [M+H]+.
[0001527] N- [5 -chi oro-3 -( 1 -{ 5 -[4-({ 1 -[4-(2,4-dioxo- 1 ,3 -diazinan- 1 -yl)phenyl]piperidin-
4-yl}methyl)piperazin-l-yl]pyrimidin-2-yl}-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2- fluorophenyl]pyrrolidine- 1 -sulfonamide (358)
LCMS: C42H46CIFN12O4S requires: 868.3, found: m/z = 869.3 [M+H]+.
[0001528] rac-7V-{5-chloro-3-[l-(5-{4-[(l-{5-[(3/?)-2,6-dioxopiperidin-3-yl]pyridin-2- yl}piperidin-4-yl)methyl]piperazin-l-yl}pyrimidin-2-yl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl]- 2-fluorophenyl}pyrrolidine-l-sulfonamide (359)
LCMS: C42H46CIFN12O4S requires: 868.3, found: m/z = 869.2 [M+H]+.
[0001529] 7V-{5-chloro-3-[l-(5-{4-[(l-{4-[(3/?)-2,6-dioxopiperidin-3- yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}pyrimidin-2-yl)-3-(pyridin-4-yl)-l/7-pyrazol- 4-yl]-2-fluorophenyl}pyrrolidine-l-sulfonamide (360)
LCMS: C43H47CIFN11O4S requires: 867.3, found: m/z = 868.2 [M+H]+.
[0001530] 7V-[5-chloro-3-(l-{4-[4-({l-[4-(2,4-dioxo-l,3-diazinan-l-yl)phenyl]piperidin- 4-yl}methyl)piperazin-l-yl]-3 -fluorophenyl} -3 -(pyridin-4-yl)- l/7-pyrazol-4-yl)-2- fluorophenyl]pyrrolidine-l -sulfonamide (361)
LCMS: C44H47CIF2N10O4S requires: 884.3, found: m/z = 885.3 [M+H]+.
[0001531] 7V-[5-(difluoromethyl)-3-[l-(4-{4-[(l-{4-[(3/?)-2,6-dioxopiperidin-3- yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}-2-fluorophenyl)-3-(pyridin-4-yl)-lZ7- pyrazol-4-yl]-2-fluorophenyl]pyrrolidine-l -sulfonamide (362)
LCMS: C46H49F4N9O4S requires: 899.4, found: m/z = 900.3 [M+H]+. [0001532] rac-7V-{5-chloro-3-[l-(4-{4-[(l-{5-[(3/?)-2,6-dioxopiperidin-3-yl]pyridin-2- yl } pi peri din-4-yl )methyl ]pi perazi n- 1 -yl } -3 -fl uorophenyl )-3 -(pyri di n-4-yl )- l //-pyrazol -4-yl ]- 2-fluorophenyl}pyrrolidine-l-sulfonamide (363)
LCMS: C44H47CIF2N10O4S requires: 8843, found: m/z = 885.2 [M+H]+.
[0001533] 7V-{5-chloro-3-[l-(4-{4-[(l-{4-[(37?)-2,6-dioxopiperidin-3- yl]phenyl }piperidin-4-yl)methyl]piperazin- 1 -yl } -3 -fluorophenyl)-3 -(pyridin-4-yl)- 1H- pyrazol-4-yl]-2-fluorophenyl}pyrrolidine-l-sulfonamide (364)
LCMS: C45H48CIF2N9O4S requires: 883.3, found: m/z = 884.2 [M+H]+.
[0001534] (3/?)-7V-[5-chloro-3-(l-{4-[4-({ l-[4-(2,4-dioxo-l,3-diazinan-l- yl)phenyl]piperidin-4-yl } methyl)piperazin- 1 -y 1 ] -3 -fluorophenyl } -3 -(pyridin-4-yl)- 1H- pyrazol-4-yl)-2-fluorophenyl]-3-fluoropyrrolidine-l-sulfonamide (365)
LCMS: C44H46CIF3N10O4S requires: 902.3, found: m/z = 903.2 [M+H]+.
[0001535] (3/?)-7V-{5-chloro-3-[l-(4-{4-[(l-{5-[(3/?5)-2,6-dioxopiperidin-3-yl]pyridin-2- yl}piperidin-4-yl)methyl]piperazin-l-yl}-3-fluorophenyl)-3-(pyridin-4-yl)-lZ7-pyrazol-4-yl]- 2-fluorophenyl } -3 -fluoropyrrolidine- 1 -sulfonamide (366)
LCMS: C44H46CIF3N10O4S requires: 902.3, found: m/z = 903.2 [M+H]+.
[0001536] (3/?)-N-{5-chloro-3-[l-(4-{4-[(l-{4-[(3/?)-2,6-dioxopiperidin-3- yl]phenyl }piperidin-4-yl)methyl]piperazin- 1 -yl } -3 -fluorophenyl)-3 -(pyridin-4-yl)- 1H- pyrazol-4-yl]-2-fluorophenyl } -3 -fluoropyrrolidine- 1 -sulfonamide (367)
LCMS: C45H47CIF3N9O4S requires: 901.3, found: m/z = 902.3 [M+H]+.
[0001537] 7V-[5-chloro-3-(l-{4-[4-({ l-[5-(2,4-dioxo-l,3-diazinan-l-yl)pyridin-2- yl]piperidin-4-yl }methyl)piperazin- 1 -yl]phenyl } -3 -(pyridin-4-yl)- l/7-pyrazol-4-yl)-2- fluorophenyl]-3 -fluoroazetidine- 1 -sulfonamide (368)
LCMS: C42H44CIF2N11O4S requires: 871.3, found: m/z = 872.3 [M+H]+. 'H NMR (500 MHz, DMSO-de) 5 10.34 (s, 1H), 8.76 (s, 1H), 8.60 - 8.53 (m, 2H), 8.14 (s, 1H), 8.05 (d, J= 2.8 Hz, 1H), 7.79 (d, J= 8.6 Hz, 2H), 7.54 - 7.36 (m, 4H), 7.12 (s, 2H), 6.86 (d, J= 9.1 Hz, 1H), 4.29 (d, J= 12.7 Hz, 2H), 4.07 (s, 2H), 3.89 (dd, J= 24.4, 10.0 Hz, 2H), 3.70 (t, J= 6.7 Hz, 2H), 2.82 (d, J= 12.5 Hz, 1H), 2.71 (t, J= 6.7 Hz, 2H), 2.64 (q, J= 1.9 Hz, 1H), 2.37 (p, J= 1.9 Hz, 1H), 1.81 (d, J= 12.9 Hz, 2H), 1.14 (s, 2H). [0001538] 7V-[5-chloro-3-(l-{4-[4-({ l-[5-(2,4-dioxo-l,3-diazinan-l-yl)pyridin-2- yl]piperidin-4-yl Jmethyl)piperazin- l -yl]-2-fluorophenyl J-3-(pyridin-4-yl)- IT/-pyrazol-4-yl)- 2-fluorophenyl] -3 -fluoroazetidine- 1 -sulfonamide (369)
LCMS: C42H43CIF3N11O4S requires: 889.3, found: m/z = 890.2 [M+H]+. 'H NMR (500 MHz, DMSO-tL) 8 10.34 (s, 1H), 8.62 - 8.54 (m, 2H), 8.45 (s, 1H), 8.14 (s, 1H), 8.05 (d, J= 2.9 Hz, 1H), 7.67 (t, J= 9.1 Hz, 1H), 7.56 - 7.45 (m, 2H), 7.45 - 7.40 (m, 2H), 7.36 (s, 1H), 7.06 (d, J= 14.9 Hz, 1H), 6.95 (d, J= 9.1 Hz, 1H), 6.85 (d, J= 9.0 Hz, 1H), 5.34 (s, 1H), 4.29 (d, J= 12.8 Hz, 2H), 4.05 (d, J= 19.6 Hz, 2H), 3.95 - 3.80 (m, 2H), 3.70 (t, J= 6.7 Hz, 2H), 2.83 (t, J= 12.3 Hz, 2H), 2.70 (t, J= 6.7 Hz, 2H), 2.66 - 2.62 (m, 1H), 2.39 - 2.35 (m, 1H), 1.81 (d, J= 13.0 Hz, 2H), 1.13 (d, J= 12.9 Hz, 2H).
[0001539] 7V-[5-chloro-3-(l-{4-[4-({ l-[5-(2,4-dioxo-l,3-diazinan-l-yl)pyridin-2- yl]piperidin-4-yl}methyl)piperazin-l-yl]-2-fluorophenyl}-3-(pyridin-4-yl)-lZ7-pyrazol-4-yl)- 2-fluorophenyl]pyrrolidine-l -sulfonamide (370)
LCMS: C43H46CIF2N11O4S requires: 885.3, found: m/z = 886.2 [M+H]+. 'H NMR (500 MHz, DMSO-tL) 6 10.34 (s, 1H), 9.94 (s, 1H), 8.60 - 8.54 (m, 2H), 8.44 (d, J= 2.0 Hz, 1H), 8.05 (d, J= 2.8 Hz, 1H), 7.68 (d, J= 9.4 Hz, 1H), 7.54 - 7.45 (m, 2H), 7.45 - 7.39 (m, 2H), 7.35 (dd, J= 5.6, 2.7 Hz, 1H), 7.05 (s, 1H), 6.94 (s, 1H), 6.85 (d, J= 9.1 Hz, 1H), 4.29 (d, J= 12.8 Hz, 2H), 3.70 (t, J= 6.7 Hz, 2H), 3.15 (td, J= 5.5, 3.3 Hz, 4H), 2.83 (t, J= 12.4 Hz, 2H), 2.70 (t, J= 6.7 Hz, 2H), 2.22 (s, 2H), 1.81 (d, J= 13.0 Hz, 2H), 1.78 - 1.70 (m, 4H), 1.13 (s, 2H).
[0001540] (37?)-7V-[5-chloro-3-(l-{4-[4-({ l-[5-(2,4-dioxo-l,3-diazinan-l-yl)pyridin-2- yl]piperidin-4-yl}methyl)piperazin-l-yl]-2-fluorophenyl}-3-(pyridin-4-yl)-lZ7-pyrazol-4-yl)- 2-fluorophenyl] -3 -fluoropyrrolidine- 1 -sulfonamide (371)
LCMS: C43H45CIF3N11O4S requires: 903.3, found: m/z = 904.2 [M+H]+. 'H NMR (500 MHz, DMSO-tL) 6 10.34 (s, 1H), 10.08 (s, 1H), 8.61 - 8.51 (m, 2H), 8.43 (d, J= 1.9 Hz, 1H), 8.05 (d, J= 2.8 Hz, 1H), 7.68 (s, 1H), 7.57 - 7.45 (m, 2H), 7.45 - 7.37 (m, 2H), 7.34 (dd, J= 5.7, 2.6 Hz, 1H), 7.06 (s, 1H), 6.95 (s, 1H), 6.86 (d, J= 9.1 Hz, 1H), 4.29 (d, J= 12.8 Hz, 2H), 3.70 (t, J= 6.8 Hz, 2H), 3.44 - 3.35 (m, 2H), 2.84 (t, J= 12.4 Hz, 2H), 2.71 (t, J= 6.7 Hz, 2H), 2.31 - 1.89 (m, 2H), 1.81 (d, J= 13.0 Hz, 2H), 1.14 (s, 2H).
[0001541] 7V-{5-chloro-3-[l-(4-{4-[(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2- yl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl]-2- fluorophenyl} cyclopentanesulfonamide (372) LCMS: C45H49CIFN9O4S requires: 865.3, found: m/z = 866.2 [M+H]+.
[0001542] rac-7V-{5-chloro-3-[l-(4-{4-[(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2- yl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl]-2- fluorophenyl} cyclopentanesulfonamide (373)
LCMS: C45H49CIFN9O4S requires: 865.3, found: m/z = 866.3 [M+H]+.
[0001543] 7V-{5-chloro-3-[l-(4-{4-[(l-{4-[(3/?)-2,6-dioxopiperidin-3- yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl]-2- fluorophenyl} cyclopentanesulfonamide (374)
LCMS: C46H50CIFN8O4S requires: 864.3, found: m/z = 865.2 [M+H]+.
[0001544] (3/?)-3-(6-{4-[(4-{4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2,5- difluorophenyl)-3 -(pyridin-4-yl)- 1/7-pyrazol- 1 -yl]phenyl Jpiperazin- 1 -yl)methyl]piperidin- 1 - yl}pyridin-3-yl)piperidine-2, 6-dione (375)
LCMS: C43H48F2N10O4S requires: 838.4, found: m/z = 839.3 [M+H]+.
[0001545] rac-(3/?)-3-(6-{4-[(4-{4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2,5- difluorophenyl)-3 -(pyridin-4-yl)- 1/7-pyrazol- 1 -yl]phenyl Jpiperazin- 1 -yl)methyl]piperidin- 1 - yl}pyridin-3-yl)piperidine-2, 6-dione (376)
LCMS: C43H48F2N10O4S requires: 838.4, found: m/z = 839.3 [M+H]+.
[0001546] (3/?)-3-(4-{4-[(4-{4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2,5- difluorophenyl)-3 -(pyridin-4-yl)- 1/7-pyrazol- 1 -yl]phenyl Jpiperazin- 1 -yl)methyl]piperidin- 1 - yl}phenyl)piperidine-2, 6-dione (377)
LCMS: C44H49F2N9O4S requires: 837.4, found: m/z = 838.3 [M+H]+.
[0001547] 7V-[3-(l-{4-[(3/?)-4-[(l-{4-[(3/?)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4- yl)methyl]-3-methylpiperazin-l-yl]phenyl}-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2- fluoropheny 1 ] prop ane- 1 - sulfonami de (378)
LCMS: C45H51FN8O4S requires: 818.4, found: m/z = 819.3 [M+H]+.
[0001548] (3/?)-3-(6-{4-[(4-{4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-
3-(pyridin-4-yl)-l/7-pyrazol-l-yl]-3-fluorophenyl}piperazin-l-yl)methyl]piperidin-l- yl}pyridin-3-yl)piperidine-2, 6-dione (379)
LCMS: C43H48F2N10O4S requires: 838.4, found: m/z = 839.3 [M+H]+. [0001549] (35)-3 -(6- {4-[(4-{4-[4-(3 - { [ethyl(methyl)sulfamoyl] amino } -2-fluoropheny 1)-
3 -(pyridin-4-yl)- I //-pyrazol - 1 -yl]-2-fluorophenyl } piperazin- 1 -yl)methyl]piperidin- 1 - yl}pyridin-3-yl)piperidine-2, 6-dione (380)
LCMS: C43H48F2N10O4S requires: 838.4, found: m/z = 839.2 [M+H]+.
[0001550] rac-(/?)-N-(3 -( 1 -(4-(4-((4-(4-(2,6-dioxopiperi din-3 -yl)phenyl)piperazin- 1 - yl)methyl)piperidin-l-yl)phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2-fluorophenyl)propane-
1 -sulfonamide (381)
LCMS: C44H49FN8O4S requires: 804.4, found: m/z = 805.2 [M+H]+.
[0001551] 7V-(5-chloro-3-(l-(4-((3/?,5/?)-4-((l-(5-((/?5)-2,6-dioxopiperidin-3-yl)pyridin-
2-yl)piperidin-4-yl)methyl)-3,5-dimethylpiperazin-l-yl)-2-fluorophenyl)-3-(pyridin-4-yl)- l/Z-pyrazol-4-yl)-2-fluorophenyl)pyrrolidine-l -sulfonamide (382)
LCMS: C46H51CIF2N10O4S requires: 912.3, found: m/z = 913.2 [M+H]+.
[0001552] 7V-{5-chloro-3-[l-(5-{4-[(l-{5-[(35)-2,6-dioxopiperidin-3-yl]pyridin-2- yl}piperidin-4-yl)methyl]piperazin-l-yl}pyridin-2-yl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl]-2- fluorophenyl}pyrrolidine-l-sulfonamide (383)
LCMS: C43H47CIFN11O4S requires: 867.3, found: m/z = 868.2 [M+H]+.
[0001553] 7V-{5-chloro-3-[l-(4-{4-[(l-{4-[(35)-2,6-dioxopiperidin-3-yl]-3- fluorophenyl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4-yl)-lZ7-pyrazol-4- yl]-2-fluorophenyl}pyrrolidine-l-sulfonamide (384)
LCMS: C45H48CIF2N9O4S requires: 883.3, found: m/z = 884.2 [M+H]+.
[0001554] rac-7V-{5-chloro-3-[l-(4-{4-[(l-{4-[(3/?)-2,6-dioxopiperidin-3-yl]-2,3- difluorophenyl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4-yl)-lZ7-pyrazol-4- yl]-2-fluorophenyl}pyrrolidine-l-sulfonamide (385)
LCMS: C45H47CIF3N9O4S requires: 901.3, found: m/z = 902.2 [M+H]+.
[0001555] rac-7V-{5-chloro-3-[l-(4-{4-[(l-{4-[(3/?)-2,6-dioxopiperidin-3-yl]-2,5- difluorophenyl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4-yl)-lZ7-pyrazol-4- yl]-2-fluorophenyl}pyrrolidine-l-sulfonamide (386)
LCMS: C45H47CIF3N9O4S requires: 901.3, found: m/z = 902.2 [M+H]+. [0001556] rac-A-{5-chloro-3-[l-(4-{4-[(l-{4-[(3A)-2,6-dioxopiperidin-3-yl]-3,5- difluorophenyl }piperidin-4-yl)methyl]piperazin-l-yl }phenyl)-3-(pyridin-4-yl)-U/-pyrazol-4- yl]-2-fluorophenyl}pyrrolidine-l-sulfonamide (387)
LCMS : C45H47CIF3N9O4S requires: 901.3, found: m/z = 902.2 [M+H]+.
[0001557] 7V-[5-chloro-3-(l-{4-[4-({ l-[5-(2,4-dioxo-l,3-diazinan-l-yl)pyridin-2- yl]piperidin-4-yl }methyl)piperazin- 1 -yl]phenyl } -3 -(pyridin-4-yl)- U/-pyrazol-4-yl)-2- fluorophenyl]cyclopentanesulfonamide (388)
LCMS: C44H48CIFN10O4S requires: 866.3, found: m/z = 867.2 [M+H]+.
[0001558] Cell Line Generation for HiBiT Evaluation
[0001559] An A375 cell line expressing a homozygous V600E mutation was purchased from ATCC (Manassas, VA, USA). An A375 clone 1F10 cell line with an endogenous C- terminal HiBiT fusion tag on BRAF V600E allele was generated internally using CRISPR- Cas9 technology and cultured in DMEM, high glucose supplemented with 10% FBS and IX GlutaMAX. A HCT-116 BRAF-/- cell line overexpressing the C-terminal HiBiT-tagged G466V, G469A, and D594G mutants were generated by lentiviral transduction, externally at Biosettia Inc (San Diego, CA, USA). The stably transfected cells were cultured in RPMI media supplemented with 10% FBS, IX GlutaMAX, and 0.25 pg/ml puromycin. DMEM medium, RPMI 1640 medium, GlutaMAX, fetal bovine serum (FBS), and puromycin were purchased from Gibco (Grand Island, NY, USA). HCT-116 BRAF -I- cells were purchased from Horizon Discovery (Waterbeach, UK).
[0001560] BRAF HiBiT Degradation Assay Protocol
[0001561] The C-terminal HiBiT tagged BRAF A375 cells (monoclonal cell line, cell clone 1F10) were seeded at a density of 10,000 cells/well in 30 pL media (DMEM, high glucose supplemented with 10% FBS and IX GlutaMAX) in white opaque 384-well plates (Corning #3570) from column 1 to column 23. The wildtype A375 cells were seeded in column 24 at the same cell density in 30 pL media. Cells were incubated at 37 °C with 5% CO2 for 24 h.
[0001562] The C-terminal HiBiT tagged mutant BRAF G466V, G469A, and D594G overexpressed in HCT-116 BRAF -I- cells (monoclonal cell line, cell clones 8, 34, and 63, respectively) were seeded at the density of 3,000 cells/well in 30 pL media (RPMI supplemented with 10% FBS and IX GlutaMAX) in white opaque 384-well plates (Corning #3570) from column 1 to column 23. Wildtype HCT-116 BRAF cells were seeded in column
24 at the same cell density in 30 pL media. Cells were incubated at 37 °C with 5% CO2 for 24 h.
[0001563] Intermediate compound dilution series (5-point, ranging from 5 mM to 0.5 pM, 10-fold dilutions in DMSO) were prepared in a source plate (Beckman Coulter cat. no. 001- 16128). Final compound dilution series (11-point, ranging from 1 pM to 0.01 nM, half-log dilutions in DMSO) were stamped into the assay plate (Coming #3570, column 1-11 and 12- 22) using the Echo Acoustic Liquid Handler (Beckman Coulter). Each compound was plated in duplicate, and the total volume of compound DMSO solution was 60 nL/well (0.2% final DMSO concentration). DMSO was included in wells A23-L23 and A24-L24. The DMSO- treated HiBiT-tagged samples served as Negative Control (NC) and the DMSO-treated wildtype samples served as Background Control (BC) for the HiBiT assay.
[0001564] HiBiT signal was measured by a Nano-Gio HiBiT Lytic assay (Promega cat. no. N3050). HiBiT lytic detection reagent (Nano-Gio HiBiT Lytic Buffer with 1 :50 Nano-Gio HiBiT Lytic Substrate and 1 : 100 LgBiT Protein, 40 pL) was added using Bravo. The mixture was incubated at room temperature, in the dark, and with gentle shaking for 10 min. Luminesce units (LU) were read on an EnVision plate reader 2105 (Perkin Elmer).
[0001565] HiBiT Data Analysis
[0001566] Percent protein remaining and viability remaining per sample were calculated as follows:
[0001567] % Protein remaining values were plotted as a function of compound concentration. XC50 (DC50) values were determined by fitting curves using the following equation:
Y = LowerBound + (UpperBound — LowerBound) / (1 + ((X C 50 fx Hili')
[0001568] For the HiBiT degradation assay, the key parameters reported include:
• The dose of compound that produces 50% degradation (DC50 at 50%):
DC50 at 50%: the Fitted X value (Cone.) at Y = 50 (response) Observed Dmax (Obs. Dmax) is the percentage protein degraded at maximal compound effect relative to DMSO-treated control:
Obs. Dmax = 100 - minimum Y value (response)
[0001569] Hibit Assay Results
DCso (nM): D > 500; 50 < C < 500; 10 < B < 50; A < 10
Dmax (%): C < 30; 30 < B < 70, A > 70
OTHER EMBODIMENTS
[0001570] It is to be understood that the foregoing description is intended to illustrate and not limit the scope of this disclosure, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

WHAT IS CLAIMED IS:
1. A compound of F ormula (I) wherein
R1 is alkyl, aryl, amino, alkylamino, dialkylamino, cycloalkyl, or heterocycloalkyl, each unsubstituted or substituted with one or more halogen or hydroxyl;
Rla is halogen;
Rih is hydrogen, haloalkyl, or halogen;
R2 is hydrogen, alkyl, cycloalkyl, haloalkyl, or -[Ar1-Z1]n-Z2-Cy1-Z3-L-UBM;
X1 is carbon or nitrogen;
X2 is carbon or nitrogen;
X3 is sulfur, nitrogen, oxygen, or carbon; the bonds among X1, X2, and X3 comprise single and double bonds, and the ring containing X1, X2, and X3 is aromatic;
X4 is carbon or nitrogen;
X5 is hydrogen or -NR3R4;
R3 is hydrogen or alkyl where alkyl is unsubstituted or substituted with hydroxyl;
R4 is hydrogen, alkyl, cycloalkyl, or -[Ar1-Z1]n-Z2-Cy1-Z3-L-UBM wherein
Ar1 is arylene or heteroarylene, each unsubstituted or substituted with one or more alkyl or one or more halogen;
Z1 is a bond or -CH2-; n is zero or one;
Z2 is absent, -C(O)-, -O-, C1-10 alkylene, C1-10 alkylene-C(Me)(Me)-, three- to six-membered cycloalkylene, three- to six-membered cycloalkylene-Ci-10 alkylene, heterocycloalkylene, or -C(Me)(Me)-;
Cy1 is absent or heterocycloalkylene, unsubstituted or substituted with one or more alkyl or one or more halogen; Z3 is absent, Ci-io alkylene, or -C(O)-;
L is a linker according to -L1-L2-L3-L4- or -L4-L3-L2-L1-, wherein
-L1- is absent, -N(R10)-, -C(Rn)2-, -C(O)-, -Ci-8 alkylene-, -C2-8 alkynylene-, -Ce-io aryl-, -C4-10 heteroaryl-, -Q1-, or -Q2-; each -L2-, -L3-, and -L4- is independently, absent, -N(R10)-, -C(Rn)2-, -C(O)-, -O-, -(CH2CH2-O)I-8-, -C1-8 alkylene-, -C2-8 alkynylene-, -Ce-io aryl-, -C4-10 heteroaryl-, -Q1-, -Q2-, or -Q3-; each R10 is independently, hydrogen or methyl; each R11 is, independently, hydrogen, methyl, aryl, or heteroaryl; each -Q1- is a three- to seven-membered heterocycloalkylene comprising at least one nitrogen and is unsubstituted or substituted with one or more methyl, hydroxyl, or halogen; each -Q2- is a five- to thirteen-membered bicyclic heterocycloalkylene comprising at least one nitrogen, wherein the five- to thirteen-membered bicyclic heterocycloalkylene is optionally a spiro bicyclic heterocycloalkylene ring; each -Q3- is a three- to six-membered cycloalkylene;
UBM is a ubiquitin ligase binding moiety; wherein at least one of R2 or R4 is -[Ar1-Z1]n-Z2-Cy1-Z3-L-UBM; or a stereoisomer and/or pharmaceutical salt thereof.
2. The compound of claim 1, having the following Formula (I) wherein
R1 is alkyl, aryl, amino, alkylamino, dialkylamino, cycloalkyl, or heterocycloalkyl, each unsubstituted or substituted with one or more halogen or hydroxyl;
Rla is halogen;
Rlb is hydrogen or halogen; R2 is hydrogen, alkyl, cycloalkyl, haloalkyl, or -[Ar1-Z1]n-Z2-Cy1-Z3-L-UBM;
X1 is carbon or nitrogen;
X2 is carbon or nitrogen;
X3 is sulfur, nitrogen, oxygen, or carbon; the bonds among X1, X2, and X3 comprise single and double bonds, and the ring containing X1, X2, and X3 is aromatic;
X4 is carbon or nitrogen;
X5 is hydrogen or -NR3R4;
R3 is hydrogen or alkyl where alkyl is unsubstituted or substituted with hydroxyl;
R4 is hydrogen, alkyl, cycloalkyl, or -[Ar1-Z1]n-Z2-Cy1-Z3-L-UBM wherein
Ar1 is arylene or heteroarylene, each unsubstituted or substituted with one or more alkyl or one or more halogen;
Z1 is a bond or -CH2-; n is zero or one;
Z2 is absent, -C(O)-, -O-, C1-10 alkylene, C1-10 alkylene-C(Me)(Me)-, three- to six-membered cycloalkylene, three- to six-membered cycloalkylene-Ci-10 alkylene, heterocycloalkylene, or -C(Me)(Me)-;
Cy1 is absent or heterocycloalkylene, unsubstituted or substituted with alkyl;
Z3 is absent, C1-10 alkylene, or -C(O)-;
L is a linker according to -L4-L2-L3-L4- or -L4-L3-L2-L1-, wherein
-L1- is absent, -N(R10)-, -C(Rn)2-, -C(O)-, -Ci-8 alkylene-, -C2-8 alkynylene-, -Ce-io aryl-, -C4-10 heteroaryl-, -Q1-, or -Q2-; each -L2-, -L3-, and -L4- is independently, absent, -N(R10)-, -C(Rn)2-, -C(O)-, -O-, -(CH2CH2-O)I-8-, -CI-8 alkylene-, -C2-8 alkynylene-, -Ce-io aryl-, -C4-10 heteroaryl-, -Q1-, -Q2-, or -Q3-; each R10 is independently, hydrogen or methyl; each R11 is, independently, hydrogen, methyl, aryl, or heteroaryl; each -Q1- is a three- to seven-membered heterocycloalkylene comprising at least one nitrogen and is unsubstituted or substituted with methyl, hydroxyl, or halogen; each -Q2- is a five- to thirteen-membered bicyclic heterocycloalkylene comprising at least one nitrogen, wherein the five- to thirteen-membered bicyclic heterocycloalkylene is optionally a spiro bicyclic heterocycloalkylene ring; each -Q3- is a three- to six-membered cycloalkylene;
UBM is a ubiquitin ligase binding moiety; wherein at least one of R2 or R4 is -[Ar1-Z1]n-Z2-Cy1-Z3-L-UBM; or a stereoisomer and/or pharmaceutical salt thereof.
3. The compound of claim 2, wherein X1 is nitrogen; X2 is carbon, X3 is sulfur; and X4 is carbon or nitrogen.
4. The compound of claim 3, wherein
R1 is alkyl;
Rla is fluoro;
R2 is -[A Z^n-Z^Cy^Z’-L-UBM; n is zero;
Z2 is absent; and
Cy1 is an unsubstituted heterocycloalkylene.
5. The compound of claim 4, wherein Z3 is -C(O)-.
6. The compound of claim 5, wherein L1 is Q1.
7. The compound of claim 6, wherein L2 is -C(O)-.
8. The compound of claim 7, wherein L3 is Q1; and L4 is absent.
9. The compound of any one of claims 4-8, wherein R1 is -CH2CH2CH3.
10. The compound of claim 2, wherein X1 is carbon or nitrogen; X2 is nitrogen, and X3 is carbon or nitrogen.
11. The compound of claim 10, wherein X1 is carbon; X2 is nitrogen, and X3 is nitrogen.
12. The compound of claim 11, wherein
R1 is alkyl;
Rla is fluoro;
R2 is -[A Z^n-Z^Cy^Z’-L-UBM;
Z1 is a bond; n is one;
Z2 and Z3 are absent; and Cy1 is an unsubstituted heterocycloalkylene.
13. The compound of claim 12, wherein X4 is carbon and X5 is hydrogen.
14. The compound of claim 13, wherein L1 is -C(Rn)2-.
15. The compound of claim 14, wherein is R11 hydrogen.
16. The compound of claim 15, wherein L2 is Q1; and L3 and L4 are absent.
17. The compound of any one of claims 11-16, wherein R1 is -CH2CH2CH3.
18. The compound of claim 2, wherein X1 is nitrogen; X2 is carbon, X3 is sulfur; and X4 is nitrogen.
19. The compound of claim 18, wherein
R1 is alkyl;
Rla is fluoro;
R2 is alkyl; n is zero;
Z2 is absent; and
Cy1 is an unsubstituted heterocycloalkylene.
20. The compound of claim 19, wherein Z3 is absent, -CH2- or -C(O)-.
21. The compound of claim 20, wherein L1 is Q1, -C(Rn)2-, or -CH2CH2CH2CH2CH2-, or
Q3
22. The compound of claim 21, wherein L2 is absent, Q1, Q2, -C(Rn)2-, -C(O)-, or -O-.
23. The compound of claim 22, wherein L3 is absent, Q1, or -CH2CH2CH2-; and L4 is absent.
24. The compound of any one of claims 19-23, wherein R1 is -CH2CH2CH3.
25. The compound of claim 2, wherein UBM binds an E3 ubiquitin ligase.
26. The compound of claim 2, wherein UBM binds SCFP-TRCP, VHL, MDM2, IAP, or CRBN.
27. The compound of claim 2, wherein UBM binds VHL.
28. The compound of claim 27, wherein UBM binds VHL and has the following chemical formula L designates attachment to L;
Z4 is a bond, -CH2-, -C(O)-, -C(O)N(R12)-, or -N(R12)-, wherein R12 is hydrogen or methyl;
X6 is C-H or nitrogen;
R8 is alkyl, alkenyl, alkylene, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, - S(O)(R13), or -S(O)2(R13); wherein R13 is hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, aryl, heterocycle, or heteroaryl, wherein each alkyl, alkenyl, alkylene, alkynyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl is unsubstituted or substituted;
R9 is hydrogen, unsubstituted or substituted C1-8 alkyl, or -AA’-AA2-R14 wherein each AA1 and AA2 is an amino acid residue, and R14 is hydrogen or methyl.
29. The compound of claim 27, wherein UBM binds VHL and has the following chemical formula wherein
L designates attachment to L;
Z5 is a bond, -CH2-, -C(O)-, -C(O)N(R12)-, -N(R12)-, or -O-, wherein R12 is hydrogen or methyl;
A is phenyl or C4-heteroaryl;
X7 is -CH2, -NR12, oxygen, or sulfur, wherein R12 is hydrogen or methyl; p is zero or one;
R15 is unsubstituted or substituted C1-8 alkyl, -AA4-AA2-R14, wherein each AA1 and AA2 is an amino acid residue, and R14 is hydrogen or methyl.
30. The compound of claim 27, wherein UBM binds VHL and has the following chemical formula wherein
L designates attachment to L; Z6 is a bond, -CH2., -C(O)-, -C(O)N(R12)-, or N(R12), wherein R12 is hydrogen or methyl;
5 designates attachment to X8, wherein designates attachment to X9, and wherein,
§ iz6 designates attachment to Z6;
X8 is carbon or nitrogen;
X9 is C-H or -CH2-;
R16 is hydrogen, -OH, halogen, -NH2, -C1-3 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C1-3 alkoxy, -C1-3 thioalkyl, -C1-3 alkylamine, -Ce-io aryl, cycloalkyl, heterocycloalkyl, or heteroaryl;
R17 is -C(0)N(H)-C6-IO aralkyl, -C(O)CH(Cbutyl)-N(H)-C3-6 cycloalkyl, n amino acid residue and R14 is hydrogen or methyl; and
R18 is halogen
31. The compound of claim 2, wherein UBM binds CRBN.
32. The compound of claim 31, wherein UBM binds CRBN and has the following chemical formula wherein
X6 absent or NR3;
X7 absent or -C(O)-; and
X8 is arylene or heteroarylene.
33. The compound of claim 32, wherein UBM binds CRBN and is selected from the group
X9 is absent or halogen; and m is one, two, three, or four.
34. A compound of Formula (II) wherein
R1 is alkyl, aryl, amino, alkylamino, dialkylamino, cycloalkyl, or heterocycloalkyl, each unsubstituted or substituted with one or more halogen or hydroxyl;
Rla is halogen;
Rlb is hydrogen or halogen;
R2 is -[Ar1-Z1]n-Z2-Cy1-Z3-L-UBM wherein
Ar1 is arylene or heteroarylene, each unsubstituted or substituted with one or more alkyl or one or more halogen;
Z1 is a bond or -CH2-; n is zero or one;
Z2 is absent, -C(O)-, -O-, C1-10 alkylene, C1-10 alkylene-C(Me)(Me)-, three- to six-membered cycloalkylene, three- to six-membered cycloalkylene-Ci-10 alkylene, heterocycloalkylene, or -C(Me)(Me)-;
Cy1 is absent or heterocycloalkylene, unsubstituted or substituted with alkyl;
Z3 is absent, C1-10 alkylene, or -C(O)-;
L is a linker according to -L1-L2-L3-L4- or -L4-L3-L2-L1-, wherein
-L1- is absent, -N(R10)-, -C(Rn)2-, -C(O)-, -Ci-8 alkylene-, -C2-8 alkynylene-, -Ce-io aryl-, -C4-10 heteroaryl-, -Q1-, or -Q2-; each -L2-, -L3-, and -L4- is independently, absent, -N(R10)-, -C(Rn)2-, -C(O)-, -O-, -(CH2CH2-O)I-8-, -CI-8 alkylene-, -C2-8 alkynylene-, -Ce-io aryl-, -C4-10 heteroaryl-, -Q1-, -Q2-, or -Q3-; each R10 is independently, hydrogen or methyl; each R11 is, independently, hydrogen, methyl, aryl, or heteroaryl; each -Q1- is a three- to seven-membered heterocycloalkylene comprising at least one nitrogen and is unsubstituted or substituted with methyl, hydroxyl, or halogen; each -Q2- is a five- to thirteen-membered bicyclic heterocycloalkylene comprising at least one nitrogen, wherein the five- to thirteen-membered bicyclic heterocycloalkylene is optionally a spiro bicyclic heterocycloalkylene ring; each -Q3- is a three- to six-membered cycloalkylene;
UBM is a ubiquitin ligase binding moiety;
X1 is nitrogen or oxygen;
X3 is sulfur when X1 is nitrogen; oxygen when X1 is nitrogen; or nitrogen when X1 is oxygen; the bonds among X1 and X3 comprise single and double bonds, and the ring containing X1 and X3 is aromatic;
X4 is carbon or nitrogen;
X5 is hydrogen or -NR3R4;
R3 is hydrogen or alkyl where alkyl is unsubstituted or substituted with hydroxyl;
R4 is hydrogen, alkyl, or cycloalkyl; or a stereoisomer and/or pharmaceutical salt thereof.
35. The compound of claim 34, wherein X1 is nitrogen; X3 is oxygen; and X4 is carbon or nitrogen.
36. The compound of claim 34, wherein X1 is oxygen; X3 is nitrogen; and X4 is carbon or nitrogen.
37. The compound of claim 34, wherein X1 is nitrogen; X3 is sulfur; and X4 is carbon or nitrogen.
38. The compound of claim 37, wherein
R1 is alkyl;
Rla is fluoro;
R2 is -[A Z^n-Z^Cy^Z’-L-UBM; n is zero;
Z2 is absent; and
Cy1 is an unsubstituted heterocycloalkylene.
39. The compound of claim 38, wherein Z3 is -C(O)-.
40. The compound of claim 39, wherein L1 is Q1.
41. The compound of claim 40, wherein L2 is -C(O)-.
42. The compound of claim 41, wherein L3 is Q1 and L4 is absent.
43. The compound of any one of claims 38-42, wherein R1 is -CH2CH2CH3.
44. The compound of claim 34, wherein UBM binds an E3 ubiquitin ligase.
45. The compound of claim 34, wherein UBM binds SCFP-TRCP, VHL, MDM2, IAP, or
CRBN.
46. The compound of claim 45, wherein UBM binds VHL.
47. The compound of claim 46, wherein UBM binds VHL and has the following chemical formula wherein
' designates attachment to L;
Z4 is a bond, -CH2-, -C(O)-, -C(O)N(R12)-, or -N(R12)-, wherein R12 is hydrogen or methyl;
X6 is C-H or nitrogen;
R8 is alkyl, alkenyl, alkylene, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, - S(O)(R13), or -S(O)2(R13); wherein R13 is hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, aryl, heterocycle, or heteroaryl, wherein each alkyl, alkenyl, alkylene, alkynyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl is unsubstituted or substituted;
R9 is hydrogen, unsubstituted or substituted C1-8 alkyl, or -AA’-AA2-R14 wherein each AA1 and AA2 is an amino acid residue, and R14 is hydrogen or methyl.
48. The compound of claim 46, wherein UBM binds VHL and has the following chemical formula wherein designates attachment to L; Z5 is a bond, -CH2-, -C(O)-, -C(O)N(R12)-, -N(R12)-, or -O-, wherein R12 is hydrogen or methyl;
A is phenyl or C4-heteroaryl;
X7 is -CH2, -NR12, oxygen, or sulfur, wherein R12 is hydrogen or methyl; p is zero or one;
R15 is unsubstituted or substituted C1-8 alkyl, -AA1-AA2-R14, wherein each AA1 and AA2 is an amino acid residue, and R14 is hydrogen or methyl.
49. The compound of claim 46, wherein UBM binds VHL and has the following chemical formula wherein
L designates attachment to L;
Z6 is a bond, -CH2-, -C(O)-, -C(O)N(R12)-, or N(R12), wherein R12 is hydrogen or methyl;
X8 X9 designates attachment to X8, wherein designates attachment to X9, and wherein, z6 designates attachment to Z6;
X8 is carbon or nitrogen;
X9 is C-H or -CH2-;
R16 is hydrogen, -OH, halogen, -NH2, -C1-3 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C1-3 alkoxy, -C1-3 thioalkyl, -C1-3 alkylamine, -Ce-io aryl, cycloalkyl, heterocycloalkyl, or heteroaryl; R17 is -C(0)N(H)-C6-IO aralkyl, -C(O)CH(t-butyl)-N(H)-C3-6 cycloalkyl,
-C(O)-CH(t-butyl)-N(H)C(O)-C3-C6 cycloalkyl, amino acid residue and R14 is hydrogen or methyl; and
R18 is halogen
50. The compound of claim 34, wherein UBM binds CRBN.
51. The compound of claim 50, wherein UBM binds CRBN and has the following chemical formula wherein
X6 is absent or NR3;
X7 is absent or -C(O)-; and
X8 is arylene or heteroarylene.
52. The compound of claim 51, wherein UBM binds CRBN and is selected from the group consisting
X9 is absent or halogen; and m is one, two, three, or four.
53. The compound of claim 2 Formula (I) or claim 34 Formula (II), wherein L comprises at least one -Q1-; at least one -Q2-; at least one -Q3-; at least one -C(R11)2-; or at least one Ci-8 alkylene-.
54. The compound of claim 53, wherein L is selected from the group consisting of a. -Q1-; b. -Qi-QCO-Q1-; c. -C(R11)2-Q1-; d. -Q1-C(R11)2-Q1-; e. -C(R11)2-O-; f. -Q3-O-; g. -CCRl^-Ql-Ql-; h i. -C(Rn)2-Q2-; j. -Ci-8 alkylene-; k. -C(R11)2-Q1-CI-8 alkylene-; l. -Q3-C(R11)2-; m. -C(Rn)2-; n. -Q2-; o. -Q1-C(O)-C(R11)2-; p. -Q1-C(O)-Q3-O-; q. -Q1-C(O)-C(R11)2-Q1-; r. -Q^ R^-Q3-©-; and s. -Q1-C(R11)2-.
55. The compound of claim 54, wherein wherein R19 is hydrogen, hydroxyl, halogen, or unsubstituted alkyl, n1 is one or two, n2 is one or two, and n3 is one or two.
56. The compound of claim 55, wherein -Q1- is selected from the group consisting of wherein R19 is hydrogen, hydroxyl, fluoro, or methyl.
57. The compound of claim 54, wherein wherein n4 is one or two, n5 is one or two, and n6 is one or two.
N
58. The compound of claim 57, wherein -Q2- is selected from the group consisting of
59. T he compound of claim 54, wherein - , wherein n7 is one or two, and n8 is one or two.
60. The compound of claim 59, wherein -Q3- is selected from the group consisting of
61. The compound of claim 54, wherein each R11 is, independently, hydrogen or methyl.
62. The compound of claim 61, wherein both R11 are hydrogen; one R11 is hydrogen and one
R11 is methyl; or both R11 are methyl.
63. The compound of claim 54, wherein -Ci-s alkylene- is selected from the group consisting of -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -
CH2CH2CH2CH2CH2-,
-CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2-, and
-CH2CH2CH2CH2CH2CH2CH2CH2-.
64. The compound of claim 54, wherein the linker L is selected from
Z3 UBM indicates attachment to Z3, and indicates attachment to UBM.
65. The compound of any one of claims 2-9, 31-33, or 53-64 selected from the group consisting of (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(l-(l-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(l-(l-(5- (2,6-dioxopiperidin-3-yl)pyridin-2-yl)-4-methylpiperidine-4-carbonyl)piperidine-4- carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)- V-(3-(5-(2- aminopyrimidin-4-yl)-2-(l -(l-(l-(5-(2,6-di oxopiperi din-3 -yl)pyri din-2 -yl)piperidine-4- carbonyl)-4-methylpiperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(l-(l-(4- (2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)-4-methylpiperidine-4- carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(l- (l-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)piperidine-4- carbonyl)piperidin-4-yl)-5-(pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (5)-7V-(3-(2-(l-(l-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4- carbonyl)-4-methylpiperidine-4-carbonyl)piperidin-4-yl)-5-(pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, and (5)-7V-(3-(2-(l-(l-(l-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidine-4-carbonyl)-4-methylpiperidine-4-carbonyl)piperidin-4-yl)-5- (pyridin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide.
66. The compound of any one of claims 2, 31-33, or 53-64 selected from the group consisting of (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-(2-(4-(3-(2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-4-yl)propyl)piperazin-l-yl)acetyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)- 2-fluorophenyl)propane- 1 -sulfonamide, N-(3 -(5 -(2-aminopyrimidin-4-yl)-2-( 1 -(( 15,4r)-4-((6- ((5)-2,6-dioxopiperidin-3-yl)-3,4-dihydroisoquinolin-2(lJ7)-yl)methyl)cyclohexane-l- carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(l- (l-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperidine-4- carbonyl)piperidin-4-yl)-5-(pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-
1.3-dioxoisoindolin-5-yl)piperazin-l-yl)acetyl)-4-methylpiperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(2-(T-(2- (2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)-[l,4'-bipiperidin]-4-yl)acetyl)-4- methylpiperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)- V-(3-(5-(2- aminopyrimidin-4-yl)-2-(l-(l-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)methyl)piperidine-4-carbonyl)-4-methylpiperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-((l-(2-(6- (2,6-dioxopiperidin-3-yl)-3,4-dihydroisoquinolin-2(lJ7)-yl)acetyl)piperidin-4- yl)methyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)- V-(3-(5-(2- aminopyrimidin-4-yl)-2-(3-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)-3- azaspiro[5.5 ]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (S)-N-(3-(2- (l-(l-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperidine-4- carbonyl)piperidin-4-yl)-5-(pyridin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(2-(r-(2-(2,6-dioxopiperidin-3-yl)-
1.3-dioxoisoindolin-5-yl)-[l,4'-bipiperidin]-4-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(2-(4-(2- (2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperazin-l-yl)acetyl)piperidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4- yl)-2-(2-( 1 -( 1 -(1 -(2-(2,6-dioxopiperi din-3 -yl)- 1 ,3 -dioxoisoindolin-5-yl)piperidin-4- yl)azetidine-3-carbonyl)piperidin-4-yl)propan-2-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, 7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-((l-((17?,4r)-4-(3-(( ?)-2,6- dioxopiperi din-3 -yl)phenoxy)cy cl ohexane-l-carbonyl)piperidin-4-yl)methyl)piperi din-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4- yl)-2-(3-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)-3- azaspiro[5.5 ]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)- V-(3-(5- (2-aminopyrimidin-4-yl)-2-(l-(l-(2-(l-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)- 4-hydroxypiperidin-4-yl)acetyl)azetidin-3-yl)piperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(l-(2-(l-(5- (2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)acetyl)piperidin-4-yl)phenyl)thiazol-4- yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(4-((l- (4-(2, 6-dioxopiperi din-3 -yl)phenyl)piperidin-4-yl)methyl)piperazin-l-yl)phenyl)thi azol -4- yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(l-(2- (l-(4-((2,6-dioxopiperi din-3 -yl)amino)phenyl)piperi din-4-yl)acetyl)piperi din-4- yl)phenyl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)- V-(3-(5-(2- aminopyrimidin-4-yl)-2-(4-(l-(l-(5-(2,6-dioxopiperi din-3-yl)pyri din-2 -yl)piperidine-4- carbonyl)piperidin-4-yl)phenyl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (S)-N- (3-(5-(2-aminopyrimidin-4-yl)-2-(4-(l-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)methyl)piperidin-4-yl)phenyl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, N-(3- (5-(2-aminopyrimidin-4-yl)-2-(3-(((15,4r)-4-((5-((5)-2,6-dioxopiperidin-3-yl)pyridin-2- yl)oxy)cyclohexyl)methyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(4-(l-(4- (2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)piperazin-l-yl)phenyl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-5-(4-(9-(5-(2-aminopyrimidin-4-yl)-4-(2-fluoro-3- (propylsulfonamido)phenyl)thiazol-2-yl)-3-azaspiro[5.5]undecane-3-carbonyl)piperidin-l- yl)-7V-(2,6-dioxopiperidin-3-yl)picolinamide, 7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-(2-((5)-l- (5-((5)-2,6-dioxopiperidin-3-yl)pyridin-2-yl)pyrrolidin-3-yl)ethyl)-3-azaspiro[5.5]undecan-9- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)- 2-(l-(l-(2-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)acetyl)azetidin-3- yl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)- V-(3-(5-(2- aminopyrimidin-4-yl)-2-(3-(l -(5-(2,6-di oxopiperidin-3-yl)pyri din-2 -yl)piperidine-4- carbonyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(l-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2- yl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (5)-7V-(3-(2-(l-(l-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4- carbonyl)piperidine-4-carbonyl)piperidin-4-yl)-5-(pyridin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(l-(l-((l-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidin-4-yl)methyl)piperidine-4-carbonyl)piperidin-4-yl)-5-(2- (methylamino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (R)-N-(3 - (5-(2-aminopyrimidin-4-yl)-2-(2-(2-(l'-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)-[l,4'-bipiperidin]-4-yl)acetyl)-2-azaspiro[3.5]nonan-7-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(l-(l-(l-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidin-4-yl)-5-(pyridin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, 7V-(3-(5-(2-aminopyrimidin-4-yl)-2- (l-((l-(((15,4r)-4-(4-((5)-2,6-dioxopiperidin-3-yl)phenoxy)cyclohexyl)methyl)piperidin-4- yl)methyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-N-(3- 5-
(2-aminopyrimidin-4-yl)-2-(2-(l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)piperidine-4-carbonyl)-2-azaspiro[3.5]nonan-7-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (5)-7V-(3-(2-(l-(l-(2-(l-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4- yl)acetyl)piperidine-4-carbonyl)piperidin-4-yl)-5-(pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(2-(l-(l-(l-(5- (2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidin- 4-yl)ethyl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (R)-N-(3- 5-(2- aminopyrimidin-4-yl)-2-(2-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)piperazin-l-yl)acetyl)-2-azaspiro[3.5]nonan-7-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, ( ?)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(4-(l-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidine-4-carbonyl)piperazin-l-yl)phenyl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(l-(l-(l-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidin-4-yl)-5-(pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4- yl)-2-(l-(l-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)piperidine-4- carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamidef, (R)-N-(3- 5-(2- aminopyrimidin-4-yl)-2-(4-(4-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)methyl)piperazin-l-yl)phenyl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, S)-N- (3-(5-(2-aminopyrimidin-4-yl)-2-(l-((l-(l-(5-(2,6-dioxopiperidin-3-yl)pyri din-2- yl)piperidine-4-carbonyl)piperidin-4-yl)methyl)piperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(4-(2-(l-(5- (2, 6-dioxopiperi din-3 -yl)pyri din-2 -yl)piperi din-4-yl)acetyl)piperazin- l-yl)phenyl)thi azol-4- yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-(2-(r- (2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)-[l,4'-bipiperidin]-4-yl)acetyl)-3- azaspiro[5.5 ]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)- V-(3-(5- (2-aminopyrimidin-4-yl)-2-(l-(l-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)methyl)piperidine-4-carbonyl)-4-methylpiperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(l-(l-(l-(4-(2,6-dioxopiperidin-3- yl)phenyl)piperidine-4-carbonyl)-4-methylpiperidine-4-carbonyl)piperidin-4-yl)-5-(2- (isopropylamino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-N- (3-(5-(2-aminopyrimidin-4-yl)-2-(3-(2-(4-(2-(2, 6-dioxopiperi din-3-yl)-l,3-dioxoisoindolin-5- yl)piperazin-l-yl)acetyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, 7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-((l-((17?,4r)-4-(4-(( ?)-2,6- dioxopiperi din-3 -yl)phenoxy)cy cl ohexane-l-carbonyl)piperidin-4-yl)methyl)piperidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4- yl)-2-(2-(6-(2-(2, 6-dioxopiperi din-3-yl)-3-oxoisoindolin-5-yl)hexanoyl)-2- azaspiro[3.5]nonan-7-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, 7V-(3-(2-(l-(l- (l-(5-((5)-2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4- carbonyl)piperidin-4-yl)-5-(2-((( ?)-l-hydroxypropan-2-yl)amino)pyrimidin-4-yl)thiazol-4- yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(4-((l- (5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-l-yl)phenyl)thiazol- 4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, rac-(37?)-3 - { 6-[4-(4-{4-[5-(2-aminopyrimidin- 4-yl)-4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3-thiazol-2-yl]piperidine-l- carbonyl}piperidine-l-carbonyl)piperidin-l-yl]pyridin-3-yl}piperidine-2, 6-dione, rac-(37?)-3- {6-[4-(4-{4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-5-{2-[(propan-2- yl)amino]pyrimidin-4-yl } - 1 ,3 -thiazol-2-yl]piperidine- 1 -carbonyl } piperi dine- 1 - carbonyl)piperidin-l-yl]pyridin-3-yl}piperidine-2, 6-dione, (5)-7V-(3-(5-(2-aminopyrimidin-4- yl)-2-(l-(l-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperidine-4- carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)- V-(3-(5-(2- aminopyrimidin-4-yl)-2-(l-(l-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)methyl)piperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, ( ?)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-((l-(2-(2,6-dioxopiperidin-3-yl)-l- oxoisoindolin-5-yl)piperidin-4-yl)methyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(2-(2-(2- (2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)acetyl)-4- methylpiperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-N-(3- 5-(2- aminopyrimidin-4-yl)-2-(3-(l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)piperidine-4-carbonyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, ( ?)-7V-(3-(2-(l-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)- 2,7 -di azaspiro [3.5 ]nonan-7 -yl)acetyl)piperidin-4-yl)-5-(2-(methylamino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4- yl)-2-(3-(6-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)hexanoyl)-3- azaspiro[5.5 ]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-N-(3-(5- (2-aminopyrimidin-4-yl)-2-(l-(l-(2-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)acetyl)-4-methylpiperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(l-(l-(l-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidin-4-yl)-5-(2-
(methylamino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (R)-N-(3 - (5-(2-aminopyrimidin-4-yl)-2-(l-(l-(2-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin- 4-yl)acetyl)piperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (5)-7V-(3-(2-(l-(l-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4- carbonyl)piperidine-4-carbonyl)piperidin-4-yl)-5-(2-(isopropylamino)pyrimidin-4-yl)thiazol- 4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(5-(2-(cyclopropylamino)pyrimidin-4- yl)-2-(l-(l-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4- carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(l- (l-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)-4-methylpiperidine-4- carbonyl)piperidin-4-yl)-5-(pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, 7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-(2-( (R)-l-(4-(() )-2,6-dioxopiperidin-3- yl)phenyl)pyrrolidin-3-yl)acetyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(2-(2-(2-(2- (2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)acetyl)-2- azaspiro[3.5]nonan-7-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (R)-N-(3-(5-(2- aminopyrimidin-4-yl)-2-(l-((l-(2-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)acetyl)piperidin-4-yl)methyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, ( ?)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-
1.3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-(l-(l-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-17/-benzo[d]imidazol-4-yl)piperidine-4- carbonyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (R)-7V-(3-(2-(l-(l-((l-(4-(2, 6-dioxopiperi din-3 -yl)phenyl)piperi din-4-yl)methyl)piperi dine-4- carbonyl)piperidin-4-yl)-5-(2-(methylamino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(l-(l-(2- (2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperidin-4-yl)azetidine-3- carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-N-(3-(5-(2- aminopyrimidin-4-yl)-2-(2-(l-(l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)piperidin-4-yl)azetidine-3-carbonyl)-2-azaspiro[3.5]nonan-7-yl)thiazol-4-yl)-2- fluorophenyl)propane- 1 -sulfonamide, (S)-N-(3 -(5-(2-aminopyrimidin-4-yl)-2-(l -( 1 -(( 1 -( 1 -
(2, 6-dioxopiperi din-3 -yl)-3-methyl-2-oxo-2, 3 -dihydro- 17/-benzo[d]imidazol-4-yl)piperi din- 4-yl)methyl)piperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, ( ?)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-
1.3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)acetyl)-3-azaspiro[5.5]undecan-9- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4- yl)-2-(2-(l-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)-2,7- diazaspiro[3.5]nonan-7-yl)acetyl)piperidin-4-yl)propan-2-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, and (R)-4-((4-(5-(2-aminopyrimidin-4-yl)-4-(2-fluoro- 3 -(propylsulfonamido)phenyl)thiazol-2-yl)piperi din- l-yl)methyl)-7V-(2, 6-dioxopiperi din-3 - yl)benzamide.
67. The compound of any one of claims 2, 18-24, 31-33, or 53-64 selected from the group consisting of (R)-4-(4-((6-((4-(2-(tert-butyl)-4-(2-fluoro-3-(propylsulfonamido)phenyl)thiazol-5- yl)pyrimidin-2-yl)amino)-2-azaspiro[3.3]heptan-2-yl)methyl)piperidin-l-yl)-7V-(2,6- di oxopiperi din-3 -yl)benzamide, 7V-(3-(2-(tert-butyl)-5-(2-((2-(2-((5)-l-(5-((5)-2,6- dioxopiperidin-3-yl)pyridin-2-yl)pyrrolidin-3-yl)ethyl)-2-azaspiro[3.3]heptan-6- yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (R)-N-(3-(2- (tert-butyl)-5-(2-((2-(2-(l'-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)-[l,4'- bipiperidin]-4-yl)acetyl)-2-azaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(2-(tert-butyl)-5-(2-((2-(l-(l-(2,6- di oxopiperidin-3-yl)-3-m ethyl -2-oxo-2, 3-dihydro- l 7/-benzo[t/]imidazol -4-yl )piperidine-4- carbonyl)-2-azaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(2-(tert-butyl)-5-(2-((2-(l-(l-(2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperidin-4-yl)azetidine-3-carbonyl)-2- azaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (R)-7V-(3-(2-(tert-butyl)-5-(2-((2-(2-(2-(2-(2,6-dioxopiperi din-3 -yl)- 1,3- dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)acetyl)-2-azaspiro[3.3]heptan-6- yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (R)-N-(3-(2- (tert-butyl)-5-(2-((2-(6-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)hexanoyl)-2- azaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (R)-7V-(3-(2-(tert-butyl)-5-(2-((2-((l-((l-(4-(2,6-dioxopiperidin-3- yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)-2-azaspiro[3.3]heptan-6- yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (R)-N-(3-(2- (tert-butyl)-5-(2-((2-(2-(4-(3-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)propyl)piperazin-l-yl)acetyl)-2-azaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4- yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(2-(tert-butyl)-5-(2-((2-(l-((l-(4-(2,6- dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)-4-fluoropiperidine-4-carbonyl)-2- azaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (R)-7V-(3-(2-(tert-butyl)-5-(2-((2-((l-(l-(4-(2,6-dioxopiperidin-3- yl)phenyl)piperidine-4-carbonyl)piperidin-4-yl)methyl)-2-azaspiro[3.3]heptan-6- yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, S)-N-(3-(2- (tert-butyl)-5-(2-((r-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)- [ 1 ,4'-bipiperidin]-4-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 - sulfonamide, (R)-7V-(3-(2-(tert-butyl)-5-(2-((7-(2-(4-(4-((2,6-dioxopiperidin-3- yl)amino)phenyl)piperidin-l-yl)acetyl)-7-azaspiro[3.5]nonan-2-yl)amino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, 7V-(3-(2-(tert-butyl)-5-(2-((7- (((15,4r)-4-(4-((5)-2,6-dioxopiperidin-3-yl)phenoxy)cyclohexyl)methyl)-7- azaspiro[3.5]nonan-2-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (R)-7V-(3-(2-(tert-butyl)-5-(2-((7-((l-(2-(2,6-dioxopiperidin-3-yl)-l-oxo-l,2- dihydroisoquinolin-6-yl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)amino)pyrimidin- 4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(2-(tert-butyl)-5-(2-((7-
((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2- yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, and (R)-N-(3- (2-(tert-butyl)-5-(2-((7-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperazin- l-yl)acetyl)-7-azaspiro[3.5]nonan-2-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluoropheny l)prop ane- 1 - sulfonami de .
68. The compound of any one of claims 2, 31-33, or 53-64 selected from the group consisting of (5)-7V-(3-(2-(tert-butyl)-5-(2-((4-(l-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidin-4- yl)methyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (R)-7V-(3-(2-(tert-butyl)-5-(2-((4-(l-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-5-yl)oxy)acetyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(2-(tert-butyl)-5-(2-((4-(l-(2-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)oxy)acetyl)piperidin-4- yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (R)-N- (3-(2-(te/7-butyl)-5-(2-((4-(l-(2-(4-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperazin-l- yl)acetyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, 7V-(3-(2-(tert-butyl)-5-(2-((4-(l-(2-((5)-l-(5-((, )-2,6-dioxopiperidin-3- yl)pyridin-2-yl)pyrrolidin-3-yl)ethyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4- yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-4-(4-((4-(4-((4-(2-(tert-butyl)-4-(2-fluoro-3- (propylsulfonamido)phenyl)thiazol-5-yl)pyrimidin-2-yl)amino)phenyl)piperidin-l- yl)methyl)piperi din- l-yl)-7V-(2,6-dioxopiperi din-3 -yl)benzamide, (R)-5-(4-((4-(4-((4-(2-(7ert- butyl)-4-(2-fluoro-3-(propylsulfonamido)phenyl)thiazol-5-yl)pyrimidin-2- yl)amino)phenyl)piperidin-l-yl)methyl)piperidin-l-yl)-7V-(2,6-dioxopiperidin-3- yl)picolinamide, 7V-(3-(2-(tert-butyl)-5-(2-((4-(l-(((15,4r)-4-((5-((5)-2,6-dioxopiperidin-3- yl)pyridin-2-yl)oxy)cyclohexyl)methyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol- 4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(tert-butyl)-5-(2-((4-(l-((l-(4-(2,6- dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)amino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, 7V-(3-(2-(tert-butyl)-5-(2-((4-(l-(2- ((5)-l-(4-((5)-2,6-dioxopiperidin-3-yl)phenyl)pyrrolidin-3-yl)acetyl)piperidin-4- yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, 7V-(3- (2-(tert-butyl)-5-(2-((4-(l-(2-( (R)-l-(4-((5)-2,6-dioxopiperidin-3-yl)phenyl)pyrrolidin-3- yl)acetyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, 7V-(3-(2-(tert-butyl)-5-(2-((4-(l-( (R)-l-(5-((, )-2,6-dioxopiperidin-3- yl)pyridin-2-yl)pyrrolidine-3-carbonyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4- yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(terZ-butyl)-5-(2-((4-(l-(l-(4-(2,6- dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)piperidin-4- yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (R)-N- (3-(2-(terZ-butyl)-5-(2-((4-(l-(2-(l'-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)- [l,4'-bipiperidin]-4-yl)acetyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(tert-butyl)-5-(2-((4-(l-(l-(5-(2,6- dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)piperidin-4- yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, N-(3- (2-(tert-butyl)-5-(2-((4-(l-(2-((5)-l-(l-( (R)-2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-l/Z-benzo[ ]imidazol-5-yl)pyrrolidin-3-yl)acetyl)piperidin-4- yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (R)-N- (3-(2-(terZ-butyl)-5-(2-((4-(l-(l-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro- l/Z-benzo[ ]imidazol-4-yl)piperidine-4-carbonyl)piperidin-4-yl)phenyl)amino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(terZ-butyl)-5-(2-((4-(l- (l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)azetidine-3-carbonyl)piperidin-4- yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (R)-N- (3-(2-(terZ-butyl)-5-(2-((4-(l-(l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)piperidine-4-carbonyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(2-(terZ-butyl)-5-(2-((4-(l-(2-(2-(2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7- yl)acetyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (R)-7V-(3-(2-(tert-butyl)-5-(2-((4-(l-(6-(2-(2,6-dioxopiperidin-3-yl)-3- oxoisoindolin-5-yl)hexanoyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(2-(terZ-butyl)-5-(2-((4-(l-(2-(4-(2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperazin-l-yl)acetyl)piperidin-4- yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (S)-5- (4-((4-(((4-(2-(tert-butyl)-4-(2-fluoro-3-(propylsulfonamido)phenyl)thiazol-5-yl)pyrimidin-2- yl)amino)methyl)piperidin- 1 -yl)methyl)piperidin- 1 -yl)-7V-(2,6-dioxopiperi din-3 - yl)picolinamide, (5)-5-(4-((4-(l-((4-(2-(tert-butyl)-4-(2-fluoro-3-
(propylsulfonamido)phenyl)thiazol-5-yl)pyrimidin-2-yl)amino)-2-methylpropan-2- yl)piperi din- l-yl)methyl)piperi din- l-yl)-7V-(2,6-dioxopiperi din-3 -yl)picolinamide, (R)-N-(3- (2-(tert-butyl)-5-(2-(((l-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)methyl)piperidin-4-yl)methyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (R)-7V-(3-(2-(terZ-butyl)-5-(2-((2-(l-((l-(4-(2,6-dioxopiperidin-3- yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-2-methylpropyl)amino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, 5-(4-(( (R)-3-(((4-(2-(tert-butyl)-4-(2- fluoro-3-(propylsulfonamido)phenyl)thiazol-5-yl)pyrimidin-2-yl)amino)methyl)pyrrolidin-l- yl)methyl)piperi din- l-yl)-7V-((5)-2,6-dioxopiperi din-3 -yl)picolinamide, 7V-(3-(2-(tert-butyl)- 5-(2-(((lr,4r)-4-((4-((l-(4-((5)-2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)methyl)piperazin-l-yl)methyl)cyclohexyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, 7V-(3-(2-( e^butyl)-5-(2-(((l ,4 )-4-(4-(l-(5-((5')-2,6- dioxopiperi din-3 -yl)pyri din-2-yl)piperi dine-4-carbonyl)piperazin- 1- yl)cyclohexyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, N- (3-(2-(terZ-butyl)-5-(2-(((lr,4r)-4-(4-(l-(5-((5)-2,6-dioxopiperidin-3-yl)pyridin-2- yl)piperidine-4-carbonyl)piperazin-l-yl)cyclohexyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, 7V-(3-(2-(terZ-butyl)-5-(2-(((lr,4r)-4-(4-((l-(5-((5)-2,6- dioxopiperi din-3 -yl)pyri din-2-yl)piperi din-4-yl)methyl)piperazin- 1- yl)cyclohexyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, N- (3-(2-(terZ-butyl)-5-(2-(((15,45)-4-(4-((l-(5-((5)-2,6-dioxopiperidin-3-yl)pyridin-2- yl)piperidin-4-yl)methyl)piperazin-l-yl)cyclohexyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (37?)-3-{4-[4-({4-[6-({4-[2-tert-butyl-4-(3-
{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3-thiazol-5-yl]pyrimidin-2- yl } amino)pyri din-3 -yl]piperazin- 1 -yl }methyl)piperidin- 1 -yl]phenyl }piperidine-2, 6-dione, (35)-3-{4-[4-({4-[6-({4-[2-tert-butyl-4-(3-{[ethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)-l,3-thiazol-5-yl]pyrimidin-2-yl}amino)pyridin-3-yl]piperazin-l- yl}methyl)piperi din- l-yl]phenyl}piperidine-2, 6-dione, rac-(35)-3-{6-[4-({4-[6-({4-[2-tert- butyl-4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3-thiazol-5-yl]pyrimidin-2- yl } amino)pyri din-3 -yl]piperazin- 1 -yl }methyl)piperidin- 1 -yl]pyri din-3 -yl }piperidine-2,6- dione, rac-(3 S)-3 -(2- { [( 1 r,4r)-4- {4-[6-({4-[2-tert-butyl-4-(3 -
{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3-thiazol-5-yl]pyrimidin-2- yl }amino)pyri din-3 -yl]piperazine-l -carbonyl }cy cl ohexyl]methyl}- 1,2, 3,4- tetrahydroisoquinolin-6-yl)piperidine-2, 6-dione, rac-(3S)-3-(2-{[(lr,4r)-4-{4-[6-({4-[2-tert- butyl-4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3-thiazol-5-yl]pyrimidin-2- yl }amino)pyri din-3 -yl]piperazine-l -carbonyl }cy cl ohexyl]methyl}- 1,2, 3,4- tetrahydroisoquinolin-7-yl)piperidine-2, 6-dione, (R)-7V-(3-(2-(terZ-butyl)-5-(2-((2-(2-(4-(4-
((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-l-yl)acetyl)-l,2,3,4-tetrahydroisoquinolin- 6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, ( ?)-5-(4-(6- ((4-(2-(tert-butyl)-4-(2-fluoro-3-(propylsulfonamido)phenyl)thiazol-5-yl)pyrimidin-2- yl)amino)-l,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidin-l-yl)-7V-(2,6-dioxopiperidin-3- yl)picolinamide, V-(3-(2-(ferZ-butyl)-5-(2-((2-( (R)-l-(5-((5)-2,6-dioxopiperidin-3-yl)pyridin-
2-yl)pyrrolidine-3-carbonyl)-l,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(terZ-butyl)-5-(2-((2-(2- (4-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperazin-l-yl)acetyl)-l, 2,3,4- tetrahydroisoquinolin-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (5)-7V-(3-(2-(tert-butyl)-5-(2-((l-((l-(2-(6-(2,6-dioxopiperidin-3-yl)-3,4- dihydroisoquinolin-2(U7)-yl)acetyl)piperidin-4-yl)methyl)-lJH-pyrazol-4- yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, N-(3-(2-(tert- butyl)-5-(2-((l-((l-((15,4r)-4-(4-((5)-2,6-dioxopiperidin-3-yl)phenoxy)cyclohexane-l- carbonyl)piperidin-4-yl)methyl)-lJH-pyrazol-4-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, 7V-(3-(2-(ter -butyl)-5-(2-((l-((l-((15',4r)-4-((5-((, )-2, 6- dioxopiperi din-3 -yl)pyridin-2-yl)oxy)cy cl ohexane-l-carbonyl)piperidin-4-yl)methyl)- 1H- pyrazol-4-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (R)- 7V-(3-(2-(terZ-butyl)-5-(2-((l-((l-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin- l-yl)acetyl)piperidin-4-yl)methyl)-lJH-pyrazol-4-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-5-(4-(4-((4-((4-(2-(tert-butyl)-4-(2-fluoro-3- (propylsulfonamido)phenyl)thiazol-5-yl)pyrimidin-2-yl)amino)-l/Z-pyrazol-l- yl)methyl)piperi dine- l-carbonyl)piperi din- l-yl)-7V-(2,6-dioxopiperi din-3 -yl)picolinamide, N- (3-(2-(terZ-butyl)-5-(2-((l-((l-( (R)-l-(5-((5)-2,6-dioxopiperidin-3-yl)pyridin-2-yl)pyrrolidine-
3-carbonyl)piperidin-4-yl)methyl)-lJH-pyrazol-4-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(tert-butyl)-5-(2-((l-((l-(2-(4-(4-(2,6- dioxopiperidin-3-yl)pyridin-2-yl)piperazin-l-yl)acetyl)piperidin-4-yl)methyl)-lJH-pyrazol-4- yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, N-(3-(2-(tert- butyl)-5-(2-((l-((l-(2-((5)-l-(4-((5)-2,6-dioxopiperidin-3-yl)phenyl)pyrrolidin-3- yl)acetyl)piperidin-4-yl)methyl)-lJH-pyrazol-4-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, 7V-(3-(2-(Zert-butyl)-5-(2-((l-((l-(2-( (R)-l-(4-((5)-2,6- dioxopiperi din-3 -yl)phenyl)pyrrolidin-3-yl)acetyl)piperidin-4-yl)m ethyl)- l/f-pyrazol-4- yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, N-(3-(2-(tert- butyl)-5 -(2-(( 1 -( 1 -(( 15,4r)-4-(4-((5)-2, 6-dioxopiperi din-3 -yl)phenoxy)cy clohexane- 1 - carbonyl)piperidin-4-yl)-lJH-pyrazol-4-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, jV-(3-(2-(tert-butyl)-5-(2-((l-(l-((15,4r)-4-((5-((5)-2,6- dioxopiperidin-3-yl)pyridin-2-yl)oxy)cyclohexane-l-carbonyl)piperidin-4-yl)-lJH-pyrazol-4- yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (7?)-7V-(3-(2- (tert-butyl)-5-(2-((l-(l-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-l- yl)acetyl)piperidin-4-yl)-lJH-pyrazol-4-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-5-(4-(4-(4-((4-(2-(tert-butyl)-4-(2-fluoro-3- (propylsulfonamido)phenyl)thiazol-5-yl)pyrimidin-2-yl)amino)-l/Z-pyrazol-l-yl)piperidine- l-carbonyl)piperi din- l-yl)-7V-(2,6-dioxopiperi din-3 -yl)picolinamide, 7V-(3-(2-(tert-butyl)-5- (2-((l-(l-( (R)-l-(5-((5)-2,6-dioxopiperidin-3-yl)pyridin-2-yl)pyrrolidine-3- carbonyl)piperidin-4-yl)-lJH-pyrazol-4-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, 7V-(3-(2-(tert-butyl)-5-(2-((l-(l-(2-((5)-l-(4-((5)-2,6- dioxopiperi din-3 -yl)phenyl)pyrrolidin-3 -yl)acetyl)piperi din-4-yl)- l/f-pyrazol-4- yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (S)-N-(3-(2- (tert-butyl)-5-(2-((3-(l-(2-(6-(2,6-dioxopiperidin-3-yl)-3,4-dihydroisoquinolin-2(lJ7)- yl)acetyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (R)-7V-(3-(2-(terZ-butyl)-5-(2-((3-(l-(2-(4-(4-((2,6-dioxopiperidin-3- yl)amino)phenyl)piperidin-l-yl)acetyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4- yl)-2-fluorophenyl)propane- 1 -sulfonamide, N-(3 -(2-(terZ-butyl)-5 -(2-((3 -( 1 -((R)- 1 -(5 -((5)-
2,6-dioxopiperidin-3-yl)pyridin-2-yl)pyrrolidine-3-carbonyl)piperidin-4- yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (S)-N- (3-(2-(7erZ-butyl)-5-(2-((3-((l-(2-(6-(2,6-dioxopiperidin-3-yl)-3,4-dihydroisoquinolin-2(lJ7)- yl)acetyl)piperidin-4-yl)oxy)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane- 1 -sulfonamide, (S)-N-(3 -(2-(terZ-butyl)-5 -(2-((3 -(( 1 -( 1 -(4-(2, 6- dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)piperidin-4- yl)oxy)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (S)-N-(3 -(2-(te/7-buty 1 )-5 -(2-((3 -(( 1 -( 1 -(3 -(2, 6-dioxopiperi din-3 -yl)phenyl)piperidine-4- carbonyl)piperidin-4-yl)oxy)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, jV-(3-(2-(tert-butyl)-5-(2-((3-((l-((15,4r)-4-(4-((5)-2,6- dioxopiperi din-3 -yl)phenoxy)cy cl ohexane-1 -carbonyl)piperi din-4- yl)oxy)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, N- (3-(2-(terZ-butyl)-5-(2-((3-((l-((15,4r)-4-((5-((,S)-2,6-dioxopiperidin-3-yl)pyridin-2- yl)oxy)cy cl ohexane-1 -carbonyl)piperidin-4-yl)oxy)phenyl)amino)pyrimidin-4-yl)thi azol -4- yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(2-(terZ-butyl)-5-(2-((3-((l-(2-(4-(4- ((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-l-yl)acetyl)piperidin-4- yl)oxy)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (R)-5-(4-(4-(3-((4-(2-(terZ-butyl)-4-(2-fluoro-3-(propylsulfonamido)phenyl)thiazol-5- yl)pyrimidin-2-yl)amino)phenoxy)piperidine-l-carbonyl)piperidin-l-yl)-7V-(2,6- dioxopiperidin-3-yl)picolinamide, 7V-(3-(2-(tert-butyl)-5-(2-((3-((l-( (R)-l-(5-((5)-2,6- dioxopiperidin-3-yl)pyridin-2-yl)pyrrolidine-3-carbonyl)piperidin-4- yl)oxy)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-7V-(3-(2-(tert-butyl)-5-(2-((3-((l-(2-(4-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperazin- l-yl)acetyl)piperidin-4-yl)oxy)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, 7V-(3-(2-(terZ-butyl)-5-(2-((3-((l-(2-((5)-l-(4-((5)-2,6- dioxopiperidin-3-yl)phenyl)pyrrolidin-3-yl)acetyl)piperidin-4- yl)oxy)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, 7V- (3-(2-(terZ-butyl)-5-(2-((3-((l-(2-( (R)-l-(4-((5)-2,6-dioxopiperidin-3-yl)phenyl)pyrrolidin-3- yl)acetyl)piperidin-4-yl)oxy)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(terZ-butyl)-5-(2-((4-(l-((l-(4-(2,6- dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)amino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(2-(terZ-butyl)-5-(2-((4-(l- ((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperidin-4- yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (S)-N- (3-(2-(terZ-butyl)-5-(2-((4-(4-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)methyl)piperazin-l-yl)-3-fluorophenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(2-(terZ-butyl)-5-(2-((4-(4-((l-(4-(2,6- dioxopiperi din-3 -yl)phenyl)piperi din-4-yl)m ethyl)piperazin- 1 -yl)-3- fluorophenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (25,47?)-l-((5)-2-(5-(4-(4-((4-(2-(terZ-butyl)-4-(2-fluoro-3- (propylsulfonamido)phenyl)thiazol-5-yl)pyrimidin-2-yl)amino)phenyl)piperidin-l-yl)-5- oxopentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-7V-((5)-l-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide, (R)-7V-(3-(2-(terZ-butyl)-5-(2-((2-((l-(2-(2,6- dioxopiperi din-3-yl)- 1 -oxo-1, 2-dihydroisoquinolin-6-yl)piperidin-4-yl)methyl)-l, 2,3,4- tetrahydroisoquinolin-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, 7V-(3-(2-(terZ-butyl)-5-(2-((l-((l-(((15,4r)-4-(4-((5)-2,6-dioxopiperidin-3- yl)phenoxy)cyclohexyl)methyl)piperidin-4-yl)methyl)-lJH-pyrazol-4-yl)amino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (R)-N-(3 -(2-( ert-butyl)-5 -(2-(( 1 -(( 1 - ((l-(2-(2,6-dioxopiperidin-3-yl)-l-oxo-l,2-dihydroisoquinolin-6-yl)piperidin-4- yl )methyl)piperidin-4-yl)methyl)- l//-pyrazol -4-yl )amino)pyrimidin-4-yl )thiazol -4-yl )-2- fluorophenyl)propane-l -sulfonamide, (R)-5-(4-((4-((4-((4-(2-(terZ-butyl)-4-(2-fluoro-3- (propylsulfonamido)phenyl)thiazol-5-yl)pyrimidin-2-yl)amino)-l//-pyrazol-l- yl)methyl)piperi din- l-yl)methyl)piperi din- l-yl)-7V-(2,6-dioxopiperi din-3 -yl)picolinamide, N- (3 -(2-(terZ-butyl)-5 -(2-(( 1 -(( 1 -(2-((R)~ 1 -(5 -((5)-2, 6-dioxopiperi din-3 -yl)pyridin-2- yl)pyrrolidin-3-yl)ethyl)piperidin-4-yl)methyl)-lJ7-pyrazol-4-yl)amino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(2-(terZ-butyl)-5-(2-((l-(l- ((l-(2-(2,6-dioxopiperidin-3-yl)-l-oxo-l,2-dihydroisoquinolin-6-yl)piperidin-4- yl)methyl)piperidin-4-yl)-lJH-pyrazol-4-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-5-(4-((4-(4-((4-(2-(tert-butyl)-4-(2-fluoro-3- (propylsulfonamido)phenyl)thiazol-5-yl)pyrimidin-2-yl)amino)-l/Z-pyrazol-l-yl)piperidin-l- yl)methyl)piperi din- l-yl)-7V-(2, 6-dioxopiperi din-3 -yl)picolinamide, 7V-(3-(2-(tert-butyl)-5-(2- ((l-(l-(2-( (R)-l-(5-((5)-2,6-dioxopiperidin-3-yl)pyridin-2-yl)pyrrolidin-3-yl)ethyl)piperidin- 4-yl)-lJH-pyrazol-4-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, 7V-(3-(2-(tert-butyl)-5-(2-((l-(l-(2-((5)-l-(5-((,S)-2,6-dioxopiperidin-3- yl)pyridin-2-yl)pyrrolidin-3-yl)ethyl)piperidin-4-yl)-lJH-pyrazol-4-yl)amino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(2-(terZ-butyl)-5-(2-((3-(l- ((l-(2-(2,6-dioxopiperidin-3-yl)-l-oxo-l,2-dihydroisoquinolin-6-yl)piperidin-4- yl)methyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, N-(3 -(2-(terZ-butyl)-5 -(2-((3 -(1 -(2-((R)~ 1 -(5 -((5)-2, 6-dioxopiperi din-3 - yl)pyridin-2-yl)pyrrolidin-3-yl)ethyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4- yl)-2-fluorophenyl)propane- 1 -sulfonamide, N-(3 -(2-(terZ-butyl)-5 -(2-((3 -( 1 -(2-((5)- 1 -(5 -((5)- 2,6-dioxopiperidin-3-yl)pyridin-2-yl)pyrrolidin-3-yl)ethyl)piperidin-4- yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (S)-N- (3-(2-(terZ-butyl)-5-(2-((3-(l-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)-4-methylpiperidin- 4-yl)methyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, 7V-(3-(2-(terZ-butyl)-5-(2-((3-((l-(((15,4r)-4-(4-((5)-2, 6- dioxopiperidin-3-yl)phenoxy)cyclohexyl)methyl)piperidin-4- yl)oxy)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (R)-7V-(3-(2-(tert-butyl)-5-(2-((3-((l-((l-(2-(2,6-dioxopiperidin-3-yl)-l-oxo-l,2- dihydroisoquinolin-6-yl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)phenyl)amino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, 7V-(3-(2-(terZ-butyl)-5-(2-((3-((l-(2- ( (R)-l-(5-((5)-2,6-dioxopiperidin-3-yl)pyridin-2-yl)pyrrolidin-3-yl)ethyl)piperidin-4- yl)oxy)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, N- (3-(2-(terZ-butyl)-5-(2-((3-((l-(2-((5 -l-(5-((5)-2,6-dioxopiperidin-3-yl)pyridin-2- yl)pyrrolidin-3-yl)ethyl)piperidin-4-yl)oxy)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane- 1 -sulfonamide, (S)-N-(3 -(2-(tert-butyl)-5 -(2-((3 - (( 1 - (( 1 - (5 - (2 , 6- dioxopiperidin-3-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)methyl)piperidin-4- yl)oxy)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (R)-5-(4-((4-(4-((4-(2-(tert-butyl)-4-(2-fluoro-3-(propylsulfonamido)phenyl)thiazol-5- yl)pyrimidin-2-yl)amino)-lZZ-pyrazol-l-yl)piperidin-l-yl)methyl)piperidin-l-yl)-7V-(2,6- dioxopiperidin-3-yl)picolinamide, (R)-5-(4-((4-((4-((4-(2-(tert-butyl)-4-(2-fluoro-3-
(propylsulfonamido)phenyl)thiazol-5-yl)pyrimidin-2-yl)amino)-l/Z-pyrazol-l- yl)methyl)piperi din- l-yl)methyl)piperi din- l-yl)-7V-(2,6-dioxopiperi din-3 -yl)picolinamide, (5)-7V-(3-(2-(tert-butyl)-5-(2-((4-(4-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4- carbonyl)piperazin-l-yl)-3-fluorophenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(5-(2-((4-(l-((l-(4-(2,6-dioxopiperidin-3- yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)-2- methylthiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-((4-(l-((l-(4-(2,6- dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)amino)pyrimidin-4- yl)-2-methylthiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-7V-(3-(5-(2-((5-(4-((l- (5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-l-yl)pyridin-2- yl)amino)pyrimidin-4-yl)-2-methylthiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)- 7V-(3-(5-(2-((5-(4-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperazin-l- yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylthiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, ( ?)-7V-(3-(5-(2-((5-(4-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)methyl)piperazin-l-yl)pyri din-2 -yl)amino)pyrimi din-4-yl)-2-methylthi azol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(2-(terZ-butyl)-5-(2-((4-(4-((l-(4-(2,6- dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperazin-l-yl)phenyl)amino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(terZ-butyl)-5-(2-((4-(4- ((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperazin-l- yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (S)-N- (3-(2-(terZ-butyl)-5-(2-((4-(4-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4- carbonyl)piperazin-l-yl)-3-fluorophenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, rac-(37?)-3-[6-(4-{4-[6-({4-[2-tert-butyl-4-(3- {[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3-thiazol-5-yl]pyrimidin-2- yl}amino)pyridin-3-yl]piperazine-l-carbonyl}piperidin-l-yl)pyridin-3-yl]piperidine-2,6- dione, (5)-7V-(3-(5-(2-((4-(l-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4- carbonyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)-2-methylthiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, 7V-(3-(2-(tert-butyl)-5-(2-((4-(4-( (R)-l-(5-( (R)-2,6- dioxopiperi din-3 -yl)pyridin-2-yl)pyrrolidine-3 -carbonyl)piperazin- 1 -y l)-3 - fluorophenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (R)- 7V-(3-(5-(2-((4-(l-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)methyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)-2-methylthiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, 7V-(3-(2-(tert-butyl)-5-(2-((4-(4-( (R)-l-(5-( (R)-2,6- dioxopiperi din-3 -yl)pyridin-2-yl)pyrrolidine-3 -carbonyl)piperazin- 1 -y l)-3 - fluorophenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, rac- (35)-3-[6-(3-{4-[6-({4-[2-tert-butyl-4-(3-{ [ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)- l,3-thiazol-5-yl]pyrimidin-2-yl}amino)pyridin-3-yl]piperazine-l-carbonyl}azetidin-l- yl)pyri din-3 -yl]piperidine-2, 6-dione, (5)-7V-(3-(2-(tert-butyl)-5-(2-((4-(4-(2-(l-(4-((2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)piperazin-l-yl)- 3 -fluorophenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, ( ?)-7V-(3-(2-(tert-butyl)-5-(2-((4-(4-(2-(6-(2,6-dioxopiperidin-3-yl)-3,4-dihydroisoquinolin- 2(U7)-yl)acetyl)piperazin-l-yl)-3-fluorophenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, 7V-(3-(2-(tert-butyl)-5-(2-((4-(4-((15,4r)-4-((5-((5)-2,6- dioxopiperi din-3 -yl)pyridin-2-yl)oxy)cy cl ohexane-1 -carbonyl)piperazin- l-yl)-3- fluorophenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (R)- 7V-(3-(2-(terZ-butyl)-5-(2-((4-(4-(2-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)acetyl)piperazin-l-yl)-3-fluorophenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(terZ-butyl)-5-(2-((4-(4-((l-(5-(2,6- di oxopiperi din-3 -yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin- 1- yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (S)-N- (3-(2-(terZ-butyl)-5-(2-((4-(4-(2-(l-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4- yl)acetyl)piperazin-l-yl)-3-fluorophenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(terZ-butyl)-5-(2-((4-(4-((l-(5-(2,6- di oxopiperi din-3 -yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin- l-yl)-3- fluorophenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (5)- 7V-(3-(5-(2-((4-(l-(2-(l-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4- yl)acetyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)-2-methylthiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, rac-(35)-3-{6-[4-({4-[6-({4-[4-(3-
{ [ethyl (methyl)sulfamoyl]amino}-2-fluorophenyl)-2-methyl-l, 3-thi azol-5-yl]pyrimidin-2- yl } amino)pyri din-3 -yl]piperazin- 1 -yl }methyl)piperidin- 1 -yl]pyri din-3 -yl }piperidine-2,6- dione, rac-(35)-3-[6-(4-{4-[6-({4-[2-tert-butyl-4-(3-{ [ethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)-l, 3-thi azol-5-yl]pyrimidin-2-yl}amino)pyridin-3-yl]piperazine-l -carbonyl }-4- methylpiperi din- l-yl)pyri din-3 -yl]piperidine-2, 6-dione, (37?)-3-{4-[4-({4-[6-({4-[4-(3-
{ [ethyl (methyl)sulfamoyl]amino}-2-fluorophenyl)-2-methyl-l, 3-thi azol-5-yl]pyrimidin-2- yl } amino)pyri din-3 -yl]piperazin- 1 -yl }methyl)piperidin- 1 -yl]phenyl }piperidine-2, 6-dione, rac-(35)-3-[6-(4-{4-[6-({4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fhrorophenyl)-2- methyl-1, 3-thi azol-5-yl]pyrimidin-2-yl}amino)pyridin-3-yl]piperazine-l -carbonyl Jpiperi din- l-yl)pyri din-3 -yl]piperidine-2, 6-dione, rac-(37?)-3-{6-[4-(2-{4-[6-({4-[4-(3-
{ [ethyl (methyl)sulfamoyl]amino}-2-fluorophenyl)-2-methyl-l, 3-thi azol-5-yl]pyrimidin-2- yl}amino)pyridin-3-yl]piperazin-l-yl}-2-oxoethyl)piperidin-l-yl]pyridin-3-yl}piperidine-2,6- dione, (5)-7V-(3-(2-(tert-butyl)-5-(2-((4-(4-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine- 4-carbonyl)piperazin-l-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(tert-butyl)-5-(2-((4-(l-(l-(4-(2,6- dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)piperidin-4-yl)phenyl)amino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, rac-(35)-3-[4-(4-{4-[6-({4-[2-tert- butyl-4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l, 3-thi azol-5-yl]pyrimidin-2- yl}amino)pyridin-3-yl]piperazine-l-carbonyl}piperidin-l-yl)phenyl]piperidine-2, 6-dione, ( ?)-7V-(3-(2-(tert-butyl)-5-(2-((4-(l-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)methyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-
1 -sulfonamide, rac-(35)-3-{6-[4-({4-[6-({4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)-2 -methyl- 1 ,3 -thiazol-5-yl]pyrimidin-2-yl } amino)pyri din-3 -yl]piperazin- 1 - yl}methyl)-4-methylpiperidin-l-yl]pyridin-3-yl}piperidine-2, 6-dione, rac-(35)-3-{4-[4-({4- [6-({4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-2 -methyl-1, 3-thi azol-5- yl]pyrimidin-2-yl}amino)pyridin-3-yl]piperazin-l-yl}methyl)-4-fluoropiperidin-l- yl]phenyl}piperidine-2, 6-dione, (5 -7V-(3-(5-(2-((4-(4-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-
2-yl)-4-methylpiperidin-4-yl)methyl)piperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2- methylthiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(5-(2-((4-(4-((l-(4-(2,6- dioxopiperi din-3 -yl)phenyl)-4-fluoropiperidin-4-yl)methyl)piperazin-l- yl)phenyl)amino)pyrimidin-4-yl)-2-methylthiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, rac-(37?)-3-{6-[6-({4-[6-({4-[2-tert-butyl-4-(3-
{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3-thiazol-5-yl]pyrimidin-2- yl}amino)pyridin-3-yl]piperazin-l-yl}methyl)-2-azaspiro[3.3]heptan-2-yl]pyridin-3- yl}piperidine-2, 6-dione, (37?)-3-{6-[4-({4-[6-({4-[2-tert-butyl-4-(3-
{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3-thiazol-5-yl]pyrimidin-2- yl } amino)pyri din-3 -yl]piperazin- 1 -yl }methyl)piperidin- 1 -yl]pyri din-3 -yl }piperidine-2,6- dione, rac-(37?)-3-[2-(2-{4-[4-({4-[2-terZ-butyl-4-(3-{[ethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)-l,3-thiazol-5-yl]pyrimidin-2-yl}amino)-2-fluorophenyl]piperazin-l-yl}-2- oxoethyl)-l,2,3,4-tetrahydroisoquinolin-6-yl]piperidine-2,6-dione, and (37?)-3-{6-[4-({4-[6- ({4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-2-methyl-l,3-thiazol-5- yl]pyrimidin-2-yl}amino)pyridin-3-yl]piperazin-l-yl}methyl)piperidin-l-yl]pyridin-3- yl}piperidine-2, 6-dione.
69. The compound of any one of claims 2, 10-17, 31-33, or 53-64 selected from the group consisting of (5)-7V-(3-(l-(4-(4-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)methyl)piperazin-l-yl)phenyl)-3-(pyridin-4-yl)-17/-pyrazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, ( ?)-7V-(3-(l-(4-(4-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)methyl)piperazin-l-yl)phenyl)-3-(pyridin-4-yl)-17/-pyrazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, and (5)-7V-(3-(l-(4-(4-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin- 4-yl)methyl)piperazin-l-yl)phenyl)-3-(pyridin-4-yl)-17/-pyrazol-4-yl)-2- fluoropheny l)prop ane- 1 - sulfonami de .
70. The compound of any one of claims 2, 31-33, or 53-64 selected from the group consisting of ( ?)-7V-(3-(l-(4-(4-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4- carbonyl)piperazine-l-carbonyl)phenyl)-3-(pyridin-4-yl)-177-pyrazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(l-(4-(4-((l-(4-(2,6-dioxopiperidin-3- yl)phenyl)piperidin-4-yl)methyl)piperazine-l-carbonyl)phenyl)-3-(pyridin-4-yl)-17/-pyrazol- 4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(l-(4-(4-(l-(4-(2,6-dioxopiperidin-3- yl)phenyl)piperidine-4-carbonyl)piperazin-l-yl)phenyl)-3-(pyridin-4-yl)-17/-pyrazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(l-(4-((l-(l-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)oxy)phenyl)-3-(pyridin-4-yl)-177- pyrazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(l-(4-(4-((l-(5-(2,6- dioxopiperidin-3-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)methyl)piperazin-l-yl)phenyl)-3- (pyridin-4-yl)-l//-pyrazol-4-yl)-2-fluorophenyl)propane- l -sulfonamide, (R)-7V-(3-(l-(4-(4- ((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperazine-l-carbonyl)phenyl)-
3 -(pyridin-4-yl)- lZ7-pyrazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (S)-N-(3 -( 1 -(1 -( 1 - (l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidin-
4-yl)-3-(pyridin-4-yl)-lJH-pyrazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(l-
(4-(4-((l-(4-(2,6-dioxopiperidin-3-yl)-3-fluorophenyl)piperidin-4-yl)methyl)piperazin-l- yl)phenyl)-3-(pyridin-4-yl)-lJH-pyrazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (S)-N- (3-(l-(4-(l-((l-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin- 4-yl)phenyl)-3-(pyridin-4-yl)-lJH-pyrazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)- 7V-(3-(l-(l-(l-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4- carbonyl)piperidin-4-yl)-3-(pyridin-4-yl)-lJH-pyrazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (5)-7V-(3-(l-(4-(4-((l-(4-(2,6-dioxopiperi din-3 -yl)-2-fluorophenyl)piperi din-4- yl)methyl)piperazin-l-yl)phenyl)-3-(pyridin-4-yl)-lJH-pyrazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (5)-7V-(3-(l-(6-(4-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)methyl)piperazin-l-yl)pyri din-3 -yl)-3-(pyri din-4-yl)- 1/7-pyrazol -4-yl)-2- fluorophenyl)propane-l -sulfonamide, (7?)-7V-(3-(l-(4-(4-(2-(l-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidin-4-yl)acetyl)piperazine-l-carbonyl)phenyl)-3-(pyridin-4-yl)-lJH- pyrazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (S)-N-(3 -( 1 - ( 1 - ( 1 -(( 1 - ( 5 -(2 , 6 - dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperidine-4-carbonyl)piperidin-4-yl)- 3 -(pyridin-d-y^-l/f-pyrazol-d-y^-Z-fluoropheny^propane-l -sulfonamide, (5)-7V-(3-(l-(4-(4- ((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-l-yl)phenyl)-3- (pyridin-4-yl)-lJ7-pyrazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-7V-(3-(l-(6-(4- ((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-l-yl)pyridin-3- yl)-3-(pyridin-4-yl)-lJH-pyrazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(l-(4- (l-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)-3- (pyridin-4-yl)- 1 J7-pyrazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (S)-N-(3 -(1 -(4-( 1 -
((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)-3- (pyridin-4-yl)- 1 J7-pyrazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (S)-N-(3 -(1 -(4-( 1 -
((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)-3- (pyridin-4-yl)-lJ7-pyrazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-7V-(3-(l-(4-(4- ((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperazin-l-yl)phenyl)-3- (pyridin-4-yl)- I //-py razol -4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (S)-N-(3 -(1-(1-(1-(1- (5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)-4-methylpiperidine-4- carbonyl)piperidin-4-yl)-3-(pyridin-4-yl)- IT/-pyrazol-4-yl)-2-fluorophenyl)propane- l- sulfonamide, (5)-7V-(3-(l-(4-(l-((l-(4-(2,6-dioxopiperidin-3-yl)-3-fluorophenyl)piperidin-4- yl)methyl)piperidin-4-yl)phenyl)-3-(pyridin-4-yl)- IT/-pyrazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, and (7?)-7V-(3-(l-(4-(4-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin- 4-yl)methyl)piperazin-l-yl)phenyl)-3-(pyridin-4-yl)-17/-pyrazol-4-yl)-2- fluoropheny l)prop ane- 1 - sulfonami de .
71. The compound of any one of claims 34, 37-45, or 50-54 selected from the group consisting of (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(l-(l-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(l-(l-(5- (2,6-dioxopiperidin-3-yl)pyridin-2-yl)-4-methylpiperidine-4-carbonyl)piperidine-4- carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(5-(2- aminopyrimidin-4-yl)-2-(l -(l-(l-(5-(2,6-di oxopiperi din-3 -yl)pyri din-2 -yl)piperidine-4- carbonyl)-4-methylpiperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(l-(l-(4- (2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)-4-methylpiperidine-4- carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(l- (l-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)piperidine-4- carbonyl)piperidin-4-yl)-5-(pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (5)-7V-(3-(2-(l-(l-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4- carbonyl)-4-methylpiperidine-4-carbonyl)piperidin-4-yl)-5-(pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, and (5)-7V-(3-(2-(l-(l-(l-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidine-4-carbonyl)-4-methylpiperidine-4-carbonyl)piperidin-4-yl)-5- (pyridin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide.
72. The compound of any one of claims 34, 37, 44, 45, or 50-64 selected from the group consisting of (7?)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-(2-(4-(3-(2-(2,6-dioxopiperidin-3-yl)- l,3-dioxoisoindolin-4-yl)propyl)piperazin-l-yl)acetyl)-3-azaspiro[5.5]undecan-9-yl)thiazol- 4-yl)-2-fluorophenyl)propane-l -sulfonamide, 7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-((15,4r)- 4-((6-((5)-2,6-dioxopiperidin-3-yl)-3,4-dihydroisoquinolin-2(177)-yl)methyl)cyclohexane-l- carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(l- (l-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperidine-4- carbonyl)piperidin-4-yl)-5-(pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-
1.3-dioxoisoindolin-5-yl)piperazin-l-yl)acetyl)-4-methylpiperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(2-(r-(2- (2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)-[l,4'-bipiperidin]-4-yl)acetyl)-4- methylpiperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)- V-(3-(5-(2- aminopyrimidin-4-yl)-2-(l-(l-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)methyl)piperidine-4-carbonyl)-4-methylpiperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-((l-(2-(6- (2,6-dioxopiperidin-3-yl)-3,4-dihydroisoquinolin-2(U7)-yl)acetyl)piperidin-4- yl)methyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)- V-(3-(5-(2- aminopyrimidin-4-yl)-2-(3-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)-3- azaspiro[5.5 ]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (S)-N-(3-(2- (l-(l-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperidine-4- carbonyl)piperidin-4-yl)-5-(pyridin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(2-(r-(2-(2,6-dioxopiperidin-3-yl)-
1.3-dioxoisoindolin-5-yl)-[l,4'-bipiperidin]-4-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(2-(4-(2- (2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperazin-l-yl)acetyl)piperidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4- yl)-2-(2-( 1 -( 1 -(1 -(2-(2,6-dioxopiperi din-3 -yl)- 1 ,3-dioxoisoindolin-5-yl)piperidin-4- yl)azetidine-3-carbonyl)piperidin-4-yl)propan-2-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, 7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-((l-((17?,4r)-4-(3-(( ?)-2,6- dioxopiperi din-3 -yl)phenoxy)cy cl ohexane-l-carbonyl)piperidin-4-yl)methyl)piperi din-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4- yl)-2-(3-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)-3- azaspiro[5.5 ]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)- V-(3-(5- (2-aminopyrimidin-4-yl)-2-(l-(l-(2-(l-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)- 4-hydroxypiperidin-4-yl)acetyl)azetidin-3-yl)piperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(l-(2-(l-(5- (2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)acetyl)piperidin-4-yl)phenyl)thiazol-4- yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(4-((l- (4-(2, 6-dioxopiperi din-3 -yl)phenyl)piperidin-4-yl)methyl)piperazin-l-yl)phenyl)thi azol -4- yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(l-(2- (l-(4-((2,6-dioxopiperi din-3 -yl)amino)phenyl)piperi din-4-yl)acetyl)piperi din-4- yl)phenyl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)- V-(3-(5-(2- aminopyrimidin-4-yl)-2-(4-(l-(l-(5-(2,6-dioxopiperi din-3-yl)pyri din-2 -yl)piperidine-4- carbonyl)piperidin-4-yl)phenyl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (S)-N- (3-(5-(2-aminopyrimidin-4-yl)-2-(4-(l-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)methyl)piperidin-4-yl)phenyl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, N-(3- (5-(2-aminopyrimidin-4-yl)-2-(3-(((15,4r)-4-((5-((5)-2,6-dioxopiperidin-3-yl)pyridin-2- yl)oxy)cyclohexyl)methyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(4-(l-(4- (2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)piperazin-l-yl)phenyl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-5-(4-(9-(5-(2-aminopyrimidin-4-yl)-4-(2-fluoro-3- (propylsulfonamido)phenyl)thiazol-2-yl)-3-azaspiro[5.5]undecane-3-carbonyl)piperidin-l- yl)-7V-(2,6-dioxopiperidin-3-yl)picolinamide, 7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-(2-((5)-l- (5-((5)-2,6-dioxopiperidin-3-yl)pyridin-2-yl)pyrrolidin-3-yl)ethyl)-3-azaspiro[5.5]undecan-9- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)- 2-(l-(l-(2-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)acetyl)azetidin-3- yl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)- V-(3-(5-(2- aminopyrimidin-4-yl)-2-(3-(l -(5-(2,6-di oxopiperidin-3-yl)pyri din-2 -yl)piperidine-4- carbonyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(l-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2- yl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (5)-7V-(3-(2-(l-(l-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4- carbonyl)piperidine-4-carbonyl)piperidin-4-yl)-5-(pyridin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(l-(l-((l-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidin-4-yl)methyl)piperidine-4-carbonyl)piperidin-4-yl)-5-(2- (methylamino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (R)-N-(3 - (5-(2-aminopyrimidin-4-yl)-2-(2-(2-(l'-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)-[l,4'-bipiperidin]-4-yl)acetyl)-2-azaspiro[3.5]nonan-7-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(l-(l-(l-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidin-4-yl)-5-(pyridin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, 7V-(3-(5-(2-aminopyrimidin-4-yl)-2- (l-((l-(((15,4r)-4-(4-((5)-2,6-dioxopiperidin-3-yl)phenoxy)cyclohexyl)methyl)piperidin-4- yl)methyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-N-(3- 5- (2-aminopyrimidin-4-yl)-2-(2-(l-(2-(2, 6-dioxopiperi din-3-yl)- 1,3 -di oxoisoindolin-5- yl)piperidine-4-carbonyl)-2-azaspiro[3.5]nonan-7-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (5)-7V-(3-(2-(l-(l-(2-(l-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4- yl)acetyl)piperidine-4-carbonyl)piperidin-4-yl)-5-(pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(2-(l-(l-(l-(5- (2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidin- 4-yl)ethyl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (R)-N-(3- 5-(2- aminopyrimidin-4-yl)-2-(2-(2-(4-(2-(2, 6-dioxopiperi din-3-yl)- 1,3 -di oxoisoindolin-5- yl)piperazin-l-yl)acetyl)-2-azaspiro[3.5]nonan-7-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, ( ?)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(4-(l-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidine-4-carbonyl)piperazin-l-yl)phenyl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(l-(l-(l-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidin-4-yl)-5-(pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4- yl)-2-(l-(l-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)piperidine-4- carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-N-(3-(5-(2- aminopyrimidin-4-yl)-2-(4-(4-((l-(4-(2, 6-dioxopiperi din-3-yl)phenyl)piperidin-4- yl)methyl)piperazin-l-yl)phenyl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (S)-N- (3-(5-(2-aminopyrimidin-4-yl)-2-(l-((l-(l-(5-(2,6-dioxopiperidin-3-yl)pyri din-2- yl)piperidine-4-carbonyl)piperidin-4-yl)methyl)piperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(4-(2-(l-(5- (2, 6-dioxopiperi din-3 -yl)pyri din-2 -yl)piperi din-4-yl)acetyl)piperazin- l-yl)phenyl)thi azol-4- yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-(2-(r- (2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)-[l,4'-bipiperidin]-4-yl)acetyl)-3- azaspiro[5.5 ]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)- V-(3-(5- (2-aminopyrimidin-4-yl)-2-(l-(l-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)methyl)piperidine-4-carbonyl)-4-methylpiperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(l-(l-(l-(4-(2,6-dioxopiperidin-3- yl)phenyl)piperidine-4-carbonyl)-4-methylpiperidine-4-carbonyl)piperidin-4-yl)-5-(2- (isopropylamino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-N- (3-(5-(2-aminopyrimidin-4-yl)-2-(3-(2-(4-(2-(2, 6-dioxopiperi din-3-yl)-l,3-dioxoisoindolin-5- yl)piperazin-l-yl)acetyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, 7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-((l-((17?,4r)-4-(4-(( ?)-2,6- dioxopiperi din-3 -yl)phenoxy)cy cl ohexane-l-carbonyl)piperidin-4-yl)methyl)piperi din-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4- yl)-2-(2-(6-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)hexanoyl)-2- azaspiro[3.5]nonan-7-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, 7V-(3-(2-(l-(l- (l-(5-((5)-2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4- carbonyl)piperidin-4-yl)-5-(2-((( ?)-l-hydroxypropan-2-yl)amino)pyrimidin-4-yl)thiazol-4- yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(4-((l- (5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-l-yl)phenyl)thiazol- 4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, rac-(35)-3 - { 6- [4 - (4 - {4-[5-(2-aminopyrimidin- 4-yl)-4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3-thiazol-2-yl]piperidine-l- carbonyl}piperidine-l-carbonyl)piperidin-l-yl]pyridin-3-yl}piperidine-2, 6-dione, rac-(35)-3- {6-[4-(4-{4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-5-{2-[(propan-2- yl)amino]pyrimidin-4-yl } - 1 ,3 -thiazol-2-yl]piperidine- 1 -carbonyl } piperi dine- 1 - carbonyl)piperidin-l-yl]pyridin-3-yl}piperidine-2, 6-dione, (5)-7V-(3-(5-(2-aminopyrimidin-4- yl)-2-(l-(l-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperidine-4- carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)- V-(3-(5-(2- aminopyrimidin-4-yl)-2-(l-(l-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)methyl)piperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-((l-(2-(2,6-dioxopiperidin-3-yl)-l- oxoisoindolin-5-yl)piperidin-4-yl)methyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(2-(2-(2- (2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)acetyl)-4- methylpiperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-N-(3- 5-(2- aminopyrimidin-4-yl)-2-(3-(l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)piperidine-4-carbonyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, ( ?)-7V-(3-(2-(l-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)- 2,7 -di azaspiro [3.5 ]nonan-7 -yl)acetyl)piperidin-4-yl)-5-(2-(methylamino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4- yl)-2-(3-(6-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)hexanoyl)-3- azaspiro[5.5 ]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-N-(3- 5- (2-aminopyrimidin-4-yl)-2-(l-(l-(2-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)acetyl)-4-methylpiperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(l-(l-(l-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidin-4-yl)-5-(2- (methylamino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (R)-N-(3 - (5-(2-aminopyrimidin-4-yl)-2-(l-(l-(2-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin- 4-yl)acetyl)piperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (5)-7V-(3-(2-(l-(l-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4- carbonyl)piperidine-4-carbonyl)piperidin-4-yl)-5-(2-(isopropylamino)pyrimidin-4-yl)thiazol- 4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(5-(2-(cyclopropylamino)pyrimidin-4- yl)-2-(l-(l-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4- carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(2-(l- (l-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)-4-methylpiperidine-4- carbonyl)piperidin-4-yl)-5-(pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, 7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-(2-( (R)-l-(4-((, )-2,6-dioxopiperidin-3- yl)phenyl)pyrrolidin-3-yl)acetyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(2-(2-(2-(2- (2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)acetyl)-2- azaspiro[3.5]nonan-7-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (R)-N-(3-(5-(2- aminopyrimidin-4-yl)-2-(l-((l-(2-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)acetyl)piperidin-4-yl)methyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(2-(2-(2-(2,6-dioxopiperidin-3-yl)- l,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-(l-(l-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-17/-benzo[d]imidazol-4-yl)piperidine-4- carbonyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (R)-7V-(3-(2-(l-(l-((l-(4-(2,6-dioxopiperi din-3 -yl)phenyl)piperi din-4-yl)methyl)piperi dine-4- carbonyl)piperidin-4-yl)-5-(2-(methylamino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(l-(l-(2- (2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperidin-4-yl)azetidine-3- carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-N-(3-(5-(2- aminopyrimidin-4-yl)-2-(2-(l-(l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)piperidin-4-yl)azetidine-3-carbonyl)-2-azaspiro[3.5]nonan-7-yl)thiazol-4-yl)-2- fluorophenyl)propane- 1 -sulfonamide, (S)-N-(3 -(5-(2-aminopyrimidin-4-yl)-2-(l -( 1 -(( 1 -( 1 - (2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-17/-benzo[ ]imidazol-4-yl)piperidin- 4-yl)methyl)piperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- l - sulfonamide, ( ?)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-(2-(2-(2-(2,6-dioxopiperidin-3-yl)- l,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)acetyl)-3-azaspiro[5.5]undecan-9- yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, (R)-7V-(3-(5-(2-aminopyrimidin-4- yl)-2-(2-(l-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)-2,7- diazaspiro[3.5]nonan-7-yl)acetyl)piperidin-4-yl)propan-2-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, and (R)-4-((4-(5-(2-aminopyrimidin-4-yl)-4-(2-fluoro- 3-(propylsulfonamido)phenyl)thiazol-2-yl)piperidin-l-yl)methyl)-7V-(2,6-dioxopiperidin-3- yl)benzamide.
73. The compound of claim 1, wherein X1 is carbon; X2 is nitrogen, X3 is nitrogen; X4 is carbon; and X5 is hydrogen.
74. The compound of claim 73, wherein
R1 is alkyl, dialkylamino, cycloalkyl, or heterocycloalkyl each unsubstituted or substituted with one or more halogen;
Rla is halogen;
Rih is hydrogen, haloalkyl or halogen;
R2 is -[A Z^n-Z^Cy^Z’-L-UBM;
Ar1 is arylene or heteroarylene, each unsubstituted or substituted with one or more halogen;
Z1 is a bond; n is one;
Z2 is absent;
Cy1 is absent or heterocycloalkylene, unsubstituted or substituted with one or more alkyl or one or more halogen;
Z3 is absent or Ci-io alkylene;
L is a linker according to -L4-L2-L3-L4- or -L4-L3-L2-L1-, wherein
-L1- is -Q1- or -Q2-; each -L2-, -L3-, and -L4- is independently, absent, -Ci-8 alkylene-, or -Q1-; each -Q1- is a three- to seven-membered heterocycloalkylene comprising at least one nitrogen and is unsubstituted or substituted with one or more methyl or halogen; each -Q2- is a five- to thirteen-membered bicyclic heterocycloalkylene comprising at least one nitrogen, wherein the five- to thirteen-membered bicyclic heterocycloalkylene is optionally a spiro bicyclic heterocycloalkylene ring; and
UBM is a ubiquitin ligase binding moiety; or a stereoisomer and/or pharmaceutical salt thereof.
75. The compound of claim 73 or 74, wherein R1 is selected from the group consisting of
76. The compound of any one of claims 73-75, wherein Rla is chloro or fluoro; and Rlb is hydrogen, chloro, fluoro, or haloalkyl.
77. The compound of any one of claims 73-76, wherein Ar1 is arylene or heteroarylene unsubstituted or substituted with one or two halogen.
78. The compound of any one of claims 73-77, wherein UBM binds an E3 ubiquitin ligase.
79. The compound of claim 78, wherein UBM binds SCFP-TRCP, VHL, MDM2, IAP, or CRBN.
80. The compound of claim 79, wherein UBM binds CRBN.
81. The compound of claim 80, wherein UBM binds CRBN and has the following chemical formula wherein
X6 absent or NR3;
X7 absent or -C(O)-; and
X8 is arylene or heteroarylene.
82. The compound of claim 81, wherein UBM binds CRBN and is selected from the group
X9 is absent or halogen; and m is one, two, three, or four.
83. The compound of any one of claims 1 or 73-82, wherein the compound is selected from the group consisting of (R)-7V-(5-chloro-3-(l-(4-(4-((l-(5-(2,4-dioxotetrahydropyrimidin- l(2J7)-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-l-yl)phenyl)-3-(pyridin-4-yl)-lJT- pyrazol-4-yl)-2-fluorophenyl)-3 -fluoropyrrolidine- 1 -sulfonamide; (R)-7V-(5-chloro-3-(l-(4-(4- ((l-(5-(( ?)-2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-l- yl)phenyl)-3 -(pyridin-4-yl)- 177-pyrazol -4-yl )-2-fl uorophenyl )-3 -fluoropyrrolidine- 1 - sulfonamide; rac-( ?)-7V-(5-chloro-3-(l-(4-(4-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2- yl)piperidin-4-yl)methyl)piperazin-l-yl)phenyl)-3-(pyridin-4-yl)-17/-pyrazol-4-yl)-2- fluorophenyl)pyrrolidine-l -sulfonamide; rac- (R)-7V-(5-chloro-3-(l-(4-(4-((l-(5-(2,6- di oxopiperi din-3 -yl)pyri din-2-yl)piperi din-4-yl)methyl)piperazin- 1 -yl)-2-fluorophenyl)-3 - (pyridin-4-yl)-l//-pyrazol-4-yl)-2-fluorophenyl)pyrrolidine-l -sulfonamide; rac-(7?)-7V-(3-(l- (4-(4-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-l- yl)phenyl)-3-(pyridin-4-yl)-l//-pyrazol-4-yl)-2,5-difluorophenyl)pyrrolidine-l -sulfonamide; 7V-(5-chloro-3-(l-(4-( (R)-4-((l-(5-((7?5)-2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)methyl)-3-methylpiperazin-l-yl)phenyl)-3-(pyridin-4-yl)-lJH-pyrazol-4-yl)-2- fluorophenyl)pyrrolidine-l -sulfonamide; (7?)-7V-(3-(l-(4-(4-((l-(4-(2,6-dioxopiperidin-3-yl)- 2-fluorophenyl)piperidin-4-yl)methyl)piperazin-l-yl)-2-fluorophenyl)-3-(pyridin-4-yl)-lJH- pyrazol-4-yl)-2,5-difluorophenyl)cyclopentanesulfonamide; rac-(7?)-7V-(3-(l-(4-(4-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)methyl)piperazin-l-yl)-3-fluorophenyl)-3-(pyridin-4-yl)-lJH-pyrazol-4-yl)-2,5- difluorophenyl)cyclopentanesulfonamide; rac-(7?)-7V-(5-chloro-3-(l-(4-(4-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)methyl)piperazin-l-yl)-3-fluorophenyl)-3-(pyridin-4-yl)-lJH-pyrazol-4-yl)-2- fluorophenyl)cyclopentanesulfonamide;
(R)-N-(5 -chi oro-3 -( 1 -(4-(4-(( 1 -(4-(2, 6-dioxopiperi din-3 -yl)-2-fluorophenyl)piperidin-4- yl)methyl)piperazin-l-yl)-3-fluorophenyl)-3-(pyridin-4-yl)-lJH-pyrazol-4-yl)-2- fluorophenyl)cyclopentanesulfonamide;
(R)-N-(5 -chi oro-3 -( 1 -(4-(4-(( 1 -(4-(2, 6-dioxopiperi din-3 -yl)-2-fluorophenyl)piperidin-4- yl)methyl)-l,4-diazepan-l-yl)-2-fluorophenyl)-3-(pyridin-4-yl)-lJH-pyrazol-4-yl)-2- fluorophenyl)pyrrolidine- 1 -sulfonamide; (R)-7V-(3-(l-(4-(4-((l-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-l,4- diazepan-l-yl)-2-fluorophenyl)-3-(pyridin-4-yl)-lJH-pyrazol-4-yl)-2,5- difluorophenyl)pyrrolidine-l -sulfonamide; 7V-[5-chloro-3-(l-{4-[(37?)-4-[(l-{4-[(37?)-2,6- dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]-3-methylpiperazin-l-yl]phenyl}-3- (pyridin-4-yl)-l//-pyrazol-4-yl)-2-fluorophenyl]propane-l-sulfonamide; 7V-[5-chloro-3-(l-{4- [(37?)-4-[(l-{5-[(37?5)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]-3- methylpiperazin-l-yl]phenyl}-3-(pyridin-4-yl)-lJH-pyrazol-4-yl)-2-fluorophenyl]propane-l- sulfonamide; 7V-[5-chloro-3-(l-{4-[(37?)-4-({ l-[4-(2,4-dioxo-l,3-diazinan-l- yl)phenyl]piperidin-4-yl}methyl)-3-methylpiperazin-l-yl]phenyl}-3-(pyridin-4-yl)-lJ7- pyrazol-4-yl)-2-fluorophenyl]propane-l -sulfonamide; 7V-[5-chloro-3-(l-{4-[(35)-4-[(l-{4- [(37?)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]-3-methylpiperazin-l- yl]phenyl} -3 -(pyridin-4-yl)-lJH-pyrazol-4-yl)-2-fluorophenyl]propane-l -sulfonamide; 7V-[5- chloro-3-Cl - { 4-[(3KS')-4-[( 1 - { 5-[(3/^S')-2,6-dioxopiperidin-3-yl]pyridin-2-yl } piperidin-4- yl)methyl]-3-methylpiperazin-l-yl]phenyl }-3-(pyridin-4-yl)-U7-pyrazol-4-yl)-2- fluorophenyl]propane-l -sulfonamide; 7V-[5-chloro-3-(l-{4-[(35)-4-({l-[4-(2,4-dioxo-l,3- diazinan- 1 -yl)phenyl]piperidin-4-yl }methyl)-3 -methylpiperazin- 1 -yl]phenyl } -3 -(pyridin-4- yl)-l//-pyrazol-4-yl)-2-fluorophenyl]propane-l -sulfonamide; 7V-{5-chloro-3-[l-(4-{4-[(l-{4- [(37?)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}-2-fluorophenyl)- 3-(pyridin-4-yl)-U7-pyrazol-4-yl]-2-fluorophenyl}pyrrolidine-l -sulfonamide; 7V-{5-chloro-3- [l-(4-{4-[(l-{4-[(37?)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]piperazin-l- yl }phenyl)-3 -(pyridin-4-yl)- 1 //-pyrazol -4-yl ]-2-fl uorophenyl } pyrrol i dine- 1 -sulfonamide; N- [5-chloro-3-(l-{4-[4-({l-[4-(2,4-dioxo-l,3-diazinan-l-yl)phenyl]piperidin-4- yl}methyl)piperazin-l-yl]phenyl}-3-(pyridin-4-yl)-U7-pyrazol-4-yl)-2- fluorophenyl]pyrrolidine-l -sulfonamide; rac-7V-{5-chloro-3-[l-(4-{4-[(l-{4-[(37?)-2,6- dioxopiperidin-3-yl]phenyl}-4-fluoropiperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3- (pyridin-4-yl)-l//-pyrazol-4-yl]-2-fluorophenyl}pyrrolidine-l -sulfonamide; 7V-{5-chloro-3- [l-(4-{4-[(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-
1-yl}phenyl)-3-(pyridin-4-yl)-U7-pyrazol-4-yl]-2-fluorophenyl}pyrrolidine-l-sulfonamide; 7V-{5-chloro-3-[l-(5-{4-[(l-{4-[(37?)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4- yl)methyl]piperazin-l-yl}pyridin-2-yl)-3-(pyridin-4-yl)-U7-pyrazol-4-yl]-2- fluorophenyl}pyrrolidine-l-sulfonamide; 7V-[5-chloro-3-(l-{5-[4-({l-[4-(2,4-dioxo-l,3- diazinan- 1 -yl)phenyl]piperidin-4-yl }methyl)piperazin- 1 -yl]pyri din-2 -yl } -3 -(pyridin-4-yl)- l/Z-pyrazol-4-yl)-2-fluorophenyl]pyrrolidine-l -sulfonamide; rac-7V-{5-chloro-3-[l-(5-{4-[(l- {5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l-yl}pyridin-
2-yl)-3-(pyridin-4-yl)-lJ7-pyrazol-4-yl]-2-fluorophenyl}pyrrolidine-l-sulfonamide; 7V-(3-(l-
(4-( (R)-4-((l-(5-((7?5)-2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)-3- methylpiperazin- 1 -yl)-2-fluorophenyl)-3 -(pyridin-4-yl)- 1 H-py razol-4-yl)-2, 5 - difluorophenyl)pyrrolidine- 1 -sulfonamide; N- { 5 -chi oro-3 - [l-(5-{4-[(l-{ 5 - [ (37?) -2 , 6 - dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l-yl}pyridin-2-yl)-3- (pyridin-4-yl)-lJ7-pyrazol-4-yl]-2-fluorophenyl}pyrrolidine-l-sulfonamide; (3R)-N-{5- chloro-3-[l-(4-{4-[(l-{4-[(37?)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4- yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4-yl)-U7-pyrazol-4-yl]-2-fluorophenyl}-3- fluoropyrrolidine-1 -sulfonamide; (37?)-7V-[5-chloro-3-(l-{4-[4-({l-[4-(2,4-dioxo-l,3- diazinan- 1 -yl)phenyl]piperidin-4-yl }methyl)piperazin- 1 -yl]phenyl } -3 -(pyridin-4-yl)- 1H- pyrazol-4-yl)-2-fluorophenyl]-3 -fluoropyrrolidine- 1 -sulfonamide; (3R)-N- { 5-chl oro-3 -[ 1 -(4- {4-[(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l- yl }phenyl)-3 -(pyridin-4-yl)- 177-pyrazol -4-yl ]-2-fl uorophenyl } -3 -fluoropyrrolidine- 1 - sulfonamide; (37?)-7V-{5-chloro-3-[l-(5-{4-[(l-{4-[(37?)-2,6-dioxopiperidin-3- yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}pyridin-2-yl)-3-(pyridin-4-yl)-lJH-pyrazol-4- yl]-2-fluorophenyl}-3-fluoropyrrolidine-l-sulfonamide; (37?)-zV-[5-chloro-3-(l-{5-[4-({ l-[4- (2,4-dioxo-l,3-diazinan-l-yl)phenyl]piperidin-4-yl}methyl)piperazin-l-yl]pyridin-2-yl}-3- (pyridin-4-yl)-l//-pyrazol-4-yl)-2-fluorophenyl]-3-fluoropyrrolidine-l -sulfonamide; (3R)-N- {5-chloro-3-[l-(5-{4-[(l-{5-[(37?5)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4- yl)methyl]piperazin-l-yl}pyridin-2-yl)-3-(pyridin-4-yl)-lJ7-pyrazol-4-yl]-2-fluorophenyl}-3- fluoropyrrolidine- 1 -sulfonamide; (37?)-7V-{5-chloro-3-[l-(5-{4-[(l-{5-[(37?)-2,6- dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l-yl}pyridin-2-yl)-3- (pyridin-4-yl)-17/-pyrazol-4-yl]-2-fluorophenyl [-3-fluoropyrrolidine-l -sulfonamide; (3R)-N- {5-chloro-3-[l-(5-{4-[(7-{4-[(37?5)-2,6-dioxopiperidin-3-yl]phenyl}-7-azaspiro[3.5]nonan-2- yl)methyl]piperazin-l-yl}pyridin-2-yl)-3-(pyridin-4-yl)-177-pyrazol-4-yl]-2-fluorophenyl}-3- fluoropyrrolidine- 1 -sulfonamide; 7V-{3-[l-(4-{4-[(l-{4-[(37?)-2,6-dioxopiperidin-3- yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4-yl)-lJH-pyrazol-4-yl]-
2.5-difluorophenyl}pyrrolidine-l-sulfonamide; 7V-[3-(l-{4-[4-({l-[4-(2,4-dioxo-l,3-diazinan- l-yl)phenyl]piperidin-4-yl}methyl)piperazin-l-yl]phenyl}-3-(pyridin-4-yl)-lJH-pyrazol-4-yl)-
2.5-difluorophenyl]pyrrolidine-l-sulfonamide; 7V-{3-[l-(4-{4-[(l-{5-[(37?)-2,6- dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4- yl)-17/-pyrazol-4-yl]-2,5-difluorophenyl [pyrrolidine-1 -sulfonamide; (37?)-7V-{3-[l-(5-{4-[(l - {4-[(37?)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}pyridin-2-yl)- 3-(pyridin-4-yl)-lJH-pyrazol-4-yl]-2,5-difluorophenyl}-3-fluoropyrrolidine-l-sulfonamide; (37?)-7V-[3-(l-{5-[4-({l-[4-(2,4-dioxo-l,3-diazinan-l-yl)phenyl]piperidin-4- yl}methyl)piperazin-l-yl]pyridin-2-yl}-3-(pyridin-4-yl)-177-pyrazol-4-yl)-2,5- difluorophenyl]-3-fluoropyrrolidine-l-sulfonamide; (37?)-7V-{3-[l-(5-{4-[(l-{5-[(3R5)-2,6- dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l-yl}pyridin-2-yl)-3- (pyridin-4-yl)-177-pyrazol-4-yl]-2,5-difluorophenyl}-3-fluoropyrrolidine-l -sulfonamide; (37?)-7V-{3-[l-(5-{4-[(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4- yl)methyl]piperazin-l-yl}pyridin-2-yl)-3-(pyridin-4-yl)-177-pyrazol-4-yl]-2,5- difluorophenyl } -3 -fluoropyrrolidine- 1 -sulfonamide; (3R)-3 -(4- { 4- [(4- { 4- [4 - (5 -chi oro-3 -
{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-3-(pyridin-4-yl)-lJ7-pyrazol-l- yl]phenyl}piperazin-l-yl)methyl]piperidin-l-yl}phenyl)piperidine-2, 6-dione; l-(4-{4-[(4-{4- [4-(5-chloro-3-{ [ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-3-(pyridin-4-yl)-lJ7- pyrazol-l-yl]phenyl}piperazin-l-yl)methyl]piperidin-l-yl}phenyl)-l,3-diazinane-2, 4-dione; rac-(37?)-3-(6-{4-[(4-{4-[4-(5-chloro-3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-3- (pyridin-4-yl)- 1 //-pyrazol - 1 -yl]phenyl } piperazin- 1 -yl)methyl]piperidin- 1 -yl Jpyri din-3 - yl)piperidine-2, 6-dione; (37?)-3-(6-{4-[(4-{4-[4-(5-chloro-3-
{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-3-(pyridin-4-yl)-lJ7-pyrazol-l- yl]phenyl}piperazin-l-yl)methyl]piperidin-l-yl}pyridin-3-yl)piperidine-2, 6-dione; (37?)-3-(4- {4-[(4-{6-[4-(5-chloro-3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-3-(pyridin-4-yl)- I //-pyrazol - 1 -yl]pyri din-3 -yl } piperazin- 1 -yl)methyl]piperidin- 1 -yl [ phenyl )pi peri di ne-2, 6- dione; l-(4-{4-[(4-{6-[4-(5-chloro-3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-3- (pyridin-4-yl)-l//-pyrazol-l-yl]pyridin-3-yl [piperazin-l-yl)methyl]piperidin-l-yl [phenyl)-
1.3-diazinane-2, 4-dione; rac-(37?)-3-(6-{4-[(4-{6-[4-(5-chloro-3-
{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-3-(pyridin-4-yl)-lJ7-pyrazol-l-yl]pyridin-
3-yl}piperazin-l-yl)methyl]piperidin-l-yl}pyridin-3-yl)piperidine-2, 6-dione; l-(6-{4-[(4-{6- [4-(5-chloro-3-{ [ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-3-(pyridin-4-yl)-lJ7- pyrazol-l-yl]pyridin-3-yl}piperazin-l-yl)methyl]piperidin-l-yl}pyridin-3-yl)-l,3-diazinane-
2.4-dione; (37?)-3-(6-{4-[(4-{6-[4-(5-chloro-3-{[ethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)-3 -(pyridin-4-yl)- I //-py razol - 1 -yl]pyri din-3 -yl } piperazin- 1 - yl)methyl]piperidin-l-yl}pyridin-3-yl)piperidine-2, 6-dione; (37?)- V-[5-chloro-3-(l-{4-[(37?)-
4-({ 1 -[4-(2,4-dioxo- 1 ,3 -diazinan- 1 -yl)phenyl]piperidin-4-yl }methyl)-3 -methylpiperazin- 1 - yl]phenyl} -3 -(pyridin-4-yl)-l//-pyrazol-4-yl)-2-fluorophenyl]-3 -fluoropyrrolidine- 1- sulfonamide; 7V-[5-chloro-3-(l-{4-[(37?)-4-[(l-{4-[(37?)-2,6-dioxopiperidin-3- yl]phenyl}piperidin-4-yl)methyl]-3-methylpiperazin-l-yl]phenyl}-3-(pyridin-4-yl)-lJ7- pyrazol-4-yl)-2-fluorophenyl]pyrrolidine-l -sulfonamide; (37?)- V-[5-chloro-3-(l-{4-[(37?)-4- [(l-{4-[(37?)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]-3-methylpiperazin-l- yl]phenyl} -3 -(pyridin-4-yl)-lJH-pyrazol-4-yl)-2-fluorophenyl]-3 -fluoropyrrolidine- 1- sulfonamide; (37?)-7V-[5-chloro-3-(l-{4-[(37?)-4-[(l-{5-[(37?5)-2,6-dioxopiperidin-3- yl]pyridin-2-yl }piperidin-4-yl)methyl]-3 -methylpiperazin- 1 -yl]phenyl } -3 -(pyridin-4-yl)- 1H- pyrazol-4-yl)-2-fluorophenyl]-3-fluoropyrrolidine-l-sulfonamide; 7V-[5-chloro-3-(l-{4-[(37?)- 4-({ 1 -[4-(2,4-dioxo- 1 ,3 -diazinan- 1 -yl)phenyl]piperidin-4-yl }methyl)-3 -methylpiperazin- 1 - yl]phenyl} -3 -(pyridin-4-yl)-lJH-pyrazol-4-yl)-2-fluorophenyl]pyrrolidine-l -sulfonamide;
(37?)-7V-[5-chloro-3-(l-{5-[(37?)-4-[(l-{4-[(37?)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4- yl)methyl]-3 -methylpiperazin- 1 -yl]pyri din-2 -yl } -3 -(pyridin-4-yl)- l/7-pyrazol-4-yl)-2- fluorophenyl]-3-fluoropyrrolidine-l-sulfonamide; (37?)-7V-[5-chloro-3-(l-{5-[(37?)-4-[(l-{5- [(37?5)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]-3-methylpiperazin-l- yl]pyridin-2-yl } -3 -(pyridin-4-yl)- 17/-py razol -4-yl )-2-fl uorophenyl ]-3 -fluoropyrrolidine- 1 - sulfonamide; (37?)-7V-[5-chl oro-3 -(1 - { 5-[(37?)-4-({ 1 -[4-(2,4-dioxo- 1 ,3 -diazinan- 1 - yl)phenyl]piperidin-4-yl}methyl)-3-methylpiperazin-l-yl]pyridin-2-yl}-3-(pyridin-4-yl)-lJH- pyrazol-4-yl)-2-fluorophenyl]-3-fluoropyrrolidine-l-sulfonamide; 7V-[5-chloro-3-(l-{5-[(37?)- 4-[(l-{5-[(37?5)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]-3- methylpiperazin-l-yl]pyridin-2-yl}-3-(pyridin-4-yl)-lJH-pyrazol-4-yl)-2- fluorophenyl]pyrrolidine- 1 -sulfonamide; 7V-[5-chloro-3 -( 1 -{ 5 - [(37?)-4-( { 1 -[4-(2,4-dioxo- 1,3- diazinan- 1 -yl)phenyl]piperidin-4-yl }methyl)-3 -methylpiperazin- 1 -yl]pyridin-2-yl }-3- (pyridin-4-yl)-lJ7-pyrazol-4-yl)-2-fluorophenyl]pyrrolidine-l-sulfonamide; 7V-[5-chloro-3-(l- {5-[(37?)-4-[(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]-3- methylpiperazin-l-yl]pyridin-2-yl}-3-(pyridin-4-yl)-lJH-pyrazol-4-yl)-2- fluorophenyl]pyrrolidine-l -sulfonamide; 7V-[5-chloro-3-(l-{5-[(37?)-4-[(l-{4-[(37?)-2,6- dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]-3-methylpiperazin-l-yl]pyridin-2-yl}-3- (pyridin-4-yl)-lJ7-pyrazol-4-yl)-2-fluorophenyl]pyrrolidine-l-sulfonamide; (7?5)-7V-(5-chloro- 3-(l-(4-(4-((l-(5-((7?)-2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin- 1 -yl)phenyl)-3 -(pyridin-4-yl)- 17/-py razol -4-yl )-2-fl uorophenyl )butane-2-sulfonami de; rac-
(27?)-7V-[5-chl oro-3 -(1 - { 4- [4-({ 1 -[4-(2,4-dioxo- 1 ,3 -diazinan- 1 -yl)phenyl]piperidin-4- yl}methyl)piperazin-l-yl]phenyl}-3-(pyridin-4-yl)-lJH-pyrazol-4-yl)-2-fluorophenyl]butane- 2-sulfonamide; rac- (R)-7V-(5-chloro-3-(l-(4-(4-((l-(5-((5)-2,6-dioxopiperidin-3-yl)pyridin-2- yl)piperidin-4-yl)methyl)piperazin-l-yl)phenyl)-3-(pyridin-4-yl)-lJH-pyrazol-4-yl)-2- fluorophenyl)butane-2-sulfonamide; (27?S)-7V-{5-chloro-3-[l-(4-{4-[(l-{4-[(37?)-2,6- dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4-yl)- l//-pyrazol-4-yl]-2-fluorophenyl }butane-2-sulfonamide; 7V-{5-chloro-3-[l-(4-{4-[(l-{5- [(37?)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3- (pyridin-4-yl)-lJ7-pyrazol-4-yl]-2-fluorophenyl}-3-fluoroazetidine-l-sulfonamide; rac-7V-{5- chloro-3-[l-(4-{4-[(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4- yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4-yl)-lJH-pyrazol-4-yl]-2-fluorophenyl}-3- fluoroazetidine-1 -sulfonamide; 7V-{5-chloro-3-[l-(4-{4-[(l-{4-[(37?)-2,6-dioxopiperidin-3- yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4-yl)-lJH-pyrazol-4-yl]-2- fluorophenyl } -3 -fluoroazetidine- 1 -sulfonamide; (3R)-N- { 5 -chi oro-3 -[l-(4-{4-[(l-{5 -[(37?)-
2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l-yl}-2-fluorophenyl)- 3-(pyridin-4-yl)-l//-pyrazol-4-yl]-2-fluorophenyl ( -3 -fluoropyrrolidine- 1 -sulfonamide; (37?)- 7V-{5-chloro-3-[l-(4-{4-[(l-{5-[(37?S)-2,6-dioxopiperidin-3-yl]pyridin-2-yl(piperidin-4- yl)methyl]piperazin-l-yl(-2-fluorophenyl)-3-(pyridin-4-yl)-177-pyrazol-4-yl]-2- fluorophenyl} -3 -fluoropyrrolidine- 1 -sulfonamide; (37?)-7V-{5-chloro-3-[l-(4-{4-[(l-{4-[(37?)- 2,6-dioxopiperidin-3-yl]phenyl(piperidin-4-yl)methyl]piperazin-l-yl(-2-fluorophenyl)-3- (pyridin-4-yl)- l//-pyrazol-4-yl]-2-fluorophenyl }-3-fluoropyrrolidine- l -sulfonamide; rac-7V- {5-chloro-3-[l-(4-{4-[(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2-yl(piperidin-4- yl)methyl]piperazin-l-yl(-2-fluorophenyl)-3-(pyridin-4-yl)-177-pyrazol-4-yl]-2- fluorophenyl} -3 -fluoroazetidine- 1 -sulfonamide; 7V-{5-chloro-3-[l-(4-{4-[(l-{4-[(37?)-2,6- dioxopiperidin-3-yl]phenyl(piperidin-4-yl)methyl]piperazin-l-yl(-2-fluorophenyl)-3- (pyridin-4-yl)-177-pyrazol-4-yl]-2-fluorophenyl(-3-fluoroazetidine-l-sulfonamide; 7V-[5- chl oro-3-(l-{4-[4-({l-[4-(2,4-di oxo-1, 3-diazinan-l -yl)phenyl]piperidin-4- yl }methyl)piperazin- 1 -yl]-2-fluorophenyl ( -3 -(pyridin-4-yl)- 177-pyrazol-4-yl)-2- fluorophenyl]-3 -fluoroazetidine- 1 -sulfonamide; 7V-{3-[l-(4-{4-[(l-{4-[(37?)-2,6- dioxopiperidin-3-yl]phenyl(piperidin-4-yl)methyl]piperazin-l-yl(-2-fluorophenyl)-3- (pyridin-4-yl)-177-pyrazol-4-yl]-2,5-difluorophenyl(pyrrolidine-l-sulfonamide; rac-7V-{3-[l- (4-{4-[(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2-yl(piperidin-4-yl)methyl]piperazin-l- yl ( -2-fluorophenyl)-3 -(pyridin-4-yl)- 177-pyrazol-4-yl]-2, 5 -difluorophenyl (pyrrolidine- 1 - sulfonamide; 7V-{3-[l-(5-{4-[(l-{4-[(37?)-2,6-dioxopiperidin-3-yl]phenyl(piperidin-4- yl)methyl]piperazin-l-yl(pyrimidin-2-yl)-3-(pyridin-4-yl)-177-pyrazol-4-yl]-2,5- difluorophenyl ( pyrrolidine- 1 -sulfonamide; rac-7V- { 3 - [ 1 -(5 - { 4- [( 1 - { 5 - [(37?)-2, 6- dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l-yl}pyrimidin-2-yl)-3- (pyridin-4-yl)-177-pyrazol-4-yl]-2,5-difluorophenyl}pyrrolidine-l-sulfonamide; 7V-{5-chloro- 3-[l-(4-{4-[(l-{4-[(37?)-2,6-dioxopiperidin-3-yl]-3-fluorophenyl}piperidin-4- yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4-yl)-lJH-pyrazol-4-yl]-2- fluorophenyl}pyrrolidine-l-sulfonamide; rac-7V-{5-chloro-3-[l-(4-{4-[(l-{5-[(37?)-2,6- dioxopiperi din-3 -yl]pyridin-2-yl }piperidin-4-yl)methyl]- 1 ,4-diazepan- 1 -yl } -2-fluorophenyl)- 3-(pyridin-4-yl)-lJH-pyrazol-4-yl]-2-fluorophenyl}pyrrolidine-l -sulfonamide; 7V-{5-chloro-3- [l-(4-{4-[(l-{4-[(37?)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]-l,4-diazepan-l- yl } -2-fluorophenyl)-3 -(pyridin-4-yl)- 17/-py razol -4-yl ]-2-fl uorophenyl (pyrrolidine- 1 - sulfonamide; rac-7V-{5-chloro-3-[l-(4-{4-[(l-{4-[(37?)-2,6-dioxopiperidin-3-yl]-2- fluorophenyl(piperidin-4-yl)methyl]piperazin-l-yl(phenyl)-3-(pyridin-4-yl)-lJH-pyrazol-4- yl]-2-fluorophenyl(pyrrolidine-l-sulfonamide; rac-7V-{5-chloro-3-[l-(4-{4-[(l-{4-[(37?)-2,6- dioxopiperidin-3-yl]-3-fluorophenyl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3- (pyridin-4-yl)-l//-pyrazol-4-yl]-2-fluorophenyl [pyrrolidine-1 -sulfonamide; 7V-[5-
(difluoromethyl)-3-[l-(4-{4-[(l-{4-[(37?)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4- yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4-yl)-lJH-pyrazol-4-yl]-2- fluorophenyl]pyrrolidine-l -sulfonamide; rac-7V-[5-(difluoromethyl)-3-[l-(4-{4-[(l-{5-[(37?)- 2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3- (pyridin-4-yl)-l//-pyrazol-4-yl]-2-fluorophenyl]pyrrolidine-l -sulfonamide; 7V-{5-chloro-3-[l- (6-{4-[(l-{4-[(37?)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]piperazin-l- yl}pyridin-3-yl)-3-(pyridin-4-yl)-lJH-pyrazol-4-yl]-2-fluorophenyl}pyrrolidine-l- sulfonamide; rac-7V-{5-chloro-3-[l-(6-{4-[(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2- yl}piperidin-4-yl)methyl]piperazin-l-yl}pyridin-3-yl)-3-(pyridin-4-yl)-lJH-pyrazol-4-yl]-2- fluorophenyl}pyrrolidine-l-sulfonamide; 7V-{5-chloro-3-[l-(4-{4-[(l-{4-[(37?)-2,6- dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}-2,5-difluorophenyl)-3- (pyridin-4-yl)- l//-pyrazol-4-yl]-2-fluorophenyl J pyrrolidine-1 -sulfonamide; rac-7V-{5-chloro-
3-[l-(4-{4-[(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4- yl)methyl]piperazin-l-yl}-2,5-difluorophenyl)-3-(pyridin-4-yl)-lJH-pyrazol-4-yl]-2- fluorophenyl}pyrrolidine-l-sulfonamide; 7V-[5-chloro-3-(l-{4-[4-({l-[5-(2,4-dioxo-l,3- diazinan- 1 -yl)pyri din-2 -y 1 ] piperi din-4-yl }methyl)piperazin- 1 -yl]phenyl } -3 -(pyridin-4-yl)- l//-pyrazol-4-yl)-2-fluorophenyl]pyrrolidine-l -sulfonamide; 7V-[5-(difluoromethyl)-3-(l-{4- [4-({l-[4-(2,4-dioxo-l,3-diazinan-l-yl)phenyl]piperidin-4-yl}methyl)piperazin-l-yl]-2- fluorophenyl} -3 -(pyridin-4-yl)-lJH-pyrazol-4-yl)-2-fluorophenyl]pyrrolidine-l -sulfonamide; rac-7V-[5-(difluoromethyl)-3-[l-(4-{4-[(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2- yl}piperidin-4-yl)methyl]piperazin-l-yl}-2-fluorophenyl)-3-(pyridin-4-yl)-lJH-pyrazol-4-yl]- 2-fluorophenyl]pyrrolidine-l -sulfonamide; 7V-[5-chloro-3-(l-{5-[4-({l-[4-(2,4-dioxo-l,3- diazinan- 1 -yl)phenyl]piperidin-4-yl }methyl)piperazin- 1 -yl]pyrimidin-2-yl } -3 -(pyridin-4-yl)- l#-pyrazol-4-yl)-2-fluorophenyl]pyrrolidine-l -sulfonamide; rac-7V-{5-chloro-3-[l-(5-{4-[(l- {5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l- yl}pyrimidin-2-yl)-3-(pyridin-4-yl)-lJH-pyrazol-4-yl]-2-fluorophenyl}pyrrolidine-l- sulfonamide; 7V-{5-chloro-3-[l-(5-{4-[(l-{4-[(37?)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-
4-yl)methyl]piperazin-l-yl}pyrimidin-2-yl)-3-(pyridin-4-yl)-lJH-pyrazol-4-yl]-2- fluorophenyl}pyrrolidine-l -sulfonamide; 7V-[5-chloro-3-(l-{4-[4-({l-[4-(2,4-dioxo-l,3- diazinan- 1 -yl)phenyl]piperidin-4-yl }methyl)piperazin- 1 -y 1 ] -3 -fluorophenyl } -3 -(pyridin-4- yl)-l#-pyrazol-4-yl)-2-fluorophenyl]pyrrolidine-l -sulfonamide; 7V-[5-(difluoromethyl)-3-[l- (4-{4-[(l-{4-[(37?)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}-2- fl uorophenyl )-3 -(pyri di n-4-yl )-l//-pyrazol -4-yl ]-2-fluorophenyl]pyrroli di ne-1 -sulfonamide; rac-7V-{5-chloro-3-[l-(4-{4-[(l-{5-[(37?)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4- yl)methyl]piperazin- 1 -yl } -3 -fluorophenyl)-3 -(pyridin-4-yl)- lJ7-pyrazol-4-yl]-2- fluorophenyl}pyrrolidine-l-sulfonamide; 7V-{5-chloro-3-[l-(4-{4-[(l-{4-[(37?)-2,6- dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}-3-fluorophenyl)-3- (pyridin-4-yl)- l//-pyrazol-4-yl]-2-fluorophenyl J pyrrolidine-1 -sulfonamide; (3R)-N-[5- chloro-3-(l-{4-[4-({l-[4-(2,4-di oxo-1, 3-diazinan-l -yl)phenyl]piperidin-4- yl } methyl)piperazin- 1 -yl] -3 -fluorophenyl } -3 -(py ridin-4-yl)- lJ7-pyrazol-4-yl)-2- fluorophenyl]-3-fluoropyrrolidine-l-sulfonamide; (37?)-7V-{5-chloro-3-[l-(4-{4-[(l-{5- [(37?5)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l-yl}-3- fluorophenyl)-3 -(pyridin-4-yl)- lZ/-pyrazol-4-yl]-2-fluorophenyl } -3 -fluoropyrrolidine- 1 - sulfonamide; (37?)-N-{5-chloro-3-[l-(4-{4-[(l-{4-[(37?)-2,6-dioxopiperidin-3- yl]phenyl }piperidin-4-yl)methyl]piperazin- 1 -yl } -3 -fluorophenyl)-3 -(pyridin-4-yl)- 1H- pyrazol-4-yl]-2-fluorophenyl}-3-fluoropyrrolidine-l-sulfonamide; 7V-[5-chloro-3-(l-{4-[4- ({1 -[5-(2,4-dioxo- 1 ,3 -diazinan- 1 -yl)pyri din-2 -y 1 ]piperi din-4-yl }methyl)piperazin- 1 - yl]phenyl} -3 -(pyridin-4-yl)- l//-pyrazol-4-yl)-2-fluorophenyl]-3 -fluoroazetidine- 1- sulfonamide; 7V-[5-chloro-3-(l-{4-[4-({l-[5-(2,4-dioxo-l,3-diazinan-l-yl)pyridin-2- yl]piperidin-4-yl}methyl)piperazin-l-yl]-2-fluorophenyl}-3-(pyridin-4-yl)-lJH-pyrazol-4-yl)-
2-fluorophenyl] -3 -fluoroazetidine- 1 -sulfonamide; 7V-[5-chloro-3-(l-{4-[4-({l-[5-(2,4-dioxo- l,3-diazinan-l-yl)pyridin-2-yl]piperidin-4-yl}methyl)piperazin-l-yl]-2-fluorophenyl}-3- (pyridin-4-yl)-l//-pyrazol-4-yl)-2-fluorophenyl]pyrrolidine-l -sulfonamide; (37?)-7V-[5-chloro-
3-(l-{4-[4-({l-[5-(2,4-dioxo-l,3-diazinan-l-yl)pyridin-2-yl]piperidin-4-yl}methyl)piperazin- l-yl]-2-fluorophenyl}-3-(pyridin-4-yl)-l//-pyrazol-4-yl)-2-fluorophenyl]-3- fluoropyrrolidine-1 -sulfonamide; 7V-{5-chloro-3-[l-(4-{4-[(l-{5-[(37?)-2,6-dioxopiperidin-3- yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4-yl)-lJH-pyrazol-4- yl]-2-fluorophenyl}cyclopentanesulfonamide; rac-7V-{5-chloro-3-[l-(4-{4-[(l-{5-[(37?)-2,6- dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4- yl)-l//-pyrazol-4-yl]-2-fluorophenyl } cyclopentanesulfonamide; 7V-{5-chloro-3-[l-(4-{4-[(l- {4-[(37?)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3- (pyridin-4-yl)-l//-pyrazol-4-yl]-2-fluorophenyl}cyclopentanesulfonamide; (37?)-3-(6-{4-[(4- {4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2,5-difluorophenyl)-3-(pyridin-4-yl)-lJH-pyrazol-
1 -yl]phenyl Jpiperazin- 1 -yl)methyl]piperidin- 1 -yl }pyri din-3 -yl)piperidine-2, 6-dione; rac- (3A)-3-(6-{4-[(4-{4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2,5-difluorophenyl)-3-(pyridin- 4-yl)- I //-py razol - 1 -yl]phenyl } piperazin- 1 -yl)methyl]piperidin- 1 -yl Jpyri din-3 -yl)piperidine- 2, 6-dione; (37?)-3-(4-{4-[(4-{4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2,5-difluorophenyl)- 3 -(pyridin-4-yl)- 1 //-pyrazol - 1 -yl]phenyl } piperazin- 1 -yl)methyl]piperidin- 1 - yl}phenyl)piperidine-2, 6-dione; 7V-[3-(l-{4-[(3A)-4-[(l-{4-[(3A)-2,6-dioxopiperidin-3- yl]phenyl }piperidin-4-yl)methyl]-3-methylpiperazin-l -yl]phenyl }-3-(pyridin-4-yl)-lJ7- pyrazol-4-yl)-2-fluorophenyl]propane-l -sulfonamide; (37?)-3-(6-{4-[(4-{4-[4-(3-
{ [ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-3-(pyridin-4-yl)-lJ7-pyrazol-l-yl]-3- fluorophenyl } piperazin- 1 -yl)methyl]piperidin- 1 -yl Jpyri din-3 -yl)piperidine-2, 6-dione; (35)-3 - (6-{4-[(4-{4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-3-(pyridin-4-yl)-lZ7- pyrazol-l-yl]-2-fluorophenyl}piperazin-l-yl)methyl]piperidin-l-yl}pyridin-3-yl)piperidine- 2,6-dione; rac-(7?)-N-(3-(l-(4-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l- yl )methyl)pi peri din-l-yl)phenyl )-3-(pyri di n-4-yl)-l/7-pyrazol -4-yl )-2-fl uorophenyl )propane-
1 -sulfonamide; 7V-(5-chloro-3-(l-(4-((3A,5A)-4-((l-(5-((A5)-2,6-dioxopiperidin-3-yl)pyridin-
2-yl)piperidin-4-yl)methyl)-3,5-dimethylpiperazin-l-yl)-2-fluorophenyl)-3-(pyridin-4-yl)- l/Z-pyrazol-4-yl)-2-fluorophenyl)pyrrolidine-l -sulfonamide; 7V-{5-chloro-3-[l-(5-{4-[(l-{5- [(35)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l-yl}pyridin-2- yl)-3-(pyridin-4-yl)-l//-pyrazol-4-yl]-2-fluorophenyl [pyrrolidine-1 -sulfonamide; N-{5- chloro-3-[l-(4-{4-[(l-{4-[(35)-2,6-dioxopiperidin-3-yl]-3-fluorophenyl}piperidin-4- yl)methyl]piperazin-l -yl [phenyl)-3-(pyridin-4-yl)-l//-pyrazol-4-yl]-2- fluorophenyl}pyrrolidine-l-sulfonamide; rac-7V-{5-chloro-3-[l-(4-{4-[(l-{4-[(3A)-2,6- dioxopiperidin-3-yl]-2,3-difluorophenyl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3- (pyridin-4-yl)- l//-pyrazol-4-yl]-2-fluorophenyl J pyrrolidine-1 -sulfonamide; rac-7V-{5-chloro-
3-[l-(4-{4-[(l-{4-[(3A)-2,6-dioxopiperidin-3-yl]-2,5-difluorophenyl}piperidin-4- yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl]-2- fluorophenyl}pyrrolidine-l-sulfonamide; rac-7V-{5-chloro-3-[l-(4-{4-[(l-{4-[(3A)-2,6- dioxopiperidin-3-yl]-3,5-difluorophenyl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3- (pyridin-4-yl)-lJ7-pyrazol-4-yl]-2-fluorophenyl}pyrrolidine-l-sulfonamide; and 7V-[5-chloro- 3-(l-{4-[4-({ l-[5-(2,4-dioxo-l,3-diazinan-l-yl)pyridin-2-yl]piperidin-4-yl}methyl)piperazin- l-yl]phenyl}-3-(pyridin-4-yl)-lJH-pyrazol-4-yl)-2-fluorophenyl]cyclopentanesulfonamide.
84. A pharmaceutical composition comprising the compound of any one of the previous claims and a pharmaceutically acceptable carrier, excipient, and/or diluent.
85. A method of treating a disease or disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound or composition of any one of the previous claims.
86. The method of claim 85, wherein the disease or disorder is cancer.
87. The compound or composition of any one of the previous claims for use in therapy.
88. The compound or composition of any one of the previous claims for use in the treatment of cancer.
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