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EP-4737444-A1 - PROCESSES AND INTERMEDIATES FOR PREPARING MCL1 INHIBITORS

EP4737444A1EP 4737444 A1EP4737444 A1EP 4737444A1EP-4737444-A1

Abstract

The present disclosure provides methods for preparing MCL1 inhibitors or a salt thereof and related key intermediates.

Inventors

  • BRAK, KATRIEN
  • JOHNSON, TREVOR C.
  • MERIT, JEFFREY E.
  • REGENS, Christopher S.
  • STANDLEY, Eric A.
  • STEINHUEBEL, DIETRICH P.
  • SU, Justin Y.
  • WU, TAO
  • YOUNG, Marshall D.
  • BULLOCK, Kae M.
  • CIZIO, Greg
  • DAO, Kathy
  • DIXON, Darryl D.
  • DUNETZ, JOSHUA R.
  • HUMPHREYS, Luke D.
  • HUYNH, Valerie
  • ISCHAY, Michael A.

Assignees

  • Gilead Sciences, Inc.

Dates

Publication Date
20260506
Application Date
20201120

Claims (15)

  1. A method of preparing a compound of Formula 9-E, comprising the step of performing a ring-closing metathesis on a compound of Formula 9-B to form the compound of Formula 9-E; wherein: R x is selected from hydrogen, C 1-6 alkyl and C 6-10 aryl, wherein the alkyl is optionally substituted with C 6-10 aryl; R y is selected from hydrogen, C 1-6 alkyl and optionally substituted aryl; R 2 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or 3-12 membered heterocycloalkyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, and 3-12 membered heterocycloalkyl are optionally substituted with 1-5 R 10 groups; R 3 is hydrogen, C 1-6 alkyl, -OR 7 , C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-12 membered heterocycloalkyl, -C(O)R 7 , or -CN, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, and 3-12 membered heterocycloalkyl are optionally substituted with 1-5 R 10 groups; each R 7 is independently hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein said C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 aryl, and 5-10 membered heteroaryl are optionally substituted with from 1-5 R 10 groups; each R 10 is independently C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 haloalkyl, 3-12 membered heterocycloalkyl, C 6 - 10 aryl, 5-10 membered heteroaryl, halogen, oxo, -OR a , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -OC(O)NR a R b , -NR a R b , -NR a C(O)R b , -NR a C(O)OR b , -S(O) q R a , -S(O) Z NR a R b , -NR a S(O) 2 R b , -N 3 , -CN, or -NO 2 , or two R 10 groups form a fused, spiro, or bridged C 3 - 10 cycloalkyl or 3-12 membered heterocycloalkyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5-10 membered heteroaryl are optionally substituted with 1-5 R 20 groups; wherein R a and R b are each independently hydrogen, C 1-6 alkyl, C 2 - 6 alkenyl, C 3-10 cycloalkyl, C 1-6 haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, or R a and R b together with the atoms to which they are attached form a 3-12 membered heterocycloalkyl, wherein said C 1-6 alkyl, C 2 - 6 alkenyl, C 3-10 cycloalkyl, C 1-6 haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 aryl, and 5-10 membered heteroaryl are optionally substituted with 1-5 R 20 groups; each R 20 is independently C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 haloalkyl, 3-12 membered heterocycloalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, hydroxyl, C 1-6 alkoxy, amino, -CN, -C(O)H, -C(O)NH 2 , -C(O)NH(C 1-6 alkyl), -C(O)N(C 1-6 alkyl) 2 , -COOH, -C(O)C 1-6 alkyl, -C(O)OC 1-6 alkyl, or halogen; q is 0, 1, or 2; R 5 is selected from C 1-6 alkyl and C 1-6 haloalkyl, each optionally substituted with 1-3 groups selected from halogen, oxo, C 3-6 cycloalkyl, and 4-6 membered heterocycloalkyl; and R 6 is hydrogen or halogen.
  2. The method of claim 1, wherein R y is hydrogen.
  3. The method of claim 1 or 2, wherein R x is hydrogen.
  4. The method of any one of claims 1 to 3, wherein R 2 is hydrogen or C 1-6 alkyl.
  5. The method of claim 4, wherein R 2 is methyl.
  6. The method of any one of claims 1 to 5, wherein R 3 is hydrogen, C 1-6 alkyl, or -OR 7 , wherein R 7 is C 1-6 alkyl.
  7. The method of claim 6, wherein R 7 is methyl.
  8. The method of any one of claims 1 to 7, wherein R 3 is hydrogen or C 1-6 alkyl.
  9. The method of claim 8, wherein R 3 is methyl.
  10. The method of any one of claims 1 to 3, wherein R 2 is hydrogen and R 3 is C 1-6 alkyl.
  11. The method of any one of claims 1 to 3, wherein R 2 is hydrogen and R 3 is methyl.
  12. The method of any one of claims 1 to 11, wherein R 5 is C 1-6 alkyl.
  13. The method of claim 12, wherein R 5 is methyl.
  14. The method of any one of claims 1 to 13, wherein R 6 is halogen.
  15. The method of claim 14, wherein R 6 is Cl.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. provisional application serial number 62/940,387 filed on November 26, 2019. The entire contents of the application are incorporated herein by reference in its entirety. FIELD The present disclosure relates to methods and intermediates for the synthesis of certain compounds which inhibit MCL1, for use in the treatment of cancers. BACKGROUND Apoptosis (programmed cell death) is a process for elimination of unwanted or potentially dangerous cells from an organism. Avoidance of apoptosis is critical for the development and sustained growth of tumors. Myeloid cell leukemia 1 protein (MCL1) is an antiapoptotic member of the Bcl-2 family of proteins. MCL1 is overexpressed in many cancers. Overexpression of MCL1 prevents cancer cells from undergoing apoptosis. Research has shown that MCL1 inhibitors can be used to treat cancers. Compounds that inhibit MCL1 have been disclosed, but there remains a need for synthetic methods for preparing such compounds on a manufacturing scale. PCT Application No. PCT/US2019/032053 (WO 2019/222112) discloses novel compounds useful as MCL1 inhibitors. This patent publication discloses that compounds according to Formula (A), and pharmaceutically acceptable salts thereof, are effective as inhibitors of MCL1, and are useful in the treatment of cancers. There is currently a need for synthetic methods and intermediates that can be used to prepare the compound of formula I and salts thereof. There is also a need for methods for preparing intermediate compounds that can be used to prepare the compound of formula I and salts thereof. SUMMARY The present disclosure provides methods for making compounds according to Formula (A), as shown above. In some embodiments, the present disclosure provides compounds according to Formula (I), wherein: - - - is a single or double bond; R12 is hydrogen or -C(O)R1;R1 is C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-10aryl, 3-12 membered heterocycloalkyl, 5-10 membered heteroaryl, -OR7, or -NR8R9, wherein said C1-6alkyl, C1-6haloalkyl, C2-6alkynyl, C3-10cycloalkyl, C6-10aryl, 3-12 membered heterocycloalkyl, and 5-10 membered heteroaryl are optionally substituted with 1-5 R10 groups;R2 is hydrogen, C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, or 3-12 membered heterocycloalkyl, wherein said C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, and 3-12 membered heterocycloalkyl are optionally substituted with 1-5 R10 groups;R3 is hydrogen, C1-6alkyl, -OR7, C1-6haloalkyl, C3-10cycloalkyl, 3-12 membered heterocycloalkyl, -C(O)R7, or -CN, wherein said C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, and 3-12 membered heterocycloalkyl are optionally substituted with 1-5 R10 groups;R4 is hydrogen;R5 is C1-6alkyl, -(CH2CH2O)pR7, C1-6haloalkyl, or C3-10cycloalkyl, wherein said C1-6alkyl, C1-6haloalkyl, or C3-10cycloalkyl, are optionally substituted with 1-5 R10 groups;R6 is hydrogen or halogen;each R7 is independently hydrogen, C1-6alkyl, C3-10cycloalkyl, C1-6haloalkyl, 3-12 membered heterocycloalkyl, C6-10aryl, or 5-10 membered heteroaryl, wherein said C1-6alkyl, C3-10cycloalkyl, C1-6haloalkyl, 3-12 membered heterocycloalkyl, C6-10 aryl, and 5-10 membered heteroaryl are optionally substituted with from 1-5 R10 groups;each R8 and R9 are independently hydrogen, C1-6alkyl, C3-10cycloalkyl, C1-6haloalkyl, 3-12 membered heterocycloalkyl, C6-10aryl, or 5-10 membered heteroaryl, or R8 and R9 together with the atoms to which they are attached form a 3-12 membered heterocycle, wherein said C1-6alkyl, C3-10cycloalkyl, C1-6haloalkyl, 3-12 membered heterocycloalkyl, C6-10aryl, and 5-10 membered heteroaryl are optionally substituted with 1-5 R10 groups;each R10 is independently C1-6alkyl, C3-10cycloalkyl, C1-6haloalkyl, 3-12 membered heterocycloalkyl, C6-10aryl, 5-10 membered heteroaryl, halogen, oxo, -ORa, - C(O)Ra, -C(O)ORa, -C(O)NRaRb, -OC(O)NRaRb, -NRaRb, -NRaC(O)Rb, - NRaC(O)ORb, -S(O)qRa, -S(O)2NRaRb, -NRaS(O)2Rb , -N3, -CN, or -NO2, or two R10 groups form a fused, spiro, or bridged C3-10cycloalkyl or 3-12 membered heterocycloalkyl, wherein said C1-6alkyl, C1-6haloalkyl, C2-6alkynyl, C3-10cycloalkyl, C6-10aryl, 3-12 membered heterocycle, and 5-10 membered heteroaryl is optionally substituted with 1-5 R20 groups;each Ra and Rb is independently hydrogen, C1-6alkyl, C2-6 alkenyl, C3-10cycloalkyl, C1-6haloalkyl, 3-12 membered heterocycloalkyl, C6-10aryl, 5-10 membered heteroaryl, or Ra and Rb together with the atoms to which they are attached form a 3-12 membered heterocycloalkyl, wherein said C1-6alkyl, C2-6alkenyl, C3-10cycloalkyl, C1-6haloalkyl, 3-12 membered heterocycloalkyl, C6-10aryl, 5-10 membered heteroaryl is optionally substituted with 1-5 R20 groups;each R20 is independently C1-6 alkyl, C3-10 cycloalkyl, C1-6haloalkyl, 3-12 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, hydroxyl, C1-6 alkoxy, amino, -CN, -C(O)H, -C(O)NH2, -C(O)NH(C1-6 alkyl), -C(O)N(C1-6