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US-12617799-B2 - Pyrazolopyrimidinone compounds

US12617799B2US 12617799 B2US12617799 B2US 12617799B2US-12617799-B2

Abstract

Provided herein are pyrazolopyrimidinone compounds and pharmaceutical compositions comprising said compounds.

Inventors

  • Neil RAHEJA
  • Paul CROWE
  • Haiyan TAO
  • Scott Thacher

Assignees

  • Orphagen Pharmaceuticals, Inc.

Dates

Publication Date
20260505
Application Date
20220325

Claims (20)

  1. 1 . A compound having the structure of Formula (I): wherein: X is a bond or C 1 -C 6 alkylene; R 1 is selected from C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, —CH 2 C 6-10 aryl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, —CH 2 C 6-10 aryl, C 6-10 aryl and C 1-9 heteroaryl are optionally substituted with one, two, three, four, or five R 4 ; R 2 is selected from C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl and C 1-9 heteroaryl, wherein C 3-8 cycloalkyl, C 2-9 heterocyclkyl, C 6-10 aryl and C 1-9 heteroaryl are optionally substituted with one, two, three, four, or five R 5 ; R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 3-8 cycloalkyl; each R 4 and each R 5 are each independently selected from halogen, —CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, —OR 6 , —SR 6 , —C(O)OR 6 , —OC(O)N(R 6 )(R 7 ), —N(R 8 )C(O)N(R 6 )(R 7 ), —N(R 8 )C(O)R 9 , —N(R 8 )C(O)OR 9 , —N(R 8 )S(O) 2 R 9 , —C(O)R 9 , —OC(O)R 9 , —C(O)N(R 6 )(R 7 ), —C(O)C(O)N(R 6 )(R 7 ), —S(O)R 9 , —S(O) 2 R 9 , and —S(O) 2 N(R 6 )(R 7 ), wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, —OR 10 , —SR 10 , —C(O)OR 10 , —OC(O)N(R 10 )(R 11 ), —N(R 12 )C(O)N(R 10 )(R 11 ), —N(R 12 )C(O)R 13 , —N(R 12 )C(O)OR 13 , —N(R 12 )S(O) 2 R 13 , —C(O)R 13 , —OC(O)R 13 , —C(O)N(R 10 )(R 11 ), —C(O)C(O)N(R 10 )(R 11 ), —S(O)R 13 , —S(O) 2 R 13 , and —S(O) 2 N(R 10 )(R 11 ); each R 6 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl; each R 7 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl; each R 8 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl; each R 9 is independently selected C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl; each R 10 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl; each R 11 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl; each R 12 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl; and each R 13 is independently selected C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl; or a pharmaceutically acceptable salt or solvate thereof.
  2. 2 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is selected from C 6-10 aryl and C 1-9 heteroaryl, wherein C 6-10 aryl and C 1-9 heteroaryl are optionally substituted with one, two, three, four, or five R 4 .
  3. 3 . The compound of claim 2 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is phenyl optionally substituted with one, two, or three R 4 .
  4. 4 . The compound of claim 3 or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 is independently selected from halogen, —CN, C 1-6 alkyl, C 1-6 haloalkyl, and —OR 6 .
  5. 5 . The compound of claim 4 , or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 is independently selected from C 1-6 haloalkyl.
  6. 6 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C 3-8 cycloalkyl optionally substituted with one, two, three, four, or five R 5 .
  7. 7 . The compound of claim 6 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is cyclohexyl optionally substituted with one, two, or three R 5 .
  8. 8 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C 6-10 aryl optionally substituted with one, two, three, four, or five R 5 .
  9. 9 . The compound of claim 8 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is phenyl optionally substituted with one, two, or three R 5 .
  10. 10 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein each R 5 is independently selected from halogen, C 1-6 haloalkyl, —OR 6 , and C 1-6 alkyl optionally substituted with one group selected from —OR 10 , —C(O)OR 10 , —C(O)N(R 10 )(R 11 ), —S(O) 2 R 13 , and —S(O) 2 N(R 10 )(R 11 ).
  11. 11 . The compound of claim 10 , or a pharmaceutically acceptable salt or solvate thereof, wherein each R 5 is independently selected from halogen, —OR 6 , and C 1-6 alkyl optionally substituted with one group selected from —OR 10 , —C(O)OR 10 , —C(O)N(R 10 )(R 11 ), and —S(O) 2 R 13 .
  12. 12 . The compound of claim 11 , or a pharmaceutically acceptable salt or solvate thereof, wherein each R 6 is independently selected from hydrogen and C 1-6 alkyl optionally substituted with one, two, or three groups selected from halogen and hydroxy.
  13. 13 . The compound of claim 11 , or a pharmaceutically acceptable salt or solvate thereof, wherein each R 10 is independently selected hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl.
  14. 14 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is C 1 -C 6 alkyl.
  15. 15 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein X is a bond.
  16. 16 . The compound of claim 1 selected from: or a pharmaceutically acceptable salt or solvate thereof.
  17. 17 . A pharmaceutical composition comprising a pharmaceutically acceptable diluent, excipient or binder, and a compound of claim 1 ; or a pharmaceutically acceptable salt or solvate thereof.
  18. 18 . A method of treating cancer in a mammal, comprising administering to the mammal a compound of claim 1 ; or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is selected from adrenocortical carcinoma, ovarian cancer , head and neck cancer, edometrial cancer, hormone-dependent prostate cancer, non-small cell lung carcinoma (NSCLC), melanoma, pituitary gonadotroph adenomas, and sex cord stromal tumors.
  19. 19 . The method of claim 18 , wherein the cancer is adrenocortical carcinoma.
  20. 20 . A method of treating an endocrine disease in a mammal, comprising administering to the mammal a compound of claim 1 ; or a pharmaceutically acceptable salt or solvate thereof, wherein the endocrine disease is selected from endogenous Cushing's syndrome,congenital adrenal hyperplasia, and polycystic ovary syndrome.

Description

CROSS-REFERENCE This application claims benefit of U.S. Provisional Patent Application No. 63/166,739, filed on Mar. 26, 2021 which is incorporated herein by reference in its entirety. BACKGROUND Steroidogenic factor 1 (SF-1, NR5A1) is a transcriptional regulator of genes involved in the development and function of steroidogenic tissues. SF-1 modulators provide an opportunity for new therapeutic compounds that regulate the growth and function of SF-1-dependent tissues. BRIEF SUMMARY OF THE INVENTION This disclosure provides, for example, pyrazolopyrimidine compounds, their use as medicinal agents for the treatment of cancer, processes for their preparation, and pharmaceutical compositions that include disclosed compounds as at least one active ingredient. The disclosure also provides for the use of compounds described herein as medicaments and/or in the manufacture of medicaments for the treatment of cancer, endocrine diseases, and endometriosis. In one aspect is a compound of Formula (I): wherein: X is a bond or C1-C6alkylene;R1 is selected from C3-8cycloalkyl, C2-9heterocycloalkyl, —CH2C6-10aryl, C6-10aryl, and C1-9heteroaryl, wherein C3-8cycloalkyl, C2-9heterocycloalkyl, —CH2C6-10aryl, C6-10aryl and C1-9heteroaryl are optionally substituted with one, two, three, four, or five R4;R2 is selected from C3-8cycloalkyl, C2-9heterocycloalkyl, C6-10aryl and C1-9heteroaryl, wherein C3-8cycloalkyl, C2-9heterocycloalkyl, C6-10aryl and C1-9heteroaryl are optionally substituted with one, two, three, four, or five R5;R3 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, or C3-8cycloalkyl;each R4 and each R5 are each independently selected from halogen, —CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, —OR6, —SR6, —C(O)OR6, —OC(O)N(R6)(R7), —N(R8)C(O)N(R6)(R7), —N(R8)C(O)R9, —N(R8)C(O)OR9, —N(R8)S(O)2R9, —C(O)R9, —OC(O)R9, —C(O)N(R6)(R7), —C(O)C(O)N(R6)(R7), —S(O)R9, —S(O)2R9, and —S(O)2N(R6)(R7), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, —OR10, —SR10, —C(O)OR10, —OC(O)N(R10)(R11), —N(R12)C(O)N(R10)(R11), —N(R12)C(O)R13, —N(R12)C(O)OR13, —N(R12)S(O)2R13, —C(O)R13, —OC(O)R13, —C(O)N(R10)(R11), —C(O)C(O)N(R10)(R11), —S(O)R13, —S(O)2R13, and —S(O)2N(R10)(R11);each R6 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl;each R7 is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl;each R8 is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl;each R9 is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl;each R10 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl;each R11 is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl;each R12 is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; andeach R13 is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; or a pharmaceutically acceptable salt or solvate thereof. In another embodiment is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R1 is selected from C6-10aryl and C1-9heteroaryl, wherein C6-10aryl and C1-9heteroaryl are optionally substituted with one, two, three, four, or five R4. In another