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US-12624024-B2 - EP2 antagonist compounds

US12624024B2US 12624024 B2US12624024 B2US 12624024B2US-12624024-B2

Abstract

Described herein are compounds of Formula (II): that are EP2 antagonists, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of diseases or conditions associated with EP2 activity.

Inventors

  • Matthew Alexander James Duncton
  • Vladimir V. SENATOROV, Jr.
  • Aaron R. FRIEDMAN
  • Steven Howard Olson

Assignees

  • RESERVOIR NEUROSCIENCE, INC.

Dates

Publication Date
20260512
Application Date
20231222

Claims (20)

  1. 1 . A compound having the structure of Formula (II): or a pharmaceutically acceptable salt thereof, wherein: R 1 and R 2 are each independently hydrogen, deuterium, halogen, or C 1-4 alkyl; R 3 and R 4 are each independently hydrogen, deuterium, halogen, or C 1-4 alkyl; R 5 and R 6 are each independently hydrogen, deuterium, halogen, or C 1-4 alkyl; or R 5 and R 6 are taken together with the carbon atom to which they are attached to form an oxetane; R 7 and R 8 are each independently hydrogen, deuterium, halogen, —CN, —C 1-4 alkyl, —C 1-4 haloalkyl, —OH, —O(C 1-4 alkyl), —O(C 1-4 haloalkyl), —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —(C 1-4 alkyl)O(C 1-4 alkyl), —C(O)OH, —C(O)O(C 1-4 alkyl), —C(O)NH 2 , —C(O)NH(C 1-4 alkyl), —C(O)N(C 1-4 alkyl) 2 , substituted or unsubstituted C 3-6 cycloalkyl, or substituted or unsubstituted 3- to 6-membered heterocycloalkyl; or R 7 and R 8 are taken together with the carbon atom to which they are attached to form a cyclopropane or an oxetane; R 9 and R 10 are each independently hydrogen, deuterium, halogen, or C 1-4 alkyl; or R 9 and R 10 are taken together with the carbon atom to which they are attached to form an oxetane; R A1 is halogen, C 1-4 alkyl, or cyclopropyl; and R A2 is hydrogen, deuterium, halogen, or optionally deuterated or halogenated methyl; each R B is independently selected from the group consisting of halogen, —CN, —C 1-4 alkyl, —C 1-4 haloalkyl, —C 1-4 aminoalkyl, —C 1-4 hydroxyalkyl, —C 1-4 methoxyalkyl, —(C 1-4 alkyl)O(C 1-4 alkyl), —C(O)(C 1-4 alkyl), —C(O)OH, —C(O)O(C 1-4 alkyl), —C(O)NH 2 , —C(O)NH(C 1-4 alkyl), —C(O)N(C 1-4 alkyl) 2 , —NH 2 , —NH(C 1-4 alkyl), —NH(C 3-6 cycloalkyl), —NH(C 3-6 heterocycloalkyl), —N(C 1-4 alkyl) 2 , —NHC(O)C 1-4 alkyl, —NHC(O)O(C 1-4 alkyl), —NHS(O) 2 C 1-4 alkyl, —OH, —O(C 1-4 alkyl), —O(C 1-4 haloalkyl), —SH, —S(C 1-4 alkyl), —S(O)(C 1-4 alkyl), —S(O)(NH)(C 1-4 alkyl), —S(O) 2 (C 1-4 alkyl), —S(O) 2 NH 2 , —S(O 2 )NHCH 3 , substituted or unsubstituted C 3-6 cycloalkyl, or substituted or unsubstituted 3- to 6-membered heterocyclyl; Ring C is bicyclic heterocycle having one or more nitrogen atoms; or Ring C is Ring C′; each R C is independently selected from the group consisting of halogen, —CN, —C 1-4 alkyl, —C 1-4 haloalkyl, —(C 1-4 alkyl)O(C 1-4 alkyl), —C(O)OH, —C(O)O(C 1-4 alkyl), —C(O)NH 2 , —C(O)NH(C 1-4 alkyl), —C(O)N(C 1-4 alkyl) 2 , —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —OH, —O(C 1-4 alkyl), —O(C 1-4 haloalkyl), —S(C 1-4 alkyl), —SO 2 C 1-4 alkyl, —SO 2 NHC 1-4 alkyl, substituted or unsubstituted C 3-6 cycloalkyl, or substituted or unsubstituted 3- to 6-membered heterocyclyl; or two R C taken together form a carbonyl; m is 0 to 3; n is 1, 2 or 3; and Ring C′ is selected from the group consisting of:
  2. 2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R A1 is halogen.
  3. 3 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R A1 is —Cl.
  4. 4 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of:
  5. 5 . The compound of claim 1 , having the structure: or a pharmaceutically acceptable salt thereof.
  6. 6 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having the structure: or a pharmaceutically acceptable salt thereof, wherein: Ring C is bicyclic heterocycle having one or more nitrogen atoms; or Ring C is Ring C′; each R C is independently selected from the group consisting of halogen, —CN, —C 1-4 alkyl, —C 1-4 haloalkyl, —(C 1-4 alkyl)O(C 1-4 alkyl), —C(O)OH, —C(O)O(C 1-4 alkyl), —C(O)NH 2 , —C(O)NH(C 1-4 alkyl), —C(O)N(C 1-4 alkyl) 2 , —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —OH, —O(C 1-4 alkyl), —O(C 1-4 haloalkyl), —S(C 1-4 alkyl), —SO 2 C 1-4 alkyl, —SO 2 NHC 1-4 alkyl, substituted or unsubstituted C 3-6 cycloalkyl, or substituted or unsubstituted 3- to 6-membered heterocyclyl; or two R C taken together form a carbonyl; m is 0 to 3; n is 1, 2 or 3; and Ring C′ is selected from the group consisting of:
  7. 7 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring C is bicyclic heteroaryl having one, two or three nitrogen atoms.
  8. 8 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring C is bicyclic heteroaryl consisting of a pyrrole ring or pyrazole ring fused to a phenyl ring, a pyridine ring, or a pyrimidine ring.
  9. 9 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring C is a substituted or unsubstituted indole, or a substituted or unsubstituted azaindole.
  10. 10 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring C is a substituted or unsubstituted indole.
  11. 11 . The compound of claim 1 , wherein Ring C is a bicyclic heterocycle having one or more nitrogens, selected from the group consisting of:
  12. 12 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R C is halogen, and m is 0, 1, or 2.
  13. 13 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring C is indole; Re is halogen, and m is 1.
  14. 14 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R B is independently halogen, C 1-4 alkyl, C 1-4 haloalkyl, —C(O)OH, —C(O)O(C 1-4 alkyl), —C(O)NH 2 , —C(O)NH(C 1-4 alkyl), or —C(O)N(C 1-4 alkyl) 2 .
  15. 15 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R B is independently selected from the group consisting of —F, —Cl, —CN, —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , —OH, and —OCH 3 .
  16. 16 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R B is independently selected from the group consisting of —F, —Cl, —CN, —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , CH 2 NH 2 , —CH 2 NHBoc, —CH 2 OH, —CH 2 OCH 3 , —C(O)NH 2 , —C(O)NHCH 3 , —C(O)N(CH 3 ) 2 , —C(O)OH, —C(O)OCH 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NH(oxetanyl), —NHC(O)CH 3 , —NHS(O) 2 CH 3 , —OH, —OCH 3 , —OCH 2 CF 3 , —S(O)(NH)CH 3 , methylpyrazolyl, and pyrazolyl.
  17. 17 . The compound of claim 1 , having the structure: or a pharmaceutically acceptable salt thereof.
  18. 18 . The compound of claim 1 , having the structure: or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein: each R B is independently selected from the group consisting of halogen, —CN, —C 1-4 alkyl, —C 1-4 haloalkyl, —C 1-4 aminoalkyl, —C 1-4 hydroxyalkyl, —C 1-4 methoxyalkyl, —(C 1-4 alkyl)((C 1-4 alkyl), —C(O)(C 1-4 alkyl), —C(O)OH, —C(O)O(C 1-4 alkyl), —C(O)NH 2 , —C(O)NH(C 1-4 alkyl), —C(O)N(C 1-4 alkyl) 2 , —NH 2 , —NH(C 1-4 alkyl), —NH(C 3-6 cycloalkyl), —NH(C 3-6 heterocycloalkyl), —N(C 1-4 alkyl) 2 , —NHC(O)C 1-4 alkyl, —NHC(O)O(C 1-4 alkyl), —NHS(O) 2 C 1-4 alkyl, —OH, —O(C 1-4 alkyl), —O(C 1-4 haloalkyl), —SH, —S(C 1-4 alkyl), —SO(C 1-4 alkyl), —S(O) 2 (C 1-4 alkyl), —S(O) 2 NH 2 , —S(O 2 )NHCH 3 , substituted or unsubstituted C 3-6 cycloalkyl, or substituted or unsubstituted 3- to 6-membered heterocyclyl; and each R C is independently selected from the group consisting of halogen, —CN, —C 1-4 alkyl, —C 1-4 haloalkyl, —(C 1-4 alkyl)O(C 1-4 alkyl), —C(O)OH, —C(O)O(C 1-4 alkyl), —C(O)NH 2 , —C(O)NH(C 1-4 alkyl), —C(O)N(C 1-4 alkyl) 2 , —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —OH, —O(C 1-4 alkyl), —O(C 1-4 haloalkyl), —S(C 1-4 alkyl), —SO 2 C 1-4 alkyl, —SO 2 NHC 1-4 alkyl, substituted or unsubstituted C 3-6 cycloalkyl, or substituted or unsubstituted 3- to 6-membered heterocyclyl; or two R C taken together form a carbonyl.
  19. 19 . The compound of claim 1 , wherein n is 1.
  20. 20 . The compound of claim 1 , wherein n is 2.

Description

CROSS-REFERENCE This application is a continuation of PCT Application No. US2022/034901, filed Jun. 24, 2022, which claims the benefit of the earlier filing date of U.S. Provisional Patent Application No. 63/214,645, filed on Jun. 24, 2021. Both prior applications are incorporated herein by reference in their entireties. FIELD OF THE INVENTION Described herein are compounds that are inhibitors of prostaglandin E2 receptor 2, also known as EP2, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of diseases or conditions associated with EP2 activity. BACKGROUND OF THE INVENTION EP2 is a prostaglandin receptor that functions, for example, as a mediator of inflammation. EP2 signaling is implicated in, for example, inflammatory conditions, allergic diseases, ocular diseases, nervous system diseases, bone diseases, fibrotic conditions, cardiovascular diseases, and certain forms of cancer. SUMMARY OF THE INVENTION Compounds described herein are antagonists of EP2. In some embodiments, the compounds described herein are used in the treatment or prevention of diseases or conditions in which EP2 activity contributes to the symptomology or progression of the diseases or conditions, such as, for example, inflammatory diseases or conditions. In an aspect, disclosed herein is a compound having the structure of Formula (II): or a pharmaceutically acceptable salt thereof, wherein:R1 and R2 are each independently hydrogen, deuterium, halogen, or C1-4 alkyl;A1 is —O—, —CR5R6—, —S—, —S(═O)2— or absent;A2 is —CR7R8— or —S(═O)2—;A3 is —CR9R10— or absent;R3 and R4 are each independently hydrogen, deuterium, halogen, or C1-4 alkyl;R5 and R6 are each independently hydrogen, deuterium, halogen, or C1-4 alkyl; or R5 and R6 are taken together with the carbon atom to which they are attached to form an oxetane;R7 and R8 are each independently hydrogen, deuterium, halogen, —CN, —C1-4 alkyl, —C1-4 haloalkyl, —OH, —O(C1-4 alkyl), —O(C1-4 haloalkyl), —NH2, —NH(C1-4 alkyl), —N(C1-4 alkyl)2, —(C1-4 alkyl)O(C1-4 alkyl), —C(O)OH, —C(O)O(C1-4 alkyl), —C(O)NH2, —C(O)NH(C1-4 alkyl), —C(O)N(C1-4 alkyl)2, substituted or unsubstituted C3-6 cycloalkyl, or substituted or unsubstituted 3- to 6-membered heterocycloalkyl; or R7 and R8 are taken together with the carbon atom to which they are attached to form a cyclopropane or an oxetane;R9 and R10 are each independently hydrogen, deuterium, halogen, or C1-4 alkyl; or R9 and R10 are taken together with the carbon atom to which they are attached to form an oxetane;RA1 is halogen, C1-4 alkyl, or cyclopropyl; andRA2 is hydrogen, deuterium, halogen, or optionally deuterated or halogenated methyl;Ring B is C3-6 cycloalkyl, phenyl, 5-membered heteroaryl, or 6-membered heteroaryl containing two or more nitrogen atoms; or Ring B is Ring B′;each RB is independently selected from the group consisting of halogen, —CN, —C1-4 alkyl, —C1-4 haloalkyl, —C1-4 aminoalkyl, —C1-4 hydroxyalkyl, —C1-4 methoxyalkyl, —(C1-4 alkyl)O(C1-4 alkyl), —C(O)(C1-4 alkyl), —C(O)OH, —C(O)O(C1-4 alkyl), —C(O)NH2, —C(O)NH(C1-4 alkyl), —C(O)N(C1-4 alkyl)2, —NH2, —NH(C1-4 alkyl), —NH(C3-6 cycloalkyl), —NH(C3-6 heterocycloalkyl), —N(C1-4 alkyl)2, —NHC(O)C1-4 alkyl, —NHC(O)O(C1-4 alkyl), —NHS(O)2C1-4 alkyl, —OH, —O(C1-4 alkyl), —O(C1-4 haloalkyl), —SH, —S(C1-4 alkyl), —S(O)(C1-4 alkyl), —S(O)(NH)(C1-4 alkyl), —S(O)2(C1-4 alkyl), —S(O)2NH2, —S(O2)NHCH3, substituted or unsubstituted C3-6 cycloalkyl, or substituted or unsubstituted 3- to 6-membered heterocyclyl; or two RB taken together form a carbonyl;Ring C is bicyclic heterocycle having one or more nitrogen atoms; or Ring C is Ring C′;each RC is independently selected from the group consisting of halogen, —CN, —C1-4 alkyl, —C1-4 haloalkyl, —(C1-4 alkyl)O(C1-4 alkyl), —C(O)OH, —C(O)O(C1-4 alkyl), —C(O)NH2, —C(O)NH(C1-4 alkyl), —C(O)N(C1-4 alkyl)2, —NH2, —NH(C1-4 alkyl), —N(C1-4 alkyl)2, —OH, —O(C1-4 alkyl), —O(C1-4 haloalkyl), —S(C1-4 alkyl), —SO2C1-4 alkyl, —SO2NHC1-4 alkyl, substituted or unsubstituted C3-6 cycloalkyl, or substituted or unsubstituted 3- to 6-membered heterocyclyl; or two RB taken together form a carbonyl;m is 0 to 3;n is 0 to 3; andRing B′ is selected from the group consisting of: and Ring C′ is selected from the group consisting of: In another embodiment is a compound having the structure of Formula III: or a pharmaceutically acceptable salt thereof, wherein:Ring B is C3-6 cycloalkyl, phenyl, 5-membered heteroaryl, or 6-membered heteroaryl containing two or more nitrogen atoms;each RB is independently selected from the group consisting of halogen, —CN, —C1-4 alkyl, —C1-4 haloalkyl, —C1-4 aminoalkyl, —C1-4 hydroxyalkyl, —C1-4 methoxyalkyl, —(C1-4 alkyl)O(C1-4 alkyl), —C(O)(C1-4 alkyl), —C(O)OH, —C(O)O(C1-4 alkyl), —C(O)NH2, —C(O)NH(C1-4 alkyl), —C(O)N(C1-4 alkyl)2, —NH2, —NH(C1-4 alkyl), —NH(C3-6 cycloalkyl), —NH(C3-6 heterocycloalkyl), —N(C1-4 alkyl)2, —NHC(O)C1-4 alkyl,