Aryl alkynamide derivatives

Patent metadata

Field	Value
Publication number	US-11912679-B2
Application number	US-202318372771-A
Country	US
Kind code	B2
Filing date	Sep 26, 2023
Priority date	Feb 28, 2022
Publication date	Feb 27, 2024
Grant date	Feb 27, 2024

Abstract

[Problem] A compound which is useful as a STING inhibitor is provided.
[Means for Solution] The present inventors have found aryl alkynamide derivatives having an inhibitory action on STING. The aryl alkynamide derivatives of the present invention have an inhibitory action on STING and can be used as an agent for treating an autoimmune disease, a neurodegenerative disease, a type I interferonopathy and/or other STING-mediated disease.

First claim

The invention claimed is:

1. A compound of formula (I) or a salt thereof:

wherein,
Ring A is phenyl,
Ring B is formula (V):

X is CH or N,
R a1 , R a2 and R b1 are H,
R b2 is halogeno-C 1-6 alkyl,
R 1 is H,
R 2 is C 1-6 alkyl which is substituted by one or two R 3 ,
or, R 1 and R 2 are linked to each other to form azetidinyl, pyrrolidinyl, piperidinyl or thiomorpholinyl together with the nitrogen atom to which R 1 and R 2 are attached, wherein the azetidinyl, pyrrolidinyl, piperidinyl or thiomorpholinyl may be optionally substituted with one or two R 7 ,
each R 3 is independently —OH or —C(═O)—NH 2 , and
each R 7 is independently —C 1-6 alkylene-OH, —OH, —C(═O)—NH 2 , oxo or imino.

2. The compound or a salt thereof according to claim 1 , wherein the compound is a compound selected from the following group of:
N 2 -{3-[2-(trifluoromethyl)[1,1′-biphenyl]-4-yl]prop-2-ynoyl}-L-serinamide,
1-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-3-[2-(trifluoromethyl)[1,1′-biphenyl]-4-yl]prop-2-yn-1-one,
1-{3-[2-(trifluoromethyl)[1,1′-biphenyl]-4-yl]prop-2-ynoyl}piperidine-4-carboxamide,
1-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-3-[2-(trifluoromethyl)[1,1′-biphenyl]-4-yl]prop-2-yn-1-one,
1-[3,3-bis(hydroxymethyl)azetidin-1-yl]-3-[2-(trifluoromethyl)[1,1′-biphenyl]-4-yl]prop-2-yn-1-one,
N-[(2R)-2,3-dihydroxypropyl]-3-[2-(trifluoromethyl)[1,1′-biphenyl]-4-yl]prop-2-ynamide,
N-[(2S)-2,3-dihydroxypropyl]-3-[2-(trifluoromethyl)[1,1′-biphenyl]-4-yl]prop-2-ynamide,
1-[(3S,4S)-3,4-dihydroxypyrrolidin-1-yl]-3-[2-(trifluoromethyl)[1,1′-biphenyl]-4-yl]prop-2-yn-1-one,
(3R)-1-{3-[2-(trifluoromethyl)[1,1′-biphenyl]-4-yl]prop-2-ynoyl}pyrrolidine-3-carboxamide,
1-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-3-[6-phenyl-5-(trifluoromethyl)pyridin-3-yl]prop-2-yn-1-one, and
1-imino-4-{3-[2-(trifluoromethyl)[1,1′-biphenyl]-4-yl]prop-2-ynoyl}-1λ 6 -thiomorpholin-1-one.

3. A pharmaceutical composition comprising the compound or a salt thereof according to claim 1 and one or more pharmaceutically acceptable excipients.

4. A method for therapeutic treatment of an autoimmune disease, a neurodegenerative disease, a type I interferonopathy and/or other STING-mediated disease comprising administering to a subject an effective amount of the compound or a salt thereof according to claim 1 .

5. The compound or a salt thereof according to claim 2 wherein the compound is N 2 -{3-[2-(trifluoromethyl)[1,1′-biphenyl]-4-yl]prop-2-ynoyl}-L-serinamide.

6. The compound or a salt thereof according to claim 2 , wherein the compound is 1-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-3-[2-(trifluoromethyl)[1,1′-biphenyl]-4-yl]prop-2-yn-1-one.

7. The compound or a salt thereof according to claim 2 , wherein the compound is 1-{3-[2-(trifluoromethyl)[1,1′-biphenyl]-4-yl]prop-2-ynoyl}piperidine-4-carboxamide.

8. The compound or a salt thereof according to claim 2 , wherein the compound is 1-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-3-[2-(trifluoromethyl)[1,1′-biphenyl]-4-yl]prop-2-yn-1-one.

9. The compound or a salt thereof according to claim 2 , wherein the compound is 1-[3,3-bis(hydroxymethyl)azetidin-1-yl]-3-[2-(trifluoromethyl)[1,1′-biphenyl]-4-yl]prop-2-yn-1-one.

10. The compound or a salt thereof according to claim 2 , wherein the compound is N-[(2R)-2,3-dihydroxypropyl]-3-[2-(trifluoromethyl)[1,1′-biphenyl]-4-yl]prop-2-ynamide.

11. The compound or a salt thereof according to claim 2 , wherein the compound is N-[(2S)-2,3-dihydroxypropyl]-3-[2-(trifluoromethyl)[1,1′-biphenyl]-4-yl]prop-2-ynamide.

12. The compound or a salt thereof according to claim 2 , wherein the compound is 1-[(3S,4S)-3,4-dihydroxypyrrolidin-1-yl]-3-[2-(trifluoromethyl)[1,1′-biphenyl]-4-yl]prop-2-yn-1-one.

13. The compound or a salt thereof according to claim 2 , wherein the compound is (3R)-1-{3-[2-(trifluoromethyl)[1,1′-biphenyl]-4-yl]prop-2-ynoyl}pyrrolidine-3-carboxamide.

14. The compound or a salt thereof according to claim 2 , wherein the compound is 1-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-3-[6-phenyl-5-(trifluoromethyl)pyridin-3-yl]prop-2-yn-1-one.

15. The compound or a salt thereof according to claim 2 , wherein the compound is 1-imino-4-{3-[2-(trifluoromethyl)[1,1′-biphenyl]-4-yl]prop-2-ynoyl}-1λ 6 -thiomorpholin-1-one.

16. A pharmaceutical composition comprising the compound or a salt thereof according to claim 2 and one or more pharmaceutically acceptable excipients.

17. A method for therapeutic treatment of systemic lupus erythematosus and/or Sjogren's syndrome comprising administering to a subject an effective amount of the compound or a salt thereof according to claim 1 .

18. A method for therapeutic treatment of an autoimmune disease, a neurodegenerative disease, a type I interferonopathy and/or other STING-mediated disease comprising administering to a subject an effective amount of the compound or a salt thereof according to claim 2 .

19. A method for therapeutic treatment of systemic lupus erythematosus and/or Sjogren's syndrome comprising administering to a subject an effective amount of the compound or a salt thereof according to claim 2 .

Assignees

• Astellas Pharma Inc
• Mitobridge Inc

Inventors

• Maeda Junko
• Kuriwaki Ikumi
• Kitamura Kai
• Yamashita Yumi
• Kakefuda Kenichi
• Kamikawa Akio
• Negoro Kenji
• Hamaguchi Wataru
• Seo Ryushi
• Ciavarri Jeffrey

Classifications

• C07F7/12

  Organo silicon halides · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• A61K31/695

  Silicon compounds · CPC title

• A61K31/40

  having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil · CPC title

• C07C311/24

  of an acyclic saturated carbon skeleton · CPC title