Quinoline cGAS antagonist compounds

Patent metadata

Field	Value
Publication number	US-12134609-B2
Application number	US-202318334325-A
Country	US
Kind code	B2
Filing date	Jun 13, 2023
Priority date	Sep 3, 2020
Publication date	Nov 5, 2024
Grant date	Nov 5, 2024

Abstract

The present disclosure provides compounds that are cGAS antagonists, methods of preparation of the compounds, pharmaceutical compositions comprising the compounds, and their use in medical therapy.

First claim

What is claimed is:

1. A compound, wherein the compound is of formula I*:

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is an optionally substituted imidazole, pyrazole, pyrrole, furan, or pyridine;
R 2 is —NRR 5 ,

each R 3 is independently halogen, —OMe, —OEt, —NR 2 , or —SR;
Ring B1 is substituted phenyl;
Ring B2 is a 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each R is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic; benzyl; phenyl; a 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
R 5 is —(CH 2 ) 2-4 OH, —(CH 2 ) 2-4 O(CH 2 ) 1-5 CO 2 H, —(CH 2 ) 2-4 O(CH 2 ) 1-5 CO 2 C 1-4 alkyl, —(CH 2 ) 0-3 CH(CH 2 OH) 2 , —(CH 2 ) 2-4 OC 1-4 alkyl, —(CR 2 ) 0-5 CO 2 R, —(CR 2 ) 0-5 CONR 2 , —(CR 2 ) 0-4 C(O)NR(CR 2 ) 0-4 CO 2 R, —(CR 2 ) 0-4 C(O)NR(CR 2 ) 0-4 CONR 2 , —(CR 2 ) 0-4 NRC(O)R, —(CR 2 ) 0-4 SO 3 R, —(CR 2 ) 0-4 SO 2 NR 2 , —(CR 2 ) 0-4 OSO 2 NR 2 , —(CR 2 ) 0-4 NRSO 2 R, —(CR 2 ) 0-4 NRSO 2 OR, —(CR 2 ) 0-4 OP(OR) 2 , —(CR 2 ) 0-4 OP(O)(OR) 2 , —(CR 2 ) 0-4 P(O)(OR) 2 , —(CR 2 ) 0-4 OP(O)(H)OR;
each R 6 is independently halogen, —CN, —COR, —(CR 2 ) 0-4 CO 2 R, —(CR 2 ) 0-4 CONR 2 , —OR, —(CR 2 ) 1-4 OR, —NR 2 , —(CR 2 ) 1-4 NR 2 , —NRC(O)OR, —NRC(O)R, —NRC(O)NR 2 , —SR, —SO 2 R, —S(O)R, —(CR 2 ) 0-4 SO 3 R, —(CR 2 ) 0-4 SO 2 NR 2 , —(CR 2 ) 0-4 OSO 2 NR 2 , —(CR 2 ) 0-4 NRSO 2 R, —(CR 2 ) 0-4 NRSO 2 OR, —(CR 2 ) 0-4 OP(OR) 2 , —(CR 2 ) 0-4 OP(O)(OR) 2 , —(CR 2 ) 0-4 P(O)(OR) 2 , —(CR 2 ) 0-4 OP(O)(H)OR, —B(OR) 2 , or R B ,
R B and R C , independently, are an optionally substituted group selected from C 1-6 aliphatic; phenyl; a 4- to 10-membered saturated or partially unsaturated monocyclic or bicyclic carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each R a is independently H or C 1-6 alkyl;
each m is 1, 2, 3, or 4;
n is 1, 2, 3, or 4;
q is 0, 1, or 2.

2. The compound of claim 1 , wherein R 1 is optionally substituted imidazole.

3. The compound of claim 1 , wherein R 1 is

4. The compound of claim 1 , wherein R 1 is optionally substituted pyrrole.

5. The compound of claim 1 , wherein R 1 is pyrazole.

6. The compound of claim 1 , wherein R 1 is

7. The compound of claim 1 , wherein R 1 is optionally substituted furan.

8. The compound of claim 1 , wherein R 1 is optionally substituted pyridine.

9. The compound of claim 1 , wherein at least one occurrence of R 3 is halogen.

10. The compound of claim 9 , wherein at least one occurrence of R 3 is chloro.

11. The compound of claim 1 , wherein R 2 is —NRR 5 .

12. The compound of claim 1 , wherein R 5 is —(CH 2 ) 2-4 OH, —(CH 2 ) 2-4 O(CH 2 ) 1-5 CO 2 H, —(CH 2 ) 2-4 O(CH 2 ) 1-5 CO 2 C 1-4 alkyl, —(CH 2 ) 0-3 CH(CH 2 OH) 2 , —(CH 2 ) 2-4 OC 1-4 alkyl, —(CH 2 ) 1-4 CO 2 H, —(CH 2 ) 1-4 CO 2 C 1-4 alkyl, —(CH 2 ) 1-4 CONH 2 , —(CH 2 ) 1-4 CONHC 1-4 alkyl, —(CH 2 ) 1-4 CON(C 1-4 alkyl) 2 , —(CH 2 ) 1-4 C(O)NR a (CH 2 ) 1-4 CO 2 H, —(CH 2 ) 1-4 C(O)NR a (CH 2 ) 1-4 CONH 2 , —(CH 2 ) 1-4 C(O)NR a (CH 2 ) 1-4 CONHC 1-4 alkyl, —(CH 2 ) 1-4 C(O)NR a (CH 2 ) 1-4 CON(C 1-4 alkyl) 2 , —(CH 2 ) 0-4 NR a C(O)(CH 2 ) 1-5 CO 2 H, —(CH 2 ) 0-4 NR a C(O)(CH 2 ) 1-5 CO 2 C 1-4 alkyl, —(CH 2 ) 2-4 SO 3 H, —(CH 2 ) 2-4 SO 3 C 1-4 alkyl, —(CH 2 ) 2-4 SO 2 NH 2 , —(CH 2 ) 2-4 SO 2 NHC 1-4 alkyl, —(CH 2 ) 2-4 SO 2 N(C 1-4 alkyl) 2 , —(CH 2 ) 2-4 OSO 2 NH 2 , —(CH 2 ) 2-4 NR a SO 2 C 1-4 alkyl, —(CH 2 ) 2-4 NR a SO 3 H, —(CH 2 ) 1-4 OP(OH) 2 , —(CH 2 ) 1-4 P(O)(OH) 2 , —(CH 2 ) 1-4 P(O)(OH)(OC 1-4 alkyl), or —(CH 2 ) 2-4 OP(O)(H)OH, wherein R a independently for each occurrence, is H or C 1-6 alkyl.

13. The compound of claim 1 , wherein R 2 is substituted phenyl.

14. The compound of claim 1 , wherein R 2 is

15. The compound of claim 1 , wherein each R 6 is independently fluoro, —CN, methyl, —CF 3 , —CO 2 H, —NH 2 , —OH, —OC 1-4 alkyl, —C 3-6 cycloalkyl, ═CH 2 , ═O, tetrazolyl, imidazoyl, thiophenyl, 1,2,4-oxadiazol-3(2H)-onyl, morpholinyl, phenyl, —(CH 2 ) 1-4 OC 1-4 alkyl, —(CH 2 ) 0-4 O(CH 2 ) 1-5 CO 2 H, —(CH 2 ) 0-4 O(CH 2 ) 1-5 CO 2 C 1-4 alkyl, —(CH 2 ) 1-4 O(CH 2 ) 1-4 CHFCO 2 H, —(CH 2 ) 1-4 O(CH 2 ) 1-4 CHFCO 2 C 1-4 alkyl, —(CH 2 ) 1-4 OCH(CH 3 )(CH 2 ) 1-4 CO 2 H, —(CH 2 ) 1-4 OCH(CH 3 )(CH 2 ) 1-4 CO 2 C 1-4 alkyl, —(CH 2 ) 1-4 O(CH 2 ) 1-4 CH(CH 3 )CO 2 H, —(CH 2 ) 1-4 O(CH 2 ) 1-4 CH(CH 3 )CO 2 C 1-4 alkyl, —CHOH(CH 2 ) 1-4 O(CH 2 ) 1-5 CO 2 H, —CHOH(CH 2 ) 1-4 O(CH 2 ) 1-5 CO 2 C 1-4 alkyl, —CHCF 3 (CH 2 ) 1-4 O(CH 2 ) 1-5 CO 2 H, —CHCF 3 (CH 2 ) 1-4 O—(CH 2 ) 1-5 CO 2 C 1-4 alkyl, —(CH 2 ) 1-4 O(CH 2 ) 1-5 CONR a 2 , —(CH 2 ) 1-4 O(CH 2 ) 1-5 CONR a OH, —(CH 2 ) 1-4 O(CH 2 ) 1-5 CONR a CN, —(CH 2 ) 1-4 O(CH 2 ) 1-5 P(O)OH 2 , —CH(OH)CF 3 , —COH(CF 3 ) 2 , —(CH 2 ) 1-5 CO 2 H, —(CH 2 ) 1-5 CO 2 C 1-4 alkyl, —(CH 2 ) 0-4 CHCHCO 2 H, —(CH 2 ) 0-4 CHCHCO 2 C 1-4 alkyl, —CO 2 C 1-4 alkyl, —CO 2 C 1-4 haloalkyl, —OCOC 1-4 alkyl, —O(CH 2 ) 1-4 CO 2 H, —O(CH 2 ) 1-4 CO 2 C 1-4 alkyl, —OCONR a (CH 2 ) 0-4 CO 2 H, —OCONR a (CH 2 ) 0-4 CO 2 C 1-4 alkyl, —OCO—(N-morpholine), —CONH 2 , —CONHOH, —CONHOC 1-4 alkyl, —(CH 2 ) 0-4 C(O)NR a CH 2 ) 1-4 CO 2 H, —(CH 2 ) 0-4 C(O)NR a (CH 2 ) 1-4 CO 2 C 1-4 alkyl, —(CH 2 ) 0-4 C(O)NR a (CH 2 ) 1-4 (pyrrolid-2-one), —(CH 2 ) 0-4 C(O)NR a (CH 2 ) 1-4 (piperidin-2-one), —(CH 2 ) 0-4 C(O)NR a (CH 2 ) 1-4 C(OH)(CF 3 ) 2 , —(CH 2 ) 0-4 C(O)NR a (CH 2 ) 1-4 CONH 2 , —(CH 2 ) 0-4 CONR a SO 2 C 1-4 haloalkyl, —(CH 2 ) 0-4 CO(N-pyrrolidine)-(CH 2 ) 0-4 CO 2 H, —(CH 2 ) 0-4 CO(N-pyrrolidine)-(CH 2 ) 0-4 CO 2 C 1-4 alkyl, —(CH 2 ) 0-4 (N-pyrazole)-(CH 2 ) 0-4 CO 2 H, —(CH 2 ) 0-4 CO(N-pyrazole)-(CH 2 ) 0-4 CO 2 C 1-4 alkyl, —(CH 2 ) 0-4 (N-pyrrole)-(CH 2 ) 0-4 CO 2 H, —(CH 2 ) 0-4 CO(N-pyrrole)-(CH 2 ) 0-4 CO 2 C 1-4 alkyl, —(CH 2 ) 0-4 —O((phenyl)—(CH 2 ) 0-4 CO 2 H, —(CH 2 ) 0-4 —O(phenyl)-(CH 2 ) 0-4 CO 2 C 1-4 alkyl, —(CH 2 ) 0-4 —O(cycloalkane)-(CH 2 ) 0-4 CO 2 H, —(CH 2 ) 0-4 —O(cycloalkane)-(CH 2 ) 0-4 CO 2 C 1-4 alkyl, —(CH 2 ) 0-4 CO(N-pyrrolidine)-(CH 2 ) 0-4 SO 2 NH 2 , —(CH 2 ) 0-4 CO(N-pyrrolidine)-(tetrazole), —(CH 2 ) 0-4 CO(N-piperdine)-(CH 2 ) 0-4 CO 2 H, —(CH 2 ) 0-4 CO(N-piperdine)-(CH 2 ) 0-4 CO 2 C 1-4 alkyl, —(CH 2 ) 0-4 CO(N-morpholine)-(CH 2 ) 0-4 CO 2 H, —CONR a (bicyclo[1.1.1]pentane)-(CH 2 ) 0-4 CO 2 H, —NH 2 , —(CH 2 ) 0-4 NR a (CH 2 ) 1-4 CO 2 H, —(CH 2 ) 0-4 NR a (CH 2 ) 1-4 CO 2 C 1-4 alkyl, —(CH 2 ) 0-4 N[(CH 2 ) 1-4 CO 2 C 1-4 alkyl] 2 , —(CH 2 ) 0-4 NR a CO(i

Assignees

• Immunesensor Therapeutics Inc
• Univ Texas

Inventors

• Qiu Jian
• Wei Qi
• Tschantz Matt
• Shi Heping
• Wu youtong
• Tan Huiling
• Sun Lijun
• Chen Chuo
• Chen Zhijian

Classifications

• C07F9/6506

  having the nitrogen atoms in positions 1 and 3 · CPC title

• C07F9/65031

  having the nitrogen atoms in the positions 1 and 2 · CPC title

• C07D491/048

  the oxygen-containing ring being five-membered · CPC title

• C07D471/08

  Bridged systems · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title