Quinoline cGAS antagonist compounds

Patent metadata

Field	Value
Publication number	US-11873291-B2
Application number	US-202117446951-A
Country	US
Kind code	B2
Filing date	Sep 3, 2021
Priority date	Sep 3, 2020
Publication date	Jan 16, 2024
Grant date	Jan 16, 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-a-4:

or a pharmaceutically acceptable salt thereof, wherein:
Ring A is an optionally substituted heteroaryl ring, having 0 to 3 heteroatoms (in addition to the nitrogen already depicted in Ring A) independently selected from nitrogen, oxygen, phosphorus, and sulfur;
R 2 is —NRR 5 , —NR a R 5 ,

each R 3 is independently halogen, —OMe, —OEt, —NR 2 , —SR, or R C ;
Ring B1 is 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; or a benzotriazolyl, benzo[d]oxazol-2(3H)-one, benzo[d][1,3]dioxole, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or indolizinyl ring;
Ring B2 is 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; 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 —(CR 2 ) 0-4 OR, —(CR 2 ) 0-5 CO 2 R, —(CR 2 ) 0-5 CONR 2 , —(CR 2 ) 0-4 C(O)NR(CR 2 )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, or R B ;
each R 6 is independently halogen, —CN, ═CH 2 , ═O, —C(O)NHOH, —C(O)N(CH 3 )OH, —C(O)N(CH 3 )OCH 3 , —C(O)NHSO 2 CHF 2 , —OCONHCH 2 CO 2 Me, —OCONHCH 2 CO 2 H, —NHCOCH 2 CH 2 CO 2 H, —NHCOCH 2 CH 2 CO 2 CH 3 , —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 0, 1, 2, 3, or 4;
n is 1, 2, 3, or 4; and
q is 0, 1, or 2.

2. A compound, wherein the compound is of Formula I-b-3:

or a pharmaceutically acceptable salt thereof, wherein:
Ring B1 is 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, phosphorus, and sulfur; or a benzotriazolyl, benzo[d]oxazol-2(3H)-one, benzo[d][1,3]dioxole, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or indolizinyl ring;
R 1 is

or an optionally substituted 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each R 3 is independently halogen, —OMe, —OEt, —NR 2 , or —SR;
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 4 is hydrogen or an optionally substituted C 1-6 aliphatic;
each R 6 is independently halogen, —CN, ═CH 2 , ═O, —C(O)NHOH, —C(O)N(CH 3 )OH, —C(O)N(CH 3 )OCH 3 , —C(O)NHSO 2 CHF 2 , —OCONHCH 2 CO 2 Me, —OCONHCH 2 CO 2 H, —NHCOCH 2 CH 2 CO 2 H, —NHCOCH 2 CH 2 CO 2 CH 3 , —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 is 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 0, 1, 2, 3, or 4; and
n is 1, 2, 3, or 4.

3. The compound of claim 1 , wherein Ring A is an optionally substituted imidazole.

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

5. The compound of claim 1 , wherein Ring A is an optionally substituted pyrazole.

6. The compound of claim 2 , wherein R 1 is an optionally substituted pyrazole.

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

8. The compound of claim 1 , wherein Ring B1 is

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 9 , wherein n is 2 and both R 3 are chloro.

12. The compound of claim 9 , wherein n is 2 and R 3 is chloro at the 7- and 8-positions with respect to the quinoline ring.

13. The compound of claim 2 , wherein at least one occurrence of R 3 is halogen.

14. The compound of claim 13 , wherein at least one occurrence of R 3 is chloro.

15. The compound of claim 13 , wherein n is 2 and both R 3 are chloro.

16. The compound of claim 13 , wherein n is 2 and R 3 is chloro at

Assignees

• Immunesensor Therapeutics Inc
• Univ Texas

Inventors

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

Classifications

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• C07D215/38

  Nitrogen atoms (nitro radicals C07D215/18) · CPC title

• C07D215/42

  attached in position 4 · CPC title

• C07D215/46

  with hydrocarbon radicals, substituted by nitrogen atoms, attached to said nitrogen atoms · CPC title

• C07D401/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title