Quinoline cGAS antagonist compounds

Patent metadata

Field	Value
Publication number	US-12091387-B2
Application number	US-202318353718-A
Country	US
Kind code	B2
Filing date	Jul 17, 2023
Priority date	Mar 2, 2022
Publication date	Sep 17, 2024
Grant date	Sep 17, 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 is a pharmaceutically acceptable salt thereof, wherein:
Ring A is an optionally substituted triazole, wherein substitution
(a) when on a substitutable carbon atom, is with one or more groups selected from halogen; —(CH 2 ) 0-6 R ∘ ; —(CH 2 ) 0-6 OR ∘ ; —O(CH 2 ) 0-6 R ∘ ; —O—(CH 2 ) 0-6 C(O)OR ∘ ; —(CH 2 ) 0-6 CH(OR ∘ ) 2 ; —(CH 2 ) 0-6 SR ∘ ; —(CH 2 ) 0-6 Ph, which Ph may be substituted with R ∘ ; —(CH 2 ) 0-6 O(CH 2 ) 0-1 Ph which Ph may be substituted with R ∘ ; —CH═CHPh, which Ph may be substituted with R ∘ ; —(CH 2 ) 0-6 O(CH 2 ) 0-1 -pyridyl which pyridyl may be substituted with R ∘ ; —NO 2 ; —CN; —N 3 ; —(CH 2 ) 0-6 N(R ∘ ) 2 ; —(CH 2 ) 0-6 N(R ∘ )C(O)R ∘ ; —N(R ∘ )C(S)R ∘ ; —(CH 2 ) 0-6 N(R ∘ )C(O)NR ∘ 2 ; —N(R ∘ )C(S)NR ∘ 2 ; —(CH 2 ) 0-6 N(R ∘ )C(O)OR ∘ ; —N(R ∘ )N(R ∘ )C(O)R ∘ ; —N(R ∘ )N(R ∘ )C(O)NR ∘ 2 ; —N(R ∘ )N(R ∘ )C(O)OR ∘ ; —(CH 2 ) 0-6 C(O)R ∘ ; —C(S)R ∘ ; —(CH 2 ) 0-6 C(O)OR ∘ ; —(CH 2 ) 0-6 C(O)SR ∘ ; —(CH 2 ) 0-6 C(O)OSiR ∘ 3 ; —(CH 2 ) 0-6 OC(O)R ∘ ; —OC(O)(CH 2 ) 0-6 SR ∘ , —(CH 2 ) 0-6 SC(O)R ∘ ; —(CH 2 ) 0-6 C(O)NR ∘ 2 ; —C(S)NR ∘ 2 ; —C(S)SR ∘ ; —SC(S)SR ∘ , —(CH 2 ) 0-6 OC(O)NR ∘ 2 ; —C(O)N(OR ∘ )R ∘ ; —C(O)C(O)R ∘ ; —C(O)CH 2 C(O)R ∘ ; —C(NOR ∘ )R ∘ ; —(CH 2 ) 0-6 SSR ∘ ; —(CH 2 ) 0-6 S(O) 2 R ∘ ; —(CH 2 ) 0-6 S(O) 2 OR ∘ ; —(CH 2 ) 0-6 OS(O) 2 R ∘ ; —S(O) 2 NR ∘ 2 ; —(CH 2 ) 0-6 S(O)R ∘ ; —N(R ∘ )S(O) 2 NR ∘ 2 ; —N(R ∘ )S(O) 2 R ∘ ; —N(OR ∘ )R ∘ ; —C(NH)NR ∘ 2 ; —P(O) 2 R ∘ ; —P(O)R ∘ 2 ; —P(O)(OR ∘ ) 2 ; —OP(O)(R ∘ )OR ∘ ; —OP(O)R ∘ 2 ; —OP(O)(OR ∘ ) 2 ; SiR ∘ 3 ; —(C 1-4 straight or branched alkylene)O—N(R ∘ ) 2 ; or —(C 1-4 straight or branched alkylene)C(O)O—N(R ∘ ) 2 , wherein each R ∘ is independently hydrogen, C 1-6 aliphatic, —CH 2 Ph, —O(CH 2 ) 0-1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or
(b) when on a substitutable nitrogen atom, is with one or more groups selected from —R†, —NR† 2 , —C(O)R†, —C(O)OR†, —C(O)C(O)R†, —C(O)CH 2 C(O)R†, —S(O) 2 R†, —S(O) 2 NR† 2 , —C(S)NR† 2 , —C(NH)NR† 2 , or —N(R†)S(O) 2 R†, wherein each RT is independently hydrogen, C 1-6 aliphatic, —OPh, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R 2 is —NR a R 5 ,

each R 3 is independently halogen, —OR, —NR 2 , or —SR;
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 A nitrogen, oxygen, and sulfur; or a thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, or pyrido[2,3-b]-1,4-oxazin-3(4H)-one 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 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; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur, or:
two R groups on the same nitrogen are optionally taken together with their intervening atoms to form an optionally substituted 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having 0 to 3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, phosphorus, 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 ) 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, or R B ;
each R 6 is independently halogen, —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;
n is 1, 2, 3, or 4;
q is 0, 1, or 2.

2. The compound of claim 1 , wherein Ring A is selected from

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

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

5. The compound of claim 3 , wherein at least one occurrence of R 3 is bromo.

6. The compound of claim 3 , wherein n is 2 or 3 and all occurrences of R 3 are halogen.

7. The compound of claim 1 , wherein R 2 is —NR a R 5 .

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

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, and sulfur.

9. The compound of claim 8 , wherein R 2 is

10. The compound of claim 8 , wherein R 2 is

11. The compound of claim 8 , wherein each R 6 is independently halogen, ═CH 2 , ═O, —C 1-4 alkyl, —C 1-4 haloalkyl, —(CH 2 ) 0-4 CO 2 H, —(CH 2 ) 0-4 CO 2 C 1-4 alkyl, —(CH 2 ) 0-4 CO 2 C 1-4 haloalkyl, —(CH 2 ) 0-4 CONH 2 , —(CH 2 ) 0-4 CONHC 1-4 alkyl, —(CH 2 ) 0-4 CON(C 1-4 alkyl) 2 , —(CH 2 ) 0-4 CO(N-proline), —(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 CONH 2 , —(CH 2 ) 0-4 C(O)NR a (CH 2 ) 1-4 CONHC

Assignees

• Immunesensor Therapeutics Inc
• Univ Texas

Inventors

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

Classifications

• C07D487/08

  Bridged systems · CPC title

• C07D401/04

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

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D409/14

  containing three or more hetero rings · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title