Pyrido oxazine amino derivatives as alk5 inhibitors

Patent metadata

Field	Value
Publication number	US-2024190891-A1
Application number	US-202118014770-A
Country	US
Kind code	A1
Filing date	Jul 14, 2021
Priority date	Jul 15, 2020
Publication date	Jun 13, 2024
Grant date	—

Abstract

The present invention relates to a compound of general formula (I) inhibiting the transforming growth factor-β (TGF-β) type I receptor (ALK5), methods of preparing such compounds, pharmaceutical compositions containing them and therapeutic use thereof. The compounds of the invention may be useful in the treatment of diseases or conditions associated with a dysregulation of ALK5 signaling pathway in a mammal.

First claim

1 : A compound of formula (I)

wherein
A is selected from the group consisting of A1 and A2

X 1 and X 2 are independently C or N;
R 1 is H or is selected from the group consisting of —NR 3 R 4 , —C(O)NR 3 R 5 , —NR 3 C(O)R 6 and —C(O)OR 7 ;
R 2 is H or is selected from the group consisting of —C(O)OR 3 and —C(O)NR 3 R 6 ; or R 2 is absent when X 1 or X 2 is N;
R 3 is H or —(C 1 -C 6 )alkyl;
R 4 is H or —(C 1 -C 6 )alkyl;
R 5 is H or is selected from the group consisting of —(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkylene-NR A R B , cycloalkyl, heterocycloalkyl optionally substituted by one or more —(C 1 -C 6 )alkyl, and —(C 1 -C 6 )alkylene-heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by one or more groups selected from the group consisting of —(C 1 -C 6 )alkyl, —C(O)—(C 1 -C 6 )alkyl and —SO 2 —(C 1 -C 6 )alkyl;
R 6 is selected from the group consisting of —(C 1 -C 6 )alkylene-NR 3 R 4 and —(C 1 -C 6 )alkylene-heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by one or more —(C 1 -C 6 )alkyl;
R 7 is H or is selected from the group consisting of —(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkylene-NR 3 R 4 and —(C 1 -C 6 )alkylene-heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by one or more —(C 1 -C 6 )alkyl;
R A is H or is selected from the group consisting of —(C 1 -C 6 )alkyl and —(C 1 -C 6 )hydroxyalkyl;
R B is selected from the group consisting of —(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkylene-C(O)O—(C 1 -C 6 )alkyl, heterocycloalkyl and —(C 1 -C 6 )hydroxyalkyl;
R 8 is selected from the group consisting of aryl and heteroaryl, wherein said aryl is optionally substituted by one or more groups selected from halogen atoms, —(C 1 -C 6 )alkyl and —(C 1 -C 4 )haloalkyl, and said heteroaryl is optionally substituted by one or more groups selected from —(C 1 -C 6 )alkyl, halogen atoms and —O—(C 1 -C 6 )alkyl;
and pharmaceutically acceptable salts thereof.

2 : The compound or salt thereof according to claim 1 , wherein A is group A1

represented by the formula (Ia)

R 1 is H or is selected from the group consisting of —NR 3 R 4 , —C(O)NR 3 R 5 , —NR 3 C(O)R 6 and —C(O)OR 7 ;
R 3 is H or —(C 1 -C 6 )alkyl;
R 4 is H or —(C 1 -C 6 )alkyl;
R 5 is H or is selected from the group consisting of —(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkylene-NR A R B , cycloalkyl, heterocycloalkyl optionally substituted by a —(C 1 -C 6 )alkyl, and —(C 1 -C 6 )alkylene-heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by a group selected from —(C 1 -C 6 )alkyl, —C(O)—(C 1 -C 6 )alkyl and —SO 2 —(C 1 -C 6 )alkyl;
R 6 is selected from the group consisting of —(C 1 -C 6 )alkylene-NR 3 R 4 and —(C 1 -C 6 )alkylene-heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by a —(C 1 -C 6 )alkyl;
R 7 is H or is selected from the group consisting of —(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkylene-NR 3 R 4 and —(C 1 -C 6 )alkylene-heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by a —(C 1 -C 6 )alkyl;
R A is H or is selected from the group consisting of —(C 1 -C 6 )alkyl and —(C 1 -C 6 )hydroxyalkyl;
R B is selected from the group consisting of —(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkylene-C(O)O—(C 1 -C 6 )alkyl, heterocycloalkyl and —(C 1 -C 6 )hydroxyalkyl; and
R 8 is selected from the group consisting of aryl and heteroaryl, wherein said aryl is optionally substituted by one or more groups selected from the group consisting of halogen atoms, —(C 1 -C 6 )alkyl and —(C 1 -C 4 )haloalkyl, and said heteroaryl is optionally substituted by one or more groups selected from the group consisting of —(C 1 -C 6 )alkyl, halogen atoms and —O—(C 1 -C 6 )alkyl.

3 : The compound or salt thereof according to claim 2 , wherein the compound is selected from the group consisting of:
N-[6-(5-chloro-2-fluorophenyl)-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-8-yl]pyridin-4-amine; 4-{[6-(5-chloro-2-fluorophenyl)-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-8-yl]amino}-N-methylpyridine-3-carboxamide; N4-[6-(5-chloro-2-fluorophenyl)-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-8-yl]pyridine-2,4-diamine; N-[6-(4-methyl-1,3-thiazol-2-yl)-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-8-yl]pyridin-4-amine; N-[6-(6-methylpyridin-2-yl)-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-8-yl]pyridin-4-amine; 4-{[6-(5-chloro-2-fluorophenyl)-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-8-yl]amino}-N-methylpyridine-2-carboxamide; N4-[6-(5-chloro-2-fluorophenyl)-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-8-yl]pyridine-3,4-diamine; N-[6-(2-fluoro-5-methylphenyl)-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-8-yl]pyridin-4-amine; 4-{[6-(5-chloro-2-fluorophenyl)-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-8-yl]amino}-N-[2-(morpholin-4-yl)ethyl]pyridine-3-carboxamide; 4-{[6-(5-chloro-2-fluorophenyl)-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-8-yl]amino}-N-[2-(dimethylamino)ethyl]pyridine-3-carboxamide; N-[6-(2-fluorophenyl)-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-8-yl]pyridin-4-amine; 4-{[6-(5-chloro-2-fluorophenyl)-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-8-yl]amino}-N-[2-(piperazin-1-yl)ethyl]pyridine-3-carboxamide; N-[6-(6-chloropyridin-2-yl)-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-8-yl]pyridin-4-amine; N-[6-(2,5-difluorophenyl)-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-8-yl]pyridin-4-amine; N-[6-(3-chlorophenyl)-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-8-yl]pyridin-4-amine; 4-{[6-(5-chloro-2-fluorophenyl)-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-8-yl]amino}pyridine-3-carboxylate; methyl 4-{[6-(5-chloro-2-fluorophenyl)-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-8-yl]amino}pyridine-3-carboxylate; N-[6-(3-methylphenyl)-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-8-yl]pyridin-4-amine; N-[6-(3-chloro-4-fluorophenyl)-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-8-yl]pyridin-4-amine; N-(4-{[6-(5-chloro-2-fluorophenyl)-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-8-yl]amino}pyridin-2-yl)-3-(morpholin-4-yl)propenamide; 4-{[6-(5-chloro-2-fluorophenyl)-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-8-yl]amino}-N-[2-(methylamino)ethyl]pyridine-3-carboxamide; 4-{[6-(5-chloro-2-fluorophenyl)-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-8-yl]amino}-N-(propan-2-yl)pyridine-3-carboxamide; 4-{[6-(5-chloro-2-fluorophenyl)-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-8-yl]amino}-N-cyclopropylpyridine-3-carboxamide; 4-{[6-(5-chloro-2-fluorophenyl)-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-8-yl]amino}-N-(piperidin-4-yl)pyridine-3-carboxamide; N-[6-(5-fluoropyridin-2-yl)-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-8-yl]pyridin-4-amine; 2-(dimethylamino)ethyl 4-{[6-(5-chloro-2-fluorophenyl)-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-8-yl]amino}pyridine-3-carboxylate; 4-{[6-(5-chloro-2-fluorophenyl)-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-8-yl]amino}-N-[2-(4-methylpiperazin-1-yl)ethyl]pyridine-3-carboxamide; 2-(4-methylpiperazin-1-yl)ethyl 4-{[6-(5-chloro-2-fluorophenyl)-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-8-yl]amino}pyridine-3-carboxylate; methyl 4-{[6-(6-methylpyridin-2-yl)-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-8-yl]amino}pyridine-3-carboxylate; 4-{[6-(5-chloro-2-fluorophenyl)-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-8-yl]amino}-N-(1-methylpiperidin-4-yl)pyridine-3-carboxamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-8-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propenamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-8-yl]amino}pyridin-2-yl)-3-(dimethylamino)propenamide; N-{2

Assignees

• Chiesi Farm Spa

Inventors

• Pala Daniele
• Pizzirani Daniela
• Bruno Paolo
• Biagetti Matteo
• Ronchi Paolo
• Guariento Sara
• Fiorelli Claudio
• Bertani Barbara

Classifications

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61K31/5383

  ortho- or peri-condensed with heterocyclic ring systems · CPC title

• C07D498/04 Primary

  Ortho-condensed systems · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title