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US 2024/0190891 A1Published application
Pyrido oxazine amino derivatives as alk5 inhibitors
AssigneeChiesi Farmaceutici S.p.A.
InventorsDaniele PALA, Daniela PIZZIRANI, Paolo BRUNO, Matteo BIAGETTI, Paolo RONCHI, Sara GUARIENTO, Claudio FIORELLI, Barbara BERTANI
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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.
Claims15
1:
- A compound of formula (I)
- wherein
- A is selected from the group consisting of A1 and A2
- X1 and X2 are independently C or N;
- R1 is H or is selected from the group consisting of —NR3R4, —C(O)NR3R5, —NR3C(O)R6 and —C(O)OR7;
- R2 is H or is selected from the group consisting of —C(O)OR3 and —C(O)NR3R6;
- or R2 is absent when X1 or X2 is N;
- R3 is H or —(C1-C6)alkyl;
- R4 is H or —(C1-C6)alkyl;
- R5 is H or is selected from the group consisting of —(C1-C6)alkyl, —(C1-C6)alkylene-NRARB, cycloalkyl, heterocycloalkyl optionally substituted by one or more —(C1-C6)alkyl, and —(C1-C6)alkylene-heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by one or more groups selected from the group consisting of —(C1-C6)alkyl, —C(O)—(C1-C6)alkyl and —SO2—(C1-C6)alkyl;
- R6 is selected from the group consisting of —(C1-C6)alkylene-NR3R4 and —(C1-C6)alkylene-heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by one or more —(C1-C6)alkyl;
- R7 is H or is selected from the group consisting of —(C1-C6)alkyl, —(C1-C6)alkylene-NR3R4 and —(C1-C6)alkylene-heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by one or more —(C1-C6)alkyl;
- RA is H or is selected from the group consisting of —(C1-C6)alkyl and —(C1-C6)hydroxyalkyl;
- RB is selected from the group consisting of —(C1-C6)alkyl, —(C1-C6)alkylene-C(O)O—(C1-C6)alkyl, heterocycloalkyl and —(C1-C6)hydroxyalkyl;
- R8 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, —(C1-C6)alkyl and —(C1-C4)haloalkyl, and said heteroaryl is optionally substituted by one or more groups selected from —(C1-C6)alkyl, halogen atoms and —O—(C1-C6)alkyl;
- and pharmaceutically acceptable salts thereof.
13 more elements
2:
- The compound or salt thereof according to claim 1, wherein A is group A1
- represented by the formula (Ia)
- R1 is H or is selected from the group consisting of —NR3R4, —C(O)NR3R5, —NR3C(O)R6 and —C(O)OR7;
- R3 is H or —(C1-C6)alkyl;
- R4 is H or —(C1-C6)alkyl;
- R5 is H or is selected from the group consisting of —(C1-C6)alkyl, —(C1-C6)alkylene-NRARB, cycloalkyl, heterocycloalkyl optionally substituted by a —(C1-C6)alkyl, and —(C1-C6)alkylene-heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by a group selected from —(C1-C6)alkyl, —C(O)—(C1-C6)alkyl and —SO2—(C1-C6)alkyl;
- R6 is selected from the group consisting of —(C1-C6)alkylene-NR3R4 and —(C1-C6)alkylene-heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by a —(C1-C6)alkyl;
- R7 is H or is selected from the group consisting of —(C1-C6)alkyl, —(C1-C6)alkylene-NR3R4 and —(C1-C6)alkylene-heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by a —(C1-C6)alkyl;
- RA is H or is selected from the group consisting of —(C1-C6)alkyl and —(C1-C6)hydroxyalkyl;
- RB is selected from the group consisting of —(C1-C6)alkyl, —(C1-C6)alkylene-C(O)O—(C1-C6)alkyl, heterocycloalkyl and —(C1-C6)hydroxyalkyl;
- and
- R8 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, —(C1-C6)alkyl and —(C1-C4)haloalkyl, and said heteroaryl is optionally substituted by one or more groups selected from the group consisting of —(C1-C6)alkyl, halogen atoms and —O—(C1-C6)alkyl.
9 more elements
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-[bis(2-hydroxyethyl)amino]ethyl}-4-{[6-(5-chloro-2-fluorophenyl)-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-8-yl]amino}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-(1-methylpiperidin-4-yl)-4-{[6-(6-methylpyridin-2-yl)-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-8-yl]amino}pyridine-3-carboxamide;
- 4-{[6-(5-chloro-2-fluorophenyl)-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-8-yl]amino}-N-{2-[methyl(oxetan-3-yl)amino]ethyl}pyridine-3-carboxamide;
- methyl 2-({2-[(4-{[6-(5-chloro-2-fluorophenyl)-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-8-yl]amino}pyridin-3-yl)formamido]ethyl}(methyl)amino)acetate;
- 4-{[6-(5-chloro-2-fluorophenyl)-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-8-yl]amino}-N-[2-(4-methanesulfonylpiperazin-1-yl)ethyl]pyridine-3-carboxamide;
- and
- N-[2-(4-acetylpiperazin-1-yl)ethyl]-4-{[6-(5-chloro-2-fluorophenyl)-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-8-yl]amino}pyridine-3-carboxamide.
38 more elements
4:
- The compound or salt thereof according to claim 2, wherein A is A1a
- represented by the formula (Iaa)
- R1 is H;
- and
- R8 is phenyl substituted by fluorine and chlorine.
2 more elements
5:
- The compound or salt thereof according to claim 2, wherein A is A1a
- represented by the formula (Iaa)
- R1 is —NHC(O)R6;
- and
- R6 is selected from the group consisting of 4-ethyl morpholine, 1-ethyl-4-methylpiperazine and N,N-dimethylethanamine.
2 more elements
6:
- The compound or salt thereof according to claim 2, wherein A is Alb, represented by the formula (Iab)
- R1 is selected from the group consisting of —C(O)NHR5 and —C(O)OR7;
- R5 is selected from the group consisting of methyl, 2-(methylamino)ethyl, cyclopropyl, 2-(4-methylpiperazin-1-yl)ethyl, 2-(dimethylamino)ethyl, 2-(piperazin-1-yl)ethyl, (piperidin-4-yl), 1-methylpiperidin-4-yl and 2-[bis(2-hydroxyethyl)amino]ethyl;
- and
- R7 is H or is selected from the group consisting of methyl and 2-(piperazin-1-yl)ethyl.
2 more elements
7:
- The compound or salt thereof according to claim 1, wherein A is group A2
- represented by the formula (Ib)
- X1 and X2 are independently C or N;
- R2 is H or is selected from the group consisting of —C(O)OR3 and —C(O)NR3R6;
- or R2 is absent when X1 or X2 is N;
- R3 is H or —(C1-C6)alkyl;
- R6 is selected from the group consisting of —(C1-C6)alkylene-NR3R4 and —(C1-C6)alkylene-heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by a —(C1-C6)alkyl;
- and
- R8 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, —(C1-C6)alkyl and —(C1-C4)haloalkyl, and said heteroaryl is optionally substituted by one or more groups selected from the group consisting of —(C1-C6)alkyl, halogen atoms and —O—(C1-C6)alkyl.
6 more elements
8:
- The compound or salt thereof according to claim 7, wherein the compound is selected from the group consisting of:
- 6-(5-chloro-2-fluorophenyl)-N-{1H-pyrazolo[3,4-b]pyridin-4-yl}-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-8-amine;
- 6-(5-chloro-2-fluorophenyl)-N-{1H-pyrrolo[2,3-b]pyridin-4-yl}-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-8-amine;
- 6-(5-chloro-2-fluorophenyl)-N-{3H-imidazo[4,5-b]pyridin-7-yl}-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-8-amine;
- methyl 4-{[6-(5-chloro-2-fluorophenyl)-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-8-yl]amino}-1H-pyrrolo[2,3-b]pyridine-3-carboxylate;
- methyl 4-{[6-(5-chloro-2-fluorophenyl)-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-8-yl]amino}-1H-pyrrolo[2,3-b]pyridine-2-carboxylate;
- N-{3H-imidazo[4,5-b]pyridin-7-yl}-6-(6-methylpyridin-2-yl)-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-8-amine;
- 6-(6-methylpyridin-2-yl)-N-{11H-pyrazolo[3,4-b]pyridin-4-yl}-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-8-amine;
- 6-(6-methylpyridin-2-yl)-N-{1H-pyrrolo[2,3-b]pyridin-4-yl}-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-8-amine;
- 4-{[6-(5-chloro-2-fluorophenyl)-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-8-yl]amino}-N-[2-(1-methylpiperidin-4-yl)ethyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide;
- and
- 4-{[6-(5-chloro-2-fluorophenyl)-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-8-yl]amino}-N-[2-(dimethylamino)ethyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide.
9 more elements
9:
- A pharmaceutical composition comprising the compound or salt thereof according to claim 1, in admixture with one or more pharmaceutically acceptable camer-or-excipient carriers or excipients.
10:
- The pharmaceutical composition according to claim 9, adapted for administration by inhalation.
(canceled)
12:
- A method for treating a disease, disorder or condition mediated by ALK5 signaling pathway in a mammal, comprising administering to a subject in need thereof the pharmaceutical composition according to claim 9.
13:
- The method according to claim 12, wherein the disease, disorder or condition comprises fibrosis and/or a disease, disorder or condition that involves fibrosis.
14:
- The method according to claim 13, wherein the fibrosis or disease, disorder or condition that involves fibrosis comprises pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), hepatic fibrosis, renal fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis or systemic sclerosis.
15:
- The method according to claim 14, wherein the fibrosis comprises idiopathic pulmonary fibrosis (IPF).
Dependencies are inferred from the claim text.