Claims for Patent: 10,428,063

Summary for Patent: 10,428,063

Title:	4H-pyrrolo[3,2-C]pyridin-4-one derivatives
Abstract:	Compound of formula (I), processes for their production and their use as pharmaceuticals.
Inventor(s):	Keith Graham, Ulrich Klar, Hans Briem, Volker Schulze, Gerhard Siemeister, Philip Lienau, René TEMPEL, Jozsef BÁLINT
Assignee:	Bayer Pharma AG
Application Number:	US15/547,032
Patent Claims:	1. A compound of formula (I) wherein: R1 is hydrogen, C1-C6-alkyl or C1-C6-haloalkyl; R2 is hydrogen, C1-C6-alkyl or C1-C6-haloalkyl; or R1 and R2 are taken together with the carbon atom to which they are attached to form a 3- to 6-membered cycloalkyl ring; R3 is hydrogen, C1-C4-alkyl, C1-C4-haloalkyl, R11—C(O)—, R11O—C(O)— or phenyl-C1-C3-alkyl-, wherein said phenyl group is optionally independently substituted, one or more times, with R5; R4 is hydrogen, C1-C4-alkyl or C1-C4-alkoxy-C2-C4-alkyl-; RA is hydrogen, hydroxy or C1-C4-alkyl; RB is hydrogen; or RB and R2 are taken together to form an additional bond; A is a group selected from the group consisting of: wherein * indicates the point of attachment of said group with the rest of the molecule, and said group is optionally independently substituted, one or more times, with R5; R5 is hydroxy, halogen, cyano, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl or C1-C4-haloalkoxy; E is a group selected from the group consisting of: wherein * indicates the point of attachment of said group with the rest of the molecule; R6 and R7 are independently hydrogen, halogen, hydroxy, cyano, C1-C4-alkyl, C1-C6-alkoxy, C3-C6-cycloalkyl, or C3-C6-halocycloalkyl, wherein said C1-C6-alkoxy is optionally independently substituted one, two or three times, with halogen or is optionally substituted one time with hydroxy, C1-C4-alkoxy, R9R10N—, C3-C6-cycloalkyl, 5- to 6-membered heterocycloalkyl or phenyl, which is optionally independently substituted, one or more times, with R5; each R8 is independently halogen, hydroxy, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C6-alkoxy, C3-C6-cycloalkyl, or C3-C6-halocycloalkyl, wherein said C1-C6-alkoxy is optionally independently substituted one, two or three times, with halogen and is optionally substituted one time with hydroxy, C1-C4-alkoxy, R9R10N—, C3-C6-cycloalkyl, 4- to 7-membered heterocycloalkyl or phenyl, which is optionally independently substituted one or more times, with R5; each R9 and R10is independently hydrogen, C1-C4-alkyl, C3-C6-cycloalkyl, C1-C4-haloalkyl, C3-C6-halocycloalkyl or phenyl, wherein said phenyl group is optionally independently substituted, one or more times, with R5; or R9 and R10are taken together with the nitrogen atom to which they are attached to form a 3- to 6-membered nitrogen containing heterocyclic ring, optionally containing one additional heteroatom or heteroatom containing group selected from the group consisting of O, NH, and S, and which is optionally independently substituted, one or more times, with R5; each R11 is independently C1-C4-alkyl, C3-C6-cycloalkyl, C1-C4-haloalkyl or C3-C6-halocycloalkyl; m is 0, 1, 2, or 3; and n is 0, 1, or 2, or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer. 2. The compound of formula (I) according to claim 1, wherein: R1 is hydrogen, C1-C4-alkyl or C1-C4-haloalkyl; R2 is hydrogen, C1-C4-alkyl or C1-C4-haloalkyl; or R1 and R2 are taken together with the carbon atom to which they are attached to form a 3- to 6-membered cycloalkyl ring; R3 is hydrogen, C1-C4-alkyl, C1-C4-haloalkyl, R11—C(O)— or R11O—C(O)—; R4 is hydrogen, C1-C4-alkyl or C1-C4-alkoxy-C2-C4-alkyl-; RA is hydrogen, hydroxy or C1-C4-alkyl; RB is hydrogen; or RB and R2 are taken together to form an additional bond; A is a group wherein * indicates the point of attachment of said group with the rest of the molecule, and said group is optionally independently substituted, one or more times, with R5; R5 is hydroxy, halogen, cyano, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl or C1-C4-haloalkoxy; E is a group selected from the group consisting of: wherein * indicates the point of attachment of said group with the rest of the molecule; R6 and R7 are independently hydrogen, halogen, hydroxy, cyano, C1-C4-alkyl, C1-C6-alkoxy, C3-C6-cycloalkyl, or C3-C6-halocycloalkyl, wherein said C1-C6-alkoxy is optionally independently substituted one, two or three times, with halogen or is optionally substituted one time with hydroxy, C1-C4-alkoxy, R9R10N—, C3-C6-cycloalkyl, 5- to 6-membered heterocycloalkyl or phenyl, which is optionally independently substituted, one or more times, with R5; each R8 is independently halogen, hydroxy, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C6-alkoxy, C3-C6-cycloalkyl, or C3-C6-halocycloalkyl, wherein said C1-C6-alkoxy is optionally independently substituted one, two or three times, with halogen or is optionally substituted one time with hydroxy, C1-C4-alkoxy, R9R10N—, C3-C6-cycloalkyl, 4- to 7-membered heterocycloalkyl or phenyl, which is optionally independently substituted one or more times, with R5; each R9 and R10is independently hydrogen, C1-C4-alkyl, C3-C6-cycloalkyl, C1-C4-haloalkyl, C3-C6-halocycloalkyl or phenyl, wherein said phenyl group is optionally independently substituted, one or more times, with R5; or R9 and R10are taken together with the nitrogen atom to which they are attached to form a 3- to 6-membered nitrogen containing heterocyclic ring, optionally containing one additional heteroatom or heteroatom containing group selected from the group consisting of O, NH, and S, and which is optionally independently substituted, one or more times, with R5; each R11 is independently C1-C4-alkyl, C3-C6-cycloalkyl, C1-C4-haloalkyl or C3-C6-halocycloalkyl; m is 0, 1, 2, or 3; and n is 0 or 1, or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer. 3. The compound of formula (I) according to claim 1, wherein: R1 is hydrogen, C1-C4-alkyl or C1-C4-haloalkyl; R2 is hydrogen, C1-C4-alkyl or C1-C4-haloalkyl; or R1 and R2 are taken together with the carbon atom to which they are attached to form a 3- to 6-membered cycloalkyl ring; R3 is hydrogen, C1-C4-alkyl, C1-C4-haloalkyl, R11—C(O)— or R11O—C(O)—; R4 is hydrogen, C1-C4-alkyl or C1-C4-alkoxy-C2-C4-alkyl; RA is hydrogen, hydroxy or C1-C4-alkyl; RB is hydrogen; or RB and R2 are taken together to form an additional bond; A is a group wherein * indicates the point of attachment of said group with the rest of the molecule, and said group is optionally independently substituted, one or more times, with R5; R5 is hydroxy, halogen, cyano, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl or C1-C4-haloalkoxy; E is a group selected from the group consisting of: wherein * indicates the point of attachment of said group with the rest of the molecule; R6 and R7 are independently hydrogen, halogen, hydroxy, cyano, C1-C4-alkyl, C1-C6-alkoxy, C3-C6-cycloalkyl, or C3-C6-halocycloalkyl, wherein said C1-C6-alkoxy is optionally independently substituted one, two or three times, with halogen or is optionally substituted one time with hydroxy, C1-C4-alkoxy, R9R10N—, C3-C6-cycloalkyl, 5- to 6-membered heterocycloalkyl or phenyl, which is optionally independently substituted, one or more times, with R5; each R9 and R10is independently hydrogen or C1-C4-alkyl; and each R11 is independently C1-C4-alkyl, C3-C6-cycloalkyl or C3-C6-halocycloalkyl, or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer. 4. The compound of formula (I) according to claim 1, wherein: R1 is hydrogen or C1-C4-alkyl; R2 is hydrogen or C1-C4-alkyl; or R1 and R2 are taken together with the carbon atom to which they are attached to form a 3- to 6-membered cycloalkyl ring; R3 is hydrogen, C1-C4-alkyl, R11—C(O)— or R11O—C(O)—; R4 is hydrogen, C1-C4-alkyl or C1-C4-alkoxy-C2-C4-alkyl; RA is hydrogen; RB is hydrogen; or RB and R2 are taken together to form an additional bond; A is a group wherein * indicates the point of attachment of said group with the rest of the molecule, and said group is optionally independently substituted, one or more times, with R5; R5 is halogen; E is a group selected from the group consisting of: wherein * indicates the point of attachment of said group with the rest of the molecule; R6 and R7 are independently hydrogen, halogen, C1-C4-alkyl, or C1-C6-alkoxy, wherein said C1-C6-alkoxy is optionally independently substituted one, two or three times, with halogen or is optionally substituted one time with hydroxy, methoxy, (CH3)2N—, cyclopropyl, 5-membered heterocycloalkyl or phenyl, which is optionally substituted once with R5; each R9 and R10is independently hydrogen or C1-C4-alkyl; and each R11 is independently C1-C4-alkyl, C3-C6-cycloalkyl or C3-C6-halocycloalkyl, or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer. 5. The compound of formula (I) according to claim 1, wherein: R1 is hydrogen or methyl; R2 is hydrogen or methyl; R3 is hydrogen, methyl, iso-propyl-C(O)— or tert-butyl-O—C(O)—; R4 is hydrogen, ethyl or 2-methoxy-ethyl; RA is hydrogen; RB is hydrogen; or RB and R2 are taken together to form an additional bond; A is phenyl optionally substituted with one or two fluorine atoms; E is a group selected from the group consisting of: wherein * indicates the point of attachment of said group with the rest of the molecule; R6 is hydrogen or methyl; R7 is hydrogen, fluoro, methyl, methoxy, cyclopropylmethoxy, tetrahydrofuran-3-ylmethoxy, 2-hydroxyethoxy, 2-methoxyethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-(dimethylamino)ethoxy, propoxy, 3,3,3-trifluoropropoxy, butoxy, 3,3-dimethylbutoxy or benzyloxy; each R9 and R10is independently hydrogen or ethyl; and each R11 is independently methyl, iso-propyl, tert-butyl, cyclopropyl or fluorocyclopropyl, or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer. 6. The compound of formula (I) according to claim 1, which is selected from the group consisting of: 6,6-dimethyl-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 2-(3-methylpyridin-4-yl)-3-(phenylamino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 1-ethyl-6,6-dimethyl-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 1-ethyl-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; tert-butyl 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate; 3-[(4-fluorophenyl)amino]-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 1-(2-methoxyethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 1-ethyl-3-[(4-fluorophenyl)amino]-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 2-(2-methylpyridin-4-yl)-3-(phenylamino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 1-ethyl-2-(2-methylpyridin-4-yl)-3-(phenylamino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 2-(3-fluoropyridin-4-yl)-3-(phenylamino)-1,5-dihydro-4H-pyrrolo[3,2-c]pyridin-4-one; 2-(3-fluoropyridin-4-yl)-3-(phenylamino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 5-methyl-3 -(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo [3,2-c]pyridin-4-one; 2-(3-fluoropyridin-4-yl)-5-methyl-3 -(phenylamino)-1,5,6,7-tetrahydro-4H-pyrrolo [3,2-c]pyridin-4-one; 2-(3-methoxypyridin-4-yl)-5-methyl-3-(phenylamino)- 1,5,6,7-tetrahydro-4H-pyrrolo [3,2-c]pyridin-4-one; 2- [3 -(2-hydroxyethoxy)pyridin-4-yl]-5-methyl-3-(phenylamino)- 1,5,6,7-tetrahydro-4H-pyrrolo[3 ,2-c]pyridin-4-one; 2-[3 -(cyclopropylmethoxy)pyridin-4-yl]-5-methyl-3-(phenylamino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 5-methyl-3 -(phenylamino)-2-(3 -propoxypyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo [3,2-c]pyridin-4-one; 2-[3 -(2,2-difluoroethoxy)pyridin-4-yl]-5-methyl-3-(phenylamino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 5-methyl-3 -(phenylamino)-2-[3 -(2,2,2-trifluoroethoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 2-[3 -(2-methoxyethoxy)pyridin-4-yl]-5-methyl-3 -(phenylamino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 2-[3 -(benzyloxy)pyridin-4-yl]-5-methyl-3-(phenylamino)- 1,5,6,7-tetrahydro-4H-pyrrolo [3,2-c]pyridin-4-one; 5-methyl-3 -(phenylamino)-2-[3 -(3,3,3 -trifluoropropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 5-methyl-3 -(phenylamino)-2-{3-[(3S)-tetrahydrofuran-3-ylmethoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 2-[3 -(3,3 -dimethylbutoxy)pyridin-4-yl]-5-methyl-3 -(phenylamino)- 1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 2-(3H-imidazo[4,5-b]pyridin-7-yl)-5-methyl-3 -(phenylamino)- 1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 2-[3 -(cyclopropylmethoxy)pyridin-4-yl]-3-[(3,4-difluorophenyl)amino]- 1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 2-[3 -(cyclopropylmethoxy)pyridin-4-yl]-3 -[(4-fluorophenyl)amino]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 2-[3 -(cyclopropylmethoxy)pyridin-4-yl]-3-[(3 -fluorophenyl)amino]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 2-[3 -(2,2-difluoroethoxy)pyridin-4-yl]-3 -[(3 -fluorophenyl)amino]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 2-[3 -(2,2-difluoroethoxy)pyridin-4-yl]-3 -[(4-fluorophenyl)amino]- 1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 2-[3 -(2,2-difluoroethoxy)pyridin-4-yl]-3 -[(3,4-difluorophenyl)amino]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 2-{3-[2-(dimethylamino)ethoxy]pyridin-4-yl}-3 -[(4-fluorophenyl)amino]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 3-[(3,4-difluorophenyl)amino]-2-[3 -(2-methoxyethoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3 ,2-c]pyridin-4-one; 3 -[(4-fluorophenyl)amino]-2-[3 -(2-methoxyethoxy)pyridin-4-yl]- 1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; and 3-[(3 -fluorophenyl)amino]-2-[3 -(2-methoxyethoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one, or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer. 7. A pharmaceutical composition comprising at least one compound of formula (I) according to claim 1, or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer, together with at least one pharmaceutically acceptable auxiliary. 8. A combination comprising one or more first active ingredients selected from the compound of formula (I) according to claim 1, or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer, and one or more second active ingredients selected from the group consisting of a chemotherapeutic anti-cancer agent and a target-specific anti-cancer agent. 9. A compound of formula 1-2: wherein R1, R2, R3, RA, RB, A and E are as defined in claim 1. 10. A process for preparing the compound of formula (I) according to claim 1, comprising reacting a compound of formula 1-2: wherein R1, R2, R3, RA, RB, A and E are as defined in claim 1, with a base and/or oxidizing reagent, followed by an alkylation agent, to provide the compound of formula (I) according to claim 1, and optionally converting the compound of formula (I) to an N-oxide, a salt, a tautomer or a stereoisomer thereof, or a salt of said N-oxide, tautomer or stereoisomer. 11. The compound of claim 1 or a salt thereof. 12. The compound of claim 6 or a salt thereof. 13. The pharmaceutical composition of claim 7, comprising the compound of formula (I) or a salt thereof. 14. The combination of claim 8, comprising the compound of formula (I) or a salt thereof. 15. A compound which is selected from the group consisting of: 6,6-dimethyl-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 2-(3-methylpyridin-4-yl)-3-(phenylamino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; 1-ethyl-6,6-dimethyl-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; and 1-ethyl-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one, or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.