Granted Patent B2

US 9,464,081 · App. 14/409,878 · Granted Oct 11, 2016

Inventors: Stefanie Flohr (Loerrach, DE); Ulrich Hommel (Mulheim, DE); Edwige Liliane Jeanne Lorthiois (Niffer, FR); Jeurgen Klaus Maibaum (Weil-Haltingen, DE); Nils Ostermann (Binzen, DE); Jean Quancard (Huningue, FR); Stefan Andreas Randl (Frankfurt am Main, DE); Olivier Rogel (Hesingue, FR); Anna Vulpetti (Basel, CH)

Assignee: Novartis AG

C07D471/04C07D403/06C07D403/12C07D403/14

Abstract

Claims (67)

1. A compound, or a salt thereof, according to formula (II):

wherein

A is a group selected from:

Z 1 is C(R 1 ) or N;

Z 2 is C(R 2 ) or N;

Z 3 is C(R 3 ) or N, wherein at least one of Z 1 , Z 2 or Z 3 is not N;

R 1 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, haloC-C 6 alkyl, haloC-C 6 alkoxy C 1 -C 6 alkoxycarbonyl, CO 2 H and C(O)NR A R B ;

R 2 and R 3 are independently selected from the group consisting of hydrogen, halogen, hydroxy, NR C R D , cyano, CO 2 H, CONR A R B SO 2 C 1 -C 6 alkyl, and SO 2 NH 2 , SO 2 NR A R B , C 1 -C 6 alkoxycarbonyl, —C(NR A )NR C R D , C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, haloC 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, wherein each alkyl, alkenyl, alkoxy and alkenyloxy is unsubstituted or substituted with up to 4 substitutents independently selected from halogen, hydroxy, cyano, tetrazoloe, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, CO 2 H, C 1 -C 6 alkoxycarbonyl, C(O)NR A R B , NR C R D , optionally substituted phenyl, heterocycle having 4 to 7 ring atoms and 1, 2, or 3 ring heteroatoms selected from N, O or S, optionally substituted heteroaryl having 5 or 6 ring atoms and 1 or 2 or 3 ring heteroatoms selected from N, O or S, and wherein optional phenyl and heteroaryl substituents are selected from halogen, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and CO 2 H;

R 4 is selected from the group consisting of hydrogen, halogen, and C 1 -C 6 alkyl;

R 5 is C 1 -C 4 alkyl, hydroxyC 1 -C 4 alkyl, C 1 -C 4 alkoxyC 1 -C 4 alkyl, haloC 1 -C 4 alkyl, amino, methylamino

R 6 is hydrogen;

R 7 is hydrogen or fluoro;

R 8 is hydrogen, methyl or hydroxymethyl;

R 9 is hydrogen, halogen, hydroxy or methoxy; or

R 6 and R 7 , taken in combination, form a cyclopropane ring; or

R 8 and R 9 , taken in combination, form a cyclopropane ring;

R 10 and R 11 are independently selected from hydrogen, halogen, C 1 -C 4 alkyl, hydroxyC 1 -C 4 alkyl, C 1 -C 4 alkoxyC 1 -C 4 alkyl and haloC 1 -C 4 alkyl; or

R 10 and R 11 taken together can form a 3 to 6 carbocycle or heterocycle containing 1 heteroatom O or S optionally substituted with 1 or 2 groups independently selected from hydroxyl, halogen C 1 -C 4 alkyl and C 1 -C 4 alkoxy;

R 12 is hydrogen, C 1 -C 4 alkyl haloC 1 -C 4 alkyl, hydroxylC 1 -C 4 alkyl or C 1 -C 4 alkoxyC 1 -C 4 alkyl;

R A and R B are independently selected from the group consisting of hydrogen, and C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, hydroxyC 1 -C 6 alkyl, or NR A R B , taken in combination, form a heterocycle having 4 to 7 ring atoms and 0 or 1 additional ring N, O or S atoms, which heterocycle is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1 -C 4 alkyl, halogen, hydroxy, C 1 -C 4 alkoxy; and

R C and R D , are each independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, or hydroxyC 1 -C 6 alkyl.

2. The compound of claim 1 , or a salt thereof, according to formula (III):

3. The compound of claim 1 , or a salt thereof, wherein at least two of Z 1 , Z 2 and Z 3 are not N.

4. The compound of claim 1 , or a salt thereof, wherein Z 3 is CR 3 ;

R 1 is hydrogen, halogen or C 1 -C 4 alkyl;

R 2 and R 3 are independently selected from the group consisting of hydrogen, halogen, CO 2 H, C 1 -C 4 alkyl and C 1 -C 4 alkoxy; wherein alkoxy is unsubstituted or substituted with optionally substituted heteroaryl having 5 or 6 ring atoms and 1, 2 or 3 ring heteroatoms selected from N, O or S, and wherein the heteroaryl is optionally substituted with 1 or 2 halogen or C 1 -C 4 alkyl groups;

R 4 is hydrogen; and

R 5 is amino or C 1 -C 4 alkyl.

5. The compound of claim 1 , or a salt thereof, wherein

R 6 and R 7 taken in combination form a cyclopropane ring;

R 8 is hydrogen, methyl or hydroxymethyl; and

R 9 is hydrogen.

6. The compound of claim 1 or a salt thereof, wherein

R 6 and R 7 are hydrogen; and

R 8 and R 9 taken in combination form a cyclopropane ring.

7. The compound of claim 1 , or a salt thereof, wherein

R 6 and R 8 are hydrogen;

R 7 is fluoro; and

R 9 is hydrogen or methoxy.

8. The compound of claim 1 , or a salt thereof, wherein R 10 and R 11 are methyl.

9. The compound of claim 1 , or a salt thereof, wherein R 12 is hydrogen.

10. The compound of claim 1 , or a salt thereof, wherein R 12 is methyl.

11. The compound of claim 1 , or a salt thereof, selected from the group consisting of

6-Chloro-1-{2-[(1R,3S,5R)-3-(2-fluoro-3-methyl-but-2-enylcarbamoyl)-2-aza-bicyclo[3.1.0]hex-2-yl]-2-oxo-ethyl}-1H-indazole-3-carboxylic acid amide;

1-{2-[(1R,3S,5R)-3-(2-Fluoro-3-methyl-but-2-enylcarbamoyl)-2-aza-bicyclo[3.1.0]hex-2-yl]-2-oxo-thyl}-1H-indazole-3-carboxylic acid amide;

1-{2-[(2S,4R)-4-Fluoro-2-(2-fluoro-3-methyl-but-2-enylcarbamoyl)-pyrrolidin-1-yl]-2-oxo-ethyl}-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid amide;

1-{2-[(1R,3S,5R)-3-(2-Fluoro-3-methyl-but-2-enylcarbamoyl)-2-aza-bicyclo[3.1.0]hex-2-yl]-2-oxo-ethyl}-6-methyl-1H-indazole-3-carboxylic acid amide;

1-{2-[(2S,3S,4S)-4-Fluoro-2-(2-fluoro-3-methyl-but-2-enylcarbamoyl)-3-methoxy-pyrrolidin-1-yl]-2-oxo-ethyl}-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid amide;

1-{2-[(1R,3S,5S)-3-(2-Fluoro-3-methyl-but-2-enylcarbamoyl)-5-hydroxymethyl-2-aza-bicyclo [3.1.0]hex-2-yl]-2-oxo-ethyl}-1H-indazole-3-carboxylic acid amide;

1-{2-[(2S,4R)-4-Fluoro-2-(2-fluoro-3-methyl-but-2-enylcarbamoyl)-pyrrolidin-1-yl]-2-oxo-ethyl}-1H-indazole-3-carboxylic acid amide;

1-{2-[(2S,3S,4S)-4-Fluoro-2-(2-fluoro-3-methyl-but-2-enylcarbamoyl)-3-methoxy-pyrrolidin-1-yl]-2-oxo-ethyl}-1H-indazole-3-carboxylic acid amide;

1-{2-[(1R,3S,5R)-3-(2-Fluoro-3-methyl-but-2-enylcarbamoyl)-2-aza-bicyclo[3.1.0]hex-2-yl]-2-oxo-ethyl}-5,7-dimethyl-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid amide;

1-{2-[(1R,3S,5R)-3-(2-Fluoro-3-methyl-but-2-enylcarbamoyl)-2-aza-bicyclo[3.1.0]hex-2-yl]-2-oxo-ethyl}-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid amide;

(1R,3S,5R)-2-[2-(3-Acetyl-indazol-1-yl)-acetyl]-2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid (2-fluoro-3-methyl-but-2-enyl)-amide;

1-{2-[(1R,3S,5R)-3-(2-Fluoro-3-methyl-but-2-enylcarbamoyl)-2-aza-bicyclo[3.1.0]hex-2-yl]-2-oxo-ethyl}-5-methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid amide;

(1R,3S,5R)-2-[2-(3-Acetyl-pyrazolo[3,4-c]pyridin-1-yl)-acetyl]-2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid (2-fluoro-3-methyl-but-2-enyl)-amide;

1-{2-[(1R,3S,5R)-3-(2-Fluoro-3-methyl-but-2-enylcarbamoyl)-2-aza-bicyclo[3.1.0]hex-2-yl]-2-oxo-ethyl}-7-methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid amide;

5-Ethyl-1-{2-[(1R,3S,5R)-3-(2-fluoro-3-methyl-but-2-enylcarbamoyl)-2-aza-bicyclo[3.1.0]hex-2-yl]-2-oxo-ethyl}-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid amide;

(1R,3S,5R)-2-{2-[3-Acetyl-5-(pyrimidin-2-ylmethoxy)-indazol-1-yl]-acetyl}-2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid (2-fluoro-3-methyl-but-2-enyl)-amide;

1-{2-[(1R,3S,5R)-3-(2-Cyclopentylidene-2-fluoro-ethylcarbamoyl)-2-aza-bicyclo[3.1.0]hex-2-yl]-2-oxo-ethyl}-1H-indazole-3-carboxylic acid amide;

1-{2-[(1R,3S,5R)-3-(2-Fluoro-3-di-(trideutero-methyl)-allylcarbamoyl)-2-aza-bicyclo[3.1.0]hex-2-yl]-2-oxo-ethyl}-1H-indazole-3-carboxylic acid amide; and

1-{2-[(1R,3S,5R)-3-(2-Fluoro-1,3-dimethyl-but-2-enylcarbamoyl)-2-aza-bicyclo[3.1.0]hex-2-yl]-2-oxo-ethyl}-1H-indazole-3-carboxylic acid amide.

12. The compound of claim 1 , or a salt thereof, selected from the group consisting of

1-(2-oxo-2-((1R,3S,5R)-3-(((Z)-2,4,4,4-tetrafluorobut-2-en-1-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)ethyl)-1H-indazole-3-carboxamide;

1-(2-((1R,3S,5R)-3-((S)-3-fluoro-4-methylpent-3-en-2-ylcarbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1H-indazole-3-carboxamide; and

1-(2-((1R,3S,5R)-3-((R)-3-fluoro-4-methylpent-3-en-2-ylcarbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1H-indazole-3-carboxamide.

13. A pharmaceutical composition comprising one or more pharmaceutically acceptable carriers and a therapeutically effective amount of a compound of claim 1 .

Assignments (8)

Continuity (3)