Triaza-spirodecanones as DDR1 inhibitors

Patent metadata

Field	Value
Publication number	US-10239876-B2
Application number	US-201715850826-A
Country	US
Kind code	B2
Filing date	Dec 21, 2017
Priority date	Jul 3, 2015
Publication date	Mar 26, 2019
Grant date	Mar 26, 2019

Abstract

The present invention relates to compounds of formula (I):

or pharmaceutically acceptable salts thereof, wherein L and R 1 to R 5 are as described herein, as well as processes for their manufacture, pharmaceutical compositions comprising them, and their use as medicaments.

First claim

We claim:

1. A compound of formula (I)

wherein
L is —(CHR 8 ) m —(CHR 9 ) n —(CO) q —
R 1 is —NR 6 R 7 , aryl, or C 3-7 cycloalkyl, wherein each of aryl, and C 3-7 cycloalkyl and are optionally substituted with one or more R 1′ ;
each R 1′ is independently selected from halogen, cyano, C 1-7 alkyl, halo-C 17 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C 17 alkyl, phenyl, benzyl, amino, hydroxy, C 1-7 alkoxy, halo-C 1-7 alkoxy, C 1-7 alkoxy-C 1-7 alkyl, oxo, —CH 2 —OR 16 , —C(O)—OR 16 , —CH 2 —NHR 16 , —CH 2 —CH 2 —NR 17 R 18 , —CH 2 —C(O)—NHR 16 and —C(O)—NHR 16 ;
or two R 1′ together are —(CR 12 R 13 ) s —;
R 2 is hydrogen, fluorine, C 1-7 alkyl, or halo-C 1-7 alkyl;
R 3 is hydrogen or C 1-7 alkyl;
R 4 is aryl optionally substituted by one or more R 4′ ;
each R 4′ is independently selected from halogen, cyano, C 1-7 alkyl, halo-C 1-7 alkyl, C 3-7 cycloalkyl, amino, hydroxy, C 1-7 alkoxy and halo-C 1-7 alkoxy;
R 5 is indazole optionally substituted with one or more R 5′ ;
each R 5′ is independently selected from halogen, cyano, C 1-7 alkyl, halo-C 1-7 alkyl, C 3-7 cycloalkyl, amino, hydroxy, C 1-7 alkoxy and —C(O)NH 2 ;
R 6 is C 1-7 alkyl, halo-C 1-7 alkyl, hydroxy-C 1-7 alkyl, C 1-7 alkoxy-C 1-7 alkyl, C 3-7 cycloalkyl, aryl, —CH 2 —CH 2 —NR 17 R 18 , wherein C 1-7 alkyl, C 3-7 cycloalkyl, aryl or benzyl, are optionally substituted with one or more R 6′ ;
each R 6′ is independently selected from halogen, cyano, C 1-7 alkyl, halo-C 1-7 alkyl, C 3-7 cycloalkyl, amino, hydroxy, C 1-7 alkoxy, halo-C 1-7 alkoxy, C 1-7 alkoxy-C 1-7 alkyl, oxo, —CH 2 —C(O)—NHR 16 , phenyl, optionally substituted with C 1-7 alkyl or benzyl;
R 7 is hydrogen, C 1-7 alkyl, C 3-7 cycloalkyl or is halo-C 1-7 alkyl;
R 8 is hydrogen, C 1-7 alkyl, hydroxy-C 1-7 alkyl, C 1-7 alkoxy-C 1-7 alkyl, halo-C 1-7 alkoxy-C 1-7 alkyl, —(CH 2 ) r -phenyl, or —(CH 2 ) r NR 10 R 11 ;
R 9 is hydrogen, C 1-7 alkyl, or halo-C 1-7 alkyl;
R 10 and R 11 are independently selected from hydrogen and C 1-7 alkyl;
R 12 , R 13 , R 14 and R 15 are each independently selected from hydrogen, halogen and C 1-7 alkyl;
R 16 is hydrogen, C 1-7 alkyl, halo-C 1-7 alkyl or C 3-7 cycloalkyl;
R 17 and R 18 are independently selected from hydrogen and C 1-7 alkyl;
m is 0, 1 or 2;
n is 0, 1 or 2;
q is 0 or 1;
r is 0, 1 or 2;
s is 2, 3 or 4;
or a pharmaceutically acceptable salt thereof;
with the proviso that if R 1 is —NR 6 R 7 then:
if q=0 then m+n≥2, or
if q=1 then m+n≥1.

2. The compound of formula (I) according to claim 1 , wherein m, n and q are each 0, m and q are both 0, n is 1 and R 9 is hydrogen, or m is 0, n and q are 1 and R 9 is hydrogen.

3. The compound of formula (I) according to claim 1 wherein m is 0, n and q are 1 and R 9 is hydrogen.

4. The compound of formula (I) according to claim 1 wherein R 1 is NR 6 R 7 or aryl, wherein each of aryl is optionally substituted with one or more R 1′ .

5. The compound of formula (I) according to claim 4 , wherein R 1 is:
—NR 6 R 7 ; or
phenyl;
wherein each of phenyl is optionally substituted with one, two or three R 1′ .

6. The compound of formula (I) according to claim 1 wherein each R 1′ is independently selected from halogen, cyano, C 1-7 alkyl, halo-C 1-7 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C 1-7 alkyl, amino, hydroxy, C 1-7 alkoxy, C 1-7 alkoxy-C 1-7 alkyl, oxo, phenyl and benzyl.

7. The compound of formula (I) according to claim 6 wherein each R 1′ is independently selected from the group consisting of fluoro, chloro, cyano, methyl, ethyl, tert-butyl, trifluoromethyl, trifluoroethyl, cyclopropyl, cyclopropyl-methyl, dimethylamino, hydroxy, methoxy, methoxymethyl, oxo, phenyl and benzyl.

8. The compound of formula (I) according to claim 1 wherein R 2 is hydrogen.

9. The compound of formula (I) according to claim 1 wherein R 3 is hydrogen.

10. The compound of formula (I) according to claim 1 wherein R 4 is aryl optionally substituted by one or more R 4′ .

11. The compound of formula (I) according to claim 1 wherein R 4 is phenyl optionally substituted with one or two halogen independently selected from fluoro and chloro.

12. The compound of formula (I) according to claim 11 , wherein R 4 is unsubstituted phenyl.

13. The compound of formula (I) according to claim 1 wherein each R 4′ is independently selected from fluoro and chloro.

14. The compound of formula (I) according claim 1 , wherein R 5 is selected from:

each optionally substituted by with one or more R 5′ .

15. The compound of formula (I) according to claim 14 , wherein R 5′ is amino.

16. The compound of formula (I) according to claim 1 wherein R 6 is C 1-7 alkyl, halo-C 1-7 alkyl, C 3-7 cycloalkyl, or aryl each optionally substituted with one R 6′ .

17. The compound of formula (I) according to claim 16 , wherein R 6 is methyl, ethyl, trifluoroethyl, cyclopropyl, adamantyl or phenyl each optionally substituted with one R 6′ .

18. The compound of formula (I) according to claim 17 , wherein R 6 is trifluoroethyl.

19. The compound of formula (I) according to claim 1 , wherein each R 6′ is independently selected from halo-C 1-7 alkoxy or phenyl.

20. The compound of formula (I) according to claim 19 , wherein each R 6′ is independently selected from trifluoromethoxy, or phenyl.

21. The compound of formula (I) according to claim 1 , wherein R 7 is hydrogen or C 1-7 alkyl.

22. The compound of formula (I) according to claim 21 , wherein R 7 is hydrogen, methyl or isopropyl.

23. The compound of formula (I) according to claim 1 selected from the group consisting of:
2-(1-(3,4-Dichlorophenyl)-8-(1H-indazole-5-carbonyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)-N-(2,2,2-trifluoroethyl)acetamide;
2-(1-(4-Chlorophenyl)-8-(1H-indazole-5-carbonyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)-N-(2,2,2-trifluoroethyl)acetamide;
2-(8-(1H-Indazole-5-carbonyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-N-phenylacetamide;
2-(8-(1H-Indazole-5-carbonyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-N-(2,2,2-trifluoroethyl)acetamide;
(rac, trans)-2-(8-(1H-Indazole-5-carbonyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-N-(2-phenylcyclopropyl)acetamide;
2-(8-(1H-Indazole-5-carbonyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-N-(3-(trifluoromethoxy)phenyl)acetamide;
2-(8-(1H-Indazole-6-carbonyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-N-phenylacetamide;
2-[8-(3-Amino-H-indazole-6-carbonyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl]-N-(2,2,2-trifluoroethyl)acetamide;
2-[8-(1H-Indazole-6-carbonyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl]-N-(2,2,2-trifluoroethyl)acetamide;
2-[8-(1H-Indazole-5-carbonyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;
3-(5-Chloro-2-fluorophenyl)-8-(1H-indazole-5-carbonyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one;
(RS)-2-[8-(1H-Indazole-5-carbonyl)-2-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl]-N-(2,2,2-trifluoroethyl)acetamide;

Assignees

• Hoffmann La Roche

Inventors

• Buettelmann Bernd
• Kocer Buelent
• Kuhn Bernd
• Prunotto Marco
• Richter Hans
• Ritter Martin
• Rudolph Markus
• Satz Alexander Lee

Classifications

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• 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

• C07D471/10 Primary

  Spiro-condensed systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title