Spiroindolinones as DDR1 inhibitors

Patent metadata

Field	Value
Publication number	US-10618897-B2
Application number	US-201816057436-A
Country	US
Kind code	B2
Filing date	Aug 7, 2018
Priority date	Feb 8, 2016
Publication date	Apr 14, 2020
Grant date	Apr 14, 2020

Abstract

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

or pharmaceutically acceptable salts thereof, as well as processes for their manufacture, pharmaceutical compositions comprising them, and their use as medicaments.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein
W is CHR 2 or N;
X is CHR 3 or N;
Y is CHR 4 or N;
Z is CHR 5 or N;
with the proviso that not more than two of W, X, Y and Z are N,
L is —(CHR 7 ) m —(CHR 8 ) n —(CO) q —;
R 1 is NR 9 R 10 , aryl, heteroaryl, C 3-7 cycloalkyl, heterocycloalkyl, aryl annelated to cycloalkyl, aryl annelated to heterocycloalkyl, or heteroaryl annelated to heterocycloalkyl, wherein each of aryl, heteroaryl, C 3-7 cycloalkyl and heterocycloalkyl are optionally substituted with one or more R 1′ ;
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, heterocycloalkyl, heterocycloalkyl-C 1-7 alkyl, phenyl, benzyl, heteroaryl, amino, hydroxy, C 1-7 alkoxy, halo-C 1-7 alkoxy, C 1-7 alkoxy-C 1-7 alkyl, oxo, —CH 2 —OR 11 , —C(O)—OR 11 , and —C(O)—NHR 11 ;
or if R 1 is C 3-7 cycloalkyl or heterocycloalkyl then two R 1′ together are forming —(CR 12 R 13 ) s — or —(CR 12 R 13 ) t —O—(CR 14 R 15 ) u —;
R 2 is hydrogen, halogen, cyano, C 1-7 alkyl, halo-C 1-7 alkyl, hydroxy-C 1-7 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C 1-7 alkyl, amino, hydroxy, C 1-7 alkoxy, halo-C 1-7 alkoxy, C 1-7 alkoxy-C 1-7 alkyl, —C(O)—C 1-7 alkoxy or —C(O)-amino;
R 3 is hydrogen, halogen, cyano, C 1-7 alkyl, halo-C 1-7 alkyl, hydroxy-C 1-7 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C 1-7 alkyl, amino, hydroxy, C 1-7 alkoxy, halo-C 1-7 alkoxy, C 1-7 alkoxy-C 1-7 alkyl, —C(O)—C 1-7 alkoxy or —C(O)-amino;
R 4 is hydrogen, halogen, cyano, C 1-7 alkyl, halo-C 1-7 alkyl, hydroxy-C 1-7 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C 1-7 alkyl, amino, hydroxy, C 1-7 alkoxy, halo-C 1-7 alkoxy, C 1-7 alkoxy-C 1-7 alkyl, —C(O)—C 1-7 alkoxy or —C(O)-amino;
R 5 is hydrogen, halogen, cyano, C 1-7 alkyl, halo-C 1-7 alkyl, hydroxy-C 1-7 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C 1-7 alkyl, amino, hydroxy, C 1-7 alkoxy, halo-C 1-7 alkoxy, C 1-7 alkoxy-C 1-7 alkyl, —C(O)—C 1-7 alkoxy or —C(O)-amino;
R 6 is mono- or bicyclic heteroaryl comprising 2 to 5 heteroatoms selected from N, O or S, wherein R 6 is 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, —C(O)OH, —C(O)OCH 3 and —C(O)NH 2 ;
R 7 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, —(CH 2 ) r -heteroaryl, —(CH 2 ) x —NR 16 R 17 or R 7 is forming C 1-7 alkylene with R 10 ;
R 8 is hydrogen, C 1-7 alkyl, or halo-C 1-7 alkyl;
R 9 is C 1-7 alkyl, C 3-7 cycloalkyl, heterocycloalkyl, heterocycloalkyl-C 1-7 alkyl, aryl, aryl annelated to C 5-6 cycloalkyl, heteroaryl, or —CH 2 —CH 2 —NR 18 R 19 , wherein C 1-7 alkyl, is optionally substituted with one or more R 9′ , and wherein C 3-7 cycloalkyl, heterocycloalkyl, aryl annelated to C 5-6 cycloalkyl, aryl, benzyl, and heteroaryl are optionally substituted with one or more R 9″ ;
each R 9′ is independently selected from halogen, cyano, amino, hydroxy, C 1-7 alkoxy, C 1-7 alkyl, halo-C 1-7 alkoxy, C 3-7 cycloalkyl, halo-C 3-7 cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl;
each R 9 ″ 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)—NHC 1-7 alkyl, heterocycloalkyl, phenyl, benzyl, heteroaryl and C 1-7 alkyl-heteroaryl;
R 10 is hydrogen, C 1-7 alkyl, C 3-7 cycloalkyl, halo-C 1-7 alkyl, or R 10 is forming C 1-7 alkylene with R 7 ;
R 11 is hydrogen, C 1-7 alkyl, halo-C 1-7 alkyl, C 3-7 cycloalkyl, or heterocycloalkyl bound via C-atom;
R 12 , R 13 , R 14 and R 15 are each independently selected from hydrogen, halogen and C 1-7 alkyl;
R 16 and R 17 are independently selected from hydrogen and C 1-7 alkyl or R 16 and R 17 together with the nitrogen to which they are bound form heterocycloalkyl optionally substituted by R 21 ;
R 18 and R 19 are independently selected from hydrogen and C 1-7 alkyl or R 18 and R 19 together with the nitrogen to which they are bound form heterocycloalkyl;
R 21 is C 1-7 alkyl, C 3-7 cycloalkyl, halo-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;
t is 1 or 2;
u is 1 or 2;
v is 0 or 1;
w is 0 or 1;
x is 1 or 2;
or a pharmaceutically acceptable salt thereof;
with the proviso that if m=n=q=0 then R 1 is not heterocycloalkyl bound via a nitrogen ring atom or —NR 9 R 10 ;
with the proviso that if R 1 is heterocycloalkyl bound to L via a nitrogen ring atom or R 1 is —NR 9 R 10 then m+n≥2 if q=0;
with the proviso that 1′-(1-methylimidazole-2-carbonyl)-1-(3-quinolyl)spiro[indoline-3,4′-piperidine]-2-one and salts thereof are excluded.

2. The compound of formula (I) according to claim 1 , wherein W is C H R 2 .

3. The compound of formula (I) according to claim 1 , wherein X is C H R 3 .

4. The compound of formula (I) according to claim 1 , wherein Y is C H R 4 .

5. The compound of formula (I) according to claim 1 , wherein Z is C H R 5 .

6. The compound of formula (I) according to claim 1 , wherein L is —CH 2 —, —CH 2 —C(O)—, —CH(CH 2 -morpholinyl)-C(O)—, —CH(R 7 )—C(O)— or —CH 2 —CH 2 —C(O)—; wherein R 7 is forming ethylene with R 10 .

7. The compound of formula (I) according to claim 1 , wherein R 1 is —NR 9 R 10 , aryl, heteroaryl, heterocycloalkyl, aryl annelated to heterocycloalkyl, or heteroaryl annelated to heterocycloalkyl, wherein each of aryl, heteroaryl, and heterocycloalkyl are optionally substituted with one or more R 1′ .

8. The compound of formula (I) according to claim 1 , wherein R 1 is —NR 9 R 10 , phenyl, oxadiazolyl, pyridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, hexahydrocyclopenta[b]pyrrolyl, hexahydrocyclopenta[c]pyrrolyl, hexahydropyrrolo[1,2-a]pyrazinyl, 2-azaspiro[3.3]heptanyl, 5-azaspiro[2.5]octanyl, 2-oxa-7-azaspiro[3.4]octanyl, dihydroindolyl, benzo[b][1,4]oxazinyl, dihydropyrrolo[1,2-a]pyrazinyl, or tetrahydropyrrolo[3,2-c]pyridinyl, each except —NR 9 R 10 optionally substituted with one, two, three or four R 1′ .

9. 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, heterocycloalkyl-C 1-7 alkyl, hydroxy, C 1-7 alkoxy, C 1-7 alkoxy-C 1-7 alkyl, oxo, amino and —C(O)—OR 11 .

10. The compound of formula (I) according to claim 1 , wherein each R 1′ is independently selected from fluoro, cyano, methyl, —CH 2 F, —CF 3 , —CH 2 —CF 3 , cyclopropyl, morpholinyl-CH 2 —, hydroxy, methoxy, methoxy-methyl, oxo, dimethylamino and —C(O)—OCH 3 .

11. The compound of formula (I) according to claim 1 , wherein R 2 is hydrogen, halogen, cyano, C 1-7 alkyl, halo-C 1-7 alkyl, hydroxy-C 1-7 alkyl, C 3-7 cycloalkyl, hydroxy, C 1-7 alkoxy, or —C(O)—C 1-7 alkoxy.

12. The compound of formula (I) according to claim 1 , wherein R 2 is hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, —CF

Assignees

• Hoffmann La Roche

Inventors

• Buettelmann Bernd
• Kocer Buelent
• Kuhn Bernd
• Prunotto Marco
• Richter Hans
• Ritter Martin

Classifications

• C07D487/10

  Spiro-condensed systems · CPC title

• C07D471/10 Primary

  Spiro-condensed systems · 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

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title