Substituted isoxazole amine compounds as inhibitors of SCD1

Patent metadata

Field	Value
Publication number	US-9290465-B2
Application number	US-201314443849-A
Country	US
Kind code	B2
Filing date	Nov 29, 2013
Priority date	Dec 3, 2012
Publication date	Mar 22, 2016
Grant date	Mar 22, 2016

Abstract

The invention is concerned with a compound of formula (I) wherein R1 to R3 are defined as in the description and in the claims. The compound of formula (I) can be used as a medicament.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein
A is —CH— or nitrogen;
R1 is —O(CH 2 ) n R4, —CH 2 NHR4, —CH 2 CH 2 R4, —OCH 2 C(O)R4 or —CH 2 OR4;
R2 is hydrogen or halogen;
R3 is hydrogen or lower alkyl;
R4 is phenyl, pyridinyl, 1,1-dioxo-2,3-dihydro-1H-1lambda*6*-benzo[b]thiophenyl or 1,1-dioxo-1H-1lambda*6*-benzo[b]thiophenyl, said phenyl optionally mono- or bi-substituted independently with halogen, lower alkyl, alkoxy, —C(O)OCH 3 , —S(O) 2 CH 3 , —NO 2 , —CN, —CF 3 , —OCF 3 , —SCH 3 , —SO 2 -phenyl, —SCF 3 or —SO 2 CH 2 CH 3 ; and
n is 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , wherein A is —CH—.

3. The compound according to claim 1 , wherein R1 is —O(CH 2 ) n R4 or —CH 2 NHR4.

4. The compound according to claim 1 , wherein R1 is —O(CH 2 ) n R4.

5. The compound according to claim 1 , wherein R1 is —OCH 2 R4.

6. The compound according to claim 1 , wherein R2 is hydrogen.

7. The compound according to claim 1 , wherein R3 is hydrogen or methyl.

8. The compound according to claim 1 , wherein R4 is unsubstituted phenyl, pyridinyl, 1,1-dioxo-2,3-dihydro-1H-1lambda*6*-benzo[b]thiophenyl or 1,1-dioxo-1H-1lambda*6*-benzo[b]thiophenyl.

9. The compound according to claim 1 , wherein R4 is unsubstituted phenyl.

10. The compound according to claim 1 , wherein R4 is phenyl mono-substituted with Cl, F, I, methyl, isopropyl, —OCH 3 , —C(O)OCH 3 , —S(O) 2 CH 3 , —NO 2 , —CN, —CF 3 , —OCF 3 , —SCH 3 , —SO 2 -phenyl, —SCF 3 or —SO 2 CH 2 CH 3 .

11. The compound according to claim 1 , wherein R4 is phenyl bi-substituted independently with methyl or halogen.

12. The compound according to claim 1 , selected from the group consisting of:
3-[4-(4-Fluoro-benzyloxy)-phenyl]-isoxazol-4-ylamine;
3-(4-Benzyloxy-phenyl)-isoxazol-4-ylamine;
3-[4-(4-Methoxy-benzyloxy)-phenyl]-isoxazol-4-ylamine;
4-[4-(4-Amino-isoxazol-3-yl)-phenoxymethyl]-benzoic acid methyl ester hydrochloride;
3-[4-(4-Methanesulfonyl-benzyloxy)-phenyl]-isoxazol-4-ylamine;
3-{4-[(4-methanesulfonyl-phenylamino)-methyl]-phenyl}-isoxazol-4-ylamine hydrochloride;
3-[4-(2-Chloro-4-methanesulfonyl-benzyloxy)-phenyl]-isoxazol-4-ylamine;
3-{4-[2-(4-Methanesulfonyl-phenyl)-ethyl]-phenyl}-isoxazol-4-ylamine;
3-(5-Phenethyloxy-pyridin-2-yl)-isoxazol-4-ylamine;
3-[4-(3-Phenyl-propoxy)-phenyl]-isoxazol-4-ylamine;
3-[5-(4-Methanesulfonyl-benzyloxy)-pyridin-2-yl]-isoxazol-4-ylamine;
3-[4-(4-Methanesulfonyl-benzyloxy)-phenyl]-5-methyl-isoxazol-4-ylamine;
3-[4-(Pyridin-3-ylmethoxy)-phenyl]-isoxazol-4-ylamine;
2-[4-(4-Amino-isoxazol-3-yl)-phenoxy]-1-phenyl-ethanone hydrochloride;
3-[4-(4-Nitro-benzyloxy)-phenyl]-isoxazol-4-ylamine hydrochloride;
4-[4-(4-Amino-isoxazol-3-yl)-phenoxymethyl]-benzonitrile hydrochloride;
3-[4-(4-Amino-isoxazol-3-yl)-phenoxymethyl]-benzonitrile hydrochloride;
3-[4-(4-Trifluoromethyl-benzyloxy)-phenyl]-isoxazol-4-ylamine hydrochloride;
3-[4-(4-Trifluoromethoxy-benzyloxy)-phenyl]-isoxazol-4-ylamine hydrochloride;
3-[4-(3,5-Difluoro-benzyloxy)-phenyl]-isoxazol-4-ylamine hydrochloride;
3-[4-(2-Chloro-benzyloxy)-phenyl]-isoxazol-4-ylamine hydrochloride;
3-[4-(3,4-Dimethyl-benzyloxy)-phenyl]-isoxazol-4-ylamine hydrochloride;
3-[4-(3-Trifluoromethoxy-benzyloxy)-phenyl]-isoxazol-4-ylamine hydrochloride;
3-[4-(4-Chloro-benzyloxy)-phenyl]-isoxazol-4-ylamine;
3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-isoxazol-4-ylamine hydrochloride;
3-[4-(4-Methyl-benzyloxy)-phenyl]-isoxazol-4-ylamine hydrochloride;
3-[4-(4-Iodo-benzyloxy)-phenyl]-isoxazol-4-ylamine;
3-[4-(4-Isopropyl-benzyloxy)-phenyl]-isoxazol-4-ylamine;
3-[4-(4-Methanesulfonyl-benzyloxy)-phenyl]-isoxazol-4-ylamine hydrochloride;
3-[4-(4-Ethanesulfonyl-benzyloxy)-phenyl]-isoxazol-4-ylamine;
3-[4-(1,1-Dioxo-2,3-dihydro-1H-1lambda*6*-benzo[b]thiophen-5-ylmethoxy)-phenyl]-isoxazol-4-ylamine;
3-[4-(1,1-Dioxo-1H-1lambda*6*-benzo[b]thiophen-5-ylmethoxy)-phenyl]-isoxazol-4-ylamine;
3-[4-(4-Benzenesulfonyl-benzyloxy)-phenyl]-isoxazol-4-ylamine;
3-[4-(4-Methylsulfanyl-benzyloxy)-phenyl]-isoxazol-4-ylamine; and
3-[4-(4-Trifluoromethylsulfanyl-benzyloxy)-phenyl]-isoxazol-4-ylamine.

13. A pharmaceutical composition, comprising a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier.

14. A method for treating cancer, comprising the step of administering a therapeutically effective amount of a compound according to claim 1 to a subject in need thereof.

Assignees

• Hoffmann La Roche

Inventors

• Derryberry Johnmark
• Erickson Shawn David
• Gillespie Paul
• Mertz Eric

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D261/14 Primary

  Nitrogen atoms · CPC title

• C07D413/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D413/12

  linked by a chain containing hetero atoms as chain links · CPC title