RAF inhibitor compounds

Patent metadata

Field	Value
Publication number	US-9334267-B2
Application number	US-201314383799-A
Country	US
Kind code	B2
Filing date	Mar 5, 2013
Priority date	Mar 7, 2012
Publication date	May 10, 2016
Grant date	May 10, 2016

Abstract

This invention provides compounds of Formula I: (Formula I should be inserted here) or a pharmaceutically acceptable salt thereof; pharmaceutical compositions comprising a compound of Formula I; and use of a compound of Formula I for treating specified cancers.

First claim

We claim:

1. A compound of the formula:

wherein:
Ri is hydrogen, Ci-C 4 alkyl, or halo;
R 2 is Ci-C 4 alkyl or hydrogen;
R 3 is Ci-C 4 alkyl, hydrogen, —C(O)R 8 , oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl; and wherein the C 1 -C 4 alkyl is optionally substituted with hydroxyl, C 1 -C 2 alkoxy, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, N-azetidinyl, N-piperazinyl, C5-C 6 heteroaryl, N-morpholino, N-piperidinyl, N-pyrrolidinyl, or (C 1 -C 4 alkyl) n amino- wherein n is 0, 1, or 2; and wherein each of the rings as substituents on a C 1 -C 4 alkyl are further optionally substituted with one to three of the same or different C 1 -C 4 alkyl, fluoro, C1-C4 alkoxy, —C(0)Rg, or (C1-C4 alkyl) m amino, where m is 0, 1 or 2;
Rt is R5-(CH 2 )—, or C 4 -C 6 cycloalkyl optionally substituted with one or two of the same or different methyl, ethyl, or fluoro;
Rs is —CHR 6 R7 or C3-C 6 cycloalkyl optionally substituted with one or two of the same or different C 1 -C 2 alkyl;
R6 is hydrogen or hydroxyl, or C 1 -C 4 alkoxy;
R 7 is isopropyl, t-butyl, 1-fluoro-1-methyl-ethyl, 1-cyano-1-methyl-ethyl, 1-(Ci-C 4 alkoxy)-1-methyl-ethyl, 1-(Ci-C 4 alkyl)-cycloprop-1-yl, 1-(fluoro(Ci-C 2 alkyl)cycloprop-1-yl, or 2,2,2-trifluoro-1,1-dimethyl-ethyl where fluoro(Ci-C 2 alkyl) has one to five fluoro substituents;
Rs is hydrogen, Ci-C 6 linear or branched alkyl, or (Ci-C 4 ) p amino where p is 0, 1, or 2, and each alkyl is optionally substituted with the same or different Ci-C 4 alkoxy, hydroxyl, or (Ci-C 4 alkyl) q amino and q is 0, 1, or 2;
provided that the following substituents as a group are not simultaneously allowed:
Ri is methyl;
R 2 is methyl;
R 3 is methyl;
R, is R 5 —(CH 2 )—;
R 5 is —CHR 6 R 7 ;
Re is hydrogen;
R 7 is t-butyl;
or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1 wherein:
Ri is hydrogen, methyl, fluoro or bromo;
R 2 is hydrogen or methyl;
R3 is hydrogen, methyl, ethyl, acetyl, 2-methoxy ethyl, 2-hydroxy ethyl, oxetan-3-yl, 2-dimethylaminoethyl, N-morpholinoethyl, (1-methylimidazol-4-yl)methyl;
R4 is R 5 —(CH 2 )—, or 3,3-dimethylcyclobutyl;
R 5 is —CHR 6 R 7 , or 2,2-dimethylcycloprop-1-yl);
Re is hydrogen or hydroxyl;
R 7 is t-butyl, 1-fluoro-1-methyl-ethyl, 1-cyano-1-methyl-ethyl, 1-methoxy-1-methyl-ethyl, 1-methylcycloprop-1-yl, 1-trifluoromethylcycloprop-1-yl, or 2,2,2-trifluoro-1,1-dimethyl-ethyl;
or a pharmaceutically acceptable salt thereof.

3. A compound of claim 1 wherein:
Ri is hydrogen, methyl or fluoro;
R 2 is hydrogen or methyl;
R 3 is hydrogen, methyl, acetyl, 2-hydroxyethyl, or N-morpholinoethyl;
R 4 is R 5 —(CH 2 )—, or 3,3-dimethylcyclobutyl;
R 5 is —CHR 6 R 7 ;
Re is hydrogen or hydroxyl;
R 7 is t-butyl, 1-cyano-1-methyl-ethyl, 1-methylcycloprop-1-yl, 1-trifluoromethylcycloprop-1-yl, or 2,2,2-trifluoro-1,1-dimethyl-ethyl;
or a pharmaceutically acceptable salt thereof.

4. A compound of any one of claims 1 to 3 wherein:
Ri is hydrogen;
R 2 is methyl;
R 3 is methyl;
R 4 is R 5 —(CH 2 )—;
R 5 is —CHR 6 R 7 ;
Re is hydrogen;
R 7 is t-butyl;
or a pharmaceutically acceptable salt thereof.

5. A compound of any one of claims 1 to 3 wherein:
Ri is methyl;
R 2 is methyl;
R 3 is hydrogen;
R 4 is R 5 —(CH 2 )—;
R 5 is —CHR 6 R 7 ;
Re is hydrogen;
R 7 is t-butyl;
or a pharmaceutically acceptable salt thereof.

6. A compound of any one of claims 1 to 3 wherein:
Ri is fluoro;
R 2 is methyl;
R 3 is methyl;
R 4 is R 5 —(CH 2 )—;
R 5 is —CHR 6 R 7 ;
Re is hydrogen;
R 7 is t-butyl;
or a pharmaceutically acceptable salt thereof.

7. A compound of any one of claims 1 to 3 wherein: Ri is methyl;
R 2 is hydrogen;
R 3 is methyl;
R 4 is R 5 —(CH 2 )—;
R 5 is —CHR 6 R 7 ;
Re is hydrogen;
R 7 is t-butyl;
or a pharmaceutically acceptable salt thereof.

8. A compound of any one of claims 1 to 3 wherein: Ri is hydrogen, methyl, or fluoro;
R 2 is methyl;
R 3 is methyl;
R 4 is R 5 —(CH 2 )—;
R 5 is —CHR 6 R 7 ;
Re is hydrogen;
R 7 is 1-cyano-1-methyl-ethyl;
or a pharmaceutically acceptable salt thereof.

9. A compound of any one of claims 1 to 3 wherein:
Ri is hydrogen, methyl, or fluoro;
R 2 is methyl;
R3 is methyl;
R 4 is 3,3-dimethylcyclobutyl;
or a pharmaceutically acceptable salt thereof.

10. A compound of any one of claims 1 to 3 wherein: Ri is hydrogen, methyl, or fluoro;
R 2 is methyl;
R 3 is methyl;
R 4 is R 5 —(CH 2 )—;
R 5 is —CHR 6 R 7 ;
Re is hydrogen;
R 7 is 1-methylcycloprop-1-yl;
or a pharmaceutically acceptable salt thereof.

11. A compound of any one of claims 1 to 3 wherein: Ri is hydrogen, methyl, or fluoro;
R 2 is methyl;
R 3 is methyl;
R 4 is R 5 —(CH 2 )—;
R 5 is —CHR 6 R 7 ;
Re is hydrogen;
R 7 is 1-trifluoromethylcycloprop-1-yl;
or a pharmaceutically acceptable salt thereof.

12. A compound of any one of claims 1 to 3 wherein:
Ri is hydrogen, methyl, or fluoro;
R 2 is methyl;
R 3 is methyl;
R 4 is R 5 —(CH 2 )—;
R 5 is —CHR 6 R 7 ;
Re is hydrogen;
R 7 is 2,2,2-trifluoro-1,1-dimethyl-ethyl;
or a pharmaceutically acceptable salt thereof.

13. A compound of any one of claims 1 to 3 wherein:
Ri is hydrogen, methyl, or fluoro;
R 2 is methyl;
R 3 is 2-hydroxyethyl;
R4 is R 5 —(CH 2 )—;
R 5 is —CHR 6 R 7 ;
Re is hydrogen;
R 7 is t-butyl;
or a pharmaceutically acceptable salt thereof.

14. A compound of any one of claims 1 to 3 wherein:
Ri is hydrogen, methyl, or fluoro;
R 2 is methyl;
R3 is methyl;
R 4 is R 5 —(CH 2 )—;
R 5 is —CHR 6 R 7 ;
Re is hydroxyl;
R 7 is t-butyl;
or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.

16. A method of treating a cancer which is thyroid cancer, ovarian cancer, melanoma, AML or colorectal cancer in a patient comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

17. A method of treating melanoma in a patient comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

Assignees

• Deciphera Pharmaceuticals Llc
• Lilly Co Eli

Inventors

• Flynn Daniel L
• Kaufman Michael D
• Vogeti Lakshminarayana
• Wise Scott
• Lu Wei-Ping
• Smith Bryan
• Henry James R
• Hipskind Philip A
• Peng Sheng-Bin

Classifications

• A61P43/00

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

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D471/12

  in which the condensed system contains three hetero rings · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title