Biaryl amide compounds as kinase inhibitors

Patent metadata

Field	Value
Publication number	US-9242969-B2
Application number	US-201414204823-A
Country	US
Kind code	B2
Filing date	Mar 11, 2014
Priority date	Mar 14, 2013
Publication date	Jan 26, 2016
Grant date	Jan 26, 2016

Abstract

The present invention provides compounds of Formula (I)

as described herein, and salts thereof, and therapeutic uses of these compounds for treatment of disorders associated with Raf kinase activity. The invention further provides pharmaceutical compositions comprising these compounds, and compositions comprising these compounds and a therapeutic co-agent.

First claim

The invention claimed is:

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
Z 1 is O, S, S(═O) or SO 2 ;
Z 2 is N or CR a , where R a is H;
R 1 is CN, halo, OH, C 1-4 alkoxy, or C 1-4 alkyl that is optionally substituted with one to three groups selected from halo, C 1-4 alkoxy, CN, and hydroxyl;
Ring B is selected from

wherein [Z 1 ] indicates where the ring containing Z 1 is attached to ring B, and [Z 3 ] indicates where the ring containing Z 3 is attached to ring B,
and R 15 , R 16 , R 17 and R 18 are each selected from R 20 , CN, halo, —N(R 20 ) 2 , —OR 20 , and C 4-8 heterocycloalkyl optionally substituted with up to two groups selected from hydroxyl, C 1-4 alkyl, oxo, and halo; where each R 20 is independently H or C 1-4 alkyl optionally substituted with up to three groups independently selected from halo, oxo, C 1-4 alkoxy, hydroxyl, amino, and CN;
each Y is independently selected from C 1-4 alkyl, C 1-4 alkoxy, CN, halo, oxo, —(CH 2 ) p OR 4 , —(CH 2 ) p N(R 4 ) 2 , —(CH 2 ) p NHC(O)R 4 , —(CH 2 ) p NHCOO(C 1-4 alkyl),
or two Y groups on Ring A are optionally taken together to form a ring fused to or bridging Ring A, where said fused or bridging ring optionally contains a heteroatom selected from N, O and S as a ring member, and is optionally substituted with up to two groups selected from C 1-4 alkyl, C 1-4 alkoxy, CN, halo, oxo, —(CH 2 ) p OR 4 , —(CH 2 ) p N(R 4 ) 2 , —(CH 2 ) p NHC(O)R 4 , and —(CH 2 ) p NHCOO(C 1-4 alkyl);
each R 4 is independently H or C 1-4 alkyl;
each p is independently 0, 1, or 2;
q is 0, 1 or 2;
Z 3 , Z 4 , and Z 5 are independently selected from CH and N;
L is —C(═O)—NH—[CY] or —NH—C(═O)—[CY], where [CY] indicates which atom of L is attached to CY; and
CY is an aromatic ring selected from phenyl, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, thiazole, isothiazole, oxazole, pyrazole, and isoxazole, wherein the ring is optionally fused to a thiophene, imidazole, oxazolone, or pyrrole ring;
and CY is substituted with up to two groups selected from halo, CN, R 5 , OR 5 , SO 2 R 5 , OH, NH 2 , NHR 5 , and —N(R 5 ) 2 ;
wherein each R 5 is independently C 1-4 alkyl, C 4-6 heterocyclyl, or C 3-8 cycloalkyl, and R 5 is optionally substituted with up to three groups selected from oxo, halo, CN, R 6 , OH, OR 6 , SO 2 R 6 , NH 2 , NHR 6 , N(R 6 ) 2 , NHSO 2 R 6 , NHCOOR 6 , NHC(═O)R 6 , —CH 2 OR 7 , —CH 2 N(R 7 ) 2 , wherein each R 6 is independently C 1-4 alkyl, and each R 7 is independently H or C 1-4 alkyl;
and two R 4 , R 5 , R 6 , or R 7 on the same nitrogen atom can be taken together to form a 5-6 membered heterocyclic ring optionally containing an additional N, O or S as a ring member and optionally substituted with up to two groups selected from C 1-4 alkyl, oxo, halo, OH, and C 1-4 alkoxy.

2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Z 1 is O.

3. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Z 2 is CH.

4. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein CY is selected from phenyl, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, thiazole, and oxazole.

5. A compound according to any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 1 is methyl or CF 3 .

6. A compound of claim 1 , or a pharmaceutically thereof, wherein Ring B is pyridine or pyrimidine or pyridone.

7. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein CY is substituted phenyl or substituted pyridin-4-yl.

8. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein CY is substituted with at least one group selected from CF 3 , OCF 3 , t-butyl, —C(Me) 2 CN, and —SO 2 Me.

9. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z 4 is CH.

10. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z 4 is N.

11. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is —C(═O)—NH—[CY], where [CY] indicates which atom of L is attached to ring CY.

12. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is —NH—C(═O)—[CY], where [CY] indicates which atom of L is attached to ring CY.

13. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z 3 is N.

14. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, selected from:

Assignees

• Novartis Ag

Inventors

• Barsanti Paul A
• Burger Matthew
• Lou Yan
• Nishiguchi Gisele
• Polyakov Valery
• Ramurthy Savithri
• Rico Alice
• Setti Lina
• Smith Aaron
• Taft Benjamin
• Tanner Huw
• Dipesa Alan
• Yusuff Naeem

Classifications

• A61P43/00

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

• A61P35/00

  Antineoplastic agents · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• A61K31/444

  containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone · CPC title

• C07D413/04 Primary

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