Fused heterocyclic compounds as CaM kinase inhibitors

Patent metadata

Field	Value
Publication number	US-10100058-B2
Application number	US-201715825993-A
Country	US
Kind code	B2
Filing date	Nov 29, 2017
Priority date	Nov 30, 2016
Publication date	Oct 16, 2018
Grant date	Oct 16, 2018

Abstract

The present disclosure relates to compounds that are CaM Kinase inhibitors and to their use in the treatment of various disease states, including atrial fibrillation and myocardial infarction. In particular embodiments, the general structure of the compounds is given by Formula I:

wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 and R 10 are as described herein, to methods for the preparation and use of the compounds and to pharmaceutical compositions containing the same.

First claim

What is claimed is:

1. A compound of formula I:

wherein
R 1 is aryl, heteroaryl or heterocyclic; wherein the aryl, heteroaryl or heterocyclic group is optionally substituted with one, two or three groups independently selected from the group consisting of halo, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, —OC 1 -C 6 haloalkyl, —SC 1 -C 6 alkyl, —NHSO 2 R a , and C 0 -C 6 alkylene-NR a R b ;
R 2 and R 3 are each independently selected from the group consisting of H, halo and C 1 -C 6 alkyl;
X is CH or N;
R 4 is is H, halo, cyano, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkylOH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylC 3 -C 6 cycloalkyl, —NR a R b , C 1 -C 6 alkylNR a R b , C 1 -C 6 alkyl-O—C 1 -C 6 alkylNR a R b , —OC 2 -C 6 alkylNR a R b , —C(O)NR a R b , —NR a C(O)NR a R b , —NR a C(O)R a , —NR a C(O)OR a , aryl, heteroaryl, mono, bicyclic, bridged or spirocyclic carbocyclic or heterocyclic group, —O—C 0 -C 3 alkylheterocyclic, or C 1 -C 6 alkylheterocyclic, wherein the alkyl, cycloalkyl, aryl, heteroaryl, carbocyclic or heterocyclic group is optionally substituted with one to four groups independently selected from —OH, oxo, halo, cyano, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkylOH, C 1 -C 6 alkoxy, —OC 1 -C 6 haloalkyl, C 1 -C 6 alkyl C 3 -C 8 cycloalkyl, C 1 -C 6 alkyl-O—C 1 -C 6 alkyl, C 0 -C 3 alkylNR a CHR a C(O)NHR a , —C(O)R a , —COOR a , —NHC(O)NHR a , —NHC(O)R a , —NHC(O)OR a , C(O)NR a R b , —NR a R b , —NHC 1 -C 3 alkylNR a R b , SO 2 R a , —NHSO 2 R a , SO 2 NR a R b , aryl, heteroaryl, mono, bicyclic, bridged or spirocyclic carbocyclic or heterocyclic group, and C 1 -C 6 alkylheterocyclic; or two substituents on the aryl, heteroaryl, mono, bicyclic, bridged or spirocyclic carbocyclic or heterocyclic group combine to form a mono, bicyclic, spirocyclic, or bridged carbocyclic or heterocyclic ring; wherein said heteroaryl, mono, bicyclic, bridged or spirocyclic carbocyclic or heterocyclic ring is optionally substituted with one to four groups independently selected from the group consisting of OH, oxo, halo, cyano, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkylOH, —OC 1 -C 6 alkyl, —OC 1 -C 6 haloalkyl, C 1 -C 6 alkyl C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl-O—C 1 -C 6 alkyl, C 0 -C 3 alkylNR a CHR a C(O)NHR a , C(O)NR a R b , —SO 2 R a , and SO 2 NR a R b ;
R a and R b are each independently H, OH, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkylOH, C 1 -C 6 alkoxy, —C(O)C 1 -C 6 alkyl, —C(O)OC 1 -C 6 alkyl, C 0 -C 3 alkylNR c R d , C 1 -C 3 alkylC(O)NH 2 , C 1 -C 3 alkylC(O)NHC 1 -C 3 alkyl, C 1 -C 6 alkylC 3 -C 6 cycloalkyl, SO 2 C 1 -C 3 alkyl, SO 2 C 3 -C 6 cycloalkyl, —C 1 -C 3 alkylSO 2 NR c R d , aryl, heteroaryl, heterocyclic, C 1 -C 6 alkylheterocyclic, wherein the cycloalkyl, aryl, heteroaryl or heterocyclic group is optionally substituted with one to four groups independently selected from —OH, oxo, halo, cyano, NH 2 , NHC 1 -C 3 alkyl, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkylOH, C 1 -C 6 alkoxy, C 1 -C 6 alkylC 3 -C 6 cycloalkyl, C 1 -C 6 alkyl-O—C 1 -C 6 alkyl, and heterocyclyl; or R a and R b combine with a nitrogen atom to which they are attached to form a mono, bicyclic, bridged or spirocyclic heterocyclic group optionally substituted with one to four groups independently selected from OH, oxo, halo, cyano, NH 2 , NHC 1 -C 3 alkyl, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkylOH, C 1 -C 6 alkoxy, C 1 -C 6 alkylC 3 -C 6 cycloalkyl, —C(O)NR c R d , —SO 2 R c , SO 2 NR c R d and C 1 -C 6 alkyl-O—C 1 -C 6 alkyl;
R c and R d are independently selected from H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 6 haloalkyl, C 2 -C 6 alkylOH, C 1 -C 6 alkylC 3 -C 6 cycloalkyl, SO 2 C 1 -C 6 alkyl, and C 1 -C 6 alkyl-O—C 1 -C 6 alkyl; or R c and R d combine to form mono, bicyclic, bridged or spirocyclic heterocyclic group optionally substituted with a group selected from OH, oxo, halo, cyano, NH 2 , NHC 1 -C 3 alkyl, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkylOH, C 1 -C 6 alkoxy, C 1 -C 6 alkylC 3 -C 6 cycloalkyl, —C(O)NR e R f , —SO 2 R e , SO 2 NR e R f and C 1 -C 6 alkyl-O—C 1 -C 6 alkyl;
R e and R f are at each occurrence independently selected from the group consisting of: C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 6 haloalkyl, C 1 -C 6 haloalkyl, —OC 1 -C 6 haloalkyl, and C 1 -C 6 alkylOH;
R 5 is H, halo, cyano, NH 2 , NHC 1 -C 6 alkyl, N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkylC 3 -C 8 cycloalkyl, C 1 -C 6 haloalkyl, —OC 1 -C 6 haloalkyl, C 1 -C 6 alkyl-OH, or C 1 -C 6 alkoxy;
R 6 is H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 6 haloalkyl, C 2 -C 6 alkyl-OH, or C 1 -C 6 alkoxy; or R 6 combines with Y, R 9 , or R 10 to form an optionally substituted 4-8 membered nitrogen containing heterocyclic group;
Y is —(CR 7 R 8 ) n wherein n is 2 or 3;
each R 7 or R 8 is independently selected from H, C 1 -C 6 alkyl, C 1 -C 3 alkylOH, C 1 -C 3 alkylNH 2 and C 1 -C 3 alkyl-O-heterocyclic; or one R 7 or R 8 group combines with the R 6 group to form an optionally substituted nitrogen containing heterocyclic group; or one R 7 group combines with another R 7 or an R 8 group to form an optionally substituted monocyclic or bicyclic, bridged or spirocyclic ring system having from 4 to 10 carbon atoms in the ring; wherein the optional substituents include 1 or 2 groups independently selected from halo, —OH, NH 2 , cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkylOH, and C 3 -C 8 cycloalkyl;
each R 9 and R 10 is independently H, C 1 -C 6 alkyl, C 2 -C 6 haloalkyl, C 2 -C 6 alkylOH, C 3 -C 8 cycloalkyl, C 1 -C 6 alkylC 3 -C 8 cycloalkyl, —C(O)OR 13 , —C(O)NR 13 R 14 or heterocyclic, wherein the alkyl, cycloalkyl or heterocyclic group is optionally substituted with one or two groups independently selected from the group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkylOH, C 3 -C 8 cycloalkyl, —OR 12 , —NR 13 R 14 , —C(O)NR 13 R 14 , —NR 13 COR 14 , —SO 2 NR 13 R 14 , —NR 13 SO 2 R 14 , —NR 12 SO 2 NR 13 R 14 , —NR 12 C(O)NR 13 R 14 , —NR 13 CO 2 R 14 , and —OC(O)NR 13 R 14 ; or R 9 and R 10 together with the nitrogen atom to which they are attached form a mono, bicyclic, bridged or spirocyclic heterocyclic ring optionally substituted with one or two groups independently selected from the group consisting of halo, —OH, —NH 2 , —NH—C 1 -C 6 alkyl, —C 1 -C 6 alkyl, —C 1 -C 6 alkylOH, C 3 -C 8 cycloalkyl, aryl, and heterocyclic; wherein the cycloalkyl, aryl or heterocyclic group is optionally substituted with halo, —OH, —NH 2 , —NH—C 1 -C 6 alkyl, —C 1 -C 6 alkyl, and —C 1 -C 6 alkylOH; or R 9 and/or R 10 combines with Y to form a mono, bicyclic, bridged or spirocyclic nitrogen containing heterocycle optionally substituted with one or two groups independently selected from the group consisting of —C 1 -C 6 alkyl, —C 1 -C 6 alkylOH, C 3 -C 8 cycloalkyl, —OH, —NH 2 , and —NH—C 1 -C 6 alkyl;
each R 12 , R 13 and R 14 is independently H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, or heterocyclic, wherein the C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl group, or heterocyclic, group is optionally substituted with one or two groups independently selected from the group consisting of —OH, —NH 2 , —N(CH 3 ) 2 , C 1 -C 6 haloalkyl; or R 13 and R 14 together with the atom to which they are attached form a heterocyclic ring;
or a pharmaceutically acceptable salt, stere

Assignees

• Gilead Sciences Inc

Inventors

• Elzein Elfatih
• Kalla Rao V
• Koltun Dmitry
• Li Xiaofen
• Parkhill Eric Q
• Perry Thao
• Simonovich Scott Preston
• Zablocki Jeff
• Ziebenhaus Christopher Allen

Classifications

• A61P9/06

  Antiarrhythmics · CPC title

• A61K9/4866

  Organic macromolecular compounds · CPC title

• A61K9/2059

  Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin · CPC title

• A61K9/2054

  Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose · 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