Bicyclic aromatic carboxamide compounds useful as Pim kinase inhibitors

Patent metadata

Field	Value
Publication number	US-9278950-B2
Application number	US-201414155134-A
Country	US
Kind code	B2
Filing date	Jan 14, 2014
Priority date	Jan 14, 2013
Publication date	Mar 8, 2016
Grant date	Mar 8, 2016

Abstract

The present disclosure describes bicyclic aromatic carboxamide derivatives, as well as their compositions and methods of use. The compounds inhibit the activity of the Pim kinases, and are useful in the treatment of diseases related to the activity of Pim kinases including, e.g., cancer and other diseases.

First claim

What is claimed is:

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
Cy is a group of the following formula (Cy-1):

wherein:
R x is H;
R y is H;
a is 1; and
b is 1;

wherein the substituted piperidin-1-yl ring forming Cy is substituted with 1, 2, 3, 4 or 5 substituents each independently selected from halogen, R Cy1 , C 1-6 haloalkyl, CN, OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)NR c1 R d1 , NR c1 C(O)OR a1 , C(═NR e1 )NR c1 R d1 , NR c1 C(═NR e1 )NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , NR c1 S(O) 2 R b1 and S(O) 2 NR c1 R d1 ,
wherein each R Cy1 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-7 cycloalkyl and 4-7 membered heterocycloalkyl, each of which is independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, R Cy2 , C 1-6 haloalkyl, CN, OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)NR c1 R d1 , NR c1 C(O)OR a1 , C(═NR e1 )NR c1 R d1 , NR c1 C(═NR e1 )NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , NR c1 S(O) 2 R b1 and S(O) 2 NR c1 R d1 , and
wherein each R Cy2 is independently C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-7 cycloalkyl and 4-7 membered heterocycloalkyl, each of which is independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, CN, OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)NR c1 R d1 , NR c1 C(O)OR a1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 and S(O) 2 NR c1 R d1 ;
A 1 is CR 1 ;
R 1 is H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)NR c2 R d2 , NR c2 C(O)OR a2 , C(═NR e2 )NR c2 R d2 , NR c2 C(═NR e2 )NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , NR c2 S(O) 2 R b2 or S(O) 2 NR c2 R d2 ; and
R 2 is H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)NR c2 R d2 , NR c2 C(O)OR a2 , C(═NR e2 )NR c2 R d2 , NR c2 C(═NR e2 )NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , NR c2 S(O) 2 R b2 or S(O) 2 NR c2 R d2 ;
or A 1 and R 2 in combination, together with the carbon atom to which R 2 is attached, form a 5, 6 or 7-membered unsaturated or partially saturated carbocyclic or heterocyclic ring containing 3 to 7 ring carbon atoms and 0, 1 or 2 ring heteroatoms, each independently selected from N, O and S, wherein the ring formed by the combination of A 1 and R 2 is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from halogen, C 1-6 alkyl, CN, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c C(O)R b2 , NR c2 C(O)NR c2 R d2 , NR c2 (O)OR a2 and oxo;
R 3 is H, halogen or NH 2 ;
R 4 is H or halogen;
A 5 is N or CR 5 ;
A 6 is N or CR 6 ;
A 7 is N or CR 7 ;
A 8 is N or CR 8 ;
provided that 0, 1 or 2 of A 5 , A 6 , A 7 and A 8 are N;
R 5 is H or halogen;
R 6 is H or halogen;
R 7 is H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, Cy 7 , -L 7 -Cy 7 , CN, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)NR c3 R d3 , NR c3 C(O)OR a3 , C(═NR e3 )NR c3 R d3 , NR c3 C(═NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , NR c3 S(O) 2 R b3 or S(O) 2 NR c3 R d3 ,
wherein said C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl forming R 7 are each independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)NR c3 R d3 , NR c3 C(O)OR a3 , C(═NR e3 )NR c3 R d3 , NR c3 C(═NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , NR c3 S(O) 2 R b3 and S(O) 2 NR c3 R d3 ;
Cy 7 is unsubstituted or substituted C 6-10 aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C 3-6 cycloalkyl or unsubstituted or substituted 4-7 membered heterocycloalkyl,
wherein the substituted C 6-10 aryl, 5-10 membered heteroaryl, C 3-6 cycloalkyl or 4-7 membered heterocycloalkyl forming Cy 7 is substituted with 1, 2, 3, 4 or 5 substituents each independently selected from halogen, R Cy7 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)NR c3 R d3 , NR c3 C(O)OR a3 , C(═NR e3 )NR c3 R d3 , NR c3 C(═NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , NR c3 S(O) 2 R b3 and S(O) 2 NR c3 R d3 ,
wherein each R Cy7 is C 1-6 alkyl, each of which is independently unsubstituted or substituted by 1, 2 or 3 substituents independently selected from halogen, CN, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)NR c3 R d3 , NR c3 C(O)OR a3 , C(═NR e3 )NR c3 R d3 , NR c3 C(═NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 NR c3 S(O) 2 R b3 and S(O) 2 NR c3 R d3 ;
L 7 is unsubstituted C 1-6 alkylene or C 1-6 alkylene substituted with 1, 2 or 3 substituents independently selected from F, Cl, CN, OH, O(C 1-6 alkyl), NH 2 , NH(C 1-6 alkyl) and N(C 1-6 alkyl) 2 ;
R 8 is H, halogen, CN or C 1-6 alkyl;
R a1 , R b1 , R c1 and R d1 are each independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-3 alkyl, 5-10 membered heteroaryl-C 1-3 alkyl, C 3-7 cycloalkyl-C 1-3 alkyl and 4-10 membered heterocycloalkyl-C 1-3 alkyl, wherein said C 6-10 aryl-C 1-3 alkyl, 5-10 membered heteroaryl-C 1-3 alkyl, C 3-7 cycloalkyl-C 1-3 alkyl and 4-10 membered heterocycloalkyl-C 1-3 alkyl forming R a1 , R b1 , R c1 and R d1 are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from C 1-6 alkyl, halo, CN, OR a4 , SR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)NR c4 R d4 , NR c4 C(O)OR a4 , C(═NR e4 )NR c4 R d4 , NR c4 C(═NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , NR c4 S(O) 2 R b4 and S(O) 2 NR c4 R d4 ;
or R c1 and R d1 attached to the same N atom, together with the N atom to which they are both attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or 5-membered heteroaryl group, each optionally substituted with 1, 2 or 3 substituents independently selected from C 1-6 alkyl, halo, CN, OR a4 , SR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)NR c4 R d4 , NR c4 C(O)OR a4 , C(═NR e4 )NR c4 R d4 , NR c4 C(═NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , NR c4 S(O) 2 R b4 and S(O) 2 NR c4 R d4 ;

Assignees

• Incyte Corp
• Incyte Holdings Corp

Inventors

• Li Yun-Long
• Burns David M
• Feng Hao
• Xue Chu-Biao
• Wang Anlai
• Pan Jun

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P43/00

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