Bicyclic heterocycles as fgfr4 inhibitors

Patent metadata

Field	Value
Publication number	US-2016115164-A1
Application number	US-201514918868-A
Country	US
Kind code	A1
Filing date	Oct 21, 2015
Priority date	Oct 22, 2014
Publication date	Apr 28, 2016
Grant date	—

Abstract

The present invention relates to bicyclic heterocycles, and pharmaceutical compositions of the same, that are inhibitors of the FGFR4 enzyme and are useful in the treatment of FGFR4-associated diseases such as cancer.

First claim

What is claimed is:

1 . A compound of Formula (I′):

or a pharmaceutically acceptable salt thereof, wherein:
X is N or CR 6 ;
Y is O or NR 8 ;
R 1 is C 1-3 alkyl or C 1-3 haloalkyl;
R 2 is H, halo, C 1-3 alkyl, C 1-3 haloalkyl, CN, or C 1-3 alkoxy;
R 3 is H, halo, C 1-3 alkyl, C 1-3 haloalkyl, CN, or C 1-3 alkoxy;
R 4 is C 1-3 alkyl or C 1-3 haloalkyl;
R 5 is H, halo, C 1-3 alkyl, C 1-3 haloalkyl, CN, or C 1-3 alkoxy;
R 6 is H, halo, CN, OR a4 , SR a4 , C(O)NR c4 R d4 , OC(O)NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)OR a4 , NR c4 C(O)NR c4 R d4 , NR c4 S(O)R b4 , NR c4 S(O) 2 R b4 , NR c4 S(O) 2 NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , S(O) 2 NR c4 R d4 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, phenyl, C 3-6 cycloalkyl, a 5-6 membered heteroaryl moiety comprising carbon and 1, 2, or 3 heteroatoms independently selected from N, O and S, and a 4-7 membered heterocycloalkyl moiety comprising carbon and 1, 2, or 3 heteroatoms independently selected from N, O and S; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl groups of R 6 are each optionally substituted with 1, 2, or 3 substituents independently selected from R 10A ;
L is a bond or *—CR 7A R 7B CR 7C R 7D —NR 7E —, wherein the symbol * indicates the point of attachment to Y in Formula (I′); wherein the symbol represents a single or double bond; and wherein R 7B and R 7D are absent when is a double bond;
R 7A is selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, phenyl, C 3-7 cycloalkyl, a 5-6 membered heteroaryl moiety comprising carbon and 1, 2, or 3 heteroatoms independently selected from N, O and S, and a 4-7 membered heterocycloalkyl moiety comprising carbon and 1, 2, or 3 heteroatoms independently selected from N, O and S; wherein said C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl groups of R 7A are each optionally substituted with 1, 2, or 3 substituents independently selected from R 17 ;
R 7B is H or C 1-4 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from R 17 ;
or R 7A and R 7B together with the carbon atom to which they are attached form a C 3-7 cycloalkyl group or a 4-7 membered heterocycloalkyl moiety comprising carbon and 1, 2, or 3 heteroatoms independently selected from N, O and S; wherein said C 3-7 cycloalkyl and 4-7 membered heterocycloalkyl groups are each optionally substituted with 1, 2, or 3 substituents independently selected from R 17 ;
R 7C is selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, phenyl, C 3-7 cycloalkyl, a 5-6 membered heteroaryl moiety comprising carbon and 1, 2, or 3 heteroatoms independently selected from N, O and S, and a 4-7 membered heterocycloalkyl moiety comprising carbon and 1, 2, or 3 heteroatoms independently selected from N, O and S; wherein said C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl group of R 7C are each optionally substituted with 1, 2, or 3 substituents independently selected from R 17 ;
R 7D is H or C 1-4 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from R 17 ;
or R 7C and R 7D together with the carbon atom to which they are attached form a C 3-7 cycloalkyl group or a 4-7 membered heterocycloalkyl moiety comprising carbon and 1, 2, or 3 heteroatoms independently selected from N, O and S; wherein said C 3-7 cycloalkyl and 4-7 membered heterocycloalkyl groups are each optionally substituted with 1, 2, or 3 substituents independently selected from R 17 ;
R 7E is selected from H, C 1-4 alkyl, C 2-4 alkenyl, and C 2-4 alkynyl;
alternatively, when is a double bond, R 7A and R 7C together with the carbon atoms to which they are attached form a phenyl group or a 5-6 membered heteroaryl moiety comprising carbon and 1, 2, or 3 heteroatoms independently selected from N, O and S, wherein said phenyl and 5-6 membered heteroaryl groups are each optionally substituted with 1, 2, or 3 substituents independently selected from R 17 ;
alternatively, when is a single bond, R 7A and R 7C together with the carbon atoms to which they are attached form a C 3-7 cycloalkyl group or a 4-7 membered heterocycloalkyl moiety comprising carbon and 1, 2, or 3 heteroatoms independently selected from N, O and S; wherein said C 3-7 cycloalkyl group and 4-7 membered heterocycloalkyl group are each optionally substituted with 1, 2, or 3 substituents independently selected from R 17 ;
alternatively, R 7A and R 7E together with the carbon and nitrogen atoms to which they are attached form a 5-6 membered heteroaryl moiety comprising carbon and 1, 2, or 3 nitrogen atoms, or a 4-7 membered heterocycloalkyl moiety comprising carbon and 1 or 2 nitrogen atoms; wherein said 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl group are each optionally substituted with 1, 2, or 3 substituents independently selected from R 17 ;
alternatively, R 7C and R 7E together with the carbon and nitrogen atoms to which they are attached form a 5-6 membered heteroaryl moiety comprising carbon and 1, 2, or 3 nitrogen atoms, or a 4-7 membered heterocycloalkyl moiety comprising carbon and 1 or 2 nitrogen atoms; wherein said 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl group are each optionally substituted with 1, 2, or 3 substituents independently selected from R 17 ;
R 8 is H or C 1-4 alkyl which is optionally substituted by halo, CN, OR a9 , C(O)NR c9 R d9 , NR c9 R d9 , NR c9 C(O)R b9 , NR c9 C(O)OR a9 , NR c9 C(O)NR c9 R d9 , NR c9 S(O)R b9 , NR c9 S(O) 2 R b9 , NR c9 S(O) 2 NR c9 R d9 , S(O)R b9 , S(O)NR c9 R d9 , S(O) 2 R b9 , S(O) 2 NR c9 R d9 , phenyl, C 3-7 cycloalkyl, a 5-6 membered heteroaryl moiety comprising carbon and 1, 2, or 3 heteroatoms independently selected from N, O and S, or a 4-7 membered heterocycloalkyl moiety comprising carbon and 1, 2, or 3 heteroatoms independently selected from N, O and S; wherein said phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl groups of R 8 are each optionally substituted with 1 or 2 R 19 ;
R 10 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, a 5-10 membered heteroaryl moiety comprising carbon and 1, 2, or 3 heteroatoms independently selected from N, O and S, and a 4-10 membered heterocycloalkyl moiety comprising carbon and 1, 2, or 3 heteroatoms independently selected from N, O and S; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl groups of R 10 are each optionally substituted with 1, 2, 3, or 4 R 10A ;
R 10A , at each occurrence, is independently selected from halo, CN, NO 2 , 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 , C(═NR e4 )NR c4 R d4 , NR c4 C(═NR e4 )NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)OR a4 , NR c4 C(O)NR c4 R d4 , NR c4 S(O)R b4 , NR c4 S(O) 2 R b4 , NR c4 S(O) 2 NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 S(O) 2 NR c4 R d4 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, phenyl, C 3-6 cycloalkyl, a 5-6 membered heteroaryl moiety comprising carbon and 1, 2, or 3 heteroatoms independently selected from N, O and S, and a 4-7 membered heterocycloalkyl moiety comprising carbon and 1, 2, or 3 heteroatoms independently selected from N, O and S; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl

Assignees

• Incyte Corp

Inventors

• Wu Liangxing
• Lu Liang
• Qian Ding-Quan
• Shen Bo
• Yao Wenqing

Classifications

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D491/20

  Spiro-condensed systems · CPC title

• C07D471/10 Primary

  Spiro-condensed systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title