Heterocyclic compounds and uses thereof

Patent metadata

Field	Value
Publication number	US-9840503-B2
Application number	US-201615151259-A
Country	US
Kind code	B2
Filing date	May 10, 2016
Priority date	May 11, 2015
Publication date	Dec 12, 2017
Grant date	Dec 12, 2017

Abstract

The present disclosure relates to heterocyclic compounds, and pharmaceutical compositions of the same, that are inhibitors of the TAM protein kinases and are useful in the treatment of TAM-associated diseases such as cancer.

First claim

What is claimed is:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt, a tautomer or an isomer thereof, wherein:
ring A is fused C 6-10 aryl, fused 5- or 6-membered heteroaryl or fused 4 to 10-membered heterocycloalkyl, wherein the fused 5- or 6-membered heteroaryl or fused 4 to 10-membered heterocycloalkyl has a carbon and 1-4 heteroatoms as ring members selected from O, N, and S, wherein the N and S as ring members are each optionally oxidized, with the proviso that ring A is other than pyrazolyl having the formula:

wherein the single wavy line indicates the point of attachment to the X linkage in Formula (I), the double wavy line indicates the point of attachment to the ring carbon atom of the pyrimidine ring in Formula (I) and the dashed circular line indicates a single or a double bond and wherein a ring carbon in pyrazolyl is optionally replaced by a carbonyl group;
ring B is C 6-10 aryl, 5- or 6-membered heteroaryl, C 3-6 cycloalkyl or 4 to 10-membered heterocycloalkyl, wherein the 5- or 6-membered heteroaryl or 4 to 10-membered heterocycloalkyl has a carbon and 1-4 heteroatoms as ring members selected from O, N and S, wherein the N and S as ring members are each optionally oxidized and a ring carbon in ring B is optionally replaced by a carbonyl group;
L is a bond, —(CR 5 R 6 ) m —, —C(O)—, —S(O) or —SO 2 —; R 5 and R 6 are each independently selected from H, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, halogen, OH, CN and NH 2 , wherein C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl and C 1-4 haloalkoxy of R 5 and R 6 are each further optionally substituted with 1-2 members independently selected from halo, OH, CN, NH 2 , OR 7 , NHR 7 , NR 7 R 7 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl and C 1-4 haloalkoxy;
or R 5 and R 6 taken together with the carbon atom to which they are attached form a C 3-6 cycloalkyl ring, optionally substituted with 1-2 members independently selected from OH, CN, NH 2 , OR 7 , NHR 7 , NR 7 R 7 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl and C 1-4 haloalkoxy;
each R 7 is independently C 1-4 alkyl;
the subscript m is 1, 2 or 3;
X is a bond, —C(O)— or —CR 8 R 9 —;
R 8 and R 9 are each independently H, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl or C 1-4 haloalkoxy, wherein the C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl and C 1-4 haloalkoxy of R 8 and R 9 are each optionally substituted with 1-2 members independently selected from OH, CN, NH 2 , OR 7 , NHR 7 , NR 7 R 7 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, and C 1-4 haloalkoxy;
or R 8 and R 9 taken together with the carbon atom to which they are attached form a C 3-6 cycloalkyl ring, optionally substituted with 1-2 members independently selected from OH, CN, NH 2 , OR 7 , NHR 7 , NR 7 R 7 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, and C 1-4 haloalkoxy;
each R 1 is independently selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, CN, NO 2 , OR a , SR a , NHOR a , C(O)R a , C(O)NR a R a , C(O)OR a , OC(O)R a , OC(O)NR a R a , NH 2 , NHR a , NR a R a , NR a C(O)R a , NR a C(O)OR a , NR a C(O)NR a R a , C(═NR a )R a , C(═NR a )NR a R a , NR a C(═NR a )NR a R a , NR a S(O)R a , NR a S(O) 2 R a , NR a S(O) 2 NR a R a , S(O)R a , S(O)NR a R a , S(O) 2 R a , and S(O) 2 NR a R a , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R 1 are each optionally substituted with 1, 2, 3, or 4 R b substituents;
each R b is independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, CN, NO 2 , NHOR c , OR c , SR c , C(O)R c , C(O)NR c R c , C(O)OR c , OC(O)R c , OC(O)NR c R c , C(═NR c )NR c R c , NR c C(═NR c )NR c R c , NR c R c , NR c C(O)R c , NR c C(O)OR c , NR c C(O)NR c R c , NR c S(O)R c , NR c S(O) 2 R c , NR c S(O) 2 NR c R c , S(O)R c , S(O)NR c R c , S(O) 2 R c and S(O) 2 NR c R c ; wherein the C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl- and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R b are each further optionally substituted with 1-3 R d substituents;
or two R 1 substituents attached to the same carbon of ring A are taken together to form an oxo group or a C 3-6 cycloalkyl optionally substituted with 1-2 members independently selected from OH, CN, NH 2 , OR 7 , NHR 7 , NR 7 R 7 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, and C 1-4 haloalkoxy;
each R a is independently selected from H, C 1-6 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl- and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R a are each optionally substituted with 1, 2, 3, 4, or 5 R d substituents;
each R d is independently selected from C 1-4 alkyl, C 1-4 haloalkyl, halo, CN, R e , NHOR e , OR e , SR e , C(O)R e , C(O)NR e R e , C(O)OR e , OC(O)R e , OC(O)NR e R e , NH 2 , NHR e , NR e R e , NR e C(O)R e , NR e C(O)NR e R e , NR e C(O)OR e , C(═NR e )NR e R e , NR e C(═NR e )NR e R e , S(O)R e , S(O)NR e R e , S(O) 2 R e , NR e S(O) 2 R e , NR e S(O) 2 NR e R e , and S(O) 2 NR e R e ;
each R c is independently selected from H, C 1-6 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl- and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R c are each optionally substituted with 1, 2, 3, 4, or 5 R f substituents;
each R f is independently selected from C 1-4 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, halo, CN, NHOR g , OR g , SR g , C(O)R g , C(O)NR g R g , C(O)OR g , OC(O)R g , OC(O)NR g R g , NH 2 , NHR g , NR g R g , NR g C(O)R g , NR g C(O)NR g R g , NR g C(O)OR g , C(

Assignees

• Incyte Corp

Inventors

• Sun Yaping
• Li Yun-Long
• Burns David M

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title