Pyrrolopyrimidine derivatives as TAM inhibitors

Patent metadata

Field	Value
Publication number	US-10053465-B2
Application number	US-201615247499-A
Country	US
Kind code	B2
Filing date	Aug 25, 2016
Priority date	Aug 26, 2015
Publication date	Aug 21, 2018
Grant date	Aug 21, 2018

Abstract

This application relates to compounds of Formula I:

or pharmaceutically acceptable salts thereof, which are inhibitors of TAM kinases which are useful for the treatment of disorders such as cancer.

First claim

What is claimed is:

1. A compound having Formula IVa, IVb, IVc, IVd, or IVe:

or a pharmaceutically acceptable salt thereof, wherein
R 1 is H, halo, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, 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 OR d1 , NR c1 C(O)R b1 , NR c1 C(O)OR b1 , NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 , NR c1 S(O) 2 R b1 , NR c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , S(O) 2 NR c1 R d1 , C 3-7 cycloalkyl, phenyl, 5-6membered heteroaryl, 4-6 membered hererocycloalkyl, C 3-7 cycloalkyl-C 1-3 alkylene, 5-6 membered heteroaryl-C 1-3 alkylene, or 4-6 membered heterocycloalkyl-C 1-3 alkylene; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, C 3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C 3-7 cycloalkyl-C 1-3 alkylene, phenyl-C i-3 alkylene, 5-6 membered heteroaryl-C 1-3 alkylene, and 4-6 membered heterocycloalkyl-C 1-3 alkylene are each optionally substituted with 1, 2, 3, or 4 independently selected R 11 groups;
R 2 is H, halo, OH, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-6 alkoxy, C 1-4 haloalkoxy, amino, C 1-6 alkylamine, or di(C 1-6 alkyl)amino;
each R 7 is independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, CN, NO 2 , Cy, —C 1-4 alkylene-Cy, OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c OR d , NR c C(O)R b , NR c C(O)OR b , NR c C(O)NR c R d ,C(═NR e )R b , C(═NR e )NR c R d , NR c C(═NR e )NR c R d , NR c S(O) 2 R b , NR c S(O) 2 R b , NR c S(O) 2 NR c R d , S(O)R b , S(O)NR c R d S(O) 2 R b and S(O) 2 NR c R d ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-4 haloalkyl are optionally substituted with 1, 2, 3, or 4 independently selected R 8 groups;
each R 8 is independently selected from halo, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, Cy 2 , —C 1-4 alkylene-Cy 2 , 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 OR d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , C(═NR e )R b2 , C(═NR e )NR c2 R d2 , NR c2 C(═NR e )NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O) 2 R b2 , NR c2 S(O) 2 NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 S(O) 2 NR c2 R d2 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-4 haloalkyl are each optionally substituted with 1 ,2, 3 , or 4 independently selected R g groups;
Z is C 1-6 alkyl, C 1-6 haloalkyl, or —C 1-6 alkylene-Z 1 ;
Z 1 is CN, Cy 3 , OR 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)OR b3 , NR c3 C(O)NR c3 R d3 , NR c3 S(O)R b3 , NR c3 S(O) 2 R b3 , NR c3 S(O) 2 NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , or S(O) 2 NR c3 R d3 ;
each R 11 is independently selected from OH, NO 2 , CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl,C 1-6 alkoxy, C 1-6 haloalkoxy, cyano-C 1-3 alkykl, HO—C 1-3 alkyl, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, di(C 1-6 alkyl)aminocarbonylamino, C 3-7 cycloalky, phenyl, 5-6 membred heteroaryl, 4-6 membered heterocycloalkyl, C 3-7 cycloalkyl-C 1-3 alkylene, phenyl-C 1-3 alkylene, 5-6 membered heteroaryl-C 1-3 alkylene, and 4-6 membered heterocycloalkyl-C 1-3 alkylene; wherein said C 1-6 alkyl, C 3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-6membered heterocycloalkyl, C 3-7 cycloalkyl-C 1-3 alkylene, phenyl-C 1-3 alkylene, 5-6 membered heteroaryl-C 1-3 alkylene, and 4-6 membered heterocycloalkykl-C 1-3 alkylene are each optionally substituted with 1, 2, 3 , or 4 groups independently selected from OH, CN, halo, C 1-4 alkyl, C 1-3 haloalkyl, C 1-4 alkoxy, C 1-3 haloalkoxy, cyano-C 1-3 alkyl, HO—C 1-3 alkyl, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-4 alkysulfinyl, C 1-4 alkoxycarbonyl, C 1-4 alkycarbonylamino, C 1-4 alkyl)carbamyl, carboxy, C 1-4 alkylcarbonyl, C 1-4 alkoxycarbonyl, C 1-4 alkylcarbonylamino, C 1-4 alkylsulfonylamino, aminosulfonyl, C 1-4 alkylaminosulfonyl, and di(C 1-4 alkyl)aminosulfonyl;
each Cy is independently selected from 3-12 membered cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, and 4-12 membered heterocycloalkyl, each of which is optionally substituted by 1, 2, 3 , or 4 independently selected R 8 groups;
each Cy 1 is independently selected from 3-7 membered cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl, each of which is optionally substituted by 1, 2, 3, or 4 independently selected R 11 groups;
each Cy 2 is independently selected from 3-7 membered cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl, each of which is optionally substituted by 1, 2, 3, or 4 independently selected R g groups;
each Cy 3 is independently selected from 3-7 membered cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4 -6 membered heterocycloalkyl, each of which is optionally substituted by 1, 2, 3 , or 4 independently selected from halo, OH, CN, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkkoxy, C 1-3 haloalkoxy, amino, C 1-3 alkylamine, and di(C 1-3 alkyl)amino;
each R a , R c , and R d is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, Cy, and —C 1-4 alkylene-Cy; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-4 haloalkyl are each optionally substituted with 1, 2, 3 , or 4 independently selected R 8 groups;
each R b is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, Cy, and —C 1-4 alkylene-Cy; wherein said C 1-6 alkyl, C 2-6 aldenyl, C 2-6 alkynyl, and C 1-4 haloalkyl are each optionally substituted with 1, 2, 3 , or 4 independently selected R 8 groups; alternatively, any R c and R d attache to the same N atom, together with the N atom to which they are attached, from a 4-6 membered heterocycloalkyl group or a 5-6 membered heteroaryl group, each optionally substituted with 1, 2, 3 independently selected R 8 groups;
each R e is independently selected from H, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkylthio, C 1-6 alkylsulfonyl, C 1-6 alkylcarbonyl, C 1-6 alkylaminosulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl) carbamyl,aminosulfonyl, C 1-6 alkylaminosulfonyl, and di(C 1-6 alkyl)aminsosulfonyl;
R a1 ,R c1 ,and R d1 are each independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-4 haloalkyl, Cy 1 , and —C 1-4 alkylene-Cy 1 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-4 haloalkyl are each optionally substituted with 1, 2, 3, or 4independently selected R 11 groups;
R b1 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, Cy 1 , and —C 1-4 alkylene-Cy 1 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-4 haloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 11 groups; or alternatively, any R c1 and R d1 attached to the same N atom, together with the N atom to which they are attached, from a 4-, 5-, 6-, 7-membered heterocycloalkyl group optionally substitusted with 1, 2 or 3 independently selected R 11 groups;
each R a2 , R c2 , and R

Assignees

• Incyte Corp

Inventors

• Li Yun-Long
• Burns David M
• Feng Hao
• Glenn Joseph
• He Chunhong
• Huang Taisheng
• Mei Song
• Pan Jun
• Wang xiaozhao
• Ye Yingda

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07D471/04

  Ortho-condensed systems · 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