Pyrrolotriazine compounds as tam inhibitors

Patent metadata

Field	Value
Publication number	US-12415809-B2
Application number	US-202318151688-A
Country	US
Kind code	B2
Filing date	Jan 9, 2023
Priority date	Mar 28, 2016
Publication date	Sep 16, 2025
Grant date	Sep 16, 2025

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 method for treating a cancer in a patient, wherein the cancer is selected from lung cancer, prostate cancer, colon cancer, breast cancer, melanoma, renal cell carcinoma, gastric cancer, rhabdomyosarcoma, glioblastoma, endometrial cancer, ovarian cancer, Kaposi sarcoma, esophageal cancer, pancreatic cancer, thyroid cancer, osteosarcoma, and hepatocellular cancer, said method comprising: administering to the patient a therapeutically effective amount of a compound of Formula (IIg1) or Formula (IIg2):

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is Cy A3 -R A ;
R A is H, C 1-6 alkyl, C 1-6 haloalkyl, halo, C 3-6 cycloalkyl, CN, NO 2 , 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 a1 , NR c1 C(O)NR c1 R d1 , C(═NR e1 )R b1 , C(═NR e1 )NR c1 R d1 , NR c1 C(═NR e1 )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 , or S(O) 2 NR c1 R d1 ; wherein said C 1-6 alkyl or C 1-6 haloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 11 ;
Cy A3 is piperidinyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R A3 ;
each R A3 is independently selected from OH, NO 2 , CN, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano-C 1-3 alkyl, HO—C 1-3 alkyl, H 2 N—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 alkylcarbonyl, C 1-6 alkoxycarbonyl, 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, and di(C 1-6 alkyl)aminocarbonylamino;
each R B is independently selected from halo, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, CN, NO 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 , NR e2 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 NR c2 R d2 ; wherein said C 1-6 alkyl, C 2-6 alkynyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 12 ;
R C is selected from OH, halo, C 1-4 alkyl, and C 1-3 haloalkyl;
each R 11 is independently selected from CN, NO 2 , 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 OR d3 , NR c3 C(O)R b3 , NR c3 C(O)OR a3 , 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 , and S(O) 2 NR c3 R d3 ;
each R 12 is independently selected from halo, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, 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 OR 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 , and S(O) 2 NR c4 R d4 ; wherein said C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R g ;
R a1 , R c1 and R d1 are each independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl; wherein said C 1-6 alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R g ; or
alternatively, R c1 and R d1 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents independently selected from R g ;
R b1 is selected from C 1-6 alkyl and C 1-6 haloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R g ;
R e1 is 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)aminosulfonyl;
each R a2 , R c2 , and R d2 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl; wherein said C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 12 ; or
alternatively, any R c2 and R d2 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents independently selected from R 12 ;
each R b2 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 12 ;
each R a3 , R c3 and R d3 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-4 alkylene, phenyl-C 1-4 alkylene, 5-6 membered heteroaryl-C 1-4 alkylene, and 4-7 membered heterocycloalkyl-C 1-4 alkylene; wherein said C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-4 alkylene, phenyl-C 1-4 alkylene, 5-6 membered heteroaryl-C 1-4 alkylene, and 4-7 membered heterocycloalkyl-C 1-4 alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R g ; or
alternatively, any R c3 and R d3 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents independently selected from R g ;
each R b3 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-4 alkylene, phenyl-C 1-4 alkylene, 5-6 membered heteroaryl-C 1-4 alkylene, and 4-7 membered heterocycloalkyl-C 1-4 alkylene, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R g ;
each R a4 , R c4 and R d4 , is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl; wherein said C 1-6 alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R g ; or
alternatively, any R c4 and R d4 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents independently selected from R g ;
each R b4 is independently selected from C 1-6 alkyl and C 1-6 haloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 subs

Assignees

• Incyte Corp

Inventors

• Li Yun-Long
• Wang xiaozhao
• Barbosa Joseph
• Burns David M
• Feng Hao
• Glenn Joseph
• He Chunhong
• Huang Taisheng
• Mei Song
• Zhuo Jincong

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D403/14

  containing three or more hetero rings · CPC title

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61K31/53

  having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine (melarsoprol A61K31/555 {; with four nitrogen atoms A61K31/495}) · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title