Bicyclic fused pyrimidine compounds as tam inhibitors

Patent metadata

Field	Value
Publication number	US-2018009815-A1
Application number	US-201715624850-A
Country	US
Kind code	A1
Filing date	Jun 16, 2017
Priority date	Aug 12, 2015
Publication date	Jan 11, 2018
Grant date	—

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

1 - 59 . (canceled)

60 . A method for treating a cancer in a patient, said method comprising: administering to the patient a therapeutically effective amount of compound of Formula IV:

or a pharmaceutically acceptable salt thereof, wherein
R 2 is C 1-6 alkyl or 6-10 membered aryl-C 1-4 alkylene;
L is —C 1-6 alkylene-;
n is 0 or 1;
each R A is independently selected from OH, C 1-6 alkoxy, amino, C 1-6 alkylamino, and di(C 1-6 alkyl)amino;
Cy B is 6-10 membered aryl or 5-10 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, or 4 independently selected R B groups;
each R B is independently selected from halo, C 1-6 alkyl, 4-6 membered heterocycloalkyl, 4-6 membered heterocycloalkyl-C 1-4 alkylene, and NR c2 C(O)R b2 ; wherein said C 1-6 alkyl, 4-6 membered heterocycloalkyl, and 4-6 membered heterocycloalkyl-C 1-4 alkylene are optionally substituted with 1, 2, 3, or 4 independently selected R 12 groups;
each R 12 is independently selected from halo, CN, C 1-6 alkyl, C 1-4 haloalkyl, 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 a3 , NR c3 S(O) 2 R b3 , NR c3 S(O) 2 NR c3 R d3 , S(O) 2 R b3 , and S(O) 2 NR c3 R d3 ;
each R c2 is independently selected from H, C 1-6 alkyl, C 1-4 haloalkyl, C 3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl; wherein said C 1-6 alkyl, C 1-4 haloalkyl, C 3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 independently selected R 12 groups;
each R b2 is independently selected from C 1-6 alkyl, C 1-4 haloalkyl, C 3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl; each of which is optionally substituted with 1, 2, or 3 independently selected R 12 groups;
R a3 , R c3 , and R d3 is independently selected from H, C 1-6 alkyl, C 1-4 haloalkyl, C 3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl; and
each R b3 is independently selected from C 1-6 alkyl, C 1-4 haloalkyl, C 3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl.

61 . The method of claim 60 , wherein the cancer is selected from hepatocellular cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, e cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, esophageal cancer, gall bladder cancer, pancreatic cancer, thyroid cancer, skin cancer, leukemia, multiple myeloma, chronic lymphocytic lymphoma, adult T cell leukemia, B-cell lymphoma, acute myelogenous leukemia, Hodgkin's or non-Hodgkin's lymphoma, Waldenstrom's Macroglubulinemia, hairy cell lymphoma, Burkett's lymphoma, glioblastoma, melanoma, and rhabdosarcoma.

62 . The method of claim 60 , wherein the cancer is lung cancer.

63 . The method of claim 60 , wherein the cancer is prostate cancer.

64 . The method of claim 60 , wherein the cancer is colon cancer.

65 . The method of claim 60 , wherein the cancer is breast cancer.

66 . The method of claim 60 , wherein the cancer is melanoma.

67 . The method of claim 60 , wherein the cancer is renal cell carcinoma.

68 . The method of claim 60 , wherein the cancer is multiple myeloma.

69 . The method of claim 60 , wherein the cancer is gastric cancer.

70 . The method of claim 60 , wherein the cancer is rhabdosarcoma.

71 . The method of claim 60 , wherein Cy B is phenyl, a pyridine ring, or an indole ring, each of which is optionally substituted by 1, 2, 3, or 4 independently selected R B groups.

72 . The method of claim 60 , wherein each R 12 is independently selected from C 1-6 alkyl, OR a3 , and NR c3 R d3 .

73 . The method of claim 60 , wherein each R B is independently selected from F, —CH 2 -(piperazinyl), —CH 2 -(4-methylpiperazinyl), —CH 2 -(morpholin-4-yl), —CH 2 —OR a3 , —CH 2 —NR c3 R d3 , and NR c2 C(O)R b2 ; each R c2 is H or C 1-6 alkyl; each R b2 is C 1-6 alkyl; each R a3 is H or C 1-6 alkyl; and each R c3 and R d3 is independently selected from H, C 1-6 alkyl, and C 3-6 cycloalkyl.

74 . The method of claim 60 , wherein n is 1.

75 . The method of claim 60 , wherein n is 0.

76 . The method of claim 60 , wherein:
R 2 is n-butyl or phenylpropyl; n is 0 or 1; L is —CH 2 —; R A is OH or amino; Cy B is phenyl, a pyridine ring, or an indole ring, each of which is optionally substituted by 1 or 2 independently selected R B groups; each R B is independently selected from F, —CH 2 -(piperazinyl), —CH 2 -(4-methylpiperazinyl), —CH 2 -(morpholin-4-yl), —CH 2 —OR a3 , —CH 2 —NR c3 RA d3 , and NR c2 C(O)R b2 ; each R c2 is independently H or C 1-6 alkyl; each R b2 is independently C 1-6 alkyl; each R a3 is independently H or C 1-6 alkyl; and each R c3 and R d3 is independently selected from H, C 1-6 alkyl, and C 3-6 cycloalkyl.

77 . The method of claim 60 , wherein the compound of Formula IV is a compound of Formulae IVa or IVb:

or a pharmaceutically acceptable salt thereof.

78 . The method of claim 60 , wherein the compound of Formula IV is selected from:
4-(2-(Butylamino)-5-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}imidazo[5,1-f][1,2,4]triazin-7-yl)cyclohexanol; 4-{2-(Butylamino)-5-[4-(morpholin-4-ylmethyl)phenyl]imidazo [5,1-f][1,2,4]triazin-7-yl}cyclohexanol; 4-{2-(Butylamino)-5-[4-(hydroxymethyl)phenyl]imidazo[5,1-f][1,2,4]triazin-7-yl}cyclohexanol; 4-[2-(Butylamino)-5-(1H-indol-5-yl)imidazo[5,1-f][1,2,4]triazin-7-yl]cyclohexanol; 4-[2-(Butylamino)-5-(4-piperazin-1-ylphenyl)imidazo[5,1-f][1,2,4]triazin-7-yl]cyclohexanol; 4-[2-(Butylamino)-5-(2-piperazin-1-ylpyridin-4-yl)imidazo[5,1-f][1,2,4]triazin-7-yl]cyclohexanol; 4-[2-(Butylamino)-5-(3-fluoro-4-morpholin-4-ylphenyl)imidazo[5,1-f][1,2,4]triazin-7-yl]cyclohexanol; 4-{2-(Butylamino)-5-[3-(hydroxymethyl)phenyl]imidazo[5,1-f][1,2,4]triazin-7-yl}cyclohexanol; N-{3-[2-(Butylamino)-7-(4-hydroxycyclohexyl)imidazo[5,1-f][1,2,4]triazin-5-yl]phenyl}acetamide; N-{4-[2-(Butylamino)-7-(4-hydroxycyclohexyl)imidazo[5,1-f][1,2,4]triazin-5-yl]phenyl}acetamide; 4-(2-(Butylamino)-5-{4-[(methylamino)methyl]phenyl}imidazo[5,1-f][1,2,4]triazin-7-yl)cyclohexanol; 4-(2-(Butylamino)-5-{4-[(cyclohexylamino)methyl]phenyl }imidazo [5,1-f][1,2,4]triazin-7-yl)cyclohexanol; 7-[(4-Aminocyclohexyl)methyl]-N-butyl-5-(4-fluorophenyl)imidazo[5,1-f][1,2,4]triazin-2-amine; 7-((4-Aminocyclohexyl)methyl)-5-(4-fluorophenyl)-N-(3-phenylpropyl)imidazo[5,1-f][1,2,4]triazin-2-amine; and 7-(4-Aminocyclohexyl)-N-butyl-5-(4-fluorophenyl)imidazo[5,1-f][1,2,4]triazin-2-amine; or a pharmaceutically acceptable salt of any of the aforementioned.

79 . The method of claim 78 , wherein the compound or salt is in cis-configuration.

80 . The method of claim 78 , wherein the compound or salt is in trans-configuration.

81 . The method of claim 60 , wherein:
each R c2 is independently H or C 1-6 alkyl; each R b2 is independently C 1-6 alkyl; each R 12 is independently selected from C 1-6 alkyl, OR a3 , and NR c3 R d3 ; each R a3 is independently H or C 1-6 alkyl; and each R

Assignees

• Incyte Corp

Inventors

• Li Yun-Long
• Burns David M

Classifications

• C07D487/04 Primary

  Ortho-condensed systems · 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

• C07D403/14

  containing three or more hetero rings · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D403/04

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