Substituted triazoles useful as Axl inhibitors

Patent metadata

Field	Value
Publication number	US-9353126-B2
Application number	US-201414540323-A
Country	US
Kind code	B2
Filing date	Nov 13, 2014
Priority date	Dec 29, 2006
Publication date	May 31, 2016
Grant date	May 31, 2016

Abstract

Substituted triazoles and pharmaceutical compositions containing the compounds are disclosed as being useful in inhibiting the activity of the receptor protein tyrosine kinase Axl. Methods of using the compounds in treating diseases or conditions associated with Axl activity are also disclosed.

First claim

What is claimed is:

1. A compound of formula (Ia1):

wherein:
R 1 , R 4 and R 5 are each independently selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, —C(O)R 8 and —C(O)N(R 6 )R 7 ;
R 2a is —R 10a —N(R 6a )R 7a where R 6a and R 7a , together with the common nitrogen to which they are both attached, form an optionally substituted pyrrolidinyl or an optionally substituted piperidinyl, and R 10a is an optionally substituted straight or branched alkylene chain;
R 2g is selected from the group consisting of hydrogen, halo, alkyl, haloalkyl, aryl, aralkyl, —R 9g —C(O)R 8g , —R 9g —C(O)OR 8g , —R 9g —N(R 6g )R 7g and —R 9g —C(O)N(R 6g )R 7g , where each R 6g , R 7g and R 8g is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl and aralkyl, and each R 9g is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;
R 3 is selected from the group consisting of aryl and heteroaryl, where the aryl and the heteroaryl are each independently optionally substituted by one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, —R 9 —OR 8 , —R 9 —O—R 10 —OR 8 , —R 9 —O—R 10 —O—R 10 —OR 8 , —R 9 —O—R 10 —C(O)OR 8 , —R 9 —O—R 10 —C(O)N(R 6 )R 7 , —R 9 —O—R 10 —S(O) p R 8 (where p is 0, 1 or 2), —R 9 —O—R 10 —N(R 6 )R 7 , —R 9 —O—R 10 —C(NR 11 )N(R 11 )H, —R 9 —OC(O)—R 8 , —R 9 —N(R 6 )R 7 , —R 9 —C(O)R 8 , —R 9 —C(O)OR 8 , —R 9 —C(O)N(R 6 )R 7 , —R 9 —N(R 6 )C(O)OR 8 , —R 9 —N(R 6 )C(O)R 8 , —R 9 —N(R 6 )S(O) t R 8 (where t is 1 or 2), —R 9 —S(O) t OR 8 (where t is 1 or 2), —R 9 —S(O) p R 8 (where p is 0, 1 or 2), and —R 9 —S(O) t N(R 6 )R 7 (where t is 1 or 2);
each R 6 and R 7 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, —R 10 —OR 8 , —R 10 —CN, —R 10 —NO 2 , —R 10 —N(R 8 ) 2 , —R 10 —C(O)OR 8 and —R 10 —C(O)N(R 8 ) 2 , or any R 6 and R 7 , together with the common nitrogen to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;
each R 8 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl;
each R 9 is independently selected from the group consisting of a direct bond, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain and an optionally substituted straight or branched alkynylene chain;
each R 10 is independently selected from the group consisting of an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain and an optionally substituted straight or branched alkynylene chain; and
each R 11 is hydrogen, alkyl, cyano, nitro or —OR 8 ;
as an isolated stereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of claim 1 , as an isolated stereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 selected from:
1-phenyl-N 3 -(4-(2-(piperidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(4-isopropylphenyl)-N 3 -(4-(2-(piperidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;
4-(5-amino-3-(4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)-1H-1,2,4-triazol-1-yl)benzenesulfonamide;
1-(2-fluorophenyl)-N 3 -(4-(2-(2-methylpyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(2-fluorophenyl)-N 3 -(4-(2-(piperidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(2-fluorophenyl)-N 3 -(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;
N 3 -(3-chloro-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1-(pyridin-2-yl)-1H-1,2,4-triazole-3,5-diamine;
1-(pyridin-2-yl)-N 3 -(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;
N 5 -methyl-1-(pyridin-2-yl)-N 3 -(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;
N 3 -(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1-(4-(trifluoromethyl)pyrimidin-2-yl)-1H-1,2,4-triazole-3,5-diamine;
1-(2-chloropyridin-4-yl)-N 3 -(4-(2-(piperidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(6-chloropyridazin-3-yl)-N 3 -(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(pyrazin-2-yl)-N 3 -(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(2-morpholinopyridin-4-yl)-N 3 -(4-(2-(piperidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(6-chloropyridin-2-yl)-N 3 -(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(5-chloropyridin-2-yl)-N 3 -(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(3-chloropyridin-2-yl)-N 3 -(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(6-chloropyridin-2-yl)-N 3 -(4-(2-(piperidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(6-morpholinopyridin-2-yl)-N 3 -(4-(2-(piperidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;
N 3 -(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1-(4-(trifluoromethyl)pyridin-2-yl)-1H-1,2,4-triazole-3,5-diamine;
N 3 -(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1-(3-(trifluoromethyl)pyridin-2-yl)-1H-1,2,4-triazole-3,5-diamine;
1-(6-methoxypyridin-2-yl)-N 3 -(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(5-bromopyridin-2-yl)-N 3 -(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(6-(methylamino)pyridin-2-yl)-N 3 -(4-(2-(piperidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(6-(dimethylamino)pyridin-2-yl)-N 3 -(4-(2-(piperidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;
2-(5-amino-3-(4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)-1H-1,2,4-triazol-1-yl)-6-methylpyrimidin-4-ol;
1-(pyrimidin-2-yl)-N 3 -(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine; and
N 3 -(3-fluoro-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1-(pyridin-2-yl)-1H-1,2,4-triazole-3,5-diamine;
1

Assignees

• Rigel Pharmaceuticals Inc

Inventors

• Goff Dane
• Zhang Jing
• Sylvain Catherine
• Singh Rajinder
• Holland Sacha
• Yu Jiaxin
• Heckrodt Thilo J
• Ding Pingyu

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title