Bridged bicyclic aryl and bridged bicyclic heteroaryl substituted triazoles useful as axl inhibitors

Patent metadata

Field	Value
Publication number	US-9353124-B2
Application number	US-201314094392-A
Country	US
Kind code	B2
Filing date	Dec 2, 2013
Priority date	Dec 29, 2006
Publication date	May 31, 2016
Grant date	May 31, 2016

Abstract

Bridged bicyclic aryl or heteroaryl 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 (Ia):

R 1 , R 4 and R 5 are each hydrogen;
R 2 is phenyl optionally substituted by one or more substitutents selected from the group consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R 15 —OR 14 , —R 15 —OC(O)—R 14 , —R 15 —N(R 14 ) 2 , —R 15 —C(O)R 14 , —R 15 —C(O)OR 14 , —R 15 —C(O)N(R 14 ) 2 , —R 15 —N(R 14 )C(O)OR 14 , —R 15 —N(R 14 )C(O)R 14 , —R 15 —N(R 14 )S(O) t R 14 (where t is 1 or 2), —R 15 —S(O) t OR 14 (where t is 1 or 2), —R 15 —S(O) p R 14 (where p is 0, 1 or 2), and —R 15 —S(O) t N(R 14 ) 2 (where t is 1 or 2), where each R 14 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R 15 is independently a direct bond or a straight or branched alkylene or alkenylene chain;
R 3 is a bridged bicyclic heteroaryl of formula (II):

where:
m and n are independently 1 to 2;
q and r are independently 0 to 2;
A 1 , A 3 and each A 4 are each independently C(R 8 ) 2 ;
the A 2 to which (A 4 ), is attached is N and the other A 2 is C(R 8 ) 2 ; and
B 1 is N, B 2 is the carbon directly bonded to the nitrogen to which R 3 is attached, B 3 is C(R 13 ) and B 4 is C(R 13 );

each R 6 and R 7 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R 11 —OR 9 , —R 11 —CN, —R 11 —NO 2 , —R 11 —N(R 9 ) 2 , —R 11 —C(O)OR 9 and —R 11 —C(O)N(R 9 ) 2 ;
each R 8 is independently selected from the group consisting of hydrogen, cyano, nitro, halo, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heteroaryl, —R 10 —OR 9 , —R 10 —OC(O)—R 9 , —R 10 —N(R 6 )R 7 , —R 10 —C(O)R 9 , —R 10 —C(O)OR 9 , —R 10 —C(O)N(R 6 )R 7 , —R 10 —N(R 6 )C(O)OR 14 , —R 10 —N(R 6 )C(O)R 9 , —R 10 —N(R 6 )S(O) t R 9 (where t is 1 or 2), —R 10 —S(O) t OR 9 (where t is 1 or 2), —R 10 —S(O) p R 9 (where p is 0, 1 or 2), and —R 10 —S(O) t N(R 6 )R 7 (where t is 1 or 2), or two R 8 's on adjacent carbons can combine to form a double bond;
each R 9 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, and optionally substituted cycloalkylalkyl;
each R 10 is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;
each R 11 is an optionally substituted straight or branched alkylene chain; and
each R 13 is independently selected from the group consisting of hydrogen, cyano, nitro, halo, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, —R 10 —OR 9 , —R 10 —OC(O)—R 9 , —R 10 —N(R 6 )R 7 , —R 10 —C(O)R 9 , —R 10 —C(O)OR 9 , —R 10 —C(O)N(R 6 )R 7 , —R 10 —N(R 6 )C(O)OR 14 , —R 10 —N(R 6 )C(O)R 9 , —R 10 —N(R 6 )S(O) t R 9 (where t is 1 or 2), —R 10 —S(O) t OR 9 (where t is 1 or 2), —R 10 —S(O) p R 9 (where p is 0, 1 or 2), and —R 10 —S(O) t N(R 6 )R 7 (where t is 1 or 2);
as an isolated stereoisomer or a mixture thereof, or as a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 selected from:
1-(1,4-ethano-8-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N 3 -(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(1,4-ethano-8-thiophen-2-yl-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N 3 -(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(1,4-ethano-8-pyridin-4-yl-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N 3 -(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(1,4-ethano-8-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N 3 -(3-fluoro-4-(3-carboxypiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(1,4-ethano-8-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N 3 -(4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(1,4-ethano-8-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N 3 -(3-fluoro-4-(4-bicyclo[2.2.1]heptan-2-ylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(1,4-ethano-8-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N 3 -(3-fluoro-4-(4-cyclohexyl piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(1,4-ethano-8-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N 3 -(3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(1,4-ethano-8-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N 3 -(3-fluoro-4-(4-ethyloxycarbonylmethylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(1,4-ethano-8-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N 3 -(3-fluoro-4-(4-carboxymethylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(1,4-ethano-8-(4-trifluoromethylphenyl)-1-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N 3 -(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(1,4-ethano-8-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N 3 -(3-fluoro-4-(4-(4-ethyloxycarbonylpiperidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(1,4-ethano-8-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N 3 -(3-fluoro-4-(4-(4-carboxypiperidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(1,4-ethano-8-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N 3 -(3-fluoro-4-(4-((2S)-2-methyloxycarbonylpyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine);
1-(1,4-ethano-8-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N 3 -(3-fluoro-4-(4-((2S)-2-carboxypyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(1,4-ethano-8-(4-methoxyphenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N 3 -(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(1,4-ethano-8-pyridin-3-yl-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N 3 -(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(1,4-ethano-8-thiophen-3-yl-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N 3 -(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(1,4-ethano-8-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N 3 -(3-fluoro-4-((3S)-3-methyloxycarbonyl-4-cyclopropylmethylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(1,4-ethano-8-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N 3 -(3-fluoro-4-((3S)-3-carboxy-4-cyclopropylmethylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(1,4-ethano-8-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N 3 -(4-(1-methylpiperidin-4-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine; and
1-(1,4-ethano-8-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N 3 -(3-methyl-4-(4-(pyrrolidin-1-yl)p

Assignees

• Rigel Pharmaceuticals Inc

Inventors

• Goff Dane
• Zhang Jing
• Singh Rajinder
• Holland Sacha
• Yu Jiaxin
• Ding Pingyu
• Litvak Joane

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P27/12

  for cataracts · CPC title

• A61P27/02

  Ophthalmic agents · CPC title