IP Library › Granted Patent US 8,809,364

Granted Patent B2

US 8,809,364 · App. 13/078,759 · Granted Aug 19, 2014

Polycyclic aryl substituted triazoles and polycyclic heteroaryl substituted triazoles useful as axl inhibitors

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 8,809,364
App. No.: 13/078,759
Granted: Aug 19, 2014
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

Polycyclic aryl and polycyclic 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 catalytic activity are also disclosed.

Claims (74)

1. A compound of formula (I):

wherein:

R 1 , R 4 and R 5 are independently selected from hydrogen, alkyl, aryl, aralkyl, —C(O)R 9 or —C(O)N(R 6 )R 7 ;

one of R 2 and R 3 is selected from one of the following and the other is selected from the other two of the following:

a) a bicyclic aryl of formula (II) or a bicyclic heteroaryl of formula (II):

where:

A is an alkylene chain containing six to eight carbons, an alkenylene chain containing six to eight carbons, or an alkynylene chain containing six to eight carbons, where one or two carbons of the alkylene, alkenylene or alkynylene chain is optionally replaced by —NR 9 —, ═N—, —O—, —S(O) p — (where p is 0, 1 or 2) or —P(O) p — (where p is 0, 1 or 2) and where each carbon in the alkylene chain, the alkenylene chain or the alkynylene chain is independently optionally substituted by one or two substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, ═N—O—R 6 , —R 10 —OR 9 , —R 10 —O—R 11 —OR 9 , —R 10 —O—R 11 —O—R 11 —OR 9 , —R 10 —O—R 11 —CN, —R 10 —O—R 11 —C(O)OR 9 , —R 10 —O—R 11 —C(O)N(R 6 )R 7 , —R 10 —O—R 11 —S(O) p R 9 (where p is 0, 1 or 2), —R 10 —O—R 11 —N(R 6 )R 7 , —R 10 —O—R 11 —C(NR 12 )N(R 12 )H, —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 8 , —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); and

B 1 , B 2 , B 3 and B 4 are each independently selected from the group consisting of ═C(R 13 )— and ═N—, provided that one of B 1 , B 2 , B 3 and B 4 is a carbon directly bonded to the nitrogen to which its corresponding R 2 or R 3 is attached;

b) a polycyclic heteroaryl containing more than 14 ring atoms optionally substituted by one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, —R 10 —OR 9 , —R 10 —O—R 11 —OR 9 , —R 10 —O—R 11 —O—R 11 —OR 9 , —R 10 —O—R 11 —CN, —R 10 —O—R 11 —C(O)OR 9 , —R 10 —O—R 11 —C(O)N(R 6 )R 7 , —R 10 —O—R 11 —S(O) p R 9 (where p is 0, 1 or 2), —R 10 —O—R 11 —N(R 6 )R 7 , —R 10 —O—R 11 —C(NR 12 )N(R 12 )H, —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 9 , —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

c) a bridged bicyclic aryl of formula (III) or a bridged bicyclic heteroaryl of formula (III):

where:

m and n are independently 1 to 4;

q and r are independently 0 to 3;

each A 1 , A 3 and A 4 is independently selected from the group consisting of C(R 8 ) 2 , O, S(O) p (where p is 0, 1 or 2), P(O) p (where p is 0, 1 or 2) and N(R 9 );

each A 2 is independently selected from the group consisting of C(R 8 ) and N; and

B 5 , B 6 , B 7 and B 8 are each independently selected from the group consisting of ═C(R 13 )— and ═N—, provided that one of B 5 , B 6 , B 7 and B 8 is a carbon directly bonded to the nitrogen to which its corresponding R 2 or R 3 is attached;

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 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 , 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, cyano, nitro, halo, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, —R 10 —OR 9 , —R 10 —O—R 11 —OR 9 , —R 10 —O—R 11 —O—R 11 —OR 9 , —R 10 —O—R 11 —CN, —R 10 —O—R 11 —C(O)OR 9 , —R 10 —O—R 11 —C(O)N(R 6 )R 7 , —R 10 —O—R 11 —S(O) p R 9 (where p is 0, 1 or 2), —R 10 —O—R 11 —N(R 6 )R 7 , —R 10 —O—R 11 —C(NR 12 )N(R 12 )H, —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 9 , —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, 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 10 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 11 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;

each R 12 is hydrogen, alkyl, cyano, nitro or —OR 9 ; 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 9 , —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 which is a compound of formula (Ia):

wherein:

R 1 , R 4 and R 5 are independently selected from hydrogen, alkyl, aryl, aralkyl, —C(O)R 9 or —C(O)N(R 6 )R 7 ;

one of R 2 and R 3 is selected from one of the following and the other is selected from the other two of the following:

a) a bicyclic aryl of formula (II) or a bicyclic heteroaryl of formula (II):

where:

A is an alkylene chain containing six to eight carbons, an alkenylene chain containing six to eight carbons, or an alkynylene chain containing six to eight carbons, where one or two carbons of the alkylene, alkenylene or alkynylene chain is optionally replaced by —NR 9 —, ═N—, —O—, —S(O) p — (where p is 0, 1 or 2) or —P(O) p — (where p is 0, 1 or 2) and where each carbon in the alkylene chain, the alkenylene chain or the alkynylene chain is independently optionally substituted by one or two substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, ═N—O—R 6 , —R 10 —OR 9 , —R 10 —O—R 11 —OR 9 , —R 10 —O—R 11 —O—R 11 —OR 9 , —R 10 —O—R 11 —CN, —R 10 —O—R 11 —C(O)OR 9 , —R 10 —O—R 11 —C(O)N(R 6 )R 7 , —R 10 —O—R 11 —S(O) p R 9 (where p is 0, 1 or 2), —R 10 —O—R 11 —N(R 6 )R 7 , —R 10 —O—R 11 —C(NR 12 )N(R 12 )H, —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 9 , —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); and

c) a bridged bicyclic aryl of formula (III) or a bridged bicyclic heteroaryl of formula (III):

where:

m and n are independently 1 to 4;

q and r are independently 0 to 3;

each A 1 , A 3 and A 4 is independently selected from the group consisting of C(R 8 ) 2 , O, S(O) p (where p is 0, 1 or 2), P(O) p (where p is 0, 1 or 2) and N(R 9 );

each A 2 is independently selected from the group consisting of C(R 8 ) and N; and

each R 12 is hydrogen, alkyl, cyano, nitro or —OR 9 ; and

as an isolated stereoisomer or a mixture thereof, or as a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 which is a compound of formula (Ib):

wherein:

R 1 , R 4 and R 5 are independently selected from hydrogen, alkyl, aryl, aralkyl, —C(O)R 9 or —C(O)N(R 6 )R 7 ;

one of R 2 and R 3 is selected from one of the following and the other is selected from the other two of the following:

a) a bicyclic aryl of formula (II) or a bicyclic heteroaryl of formula (II):

where:

A is an alkylene chain containing six to eight carbons, an alkenylene chain containing six to eight carbons, or an alkynylene chain containing six to eight carbons, where one or two carbons of the alkylene, alkenylene or alkynylene chain is optionally replaced by —NR 9 —, ═N—, —O—, —S(O) p — (where p is 0, 1 or 2) or —P(O) p — (where p is 0, 1 or 2) and where each carbon in the alkylene chain, the alkenylene chain or the alkynylene chain is independently optionally substituted by one or two substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, ═N—O—R 6 , —R 10 —OR 9 , —R 10 —O—R 11 —OR 9 , —R 10 —O—R 11 —O—R 11 —OR 9 , —R 10 —O—R 11 —CN, —R 10 —O—R 11 —C(O)OR 9 , —R 10 —O—R 11 —C(O)N(R 6 )R 7 , —R 10 —O—R 11 —S(O) p R 9 (where p is 0, 1 or 2), —R 10 —O—R 11 —N(R 6 )R 7 , —R 10 —O—R 11 —C(NR 12 )N(R 12 )H, —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 9 , —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); and

c) a bridged bicyclic aryl of formula (III) or a bridged bicyclic heteroaryl of formula (III):

where:

m and n are independently 1 to 4;

q and r are independently 0 to 3;

each A 1 , A 3 and A 4 is independently selected from the group consisting of C(R 8 ) 2 , O, S(O) p (where p is 0, 1 or 2), P(O) p (where p is 0, 1 or 2) and N(R 9 );

each A 2 is independently selected from the group consisting of C(R 8 ) and N; and

each R 12 is hydrogen, alkyl, cyano, nitro or —OR 9 ; and

as an isolated stereoisomer or a mixture thereof, or as a pharmaceutically acceptable salt thereof.

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

5. A method of inhibiting Axl activity in a cell, wherein the method comprises contacting the cell with an effective amount of a compound of claim 1 , as an isolated stereoisomer or a mixture thereof, or as a pharmaceutically acceptable salt thereof.

Assignments (2)

SECURITY INTEREST Recorded May 8, 2026

From: RIGEL PHARMACEUTICALS, INC.

To: MIDCAP FUNDING IV TRUST

Reel/Frame 075576/0880 →

SECURITY INTEREST Recorded Aug 25, 2022

From: RIGEL PHARMACEUTICALS, INC.

To: MIDCAP FINANCIAL TRUST

Reel/Frame 061327/0712 →