IP Library › Granted Patent US 8,906,922
Granted Patent B2
US 8,906,922 · App. 11/966,873 · Granted Dec 9, 2014

Substituted triazoles useful as AXl inhibitors

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Quick Facts
Patent No.
US 8,906,922
App. No.
11/966,873
Granted
Dec 9, 2014
Kind
B2
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.

Claims (172)

1. A compound of formula (Ia2):

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 2b is selected from the group consisting of hydrogen, halo, haloalkyl, —R 9b —OR 8b , —R 9b —C(O)OR 8b , —R 9b —N(R 6b )R 7b and —R 9b —C(O)N(R 6b )R 7b , where each R 6b , R 7b and R 8b is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl and aralkyl, and each R 9b is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;

R 2c is selected from the group consisting of —C(O)R 8 , hydrogen, alkyl, an optionally substituted non-bridged cycloalkyl and an optionally substituted bridged cycloalkyl;

R 2k is selected from the group consisting of hydrogen and alkyl;

R 3 is bicyclic aryl or bicyclic heteroaryl, where the bicyclic aryl and bicyclic heteroaryl are each 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 —CN, —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 and an optionally substituted straight or branched alkylene chain;

each R 10 is an optionally substituted straight or branched alkylene 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. The compound of claim 1 wherein:

R 1 , R 4 and R 5 are each independently selected from the group consisting of hydrogen and alkyl;

R 2b is selected from the group consisting of hydrogen, halo, haloalkyl, —R 9b —OR 8b , —R 9b —C(O)OR 8b , —R 9b —N(R 6b )R 7b and —R 9b —C(O)N(R 6b )R 7b , where each R 6b , R 7b and R 8b is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl and aralkyl, and each R 9b is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;

R 2c is selected from the group consisting of —C(O)R 8 , hydrogen, alkyl, an optionally substituted non-bridged cycloalkyl and an optionally substituted bridged cycloalkyl;

R 2k is selected from the group consisting of hydrogen and alkyl;

R 3 is selected from the group consisting of a bicyclic aryl and a bicyclic heteroaryl, where the bicyclic aryl and the bicyclic heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of oxo, halo, haloalkyl, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkenyl, —R 9 —OR 8 , —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, 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 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, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl;

each R 9 is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and

each R 10 is an optionally substituted straight or branched alkylene chain.

3. The compound of claim 2 wherein:

R 1 , R 4 and R 5 are each independently selected from the group consisting of hydrogen and alkyl;

R 2b is selected from the group consisting of hydrogen, halo, haloalkyl, —R 9b —OR 8b , —R 9b —C(O)OR 8b , —R 9b —N(R 6b )R 7b and —R 9b —C(O)N(R 6b )R 7b , where each R 6b , R 7b and R 8b is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl and aralkyl, and each R 9b is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;

R 2c is selected from the group consisting of —C(O)R 8 , hydrogen and alkyl;

R 2k is selected from the group consisting of hydrogen and alkyl;

R 3 is selected from the group consisting of a bicyclic aryl and a bicyclic heteroaryl, where the bicyclic aryl and the bicyclic heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of oxo, halo, haloalkyl, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkenyl, —R 9 —OR 8 , —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, 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 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, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl;

each R 9 is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and

each R 10 is an optionally substituted straight or branched alkylene chain.

4. The compound of claim 3 selected from the group consisting of:

1-(isoquinolin-1-yl)-N 3 -(4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(6-chloroquinazolin-4-yl)-N 3 -(4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(4-(4-(5-amino-1-(isoquinolin-1-yl)-1H-1,2,4-triazol-3-ylamino)phenyl)piperazin-1-yl)ethanone;

N 3 -(3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-1-(isoquinolin-1-yl)-1H-1,2,4-triazole-3,5-diamine;

1-(6,7-dimethoxyquinazolin-4-yl)-N 3 -(3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(4-(4-(5-amino-1-(6,7-dimethoxyquinazolin-4-yl)-1H-1,2,4-triazol-3-ylamino)phenyl)piperazin-1-yl)ethanone;

5-(5-amino-3-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)-1H-1,2,4-triazol-1-yl)-1,6-naphthyridin-2(1H)-one;

4-(5-amino-3-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)-1H-1,2,4-triazol-1-yl)quinazoline-6,7-diol;

4-(5-amino-3-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)-1H-1,2,4-triazol-1-yl)-6-methoxyquinazolin-7-ol;

N 3 -(4-chloro-3-(4-ethylpiperazin-1-yl)phenyl)-1-(6,7-dimethoxyquinazolin-4-yl)-1H-1,2,4-triazole-3,5-diamine;

1-(4-(5-(5-amino-1-(6,7-dimethoxyquinazolin-4-yl)-1H-1,2,4-triazol-3-ylamino)-2-chlorophenyl)piperazin-1-yl)ethanone;

5-(5-amino-1-(6,7-dimethoxyquinazolin-4-yl)-1H-1,2,4-triazol-3-ylamino)-2-(4-methylpiperazin-1-yl)benzamide; and

1-(6,7-dimethoxyquinazolin-2-yl)-N 3 -(4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine.

5. The compound of claim 2 wherein:

R 1 , R 4 and R 5 are each independently selected from the group consisting of hydrogen and alkyl;

R 2b is selected from the group consisting of hydrogen, halo, haloalkyl, —R 9b —OR 8b , —R 9b —C(O)OR 8b , —R 9b —N(R 6b )R 7b and —R 9b —C(O)N(R 6b )R 7b , where each R 6b , R 7b and R 8b is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl and aralkyl, and each R 9b is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;

R 2c is an optionally substituted non-bridged cycloalkyl;

R 2k is selected from the group consisting of hydrogen and alkyl;

R 3 is selected from the group consisting of a bicyclic aryl and a bicyclic heteroaryl, where the bicyclic aryl and the bicyclic heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of oxo, halo, haloalkyl, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkenyl, —R 9 —OR 8 , —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, 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 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, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl;

each R 9 is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and

each R 10 is an optionally substituted straight or branched alkylene chain.

6. The compound of claim 5 selected from the group consisting of:

N 5 -(4-(4-cyclohexylpiperazin-1-yl)phenyl)-1-(6,7-dimethoxyquinazolin-4-yl)-1H-1,2,4-triazole-3,5-diamine;

N 3 -(4-(4-(bicyclo[3.2.0]heptan-6-yl)piperazin-1-yl)phenyl)-1-(6,7-dimethoxyquinazolin-4-yl)-1H-1,2,4-triazole-3,5-diamine;

N 3 -(4-(4-cyclohexylpiperazin-1-yl)phenyl)-1-(isoquinolin-1-yl)-1H-1,2,4-triazole-3,5-diamine;

4-(5-amino-3-(4-(4-cyclohexylpiperazin-1-yl)phenylamino)-1H-1,2,4-triazol-1-yl)-6-methoxyquinazolin-7-ol;

N 3 -(4-(4-cyclohexylpiperazin-1-yl)-3-fluorophenyl)-1-(isoquinolin-1-yl)-1H-1,2,4-triazole-3,5-diamine;

N 3 -(3-chloro-4-(4-cyclohexylpiperazin-1-yl)phenyl)-1-(isoquinolin-1-yl)-1H-1,2,4-triazole-3,5-diamine;

4-(5-amino-3-(4-(4-cycloheptylpiperazin-1-yl)phenylamino)-1H-1,2,4-triazol-1-yl)-6-methoxyquinazolin-7-ol;

N 3 -(4-(4-cycloheptylpiperazin-1-yl)phenyl)-1-(6,7-dimethoxyquinazolin-4-yl)-1H-1,2,4-triazole-3,5-diamine;

N 3 -(4-(4-cyclooctylpiperazin-1-yl)phenyl)-1-(6,7-dimethoxyquinazolin-4-yl)-1H-1,2,4-triazole-3,5-diamine;

N 3 -(3-chloro-4-(4-cyclohexylpiperazin-1-yl)phenyl)-1-(6,7-dimethoxyquinazolin-4-yl)-1H-1,2,4-triazole-3,5-diamine;

N 3 -(4-(4-cyclohexylpiperazin-1-yl)-3-fluorophenyl)-1-(6,7-dimethoxyquinazolin-4-yl)-1H-1,2,4-triazole-3,5-diamine;

N 3 -(4-(4-cycloheptylpiperazin-1-yl)phenyl)-1-(6,7-dimethoxyisoquinolin-1-yl)-1H-1,2,4-triazole-3,5-diamine; and

1-(6,7-dimethoxyquinazolin-2-yl)-N 3 -(3-fluoro-4-(4-cyclohexylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine.

7. The compound of claim 2 wherein:

R 1 , R 4 and R 5 are each independently selected from the group consisting of hydrogen and alkyl;

R 2b is selected from the group consisting of hydrogen, halo, haloalkyl, —R 9b —OR 8b , —R 9b —C(O)OR 8b , —R 9b —N(R 6b )R 7b and —R 9b —C(O)N(R 6b )R 7b , where each R 6b , R 7b and R 8b is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl and aralkyl, and each R 9b is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;

R 2c is an optionally substituted bridged cycloalkyl;

R 2k is selected from the group consisting of hydrogen and alkyl;

R 3 is selected from the group consisting of a bicyclic aryl and a bicyclic heteroaryl, where the bicyclic aryl and the bicyclic heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of oxo, halo, haloalkyl, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkenyl, —R 9 —OR 8 , —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, 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 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, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl;

each R 9 is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and

each R 10 is an optionally substituted straight or branched alkylene chain.

8. The compound of claim 7 wherein:

R 1 , R 4 and R 5 are each independently selected from the group consisting of hydrogen and alkyl;

R 2b is selected from the group consisting of hydrogen, halo, haloalkyl, —R 9b —OR 8b , —R 9b —C(O)OR 8b , —R 9b —N(R 6b )R 7b and —R 9b —C(O)N(R 6b )R 7b , where each R 6b , R 7b and R 8b is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl and aralkyl, and each R 9b is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;

R 2c is selected from the group consisting of optionally substituted bicyclo[2.2.1]heptanyl, optionally substituted bicyclo[3.2.0]heptan-6-yl, optionally substituted bicyclo[3.3.1]nonanyl and optionally substituted adamantanyl;

R 2k is selected from the group consisting of hydrogen and alkyl;

R 3 is selected from the group consisting of a bicyclic aryl and a bicyclic heteroaryl, where the bicyclic aryl and the bicyclic heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of oxo, halo, haloalkyl, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkenyl, —R 9 —OR 8 , —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, 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 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, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl;

each R 9 is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and

each R 10 is an optionally substituted straight or branched alkylene chain.

9. The compound of claim 8 selected from the group consisting of:

1-(benzo[d]thiazol-2-yl)-N 5 -(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;

N 5 -(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1-(6,7-dimethoxyquinazolin-4-yl)-1H-1,2,4-triazole-3,5-diamine;

N 3 -(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1-(isoquinolin-1-yl)-1H-1,2,4-triazole-3,5-diamine;

1-(benzo[d]thiazol-2-yl)-N 3 -(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;

N 3 -(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1-(quinoxalin-2-yl)-1H-1,2,4-triazole-3,5-diamine;

N 3 -(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1-(6,7-dimethoxyquinazolin-4-yl)-1H-1,2,4-triazole-3,5-diamine;

N 3 -(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1-(2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-diamine;

N 3 -(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1-(2-chloro-6,7-dimethoxyquinazolin-4-yl)-1H-1,2,4-triazole-3,5-diamine;

4-(5-amino-3-(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenylamino)-1H-1,2,4-triazol-1-yl)-2-chloro-6-methoxyquinazolin-7-ol;

N 3 -(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1-(6-chloroquinazolin-4-yl)-1H-1,2,4-triazole-3,5-diamine;

4-(5-amino-3-(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)-3-fluorophenylamino)-1H-1,2,4-triazol-1-yl)-6-methoxyquinazolin-7-ol;

N 3 -(4-(4-adamantan-2-yl)piperazin-1-yl)phenyl)-1-(6,7-dimethoxy-quinazolin-4-yl)-1H-1,2,4-triazole-3,5-diamine;

N 3 -(4-(4-(bicyclo[3.3.1]nonan-9-yl)piperazin-1-yl)phenyl)-1-(6,7-dimethoxyquinazolin-4-yl)-1H-1,2,4-triazole-3,5-diamine;

N 3 -(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)-3-fluorophenyl)-1-(6,7-dimethoxyquinazolin-4-yl)-1H-1,2,4-triazole-3,5-diamine;

N 3 -(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1-(6,7-dimethoxyisoquinolin-1-yl)-1H-1,2,4-triazole-3,5-diamine;

N 3 -(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1-(thieno[2,3-d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-diamine;

N 3 -(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1-(thieno[3,2-d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-diamine;

N 3 -(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1-(6-phenylthieno[3,2-d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-diamine;

N 3 -(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-2-(6-phenylthieno[2,3-d]pyrimidin-4-yl)-2H-1,2,4-triazole-3,5-diamine;

N 3 -(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1-(furo[3,2-c]pyridin-4-yl)-1H-1,2,4-triazole-3,5-diamine;

N 3 -(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1-(6-fluoroquinazolin-4-yl)-1H-1,2,4-triazole-3,5-diamine;

N 3 -(4-(1-(bicyclo[2.2.1]heptan-2-yl)piperidin-4-yl)phenyl)-1-(2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-diamine;

N 3 -(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1-(2-methylquinazolin-4-yl)-1H-1,2,4-triazole-3,5-diamine;

N 3 -(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1-(2-(trifluoromethyl)quinazolin-4-yl)-1H-1,2,4-triazole-3,5-diamine;

N 3 -(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1-(2,5,6-trimethylthieno[2,3-d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-diamine;

N 3 -(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1-(5,6-dimethylthieno[2,3-d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-diamine;

N 3 -(4-(4-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1-(2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-diamine;

N 3 -(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)-3-fluorophenyl)-1-(2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-diamine;

N 3 -(4-(4-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1-(2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-diamine;

1-(2-chlorothieno[3,2-d]pyrimidin-4-yl)-N 3 -(4-(4-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yl)-piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(6,7-dimethoxyquinazolin-2-yl)-N 3 -(4-(4-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yl)-piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(5-(thiophen-2-yl)thieno[2,3-d]pyrimidin-4-yl)-N 3 -(4-(4-(bicyclo[2.2.1]heptan-2-yl)-piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(6-(4-chlorophenyl)thieno[3,2-d]pyrimidin-4-yl)-N 3 -(4-(4-(bicyclo[2.2.1]heptan-2-yl)-piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(6-(1,1-dimethylethyl)thieno[3,2-d]pyrimidin-4-yl)-N 3 -(4-(4-(bicyclo[2.2.1]heptan-2-yl)-piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(7-methylthieno[3,2-d]pyrimidin-4-yl)-N 3 -(4-(4-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yl)-piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(thieno[3,2-d]pyrimidin-4-yl)-N 3 -(4-(4-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yl)-piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(thieno[2,3-d]pyrimidin-4-yl)-N 3 -(4-(4-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yl)-piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(5-methylthieno[2,3-d]pyrimidin-4-yl)-N 3 -(4-(4-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yl)-piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(7-methyl-2-chlorothieno[3,2-d]pyrimidin-4-yl)-N 3 -(4-(4-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yl)-piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(7-methylthieno[3,2-d]pyrimidin-4-yl)-N 3 -(3-fluoro-4-(4-(bicyclo[2.2.1]heptan-2-yl)-piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(thieno[3,2-d]pyrimidin-4-yl)-N 3 -(3-fluoro-4-(4-(bicyclo[2.2.1]heptan-2-yl)-piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(thieno[2,3-d]pyrimidin-4-yl)-N 3 -(3-fluoro-4-(4-(bicyclo[2.2.1]heptan-2-yl)-piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(6-fluoroquinazolin-4-yl)-N 3 -(3-fluoro-4-(4-(bicyclo[2.2.1]heptan-2-yl)-piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(4-methylthieno[3,2-d]pyridazin-7-yl)-N 3 -(4-(4-(bicyclo[2.2.1]heptan-2-yl)-piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(7-methylthieno[3,2-d]pyrimidin-4-yl)-N 3 -(3-methyl-4-(4-(bicyclo[2.2.1]heptan-2-yl)-piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(7-methyl-2-chlorothieno[3,2-d]pyrimidin-4-yl)-N 3 -(2-methyl-4-(4-(bicyclo[2.2.1]heptan-2-yl)-piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(7-methylthieno[3,2-d]pyrimidin-4-yl)-N 3 -(3-fluoro-4-(4-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yl)-piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(7-methylthieno[3,2-d]pyrimidin-4-yl)-N 3 -(2-methyl-4-(4-(bicyclo[2.2.1]heptan-2-yl)-piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(4-methylthieno[3,2-d]pyridazin-7-yl)-N 3 -(3-fluoro-4-(4-(bicyclo[2.2.1]heptan-2-yl)-piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(4-methylthieno[3,2-d]pyridazin-7-yl)-N 3 -(3-methyl-4-(4-(bicyclo[2.2.1]heptan-2-yl)-piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(7-methyl-2-chlorothieno[3,2-d]pyrimidin-4-yl)-N 3 -(3-methyl-4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(4-methylthieno[3,2-d]pyridazin-7-yl)-N 3 -(3-fluoro-4-(4-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(2-chloro-6-methoxy-quinoxalin-3-yl)-N 3 -(3-fluoro-4-(4-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(6,7-dimethoxy-1-methylphthalazin-4-yl)-N 3 -(3-fluoro-4-(4-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(4-methylthieno[3,2-d]pyridazin-7-yl)-N 3 -(3-chloro-4-(4-((2S)-bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(4-methylthieno[3,2-d]pyridazin-7-yl)-N 3 -(3-methyl-4-(4-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(7-methyl-2-m-tolylthieno[3,2-d]pyrimidin-4-yl)-N 3 -(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(7-methyl-2-(3-cyanophenyl)thieno[3,2-d]pyrimidin-4-yl)-N 3 -(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(7-methyl-2-(2-chlorophenyl)thieno[3,2-d]pyrimidin-4-yl)-N 3 -(4-(4-((2S)-bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(7-methyl-2-benzo[d][1,3]dioxole-5-ylthieno[3,2-d]pyrimidin-4-yl)-N 3 -(4-(4-((2S)-bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(7-methyl-2-pyridin-4-ylthieno[3,2-d]pyrimidin-4-yl)-N 3 -(4-(4-((2S)-bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(7-methyl-2-(3-(methylsulfonyl)aminophenyl)thieno[3,2-d]pyrimidin-4-yl)-N 3 -(4-(4-((2S)-bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(7-methyl-2-(3-(pyrrolidin-1-yl)prop-1-enyl)thieno[3,2-d]pyrimidin-4-yl)-N 3 -(4-(4-((2S)-bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(7-methyl-2-(3-(4-methylpiperazin-1-yl)prop-1-enyl)thieno[3,2-d]pyrimidin-4-yl)-N 3 -(4-(4-((2S)-bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(7-methyl-2-(3-(morpholin-4-yl)prop-1-enyl)thieno[3,2-d]pyrimidin-4-yl)-N 3 -(4-(4-((2S)-bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(7-methylthieno[3,2-d]pyrimidin-4-yl)-N 3 -(3-chloro-4-(4-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-thieno[3,2-d]pyrimidin-4-yl-N 3 -(3-chloro-4-(4-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-thieno[2,3-d]pyrimidin-4-yl-N 3 -(3-chloro-4-(4-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(7-methylthieno[3,2-d]pyrimidin-4-yl)-N 3 -(3-fluoro-4-(4-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine

1-(7-methylthieno[3,2-d]pyrimidin-4-yl)-N 3 -(3-fluoro-4-(3-(R)-methyl-4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(7-methylthieno[3,2-d]pyrimidin-4-yl)-N 3 -(3-fluoro-4-(3-(S)-methyl-4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(7-methylthieno[3,2-d]pyrimidin-4-yl)-N 3 -(3-fluoro-4-(3-(R)-methyl-4-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(7-methylthieno[3,2-d]pyrimidin-4-yl)-N 3 -(3-fluoro-4-(3-(S)-methyl-4-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(7-methylthieno[3,2-d]pyrimidin-4-yl)-N 3 -(3-methyl-4-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(7-methylthieno[3,2-d]pyrimidin-4-yl)-N 3 -(3-methyl-4-(3-(S)-methyl-4-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(7-methylthieno[3,2-d]pyrimidin-4-yl)-N 3 -(3-methyl-4-(3-(R)-methyl-4-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-thieno[3,2-d]pyrimidin-4-yl-N 3 -(3-fluoro-4-(3-(S)-methyl-4-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine; and

1-(2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)-N 3 -(3-methyl-4-(3-(S)-methyl-4-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine.

10. A composition comprising a pharmaceutically acceptable excipient and an amount of a compound of claim 1 , as an isolated stereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, effective in inhibiting Axl activity.

11. 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 mixture thereof.

Assignments (3)
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 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 20, 2008
From: GOFF, DANE; ZHANG, JING; SYLVAIN, CATHERINE; SINGH, RAJINDER; HOLLAND, SACHA; YU, JIAXIN; HECKRODT, THILO J.; DING, PINGYU
To: RIGEL PHARMACEUTICALS, INC.
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