Substituted triazoles useful as Axl inhibitors

1. A method of inhibiting Axl activity in a cell, wherein the method comprises contacting the cell with an effective amount of 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 —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, 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. The method of claim 1 wherein the cell is a mammalian cell.

3. The method of claim 2 wherein the Axl activity in the mammalian cell is associated with a disease or condition in a mammal.

4. The method of claim 3 wherein the disease or condition is selected from the group consisting of rheumatoid arthritis, vascular disease, vascular injury, psoriasis, visual impairment due to macular degeneration, diabetic retinopathy, retinopathy of prematurity, kidney disease, osteoporosis, osteoarthritis and cataracts.

5. The method of claim 3 , wherein a manifestation of the disease or condition is solid tumor formation in said mammal.

6. The method of claim 5 , wherein the disease or condition is selected from the group consisting of breast carcinoma, renal carcinoma, endometrial carcinoma, ovarian carcinoma, thyroid carcinoma, non-small cell lung carcinoma, melanoma, prostate carcinoma, sarcoma, gastric cancer and uveal melanoma.

7. The method of claim 3 , wherein a manifestation of the disease or condition is liquid tumor formation in said mammal.

8. The method of claim 7 , wherein the disease or condition is myeloid leukemia or lymphoma.

9. The method of claim 3 wherein the disease or condition is endometriosis.

10. The method of claim 1 , wherein the compound is 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;

N 3 -(3-fluoro-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1-(pyridin-2-yl)-1H-1,2,4-triazole-3,5-diamine;

1-(7-(benzyloxy)-6-methoxyquinazolin-4-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-(quinoxalin-2-yl)-1H-1,2,4-triazole-3,5-diamine;

1-(benzo[d]thiazol-2-yl)-N 3 -(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(1-methyl-1H-benzo[d]imidazol-2-yl)-N 3 -(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;

N 3 -(4-(2-(2-methylpyrrolidin-1-yl)ethoxy)phenyl)-1-(quinoxalin-2-yl)-1H-1,2,4-triazole-3,5-diamine;

1-(benzo[d]thiazol-2-yl)-N 3 -(4-(2-(2-methylpyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(1-methyl-1H-benzo[d]imidazol-2-yl)-N 3 -(4-(2-(2-methylpyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(1H-benzo[d]imidazol-2-yl)-N 3 -(4-(2-(2-methylpyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(phthalazin-1-yl)-N 3 -(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(1H-benzo[d]imidazol-2-yl)-N 3 -(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;

methyl 1-(2-(4-(5-amino-1-(quinoxalin-2-yl)-1H-1,2,4-triazol-3-ylamino)phenoxy)ethyl)pyrrolidine-2-carboxylate;

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

1-(2-morpholinoquinazolin-4-yl)-N 3 -(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(benzo[d]thiazol-2-yl)-N 3 -(3-chloro-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-(1-methyl-1H-benzo[d]imidazol-2-yl)-1H-1,2,4-triazole-3,5-diamine;

N 3 -(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1-(quinolin-2-yl)-1H-1,2,4-triazole-3,5-diamine;

methyl 1-(2-(4-(5-amino-1-(benzo[d]thiazol-2-yl)-1H-1,2,4-triazol-3-ylamino)phenoxy)ethyl)pyrrolidine-2-carboxylate;

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

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

N 3 -(4-(2-(2,5-dimethylpyrrolidin-1-yl)ethoxy)phenyl)-1-(quinoxalin-2-yl)-1H-1,2,4-triazole-3,5-diamine;

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

1-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N 3 -(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(isoquinolin-1-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-(thieno[2,3-d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-diamine;

1-(6-phenylthieno[3,2-d]pyrimidin-4-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-(2-(trifluoromethyl)quinazolin-4-yl)-1H-1,2,4-triazole-3,5-diamine;

N 3 -(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1-(thieno[3,2-d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-diamine;

N 3 -(3-fluoro-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1-(quinoxalin-2-yl)-1H-1,2,4-triazole-3,5-diamine;

1-(benzo[d]thiazol-2-yl)-N 3 -(3-fluoro-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)-N 3 -(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;

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

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

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

1-(6-fluoroquinazolin-4-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-(thieno[2,3-c]pyridin-7-yl)-1H-1,2,4-triazole-3,5-diamine;

1-(2-methylquinazolin-4-yl)-N 3 -(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(furo[3,2-c]pyridin-4-yl)-N 3 -(4-(2-(pyrrolidin-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)-5,6,7,8-tetrahydroquinazolin-4-ol;

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

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

benzyl 3-(5-amino-3-(4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)-1H-1,2,4-triazol-1-yl)-′7,8-dihydropyrido[4,3-c]pyridazine-6(5H)-carboxylate;

N 3 -(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1-(5,6,7,8-tetrahydropyrido[4,3-c]pyridazin-3-yl)-1H-1,2,4-triazole-3,5-diamine;

1-(2,6-dichlorothieno[3,2-d]pyrimidin-4-yl)-N 3 -(4-(2-pyrrolidin-1-ylethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(2-chlorothieno[2,3-d]pyrimidin-4-yl)-N 3 -(4-(2-pyrrolidin-1-ylethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(2-chlorothieno[3,2-d]pyrimidin-4-yl)-N 3 -(4-(2-pyrrolidin-1-ylethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolin-2-yl)-N 3 -(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(5,6-dihydrobenzo[h]quinazolin-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-(6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-diamine;

1-(5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-N 3 -(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-4-yl)-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-(5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-diamine;

N 3 -(3-fluoro-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1-(5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-diamine;

1-(2-methyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-N 3 -(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(benzothieno[3,2-d]pyrimidin-4-yl)-N 3 -(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;

1-(7-tert-butyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-N 3 -(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine; and

1-(5,6-dihydrobenzo[h]cinnolin-3-yl)-N 3 -(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;

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