HETEROARYL COMPOUNDS AND THEIR USES
The present invention provides a compound of formula (I): and pharmaceutically acceptable salts, enantiomers, stereoisomers, rotamers, tautomers, diastereomers, or racemates thereof. Also provided is a method of treating a disease or condition mediated by CDK9.
1 . A method to treat a disease or condition selected from cancer, cardiac hypertrophy, HIV and inflammatory diseases, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the Formula:
or a pharmaceutically acceptable salt thereof, wherein:
A 1 is CR 6 ;
A 2 is CR 7 ;
A 3 is CR 8 ;
A 4 is NR 9 or O;
L is selected from optionally substituted C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, or C 2-4 alkenyl;
R 1 is X—R 16 ;
X is a bond or C 1-4 alkyl;
R 16 is selected from the group consisting of C 1-6 alkyl, C 3-6 branched alkyl, C 3-8 cycloalkyl, heterocycloalkyl, C 3-8 -partially unsaturated cycloalkyl, aryl, and heteroaryl;
wherein R 16 is substituted with one to three groups independently selected from halogen, hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 branched alkyl, C 3-4 branched haloalkyl, OH, C 1-6 alkoxy, R 22 —OR 12 , S(O) 0-2 R 12 , R 22 —S(O) 0-2 R 12 , S(O) 2 NR 13 R 14 , R 22 —S(O) 2 NR 13 R 14 , C(O)OR 12 , R 22 —C(O)OR 12 , C(O)R 19 , R 22 —C(O)R 19 , O—C 1-3 alkyl, OC 1-3 haloalkyl, OC(O)R 19 , R 22 —OC(O)R 19 , C(O)NR 13 R 14 , R 22 —C(O)NR 13 R 14 , NR 15 S(O) 2 R 12 , R 22 —NR 15 S(O) 2 R 12 , NR 17 R 18 , R 22 —NR 17 R 18 , NR 15 C(O)R 19 , R 22 —NR 15 C(O)R 19 , NR 15 C(O)OCH 2 Ph, R 22 —NR 15 C(O)OCH 2 Ph, NR 15 C(O)OR 12 , R 22 —NR 15 C(O)OR 12 , NR 15 C(O)NR 13 R 14 , and R 22 —NR 15 C(O)NR 13 R 14 ;
R 17 and R 18 are each, independently, selected from the group consisting of hydrogen, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 branched alkyl, C 3-6 cycloalkyl, R 22 —OR 12 , R 22 —S(O) 0-2 R 12 , R 22 —S(O) 2 NR 13 R 14 , R 22 —C(O)OR 12 , R 22 —C(O)R 19 , R 22 —OC(O)R 19 , R 22 —C(O)NR 13 R 14 , R 22 —NR 15 S(O) 2 R 12 , R 22 —NR 23 R 24 , R 22 —NR 15 C(O)R 19 , R 22 —NR 15 C(O)OCH 2 Ph, R 22 —NR 15 C(O)OR 12 , R 22 —NR 15 C(O)NR 13 R 14 , cycloalkyl, heterocycloalkyl and heteroaryl; alternatively, R 17 and R 18 along with the nitrogen atom to which they are attached to can be taken together to form a four to six membered heterocyclic ring wherein the carbon atoms of said ring are optionally substituted with R 20 , and the nitrogen atoms of said ring are optionally substituted with R 21 ;
R 19 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
R 20 is selected from the group consisting of C 1-6 alkyl or C 1-6 haloalkyl;
R 21 is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C(O)R 12 , C(O)OR 12 , S(O) 2 R 12 ;
R 22 is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 branched alkyl, C 3-6 branched haloalkyl;
R 23 and R 24 are each, independently, selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 branched alkyl, C 3-6 branched haloalkyl;
R 2 is selected from the group consisting of optionally substituted C 1-6 alkyl, optionally substituted C 3-6 branched alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
R 4 , R 5 , and R 6 are each, independently, selected from the group consisting of hydrogen, hydroxyl, cyano, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, amino, NR 10 R 11 , and alkoxy;
R 3 and R 7 are each, independently, selected from the group consisting of hydrogen, hydroxyl, cyano, halogen, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, NR 10 R 11 , C(O)R 12 , C(O)OR 12 , C(O)NR 13 R 14 , S(O) 0-2 R 12 , S(O) 0-2 NR 13 R 14 , and optionally substituted C 3-4 cycloalkyl;
R 8 is selected from Cl, F, and methyl;
R 9 is selected from the group consisting of hydrogen, C 1-4 alkyl, alkoxy, C(O)R 12 , C(O)OR 15 , C(O)NR 13 R 14 , S(O) 0-2 R 12 , S(O) 0-2 NR 13 R 14 , optionally substituted C 3-4 cycloalkyl, and optionally substituted heterocycloalkyl;
R 10 and R 11 are each, independently, selected from the group consisting of hydrogen, hydroxyl, alkyl, alkoxy, C(O)R 12 , C(O)OR 12 , C(O)NR 13 R 14 , S(O) 0-2 R 12 , and S(O) 0-2 NR 13 R 14 ; alternatively, R 10 and R 11 along with the nitrogen atom to which they are attached to can be taken together to form an optionally substituted four to six membered heteroaromatic, or a non-aromatic heterocyclic ring;
R 12 and R 15 are each, individually, selected from the group consisting of hydrogen, alkyl, branched alkyl, haloalkyl, branched haloalkyl, (CH 2 ) 0-3 -cycloalkyl, (CH 2 ) 0-3 -heterocycloalkyl, (CH 2 ) 0-3 -aryl, and heteroaryl;
R 13 and R 14 are each, independently, selected from the group consisting of hydrogen, hydroxyl, alkyl, branched alkyl, haloalkyl, branched haloalkyl, alkoxy, cycloalkyl or heterocycloalkyl; and alternatively, R 13 and R 14 along with the nitrogen atom to which they are attached to can be taken together to form an optionally substituted four to six membered heteroaromatic, or non-aromatic heterocyclic ring.
2 . The method of claim 1 , wherein:
R 8 is Cl.
3 . The method of claim 1 , wherein:
R 1 is X—R 16 ;
X is a bond, or C 1-2 alkyl;
R 16 is selected from the group consisting of C 1-2 -alkyl, C 4-6 cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl;
wherein R 16 is substituted with one to three groups independently selected from halogen, hydrogen, C 1-3 alkyl, C 3-6 branched alkyl, OH, C 1-2 alkoxy, R 22 —OR 12 , S(O) 1-2 R 12 , C(O)OR 12 , R 22 —C(O)OR 12 , C(O)R 19 , R 22 —OC(O)R 19 , C(O)NR 13 R 14 , NR 15 S(O) 2 R 12 , NR 17 R 18 , R 22 —NR 17 R 18 , NR 15 C(O)R 19 , R 22 —NR 15 C(O)R 19 , and NR 15 C(O)OCH 2 Ph.
4 . The method of claim 1 , wherein:
R 16 is selected from the group consisting of C 1-2 -alkyl, cyclopentyl, cyclohexyl, piperidine, piperazine, morpholine, pyridine, pyrrolidine, cyclohexenyl, and tetrahydro-2H-pyran;
wherein R 16 is substituted with one to three groups selected from amino, hydroxyl, NHCH 2 -phenyl, CH 2 -amino, COO-t-butyl, H, methoxy, NH—SO 2 -ethyl, CH 2 —NHSO 2 -ethyl, SO 2 -ethyl, t-butyl, methyl, CH 2 —COOH, CO—NHCH 3 , CON(CH 3 ) 2 , NHC(CH 3 )—CH 2 —SO 2 —CH 3 , NH—COO—CH 2 -phenyl, hydroxy-methyl, CH 2 —NH—CH 3 , CH 2 —NH-ethyl, NH—CH 2 —CH 2 -methoxy, CH 2 —NH—CO—CH 3 , NH—CH 2 —CH 2 OH, NH—CO—CH 2 —N(CH 3 ) 2 , NH—CO-methylpyrrolidine, NH—CH 2 —C(CH 3 )-dioxolane, NH—CO-pyridyl, NH-ethyl, pyrrolidine, CH 2 —NH—CO-pyridyl, NH-tetrahydropyran, COCH 2 —N(CH 3 ) 2 , NH—CH 2 —C(CH 3 )-dimethyldioxolane, tetrahydropyran, CO-methylpyrrolidine, CH 2 -methylpiperidine, NH—CO—CH 3 , NH—SO 2 —CH 3 , NH—CH(CH 2 —OCH 3 ) 2 , NH—CH 2 -tetrahydrofuran, NH—CH 2 -oxetane, NH-tetrahydropyran, NH—CH 2 -dioxane, N(CH 3 )—CH 2 CH 2 —OCH 3 , CH(OH)—CH 2 -amino, NH—CH 2 CH 2 —OCF 3 , NHCH 2 —OCH 3 , NH—CH 2 —CH(CF 3 )—OCH 3 , NH—CH(CH 3 )—CH 2 —OH, F, NH-oxetane, CH 2 —CH 2 —OCH 3 , CH 2 —OCH 3 , CH 2 -tetrahydropyran, CH 2 -methylpiperizine, NH 2 —CH 2 —CH(OH)—CF 3 , piperidine, CH 2 -pyrrolidine, NH—CH(CH 3 )CH 2 OCH 3 , NH-tetrahydrofuran, (CH 2 ) 3 —NH 2 , hydroxyethyl, propyl, CH 2 -pyridyl, CH 2 -piperidine, morpholine, NH-chloropyrimidine, NH—CH 2 CH 2 —SO 2 -methyl, (CH 3 ) 3 —N(CH 3 ) 2 , piperizine,
and CH 2 -morpholine.
5 . The method of claim 1 wherein:
R 3 is selected from H, methyl, cyano, chloro, CONH 2 , amino, cyclopropyl, ethyl, and fluoro;
R 4 is selected from halogen, methyl, hydrogen, and halo-methyl;
R 6 is H;
R 7 is selected from H, COOH, Cl, F, CONH 2 , CN, and CF 3 ;
R 8 is Cl;
R 17 and R 18 are each, independently, selected from the group consisting of hydrogen, C 1-3 alkyl, C 1-4 haloalkyl, C 3-6 branched alkyl, R 22 —OR 12 , R 22 —S(O) 2 R 12 , R 22 —NR 15 S(O) 2 R 12 , heterocycloalkyl or heteroaryl; alternatively, R 17 and R 18 along with the nitrogen atom to which they are attached to can be taken together to form a four to six membered heterocyclic ring wherein said ring carbon atoms are optionally substituted with R 20 , and the ring nitrogen atoms are optionally substituted with R 21 ;
R 19 is selected from C 1-3 -alkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;
R 20 represents the group C 1-3 alkyl; and
R 22 is selection from the group consisting of C 1-4 alkyl, and C 3-6 branched alkyl.
6 . The method of claim 1 , wherein:
L is selected from C 1-4 -alkyl, and cyclopropyl;
R 2 is selected from the group consisting of C 3-7 cycloalkyl, a five to seven membered heterocycloalkyl, phenyl, and pyridyl, wherein each said R 2 group is substituted with one, two, or three substituents independently selected from hydrogen, cyano, CO—NH 2 , halogen, methoxy, dihalo-methoxy, trihalo-methoxy, trihalo alkyl, C 1-3 -alkyl, and hydroxy; and
R 9 represents methyl, hydrogen, or ethyl.
7 . The method of claim 1 , wherein:
L is C 1-2 alkyl, or C 3-4 -cycloalkyl;
R 1 is X—R 16 ;
X is a bond, or C 1-2 alkyl;
R 16 is selected from the group consisting of C 1-2 -alkyl, cyclopentyl, cyclohexyl, piperidine, piperazine, morpholine, pyridine, pyrrolidine, cyclohexenyl, and tetrahydro-2H-pyran;
wherein R 16 is substituted with one to three groups independently selected from amino, hydroxyl, NHCH 2 -phenyl, CH 2 -amino, COO-t-butyl, H, methoxy, NH—SO 2 -ethyl, CH 2 —NHSO 2 -ethyl, SO 2 -ethyl, t-butyl, methyl, CH 2 —COOH, CO—NHCH 3 , CON(CH 3 ) 2 , NHCH 2 —CH 2 —SO 2 —CH 3 , NH—COO—CH 2 -phenyl, hydroxy-methyl, CH 2 —NH—CH 3 , CH 2 —NH-ethyl, NH—CH 2 —CH 2 -methoxy, CH 2 —NH—CO—CH 3 , NH—CH 2 —CH 2 OH, NH—CO—CH 2 —N(CH 3 ) 2 , NH—CO-methylpyrrolidine, NH—CO-pyridyl, NH-ethyl, pyrrolidine, CH 2 —NH—CO-pyridyl, COCH 2 —N(CH 3 ) 2 , tetrahydropyran, CO-methylpyrrolidine, CH 2 -methylpiperidine, NH—CO—CH 3 , NH—SO 2 —CH 3 , NH—CH 2 -tetrahydrofuran, NH—CH 2 -dioxane, N(CH 3 )—CH 2 CH 2 —OCH 3 , CH(OH)—CH 2 -amino, NH—CH 2 CH 2 —OCF 3 , NH(CH 3 )—CH 2 —OCH 3 , NH—CH 2 —CH(CF 3 )—OCH 3 , F, NH-oxetane, CH 2 —CH 2 —OCH 3 , CH 2 —OCH 3 , CH 2 -tetrahydropyran, CH 2 -methylpiperizine, NH 2 —CH 2 —CH(OH)—CF 3 , piperidine, CH 2 -pyrrolidine, NH—CH(CH 3 )CH 2 OCH 3 , NH-tetrahydrofuran, (CH 2 ) 3 —NH 2 , hydroxyethyl, propyl, CH 2 -pyridyl, CH 2 -piperidine, morpholine, NH-chloropyrimidine, NH—CH 2 CH 2 —SO 2 -methyl, (CH 3 ) 3 —N(CH 3 ) 2 , piperizine, CH 2 -morpholine, NH—CH 2 —C(CH 3 )-dioxolane, NH-tetrahydropyran, NH—CH 2 —C(CH 3 )-dimethyldioxolane, NH—CH(CH 2 —OCH 3 ) 2 , NH—CH 2 -oxetane, NH-tetrahydropyran, N(CH 3 )—CH 2 CH 2 —OCH 3 , NH—CH(CH 3 )—CH 2 —OH,
and NH—CH(CH 3 )—CH 2 —OH;
R 2 is selected from the group consisting of cyclohexyl, 1,3-dioxane, pyridinyl, phenyl, tetrahydropyranyl, cycloheptyl, 1,4-dioxane, morpholinyl, alkyl substituted dioxane, tetrahydrofuranyl, dioxepane, piperidinyl, and
wherein each said R 2 group is substituted with one, two, or three substituents independently selected from Cl, Br, F, methoxy, hydroxy-methyl, hydrogen, carboxamide, cyano, dihalo-methoxy, trihalo-methoxy, trifluoro-methyl, hydroxyl, and methyl; and
R 4 , is chloro, hydrogen, trifluoro-methyl, fluoro, or bromo;
R 5 , and R 6 are each independently hydrogen;
R 3 is selected from hydrogen, fluoro, cyano, CO—NH 2 , chloro, amino, methyl, and cyclopropyl;
R 7 is selected from H, trifluoro-methyl, COOH, CO—NH 2 , and cyano;
R 8 represents Cl; and
R 9 is selected from the group consisting of H, ethyl, and methyl.
8 . The method of claim 1 wherein the compound is selected from:
N2′-(trans-4-aminocyclohexyl)-5′-chloro-3,5-difluoro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine;
N2′-(trans-4-aminocyclohexyl)-5′-fluoro-N6-(3-fluorobenzyl)-2,4′-bipyridine-2′,6-diamine;
3,5′-dichloro-N2′-(trans-4-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)aminocyclohexyl)-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine;
5′-chloro-N6-((tetrahydro-2H-pyran-4-yl)dideuteromethyl)-N2′-(trans-4-(((S)-tetrahydrofuran-2-yl)methyl)aminocyclohexyl)-2,4′-bipyridine-2′,6-diamine;
5′-chloro-5-fluoro-N2′-(trans-4-(2-(methylsulfonyl)ethylamino)cyclohexyl)-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine;
5′-chloro-5-fluoro-N2′-(trans-4-(oxetan-2-yl-methylamino)cyclohexyl)-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine;
3,5′-dichloro-N2′-(trans-4-((R)-1-methoxypropan-2-yl-amino)cyclohexyl)-N6-(((S)-tetrahydro-2H-pyran-3-yl)methyl)-2,4′-bipyridine-2′,6-diamine;
3,5′-dichloro-N2′-(trans-4-((R)-1-methoxypropan-2-yl-amino)cyclohexyl)-N6-(((R)-tetrahydro-2H-pyran-3-yl)methyl)-2,4′-bipyridine-2′,6-diamine;
4-((5′-chloro-2′-(trans-4-((R)-1-methoxypropan-2-yl-amino)cyclohexylamino)-2,4′-bipyridin-6-yl-amino)methyl)tetrahydro-2H-pyran-4-carbonitrile;
N2′-(trans-4-aminocyclohexyl)-5′-chloro-5-fluoro-N6-(3-fluorobenzyl)-2,4′-bipyridine-2′,6-diamine;
2′-(trans-4-aminocyclohexylamino)-5′-chloro-6-(3-fluorobenzylamino)-2,4′-bipyridine-5-carbonitrile;
N2′-(trans-4-aminocyclohexyl)-3-chloro-5′-fluoro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine;
5′-chloro-N6-(3-fluorobenzyl)-N2′-((1R,3S)-3-if methylamino)methyl)cyclopentyl)-2,4′-bipyridine-2′,6-diamine;
3,5′-dichloro-N2′-(trans-4-((R)-1-methoxypropan-2-yl-amino)cyclohexyl)-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine;
5′-chloro-3-fluoro-N2′-(trans-4-((R)-1-methoxypropan-2-yl-amino)cyclohexyl)-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine;
5′-chloro-5-fluoro-N2′-(trans-4-((R)-1-methoxypropan-2-yl-amino)cyclohexyl)-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine;
5′-chloro-N6-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)-N2-(trans-4-((R)-1-methoxypropan-2-yl-amino)cyclohexyl)-2,4′-bipyridine-2′,6-diamine;
5′-chloro-N6-(((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)-N2′-(trans-4-((R)-1-methoxypropan-2-yl-amino)cyclohexyl)-2,4′-bipyridine-2′,6-diamine;
5′-chloro-5-fluoro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-N2′-(trans-4-((1,1-dioxotetrahydro-2H-thiopyran-4-yl)methyl)aminocyclohexyl)-2,4′-bipyridine-2′,6-diamine;
5′-chloro-5-fluoro-N2′-(trans-4-(2-methoxyethylamino)cyclohexyl)-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine;
N2′-(trans-4-aminocyclohexyl)-5′-chloro-N6-(3-fluorobenzyl)-2,4′-bipyridine-2′,6-diamine;
N2′-(trans-4-aminocyclohexyl)-5′-chloro-N6-(3,5-difluorobenzyl)-2,4′-bipyridine-2′,6-diamine;
N2′-(trans-4-aminocyclohexyl)-5′-chloro-N6-((5-fluoropyridin-3-yl)methyl)-2,4′-bipyridine-2′,6-diamine;
trans-4-(5′-chloro-6-(3,5-difluorobenzylamino)-2,4′-bipyridin-2-yl-amino)cyclohexanol;
(R)-5′-chloro-N6-(3-fluorobenzyl)-N2′-(2-(piperidin-3-yl)ethyl)-2,4′-bipyridine-2′,6-diamine;
N2′-(trans-4-aminocyclohexyl)-3,5′-dichloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine;
N2′-(trans-4-aminocyclohexyl)-3,5′-dichloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine;
3,5′-dichloro-N2′-(trans-4-(2-methoxyethylamino)cyclohexyl)-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine;
2-(trans-4-(3,5′-dichloro-6-((tetrahydro-2H-pyran-4-yl)methyl)amino-2,4′-bipyridin-2′-yl-amino)cyclohexylamino)ethanol;
3,5′-dichloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-N2′-(trans-4-(((R)-tetrahydrofuran-2-yl)methyl)aminocyclohexyl)-2,4′-bipyridine-2′,6-diamine;
3,5′-dichloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-N2′-(trans-4-(((S)-tetrahydrofuran-2-yl)methyl)aminocyclohexyl)-2,4′-bipyridine-2′6-diamine;
3,5′-dichloro-N2′-(trans-4-((2-methoxyethyl)(methyl)amino)cyclohexyl)-N6-((tetrahydro-2 H-pyran-4-yl)methyl)-2,4′-bipyridine-2,6-diamine;
5′-chloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-N2′-(trans-4-(((R)-tetrahydrofuran-2-yl)methyl)aminocyclohexyl)-2,4′-bipyridine-2′,6-diamine;
5′-chloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-N2′-(trans-4-(((S)-tetrahydrofuran-2-yl)methyl)aminocyclohexyl)-2,4′-bipyridine-2′,6-diamine;
N2′-(trans-4-aminocyclohexyl)-5′-chloro-3-fluoro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine;
5′-chloro-3-fluoro-N2′-(trans-4-(2-methoxyethylamino)cyclohexyl)-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine;
N2′-(trans-4-aminocyclohexyl)-3-bromo-5′-chloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′6-diamine;
3-bromo-5′-chloro-N2′-(trans-4-(2-methoxyeth ylamino)cyclohexyl)-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine;
trans-4-(3,5′-dichloro-6-((2,2-di methyltetrahydro-2H-pyran-4-yl)methyl)amino-2,4′-bipyridin-2′-yl-amino)cyclohexanol;
(2S)-3-(trans-4-(35′-dichloro-6-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methy)amino-2,4′-bipyridin-2′-yl-amino)cyclohexylamino)-1,1,1-trifluoropropan-2-ol;
(2R)-3-(trans-4-(3,5′-dichloro-6-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)amino-2,4′-bipyridin-2′-yl-amino)cyclohexylamino)-1,1,1-trifluoropropan-2-ol;
3,5′-dichloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-N2′-(trans-4-(2-(trifluoromethoxy)ethylamino)cyclohexyl)-2,4′-bipyridine-2′,6-diamine;
N2′-(trans-4-aminocyclohexyl)-5′-chloro-N6-(((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine;
N2′-(trans-4-aminocyclohexyl)-5′-chloro-N6-(((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine;
N2′-(trans-4-aminocyclohexyl)-3,5,5′-trichloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine;
N2′-(trans-4-aminocyclohexyl)-5′-chloro-5-fluoro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine;
N2′-(trans-4-aminocyclohexyl)-5′-chloro-N6-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine;
N2′-(trans-4-aminocyclohexyl)-5′-chloro-5-fluoro-N6-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine;
N2′-(trans-4-aminocyclohexyl)-5′-chloro-N6-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine;
trans-4-(5′-chloro-6-(3-fluorobenzylamino)-2,4′-bipyridin-2′-yl-amino)cyclohexanol;
5′-chloro-N2′-(trans-4-(dimethylamino)cyclohexyl)-N6-(3-fluorobenzyl)-2,4′-bipyridine-2′,6-diamine;
5′-chloro-N6-(3-fluorobenzyl)-N2′-(trans-4-(2-methoxyethylamino)cyclohexyl)-2,4′-bipyridine-2′,6-diamine;
2-(trans-4-(5′-chloro-6-(3-fluorobenzylamino)-2,4′-bipyridin-2′-yl-amino)cyclohexylamino)ethanol;
5′-chloro-N6-(3,5-difluorobenzyl)-N2′-(trans-4-(2-methoxyethylamino)cyclohexyl)-2,4′-bipyridine-2′,6-diamine;
5′-chloro-N6-(3-fluorobenzyl)-N2′-(trans-4-((2-methoxyethyl)(methyl)amino)cyclohexyl)-2,4′-bipyridin-2,6-diamine;
N2′-(trans-4-aminocyclohexyl)-5′-chloro-N6-(((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine;
4-((5′-chloro-5-fluoro-2′-(trans-4-(2-methoxyethylamino)cyclohexylamino)-2,4′-bipyridin-6-yl-amino)methyl)tetrahydro-2H-pyran-4-carbonitrile;
4-((2′-(trans-4-aminocyclohexylamino)-5′-chloro-5-fluoro-2,4′-bipyridin-6-yl-amino)methyl)tetrahydro-2H-pyran-4-carbonitrile;
4-((5′-chloro-5-fluoro-2′-(trans-4-(propylamino)cyclohexylamino)-2,4′-bipyridin-6-yl-amino)methyl)tetrahydro-2H-pyran-4-carbonitrile;
4-((5′-chloro-2′-(trans-4-(dipropylamino)cyclohexylamino)-5-fluoro-2,4′-bipyridin-6-yl-amino)methyl)tetrahydro-2 H-pyran-4-carbonitrile;
4-((5′-chloro-5-fluoro-2′-(trans-4-((R)-1-methoxypropan-2-yl-amino)cyclohexylamino)-2,4′-bipyridin-6-yl-amino)methyl)tetrahydro-2H-pyran-4-carbonitrile;
4-((5′-chloro-2′-(trans-4-((2-methyl-1,3-dioxolan-2-yl)methyl)aminocyclohexylamino)-2,4′-bipyridin-6-yl-amino)methyl)tetrahydro-2H-pyran-4-carbonitrile;
(4-((5′-chloro-2′-(trans-4-((R)-1-methoxypropan-2-yl-amino)cyclohexylamino)-2,4′-bipyridin-6-yl-amino)methyl)tetrahydro-2H-pyran-4-yl)methanol; and
5′-chloro-5-fluoro-N6-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-N2′-(trans-4-(1,1-dioxotetrahydrothiophen-3-yl-amino)cyclohexyl)-2,4′-bipyridine-2′,6-diamine.
9 . The method of claim 1 , wherein:
R 1 is X—R 16 ;
X is a bond, or C 1-2 alkyl;
R 16 is selected from the group consisting of C 1-2 -alkyl, cyclopentyl, cyclohexyl, piperidine, piperazine, morpholine, pyridine, pyrrolidine, cyclohexenyl, and tetrahydro-2H-pyran;
wherein R 16 is substituted with one to three groups selected from amino, hydroxyl, NHCH 2 -phenyl, CH 2 -amino, COO-t-butyl, H, methoxy, NH—SO 2 -ethyl, CH 2 —NHSO 2 -ethyl, SO 2 -ethyl, t-butyl, methyl, CH 2 —COOH, CO—NHCH 3 , CON(CH 3 ) 2 , NHC(CH 3 )—CH 2 —SO 2 —CH 3 , NH—COO—CH 2 -phenyl, hydroxy-methyl, CH 2 —NH—CH 3 , CH 2 —NH-ethyl, NH—CH 2 —CH 2 -methoxy, CH 2 —NH—CO—CH 3 , NH—CH 2 —CH 2 OH, NH—CO—CH 2 —N(CH 3 ) 2 , NH—CO-methylpyrrolidine, NH—CH 2 —C(CH 3 )-dioxolane, NH—CO-pyridyl, NH-ethyl, pyrrolidine, CH 2 —NH—CO-pyridyl, NH-tetrahydropyran, COCH 2 —N(CH 3 ) 2 , NH—CH 2 —C(CH 3 )-dimethyldioxolane, tetrahydropyran, CO-methylpyrrolidine, CH 2 -methylpiperidine, NH—CO—CH 3 , NH—SO 2 —CH 3 , NH—CH(CH 2 —OCH 3 ) 2 , NH—CH 2 -tetrahydrofuran, NH—CH 2 -oxetane, NH-tetrahydropyran, NH—CH 2 -dioxane, N(CH 3 )—CH 2 CH 2 —OCH 3 , CH(OH)—CH 2 -amino, NH—CH 2 CH 2 —OCF 3 , NHCH 2 —OCH 3 , NH—CH 2 —CH(CF 3 )—OCH 3 , NH—CH(CH 3 )—CH 2 —OH, F, NH-oxetane, CH 2 —CH 2 —OCH 3 , CH 2 —OCH 3 , CH 2 -tetrahydropyran, CH 2 -methylpiperizine, NH 2 —CH 2 —CH(OH)—CF 3 , piperidine, CH 2 -pyrrolidine, NH—CH(CH 3 )CH 2 OCH 3 , NH-tetrahydrofuran, (CH 2 ) 3 —NH 2 , hydroxyethyl, propyl, CH 2 -pyridyl, CH 2 -piperidine, morpholine, NH-chloropyrimidine, NH—CH 2 CH 2 —SO 2 -methyl, (CH 3 ) 3 —N(CH 3 ) 2 , piperizine,
and CH 2 -morpholine;
R 3 is selected from H, methyl, cyano, chloro, CONH 2 , amino, cyclopropyl, ethyl, and fluoro;
R 4 is selected from halogen, methyl, hydrogen, and halo-methyl;
R 6 is H;
R 7 is selected from H, COOH, Cl, F, CONH 2 , CN, and CF 3 ;
R 8 is Cl;
R 17 and R 18 are each, independently, selected from the group consisting of hydrogen, C 1-3 alkyl, C 1-4 haloalkyl, C 3-6 branched alkyl, R 22 —OR 12 , R 22 —S(O) 2 R 12 , R 22 —NR 15 S(O) 2 R 12 , heterocycloalkyl or heteroaryl; alternatively, R 17 and R 18 along with the nitrogen atom to which they are attached to can be taken together to form a four to six membered heterocyclic ring wherein said ring carbon atoms are optionally substituted with R 20 , and the ring nitrogen atoms are optionally substituted with R 21 ;
R 19 is selected from C 1-3 -alkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;
R 20 represents the group C 1-3 alkyl;
R 22 is selection from the group consisting of C 1-4 alkyl, and C 3-6 branched alkyl;
L is selected from C 1-4 -alkyl, and cyclopropyl;
R 2 is selected from the group consisting of C 3-7 cycloalkyl, a five to seven membered heterocycloalkyl, phenyl, and pyridyl, wherein each said R 2 group is substituted with one, two, or three substituents independently selected from hydrogen, cyano, CO—NH 2 , halogen, methoxy, dihalo-methoxy, trihalo-methoxy, trihalo alkyl, C 1-3 -alkyl, and hydroxy; and
R 9 represents methyl, hydrogen, or ethyl.
10 . The method of claim 1 , wherein the compound is selected from:
3,5′-dichloro-N2′-(trans-4-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)aminocyclohexyl)-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine;
3,5′-dichloro-N2′-(trans-4-((R)-1-methoxypropan-2-yl-amino)cyclohexyl)-N6-(((S)-tetrahydro-2H-pyran-3-yl)methyl)-2,4′-bipyridine-2′,6-diamine;
3,5′-di chloro-N2′-(trans-4-((R)-1-methoxypropan-2-yl-amino)cyclohexyl)-N6-(((R)-tetrahydro-2H-pyran-3-yl)methyl)-2,4′-bipyridine-2′,6-diamine;
3,5′-dichloro-N2′-(trans-4-((R)-1-methoxypropan-2-yl-amino)cyclohexyl)-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine;
5′-chloro-3-fluoro-N2′-(trans-4-((R)-1-methoxypropan-2-yl-amino)cyclohexyl)-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine;
5′-chloro-5-fluoro-N2′-(trans-4-((R)-1-methoxypropan-2-yl-amino)cyclohexyl)-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine;
5′-chloro-5-fluoro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-N2′-(trans-4-((1,1-dioxotetrahydro-2H-thiopyran-4-yl)methyl)aminocyclohexyl)-2,4′-bipyridine-2′,6-diamine;
5′-chloro-5-fluoro-N2′-(trans-4-(2-methoxyethylamino)cyclohexyl)-N6-((tetrahydro-2H-pyran-4;
3,5′-dichloro-N2′-(trans-A-(2-methoxyethylamino)cyclohexyl)-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4-bipyridine-2′,6-diamine;
2-(trans-4-(3,5′-dichloro-6-((tetrahydro-2H-pyran-4-yl)methyl)amino-2,4′-bipyridin-2′-yl-amino)cyclohexylamino)ethanol;
3,5′-dichloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-N2′-(trans-4-(((R)-tetrahydrofuran-2-yl)methyl)aminocyclohexyl)-2,4′-bipyridine-2′,6-diamine;
3,5′-dichloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-N2′-(trans-4-(((S)-tetrahydrofuran-2-yl)methyl)aminocyclohexyl)-2,4′-bipyridine-2′,6-diamine;
3,5′-dichloro-N2′-(trans-4-((2-methoxyethyl)(methyl)amino)cyclohexyl)-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2,6-diamine;
5′-chloro-3-fluoro-N2′-(trans-4-(2-methoxyethylamino)cyclohexyl)-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine;
3-bromo-5′-chloro-N2′-(trans-4-(2-methoxyethylamino)cyclohexyl)-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine;
trans-4-(3,5′-dichloro-6-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)amino-2,4′-bipyridin-2′-yl-amino)cyclohexanol;
(2S)-3-(trans-4-(3,5′-dichloro-6-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)amino-2,4′-bipyridin-2′-yl-amino)cyclohexylamino)-1,1,1-trifluoropropan-2-ol;
(2R)-3-(trans-4-(3,5′-dichloro-6-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)amino-2,4′-bipyridin-2′-yl-amino)cyclohexylamino)-1,1,1-trifluoropropan-2-ol;
3,5′-dichloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-N2′-(trans-4-(2-(trifluoromethoxy)ethylamino)cyclohexyl)-2,4′-bipyridin-2′,6-diamine;
4-((5′-chloro-5-fluoro-2′-(trans-4-(2-methoxyethylamino)cyclohexylamino)-2,4′-bipyridin-6-yl-amino)methyl)tetrahydro-2H-pyran-4-carbonitrile;
4-((2′-(trans-4-aminocyclohexylamino)-5′-chloro-5-fluoro-2,4′-bipyridin-6-yl-amino)methyl)tetrahydro-2H-pyran-4-carbonitrile;
4-((5′-chloro-5-fluoro-2′-(trans-4-(propylamino)cyclohexylamino)-2,4′-bipyridin-6-yl-amino)methyl)tetrahydro-2H-pyran-4-carbonitrile;
4-((5′-chloro-2′-(trans-4-(dipropylamino)cyclohexylamino)-5-fluoro-2,4′-bipyridin-6-yl-amino)methyl)tetrahydro-2H-pyran-4-carbonitrile;
4-((5′-chloro-5-fluoro-2′-(trans-4-((R)-1-methoxypropan-2-yl-amino)cyclohexylamino)-2,4′-bipyridin-6-yl-amino)methyl)tetrahydro-2H-pyran-4-carbonitrile;
and
5′-chloro-5-fluoro-N6-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-N2′-(trans-4-(1,1-dioxotetrahydrothiophen-3-yl-amino)cyclohexyl)-2,4′-bipyridine-2′,6-diamine.
11 . The method of claim 1 , wherein the compound is selected from:
5′-chloro-N6-((tetrahydro-2H-pyran-4-yl)dideuteromethyl)-N2′-(trans-4-(((S)-tetrahydrofuran-2-yl)methyl)aminocyclohexyl)-2,4′-bipyridine-2′,6-diamine;
4-((5′-chloro-2′-(trans-4-((R)-1-methoxypropan-2-yl-amino)cyclohexylamino)-2,4′-bipyridin-6-yl-amino)methyl)tetrahydro-2H-pyran-4-carbonitrile;
5′-chloro-N6-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)-N2′-(trans-4-((R)-1-methoxypropan-2-yl-amino)cyclohexyl)-2,4-bipyridine-2′,6-diamine;
5′-chloro-N6-(((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)-N2′-(trans-4-((R)-1-methoxypropan-2-yl-amino)cyclohexyl)-2,4′-bipyridine-2′,6-diamine;
5′-chloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-N2′-(trans-4-(((R)-tetrahydrofuran-2-yl)methyl)aminocyclohexyl)-2,4′-bipyridine-2′,6-diamine;
5′-chloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-N2′-(trans-4-(((S)-tetrahydrofuran-2-yl)methyl)aminocyclohexyl)-2,4′-bipyridine-2′,6-diamine;
4-((5′-chloro-2′-(trans-4-((2-methyl-1,3-dioxolan-2-yl)methyl)aminocyclohexylamino)-2,4′-bipyridin-6-yl-amino)methyl)tetrahydro-2H-pyran-4-carbonitrile; and
(4-((5′-chloro-2′-(trans-4-((R)-1-methoxypropan-2-yl-amino)cyclohexylamino)-2,4′-bipyridin-6-yl-amino)methyl)tetrahydro-2H-pyran-4-yl)methanol.
12 . The method of claim 1 , wherein the condition is selected from cardiac hypertrophy, HIV and inflammatory diseases.
13 . The method of claim 1 , wherein the condition is a cancer is selected from the group consisting of bladder, head and neck, breast, stomach, ovary, colon, lung, brain, larynx, lymphatic system, hematopoietic system, genitourinary tract, gastrointestinal, ovarian, prostate, gastric, bone, small-cell lung, glioma, colorectal, and pancreatic cancer.