Therapeutically active compounds and their methods of use

1. A compound having Formula I or a pharmaceutically acceptable salt or hydrate thereof:

wherein:

ring A is selected from phenyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, and thiazolyl, wherein ring A is optionally substituted with up to two substituents independently selected from halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 hydroxyalkyl, —NH—S(O) 2 —C 1 -C 4 alkyl, -S(O) 2 —NH(C 1 -C 4 alkyl), CN, S(O) 2 —C 1 -C 4 alkyl, C 1 -C 4 alkoxy, NH(C 1 -C 4 alkyl), —OH, and —NH 2 ;

ring B is an optionally substituted 5-6 member monocyclic aryl or monocyclic heteroaryl;

R 1 and R 3 are each independently selected from hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, —O—C 1 -C 4 alkyl, and CN, wherein any alkyl portion of R 1 is optionally substituted with —OH, NH 2 , NH(C 1 -C 4 alkyl), or N(C 1 -C 4 alkyl) 2 ;

R 2 is selected from: —(C 1 -C 6 alkyl), —(C 2 -C 6 alkenyl or alkynyl), —(C 1 -C 6 alkylene)-N(R 6 )—(C 1 -C 6 alkylene)-O—(C 1 -C 6 alkyl), —(C 1 -C 6 alkylene)-N(R 6 )—(C 0 -C 6 alkylene)-Q, —(C 1 -C 6 alkylene)-N(R 6 )(R 6 ), —(C 1 -C 6 alkylene)-N(R 6 )—S(O) 1-2 —(C 1 -C 6 alkyl), —(C 1 -C 6 alkylene)-N(R 6 )—S(O) 1-2 —(C 0 -C 6 alkyl)-Q, —(C 1 -C 6 alkylene)-S(O) 1-2 —N(R 6 )(R 6 ), —(C 1 -C 4 alkylene)-S(O) 1-2 —N(R 6 )—(C 1 -C 6 alkylene)-Q, —C(O)N(R 6 )—(C 1 -C 6 alkylene)-C(O)—(C 0 -C 6 alkylene)-O—(C 1 -C 6 alkyl), —C(O)N(R 6 )—(C 1 -C 6 alkylene)-C(O)—(C 0 -C 6 alkylene)-O—(C 0 -C 6 alkylene)-Q, —(C 1 -C 6 alkylene)-O—C(O)—(C 1 -C 6 alkyl), —(C 1 -C 6 alkylene)-O—C(O)—(C 0 -C 6 alkyl)-Q, —(C 1 -C 6 alkylene)-O—(C 1 -C 6 alkyl), —(C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-Q, —(C 0 -C 6 alkylene)-C(O)—(C 0 -C 6 alkylene)-O—(C 1 -C 6 alkyl), —(C 0 -C 6 alkylene)-C(O)—(C 0 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-Q, —(C 1 -C 6 alkylene)-O—C(O)—(C 1 -C 6 alkyl), —(C 1 -C 6 alkylene)-O—C(O)—(C 0 -C 6 alkylene)-Q, —(C 0 -C 6 alkylene)-C(O)N(R 6 )—(C 1 -C 6 alkyl), —(C 0 -C 6 alkylene)-C(O)N(R 6 )—(C 0 -C 6 alkylene)-Q, —(C 1 -C 6 alkylene)-N(R 6 )C(O)—(C 1 -C 6 alkyl), —(C 1 -C 6 alkylene)-N(R 6 )C(O)—(C 0 -C 6 alkylene)-Q, —(C 0 -C 6 alkylene)-S(O) 0-2 —(C 1 -C 6 alkyl), —(C 0 -C 6 alkylene)-S(O) 0-2 —(C 0 -C 6 alkylene)-Q, —(C 1 -C 6 alkylene)-N(R 6 )—C(O)—N(R 6 )—(C 1 -C 6 alkyl), —(C 0 -C 6 alkylene)-Q, —(C 0 -C 6 alkylene)-C(O)—(C 1 -C 6 alkyl), —(C 0 -C 6 alkylene)-C(O)—(C 0 -C 6 alkylene)-Q, wherein:

any alkyl or alkylene moiety present in R 2 is optionally substituted with one or more —OH, —O(C 1 -C 4 alkyl) or halo;

any terminal methyl moiety present in R 2 is optionally replaced with —CH 2 OH, CF 3 , —CH 2 F, —CH 2 Cl, C(O)CH 3 , C(O)CF 3 , CN, or CO 2 H;

each R 6 is independently selected from hydrogen and C 1 -C 6 alkyl; and

Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; or

R 1 and R 3 are optionally taken together with the carbon atom to which they are attached to form C(═O), or

R 1 and R 2 are optionally taken together to form substituted carbocyclyl, or optionally substituted heterocyclyl, wherein:

(a) when ring A is unsubstituted phenyl, and ring B is phenyl substituted by methoxy or ethoxy; then said phenyl of ring B is not further substituted by oxazolyl;

(b) when ring A is optionally substituted phenyl or optionally substituted pyridyl and ring B is optionally substituted phenyl; then the portion of the compound represented by —NH—C(R 1 )(R 2 )(R 3 ) is not —NH(CH 2 )-aryl;

(c) when ring A is optionally substituted phenyl, and ring B is optionally substituted phenyl or pyrrolyl; then the portion of the compound represented by —NH—C(R 1 )(R 2 )(R 3 ) is not —NH(CH 2 )C(O)NH 2 ;

(d) when ring A is phenyl substituted with 2 hydroxyl or methoxy, and ring B is optionally substituted phenyl; then the portion of the compound represented by —NH—C(R 1 )(R 2 )(R 3 ) is not —NH-cycloheptyl;

(e) when ring A is optionally substituted phenyl and ring B is optionally substituted phenyl; then R 1 and R 2 do not form 2,2,6,6,-tetramethylpiperidin-4-yl;

(f) when ring A and ring B are optionally substituted phenyl; then the portion of the compound represented by —NH—C(R 1 )(R 2 )(R 3 ) is not cysteine, optionally substituted phenylalanine or leucine or methyl ester thereof;

(g) when ring A is phenyl or pyridin-3-yl optionally substituted with one or more substituents selected from halo, methyl or CF 3 , and ring B is phenyl optionally substituted with one or more substituents selected from halo, methyl, CF 3 , methoxy, or CH═C(phenyl)CN; then the portion of the compound represented by —NHC(R 1 )(R 2 )(R 3 ) is other than —NH(C 1 -C 8 alkylene)-N(R a )(R a ), —NH-1-(aminomethyl)cyclopentylmethyl, —NH-4-(aminomethyl)cyclohexylmethyl, wherein each R a is hydrogen, C 1 -C 4 alkyl or two R a s are taken together with the nitrogen to which they are commonly bound to form morpholin-4-yl or pipieridin-1-yl;

(h) when ring A is phenyl, 4-chlorophenyl or 4-methylphenyl and ring B is 4-chlorophenyl or 3,4-dichlorophenyl; then the portion of the compound represented by —NHC(R 1 )(R 2 )(R 3 ) is not —NH-isopropyl;

(i) when ring A is unsubstituted phenyl and the portion of the compound represented by —NHC(R 1 )(R 2 )(R 3 ) is —NH—CH 2 CH 2 N(CH 3 ) 2 , —NH—CH 2 CH 2 -morpholin-4-yl or —NH—CH 2 CH 2 OH; then ring B is other than oxadiazole, imidazole, thiazole or oxazole each of which is substituted with —C(O)NHR b , wherein R b is isopropyl, cyclopropyl or 2-chloro-6-methylphenyl;

and

(j) the compound is other than:

(E)-3-(4-((4-((3-(diethylamino)propyl)amino)-6-phenyl-1,3,5-triazin-2-yl)amino)-2-methoxyphenyl)-2-phenylacrylonitrile,

4-((4-((furan-2-ylmethyl)amino)-6-(pyridin-4-yl)-1,3,5-triazin-2-yl)amino)phenol,

3-(4-((5-aminopentyl)amino)-6-((3-fluorophenyl)amino)-1,3,5-triazin-2-yl)phenol,

N 2 ,6-bis(3-fluorophenyl)-N 4 -(piperidin-3-yl)-1,3,5-triazine-2,4-diamine,

N 2 -butyl-6-phenyl-N 4 -(p-tolyl)-1,3,5-triazine-2,4-diamine,

N 2 -cyclohexyl-N 4 ,6-diphenyl-1,3,5-triazine-2,4-diamine,

(R)-3-((4-(3-chlorophenyl)-6-(pyrrolidin-3-ylamino)-1,3,5-triazin-2-yl)amino)-4-methylbenzamide,

2-chloro-4-(methylsulfonyl)-N-[4-(phenylamino)-6-(2-pyridinyl)-1,3,5-triazin-2-yl]-benzamide,

N 2 -(2-methoxyethyl)-N 4 -phenyl-6-[5-[6-(2,2,2-trifluoroethoxy)-3-pyridinyl]-1,2,4-oxadiazol-3-yl]-1,3,5-triazine-2,4-diamine,

N 2 -(2-furanylmethyl)-6-phenyl-N 4 -[3-(trifluoromethyl)phenyl]-1,3,5-triazine-2,4-diamine,

6-(3-methoxyphenyl)-N 2 -methyl-N 4 -(3-nitrophenyl)-1,3,5-triazine-2,4-diamine,

N 2 -butyl-N 4 -(4-methylphenyl)-6-phenyl-1,3,5-triazine-2,4-diamine, and

4-[[4-(5-chloro-2-methylphenyl)-6-(methylamino)]-1,3,5-triazin-2-yl]amino -benzenemethanol.

2. The compound of claim 1 , wherein R 1 is independently selected from hydrogen, —CH 3 , —CH 2 CH 3 , —CH 2 OH, CN, or R 1 and R 3 are taken together to form ═O.

3. The compound of claim 1 , wherein R 1 and R 2 are taken together to form substituted carbocyclyl or optionally substituted heterocyclyl, wherein the substituents, when present, are independently selected from halo. C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, CN, ═O, —OH, and —C(O)C 1 -C 4 alkyl.

4. The compound of claim 1 , wherein R 2 is selected from: —(C 1 -C 4 alkyl) optionally substituted with fluoro or —OH; —(C 0 -C 4 alkylene)-O—(C 1 -C 4 alkyl), —(C 0 -C 2 alkylene)-N(R 6 )—(C 1 -C 6 alkyl), —(C 0 -C 2 alkylene)-Q, and —O—(C 0 -C 2 alkylene)-Q, wherein Q is optionally substituted with up to 3 substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, ═O, —C(O)—C 1 -C 4 alkyl, —CN, and halo.

5. The compound of claim 1 , wherein ring B is selected from phenyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, and thiazolyl, wherein ring B is optionally substituted with up to two substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, C 1 -C 4 hydroxyalkyl, C 3 -C 6 cycloalkyl, (C 0 -C 2 alkylene)-O—C 1 -C 4 alkyl, —O—(C 1 -C 4 alkylene)-C 3 -C 6 cycloalkyl, —NH—S(O) 2 —(C 1 -C 4 alkyl), —S(O) 2 —NH(C 1 -C 4 alkyl), —S(O) 2 —NH—(C 3 -C 6 cycloalkyl), —S(O) 2 -(saturated heterocyclyl), —CN, —S(O) 2 —(C 1 -C 4 alkyl), —NH(C 1 -C 4 alkyl), —NH(C 1 -C 4 alkyl) 2 , —OH, C(O)—O—(C 1 -C 4 alkyl), saturated heterocyclyl, and —NH 2 .

6. The compound of claim 1 , wherein

R 1 is independently selected from hydrogen, —CH 3 , —CH 2 CH 3 , CH 2 OH, CN, or R 1 and R 3 are taken together to form ═O;

R 2 is selected from: —(C 1 -C 4 alkyl) optionally substituted with fluoro or —OH; —(C 0 -C 4 alkylene)-O—(C 1 -C 4 alkyl), —(C 0 -C 2 alkylene)-N(R 6 )—(C 1 -C 6 alkyl), —(C 0 -C 2 alkylene)-Q, and —O—(C 0 -C 2 alkylene)-Q, wherein Q is optionally substituted with up to 3 substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, ═O, —C(O)—C 1 -C 4 alkyl, —CN, and halo; and

B is selected from phenyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, and thiazolyl, wherein ring B is optionally substituted with up to two substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, C 1 -C 4 hydroxyalkyl, C 3 -C 6 cycloalkyl, (C 0 -C 2 alkylene)-O—C 1 -C 4 alky), —O—(C 1 -C 4 alkylene) -C 3 -C 6 cycloalkyl, —NH—S(O) 2 —(C 1 -C 4 alkyl), —S(O) 2 —NH(C 1 -C 4 alkyl), —S(O) 2 —NH—(C 3 -C 6 cycloalkyl), —S(O) 2 -(saturated heterocyclyl), —CN, —S(O) 2 —(C 1 -C 4 alkyl), —NH(C 1 -C 4 alkyl), —NH(C 1 -C 4 alkyl) 2 , —OH, C(O)—O—(C 1 -C 4 alkyl), saturated heterocyclyl, and —NH 2 .