Claims for Patent: 9,732,062

Summary for Patent: 9,732,062

Title:	Therapeutically active compounds and their methods of use
Abstract:	Provided are compounds useful for treating cancer and methods of treating cancer comprising administering to a subject in need thereof a compound described herein.
Inventor(s):	Cianchetta; Giovanni (Waltham, MA), DeLaBarre; Byron (Arlington, MA), Popovici-Muller; Janeta (Waltham, MA), Salituro; Francesco G. (Marlborough, MA), Saunders; Jeffrey O. (Lincoln, MA), Travins; Jeremy (Southborough, MA), Yan; Shunqi (Irvine, CA), Guo; Tao (Dayton, NJ), Zhang; Li (Shanghai, CN)
Assignee:	Agios Pharmaceuticals, Inc. (Cambridge, MA)
Application Number:	13/735,467
Patent Claims:	1. A compound having Formula I or a pharmaceutically acceptable salt or hydrate thereof: ##STR01113## 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.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 hydroxyalkyl, --NH--S(O).sub.2--C.sub.1-C.sub.4 alkyl, -S(O).sub.2--NH(C.sub.1-C.sub.4 alkyl), CN, S(O).sub.2--C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, NH(C.sub.1-C.sub.4 alkyl), --OH, and --NH.sub.2; ring B is an optionally substituted 5-6 member monocyclic aryl or monocyclic heteroaryl; R.sup.1 and R.sup.3 are each independently selected from hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, --O--C.sub.1-C.sub.4 alkyl, and CN, wherein any alkyl portion of R.sup.1 is optionally substituted with --OH, NH.sub.2, NH(C.sub.1-C.sub.4 alkyl), or N(C.sub.1-C.sub.4 alkyl).sub.2; R.sup.2 is selected from: --(C.sub.1-C.sub.6 alkyl), --(C.sub.2-C.sub.6 alkenyl or alkynyl), --(C.sub.1-C.sub.6 alkylene)-N(R.sup.6)--(C.sub.1-C.sub.6 alkylene)-O--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6 alkylene)-N(R.sup.6)--(C.sub.0-C.sub.6 alkylene)-Q, --(C.sub.1-C.sub.6 alkylene)-N(R.sup.6)(R.sup.6), --(C.sub.1-C.sub.6 alkylene)-N(R.sup.6)--S(O).sub.1-2--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6 alkylene)-N(R.sup.6)--S(O).sub.1-2--(C.sub.0-C.sub.6 alkyl)-Q, --(C.sub.1-C.sub.6 alkylene)-S(O).sub.1-2--N(R.sup.6)(R.sup.6), --(C.sub.1-C.sub.4 alkylene)-S(O).sub.1-2--N(R.sup.6)--(C.sub.1-C.sub.6 alkylene)-Q, --C(O)N(R.sup.6)--(C.sub.1-C.sub.6 alkylene)-C(O)--(C.sub.0-C.sub.6 alkylene)-O--(C.sub.1-C.sub.6 alkyl), --C(O)N(R.sup.6)--(C.sub.1-C.sub.6 alkylene)-C(O)--(C.sub.0-C.sub.6 alkylene)-O--(C.sub.0-C.sub.6 alkylene)-Q, --(C.sub.1-C.sub.6 alkylene)-O--C(O)--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6 alkylene)-O--C(O)--(C.sub.0-C.sub.6 alkyl)-Q, --(C.sub.1-C.sub.6 alkylene)-O--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6 alkylene)-O--(C.sub.1-C.sub.6 alkylene)-Q, --(C.sub.0-C.sub.6 alkylene)-C(O)--(C.sub.0-C.sub.6 alkylene)-O--(C.sub.1-C.sub.6 alkyl), --(C.sub.0-C.sub.6 alkylene)-C(O)--(C.sub.0-C.sub.6 alkylene)-O--(C.sub.1-C.sub.6 alkylene)-Q, --(C.sub.1-C.sub.6 alkylene)-O--C(O)--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6 alkylene)-O--C(O)--(C.sub.0-C.sub.6 alkylene)-Q, --(C.sub.0-C.sub.6 alkylene)-C(O)N(R.sup.6)--(C.sub.1-C.sub.6 alkyl), --(C.sub.0-C.sub.6 alkylene)-C(O)N(R.sup.6)--(C.sub.0-C.sub.6 alkylene)-Q, --(C.sub.1-C.sub.6 alkylene)-N(R.sup.6)C(O)--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6 alkylene)-N(R.sup.6)C(O)--(C.sub.0-C.sub.6 alkylene)-Q, --(C.sub.0-C.sub.6 alkylene)-S(O).sub.0-2--(C.sub.1-C.sub.6 alkyl), --(C.sub.0-C.sub.6 alkylene)-S(O).sub.0-2--(C.sub.0-C.sub.6 alkylene)-Q, --(C.sub.1-C.sub.6 alkylene)-N(R.sup.6)--C(O)--N(R.sup.6)--(C.sub.1-C.sub.6 alkyl), --(C.sub.0-C.sub.6 alkylene)-Q, --(C.sub.0-C.sub.6 alkylene)-C(O)--(C.sub.1-C.sub.6 alkyl), --(C.sub.0-C.sub.6 alkylene)-C(O)--(C.sub.0-C.sub.6 alkylene)-Q, wherein: any alkyl or alkylene moiety present in R.sup.2 is optionally substituted with one or more --OH, --O(C.sub.1-C.sub.4 alkyl) or halo; any terminal methyl moiety present in R.sup.2 is optionally replaced with --CH.sub.2OH, CF.sub.3, --CH.sub.2F, --CH.sub.2Cl, C(O)CH.sub.3, C(O)CF.sub.3, CN, or CO.sub.2H; each R.sup.6 is independently selected from hydrogen and C.sub.1-C.sub.6 alkyl; and Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; or R.sup.1 and R.sup.3 are optionally taken together with the carbon atom to which they are attached to form C(.dbd.O), or R.sup.1 and R.sup.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.sup.1)(R.sup.2)(R.sup.3) is not --NH(CH.sub.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.sup.1)(R.sup.2)(R.sup.3) is not --NH(CH.sub.2)C(O)NH.sub.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.sup.1)(R.sup.2)(R.sup.3) is not --NH-cycloheptyl; (e) when ring A is optionally substituted phenyl and ring B is optionally substituted phenyl; then R.sup.1 and R.sup.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.sup.1)(R.sup.2)(R.sup.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.sub.3, and ring B is phenyl optionally substituted with one or more substituents selected from halo, methyl, CF.sub.3, methoxy, or CH.dbd.C(phenyl)CN; then the portion of the compound represented by --NHC(R.sup.1)(R.sup.2)(R.sup.3) is other than --NH(C.sub.1-C.sub.8 alkylene)-N(R.sup.a)(R.sup.a), --NH-1-(aminomethyl)cyclopentylmethyl, --NH-4-(aminomethyl)cyclohexylmethyl, wherein each R.sup.a is hydrogen, C.sub.1-C.sub.4 alkyl or two R.sup.as 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.sup.1)(R.sup.2)(R.sup.3) is not --NH-isopropyl; (i) when ring A is unsubstituted phenyl and the portion of the compound represented by --NHC(R.sup.1)(R.sup.2)(R.sup.3) is --NH--CH.sub.2CH.sub.2N(CH.sub.3).sub.2, --NH--CH.sub.2CH.sub.2-morpholin-4-yl or --NH--CH.sub.2CH.sub.2OH; then ring B is other than oxadiazole, imidazole, thiazole or oxazole each of which is substituted with --C(O)NHR.sup.b, wherein R.sup.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-triaz- in-2-yl)phenol, N.sup.2,6-bis(3-fluorophenyl)-N.sup.4-(piperidin-3-yl)-1,3,5-triazine-2,4- -diamine, N.sup.2-butyl-6-phenyl-N.sup.4-(p-tolyl)-1,3,5-triazine-2,4-diam- ine, N.sup.2-cyclohexyl-N.sup.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)am- ino)-4-methylbenzamide, 2-chloro-4-(methylsulfonyl)-N-[4-(phenylamino)-6-(2-pyridinyl)-1,3,5-tria- zin-2-yl]-benzamide, N.sup.2-(2-methoxyethyl)-N.sup.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.sup.2-(2-furanylmethyl)-6-phenyl-N.sup.4-[3-(trifluoromethyl)phenyl]-1,- 3,5-triazine-2,4-diamine, 6-(3-methoxyphenyl)-N.sup.2-methyl-N.sup.4-(3-nitrophenyl)-1,3,5-triazine- -2,4-diamine, N.sup.2-butyl-N.sup.4-(4-methylphenyl)-6-phenyl-1,3,5-triazine-2,4-diamin- e, 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.sup.1 is independently selected from hydrogen, --CH.sub.3, --CH.sub.2CH.sub.3, --CH.sub.2OH, CN, or R.sup.1 and R.sup.3 are taken together to form .dbd.O. 3. The compound of claim 1, wherein R.sup.1 and R.sup.2 are taken together to form substituted carbocyclyl or optionally substituted heterocyclyl, wherein the substituents, when present, are independently selected from halo. C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkoxy, CN, .dbd.O, --OH, and --C(O)C.sub.1-C.sub.4 alkyl. 4. The compound of claim 1, wherein R.sup.2 is selected from: --(C.sub.1-C.sub.4 alkyl) optionally substituted with fluoro or --OH; --(C.sub.0-C.sub.4 alkylene)-O--(C.sub.1-C.sub.4 alkyl), --(C.sub.0-C.sub.2 alkylene)-N(R.sup.6)--(C.sub.1-C.sub.6 alkyl), --(C.sub.0-C.sub.2 alkylene)-Q, and --O--(C.sub.0-C.sub.2 alkylene)-Q, wherein Q is optionally substituted with up to 3 substituents independently selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkoxy, .dbd.O, --C(O)--C.sub.1-C.sub.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.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkynyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 hydroxyalkyl, C.sub.3-C.sub.6 cycloalkyl, (C.sub.0-C.sub.2 alkylene)-O--C.sub.1-C.sub.4 alkyl, --O--(C.sub.1-C.sub.4 alkylene)-C.sub.3-C.sub.6 cycloalkyl, --NH--S(O).sub.2--(C.sub.1-C.sub.4 alkyl), --S(O).sub.2--NH(C.sub.1-C.sub.4 alkyl), --S(O).sub.2--NH--(C.sub.3-C.sub.6 cycloalkyl), --S(O).sub.2-(saturated heterocyclyl), --CN, --S(O).sub.2--(C.sub.1-C.sub.4 alkyl), --NH(C.sub.1-C.sub.4 alkyl), --NH(C.sub.1-C.sub.4 alkyl).sub.2, --OH, C(O)--O--(C.sub.1-C.sub.4 alkyl), saturated heterocyclyl, and --NH.sub.2. 6. The compound of claim 1, wherein R.sup.1 is independently selected from hydrogen, --CH.sub.3, --CH.sub.2CH.sub.3, CH.sub.2OH, CN, or R.sup.1 and R.sup.3 are taken together to form .dbd.O; R.sup.2 is selected from: --(C.sub.1-C.sub.4 alkyl) optionally substituted with fluoro or --OH; --(C.sub.0-C.sub.4 alkylene)-O--(C.sub.1-C.sub.4 alkyl), --(C.sub.0-C.sub.2 alkylene)-N(R.sup.6)--(C.sub.1-C.sub.6 alkyl), --(C.sub.0-C.sub.2 alkylene)-Q, and --O--(C.sub.0-C.sub.2 alkylene)-Q, wherein Q is optionally substituted with up to 3 substituents independently selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkoxy, .dbd.O, --C(O)--C.sub.1-C.sub.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.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkynyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 hydroxyalkyl, C.sub.3-C.sub.6 cycloalkyl, (C.sub.0-C.sub.2 alkylene)-O--C.sub.1-C.sub.4 alky), --O--(C.sub.1-C.sub.4 alkylene) -C.sub.3-C.sub.6 cycloalkyl, --NH--S(O).sub.2--(C.sub.1-C.sub.4 alkyl), --S(O).sub.2--NH(C.sub.1-C.sub.4 alkyl), --S(O).sub.2--NH--(C.sub.3-C.sub.6 cycloalkyl), --S(O).sub.2-(saturated heterocyclyl), --CN, --S(O).sub.2--(C.sub.1-C.sub.4 alkyl), --NH(C.sub.1-C.sub.4 alkyl), --NH(C.sub.1-C.sub.4 alkyl).sub.2, --OH, C(O)--O--(C.sub.1-C.sub.4 alkyl), saturated heterocyclyl, and --NH.sub.2.