Therapeutically active compounds and their methods of use

Patent metadata

Field	Value
Publication number	US-2016159771-A1
Application number	US-201414903952-A
Country	US
Kind code	A1
Filing date	Jul 10, 2014
Priority date	Jul 11, 2013
Publication date	Jun 9, 2016
Grant date	—

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.

First claim

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

wherein:
A is t-butyl, an optionally substituted 3-7 member monocyclic carbocyclyl, or an optionally substituted 3-7 member monocyclic heterocyclyl;
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;
R 4 and R 5 are independently selected from hydrogen and C 1 -C 6 alkyl; and
Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl; and Q is optionally substituted; or
R 1 and R 3 are optionally taken together with the carbon to which they are attached to form C(═O); or
R 1 and R 2 are optionally taken together to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl or optionally substituted heteroaryl;

wherein:
(i) when A is optionally substituted cyclopropyl, then ring B is not optionally substituted oxadiazolyl;
(ii) when A is optionally substituted cyclopropyl and ring B is optionally substituted imidazolyl, oxazolyl, thiazolyl, or pyrrolyl, then N(R 4 )C(R 1 )(R 2 )(R 3 ) is not NHCH 2 CH 2 N(CH 3 ) 2 , NHCH 2 CH 2 CH 2 N(CH 3 ) 2 , NH(CH 2 ) 3 -(1H-imidazol-1-yl), NH(CH 2 ) 3 -(4-morpholinyl), NHCH 2 CH 2 OH, or NHCH 2 C(O)NH 2 ; and
(iii) the compound is not a compound selected from:
(1) N 2 -(5-cyclopropyl-1H-pyrazol-3-yl)-N 4 -(1-methyl-1-phenylethyl)-6-((4-methyl-1-piperazinyl)-1,3,5-triazine-2,4-diamine,
(2) N 2 -[5-(2-furanyl)-1H-pyrazol-3-yl]-N 4 -(1-methyl-1-phenylethyl)-6-((4-methyl-1-piperazinyl)-1,3,5-triazine-2,4-diamine,
(3) N 2 -(2,4-dimethoxyphenyl)-N 4 -(1,1-dimethylethyl)-6-(1-pyrrolidinyl)-1,3,5-triazine-2,4-diamine,
(4) N 2 -(2,4-dimethoxyphenyl)-N 4 -(1,1-dimethylethyl)-6-(4-morpholinyl)-1,3,5-triazine-2,4-diamine,
(5) N 2 -(1,1-dimethylethyl)-6-(1-piperidinyl)-N 4 -[4-(trifluoromethoxy)phenyl]-1,3,5-triazine-2,4-diamine,
(6) N 2 -(1,1-dimethylethyl)-6-(4-morpholinyl)-N 4 -[4-(trifluoromethoxy)phenyl]-1,3,5-triazine-2,4-diamine,
(7) N 2 -[4-(chlorodifluoromethoxy)phenyl]-N 4 -(1,1-dimethylethyl)-6-(1-piperidinyl)-1,3,5-triazine-2,4-diamine,
(8) N 2 -[4-(chlorodifluoromethoxy)phenyl]-N 4 -(1,1-dimethylethyl)-6-(4-morpholinyl)-1,3,5-triazine-2,4-diamine,
(9) N 2 -6-benzothiazolyl-N 4 -(1,1-dimethyl-2-phenylethyl)-6-(1-piperazinyl)-1,3,5-triazine-2,4-diamine, and
(10) 2-methyl-2-[[4-(4-morpholinyl)-6-(phenylamino)-1,3,5-triazin-2-yl]amino]-1-propanol.

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 carbocyclyl or heterocyclyl, either of which is optionally substituted with up to 3 substituents 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 4 , wherein Q is selected from pyridinyl, tetrahydrofuranyl, cyclobutyl, cyclopropyl, phenyl, pyrazolyl, morpholinyl and oxetanyl, wherein Q is optionally substituted with up to 2 substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, ═O, fluoro, chloro, and bromo.

6 . The compound of claim 1 , wherein R 1 and R 2 are taken together to form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, bicyclo[2.2.1]heptanyl, azetidinyl, phenyl and pyridinyl, any of which is optionally substituted with up to 2 substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, —OH, —C(O)CH 3 , fluoro, and chloro.

7 . The compound of claim 1 , wherein A is selected from t-butyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclobutyl, piperidinyl and 1,2,3,6-tetrahydropyridinyl, wherein said cyclohexyl, cyclohexenyl, cyclopentyl, cyclobutyl, piperidinyl and 1,2,3,6-tetrahydropyridinyl are optionally substituted with up to two substituents independently selected from —OH, ═O, and CH 3 .

8 . The compound of claim 1 , wherein ring B is selected from phenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinyl, 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, 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), —N(C 1 -C 4 alkyl) 2 , —OH, C(O)—O—(C 1 -C 4 alkyl), saturated heterocyclyl, and —NH 2 .

9 . A compound having Structural Formula II:

or a pharmaceutically acceptable salt thereof, wherein:
A′ is selected from cyclohexyl, cyclohexenyl, cyclopentyl, cyclobutyl, piperidiny

Assignees

• Guo Tao
• Travins Jeremy M
• Zhang Li
• Agios Pharmaceuticals Inc

Inventors

• Travins Jeremy M
• Guo Tao
• Zhang Li

Classifications

• C07D401/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07D251/18

  with nitrogen atoms directly attached to the two other ring carbon atoms, e.g. guanamines · CPC title

• A61K31/53

  having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine (melarsoprol A61K31/555 {; with four nitrogen atoms A61K31/495}) · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title