Therapeutically active compounds and their methods of use

Patent metadata

Field	Value
Publication number	US-10017495-B2
Application number	US-201414903952-A
Country	US
Kind code	B2
Filing date	Jul 10, 2014
Priority date	Jul 11, 2013
Publication date	Jul 10, 2018
Grant date	Jul 10, 2018

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

The invention claimed is:

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

wherein:
A is t-butyl, or optionally substituted cyclohexyl, cyclohexenyl, cyclopentyl, cyclobutyl or 1,2,3,6-tetrahydropyridinyl;
ring B is an optionally substituted 5-6 member 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, or optionally substituted heterocyclyl.

2. The compound of claim 1 or a pharmaceutically acceptable salt or hydrate thereof, 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 or a pharmaceutically acceptable salt or hydrate thereof, 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 or a pharmaceutically acceptable salt or hydrate thereof, 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 or a pharmaceutically acceptable salt or hydrate thereof, 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 or a pharmaceutically acceptable salt or hydrate thereof, wherein R 1 and R 2 are taken together to form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, bicyclo[2.2.1]heptanyl or azetidinyl, 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 or a pharmaceutically acceptable salt or hydrate thereof, wherein A is selected from t-butyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclobutyl, and 1,2,3,6-tetrahydropyridinyl, wherein said cyclohexyl, cyclohexenyl, cyclopentyl, cyclobutyl, 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 or a pharmaceutically acceptable salt or hydrate thereof, wherein ring B is selected from 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, —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), —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 or hydrate thereof,
wherein:
A′ is selected from cyclohexyl, cyclohexenyl, cyclopentyl, cyclobutyl and 1,2,3,6-tetrahydropyridinyl, wherein A′ is optionally substituted with up to two substituents independently selected from —OH, ═O, and CH 3 ; or A′ is t-butyl;
ring B′ is selected from pyridin-3-yl, pyridin-4-yl, pyridazin-4-yl, isoxazol-4-yl, isoxazol-3-yl, thiazol-5-yl, pyrimidin-5-yl and pyrazol-4-yl, wherein ring B′ is optionally substituted with one to two substituents independently selected from halo; —CN; —OH; C 1 -C 4 alkyl optionally substituted with halo, CN or —OH; —S(O) 2 —C 1 -C 4 alkyl; —S(O)—C 1 -C 4 alkyl; —S(O) 2 —NH—C 1 -C 4 alkyl; —S(O) 2 —NH—CH 2 —CF 3 ; —S(O) 2 —N(C 1 -C 4 alkyl) 2 ; —S(O) 2 -azetidin-1-yl; —O—C 1 -C 4 alkyl; —CH 2 —O—CH 3 , morpholin-4-yl, cyclopropyl, cyclopropyl-C 1 -C 4 alkyl, cyclopropyl-C 1 -C 4 alkoxy, cyclopropyl-CN, —S(O) 2 —NH-cyclopropyl; —S(O) 2 —NH—CH 2 -cyclopropyl; —C(O)—C 1 -C 4 alkyl, —C(O)—O—CH 3 ; and
—C(R 1a )(R 2a )(R 3a ) is selected from C 1 -C 6 alkyl optionally substituted with halo, —OCH 3 , —P(O) 3 2− or —OH; —(C 0 -C 1 alkylene)-cycloalkyl, wherein the alkylene is optionally substituted with methyl and the cycloalkyl is optionally substituted with —OH, —CH 2 OH, halo, —OCH 3 or methyl; saturated or partially saturated —(C 0 -C 1 alkylene)-heterocyclyl wherein the heterocyclyl is optionally substituted with halo, —S(O) 2 —CH 2 —C(O)—C 1 -C 6

Assignees

• Agios Pharmaceuticals Inc
• Agios Pharmaceuticals Inc

Inventors

• Travins Jeremy M
• Guo Tao
• Zhang Li

Classifications

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D251/18

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

• C07D401/12 Primary

  linked by a chain containing hetero atoms as chain links · 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

• A61K45/06

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