Therapeutically active compounds and their methods of use

Inventors: Zenon D. Konteatis (Chatham, NJ); Janeta Popovici-Muller (Windham, NH); Jeremy M. Travins (Southborough, MA); Robert Zahler (Pennington, NJ); Zhenwei Cai (Belle Mead, NJ); Ding Zhou (Shanghai, CN)

Assignee: Agios Pharmaceuticals, Inc.

A61K31/53 A61K31/506 A61K45/06 C07D251/18 C07D401/04 C07D401/14 C07D403/04 C07D405/12 C07D405/14 C07D413/04 C07D417/04 C07D417/14

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Quick Facts

Patent No.: US 10,028,961
App. No.: 15/093,345
Granted: Jul 24, 2018
Kind: B2

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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.

Claims (59)

1. A compound having Formula (B) or pharmaceutically acceptable salt or hydrate thereof, wherein:

X is CH or C-halo;

X a is N or C—R 9a , provided that when one X a is N, then the other two X a are both C—R 9a ;

R 9 is 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), —N(C 1 -C 4 alkyl) 2 , —OH, —OCF 3 , —CN, —NH 2 , —C(O)NH 2 , —C(O)NH(C 1 -C 4 alkyl), —C(O)—N(C 1 -C 4 alkyl) 2 , —(C 1 -C 6 alkylene)-O—(C 1 -C 6 alkyl), aryl, and cyclopropyl optionally substituted with OH;

each R 9a is independently selected from hydrogen, 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), —N(C 1 -C 4 alkyl) 2 , —OH, —OCF 3 , —CN, —NH 2 , —C(O)NH 2 , —C(O)NH(C 1 -C 4 alkyl), —C(O)—N(C 1 -C 4 alkyl) 2 , —(C 1 -C 6 alkylene)-O—(C 1 -C 6 alkyl), aryl, and cyclopropyl optionally substituted with OH;

R 1 , R 3 , R 4 , and R 6 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 each said alkyl moiety of R 1 , R 3 , R 4 , and R 6 are each independently optionally substituted with —OH, —NH 2 , —CN, —O—C 1 -C 4 alkyl, —NH(C 1 -C 4 alkyl), or —N(C 1 -C 4 alkyl) 2 ;

R 2 and R 5 are each independently selected from: —(C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)-C(O)—NH 2 , —(C 1 -C 6 alkyl)-CO 2 H, —(C 2 -C 6 alkenyl or alkynyl), —(C 1 -C 6 alkylene)-O—(C 1 -C 6 alkyl), —(C 0 -C 6 alkylene)-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), and —(C 0 -C 6 alkylene)-C(O)—(C 0 -C 6 alkylene)-Q, wherein:

any alkyl or alkylene moiety present in R 2 and R 5 is optionally substituted with one or more —OH, —O(C 1 -C 4 alkyl), —CO 2 H, or halo;

any terminal methyl moiety present in R 2 and R 5 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;

R 7 and R 8 are each 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; wherein

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

R 4 and R 6 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 an optionally substituted carbocyclyl or optionally substituted heterocyclyl; or

R 4 and R 5 are optionally taken together to form an optionally substituted carbocyclyl or an optionally substituted heterocyclyl;

wherein the compound is not selected from the group:

(1) 4,6-Pyrimidinediamine, 2-(6-methyl-2-pyridinyl)-N4,N6-dipropyl-;

(2) 4,6-Pyrimidinediamine, N4-ethyl-2-(6-methyl-2-pyridinyl)-N6-propyl-; and

(3) 4,6-Pyrimidinediamine, N4,N4-diethyl-2-(6-methyl-2-pyridinyl)-N6-propyl-.

2. The compound of claim 1 or pharmaceutically acceptable salt or hydrate thereof, wherein R 4 and R 5 are optionally taken together to form an optionally substituted carbocyclyl.

3. A compound having Formula (C) or pharmaceutically acceptable salt or hydrate thereof, wherein:

wherein:

X is CH or C-halo;

each X b is independently N—R 9b , O, S, C—H, or C—R 9c , provided that at least one X b is C—R 9c , and when one X b is C—H or C—R 9c and the other is C—R 9c then X c is N, and when one X b is N—R 9b , O, or S, then X c is C;

R 9b is hydrogen or —C 1 -C 4 alkyl;

R 9c is 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), —N(C 1 -C 4 alkyl) 2 , —OH, —OCF 3 , —CN, —NH 2 , —C(O)NH 2 , —C(O)NH(C 1 -C 4 alkyl), —C(O)—N(C 1 -C 4 alkyl) 2 , —(C 1 -C 6 alkylene)-O—(C 1 -C 6 alkyl), aryl, and cyclopropyl optionally substituted with OH;

R 2 and R 5 are each independently selected from: —(C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)-C(O)—NH 2 , —(C 1 -C 6 alkyl)-CO 2 H, —(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: