US 10,376,510 B2
2,4- or 4,6-diaminopyrimidine compounds as IDH2 mutants inhibitors for the treatment of cancer
Zenon D. Konteatis, Chatham, NJ (US); Janeta Popovici-Muller, Windham, NH (US); and Jeremy M. Travins, Southborough, MA (US)
Assigned to AGIOS PHARMACEUTICALS, INC., Cambridge, MA (US)
Appl. No. 14/903,947
Filed by AGIOS PHARMACEUTICALS, INC., Cambridge, MA (US)
PCT Filed Jul. 10, 2014, PCT No. PCT/US2014/046202
§ 371(c)(1), (2) Date Jan. 8, 2016,
PCT Pub. No. WO2015/006591, PCT Pub. Date Jan. 15, 2015.
Claims priority of provisional application 61/845,286, filed on Jul. 11, 2013.
Prior Publication US 2016/0158230 A1, Jun. 9, 2016
Int. Cl. A61K 31/506 (2006.01); C07D 239/48 (2006.01); A61K 31/505 (2006.01); C07D 403/12 (2006.01); C07D 401/14 (2006.01); C07D 405/14 (2006.01); C07D 413/14 (2006.01); C07D 401/04 (2006.01); C07D 401/12 (2006.01); C07D 403/04 (2006.01); C07D 405/12 (2006.01); C07D 413/04 (2006.01); C07D 413/12 (2006.01); C07D 417/04 (2006.01); C07D 417/12 (2006.01); C07D 493/08 (2006.01); A61K 45/06 (2006.01)
CPC A61K 31/505 (2013.01) [A61K 31/506 (2013.01); A61K 45/06 (2013.01); C07D 239/48 (2013.01); C07D 401/04 (2013.01); C07D 401/12 (2013.01); C07D 401/14 (2013.01); C07D 403/04 (2013.01); C07D 403/12 (2013.01); C07D 405/12 (2013.01); C07D 405/14 (2013.01); C07D 413/04 (2013.01); C07D 413/12 (2013.01); C07D 413/14 (2013.01); C07D 417/04 (2013.01); C07D 417/12 (2013.01); C07D 493/08 (2013.01)] 15 Claims
 
1. A compound having Formula I or a pharmaceutically acceptable salt or hydrate thereof, wherein:

OG Complex Work Unit Drawing
ring A is an optionally substituted 6-membered monocyclic heteroaryl;
ring B is an optionally substituted 6-membered monocyclic heteroaryl;
W and X are N and Y is CH;
Z is C(R1)(R2)(R3);
R1 and R3 are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, —O—C1-C4 alkyl, and CN, wherein any alkyl portion of R1 is optionally substituted with —OH, NH2, NH(C1-C4 alkyl), or N(C1-C4 alkyl)2;
R2 is selected from: —(C1-C6 alkyl), —(C2-C6 alkenyl or alkynyl), —(C1-C6 alkylene)-N(R6)—(C1-C6 alkylene)-O—(C1-C6 alkyl), —(C1-C6 alkylene)-N(R6)—(C0-C6 alkylene)-Q, —(C0-C6 alkylene)-N(R6)(R6), alkylene)-N(R6)—S(O)1-2-(C1-C6 alkyl), —(C1-C6 alkylene)-N(R6)—S(O)1-2-(C0-C6 alkyl)-Q, —(C1-C6 alkylene)-S(O)1-2—N(R6)(R6), —(C1-C4 alkylene)-S(O)1-2—N(R6)—(C1-C6 alkylene)-Q, —C(O)N(R6)—(C1-C6 alkylene)-C(O)—(C0-C6 alkylene)-O—(C1-C6 alkyl), —C(O)N(R6)—(C1-C6 alkylene)-C(O)—(C0-C6 alkylene)-O—(C0-C6 alkylene)-Q, —(C1-C6 alkylene)-O—C(O)—(C1-C6 alkyl), —(C1-C6 alkylene)-O—C(O)—(C0-C6 alkyl)-Q, —(C0-C6 alkylene)-O—(C1-C6 alkyl), —(C1-C6 alkylene)-O—(C1-C6 alkylene)-Q, —(C0-C6 alkylene)-C(O)—(C0-C6 alkylene)-O—(C1-C6 alkyl), —(C0-C6 alkylene)-C(O)—(C0-C6 alkylene)-O—(C1-C6 alkylene)-Q, —(C1-C6 alkylene)-O—C(O)—(C1-C6 alkyl), —(C1-C6 alkylene)-O—C(O)—(C0-C6 alkylene)-Q, —(C0-C6 alkylene)-C(O)N(R6)—(C1-C6 alkyl), —(C0-C6 alkylene)-C(O)N(R6)—(C0-C6 alkylene)-Q, —(C1-C6 alkylene)-N(R6)C(O)—(C1-C6 alkyl), —(C1-C6 alkylene)-N(R6)C(O)—(C0-C6 alkylene)-Q, —(C0-C6 alkylene)-S(O)0-2-(C1-C6 alkyl), —(C0-C6 alkylene)-S(O)0-2-(C0-C6 alkylene)-Q, —(C1-C6 alkylene)-N(R6)—C(O)—N(R6)—(C1-C6 alkyl), —(C0-C6 alkylene)-Q, —(C0-C6 alkylene)-C(O)—(C1-C6 alkyl), and —(C0-C6 alkylene)-C(O)—(C0-C6 alkylene)-Q, wherein:
any alkyl or alkylene moiety present in R2 is optionally substituted with one or more —OH, —O(C1-C4 alkyl) or halo;
any terminal methyl moiety present in R2 is optionally replaced with —CH2OH, CF3, —CH2F, —CH2Cl, C(O)CH3, C(O)CF3, CN, or CO2H;
each R6 is independently selected from hydrogen and C1-C6 alkyl; and
Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; or
R1 and R3 are optionally taken together with the carbon atom to which they are attached to form C(═O), or
R1 and R2 are optionally taken together to form substituted carbocyclyl or an optionally substituted heterocyclyl.