US 12,433,895 B2
Therapeutically active compounds and their methods of use
Zenon D. Konteatis, Chatham, NJ (US); Janeta Popovici-Muller, Windham, NH (US); Jeremy M. Travins, Southborough, MA (US); Robert Zahler, Pennington, NJ (US); Zhenwei Cai, Princeton, NJ (US); and Ding Zhou, Shanghai (CN)
Assigned to Servier Pharmaceuticals LLC, Boston, MA (US)
Filed by Servier Pharmaceuticals LLC, Boston, MA (US)
Filed on Oct. 5, 2023, as Appl. No. 18/376,981.
Application 18/376,981 is a continuation of application No. 17/158,867, filed on Jan. 26, 2021, granted, now 11,844,758.
Application 17/158,867 is a continuation of application No. 16/167,725, filed on Oct. 23, 2018, granted, now 10,946,023, issued on Mar. 16, 2021.
Application 16/167,725 is a continuation of application No. 15/392,681, filed on Dec. 28, 2016, granted, now 10,172,864, issued on Jan. 8, 2019.
Application 15/392,681 is a continuation of application No. 14/328,885, filed on Jul. 11, 2014, granted, now 9,579,324, issued on Feb. 28, 2017.
Claims priority of application No. PCT/CN2013/079200 (WO), filed on Jul. 11, 2013; and application No. PCT/CN2014/081957 (WO), filed on Jul. 10, 2014.
Prior Publication US 2024/0335448 A1, Oct. 10, 2024
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 31/53 (2006.01); A61K 31/506 (2006.01); A61K 31/5377 (2006.01); A61K 45/06 (2006.01); C07D 251/18 (2006.01); C07D 251/48 (2006.01); C07D 401/04 (2006.01); C07D 401/14 (2006.01); C07D 403/04 (2006.01); C07D 403/10 (2006.01); C07D 405/12 (2006.01); C07D 405/14 (2006.01); C07D 413/04 (2006.01); C07D 413/14 (2006.01); C07D 417/04 (2006.01); C07D 417/14 (2006.01)
CPC A61K 31/53 (2013.01) [A61K 31/506 (2013.01); A61K 31/5377 (2013.01); A61K 45/06 (2013.01); C07D 251/18 (2013.01); C07D 251/48 (2013.01); C07D 401/04 (2013.01); C07D 401/14 (2013.01); C07D 403/04 (2013.01); C07D 403/10 (2013.01); C07D 405/12 (2013.01); C07D 405/14 (2013.01); C07D 413/04 (2013.01); C07D 413/14 (2013.01); C07D 417/04 (2013.01); C07D 417/14 (2013.01)] 20 Claims
 
1. A method for treating a cancer characterized by the presence of an isocitrate dehydrogenase 1 (IDH1) mutation comprising administering to a patient in need thereof a therapeutically effective amount of a compound having Formula (Ia) or a pharmaceutically acceptable salt or hydrate thereof, wherein:

OG Complex Work Unit Chemistry
ring A is selected from phenyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and thiazolyl, and wherein ring A is optionally substituted with up to two substituents independently selected from halo, —C1-C4 alkyl, —C1-C4 haloalkyl, —C1-C4 hydroxyalkyl, —NH—S(O)2—(C1-C4 alkyl), —S(O)2NH(C1-C4 alkyl), —S(O)2—(C1-C4 alkyl), C1-C4 alkoxy, —NH(C1-C4 alkyl), —OH, —OCF3, —CN, —NH2, —C(O)NH2, —C(O)NH(C1-C4 alkyl), —C(O)—N(C1-C4 alkyl)2, and cyclopropyl optionally substituted with OH;
R1, R3, R4, and R6 are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, —O—C1-C4 alkyl, and CN, wherein each said alkyl moiety of R1, R3, R4, and R6 are each independently optionally substituted with —OH, —NH2, —CN, —O—C1-C4 alkyl, —NH(C1-C4 alkyl), or —N(C1-C4 alkyl)2;
R2 and R5 are each independently selected from —(C1-C6 alkyl); —(C2-C6 alkenyl) and —(C2-C6 alkynyl), wherein any alkyl or alkylene moiety present in R2 and R5 is optionally substituted with one or more —OH, —O(C1-C4 alkyl), —CO2H, or halo;
any terminal methyl moiety present in R2 and R5 is optionally replaced with —CH2OH, CF3, —CH2F, —CH2Cl, C(O)CH3, C(O)CF3, CN, or CO2H; and
R7 and R8 are each independently selected from hydrogen and C1-C6 alkyl;
provided that
(i) when A is an optionally substituted pyridyl, then (A) N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both NHCH2CH2OH, and (B) when N(R7)C(R4)(R5)(R6) is NHC(CH3)3, then N(R8)C(R1)(R2)(R3) is not NH—CH2CH3;
(ii) when A is an optionally substituted heteroaryl selected from pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and thiazolyl, then N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both N(CH2CH3)2, NHCH2CH2-i-propyl, or NHCH2CH (CH3)2;
(iii) when A is optionally substituted 1-pyrazolyl, then neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHisopropyl, NHCH2CH3, or N(CH2CH3)2;
(iv) when A is an optionally substituted phenyl, then N(R7)C(R4)(R5)(R6) is not the same as N(R8)C(R1)(R2)(R3);
(v) when A is substituted 1-pyrazolyl, then (A) N(R7)C(R4)(R5)(R6); and N(R8)C(R1)(R2)(R3) are not both NHC(CH3) 3.