Therapeutically active compounds and their methods of use

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:

• 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.