Bicyclic indole-pyrimidine pi3k inhibitor compounds selective for p110 delta, and methods of use

A compound selected from Formulas Ia and Ib:

• and stereoisomers, tautomers, or pharmaceutically acceptable salts thereof,
• wherein (i) X1 is N and X2 is S, (ii) X1 is CR7 and X2 is S, (iii) X1 is N and X2 is NR2, (iv) X1 is CR7 and X2 is O, or (v) X1 is CR7 and X2 is NR2;
• R1 is selected from C1-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C20 aryl, —(C1-C12 alkylene)-(C3-C12 carbocyclyl), —(C1-C12 alkylene)-O—(C1-C12 alkylene)-(C3-C12 heterocyclyl), —(C1-C12 alkylene)-O—(C1-C12 alkylene)-C(═O)—(C3-C12 heterocyclyl), —(C1-C12 alkylene)-(C2-C20 heterocyclyl), —(C1-C12 alkylene)-(C2-C20 heterocyclyl)-(C2-C20 heterocyclyl), —(C1-C12 alkylene)-(C2-C20 heterocyclyl)-(C3-C12 carbocyclyl), —(C1-C12 alkylene)-(C2-C20 heterocyclyl)-C(═O)—(C2-C20 heterocyclyl), —(C1-C12 alkylene)-(C1-C20 heteroaryl), —(C1-C12 alkylene)-(C2-C20 heterocyclyl)-(C1-C12 alkyl), —(C1-C12 alkylene)-(C6-C20 aryl)-(C1-C12 alkyl), —(C1-C12 alkylene)-(C1-C20 heteroaryl)-(C1-C12 alkyl), —(C1-C12 alkylene)-C(═O)—(C2-C20 heterocyclyl), —(C1-C12 alkylene)-NHR2, —(C1-C12 alkylene)-N(C1-C12 alkyl)R2, —(C1-C12 alkylene)-N(C1-C12 alkyl)(C2-C20 heterocyclyl), —(C1-C12 alkylene)-NH—(C1-C12 alkylene)-(C1-C20 heteroaryl), —(C1-C12 alkylene)-NH—(C1-C12 alkylene)-(C1-C20 heterocyclyl), —(C1-C12 alkylene)-NH—(C1-C12 alkylene)-NHC(═O)—(C1-C20 heteroaryl), —(C1-C12 alkylene)-(C2-C20 heterocyclyl)-N(C1-C12 alkyl)R2′, —(C1-C12 alkylene)-(C2-C20 heterocyclyl)-(C1-C12 alkyl)-N(C1-C12 alkyl)R2′, and —(C1-C12 alkylene)-N(C2-C20 heterocyclyl)R2′, where alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, —CH3, —CH2CH3, —C(CH3)3, —CH2OH, —CH2CH2OH, —C(CH3)2OH, —C(CH3)2OCH3, —CN, —CF3, —CO2H, —COCH3, —CO2CH3, —CONH2, —CONHCH3, —CON(CH3)2, —C(CH3)2CONH2, —NO2, —NH2, —NHCH3, —N(CH3)2, —NHCOCH3, —NHS(O)2CH3, —N(CH3)C(CH3)2CONH2, —N(CH3)CH2CH2S(O)2CH3, ═O, —OH, —OCH3, —S(O)2N(CH3)2, —SCH3, —CH2OCH3, —S(O)2CH3, cyclopropyl, morpholino, and 1,1-dioxo-thiopyran-4-yl;
• R2 and R2′ are independently selected from C1-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C12 alkylene)-(C3-C12 carbocyclyl), —(C1-C12 alkylene)-(C2-C20 heterocyclyl), —(C1-C12 alkylene)-C(═O)—(C2-C20 heterocyclyl), —(C1-C12 alkylene)-(C6-C20 aryl), and —(C1-C12 alkylene)-(C1-C20 heteroaryl), where alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, —CH3, —CH2OH, —CN, —CF3, —CO2H, —COCH3, —CO2CH3, —CONH2, —CONHCH3, —CON(CH3)2, —NO2, —NH2, —NHCH3, —NHCOCH3, —NHS(O)2CH3, —OH, —OCH3, —S(O)2N(CH3)2, —SCH3, —CH2OCH3, and —S(O)2CH3;
• R3 is selected from:
• where the wavy line indicates the site of attachment;
• each of which are optionally substituted with one or more groups independently selected from F, Cl, Br, I, —CH3, —CH2CH3, —CH2CH2CH3, —CH(CH3)2, —C(CH3)3, —CH2OCH3, —CHF2, —CN, —CF3, —CH2OH, —CH2OCH3, —CH2CH2OH, —CH2C(CH3)2OH, —CH(CH3)OH, —CH(CH2CH3)OH, —CH2CH(OH)CH3, —C(CH3)2OH, —C(CH3)2OCH3, —CH(CH3)F, —C(CH3)F2, —CH(CH2CH3)F, —C(CH2CH3)2F, —CO2H, —CONH2, —CON(CH2CH3)2, —COCH3, —CON(CH3)2, —NO2, —NH2, —NHCH3, —N(CH3)2, —NHCH2CH3, —NHCH(CH3)2, —NHCH2CH2OH, —NHCH2CH2OCH3, —NHCOCH3, —NHCOCH2CH3, —NHCOCH2OH, —NHS(O)2CH3, —N(CH3)S(O)2CH3, ═O, —OH, —OCH3, —OCH2CH3, —OCH(CH3)2, —SH, —NHC(═O)NHCH3, —NHC(═O)NHCH2CH3, —S(O)CH3, —S(O)CH2CH3, —S(O)2CH3, —S(O)2NH2, —S(O)2NHCH3, —S(O)2N(CH3)2, —CH2S(O)2CH3;
• R7 is selected from H, C1-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C12 alkylene)-(C3-C12 carbocyclyl), —(C1-C12 alkylene)-(C2-C20 heterocyclyl), —(C1-C12 alkylene)-C(═O)—(C2-C20 heterocyclyl), —(C1-C12 alkylene)-(C6-C20 aryl), and —(C1-C12 alkylene)-(C1-C20 heteroaryl), where alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, —CH3, —CH2OH, —CN, —CF3, —CO2H, —COCH3, —CO2CH3, —CONH2, —CONHCH3, —CON(CH3)2, —NO2, —NH2, —NHCH3, —NHCOCH3, —NHS(O)2CH3, —OH, —OCH3, —S(O)2N(CH3)2, —SCH3, —CH2OCH3, and —S(O)2CH3;
• mor is a morpholine group unsubstituted or substituted with one or more groups selected from F, Cl, Br, I, —CH3, —CH2CH3, —CH2CH2CH3, —CH(CH3)2, —C(CH3)3, —CH2OCH3, —CHF2, —CN, —CF3, —CH2OH, —CH2OCH3, —CH2CH2OH, —CH2C(CH3)2OH, —CH(CH3)OH, —CH(CH2CH3)OH, —CH2CH(OH)CH3, —C(CH3)2OH, —C(CH3)2OCH3, —CH(CH3)F, —C(CH3)F2, —CH(CH2CH3)F, —C(CH2CH3)2F, —CO2H, —CONH2, —CON(CH2CH3)2, —COCH3, —CON(CH3)2, —NO2, —NH2, —NHCH3, —N(CH3)2, —NHCH2CH3, —NHCH(CH3)2, —NHCH2CH2OH, —NHCH2CH2OCH3, —NHCOCH3, —NHCOCH2CH3, —NHCOCH2OH, —NHS(O)2CH3, —N(CH3)S(O)2CH3, ═O, —OH, —OCH3, —OCH2CH3, —OCH(CH3)2, —SH, —NHC(═O)NHCH3, —NHC(═O)NHCH2CH3, —S(O)CH3, —S(O)CH2CH3, —S(O)2CH3, —S(O)2NH2, —S(O)2NHCH3, —S(O)2N(CH3)2, —CH2S(O)2CH3;
• and
• wherein the IC50 binding activity to p110 delta is ten or more times lower than the binding activity to p110 alpha.