Isoindolinone inhibitors of phosphatidylinositol 3-kinase

A compound having the formula:

• or a pharmaceutically acceptable salt thereof, wherein:
• X1 is N;
• X2 is CH;
• R1 is a pyrazol-4-yl optionally substituted with 1 or 2 independent occurrences of R1a;
• R1a is chloro, fluoro, C1-8aliphatic, —(CH2)0-2C3-6cycloaliphatic, —(CH2)0-2-5-6 membered heterocyclic ring, —CN, —C(O)C1-4aliphatic, —C(O)NH(C1-4aliphatic), —C(O)N(C1-4aliphatic)2, —C(O)OC1-4aliphatic, —S(O)2NH(C1-4aliphatic), —S(O)2N(C1-4aliphatic)2, or —S(O)2C1-4aliphatic, wherein up to 3 non-adjacent carbon atoms of said aliphatic or cycloaliphatic of R1a can be substituted for by —O—, —S—, or —N(R1b)—, wherein said heterocyclic ring has up to two heteroatoms selected from nitrogen, oxygen, or sulfur, and wherein each of said aliphatic, cycloaliphatic, or heterocyclic of R1a is optionally and independently substituted with up to 4 occurrences of JR;
• each JR is independently fluoro, oxo, —(CH2)0-2CN, —(CH2)0-2CF3, —C(O)R1b, —C(O)N(R1b)2, —C(O)O(R1b), —N(R1b)2, —N(R1b)C(O)R1b, —(CH2)0-2OR1b, phenyl, 5-6 membered heteroaryl, 4-6 heterocyclyl, 9-11 fused bicyclic heteroaryl, or 9-11 fused bicyclic heterocyclyl, wherein each of said heteroaryl or heterocyclyl rings having up to 3 atoms selected from nitrogen, oxygen, or sulfur, and wherein each of said cycloaliphatic, phenyl, heteroaryl, or heterocyclyl is optionally substituted with up to 2 R1c;
• each R1b is, independently, selected from hydrogen, C1-8aliphatic, —(CH2)0-1C3-6cycloaliphatic, —(CH2)0-1C4-6heterocyclic having up to two heteroatoms selected from N or O, or two R1b together with the atom to which they are bonded form a 5-6 membered heterocyclic ring, wherein each aliphatic, cycloaliphatic, or heterocyclic is optionally substituted with up to three F atoms or up to two —OH, —C1-2alkyl, or —OC1-2alkyl groups;
• each R1c is, independently, fluoro, chloro, C1-4aliphatic, —(CH2)0-2OH, —CN, —C(O)C1-4aliphatic, or —C(O)OC1-4aliphatic;
• R2 is hydrogen or C1-2aliphatic;
• R3 is hydrogen, C1-6aliphatic, C3-6 cycloaliphatic, C4-7 heterocyclyl having 1 or 2 atoms selected from N or O, —(CH2)0-1CF3, —OH, —OC1-6aliphatic, —OC3-6cycloaliphatic, —OC3-6heterocyclyl having one oxygen atom, —O(CH2)2OC1-2aliphatic, —OC1-2alkylC(O)OC1-3aliphatic, or benzyl;
• and
• R4 is hydrogen or C1-6alkyl, wherein at least one of R3 or R4 is not hydrogen;
• or R3 and R4 together with the carbon to which they are bonded form a 3-6 membered cycloaliphatic ring, a 3-6 membered heterocyclic ring having up to two atoms selected from N or O, or a C2alkenyl, wherein each of said aliphatic, cycloaliphatic, or heterocyclyl of R3, R4, or R3 and R4 together is optionally substituted with up to three F atoms, or up to two C1-2alkyl, —C(O)C1-4alkyl, —C(O)OC1-4alkyl, —OH, or —OC1-2alkyl groups;
• A is CRA wherein RA is hydrogen;
• B is N;
• C is CRC;
• D is CRD;
• E is CRE wherein RE is hydrogen;
• RC is hydrogen, F, Cl, C1-3aliphatic, —(CH2)0-1CF3, —(CH2)0-1CHF2, —N(R1b)2, —OH, —O(CH2)0-1CF3, or —OC1-8aliphatic, wherein up to 2 non-adjacent carbon atoms of said aliphatic can be substituted for by —O—;
• RD is hydrogen, fluoro, chloro, C1-4aliphatic, —C(O)OH, —C(O)OC1-4aliphatic, —C(O)N(R1b)2, —CN, —C(RD1)═N—OR1b, —N(R1b)2, —N(RD1)C(O)C1-4aliphatic, —N(RD1)C(O)phenyl, —N(RD1)S(O)2C1-4aliphatic, —N(RD1)S(O)2N(R1b)2, —N(RD1)S(O)2phenyl, —OH, —OC1-8aliphatic, —O(CH2)0-1C3-6cycloaliphatic, —SC1-4aliphatic, —S(O)C1-4aliphatic, —S(O)2C1-4aliphatic, or —S(O)2N(R1b)2;
• wherein up to 2 non-adjacent carbon atoms of said aliphatic, cycloaliphatic, or heterocyclic of RD can be substituted for by —O— and each of said aliphatic, cycloaliphatic, or phenyl of RD can be substituted with up to 5 fluorine atoms;
• or RD and RC together with the atoms to which they are attached form a phenyl or pyridyl ring;
• and
• each RD1 is, independently, hydrogen or C1-2alkyl.