Aryl-bipyridine amine derivatives as phosphatidylinositol phosphate kinase inhibitors

A compound of Formula (I):

• or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof,
• wherein:
• X, Y, and Z are independently CH, C(C1-6 alkyl) or N, wherein at least one of X, Y, and Z is CH;
• Ring A is heteroaryl;
• R1 is pyrrolidinyl optionally substituted with one or more R5;
• R2 is —H, —NH2, or C1-6 alkyl;
• Q1 is a bond;
• each R3 is independently, at each occurrence, —H, halogen, oxo, C1-6 alkyl, C3-6 cycloalkyl, heterocyclyl, —OR6, —NR6R7, —CN, —C(O)NR6R7, —N(R6)C(O)R7, —C(O)OR6,—S(O)2R6, or —S(O)2N(R6)(R7), wherein the C1-6 alkyl or C3-6 cycloalkyl is optionally substituted with one or more R8, or
• two R3, when on adjacent atoms, with the atoms to which they are attached, form a C4-8 cycloalkyl, C5-C8 spirocycloalkyl, spiroheterocycloalkyl, or heterocyclyl, wherein the heterocyclyl, C5-C8 spirocycloalkyl, spiroheterocycloalkyl, or C4-8 cycloalkyl is optionally substituted with one or more R8;
• R4 is —H, C3-C8 cycloalkyl, C5-C8 spirocycloalkyl, spiroheterocycloalkyl, aryl, heterocyclyl, heteroaryl, —C(O)N(R10)—(C0-C6 alkylene)-R9, —C(O)N(R10)—R9, —C(O)—R9,—N(R10)—(C0-C6 alkylene)-R9, —(C0-C6 alkylene)-N(R10)C(O)—(C0-C6 alkylene)-R9,—N(R10)C(O)—(C0-C6 alkylene)-R9—N(R10)C(O)—(C0-C6 alkylene)-, —N(R10)C(O)—R9, —(CH2)q—R9, or —(CH2)r—N(R10)C(O)—(CH2)s—R9, wherein the C3-C8 cycloalkyl, C5-C8 spirocycloalkyl, spiroheterocycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R9;
• R5 is —H, halogen, —OH, C1-6 alkyl, or C1-6 alkoxy, wherein the C1-6 alkyl or C1-6 alkoxy is optionally substituted with R10;
• R6 is independently, at each occurrence, —H or C1-6 alkyl;
• R7 is independently, at each occurrence, C1-6 alkyl, aryl, or heteroaryl, wherein the C1-6 alkyl, aryl, or heteroaryl is optionally substituted with one or more R5, or
• R6 and R7 when taken together with the atoms to which they are each attached form a heterocycle, wherein the heterocycle is optionally substituted with one or more R5;
• R8 is independently, at each occurrence, —CN, halogen, —OH, —NH2, —NO2, —C(O)NH2,—C(O)OH, oxo, C1-6 alkyl, C1-6 alkoxy, aryl, C3-6cycloalkyl, C5-C8 spirocycloalkyl, spiroheterocycloalkyl, heterocyclyl, or heteroaryl, wherein the C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, C5-C8 spirocycloalkyl, spiroheterocycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R9;
• R9 is independently, at each occurrence, —H, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, —OR11, —C(O)O(R11), —C(O)N(R11)(R12), —N(R11)(R12), —CN, —N(R11)C(O)OR12, —N(R11)C(O)R12, —C(O)—V—N(R11)—F, —N(R11)C(O)—V—N(R12)—F, —C(O)—Ar, or —N(R11)C(O)—Ar, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, heterocyclyl, heteroaryl, or aryl is optionally substituted with one or more —OR11,—C(O)N(R11)(R12), —N(R1 1)(R12), —CN, —N(R1 1)C(O)OR12, —N(R1 1)C(O)R12, —C(O)—V—N(R1 1)—F, —N(R1 1)C(O)—V—N(R12)—F, —C(O)—Ar, —N(R1 1)C(O)—V—O(R12), —O-Q2-N(R11)C(O)—V—O(R12), or —N(R11)C(O)—Ar;
• each Ar is independently aryl substituted with —NR11R12, —C(O)-Q2-N(R11)—F or —N(R11)C(O)-Q2-N(R12)—F;
• each Q2 is independently —CH═CH(CH2)m—, —(CH2)m—, or —(CH2CH2O)o—CH2CH2—;
• each V is independently —CH═CH(CH2)m—, —(CH2)m—, or —(CH2CH2O)o—CH2CH2—;
• each F is independently —H, C1-6 alkyl, or —C(O)-Q2-N(R11)(R12);
• R10 is independently, at each occurrence, —H, halogen, —CN, —OH, —NO2, oxo, C1-6 alkyl, C1-6 alkoxy, C3-8 cycloalkyl, heterocyclyl, heteroaryl, or aryl;
• R11 and R12 are independently, at each occurrence, —H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, heterocyclyl, heteroaryl, or aryl is optionally substituted with one or more —H, halogen, —CN, —OH, —NO2, oxo, C1-6 alkyl, C1-6 alkoxy, C3-8 cycloalkyl, heterocyclyl, heteroaryl, aryl, —N(R13)(R14), —C(O)R13, —N(R13)C(O)R14, —C(O)N(R13)(R14), or —C(O)OR13;
• R13 and R14 are independently, at each occurrence, —H, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, heterocyclyl, heteroaryl, or aryl is optionally substituted with one or more H, halogen, —CN, —OH, —NH2, —NO2, oxo, C1-6 alkyl, C1-6 alkoxy, C3-8 cycloalkyl, heterocyclyl, heteroaryl, or aryl;
• each m is independently 1-4;
• o is 1-3;
• n is 1, 2, or 3;
• q is 1-4;
• r is 0-4;
• and
• s is 0-4;
• provided that:
• (1) A is not oxadiazolyl,
• (2) when A is thiophenyl, or 1,3,4-oxadiazolyl, both R3 and R4 are not simultaneously H;
• and
• (3) when R3 is —N(R6)(R7) and R6 is H, R7 is not methyl.