Substituted pyrrolo[3,4-b]pyridines as PI3K-α inhibitors

A compound of formula I:

• or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof,
• wherein:
• E is —C(O)—;
• Q is CH;
• R1 is -L1-R1A;
• L1 is a covalent bond;
• R1A is phenyl, wherein the phenyl is substituted with r1 instances of R1C;
• each R1C is independently (a), (b), (c), (d), or (e):
• (a) D, halogen, CN, NO2, B(OR)2, C(O)R, C(O)NRR, C(O)NROR, C(O)OR, NRR, NRC(NR)NRR, NRC(O)R, NRC(O)NRR, NRC(O)OR, NRS(O)2R, NRS(O)2NRR, OR, OC(O)NRR, OC(O)R, P(O)RR, P(O)ROR, SR, SF5, S(O)R, S(O)NRR, S(O)(NR)R, S(O)2R, S(O)2F, or S(O)2NRR;
• (b) a C1-6 aliphatic chain, wherein the C1-6 aliphatic chain is optionally substituted with one or more independently selected halogen substituents;
• (c) a saturated or partially unsaturated, monocyclic 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl contains 1 or 2 heteroatoms or heteroatomic groups independently selected from the group consisting of N, NH, O, and S, and further wherein the 3- to 7-membered heterocyclyl is optionally substituted with one or more independently selected halogen substituents;
• (d) phenyl, wherein the phenyl is optionally substituted with one or more independently selected halogen substituents;
• or
• (e) a monocyclic 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl contains 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S, and further wherein the 5- or 6-membered heteroaryl is optionally substituted with one or more independently selected halogen substituents;
• r1 is 0, 1, 2, 3, or 4;
• R2 is -L2-R2A;
• L2 is —NHC(O)—;
• R2A is a bicyclic 8- to 10-membered heteroaryl;
• wherein the bicyclic 8- to 10-membered heteroaryl contains 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S;
• and
• wherein the bicyclic 8- to 10-membered heteroaryl is substituted with r2 instances of R2C;
• each R2C is independently (a), (b), (c), (d), or (e):
• (a) D, halogen, CN, NO2, B(OR)2, C(O)R, C(O)NRR, C(O)NROR, C(O)OR, NRR, NRC(NR)NRR, NRC(O)R, NRC(O)NRR, NRC(O)OR, NRS(O)2R, NRS(O)2NRR, OR, OC(O)NRR, OC(O)R, P(O)RR, P(O)ROR, SR, SF5, S(O)R, S(O)NRR, S(O)(NR)R, S(O)2R, S(O)2F, or S(O)2NRR;
• (b) a C1-6 aliphatic chain, wherein the C1-6 aliphatic chain is optionally substituted with one or more independently selected halogen substituents;
• (c) a saturated or partially unsaturated, monocyclic 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl contains 1 or 2 heteroatoms or heteroatomic groups independently selected from the group consisting of N, NH, O, and S, and further wherein the 3- to 7-membered heterocyclyl is optionally substituted with one or more independently selected halogen substituents;
• (d) phenyl, wherein the phenyl is optionally substituted with one or more independently selected halogen substituents;
• or
• (e) a monocyclic 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl contains 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S, and further wherein the 5- or 6-membered heteroaryl is optionally substituted with one or more independently selected halogen substituents;
• r2 is 0, 1, 2, 3, or 4;
• X is CH;
• Y is CRY;
• RY is -LY-RYA;
• LY is a covalent bond;
• RYA is a monocyclic 5- or 6-membered heteroaryl;
• wherein the 5- or 6-membered heteroaryl contains 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S;
• and
• wherein the 5- or 6-membered heteroaryl is substituted with r6 instances of RYC;
• each RYC is independently (a), (b), (c), (d), or (e):
• (a) D, halogen, CN, NO2, B(OR)2, C(O)R, C(O)NRR, C(O)NROR, C(O)OR, NRR, NRC(NR)NRR, NRC(O)R, NRC(O)NRR, NRC(O)OR, NRS(O)2R, NRS(O)2NRR, OR, OC(O)NRR, OC(O)R, P(O)RR, P(O)ROR, SR, SF5, S(O)R, S(O)NRR, S(O)(NR)R, S(O)2R, S(O)2F, or S(O)2NRR;
• (b) a C1-6 aliphatic chain, wherein the C1-6 aliphatic chain is optionally substituted with one or more independently selected halogen substituents;
• (c) a saturated or partially unsaturated, monocyclic 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl contains 1 or 2 heteroatoms or heteroatomic groups independently selected from the group consisting of N, NH, O, and S, and further wherein the 3- to 7-membered heterocyclyl is optionally substituted with one or more independently selected halogen substituents;
• (d) phenyl, wherein the phenyl is optionally substituted with one or more independently selected halogen substituents;
• or
• (e) a monocyclic 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl contains 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S, and further wherein the 5- or 6-membered heteroaryl is optionally substituted with one or more independently selected halogen substituents;
• r6 is 0, 1, 2, 3, or 4;
• Z is N;
• and
• each R is independently (a), (b), (c), (d), or (e):
• (a) H;
• (b) a C1-6 aliphatic chain, wherein the C1-6 aliphatic chain is optionally substituted with one or more independently selected halogen substituents;
• (c) a saturated or partially unsaturated, monocyclic 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl contains 1 or 2 heteroatoms or heteroatomic groups independently selected from the group consisting of N, NH, O, and S, and further wherein the 3- to 7-membered heterocyclyl is optionally substituted with one or more independently selected halogen substituents;
• (d) phenyl, wherein the phenyl is optionally substituted with one or more independently selected halogen substituents;
• or
• (e) a monocyclic 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl contains 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S, and further wherein the 5- or 6-membered heteroaryl is optionally substituted with one or more independently selected halogen substituents;
• or
• any two R, taken together with the nitrogen atom to which they are attached, independently form a saturated or partially unsaturated 4- to 7-membered heterocyclyl or a 5- or 6-membered heteroaryl, wherein the 4- to 7-membered heterocyclyl or the 5- or 6-membered heteroaryl optionally contains 1, 2 or 3 additional heteroatoms or heteroatomic groups independently selected from the group consisting of N, NH, O, and S.