Pi3k-alpha inhibitors and methods of use thereof

A compound of formula I-1:

• or a pharmaceutically acceptable salt thereof, wherein:
• E is —C(O)—, —C(RE)2—, —C(RE)2C(RE)2—, —C(S)—, —S(O)2—, —OC(O)—, —N(RE)C(O)—, —C(O)N(RE)—, or —C(RE)2C(O)—;
• Q is CH, C(RQ), or N;
• X is CH, C(RX), or N;
• Y is CH, C(RY), or N;
• Z is N;
• R1 is -L1-R1A;
• R2 is -L2-R2A;
• each instance of RE is independently H or -LE-REA;
• RQ is -LQ-RQA;
• RX is -LX-RXA;
• RY is -LY-RYA;
• or
• two instances of RE are taken together with their intervening atoms to form a 3-8 membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• or an 8-12 membered saturated or partially unsaturated bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• wherein each ring is substituted with n instances of REEC;
• RQ and R1 are taken together with their intervening atoms to form a 4-8 membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• or an 8-12 membered saturated or partially unsaturated bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• wherein each ring is substituted with p instances of RQ1C;
• each of L1, L2, LE, LQ, LX, and LY is independently a covalent bond, or a C1-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —CH(RL)—, —C(RL)2—, C3-6 cycloalkylene, C3-6 heterocycloalkylene, —N(R)—, —N(R)C(O)—, —N(R)C(NR)—, —N(R)C(NOR)—, —N(R)C(NCN)—, —C(O)N(R)—, —N(R)S(O)2—, —S(O)2N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)—, or —S(O)2—;
• R1A is RA or RB substituted by r1 instances of R1C;
• R2A is RA or RB substituted by r2 instances of R2C;
• REA is RA or RB substituted by r3 instances of REC;
• RQA is RA or RB substituted by r4 instances of RQC;
• RXA is RA or RB substituted by r5 instances of RXC;
• RYA is RA or RB substituted by r6 instances of RYC;
• RL is RA or RB substituted by r8 instances of RLC;
• each instance of RA is independently oxo, deuterium, halogen, —CN, —NO2, —OR, —SF5, —SR, —NR2, —S(O)2R, —S(O)2NR2, —S(O)2F, —S(O)R, —S(O)NR2, —S(O)(NR)R, —S(O)(NCN)R, —S(NCN)R, —C(O)R, —C(O)OR, —C(O)NR2, —C(O)N(R)OR, —OC(O)R, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR2, —N(R)C(NR)NR2, —N(R)S(O)2NR2, —N(R)S(O)2R, —P(O)R2, —P(O)(R)OR, or —B(OR)2;
• each instance of RB is independently a C1-6 aliphatic chain;
• phenyl;
• naphthyl;
• cubanyl;
• adamantyl;
• a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring;
• a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring;
• a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• each instance of R1C, R2C, REC, RQC, RXC, RYC, RLC, REEC, and RQ1C is independently oxo, deuterium, halogen, —CN, —NO2, —OR, —SF5, —SR, —NR2, —S(O)2R, —S(O)2NR2, —S(O)2F, —S(O)R, —S(O)NR2, —S(O)(NR)R, —C(O)R, —C(O)OR, —C(O)NR2, —C(O)N(R)OR, —OC(O)R, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR2, —N(R)C(NR)NR2, —N(R)S(O)2NR2, —N(R)S(O)2R, —P(O)R2, —P(O)(R)OR, —B(OR)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• each instance of R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• or
• two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur;
• and
• each of n, p, r1, r2, r3, r4, r5, r6, and r8 is independently 0, 1, 2, 3, 4, or 5.