mTORC1 modulators and uses thereof

A compound represented by the structure of Formula I:

• or a pharmaceutically acceptable salt thereof, wherein:
• R1 is selected from
• R2 is selected from hydrogen and an optionally substituted C1-C6 alkoxy, wherein substituents are independently selected at each occurrence from hydroxy, halogen, —CN, —NO2, C1-C6 alkoxy, 3- to 10-membered heterocycle, and C3-10 carbocycle, wherein the 3- to 10-membered heterocycle and C3-10 carbocycle are each optionally substituted with one or more substituents independently selected from hydroxy, halogen, —CN, —NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, and C1-C6 alkoxy;
• R3 is selected from hydrogen and an optionally substituted C1-C6 alkoxy, wherein the substituents are independently selected at each occurrence from hydroxy, halogen, —CN, —NO2, C1-C6 alkoxy, 3- to 10-membered heterocycle, and C3-10 carbocycle, wherein the 3- to 10-membered heterocycle and C3-10 carbocycle, are each optionally substituted with one or more substituents independently selected from hydroxy, halogen, —CN, —NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, and C1-C6 alkoxy;
• and
• R4′ is selected from
• R5 is selected from hydrogen, hydroxy, and an optionally substituted C1-C6 alkoxy, wherein substituents are independently selected at each occurrence from hydroxy, halogen, —CN, —NO2, C1-C6 alkoxy, 3- to 10-membered heterocycle, and C3-10 carbocycle, wherein the 3- to 10-membered heterocycle, and C3-10 carbocycle are each optionally substituted with one or more substituents independently selected from hydroxy, halogen, —CN, —NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, and C1-C6 alkoxy;
• R6 and R7 come together to form
• R22 is selected from optionally substituted C1-C6 alkyl, optionally substituted 3- to 10-membered heterocycle, and optionally substituted C3-10 carbocycle, and —P(═O)(R24)2;
• R24 is optionally substituted C1-C6 alkyl;
• R100 is selected from:
• hydrogen and —(CH2—CH2-G)y-V;
• and
• C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, wherein each of which is optionally substituted with one or more substituents independently selected from halogen, —OR31, —SR31, —N(R31)2, —C(O)R31, —C(O)N(R31)2, —N(R31)C(O)R31, —C(O)OR31, —OC(O)R31, —S(O)R31, —S(O)2R31, —P(O)(OR31)2, —OP(O)(OR31)2, —NO2, —CN, C3-20 carbocycle and 3- to 20-membered heterocycle;
• and
• C3-20 carbocycle and 3- to 20-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from halogen, —OR31, —SR31, —N(R31)2, —C(O)R31, —C(O)N(R31)2, —N(R31)C(O)R31, —C(O)OR31, —OC(O)R31, —S(O)R31, —S(O)2R31, —P(O)(OR31)2, —OP(O)(OR31)2, —NO2, ═O, ═S, ═N(R31), —CN, C1-6 alkyl, C1-6 alkyl-R31, C2-6 alkenyl, and C2-6 alkynyl;
• each G is independently selected from —O—, —NR32—, —S—, or —SO2—;
• y is selected from 3-20;
• V is selected from hydrogen and optionally substituted —C1-C6 alkyl;
• R110′ is selected from:
• —S(O)R51′, and —S(O)2R51′;
• each R31 is independently selected from hydrogen, and C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —OH, —CN, —NO2, —NH2, ═O, ═S, C1-10 alkyl, —C1-10 haloalkyl, —O—C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle;
• and
• R32 is independently selected at each occurrence from:
• hydrogen;
• and C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —OH, —CN, —NO2, —NH2, ═O, ═S, C1-10 alkyl, —C1-10 haloalkyl, —O—C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle;
• wherein the optional substituents on R22, R24, R51′, V, and T are independently selected at each occurrence from:
• halogen, —OR30, —N(R30)2, —(O—CH2—(CH2)p)n—W, —SR30, —C(O)R30, —C(O)N(R30)2, —N(R30)C(O)R30, —C(O)OR30, —OC(O)R30, —S(O)R30, —S(O)2R30, —P(O)(OR30)2, —OP(O)(OR30)2, —NO2, ═O, ═S, ═N(R30), and —CN;
• C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR30, —SR30, —N(R30)2, —C(O)R30, —C(O)N(R30)2, —N(R30)C(O)R30, —C(O)OR30, —OC(O)R30, —S(O)R30, —S(O)2R30, —P(O)(OR30)2, —OP(O)(OR30)2, —NO2, ═O, ═S, ═N(R30), —CN, C3-10 carbocycle and 3- to 10-membered heterocycle;
• and
• C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from halogen, —OR30, —SR30, —N(R30)2, —C(O)R30, —C(O)N(R30)2, —N(R30)C(O)R30, —C(O)OR30, —OC(O)R30, —S(O)R30, —S(O)2R30, —P(O)(OR30)2, —OP(O)(OR30)2, —NO2, ═O, ═S, ═N(R30), —CN, C1-6 alkyl, C1-6 alkyl-R30, C2-6 alkenyl, and C2-6 alkynyl;
• R30 is independently selected at each occurrence from hydrogen;
• C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —OH, —CN, —NO2, —NH2, ═O, ═S, C1-10 alkyl, —C1-10 haloalkyl, —O—C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle;
• R51′ is independently selected at each occurrence from substituted C1-4 alkyl, optionally substituted C3-8 carbocycle, optionally substituted 3-10 membered heterocycle, —((CH2)q—CH2-D)z-T and optionally substituted C5-30 alkyl;
• q is selected from 1 to 6;
• each D is independently selected from —O—, —NR32—, —S—, or —SO2—;
• z is selected from 1-20;
• T is selected from hydrogen and optionally substituted —C1-C6 alkyl;
• each p is selected from 1 or 2;
• each n is selected from 3-7;
• and
• each W is selected from hydrogen, —OH, —C1-C4 alkyl and —O(C1-C4 alkyl).