IRAK inhibitors and uses thereof

A compound of formula XV-a, XV-b, XV-c, XV-d, XVI-a, XVI-b, XVI-c, XVI-d, XVII-a, XVII-b, or XVII-c:

• or a pharmaceutically acceptable salt thereof, wherein
• R1 is —R, halogen, —CN, —NO2, —OR, —CH2OR, —SR, —N(R)2, —SO2R, —SO2N(R)2, —SOR, —C(O)R, —CO2R, —C(O)N(R)2, —C(O)N(R)—OR, —NRC(O)OR, —NRC(O)N(R)2, Cy, or —NRSO2R;
• or R1 is selected from one of the following formulas:
• Cy is an optionally substituted ring selected from a 3-7 membered saturated or partially unsaturated carbocyclic ring or a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or 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, or sulfur;
• m is 0-4;
• p is 0-2;
• [Ar] is an optionally substituted phenyl or heteroaromatic ring;
• L1 is a covalent bond or a C1-6 bivalent hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —NR—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO2—, —SO2N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO— or —SO2;
• each L2 is independently a covalent bond or a C1-6 bivalent hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —NR—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO2—, —SO2N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO— or —SO2—;
• each R4 is independently halogen, —CN, —NO2, —OR, —SR, —N(R)2, —SO2R, —SO2N(R)2, —SOR, —C(O)R, —CO2R, C(O)N(R)2, —NRC(O)R, —NRC(O)N(R)2, —C(O)N(R)OR, —N(R)C(O)OR, —N(R)S(O)2N(R)2 , —NRSO2R, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:
• two —L2(R4)p—R4 groups are taken together with their intervening atoms to form an optionally substituted 4-7 membered fused, spiro-fused, or bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

A compound of formula I:

• or a pharmaceutically acceptable salt thereof, wherein:
• Ring A is a 3-7 membered saturated or partially unsaturated carbocyclic ring or a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• n is 0-4;
• each R1 is independently —R, halogen, —CN, —NO2, —OR, —CH2OR, —SR, —N(R)2, —SO2R, —SO2N(R)2, —SOR, —C(O)R, —CO2R, —C(O)N(R)2, —C(O)N(R)—OR, —NRC(O)OR, —NRC(O)N(R)2, Cy, or —NRSO2R;
• or R1 is selected from one of the following formulas:
• two R1 groups are taken together with their intervening atoms to form an optionally substituted 4-7 membered fused, spiro-fused, or bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• each Cy is an optionally substituted ring selected from a 3-7 membered saturated or partially unsaturated carbocyclic ring or a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or 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, or sulfur;
• Ring B is a 4-8 membered partially unsaturated carbocyclic fused ring;
• or a 4-7 membered partially unsaturated heterocyclic fused ring having 1-2 heteroatoms selected from nitrogen, oxygen, or sulfur;
• wherein said Ring B may be optionally substituted by one or more oxo, thiono, or imino groups;
• m is 0-4;
• p is 0-2;
• [Ar] is an optionally substituted 6-membered heteroaryl;
• L1 is a covalent bond or a C1-6 bivalent hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —NR—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO2—, —SO2N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO— or —SO2—;
• each L2 is independently a covalent bond or a C1-6 bivalent hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —NR—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO2—, —SO2N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO— or —SO2—;
• each R4 is independently halogen, —CN, —NO2, —OR, —SR, —N(R)2, —SO2R, —SO2N(R)2, —SOR, —C(O)R, —CO2R, —C(O)N(R)2, —NRC(O)R, —NRC(O)N(R)2, —C(O)N(R)OR, —N(R)C(O)OR, —N(R)S(O)2N(R)2, —NRSO2R, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:
• two —L2(R4)—R4 groups are taken together with their intervening atoms to form an optionally substituted 4-7 membered fused, spiro-fused, or bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

A compound of formula I:

• or a pharmaceutically acceptable salt thereof, wherein:
• Ring A is a 3-7 membered saturated or partially unsaturated carbocyclic ring or a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• n is 0-4;
• each R1 is independently —R, halogen, —CN, —NO2, —OR, —CH2OR, —SR, —N(R)2, —SO2R, —SO2N(R)2, —SOR, —C(O)R, —CO2R, —C(O)N(R)2, —C(O)N(R)—OR, —NRC(O)OR, —NRC(O)N(R)2, Cy, or —NRSO2R;
• or R1 is selected from one of the following formulas:
• two R1 groups are taken together with their intervening atoms to form an optionally substituted 4-7 membered fused, spiro-fused, or bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• each Cy is an optionally substituted ring selected from a 3-7 membered saturated or partially unsaturated carbocyclic ring or a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or 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, or sulfur;
• Ring B is a 4-8 membered partially unsaturated carbocyclic fused ring;
• or a 4-7 membered partially unsaturated heterocyclic fused ring having 1-2 heteroatoms selected from nitrogen, oxygen, or sulfur;
• wherein said Ring B may be optionally substituted by one or more oxo, thiono, or imino groups;
• m is 0-4;
• p is 0-2;
• [Ar] is an optionally substituted 5-membered heteroaryl;
• L1 is a covalent bond or a C1-6 bivalent hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —NR—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO2—, —SO2N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO— or —SO2—;
• each L2 is independently a covalent bond or a C1-6 bivalent hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —NR—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO2—, —SO2N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO— or —SO2—;
• each R4 is independently halogen, —CN, —NO2, —OR, —SR, —N(R)2, —SO2R, —SO2N(R)2, —SOR, —C(O)R, —CO2R, —C(O)N(R)2, —NRC(O)R, —NRC(O)N(R)2, —C(O)N(R)OR, —N(R)C(O)OR, —N(R)S(O)2N(R)2, —NRSO2R, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:
• two —L2—(R4)—R4 groups are taken together with their intervening atoms to form an optionally substituted 4-7 membered fused, spiro-fused, or bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.