IRAK inhibitors and uses thereof

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

Q is N;

X is N and Y is C—R x ;

Ring A is a 3-7 membered saturated or partially unsaturated carbocyclic ring;

R 1 is Cy;

each R 1′ is independently —R 2 , halogen, —CN, —NO 2 , —OR, —SR, —N(R) 2 , —S(O) 2 R, —S(O) 2 N(R) 2 , —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R) 2 , —C(O)N(R)OR, —N(R)C(O)OR, —N(R)C(O)N(R) 2 , Cy, or —N(R)S(O) 2 R;

each Cy is an optionally substituted ring selected from a 3-7 membered saturated or partially unsaturated carbocyclic ring or a 4-10 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 C 1-6 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;

each R 2 is independently an optionally substituted group selected from C 1-6 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;

R x is hydrogen, —R 2 , —CN, —NO 2 , halogen, —C(O)N(R) 2 , —C(O)OR, —C(O)R, —N(R) 2 , —NH[Ar], —OR, or —S(O) 2 N(R) 2 ;

R z is hydrogen, —N(R) 2 , or —NH[Ar];

[Ar] is a 5-membered heteroaromatic ring substituted by m instances of R 1′ ;

L 1 is a covalent bond or a C 1-6 bivalent hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —N(R)S(O) 2 —, —S(O) 2 N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)— or —S(O) 2 —;

m is 0-4; and

n is 1.

2. The compound of claim 1 of Formula IV-i:

3. The compound of claim 1 of Formula VI:

4. The compound of claim 1 wherein R z is —NH[Ar].

5. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

Q is N;

X is N and Y is C—R x ;

Ring A is a cyclohexyl ring;

each R 1 and R 1′ is independently —R 2 , halogen, —CN, —NO 2 , —OR, —SR, —N(R) 2 , —S(O) 2 R, —S(O) 2 N(R) 2 , —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R) 2 , —C(O)N(R)OR, —N(R)C(O)OR, —N(R)C(O)N(R) 2 , Cy, or —N(R)S(O) 2 R; or R 1 is selected from one of the following formulas:

or

two R 1 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 4-10 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 C 1-6 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;

each R 2 is independently an optionally substituted group selected from C 1-6 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;

R x is hydrogen, —R 2 , —CN, —NO 2 , halogen, —C(O)N(R) 2 , —C(O)OR, —C(O)R, —N(R) 2 , —NH[Ar], —OR, or —S(O) 2 N(R) 2 ;

R z is hydrogen, —N(R) 2 , or —NH-pyrazolyl, wherein the pyrazolyl ring is substituted with m instances of R 1′ ;

[Ar] is a phenyl or heteroaromatic ring substituted by m instances of R 1′ ;

L 1 is —N(R)— or —O—;

m is 0-4; and

n is 0-4.

6. A compound selected from any one of the following, or a pharmaceutically acceptable salt thereof:

7. The compound of claim 1 wherein m is 1 and R 1′ is an optionally substituted group selected from C 1-6 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.

8. The compound of claim 7 wherein R 1′ is optionally substituted C 1-6 aliphatic.

9. The compound of claim 7 wherein R 1′ is an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

10. The compound of claim 5 wherein n is 1 and R 1 is Cy.

11. The compound of claim 5 wherein m is 1 and R 1′ is an optionally substituted group selected from C 1-6 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.

12. The compound of claim 11 wherein R 1′ is an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

13. The compound of claim 11 wherein R 1′ is C 1-3 alkyl.

14. A pharmaceutical composition comprising a compound according to claim 1 , and a pharmaceutically acceptable carrier, adjuvant, or vehicle.