Heteroaryl compounds as IRAK inhibitors and uses thereof

1. A compound of formula I,

or a pharmaceutically acceptable salt thereof, wherein:

X is CR or N;

A is O, S, SO 2 , SO, —NRC(O), —NRSO 2 , or N(R); or A is absent;

R 3 is H, C 1-6 aliphatic, C 3-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, or a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; or R 3 is halogen, -haloalkyl, —OR, —SR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ; or

when A is —NRC(O), —NRSO 2 , or N(R); then R and R 3 , together with the atoms to which each is attached, may form a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted;

X′ is CR or N;

Ring Z is a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted;

R 1 is —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ;

R a is absent, —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ;

Ring Y is an optionally substituted pyridyl, pyrazole or thiadiazole;

R 2 is —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ;

R b is absent, —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ;

each R is independently hydrogen, C 1-6 aliphatic, C 3-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; or

two R groups on the same atom are taken together with the atom to which they are attached to form a C 3-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted;

wherein when X is N and A is absent, then R 3 is not H.

2. The compound of claim 1 , wherein X is CH.

3. The compound of claim 1 , wherein X is N.

4. The compound of claim 1 , wherein A is O or N(R), or A is absent.

5. The compound of claim 1 , wherein R 3 is H, C 1-6 aliphatic, C 3-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, or a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; or R 3 is -haloalkyl, —C(O)R, —CO 2 R, or —C(O)N(R) 2 .

6. The compound of claim 5 , wherein R 3 is C 1-6 aliphatic, C 3-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, or a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted.

7. The compound of claim 1 , wherein A-R 3 is —H, —CH 3 , —CF 3 ,

8. The compound of claim 1 , wherein Ring Z is:

wherein X is O, S or NR 1 ; Y is C or N; and T is C or N.

9. The compound of claim 8 , wherein Ring Z is

10. The compound of claim 1 , wherein Ring Y is

11. The compound of claim 1 , of formula I-b,

or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1 , of formula I-c,

or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1 , selected from:

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

15. A method for treating a disorder is selected from Rheumatoid Arthritis, Systemic Lupus Erythematosus, Lupus nephritis, Multiple Sclerosis, Alzheimer's disease, Parkinson's disease, and Cancer, in a patient in need thereof, comprising the step of administering to said patient a compound of claim 1 .

16. A method for treating cancer in a subject, comprising the step of administering to said subject a compound of claim 1 or a physiologically acceptable salt thereof.

17. A process for manufacturing a compound of formula I according to claim 1 , comprising the steps of:

reacting a compound of formula (A):

with

wherein X, Y, A, R, R a , R b , R 2 and R 3 are as defined in claim 1 ;

to provide a compound of formula (B):

and reacting the compound of formula (B) with

wherein Z and R 1 are as defined in claim 1 ;

to provide a compound of formula I of claim 1 .