Pyrimidine TBK/IKKe inhibitor compounds and uses thereof

1. A compound of formula I,

or a pharmaceutically acceptable salt thereof; wherein

R 1 is hydrogen, optionally substituted C 1-6 aliphatic, —OR, or halogen;

Ring Z is phenyl or a 5-6-membered heteroaryl having 1, 2, or 3 nitrogens;

each R 2 is independently

each R 3 is independently —R, halogen, —OR, —SR, —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 A is phenyl or a 5-6-membered heteroaryl having 1, 2, or 3 nitrogens;

R 4 is —R, halogen, —OR, —SR, —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 5 is independently —R, halogen, —OR, —SR, —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, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or a 6-12 membered spiro, fused, or bridged bicyclic carbocyclic or heterocyclic 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;

n is 1 or 2;

p is 0, 1, or 2; and

q is 0, 1, or 2.

2. The compound of claim 1 , wherein R 1 is H.

3. The compound of claim 1 , wherein Ring Z is phenyl, pyridine, or pyrimidine.

4. The compound of claim 1 , wherein Ring Z is

5. The compound of claim 1 , wherein each R 2 is independently —R, halogen, —OR, or —N(R) 2 .

6. The compound of claim 1 , wherein each R 3 is independently —R, halogen, —OR, or —N(R) 2 .

7. The compound of claim 1 , wherein Ring A is phenyl or pyridyl.

8. The compound of claim 1 , wherein Ring A is

9. The compound of claim 1 , wherein R 4 is —R or —OR.

10. The compound of claim 1 , wherein each R 5 is independently —R, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, or —N(R) 2 .

11. The compound of claim 1 , wherein each R 5 is independently

12. The compound of claim 1 , of formula II,

or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1 , of formula VI,

or a pharmaceutically acceptable salt thereof.

14. The compound of claim 1 , selected from

or a pharmaceutically acceptable salt thereof.

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

16. A method for inhibiting TBK and IKKε activity in a patient, comprising a step of administering to said patient an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

17. A method for treating a TBK/IKKε related disorder in a patient in need thereof, comprising the step of administering to said patient an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

18. The method of claim 17 , wherein the disorder is selected from Rheumatoid Arthritis, Psoriatic arthritis, Osteoarthritis, Systemic Lupus Erythematosus, Lupus nephritis, Ankylosing Spondylitis, Osteoporosis, Systemic sclerosis, Multiple Sclerosis, Psoriasis, Type I diabetes, Type II diabetes, Inflammatory Bowel Disease, Crohn's Disease, Ulcerative Colitis, Hyperimmunoglobulinemia D and periodic fever syndrome, Cryopyrin-associated periodic syndromes, Schnitzler's syndrome, Systemic juvenile idiopathic arthritis, Adult's onset Still's disease, Gout, Pseudogout, SAPHO syndrome, Castleman's disease, Sepsis, Stroke, Atherosclerosis, Celiac disease, DIRA (Deficiency of IL-1 Receptor Antagonist), Alzheimer's disease, Parkinson's disease, and Cancer.

19. A method for treating Systemic Lupus Erythematosus in a subject, comprising a step of administering to said subject an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.