2-oxo-imidazopyridines as reversible BTK inhibitors and uses thereof

1. A compound of formula I,

or a tautomer, or a pharmaceutically acceptable salt thereof, wherein:

Z is NR;

Ring A is a 5-6 membered aryl, 5-6 membered heteroaryl, 9-12 membered bicyclic ring;

R 1 is optionally substituted alkyl, optionally substituted 3-8 membered saturated or partially unsaturated carbocyclic ring, or halo; or R 1 is absent when Ring A is 9-12 membered bicyclic ring;

R 2 is (C(R 5 )(R 5 )) m OR 4 , (C(R 5 )(R 5 )) m N(R 4 )COR, (C(R 5 )(R 5 )) m N(R 4 )C(O)NR 2 , or (C(R 5 )(R 5 )) m N(R 4 )(R 4 ); or R 2 is a mono-, bi-, or tri-cyclic fused heterocyclic ring;

each R 3 is independently —R, halogen, —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 5-10 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 5-10 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; a 10-15 membered fused aryl ring; a 6-15 membered saturated or partially unsaturated fused carbocyclic ring; a 10-15 membered fused heteroaryl ring; or a 6-15 membered saturated or partially unsaturated fused heterocyclic ring; each of which is optionally substituted;

each m is independently 1, 2, or 3; and

n is 0, 1, or 2.

2. The compound of claim 1 , wherein Z is NH.

3. The compound of claim 1 , wherein Ring A is phenyl, pyridine, pyrazine, pyrimidine, pyridazine, or triazine.

4. The compound of claim 3 , wherein Ring A is

5. The compound of claim 4 , wherein Ring A is

6. The compound of claim 1 , wherein R 1 is methyl, ethyl, propyl, i-propyl, straight chain or branched butyl, straight chain or branched pentyl, straight chain or branched hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; each of which is optionally substituted; or R 1 is F, Cl, Br, or I.

7. The compound of claim 6 , wherein R 1 is methyl, cyclopropyl, CH 2 OH, CF 3 or F.

8. The compound of claim 1 , wherein R 2 is (C(R 5 )(R 5 )) m N(R 4 )COR, (C(R 5 )(R 5 )) m N(R 4 )C(O)NR 2 , or R 2 is a mono-, bi-, or tri-cyclic fused heterocyclic ring.

9. The compound of claim 8 , wherein R 2 is

10. The compound of claim 1 , wherein each R 3 is independently —H, -Me, or —CH 2 OH.

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

or a tautomer, or a pharmaceutically acceptable salt thereof.

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

or a tautomer, or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1 , of formula III-a,

or a tautomer, or a pharmaceutically acceptable salt thereof.

14. The compound of claim 1 , selected from Table 1:

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

16. A method for inhibiting BTK, or a mutant thereof, activity in a patient or in a biological sample, comprising the step of administering to said patient or contacting said biological sample with a compound of claim 1 , or a physiologically acceptable salt thereof.

17. A method for treating a BTK-mediated disorder, wherein the disorder is selected from multiple sclerosis, systemic lupus erythematosus (SLE), and rheumatoid arthritis, in a patient in need thereof, comprising the step of administering to said patient a compound of claim 1 .

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