Heteroaryl Btk inhibitors
View Patent ↗The present invention provides compounds useful as inhibitors of Btk, compositions thereof, and methods of using the same.
1. A compound having the formula:
wherein:
X 1 is —CR 6 R 7 —;
X 2 is ═N—;
p is 0 or 1;
y is 0 or 1;
z is 2;
each R 1 is independently an optionally substituted group selected from C 1-12 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur,
R 2 is R;
R 4 is R, —C(O)R, —CO 2 R, —C(O)C(O)R, —C(O)CH 2 C(O)R, —C(O)N(R) 2 , —S(O)R, —S(O) 2 R, or —S(O) 2 N(R) 2 ;
R 3 is R, halogen, —CN, —C(O)R, —CO 2 R, —C(O)C(O)R, —C(O)CH 2 C(O)R, —S(O)R, —S(O) 2 R, —C(O)N(R) 2 , or —SO 2 N(R) 2 ; or:
R 3 and R 4 are optionally taken together with their intervening atoms to form an optionally substituted ring selected from pyrrole, pyrazole, or 5-6 membered partially unsaturated monocyclic heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R 5 is hydrogen or —NH 2 ;
each of R 6 and R 7 is independently R;
R x is hydrogen, or:
R x and R 2 are taken together to form an optionally substituted spirocyclic heterocyclic ring selected from a 5-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Ring A 1 is an optionally substituted ring selected from phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
L is —C(O)C(R) 2 NR—; and
each R is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic or 3-7 membered saturated carbocyclic, wherein a substituent on R is selected from —CF 3 or —OH.
2. The compound of claim 1 , wherein the compound is of formula IV-a:
3. The compound of claim 1 , wherein L is:
4. The compound of claim 1 , wherein p is 0.
5. The compound of claim 1 , wherein R 2 is hydrogen or optionally substituted C 1-6 aliphatic.
6. The compound of claim 1 , wherein R x is hydrogen.
7. The compound of claim 1 , wherein R 5 is hydrogen.
8. The compound of claim 1 , wherein R 3 and R 4 are taken together with their intervening atoms to form an optionally substituted ring selected from pyrrole or pyrazole.
9. The compound of claim 8 , wherein the compound is of formula VII-a, or VIII-a:
10. The compound of claim 1 , wherein R 4 is hydrogen, —C(O)R, or optionally substituted C 1-6 aliphatic.
11. The compound of claim 1 , wherein R 3 is halogen, —CN, or substituted or unsubstituted C 1-6 alkyl.
12. The compound of claim 1 , wherein Ring A 1 is an optionally substituted ring selected from phenyl, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
13. The compound of claim 12 , wherein Ring A 1 is bicyclic.
14. The compound of claim 12 , wherein Ring A 1 is substituted phenyl.
15. The compound of claim 14 , wherein substituents on Ring A 1 are selected from halogen, —CN, —CF 3 , —OH, —NH 2 , —N(R) 2 , —COOH, —SR, —S(O)R, —S(O) 2 R, —S(O)N(R) 2 , —S(O) 2 N(R) 2 , or C 1-6 aliphatic.
16. A compound as shown in Table 1.
17. A pharmaceutical formulation comprising a compound of claim 1 and a pharmaceutically acceptable excipient.
18. A method of reducing the enzymatic activity of Bruton's tyrosine kinase comprising contacting Bruton's tyrosine kinase with an effective amount of a compound of claim 1 or a composition thereof.