Pyrimidinyl tyrosine kinase inhibitors
The present invention provides compounds and compositions thereof which are useful as inhibitors of Bruton's tyrosine kinase and which exhibit desirable characteristics for the same.
1. A method for treating a disorder associated with dysregulation of BCR signaling in a subject, the method comprising:
administering to the subject an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or
administering to the subject an effective amount of a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients;
wherein the disorder is responsive to B-cell depletion;
wherein the compound is of Formula I:
wherein:
each R 1 is independently hydrogen, an optionally substituted C 1-6 aliphatic group, an optionally substituted 3-7 membered monocyclic heterocyclic group, or an optionally substituted heterocyclylalkyl group having 3-7 carbon atoms and 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
or two R 1 groups are taken together with their intervening atoms to form an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
wherein optionally substituted groups may be substituted with halogen, —NO 2 , —CN, —OR, —SR, —N(R) 2 , —C(O)R, —CO 2 R, —N(R)C(O)OR, —C(O)N(R) 2 , —OC(O)R, —N(R)C(O)R, —S(O)R, —S(O) 2 R, or —S(O) 2 N(R) 2 ;
each R is independently hydrogen or C 1-6 aliphatic;
or two R groups attached to the same nitrogen are taken together with their intervening atoms to form an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms, in which any second heteroatom is independently selected from nitrogen, oxygen, and sulfur;
Ring A is
R 2 is —Cl or —F; and
R 3 is —CF 3 , —OCF 3 , or —F.
2. The method of claim 1 , wherein the compound is of Formula II-a:
or a pharmaceutically acceptable salt thereof.
3. The method of claim 1 , wherein the compound is of Formula II-b:
or a pharmaceutically acceptable salt thereof.
4. The method of claim 1 , wherein the compound is of Formula III:
or a pharmaceutically acceptable salt thereof.
5. The method of claim 1 , wherein the compound is Formula IV:
or a pharmaceutically acceptable salt thereof.
6. The method of claim 1 , wherein one R 1 is hydrogen and the other R 1 is an optionally substituted C 1-6 aliphatic.
7. The method of claim 1 , wherein both R 1 are optionally substituted C 1-6 aliphatic groups.
8. The method of claim 1 , wherein both R 1 are hydrogen.
9. The method of claim 1 , wherein R 2 is —Cl.
10. The method of claim 1 , wherein R 2 is —F.
11. The method of claim 1 , wherein R 3 is —CF 3 .
12. The method of claim 1 , wherein R 3 is —OCF 3 .
13. The method of claim 1 , wherein R 3 is —F.
14. The method of claim 1 , wherein the compound administered is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
15. The method of claim 1 , wherein the disorder is selected from the group consisting of autoimmune disorders, inflammatory disorders, and cancers.
16. A pharmaceutical composition comprising a compound of Formula I, or pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable excipients;
wherein the compound is of Formula I:
wherein:
each R 1 is independently hydrogen, an optionally substituted C 1-6 aliphatic group, an optionally substituted 3-7 membered monocyclic heterocyclic group, or an optionally substituted heterocyclylalkyl group having 3-7 carbon atoms and 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
or two R 1 groups are taken together with their intervening atoms to form an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
wherein optionally substituted groups may be substituted with halogen, —NO 2 , —CN, —OR, —SR, —N(R) 2 , —C(O)R, —CO 2 R, —N(R)C(O)OR, —C(O)N(R) 2 , —OC(O)R, —N(R)C(O)R, —S(O)R, —S(O) 2 R, or —S(O) 2 N(R) 2 ;
each R is independently hydrogen or C 1-6 aliphatic;
or two R groups attached to the same nitrogen are taken together with their intervening atoms to form an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms, in which any second heteroatom is independently selected from nitrogen, oxygen, and sulfur;
Ring A is
R 2 is —Cl or —F; and
R 3 is —CF 3 , —OCF 3 , or —F.
17. A pharmaceutical composition comprising a compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof; and
one or more pharmaceutically acceptable excipients.