Substituted 2,4-diaminopyrimidines as kinase inhibitors

1. A method for inhibiting Bruton's tyrosine kinase activity, TEC kinase activity, or Janus kinase 3 activity in a patient, comprising a step of administering to the patient in need thereof a compound of formula I-b:

or a pharmaceutically acceptable salt thereof, wherein:

Ring A is phenyl;

Ring B is phenyl;

R 1 is a warhead group -L-Y, wherein R 1 is in a meta- or para-position of the phenyl ring relative to the rest of the molecule;

-L-Y is selected from

L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and one or two methylene units of L are optionally and independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, —C(O)O—, cyclopropylene, —O—, —N(R)—, or —C(O)—; and Y is C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein said ring is substituted with 1-4 R e groups; or

L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and one methylene unit of L is replaced by —C(O)—, —NRC(O)—, —C(O)NR—, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—; or

L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and one methylene unit of L is replaced by —C(O)—, and one additional methylene unit of L is optionally replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—; or

L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one alkylidenyl double bond and at least one methylene unit of L is replaced by —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—, and one or two additional methylene units of L are optionally and independently replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—; or

L is —NRC(O)CH═CHCH 2 N(CH 3 )—, —NRC(O)CH═CHCH 2 O— or —NRSO 2 CH═CHCH 2 —; and

Y is hydrogen, C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein said ring is substituted with 1-4 R e groups; or

L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein one methylene unit of L is replaced by cyclopropylene and one or two additional methylene units of L are independently replaced by —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—; and Y is C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN; or

L is a covalent bond and Y is selected from:

(ii) C 2-6 alkenyl substituted with oxo, halogen, NO 2 , or CN; or

(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 R e groups; or

(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatoms selected from oxygen or nitrogen wherein said ring is substituted with 1-4 R e groups; or

(vi)

 or

(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e groups; or

(viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e groups; or

(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e groups; or

(x)

 or

(xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e groups; or

(xii)

 or

(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 R e groups; or

(xiv)

(xvi)

(xvii) an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e groups; or

L is —C(O)— and Y is selected from:

(i) C 1-6 alkyl substituted with oxo, halogen, NO 2 , or CN; or

(ii) C 2-6 alkenyl optionally substituted with oxo, halogen, NO 2 , or CN; or

(iii) C 2-6 alkynyl optionally substituted with oxo, halogen, NO 2 , or CN; or

(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 R e groups; or

(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatoms selected from oxygen or nitrogen wherein said ring is substituted with 1-4 R e groups; or

(vi)

 or

(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e groups; or

(viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e groups; or

(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e groups; or

(x)

 or

(xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e groups; or

(xii)

 or

(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 R e groups; or

(xiv)

 or

(xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 R e groups; or

(xvi)

 or

(xvii) an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e groups; or

L is —N(R)C(O)— and Y is selected from:

(i) C 1-6 alkyl substituted with oxo, halogen, NO 2 , or CN; or

(ii) C 2-6 alkenyl optionally substituted with oxo, halogen, NO 2 , or CN; or

(iii) C 2-6 alkynyl optionally substituted with oxo, halogen, NO 2 , or CN; or

(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 R e groups; or

(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatoms selected from oxygen or nitrogen wherein said ring is substituted with 1-4 R e groups; or

(vi)

 or

(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e groups; or

(viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e groups; or

(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e groups; or

(x)

 or

(xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e groups; or

(xii)

 or

(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 R e groups; or

(xiv)

 or

(xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 R e groups; or

(xvi)

 or

(xvii) an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e groups; or

L is a bivalent C 1-8 saturated or unsaturated, straight or branched, hydrocarbon chain; and Y is selected from:

(ii) C 2-6 alkenyl optionally substituted with oxo, halogen, NO 2 , or CN; or

(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 R e groups; or

(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatoms selected from oxygen or nitrogen wherein said ring is substituted with 1-4 R e groups; or

(vi)

 or

(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e groups; or

(viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e groups; or

(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e groups; or

(x)

 or

(xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e groups; or

(xii)

 or

(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 R e groups; or

(xiv)

(xvi)

 or

(xvii) an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e groups; or

L is —CH 2 —, —NH—, —C(O)—, —CH 2 NH—, —NHCH 2 —, —NHC(O)—, —NHC(O)CH 2 OC(O)—, —CH 2 NHC(O)—, —NHSO 2 —, —NHSO 2 CH 2 —, or —SO 2 NH—; and Y is selected from:

(ii) C 2-6 alkenyl substituted with oxo, halogen, NO 2 , or CN; or

(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 R e groups; or

(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatoms selected from oxygen or nitrogen wherein said ring is substituted with 1-4 R e groups; or

(vi)

 or

(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e groups; or

(viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e groups; or

(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e groups; or

(x)

 or

(xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e groups; or

(xii)

 or

(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 R e groups; or

(xiv)

(xvi)

 or

(xvii) an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e groups;

each R e is independently selected from -Q-Z, oxo, NO 2 , halogen, CN, C 1-6 saturated aliphatic substituted with halogen, NO 2 , or CN, C 2 -6 unsaturated aliphatic optionally substituted with oxo, halogen, NO 2 , or CN, or a suitable leaving group selected from alkoxy, sulfonyloxy, optionally substituted alkylsulfonyloxy, optionally substituted alkenylsulfonyloxy, optionally substituted arylsulfonyloxy, or diazonium, wherein:

Q is a bivalent C 2 -6 unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of Q are optionally and independently replaced by —N(R)—, —S—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —SO—, or —SO 2 —, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO 2 —, or —SO 2 N(R)—; and

each Z is hydrogen or C 1-6 aliphatic substituted with oxo, halogen, NO 2 , or CN;

R y is halogen, —CN, —CF 3 , C 1-4 aliphatic, C 1-4 haloaliphatic, —OR, or —C(O)R;

each R group is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 membered heterocyclic ring having 1-2 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;

W 1 is —NR 2 —;

W 2 is —NR 2 —;

R 2 is hydrogen, optionally substituted C 1-6 aliphatic, or —C(O)R;

m is 0, 1, 2, 3 or 4;

p is 0, 1, 2, 3 or 4;

each instance of R X is independently selected from —R, —OR, —O(CH 2 ) q OR, or halogen, wherein q is 1, 2, 3 or 4; and

each instance of R V is independently selected from —R, halogen, —OR, —O(CH 2 ) q OR, —CN, —NO 2 , —SO 2 R, —SO 2 N(R) 2 , —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 , wherein q is 1, 2, 3 or 4.

2. The method according to claim 1 , wherein the patient has a Bruton's tyrosine kinase-mediated disorder selected from the group consisting of an autoimmune disease, a heteroimmune disease, an inflammatory disease, a cancer, a disease of the bone and joints, and a thromboembolic disorder.

3. The method according to claim 2 , wherein the patient has a Bruton's tyrosine kinase-mediated disorder selected from the group consisting of rheumatoid arthritis, multiple sclerosis, B-cell chronic lymphocytic leukemia, acute lymphocytic leukemia, hairy cell leukemia, non-Hodgkin's lymphoma, Hodgkin's lymphoma, multiple myeloma, bone cancer, bone metastasis, osteoporosis, irritable bowel syndrome, Crohn's disease, lupus, and disorders associated with renal transplant.

4. The method according to claim 1 , wherein the patient has a TEC-kinase-mediated disorder selected from the group consisting of an autoimmune disorder, an inflammatory disorder, a proliferative disorder, a hyperproliferative disease, an immunological-mediated diseases, a disease of the respiratory tract, a disease of the bone and joints, a skin disorder, a gastrointestinal disorder, a systemic disease, and allograft rejection.

5. The method according to claim 1 , wherein the patient has a Janus kinase 3-mediated disorder selected from the group consisting of an immune response, asthma, an autoimmune disorder, an inflammatory disorder, a neurodegenerative disorder, and a solid or hematologic malignancy.

6. The method according to claim 5 , wherein the Janus kinase 3-mediated disorder is selected from the group consisting of allergic or type I hypersensitivity reactions, transplant rejections, graft versus host disease, rheumatoid arthritis, amyotrophic lateral sclerosis, multiple sclerosis, familial amyotrophic lateral sclerosis (FALS), leukemias and lymphomas.

7. The method according to claim 1 , wherein:

L is —C(O)—, —N(R)C(O)—, —NH—, —CH 2 NH—, —NHCH 2 —, —NHC(O)CH 2 OC(O)—, —CH 2 NHC(O)—, —NHSO 2 —, —NHSO 2 CH 2 —, or —SO 2 NH—, or a bivalent C 1-8 saturated or unsaturated, straight or branched, hydrocarbon chain; and

Y is selected from the following (ii), (iv), (v), (vi), (vii), (viii), (ix), (x), (xi), (xii), (xiii), (xiv), (xvi), or (xvii):

(ii) C 2-6 alkenyl substituted with oxo, halogen, NO 2 , or CN; or

(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 R e groups; or

(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatoms selected from oxygen or nitrogen wherein said ring is substituted with 1-4 R e groups; or

(vi)

 or

(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e groups; or

(viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e groups; or

(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e groups; or

(x)

 or

(xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e groups; or

(xii)

 or

(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 R e groups; or

(xiv)

 or

(xvi)

(xvii) an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e groups.

8. The method according to claim 7 , wherein L is —CH 2 —, —NH—C(O)—, —CH 2 NH—, —NHCH 2 —, —NHC(O)—, —NHC(O)CH 2 OC(O)—, —CH 2 NHC(O)—, —NHSO 2 —NHSO 2 CH 2 —, or —SO 2 NH—.

9. The method according to claim 1 , wherein -L-Y is —NHC(O)CH═CH 2 .

10. The method according to claim 9 , wherein each R 2 is hydrogen.

11. The method according to claim 10 , wherein at least one R x is selected from —C 1-6 alkyl, —OC 1-6 alkyl, —O(CH 2 ) q OC 1-6 alkyl, and halogen.

12. The method according to claim 11 , wherein at least one R x is selected from methyl, methoxy, methoxyethoxy and fluoro.

13. The method according to claim 1 , wherein L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and one methylene unit of L is replaced by —C(O)—, —NRC(O)—, —C(O)NR—, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—.

14. The method according to claim 13 , wherein L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and one methylene unit of L is replaced by —OC(O)—.

15. The method according to claim 1 , wherein L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and one methylene unit of L is replaced by —C(O)—, and one additional methylene unit of L is optionally replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—.

16. The method according to claim 1 , wherein L is —NRC(O)CH═CH—, —NRC(O)CH═CHCH 2 N(CH 3 )—, —NRC(O)CH═CHCH 2 O—, —CH 2 NRC(O)CH═CH—, —NRSO 2 CH═CHCH 2 —, or —NRC(O)C(═CH 2 )CH 2 —; wherein the R group of L is H or optionally substituted C 1-6 aliphatic; and Y is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN.

17. The method according to claim 16 , wherein L is —NHC(O)CH═CH—, —NHC(O)CH═CHCH 2 N(CH 3 )—, —NHC(O)CH═CHCH 2 O—, —CH 2 NHC(O)CH═CH—, —NHSO 2 CH═CHCH 2 —, or —NHC(O)C(═CH 2 )CH 2 —.

18. The method according to claim 1 , wherein L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one alkylidenyl double bond and at least one methylene unit of L is replaced by —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—, and one or two additional methylene units of L are optionally and independently replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—.

19. The method according to claim 1 , wherein L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein one methylene unit of L is replaced by cyclopropylene and one or two additional methylene units of L are independently replaced by —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—.

20. The method according to claim 1 , wherein Y is selected from

21. The method according to claim 1 , wherein R 1 is selected from:

wherein each R e is independently a suitable leaving group, NO 2 , CN, or oxo.

22. The method according to claim 1 , wherein R is independently selected from hydrogen, C 1-6 aliphatic, phenyl, a 4-7 membered heterocyclic ring having 1-2 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.

23. The method according to claim 1 , wherein Ring A is selected from:

24. The method according to claim 1 , wherein Ring A is selected from:

25. The method according to claim 1 , wherein Ring B is selected from:

26. The method according to claim 25 , wherein Ring B is selected from:

27. The method according to claim 1 wherein the compound of formula I-b is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.