Fused cyclic systems useful as inhibitors of TEC family protein kinases

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof,

wherein R 1 is —QR X ; wherein Q is a bond or is a C 1 -C 6 alkylidene chain wherein up to two methylene units of Q are optionally and independently replaced by —CO—, —CS—, —COCO—, —CONR—, —CONRNR—, —CO 2 —, —OCO—, —NRCO 2 —, —O—, —NRCONR—, —OCONR—, —NRNR, —NRNRCO—, —NRCO—, —S—, —SO, —SO 2 —, —NR—, —SO 2 NR—, —NRSO 2 —, —NRSO 2 NR—, and R X is R′, halogen, NO 2 , or CN; with the requirement that R1 must be either bound via an R1 carbon atom or must be H;

each occurrence of R is independently selected from hydrogen or an optionally substituted C 1-8 aliphatic group wherein if said aliphatic group contains one or more units of unsaturation, said aliphatic group is a C 2 -C 8 aliphatic chain, and wherein if said aliphatic group is a cycloaliphatic group, said cycloaliphatic group is a C 3 -C 8 cycloaliphatic group; and

R′ is selected from hydrogen or an optionally substituted group selected from C 1-8 aliphatic, C 6 -C 10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 3-10 ring atoms, or wherein R and R′ taken together with the atom(s) to which they are bound, or two occurrences of R taken together with the atom(s) to which they are bound, form an optionally substituted group selected from a 3-10 membered cycloalkyl ring, a C 6 -C 10 aryl ring, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 3-10 ring atoms;

Cy 1 is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-8-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy 1 is optionally substituted with y occurrences of —YR Y , wherein y is 0-5, Y is a bond or is a C 1 -C 6 alkylidene chain wherein up to two methylene units of Y are optionally and independently replaced by —CO—, —CS—, —COCO—, —CONR—, —CONRNR—, —CO 2 —, —OCO—, —NRCO 2 —, —O—, —NRCONR—, —OCONR—, —NRNR, —NRNRCO—, —NRCO—, —S—, —SO, —SO 2 —, —NR—, —SO 2 NR—, —NRSO 2 —, —NRSO 2 NR—, and each occurrence of R Y is independently R′, halogen, NO 2 , or CN;

R 2 and R 3 , taken together, form an optionally substituted 5-, 6-, or 7-membered monocyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur or a 5-, 6-, or 7-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring formed by R 2 and R 3 taken together is optionally substituted at one or more carbon or nitrogen atoms with m independent occurrences of —WR W ,

R 4 and R 5 , taken together, form an optionally substituted 5-, 6-, or 7-membered monocyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur or a 5-, 6-, or 7-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring formed by R 4 and R 5 , taken together is optionally substituted at one or more carbon or nitrogen atoms with n independent occurrences of Z—R Z ; m and n are each independently 0-5;

W and Z are each independently a bond or is an optionally substituted C 1 -C 6 alkylidene chain wherein up to two methylene units of W or Z are optionally replaced by —CO—, —CS—, —COCO—, —CONR—, —CONRNR—, —CO 2 —, —OCO—, —NRCO 2 —, —O—, —NRCONR—, —OCONR—, —NRNR, —NRNRCO—, —NRCO—, —S—, —SO, —SO 2 —, —NR—, —SO 2 NR—, —NRSO 2 —, —NRSO 2 NR—, and each occurrence of R W and R Z is independently R′, halogen, NO 2 , or CN;

X is O, S, or [C(R 1 ) 2 ] q , where q is 1 or 2; and

G is N or CR 6 , wherein R 6 is halogen, CN, NO 2 , or QR X ,

wherein the heteroatoms of a heterocyclyl or heteroaryl ring are selected from oxygen, sulfur, or nitrogen;

optional substituents on the unsaturated carbon atom of an aryl or heteroaryl group are selected from halogen; —R o ; —OR o ; —SR o ; 1,2-methylenedioxy; 1,2-ethylenedioxy; phenyl (Ph) optionally substituted with R o ; —O(Ph) optionally substituted with R o ; —(CH 2 ) 1-2 (Ph), optionally substituted with R o ; —CH═CH(Ph), optionally substituted with R o ; —NO 2 ; —CN; —N(R o ) 2 ; —NR o C(O)R o ; —NR o C(S)R o ; —NR o C(O)N(R o ) 2 ; —NR o C(S)N(R o ) 2 ; —NR o CO 2 R o ; —NR o NR o C(O)R o ; —NR o NR o C(O)N(R o ) 2 ; —NR o NR o CO 2 R o ; —C(O)C(O)R o ; —C(O)CH 2 C(O)R o ; —CO 2 R o ; —C(O)R o ; —C(S)R o ; —C(O)N(R o ) 2 ; —C(S)N(R o ) 2 ; —OC(O)N(R o ) 2 ; —OC(O)R o ; —C(O)N(OR o )R o ; —C(NOR o )R o ; —S(O) 2 R o ; —S(O) 3 R o ; —SO 2 N(R o ) 2 ; —S(O)R o ; —NR o SO 2 N(R o ) 2 ; —NR o SO 2 R o ; —N(OR o )R o ; —C(═NH)—N(R o ) 2 ; or —(CH 2 ) 0-2 NHC(O)R o wherein each independent occurrence of R o is selected from hydrogen, optionally substituted C 1-6 aliphatic, an unsubstituted 5-6 membered heteroaryl or heterocyclic ring, phenyl, —O(Ph), or —CH 2 (Ph), or, notwithstanding the definition above, two independent occurrences of R o , on the same substituent or different substituents, taken together with the atom(s) to which each R o group is bound, form a 5-8-membered heterocyclyl, aryl, or heteroaryl ring or a 3-8-membered cycloalkyl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur Optional substituents on the aliphatic group of R o are selected from NH 2 , NH(C 1-4 aliphatic), N(C 1-4 aliphatic) 2 , halogen, C 1-4 aliphatic, OH, O(C 1-4 aliphatic), NO 2 , CN, CO 2 H, CO 2 (C 1-4 aliphatic), O(haloC 1-4 aliphatic), or haloC 1-4 aliphatic, wherein each of the foregoing C 1-4 aliphatic groups of R o is unsubstituted;

optional substituents on the saturated carbon of an aliphatic or heteroaliphatic group, or of a non-aromatic heterocyclic ring are selected from those listed above for the unsaturated carbon of an aryl or heteroaryl group and additionally include the following: ═O, ═S, ═NNHR*, ═NN(R*) 2 , ═NNHC(O)R*, ═NNHCO 2 (alkyl), ═NNHSO 2 (alkyl), or ═NR*, where each R* is independently selected from hydrogen or an optionally substituted C 1-6 aliphatic;

optional substituents on the aliphatic group of R* are selected from NH 2 , NH(C 1-4 aliphatic), N(C 1-4 aliphatic) 2 , halogen, C 1-4 aliphatic, OH, O(C 1-4 aliphatic), NO 2 , CN, CO 2 H, CO 2 (C 1-4 aliphatic), O(halo C 1-4 aliphatic), or halo(C 1-4 aliphatic), wherein each of the foregoing C 1-4 aliphatic groups of R* is unsubstituted; and

optional substituents on the nitrogen of a non-aromatic heterocyclic ring are selected from —R + , —N(R + ) 2 , —C(O)R + , —CO 2 R + , —C(O)C(O)R + , —C(O)CH 2 C(O)R + , —SO 2 R + , —SO 2 N(R + ) 2 , —C(═S)N(R + ) 2 , —C(═NH)—N(R + ) 2 , or —NR + SO 2 R + ; wherein R + is hydrogen, an optionally substituted C 1-6 aliphatic, optionally substituted phenyl, optionally substituted —O(Ph), optionally substituted —CH 2 (Ph), optionally substituted —(CH 2 ) 1-2 (Ph); optionally substituted —CH═CH(Ph); or an unsubstituted 5-6 membered heteroaryl or heterocyclic ring having one to four heteroatoms independently selected from oxygen, nitrogen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R + , on the same substituent or different substituents, taken together with the atom(s) to which each R + group is bound, form a 5-8-membered heterocyclyl, aryl, or heteroaryl ring or a 3-8-membered cycloalkyl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

optional substituents on the aliphatic group or the phenyl ring of R + are selected from NH 2 , NH(C 1-4 aliphatic), N(C 1-4 aliphatic) 2 , halogen, C 1-4 aliphatic, OH, O(C 1-4 aliphatic), NO 2 , CN, CO 2 H, CO 2 (C 1-4 aliphatic), O(halo C 1-4 aliphatic), or halo(C 1-4 aliphatic), wherein each of the foregoing C 1-4 aliphatic groups of R + is unsubstituted;

provided that:

when X is O; R 1 is hydrogen; R 2 and R 3 , taken together are unsubstituted phenyl; R 4 and R 5 , taken together are unsubstituted phenyl; and G is N; then Cy 1 is not unsubstituted phenyl.

2. The compound of claim 1 , wherein R 1 is hydrogen, —COR′, CONRR′, or is an optionally substituted C 1 -C 6 alkyl group.

3. The compound of claim 1 , wherein R 1 is hydrogen.

4. The compound of any one of claims 1 - 3 , wherein Cy 1 is a group selected from:

5. The compound of claim 3 , wherein Cy 1 is phenyl (i), pyridyl (iii), pyrimidinyl (iv), imidazolyl (vi), pyrazolyl (vii), triazolyl (x), thiazolyl (xiv), or indazolyl (xix) or (xxi).

6. The compound of claim 5 , wherein Cy 1 is pyrazolyl (vii).

7. The compound of claim 6 , wherein each occurrence of —YR Y , when present, is independently halogen, R′, CN, NO 2 , —N(R′) 2 , —CH 2 N(R′) 2 , —(CH 2 ) 2 N(R′) 2 , —(CH 2 ) 3 N(R′) 2 , —OR′, —CH 2 OR′, —(CH 2 ) 2 OR′, —(CH 2 ) 3 OR′, —SR′, —CH 2 SR′, —(CH 2 ) 2 SR′, —(CH 2 ) 3 SR′, —COOR′, —NRCOR′, NRCOOR′, —CON(R′) 2 , or —S(O) 2 N(R′) 2 .

8. The compound of claim 6 , wherein —YR Y groups are each independently F, Cl, Br, I, —CN, —COOMe, —COOH, —OH, NH 2 , SH, —SO 2 NH 2 , —CON(CH 3 ) 2 , —O(C 1 -C 6 alkyl), —CH 2 O(C 1 -C 6 alkyl), —(CH 2 ) 2 O(C 1 -C 6 alkyl), − (CH 2 ) 3 O(C 1 -C 6 alkyl), —S(C 1 -C 6 alkyl), —CH 2 S(C 1 -C 6 alkyl), —(CH 2 ) 2 S(C 1 -C 6 alkyl), —(CH 2 ) 3 S(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —CH 2 N(C 1 -C 6 alkyl) 2 , —(CH 2 ) 2 N(C 1 -C 6 alkyl) 2 , —(CH 2 ) 3 N(C 1 -C 6 alkyl) 2 , wherein each C 1 -C 6 alkyl group is optionally substituted with R′, —OR′, —N(R′) 2 , —SR′, —SO 2 N(R′) 2 , —NRSO 2 R′, —CON(R′) 2 , or —NRCOR′, or —YR Y groups are each independently an optionally substituted group selected from C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, phenyl, phenyloxy, benzyl, benzyloxy, pyridyl, pyrimidinyl, thienyl, N-morpholinyl, N-piperidinyl, N-piperazinyl, or furanyl.

9. The compound of claim 4 , wherein R 2 and R 3 , taken together with the atoms to which they are bound, form an unsubstituted 5-, 6-, or 7-membered monocyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur or a 5-, 6-, or 7-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

10. The compound of claim 4 , wherein R 2 and R 3 , taken together with the carbon atoms to which they are bound form an optionally substituted ring selected from one of the following groups:

11. The compound of claim 4 , wherein R 2 and R 3 , taken together with the carbon atoms to which they are bound form an optionally substituted 5- or 6-membered ring selected from phenyl (a), pyridyl (b, c, d, or e), cyclohexyl (nn), or cyclopentyl (oo).

12. The compound of claim 11 , wherein —WR W , when present, is independently halogen, R′, CN, NO 2 , —N(R′) 2 , —CH 2 N(R′) 2 , —(CH 2 ) 2 N(R′) 2 , —(CH 2 ) 3 N(R′) 2 , —OR′, —CH 2 OR′, —(CH 2 ) 2 OR′, —(CH 2 ) 3 OR′, —SR′, —CH 2 SR′, —(CH 2 ) 2 SR′, —(CH 2 ) 3 SR′, —COOR′, —NRCOR′, NRCOOR′, —CON(R′) 2 , or —S(O) 2 N(R′) 2 .

13. The compound of claim 11 , wherein —WR W groups are each independently F, Cl, Br, I, —CN, —COOMe, —COOH, —OH, NH 2 , SH, —SO 2 NH 2 , —CON(CH 3 ) 2 , —O(C 1 -C 6 alkyl), —CH 2 O(C 1 -C 6 alkyl), —(CH 2 ) 2 O(C 1 -C 6 alkyl), —(CH 2 ) 3 O(C 1 -C 6 alkyl), —S(C 1 -C 6 alkyl), —CH 2 S(C 1 -C 6 alkyl), —(CH 2 ) 2 S(C 1 -C 6 alkyl), —(CH 2 ) 3 S(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —CH 2 N(C 1 -C 6 alkyl) 2 , —(CH 2 ) 2 N(C 1 -C 6 alkyl) 2 , —(CH 2 ) 3 N(C 1 -C 6 alkyl) 2 , wherein each C 1 -C 6 alkyl group is optionally substituted with R′, —OR′, —N(R′) 2 , —SR′, —SO 2 N(R′) 2 , —NRSO 2 R′, —CON(R′) 2 , or —NRCOR′, or —WR W groups are each independently an optionally substituted group selected from C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, phenyl, phenyloxy, benzyl, benzyloxy, pyridyl, pyrimidinyl, thienyl, N-morpholinyl, N-piperidinyl, N-piperazinyl, or furanyl.

14. The compound of claim 4 , wherein G is CH or C(C 1 -C 6 alkyl).

15. The compound of claim 4 , wherein G is N and compounds have the general formula II:

or a pharmaceutically acceptable salt thereof.

16. The compound of claim 4 , wherein X is O and compounds have the general formula III:

or a pharmaceutically acceptable salt thereof.

17. The compound of claim 4 , wherein X is O and G is N and compounds have the general formula IV:

or a pharmaceutically acceptable salt thereof.

18. The compound of claim 4 , wherein R 4 and R 5 , taken together with the atoms to which they are bound, form an unsubstituted 5-, 6-, or 7-membered monocyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur or a 5-, 6-, or 7-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

19. The compound of claim 4 , wherein R 4 and R 5 , taken together with the carbon atoms to which they are bound form an optionally substituted ring selected from one of the following groups:

20. The compound of claim 19 , wherein R 4 and R 5 , taken together with the carbon atoms to which they are bound form an optionally substituted 5- or 6-membered ring selected from phenyl (a-i), pyridyl (b-i, c-i, d-i, or e-i), cyclohexyl (nn-i), or cyclopentyl (oo-i).

21. The compound of claim 20 , wherein each occurrence of —ZR Z , when present, is independently halogen, R′, CN, NO 2 , —N(R′) 2 , —CH 2 N(R′) 2 , —(CH 2 ) 2 N(R′) 2 , —(CH 2 ) 3 N(R′) 2 , —OR′, —CH 2 OR′, —(CH 2 ) 2 OR′, —(CH 2 ) 3 OR′, —SR', —CH 2 SR′, —(CH 2 ) 2 SR′, —(CH 2 ) 3 SR′, —COOR′, —NRCOR′, NRCOOR′, —CON(R′) 2 , or —S(O) 2 N(R′) 2 .

22. The compound of claim 20 , wherein —ZR Z groups are each independently F, Cl, Br, I, —CN, —COOMe, —COOH, —OH, NH 2 , SH, —SO 2 NH 2 , —CON(CH 3 ) 2 , —O(C 1 -C 6 alkyl), —CH 2 O(C 1 -C 6 alkyl), —(CH 2 ) 2 O(C 1 -C 6 alkyl), —(CH 2 ) 3 O(C 1 -C 6 alkyl), —S(C 1 -C 6 alkyl), —CH 2 S(C 1 -C 6 alkyl), —(CH 2 ) 2 S(C 1 -C 6 alkyl), —(CH 2 ) 3 S(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —CH 2 N(C 1 -C 6 alkyl) 2 , —(CH 2 ) 2 N(C 1 -C 6 alkyl) 2 , —(CH 2 ) 3 N(C 1 -C 6 alkyl) 2 , wherein each C 1 -C 6 alkyl group is optionally substituted with R′, —OR′, —N(R′) 2 , —SR', —SO 2 N(R) 2 , —NRSO 2 R′, —CON(R′) 2 , or —NRCOR′, or —ZR Z groups are each independently an optionally substituted group selected from C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, phenyl, phenyloxy, benzyl, benzyloxy, pyridyl, pyrimidinyl, thienyl, N-morpholinyl, N-piperidinyl, N-piperazinyl, or furanyl.

23. The compound of any one of claim 5 - 8 , 9 - 13 , or 21 - 22 , wherein G is N, X is O and R 4 and R 5 , taken together form an optionally substituted phenyl group and compounds have formula V:

or a pharmaceutically acceptable salt thereof.

24. The compound of claim 1 , wherein G is N, X is O, and R 4 and R 5 , taken together form an optionally substituted phenyl group and compounds have formula V:

or a pharmaceutically acceptable salt thereof.

25. The compound of claim 24 , wherein R 2 and R 3 , taken together with the carbon atoms to which they are bound form an optionally substituted phenyl, cyclopentyl, cyclohexyl, piperidinyl, pyrazolyl, or pyridyl group and compounds have formula V-A, V-B, V-C, V-D, V-E, or V-F:

26. The compound claim 24 or claim 25 , wherein

a) R 1 is hydrogen, —COR′, CONRR′, or is an optionally substituted C 1 -C 6 alkyl group;

b) Cy 1 phenyl (i), pyridyl (iii), pyrimidinyl (iv), imidazolyl (vi), pyrazolyl (vii), triazolyl (x), thiazolyl (xiv), or indazolyl (xix) or (xxi);

c) each occurrence of —YR Y , when present, is independently halogen, R′, CN, NO 2 , —N(R′) 2 , —CH 2 N(R′) 2 , —(CH 2 ) 2 N(R′) 2 , —(CH 2 ) 3 N(R′) 2 , —OR′, —CH 2 OR′, —(CH 2 ) 2 OR′, —(CH 2 ) 3 OR′, —SR', —CH 2 SR′, —(CH 2 ) 2 SR′, —(CH 2 ) 3 SR′, —COOR′, —NRCOR′, NRCOOR′, —CON(R′) 2 , or —S(O) 2 N(R′) 2 ; and/or

d) m and n are each independently 0 or 1 and —WR W and —ZR Z groups, when present, are each independently F, Cl, Br, I, —CN, —COOMe, —COOH, —OH, NH 2 , SH, —SO 2 NH 2 , —CON(CH 3 ) 2 , —O(C 1 -C 6 alkyl), —CH 2 O(C 1 -C 6 alkyl), —(CH 2 ) 2 O(C 1 -C 6 alkyl), —(CH 2 ) 3 O(C 1 -C 6 alkyl), —S(C 1 -C 6 alkyl), —CH 2 S(C 1 -C 6 alkyl), —(CH 2 ) 2 S(C 1 -C 6 alkyl), —(CH 2 ) 3 S(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —CH 2 N(C 1 -C 6 alkyl) 2 , —(CH 2 ) 2 N(C 1 -C 6 alkyl) 2 , —(CH 2 ) 3 N(C 1 -C 6 alkyl) 2 , wherein each C 1 -C 6 alkyl group is optionally substituted with R′, —OR′, —N(R′) 2 , —SR', —SO 2 N(R′) 2 , —NRSO 2 R′, —CON(R′) 2 , or —NRCOR′, or —WR W and —ZR Z groups are each independently an optionally substituted group selected from C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, phenyl, phenyloxy, benzyl, benzyloxy, pyridyl, pyrimidinyl, thienyl, N-morpholinyl, N-piperidinyl, N-piperazinyl, or furanyl.

27. The compound of claim 26 , wherein R 1 is hydrogen.

28. The compound of claim 26 , wherein Cy 1 is phenyl (i) or pyrazolyl (vii).

29. The compound of claim 28 , wherein Cy 1 is pyrazolyl (vii).

30. The compound claim 29 , wherein —YR Y groups are each independently F, Cl, Br, I, —CN, —COOMe, —COOH, —OH, NH 2 , SH, —SO 2 NH 2 , —CON(CH 3 ) 2 , —O(C 1 -C 6 alkyl), —CH 2 O(C 1 -C 6 alkyl), —(CH 2 ) 2 O(C 1 -C 6 alkyl), —(CH 2 ) 3 O(C 1 -C 6 alkyl), —S(C 1 -C 6 alkyl), —CH 2 S(C 1 -C 6 alkyl), —(CH 2 ) 2 S(C 1 -C 6 alkyl), —(CH 2 ) 3 S(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —CH 2 N(C 1 -C 6 alkyl) 2 , —(CH 2 ) 2 N(C 1 -C 6 alkyl) 2 , —(CH 2 ) 3 N(C 1 -C 6 alkyl) 2 , wherein each C 1 -C 6 alkyl group is optionally substituted with R′, —OR′, —N(R′) 2 , —SR', —SO 2 N(R′) 2 , —NRSO 2 R′, —CON(R′) 2 , or —NRCOR′, or —YR Y groups are each independently an optionally substituted group selected from C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, phenyl, phenyloxy, benzyl, benzyloxy, pyridyl, pyrimidinyl, thienyl, N-morpholinyl, N-piperidinyl, N-piperazinyl, or furanyl.

31. The compound of claim 30 , wherein y is 0 or 1.

32. The compound of claim 1 , selected from:

33. A composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

34. The composition of claim 33 , further comprising an additional therapeutic agent selected from an agent for the treatment of an autoimmune, inflammatory, proliferative, hyperproliferative disease, or an immunologically-mediated disease including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS).

35. A method of inhibiting Tec family kinase activity in a biological sample, which method comprises contacting said biological sample with the compound of claim 1 .

36. A method according to claim 35 , wherein the Tec family kinase is selected from Btk, Itk/Emt/Tsk, Bmx and Txk/Rlk.