Kinase inhibitors and their uses

1. A compound according to structural formula (I):

or a salt or N-oxide thereof, wherein:

B is

R 2 is selected from the group consisting of a (C 6 -C 20 ) aryl optionally substituted with one or more R 8 , a 5-20 membered heteroaryl optionally substituted with one or more R 8 , a (C 7 -C 28 ) arylalkyl optionally substituted with one or more R 8 and a 6-28 membered heteroarylalkyl optionally substituted with one or more R 8 ;

R 4 is a saturated or unsaturated, bridged or unbridged cycloalkyl containing a total of from 3 to 16 annular carbon atoms that is substituted with an R 7 group, with the proviso that when R 4 is an unsaturated unbridged cycloalkyl, or a saturated bridged cycloalkyl, this R 7 substituent is optional, wherein R 4 is further optionally substituted with one or more R f

R 7 is selected from the group consisting of —C(O)OR d , —C(O)NR d R d , —C(O)NR d OR d , or —C(O)NR d NR d R d ;

each R 8 group is, independently of the others, selected from the group consisting of a water-solubilizing group, R a , R b , C 1 -C 8 alkyl optionally substituted with one or more R a and/or R b , C 3 -C 8 cycloalkyl optionally substituted with one or more R a and/or R b , heterocycloalkyl containing 3 to 12 annular atoms, optionally substituted with one or more R a and/or R b , C 1 -C 8 alkoxy optionally substituted with one or more R a and/or R b , and —O—(CH 2 ) x —R b , where x is 1-6;

each R a is, independently of the others, selected from the group consisting of hydrogen, C 1 -C 8 alkyl, bridged or unbridged C 3 -C 10 cycloalkyl, bridged or unbridged heterocycloalkyl containing 3 to 12 annular atoms, heteroaryl, (C 6 -C 14 ) aryl, and (C 7 -C 20 ) arylalkyl, wherein R a is optionally substituted with one or more R f ;

each R b is, independently of the others, a group selected from the group consisting of ═O, —OR a , (C 1 -C 3 ) haloalkyloxy, ═S, —SR a , ═NR a , ═NOR a , —NR c R c , halogen, —C 1 -C 3 haloalkyl, —CN, —NC, —OCN, —SCN, —NO, —NO 2 , ═N 2 , —N 3 , —S(O)R a , —S(O) 2 R a , —S(O) 2 OR a , —S(O)NR c R c , —S(O) 2 NR c R c , —OS(O)R a , —OS(O) 2 R a , —OS(O) 2 OR a , —OS(O) 2 NR c R c , —C(O)R a , —C(O)OR a , —C(O)NR c R c , —C(O)NR a OR a , —C(NH)NR c R c , —C(NR a )NR c R c , —C(NOH)R a , —C(NOH)NR c R c , —OC(O)R a , —OC(O)OR a , —OC(O)NR c R c , —OC(NH)NR c R c and —OC(NR a )NR c R c ; each R c is, independently of the others, is R a or two R c that are bonded to the same nitrogen atom taken together with the nitrogen atom to which they are both attached form a heterocycloalkyl group containing 5 to 8 annular atoms, which optionally includes from 1 to 3 additional heteroatomic groups selected from the group consisting of —O—, —S—, —N(—(CH 2 ) y —R a )—, —N(—(CH 2 ) y —C(O)R a )—, —N(—(CH 2 ) y —C(O)OR a )—, —N(—(CH 2 ) y —S(O) 2 R a )—, —N(—(CH 2 ) y —S(O) 2 OR a )— and —N(—(CH 2 ) y —C(O)NR a R 1 )—, where y is 0-6, wherein the heterocycloalkyl is optionally substituted with one or more R f ;

each R d is, independently of the others, selected from the group consisting of R a , and R c ; and

each R f is independently —C 1 -C 8 alkoxy, —C 1 -C 8 alkyl, —C 1 -C 6 haloalkyl, cyano, nitro, amino, (C 1 -C 8 alkyl)amino, di(C 1 -C 8 alkyl)amino, phenyl, benzyl, oxo, or halogen,

or any two R f bonded to adjacent atoms, taken together with the atoms to which they are each attached, form a fused saturated or unsaturated cycloalkyl or a fused saturated or unsaturated heterocycloalkyl group containing 5 to 8 annular atoms, wherein the formed cycloalkyl and heterocycloalkyl groups are optionally substituted with one or more groups which are each independently selected from halogen, C 1 -C 8 alkyl, and phenyl.

2. The compound of claim 1 in which B is optionally substituted with 1 or 2 R g , wherein each R g is independently ═O, —OH, —C 1 -C 6 alkoxy, (C 1 -C 3 ) haloalkyloxy, —NR c R c , halogen, —C 1 -C 3 alkyl, —C 1 -C 3 haloalkyl, —CN, —NO 2 , —S(O) 2 R a , —S(O) 2 OR a , —S(O) 2 NR c R c , —OS(O) 2 R a , —OS(O) 2 OR a , —OS(O) 2 NR c R c , —C(O)R a , —C(O)OR a , —C(O)NR c R c , —C(O)NR a OR a , —C(NR a )NR c R c , —C(NOH)R a , —C(NOH)NR c R c , —OC(O)R a , —OC(O)OR a , —OC(O)NR c R c , —OC(NR a )NR c R c ; aryl, or (C 7 -C 20 ) arylalkyl.

3. The compound of claim 2 in which R 2 is phenyl substituted with one or more of the same or different R 8 .

4. The compound of claim 3 in which R 2 is phenyl substituted with one R 8 group.

5. The compound of claim 4 in which the one R 8 substituent is positioned at the meta or para position.

6. The compound of claim 3 in which R 2 is phenyl substituted with two of the same or different R 8 .

7. The compound of claim 6 in which the R 8 substituents are positioned 3,4- or 3,5-.

8. The compound of claim 3 in which R 2 is phenyl substituted with three of the same or different R 8 .

9. The compound of claim 8 in which the R 8 substituents are positioned 3,4,5-.

10. The compound of claim 2 in which R 2 is of the formula

wherein one of R 11 , R 12 or R 13 is a water-solubilizing group, and the other two of R 11 , R 12 and R 13 are each, independently of one another, selected from the group consisting of hydrogen, C 1 -C 8 alkyl, halo, hydroxy, (C 1 -C 3 ) hydroxyalkyl, —O(CH 2 ) x —R b , —NR c R c , —C(O)NR c R c , and —C(O)NHR a .

11. The compound of claim 10 , wherein the water solubilizing group is of the formula,

wherein Y is selected from the group consisting of CH and N, and Z is selected from the group consisting of CH 2 , CH(R a ), O, S, N, NH, N—(CH 2 ) y —R a , N—(CH 2 ) y —C(O)R a , N—(CH 2 ) y —C(O)OR a , N—(CH 2 ) y —S(O) 2 R a , N—(CH 2 ) y —S(O) 2 OR a and N—(CH 2 ) y —C(O)NR c R c , provided that Y and Z are not simultaneously CH and CH 2 , respectively.

12. The compound of claim 11 , wherein one of R 11 , R 12 , and R 13 is halogen, one is hydrogen, and the other is the water-solubilizing group.

13. The compound of claim 12 , wherein one of R 11 , R 12 , and R 13 is fluoro, one is hydrogen, and the other is the water-solubilizing group.

14. The compound of claim 13 , wherein one of R 12 is the water solubilizing group, R 11 is hydrogen; and R 13 is fluoro.

15. The compound of claim 11 , wherein Y is N and Z is CH(R a ) or N—(CH 2 ) y —R a .

16. The compound of claim 15 , wherein Z is CH(R a1 ), wherein R a1 is —NR c R c .

17. The compound of claim 2 in which R 2 is a heteroaryl, optionally substituted with one or more R h , wherein each R h is independently ═O, —OH, —C 1 -C 6 alkoxy, —C 1 -C 3 alkyl, (C 1 -C 3 ) haloalkyloxy, —NR c R c , halogen, —C 1 -C 3 haloalkyl, —CN, —NO 2 , —S(O) 2 R a , —S(O) 2 OR a , —S(O) 2 NR c R c , —C(O)R a , —C(O)OR a , —C(O)NR c R c aryl, or (C 7 -C 20 ) arylalkyl.

18. The compound of any one of claim 17 in which R 4 is selected from the group consisting of

where s is an integer ranging from 1 to 6, and R 7 is selected from the group consisting of —C(O)OR a and —C(O)NR c R c , where R a and R c are as previously defined.

19. The compound of claim 18 , where R 4 is

20. The compound of claim 18 in which R 7 is —C(O)O(C 1 -C 8 alkyl) or —C(O)NH 2 .

21. The compound of claim 20 in which R 7 is —C(O)NH 2 .

22. A compound according to claim 1 of wherein the compound of structural formula(I) is:

or a salt or N-oxide thereof, wherein the bond including the dotted line is a single bond or a double bond.

23. The compound of claim 22 which is enriched in the corresponding diastereomer of structural formula (XIIa):

24. The compound of claim 1 which is

3-(2-(4-(4-cyclohexylpiperazine-1-carbonyl)phenylamino)thieno[3,2-d]pyrimidin-4-ylamino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

3-(2-(3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenylamino)thieno[3,2-d]pyrimidin-4-ylamino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

3-(2-(4-(1,4′-bipiperidin-1′-yl)-3-fluorophenylamino)thieno[3,2-d]pyrimidin-4-ylamino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

3-(2-(3-fluoro-4-(4-methyl-1,4′-bipiperidin-1′-yl)phenylamino)thieno[3,2-d]pyrimidin-4-ylamino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

3-(2-(4-(4-(bicyclo[3.3.1]nonan-9-yl)piperazin-1-yl)phenylamino)thieno[3,2-d]pyrimidin-4-ylamino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

3-(2-(3-fluoro-4-(4-morpholinopiperidin-1-yl)phenylamino)thieno[3,2-d]pyrimidin-4-ylamino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

3-(2-(4-((R)-3-(dimethylamino)pyrrolidine-1-carbonyl)phenylamino)thieno[3,2-d]pyrimidin-4-ylamino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

3-(2-(4-(4-(8-methyl-8-aza-bicyclo[3.2.1]octan-3-yl)piperazin-1-yl)phenylamino)thieno[3,2-d]pyrimidin-4-ylamino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

3-(2-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-ylamino)thieno[3,2-d]pyrimidin-4-ylamino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

3-(2-(4-(2-(cyclooctyl(methyl)amino)ethoxy)phenylamino)thieno[3,2-d]pyrimidin-4-ylamino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

3-(2-(4-(1-(bicyclo[2.2.1]heptan-2-yl)piperidin-4-yl)phenylamino)thieno[3,2-d]pyrimidin-4-ylamino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

(2S,3R)-3-(2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)thieno[3,2-d]pyrimidin-4-ylamino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

(2S,3R)-3-(2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)thieno[2,3-d]pyrimidin-4-ylamino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

3-(2-(4-((R)-1-methylpiperidin-3-yloxy)phenylamino)thieno[3,2-d]pyrimidin-4-ylamino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

3-(2-(3-fluoro-4-(((S)-1-methylpyrrolidin-2-yl)methoxy)phenylamino)thieno[3,2-d]pyrimidin-4-ylamino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

3-(2-(4-(4-cyclohexylpiperazin-1-yl)-3-fluorophenylamino)thieno[3,2-d]pyrimidin-4-ylamino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

3-(2-(3-fluoro-4-(4-methyl-1,4-diazepan-1-yl)phenylamino)thieno[3,2-d]pyrimidin-4-ylamino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

3-(2-(3-fluoro-4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)thieno[3,2-d]pyrimidin-4-ylamino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

3-(2-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenylamino)thieno[3,2-d]pyrimidin-4-ylamino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

3-(2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)thieno[3,2-d]pyrimidin-4-ylamino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

(1 S,2R,3 S,5R)—N,2,6,6-tetramethyl-2-(2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)thieno[3,2-d]pyrimidin-4-ylamino)bicyclo[3.1.1]heptane-3-carboxamide;

(1 S,2R,3 S,5R)-2-(2-(4-(4-cyclohexylpiperazin-1-yl)phenylamino)thieno[3,2-d]pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide;

(2S,3R)-3-(2-(4-(4-methylpiperazine-1-carbonyl)phenylamino)thieno[3,2-d]pyrimidin-4-ylamino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

(2S,3R)-3-(2-(4-((S)-3-(dimethylamino)pyrrolidin-1-yl)phenylamino)thieno[3,2-d]pyrimidin-4-ylamino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

(2S,3S)-3-(2-(4-((R)-3-(dimethylamino)pyrrolidin-1-yl)phenylamino)thieno[3,2-d]pyrimidin-4-ylamino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

(2S,3R)-3-(2-(3-fluoro-4-(5-methyl-2,5-diaza-bicyclo[2.2.1]heptan-2-yl)phenylamino)thieno[3,2-d]pyrimidin-4-ylamino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

(2S,3R)-3-(2-(4-(2-methyl-2-(pyrrolidin-1-yl)propoxy)phenylamino)thieno[3,2-d]pyrimidin-4-ylamino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

(2S,3R)-3-(2-(4-(2-(cyclopentyl(methyl)amino)ethoxy)phenylamino)thieno[3,2-d]pyrimidin-4-ylamino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

(2S,3R)-3-(2-(4-(4-(diethylamino)piperidin-1-yl)-3-fluorophenylamino)thieno[3,2-d]pyrimidin-4-ylamino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

(2S,3R)-3-(2-(3-fluoro-4-(4-(methylsulfonyl)piperazin-1-yl)phenylamino)thieno[3,2-d]pyrimidin-4-ylamino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

(2S,3R)-3-(2-(4-(4-(2-amino-2-oxoethyl)piperazin-1-yl)phenylamino)thieno[3,2-d]pyrimidin-4-ylamino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

ethyl4-(4-(4-((2R,3S)-3-carbamoylbicyclo[2.2.1]hept-5-en-2-ylamino)thieno[3,2-d]pyrimidin-2-ylamino)-2-fluorophenyl)piperazine-1-carboxylate;

(2S,3R)-3-(2-(3-fluoro-4-(4-methyl-1,4′-bipiperidin-1′-yl)phenylamino)-6-(trifluoromethyl)thieno[3,2-d]pyrimidin-4-ylamino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

(2S,3R)-3-(2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)-6-(trifluoromethyl)thieno[3,2-d]pyrimidin-4-ylamino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

(2S,3R)-3-(2-(4-(4-cyclohexylpiperazine-1-carbonyl)phenylamino)-6-(trifluoromethyl)thieno[3,2-d]pyrimidin-4-ylamino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

(2S,3R)-3-(6-chloro-2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)thieno[3,2-d]pyrimidin-4-ylamino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

(2S,3R)-3-(6-chloro-2-(4-(4-cyclohexylpiperazine-1-carbonyl)phenylamino)thieno[3,2-d]pyrimidin-4-ylamino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

(2S,3R)-3-(6-chloro-2-(3-fluoro-4-(4-methyl-1,4′-bipiperidin-1′-yl)phenylamino)thieno[3,2-d]pyrimidin-4-ylamino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

Racemic-(2-exo,3-exo-)-7-methyl-N4-(3-aminocarbonylbicyclo[2.2.1]hept-5-en-2-yl)-N2-[4-methoxyphenyl]-thieno[3,2-d]pyrimidine-2,4-diamine;

Racemic-(2-exo,3-exo-)-7-methyl-N4-(3-aminocarbonylbicyclo[2.2.1]hept-5-en-2-yl)-N2-[(3,4,5-trimethoxyphenyl]-thieno[3,2-d]pyrimidine-2,4-diamine;

Racemic-(2-exo,3-exo-)-7-methyl-N4-(3-aminocarbonylbicyclo[2.2.1]hept-5-en-2-yl)-N2-[1H-indol-5-yl]-thieno[3,2-d]pyrimidine-2,4-diamine;

Racemic-(2-exo,3-exo-)-7-methyl-N4-(3-aminocarbonylbicyclo[2.2.1]hept-5-en-2-yl)-N2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-thieno[3,2-d]pyrimidine-2,4-diamine;

Racemic-(2-exo,3-exo-)-7-methyl-N4-(3-aminocarbonylbicyclo[2.2.1]hept-5-en-2-yl)-N2-[3-fluoro-4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-thieno[3,2-d]pyrimidine-2,4-diamine; or

Racemic-(2-exo,3-exo-)-7-methyl-N4-(3-aminocarbonylbicyclo[2.2.1]hept-5-en-2-yl)-N2-(4-aminosulfonyl)phenyl-thieno[3,2-d]pyrimidine-2,4-diamine.

25. A composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier, excipient or diluent.