Claims for Patent: 9,290,504

Summary for Patent: 9,290,504

Title:	4-imidazopyridazin-1-yl-benzamides and 4-imidazotriazin-1-yl-benzamides as Btk inhibitors
Abstract:	The present invention relates to 6-5 membered fused pyridine ring compounds according to formula (I) or a pharmaceutically acceptable salt thereof or to pharmaceutical compositions comprising these compounds and to their use in therapy. In particular, the present invention relates to the use of 6-5 membered fused pyridine ring compounds according to formula I in the treatment of Brutons Tyrosine Kinase (Btk) mediated disorders. ##STR00001##
Inventor(s):	Barf; Tjeerd A. (Ravenstein, NL), Jans; Christiaan Gerardus Johannes Maria (Cuijk, NL), Man; Petrus Antonius De Adrianus (Hurwenen, NL), Oubrie; Arthur A. (Wijchen, NL), Raaijmakers; Hans C. A. (Eindhoven, NL), Rewinkel; Johannes Bernardus Maria (Berghem, NL), Sterrenburg; Jan-Gerard (Renkum, NL), Wijkmans; Jacobus C. H. M. (Oss, NL)
Assignee:	Merck Sharp & Dohme B.V. (Haarlem, NL)
Application Number:	14/233,418
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 9,290,504
Patent Claims:	1. A compound of Formula (I) ##STR00187## or a pharmaceutically acceptable salt thereof, wherein: X is CH, N, O or S; Y is C(R6), N, O or S; Z is CH, N or a bond; A is CH or N; B1 is N or C(R7); B2 is N or C(R8); B3 is N or C(R9); B4 is N or C(R10); R1 is R11C(O), R12S(O), R13SO.sub.2 or (1-6C)alkyl optionally substituted with R14; R2 is H, (1-3C)alkyl or (3-7C)cycloalkyl; R3 is H, (1-6C)alkyl or (3-7C)cycloalkyl); or R2 and R3 form, together with the N atom that R2 is attached to and the C atom that R3 is attached to, a (3-7C)heterocycloalkyl optionally substituted with one or more fluorine, hydroxyl, (1-3C)alkyl, (1-3C)alkoxy or oxo; R4 is H or (1-3C)alkyl; R5 is H, halogen, cyano, (1-4C)alkyl, (1-3C)alkoxy, (3-6C)cycloalkyl, any alkyl group of which is optionally substituted with one or more halogen; or R5 is (6-10C)aryl or (2-6C)heterocycloalkyl; R6 is H or (1-3C)alkyl; or R5 and R6 together may form a (3-7C)cycloalkenyl, or (2-6C)heterocycloalkenyl; each optionally substituted with (1-3C)alkyl, or one or more halogen; R7 is H, halogen or (1-3C)alkoxy; R8 is H or (1-3C)alkyl; or R7 and R8 form, together with the carbon atom they are attached to a (6-10C)aryl or (1-9C)heteroaryl; R9 is H, halogen or (1-3C)alkoxy; R10 is H, halogen or (1-3C)alkoxy; R11 is independently selected from the group consisting of (1-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl each alkyl, alkenyl or alkynyl optionally substituted with one or more groups selected from hydroxyl, (1-4C)alkyl, (3-7C)cycloalkyl, [(1-4C)alkyl]amino, di[(1-4C)alkyl]amino, (1-3C)alkoxy, (3-7C)cycloalkoxy, (6-10C)aryl or (3-7C)heterocycloalkyl; or R11 is (1-3C)alkyl-C(O)--S-(1-3C)alkyl; or R11 is (1-5C)heteroaryl optionally substituted with one or more groups selected from halogen or cyano; R12 and R13 are independently selected from the group consisting of (2-6C)alkenyl or (2-6C)alkynyl both optionally substituted with one or more groups selected from hydroxyl, (1-4C)alkyl, (3-7C)cycloalkyl, [(1-4C)alkyl]amino, di[(1-4C)alkyl]amino, (1-3C)alkoxy, (3-7C)cycloalkoxy, (6-10C)aryl or (3-7C)heterocycloalkyl; or (1-5C)heteroaryl optionally substituted with one or more groups selected from halogen or cyano; R14 is independently selected from the group consisting of halogen, cyano or (2-6C)alkenyl or (2-6C)alkynyl both optionally substituted with one or more groups selected from hydroxyl, (1-4C)alkyl, (3-7C)cycloalkyl, [(1-4C)alkyl]amino, di[(1-4C)alkyl]amino, (1-3C)alkoxy, (3-7C)cycloalkoxy, (6-10C)aryl, (1-5C)heteroaryl or (3-7C)heterocycloalkyl; with the proviso that 0 to 2 atoms of X, Y, Z can simultaneously be a heteroatom; when one atom selected from X, Y is O or S, then Z is a bond and the other atom selected from X, Y cannot be O or S; when Z is CH or N then Y is C(R6) or N and X is CH or N; 0 to 2 atoms of B1, B2, B3 and B4 are N. 2. The compound according to claim 1 wherein B1 is C(R7); B2 is C(R8); B3 is C(R9); B4 is C(R10); R7 is H, R9 is H, and R10 is H; and R8 is selected from the group consisting of hydrogen and methyl. 3. The compound according to claim 2 wherein R4 is selected from the group consisting of hydrogen and methyl. 4. The compound according to claim 1 wherein the ring containing X, Y and Z is selected from the group consisting of pyridyl, pyrimidyl, pyridazyl, triazinyl, thiazolyl, oxazolyl, and isoxazolyl. 5. The compound according to claim 1 wherein the ring containing X, Y and Z is selected from the group consisting of pyridyl, pyrimidyl, and thiazolyl. 6. The compound according to claim 1 wherein R5 is selected from the group consisting of hydrogen, fluorine, chlorine, (1-3C)alkyl and (1-2C) alkoxy; the (1-3C)alkyl group of which is optionally substituted with one or more halogen. 7. The compound according to claim 1 wherein R5 is selected from the group consisting of hydrogen, fluorine, methyl, ethyl, propyl, methoxy and trifluoromethyl. 8. The compound according to claim 1 wherein R2 is hydrogen or (1-3C)alkyl; and R3 is (1-6C)alkyl. 9. The compound according to claim 1 wherein R2 and R3 form, together with the N atom that R2 is attached to and the C atom that R3 is attached to, a heterocycloalkyl ring selected from azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl or morpholinyl, optionally substituted with one or more fluoro, hydroxyl, (1-3C) alkyl, (1-3C)alkoxy, or oxo. 10. The compound according to claim 1 wherein R1 is R11C(O) and R11 is independently selected from the group consisting of (1-6C)alkyl, (2-6C)alkenyl or (2-6C)alkynyl each optionally substituted with one or more groups selected from hydroxyl, (1-4C)alkyl, (3-7C)cycloalkyl, [(1-4C)alkyl]amino, di[(1-4C)alkyl]amino, (1-3C)alkoxy, (3-7C)cycloalkoxy, (6-10C)aryl or (3-7C)heterocycloalkyl; or R11 is (1-5C)heteroaryl optionally substituted with one or more groups selected from halogen or cyano. 11. The compound according to claim 1 wherein R1 is R11C(O) and R11 is selected from the group consisting of (2-6C)alkenyl or (2-6C)alkynyl each optionally substituted with one or more groups selected from hydroxyl, (1-4C)alkyl, (3-7C)cycloalkyl, di[(1-4C) alkyl]amino, (1-3C)alkoxy, (3-7C)cycloalkoxy or (3-7C)heterocycloalkyl. 12. The compound according to claim 1 selected from the group consisting of (S)-4-(3-(1-Acryloylpyrrolidin-2-yl)-8-aminoimidazo[1,5-a]pyrazin-1-yl- )-N-(pyridin-2-yl)benzamide; (S,E)-4-(8-amino-3-(1-(4-(pyrrolidin-1-yl)but-2-enoyl)pyrrolidin-2-yl)imi- dazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide; (S,E)-4-(8-Amino-3-(1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-2-yl)imida- zo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide; (S,E)-4-(8-amino-3-(1-(4-methoxybut-2-enoyl)pyrrolidin-2-yl)imidazo[1,5-a- ]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide; (S)-4-(8-amino-3-(1-(2-chloropyrimidine-4-carbonyl)pyrrolidin-2-yl)imidaz- o[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide; (S)-4-(8-amino-3-(1-but-2-ynoylpyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl- )-N-(pyridin-2-yl)benzamide; (S,E)-4-(8-Amino-3-(1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-2-yl)imida- zo[1,5-a]pyrazin-1-yl)-N-(4-fluoropyridin-2-yl)benzamide; (S)-4-(8-Amino-3-(1-but-2-ynoylpyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl- )-N-(4-methylpyridin-2-yl)benzamide; (S,E)-4-(8-Amino-3-(1-(4-methoxybut-2-enoyl)pyrrolidin-2-yl)imidazo[1,5-a- ]pyrazin-1-yl)-N-(4-propylpyridin-2-yl)benzamide; (S)-4-(8-Amino-3-(1-but-2-ynoylpyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl- )-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide; (S,E)-4-(8-Amino-3-(1-(4-methoxybut-2-enoyl)pyrrolidin-2-yl)imidazo[1,5-a- ]pyrazin-1-yl)-N-(4-ethylpyridin-2-yl)benzamide; (S)-4-(8-Amino-3-(1-but-2-ynoylpyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl- )-N-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)benzamide; (S)-4-(3-(1-acryloylpyrrolidin-2-yl)-8-aminoimidazo[1,5-a]pyrazin-1-yl)-2- -fluoro-N-(pyridin-2-yl)benzamide; (S)-4-(3-(1-Acryloylpyrrolidin-2-yl)-8-aminoimidazo[1,5-a]pyrazin-1-yl)-2- -methoxy-N-(pyridin-2-yl)benzamide; (S,E)-4-(8-Amino-3-(1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-2-yl)imida- zo[1,5-a]pyrazin-1-yl)-N-(thiazol-2-yl)benzamide; (S,E)-4-(8-Amino-3-(1-(4-methoxybut-2-enoyl)piperidin-2-yl)imidazo[1,5-a]- pyrazin-1-yl)-N-(pyridin-2-yl)benzamide; (S)-4-(3-(1-Acryloylpiperidin-2-yl)-8-aminoimidazo[1,5-a]pyrazin-1-yl)-N-- (4-fluoropyridin-2-yl)benzamide; (S)-4-(3-(1-Acryloylpiperidin-2-yl)-8-aminoimidazo[1,5-a]pyrazin-1-yl)-N-- (4-cyanopyridin-2-yl)benzamide; (S)-4-(8-Amino-3-(1-(vinylsulfonyl)piperidin-2-yl)imidazo[1,5-a]pyrazin-1- -yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide; (S)-4-(3-(1-Acryloylpiperidin-2-yl)-8-aminoimidazo[1,5-a]pyrazin-1-yl)-N-- (pyrimidin-2-yl)benzamide; (S)-4-(3-(1-Acryloylpiperidin-2-yl)-8-aminoimidazo[1,5-a]pyrazin-1-yl)-N-- (4-methylpyrimidin-2-yl)benzamide; (S)-4-(8-Amino-3-(1-but-2-ynoylpiperidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)- -N-(pyrimidin-4-yl)benzamide; (S)-4-(8-Amino-3-(1-but-2-ynoylpiperidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)- -N-(pyridazin-3-yl)benzamide; (S)-4-(8-Amino-3-(1-but-2-ynoylpiperidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)- -N-(isoxazol-3-yl)benzamide; (S,E)-4-(8-Amino-3-(1-(4-methoxybut-2-enoyl)piperidin-2-yl)imidazo[1,5-a]- pyrazin-1-yl)-N-(5-ethylthiazol-2-yl)benzamide; (S)-4-(3-(1-Acryloylpiperidin-2-yl)-8-aminoimidazo[1,5-a]pyrazin-1-yl)-2-- fluoro-N-(4-propylpyridin-2-yl)benzamide; (S,E)-4-(8-Amino-3-(1-(4-(dimethylamino)but-2-enoyl)piperidin-2-yl)imidaz- o[1,5-a]pyrazin-1-yl)-2-methoxy-N-(4-propylpyridin-2-yl)benzamide; 4-(8-Amino-3-((S)-1-but-2-ynoylpiperidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)- -3-methyl-N-(pyridin-2-yl)benzamide; 4-(3-(Acrylamidomethyl)-8-aminoimidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-y- l)benzamide; (S)-4-(8-Amino-3-(1-but-2-ynamidoethyl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyr- idin-2-yl)benzamide; (S)-S-2-(2-(8-Amino-1-(4-(pyridin-2-ylcarbamoyl)phenyl)imidazo[1,5-a]pyra- zin-3-yl)pyrrolidin-1-yl)-2-oxoethyl ethanethioate; (S)-4-(8-Amino-3-(1-(4-hydroxy-4-methylpent-2-ynoyl)pyrrolidin-2-yl)imida- zo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide; (S)-4-(8-Amino-3-(1-(6-chloropyrimidine-4-carbonyl)pyrrolidin-2-yl)imidaz- o[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide; (S)-4-(8-Amino-3-(1-pent-2-ynoylpyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-y- l)-N-(pyridin-2-yl)benzamide; (S)-4-(8-Amino-3-(1-(3-cyclopropylpropioloyl)pyrrolidin-2-yl)imidazo[1,5-- a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide; (S)-4-(8-Amino-3-(1-hex-2-ynoylpyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl- )-N-(pyridin-2-yl)benzamide; 4-(3-(1-Acryloylazepan-2-yl)-8-aminoimidazo[1,5-a]pyrazin-1-yl)-N-(pyridi- n-2-yl)benzamide; (R)-4-(8-Amino-3-(4-but-2-ynoylmorpholin-3-yl)imidazo[1,5-a]pyrazin-1-yl)- -N-(pyridin-2-yl)benzamide; (S)-4-(8-amino-3-(1-(N-methylbut-2-ynamido)ethyl)imidazo[1,5-a]pyrazin-1-- yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide; (S)-4-(8-Amino-3-(1-(4-(dimethylamino)but-2-ynoyl)pyrrolidin-2-yl)imidazo- [1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide; (S)-4-(8-Amino-3-(1-(4-methoxybut-2-ynoyl)pyrrolidin-2-yl)imidazo[1,5-a]p- yrazin-1-yl)-N-(pyridin-2-yl)benzamide; (S)-4-(3-(1-acryloylpyrrolidin-2-yl)-8-aminoimidazo[1,5-a]pyrazin-1-yl)-N- -(4-fluoropyridin-2-yl)benzamide; (S)-4-(3-(1-acryloylpyrrolidin-2-yl)-8-aminoimidazo[1,5-a]pyrazin-1-yl)-N- -(4-(pyrrolidin-1-yl)pyridin-2-yl)benzamide; (S)-4-(8-amino-3-(1-but-2-ynoylpiperidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)- -N-(4-fluoropyridin-2-yl)benzamide; (S)-4-(8-amino-3-(1-but-2-ynoylpiperidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)- -N-(pyridin-2-yl)benzamide; (S)-4-(3-(1-acryloylpiperidin-2-yl)-8-aminoimidazo[1,5-a]pyrazin-1-yl)-N-- (pyridin-2-yl)benzamide; (S)-4-(8-amino-3-(1-but-2-ynoylpyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl- )-N-(4-propylpyridin-2-yl)benzamide; (S,E)-4-(8-amino-3-(1-(4-methoxy-N-methylbut-2-enamido)ethyl)imidazo[1,5-- a]pyrazin-1-yl)-N-(4-propylpyridin-2-yl)benzamide; (S)-4-(8-amino-3-(1-(vinylsulfonyl)piperidin-2-yl)imidazo[1,5-a]pyrazin-1- -yl)-N-(4-propylpyridin-2-yl)benzamide; (S)-4-(8-amino-3-(1-but-2-ynoylpyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl- )-2-fluoro-N-(pyridin-2-yl)benzamide; (S,E)-4-(8-amino-3-(1-(4-methoxybut-2-enoyl)pyrrolidin-2-yl)imidazo[1,5-a- ]pyrazin-1-yl)-N-(4-methoxypyridin-2-yl)benzamide; (S,E)-4-(8-amino-3-(1-(4-methoxybut-2-enoyl)pyrrolidin-2-yl)imidazo[1,5-a- ]pyrazin-1-yl)-2-fluoro-N-(4-methoxypyridin-2-yl)benzamide; (S,E)-4-(8-amino-3-(1-(4-methoxybut-2-enoyl)pyrrolidin-2-yl)imidazo[1,5-a- ]pyrazin-1-yl)-N-(4-fluoropyridin-2-yl)benzamide; (S,E)-4-(8-amino-3-(1-(4-methoxybut-2-enoyl)piperidin-2-yl)imidazo[1,5-a]- pyrazin-1-yl)-N-(isoxazol-3-yl)benzamide; (S,E)-4-(8-amino-3-(1-(4-methoxybut-2-enoyl)piperidin-2-yl)imidazo[1,5-a]- pyrazin-1-yl)-N-(pyrimidin-2-yl)benzamide; 4-(8-amino-3-((S)-1-(2-chloropyrimidine-4-carbonyl)piperidin-2-yl)imidazo- [1,5-a]pyrazin-1-yl)-3-methyl-N-(pyridin-2-yl)benzamide; (S,E)-4-(8-amino-3-(1-(4-methoxybut-2-enoyl)pyrrolidin-2-yl)imidazo[1,5-a- ]pyrazin-1-yl)-N-(4-methylpyridin-2-yl)benzamide; (S,E)-4-(8-amino-3-(1-(4-methoxybut-2-enoyl)pyrrolidin-2-yl)imidazo[1,5-a- ]pyrazin-1-yl)-N-(4-isopropylpyridin-2-yl)benzamide; (S,E)-4-(8-amino-3-(1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-2-yl)imida- zo[1,5-a]pyrazin-1-yl)-N-(4-methylpyridin-2-yl)benzamide; (S)-4-(8-amino-3-(1-but-2-ynoylpyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl- )-N-(thiazol-2-yl)benzamide; (S)-4-(3-(1-acryloylpiperidin-2-yl)-8-aminoimidazo[1,5-a]pyrazin-1-yl)-N-- (4-propylpyridin-2-yl)benzamide; (S)-4-(3-(1-acryloylpyrrolidin-2-yl)-8-aminoimidazo[1,5-a]pyrazin-1-yl)-N- -(4-(trifluoromethyl)pyridin-2-yl)benzamide; (S)-4-(8-amino-3-(1-but-2-ynoylpiperidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)- -N-(4-(trifluoromethyl)pyridin-2-yl)benzamide; (S)-4-(8-amino-3-(1-but-2-ynoylpiperidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)- -N-(4-propylpyridin-2-yl)benzamide; (S,E)-4-(8-amino-3-(1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-2-yl)imida- zo[1,5-a]pyrazin-1-yl)-N-(4-isopropylpyridin-2-yl)benzamide; 4-(8-amino-3-((S)-1-(vinylsulfonyl)piperidin-2-yl)imidazo[1,5-a]pyrazin-1- -yl)-3-methyl-N-(pyridin-2-yl)benzamide; (S)-4-(8-amino-3-(1-but-2-ynoylpiperidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)- -2-fluoro-N-(4-propylpyridin-2-yl)benzamide; 4-(3-((S)-1-acryloylpiperidin-2-yl)-8-aminoimidazo[1,5-a]pyrazin-1-yl)-3-- methyl-N-(pyridin-2-yl)benzamide; (E)-4-(8-amino-3-((4-(dimethylamino)but-2-enamido)methyl)imidazo[1,5-a]py- razin-1-yl)-N-(pyridin-2-yl)benzamide; (S)-4-(8-amino-3-(1-(2-chloropyrimidine-4-carbonyl)pyrrolidin-2-yl)imidaz- o[1,5-a]pyrazin-1-yl)-N-(4-isopropylpyridin-2-yl)benzamide; (S)-4-(8-amino-3-(1-(2-chloropyrimidine-4-carbonyl)pyrrolidin-2-yl)imidaz- o[1,5-a]pyrazin-1-yl)-N-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)benzamide; (S,E)-4-(8-amino-3-(1-(4-methoxybut-2-enoyl)piperidin-2-yl)imidazo[1,5-a]- pyrazin-1-yl)-N-(pyridazin-3-yl)benzamide; (S,E)-4-(8-amino-3-(1-(4-(dimethylamino)but-2-enoyl)piperidin-2-yl)imidaz- o[1,5-a]pyrazin-1-yl)-N-(pyridazin-3-yl)benzamide; (S)-4-(8-amino-3-(1-(2-chloropyrimidine-4-carbonyl)piperidin-2-yl)imidazo- [1,5-a]pyrazin-1-yl)-N-(pyridazin-3-yl)benzamide; (S,E)-4-(8-amino-3-(1-(4-methoxy-N-methylbut-2-enamido)ethyl)imidazo[1,5-- a]pyrazin-1-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide; (S,E)-4-(8-amino-3-(1-(4-(dimethylamino)-N-methylbut-2-enamido)ethyl)imid- azo[1,5-a]pyrazin-1-yl)-N-(4-propylpyridin-2-yl)benzamide; (S,E)-4-(8-amino-3-(1-(4-(pyrrolidin-1-yl)but-2-enoyl)pyrrolidin-2-yl)imi- dazo[1,5-a]pyrazin-1-yl)-N-(4-propylpyridin-2-yl)benzamide; (S,E)-4-(8-amino-3-(1-(4-(dimethylamino)but-2-enoyl)piperidin-2-yl)imidaz- o[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide; (S)-4-(8-amino-3-(1-(2-chloropyrimidine-4-carbonyl)pyrrolidin-2-yl)imidaz- o[1,5-a]pyrazin-1-yl)-N-(4-propylpyridin-2-yl)benzamide; (S)-4-(8-amino-3-(1-(2-chloropyrimidine-4-carbonyl)piperidin-2-yl)imidazo- [1,5-a]pyrazin-1-yl)-N-(4-fluoropyridin-2-yl)benzamide; (S,E)-4-(8-amino-3-(1-(4-methoxybut-2-enoyl)piperidin-2-yl)imidazo[1,5-a]- pyrazin-1-yl)-N-(4-fluoropyridin-2-yl)benzamide; (S,E)-4-(8-amino-3-(1-(4-methoxybut-2-enoyl)pyrrolidin-2-yl)imidazo[1,5-a- ]pyrazin-1-yl)-N-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)benzamide; (S)-4-(8-amino-3-(1-(2-chloropyrimidine-4-carbonyl)pyrrolidin-2-yl)imidaz- o[1,5-a]pyrazin-1-yl)-2-methoxy-N-(pyridin-2-yl)benzamide; (S)-4-(8-amino-3-(1-(2-chloropyrimidine-4-carbonyl)pyrrolidin-2-yl)imidaz- o[1,5-a]pyrazin-1-yl)-2-fluoro-N-(pyridin-2-yl)benzamide; 4-(8-amino-3-((S)-1-((E)-4-methoxybut-2-enoyl)piperidin-2-yl)imidazo[1,5-- a]pyrazin-1-yl)-3-methyl-N-(pyridin-2-yl)benzamide; (S,E)-4-(8-amino-3-(1-(4-methoxybut-2-enoyl)piperidin-2-yl)imidazo[1,5-a]- pyrazin-1-yl)-N-(pyrimidin-4-yl)benzamide; 4-(8-amino-3-((S)-1-((E)-4-methoxybut-2-enoyl)pyrrolidin-2-yl)imidazo[1,5- -a]pyrazin-1-yl)-3-methyl-N-(4-propylpyridin-2-yl)benzamide; (S,E)-4-(8-amino-3-(1-(4-methoxybut-2-enoyl)piperidin-2-yl)imidazo[1,5-a]- pyrazin-1-yl)-N-(4-methylpyrimidin-2-yl)benzamide; (S)-4-(8-amino-3-(1-but-2-ynoylpiperidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)- -N-(4-methylpyrimidin-2-yl)benzamide; (S)-4-(8-amino-3-(1-(2-chloropyrimidine-4-carbonyl)piperidin-2-yl)imidazo- [1,5-a]pyrazin-1-yl)-N-(pyrimidin-2-yl)benzamide; (S)-4-(8-amino-3-(1-methacryloylpyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-y- l)-N-(pyridin-2-yl)benzamide; (S)-4-(8-amino-3-(1-(2-(trifluoromethyl)acryloyl)pyrrolidin-2-yl)imidazo[- 1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide; (S,E)-4-(8-amino-3-(1-but-2-enoylpyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-- yl)-N-(pyridin-2-yl)benzamide; (S)-4-(8-amino-3-(1-(cyanomethyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-- yl)-N-(pyridin-2-yl)benzamide; (E)-4-(8-amino-3-((4-methoxybut-2-enamido)methyl)imidazo[1,5-a]pyrazin-1-- yl)-N-(pyridin-2-yl)benzamide; (S)-4-(8-amino-3-(1-but-2-ynoylpyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl- )-N-(4-(pyrrolidin-1-yl)pyridin-2-yl)benzamide; (E)-4-(8-amino-3-(1-(4-methoxybut-2-enoyl)azepan-2-yl)imidazo[1,5-a]pyraz- in-1-yl)-N-(pyridin-2-yl)benzamide; (S,E)-4-(8-amino-3-(1-(4-methoxybut-2-enoyl)pyrrolidin-2-yl)imidazo[1,5-a- ]pyrazin-1-yl)-N-(4-cyanopyridin-2-yl)benzamide; (S)-4-(8-amino-3-(1-but-2-ynoylpyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl- )-2-methoxy-N-(pyridin-2-yl)benzamide; (S)-4-(3-(1-acrylamidoethyl)-8-aminoimidazo[1,5-a]pyrazin-1-yl)-N-(pyridi- n-2-yl)benzamide; (S)-4-(3-(1-acryloylpyrrolidin-2-yl)-8-aminoimidazo[1,5-a]pyrazin-1-yl)-N- -(thiazol-2-yl)benzamide; (S)-4-(8-amino-3-(1-but-2-ynoylpyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl- )-N-(4-isopropylpyridin-2-yl)benzamide; (S,E)-4-(8-amino-3-(1-(4-methoxybut-2-enoyl)pyrrolidin-2-yl)imidazo[1,5-a- ]pyrazin-1-yl)-2-methoxy-N-(pyridin-2-yl)benzamide; (S,E)-4-(8-amino-3-(1-cinnamoylpyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl- )-N-(pyridin-2-yl)benzamide; (S)-N-(1-(8-amino-1-(4-(pyridin-2-ylcarbamoyl)phenyl)imidazo[1,5-a]pyrazi- n-3-yl)ethyl)-2-chloropyrimidine-4-carboxamide; (S)-4-(8-amino-3-(1-but-2-ynoylpyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl- )-N-(4-fluoropyridin-2-yl)benzamide; (S)-4-(8-amino-3-(1-(2-chloropyrimidine-4-carbonyl)piperidin-2-yl)imidazo- [1,5-a]pyrazin-1-yl)-N-(4-propylpyridin-2-yl)benzamide; (S,E)-4-(8-amino-3-(1-(4-methoxybut-2-enoyl)piperidin-2-yl)imidazo[1,5-a]- pyrazin-1-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide; (S)-4-(3-(1-acryloylpiperidin-2-yl)-8-aminoimidazo[1,5-a]pyrazin-1-yl)-N-- (4-(trifluoromethyl)pyridin-2-yl)benzamide; (S)-4-(8-amino-3-(1-but-2-ynoylpiperidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)- -2-methoxy-N-(4-propylpyridin-2-yl)benzamide; (S,E)-4-(8-amino-3-(1-(4-methoxybut-2-enoyl)piperidin-2-yl)imidazo[1,5-a]- pyrazin-1-yl)-2-methoxy-N-(4-propylpyridin-2-yl)benzamide; 4-(8-amino-3-(but-2-ynamidomethyl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-- 2-yl)benzamide; (S)-4-(8-amino-3-(1-(N-methylbut-2-ynamido)ethyl)imidazo[1,5-a]pyrazin-1-- yl)-N-(4-propylpyridin-2-yl)benzamide; (S,E)-4-(8-amino-3-(1-(4-methoxybut-2-enoyl)piperidin-2-yl)imidazo[1,5-a]- pyrazin-1-yl)-2-fluoro-N-(4-propylpyridin-2-yl)benzamide; (S)-4-(8-amino-3-(1-(2-chloropyrimidine-4-carbonyl)piperidin-2-yl)imidazo- [1,5-a]pyrazin-1-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide; (S)-4-(8-amino-3-(1-but-2-ynoylpiperidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)- -N-(5-ethylthiazol-2-yl)benzamide; (S)-4-(3-(1-acryloylpiperidin-2-yl)-8-aminoimidazo[1,5-a]pyrazin-1-yl)-N-- (5-ethylthiazol-2-yl)benzamide; (S)-4-(8-amino-3-(1-(2-chloropyrimidine-4-carbonyl)piperidin-2-yl)imidazo- [1,5-a]pyrazin-1-yl)-N-(5-ethylthiazol-2-yl)benzamide; (S)-4-(8-amino-3-(1-(2-chloropyrimidine-4-carbonyl)pyrrolidin-2-yl)imidaz- o[1,5-a]pyrazin-1-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide; (R,E)-4-(8-amino-3-(4-(4-methoxybut-2-enoyl)morpholin-3-yl)imidazo[1,5-a]- pyrazin-1-yl)-N-(pyridin-2-yl)benzamide; (S,E)-4-(8-amino-3-(1-(4-methoxybut-2-enoyl)piperidin-2-yl)imidazo[1,5-a]- pyrazin-1-yl)-N-(4-propylpyridin-2-yl)benzamide; (S)-4-(3-(1-acryloylpyrrolidin-2-yl)-8-aminoimidazo[1,5-a]pyrazin-1-yl)-N- -(4-cyanopyridin-2-yl)benzamide; (S)-4-(8-amino-3-(1-but-2-ynoylpyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl- )-N-(4-methoxypyridin-2-yl)benzamide; (S)-4-(3-(1-acryloylpyrrolidin-2-yl)-8-aminoimidazo[1,5-a]pyrazin-1-yl)-N- -(4-methylpyridin-2-yl)benzamide; (S)-4-(3-(1-acryloylpyrrolidin-2-yl)-8-aminoimidazo[1,5-a]pyrazin-1-yl)-N- -(4-propylpyridin-2-yl)benzamide; (S)-4-(3-(1-acryloylpyrrolidin-2-yl)-8-aminoimidazo[1,5-a]pyrazin-1-yl)-N- -(4-ethylpyridin-2-yl)benzamide; (S,E)-4-(8-amino-3-(1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-2-yl)imida- zo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide; (S,E)-4-(8-amino-3-(1-(4-methoxybut-2-enoyl)pyrrolidin-2-yl)imidazo[1,5-a- ]pyrazin-1-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide; (S)-4-(8-amino-3-(1-(2-chloropyrimidine-4-carbonyl)pyrrolidin-2-yl)imidaz- o[1,5-a]pyrazin-1-yl)-N-(4-methylpyridin-2-yl)benzamide; (S)-4-(8-amino-3-(1-but-2-ynoylpyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl- )-N-(4-cyanopyridin-2-yl)benzamide; (S)-4-(8-amino-3-(1-but-2-ynoylpyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl- )-N-(4-ethylpyridin-2-yl)benzamide; (S)-4-(8-amino-3-(1-but-2-ynoylpyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl- )-N-(4-phenylpyridin-2-yl)benzamide and (S)-4-(3-(1-acryloylpyrrolidin-2-yl)-8-aminoimidazo[1,5-a]pyrazin-1-yl)-N- -(4-phenylpyridin-2-yl)benzamide. 13. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient. 14. The compound according to claim 1 selected from the group consisting of: (S)-4-(3-(1-Acryloylpyrrolidin-2-yl)-8-aminoimidazo[1,5-a]pyrazin-1-y- l)-N-(pyridin-2-yl)benzamide; (S,E)-4-(8-Amino-3-(1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-2-yl)imida- zo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide; (S,E)-4-(8-amino-3-(1-(4-methoxybut-2-enoyl)pyrrolidin-2-yl)imidazo[1,5-a- ]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide; (S)-4-(8-amino-3-(1-but-2-ynoylpyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl- )-N-(pyridin-2-yl)benzamide; (S)-4-(8-Amino-3-(1-but-2-ynoylpyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl- )-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide; (S)-4-(8-Amino-3-(1-(4-hydroxy-4-methylpent-2-ynoyl)pyrrolidin-2-yl)imida- zo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide; (R)-4-(8-Amino-3-(4-but-2-ynoylmorpholin-3-yl)imidazo[1,5-a]pyrazin-1-yl)- -N-(pyridin-2-yl)benzamide; (S)-4-(8-Amino-3-(1-(4-(dimethylamino)but-2-ynoyl)pyrrolidin-2-yl)imidazo- [1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide; (S,E)-4-(8-Amino-3-(1-(4-methoxybut-2-enoyl)piperidin-2-yl)imidazo[1,5-a]- pyrazin-1-yl)-N-(pyridin-2-yl)benzamide; (S)-4-(8-amino-3-(1-(N-methylbut-2-ynamido)ethyl)imidazo[1,5-a]pyrazin-1-- yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide; (S)-4-(8-amino-3-(1-but-2-ynoylpiperidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)- -N-(pyridin-2-yl)benzamide; and (S)-4-(8-amino-3-(1-but-2-ynoylpiperidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)- -N-(4-(trifluoromethyl)pyridin-2-yl)benzamide. 15. The compound according to claim 1, wherein X is CH; Y is CH; Z is CH; B1 is C(R7); B2 is C(R8); B3 is C(R9); B4 is C(R10); R1 is R11C(.dbd.O); R2 and R3 form, together with the N atom that R2 is attached to and the C atom that R3 is attached to, a pyrrolidinyl; R4 is H; R7 is H; R9 is H; R10 is H; and R8 is H or methyl. 16. The compound of Formula (I) according to claim 1: ##STR00188## or a pharmaceutically acceptable salt thereof, wherein: X is CH or S; Y is C(R6); Z is CH or a bond; A is CH; B1 is N or C(R7); B2 is N or C(R8); B3 is N or CH; B4 is N or CH; R1 is R11C(.dbd.O); R2 is (1-3C)alkyl; R3 is (1-3C)alkyl; R2 and R3, together with the N atom that R2 is attached to and the C atom that R3 is attached to, form a (3-7C)heterocycloalkyl ring selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, and morpholinyl, optionally substituted with one or more fluorine, hydroxyl, (1-3C)alkyl, or (1-3C)alkoxy; R4 is H; R5 is H, halogen, cyano, (1-4C)alkyl, (1-3C)alkoxy, or (3-6C)cycloalkyl, any alkyl group of which is optionally substituted with one or more halogen; R6 is H or (1-3C)alkyl; R7 is H, halogen or (1-3C)alkoxy; R8 is H or (1-3C)alkyl; or R7 and R8 form, together with the carbon atoms they are respectively attached to, a (6-10C)aryl or (1-9C)heteroaryl; R5 and R6 together may form a (3-7C)cycloalkenyl or (2-6C)heterocycloalkenyl, each optionally substituted with (1-3C)alkyl or one or more halogen; R11 is independently selected from the group consisting of (2-6C)alkenyl and (2-6C)alkynyl, wherein each alkenyl or alkynyl is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, (1-4C)alkyl, (3-7C)cycloalkyl, [(1-4C)alkyl]amino, di[(1-4C)alkyl]amino, (1-3C)alkoxy, (3-7C)cycloalkoxy, (6-10C)aryl and (3-7C)heterocycloalkyl; with the proviso that 0 to 2 atoms of B1, B2, B3 and B4 are N. 17. The compound of Formula (I) according to claim 1: ##STR00189## or a pharmaceutically acceptable salt thereof, wherein: the ring containing X, Y and Z is selected from the group consisting of pyridyl, pyrimidyl, pyridazyl, triazinyl, thiazolyl, oxazolyl and isoxazolyl; A is CH; B1 is CH; B2 is CH; B3 is CH; B4 is CH; R1 is C(.dbd.O)R11; R2 and R3 form, together with the N atom that R2 is attached to and the C atom that R3 is attached to, a (3-7C)heterocycloalkyl ring selected from azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl or morpholinyl, each optionally substituted with fluoro, hydroxyl, (1-3C)alkyl, (1-3C)alkoxy or oxo; R4 is hydrogen; R5 is H, halogen, cyano, (1-4C)alkyl, (1-3C)alkoxy, or (3-6C)cycloalkyl, any alkyl group of which is optionally substituted with one or more halogen; R11 is (2-6C)alkenyl or (2-6C)alkynyl, each optionally substituted with one or more groups selected from hydroxyl, (1-4C)alkyl, (3-7C)cycloalkyl, di[(1-4C)alkyl]amino, (1-3C)alkoxy, (3-7C)cycloalkoxy, or (3-7C)heterocycloalkyl. 18. A compound which is (S)-4-(3-(1-acryloylpyrrolidin-2-yl)-8-aminoimidazo[1,5-a]pyrazin-1-yl)-N- -(pyridin-2-yl)benzamide, having the structure: ##STR00190## 19. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and the compound of claim 18. 20. A pharmaceutically acceptable salt of a compound, the compound being (S)-4-(3-(1-acryloylpyrrolidin-2-yl)-8-aminoimidazo[1,5-a]pyrazin-1-yl)-N- -(pyridin-2-yl)benzamide and having the structure: ##STR00191## 21. The pharmaceutically acceptable salt of claim 20, wherein the salt is selected from the group consisting of acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, fumarate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, phosphate, propionate, salicylate, succinate, sulfate, tartarate, thiocyanate, and toluenesulfonate. 22. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and the pharmaceutically acceptable salt of claim 20. 23. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and the pharmaceutically acceptable salt of claim 21. 24. A compound which is (S,E)-4-(8-amino-3-(1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-2-yl)imida- zo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide, having the structure: ##STR00192## 25. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and the compound of claim 24. 26. A pharmaceutically acceptable salt of a compound, the compound being (S,E)-4-(8-amino-3-(1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-2-yl)imida- zo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide and having the structure: ##STR00193## 27. The pharmaceutically acceptable salt of claim 26, wherein the salt is selected from the group consisting of acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, fumarate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, phosphate, propionate, salicylate, succinate, sulfate, tartarate, thiocyanate, and toluenesulfonate. 28. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and the pharmaceutically acceptable salt of claim 26. 29. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and the pharmaceutically acceptable salt of claim 27. 30. A compound which is (S)-4-(8-amino-3-(1-but-2-ynoylpyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl- )-N-(pyridin-2-yl)benzamide, having the structure: ##STR00194## 31. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and the compound of claim 30. 32. A pharmaceutically acceptable salt of a compound, the compound being (S)-4-(8-amino-3-(1-but-2-ynoylpyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl- )-N-(pyridin-2-yl)benzamide and having the structure: ##STR00195## 33. The pharmaceutically acceptable salt of claim 32, wherein the salt is selected from the group consisting of acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, fumarate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, phosphate, propionate, salicylate, succinate, sulfate, tartarate, thiocyanate, and toluenesulfonate. 34. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and the pharmaceutically acceptable salt of claim 32. 35. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and the pharmaceutically acceptable salt of claim 33. 36. A compound which is (S)-4-(8-amino-3-(1-(3-cyclopropylpropioloyl)pyrrolidin-2-yl)imidazo[1,5-- a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide, having the structure: ##STR00196## 37. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and the compound of claim 36. 38. A pharmaceutically acceptable salt of a compound, the compound being (S)-4-(8-amino-3-(1-(3-cyclopropylpropioloyl)pyrrolidin-2-yl)imidazo[1,5-- a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide and having the structure: ##STR00197## 39. The pharmaceutically acceptable salt of claim 38, wherein the salt is selected from the group consisting of acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, fumarate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, phosphate, propionate, salicylate, succinate, sulfate, tartarate, thiocyanate, and toluenesulfonate. 40. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and the pharmaceutically acceptable salt of claim 38. 41. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and the pharmaceutically acceptable salt of claim 39. 42. A compound which is (S)-4-(8-amino-3-(1-hex-2-ynoylpyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl- )-N-(pyridin-2-yl)benzamide, having the structure: ##STR00198## 43. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and the compound of claim 42. 44. A pharmaceutically acceptable salt of a compound, the compound being (S)-4-(8-amino-3-(1-hex-2-ynoylpyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl- )-N-(pyridin-2-yl)benzamide and having the structure: ##STR00199## 45. The pharmaceutically acceptable salt of claim 44, wherein the salt is selected from the group consisting of acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, fumarate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, phosphate, propionate, salicylate, succinate, sulfate, tartarate, thiocyanate, and toluenesulfonate. 46. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and the pharmaceutically acceptable salt of claim 44. 47. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and the pharmaceutically acceptable salt of claim 45.