Btk inhibitors

Abstract

Provided are 6-5 membered fused pyridine ring compounds according to Formula (I) or pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising these compounds and their use in therapy. In particular, provided is the use of membered fused pyridine ring compounds in the treatment of Bruton's Tyrosine Kinase (Btk) mediated disorders.

1 . A compound according to Formula I, or a pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
       
       wherein:
 A 1 , A 2 , A 3 , and A 4  are independently C, CH, CR 11  or N and bicyclic ring system E-G is selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
         R 11  is independently selected from the group consisting of:
 a) deuterium, 
 b) H, 
 c) halogen, 
 d) Si(CH 3 ) 3 , 
 e) cyano, 
 f) C 2 H 3 , 
 g) CO 2 H, 
 h) CO 2 (1-6C)alkyl, 
 i) CO(1-6C)alkyl, 
 j) CONH(1-6C)alkoxy, 
 k) CONH(1-6C)alkyl, 
 l) CONHdi(1-6C)alkyl, 
 m) CONHheterocycloalkyl, 
 n) CONHheteroaryl(1-6C)alkyl, 
 o) (1-6C)alkyl, 
 p) (3-7C)cycloalkyl, 
 q) (6-10C)aryl, 
 r) (1-5C)heteroaryl, 
 s) (2-6C)alkenyl, 
 t) (2-6C)alkynyl, 
 u) (6-10C)aryl(2-6C)alkenyl, 
 v) (3-7C)heterocycloalkyl, and 
 w) (3-7C)heterocycloalkenyl; 
 
         R 11  is optionally substituted with one or more groups selected from: halogen, (1-6C)alkyl, (1-5C)alkoxy, hydroxyl, oxo, (6-10C)aryl, or R 16 (CO); 
         wherein in aromatic ring K 
         B 1  is N or C(R 7 ); 
         B 2  is N or C(R 8 ); 
         B 3  is N or C(R 9 ); 
         B 4  is N or C(R 10 ); 
         R 7  is H, halogen, OH, CF 3 , (1-3C)alkyl, (1-3C)alkoxy or halo(1-3C)alkyl; 
         R 8  is H, halogen, OH, CF 3 , (1-3C)alkyl, (1-3C)alkoxy or halo(1-3C)alkyl; or 
         R 7  and R 8  together with ring K they are attached to, form (6-10C)aryl or (1-9C)heteroaryl; 
         R 9  is H, halogen, OH, CF 3 , (1-3C)alkyl, (1-3C)alkoxy or halo(1-3C)alkyl; 
         R 10  is H, halogen, OH, CF 3 , (1-3C)alkyl, (1-3C)alkoxy or halo(1-3C)alkyl; 
         wherein in heteroaromatic ring L 
         W is CH or N; 
         X is CH, N, O, S or bond; 
         Y is C(R 6 ), N, O or S; 
         Z is CH, N or bond; 
         R 5  is H, halogen, cyano, (1-4C)alkyl, (1-5C)alkoxy, (3-6C)cycloalkyl; (3-6C)cycloalkoxy; any alkyl group of R 5  may optionally be substituted with one, two or three halogen; or R 5  is (6-10C)aryl, (1-5C)heteroaryl or (2-6C)heterocycloalkyl; the aryl or heterocycloalkyl of which may optionally be substituted with halogen, (1-6C)alkyl, (1-3C)alkoxy; 
         R 6  is H, halogen, (1-3C)alkyl, cyano, (1-6C)alkyl or (1-6C)alkoxy; R 6  may optionally be substituted with one, two or three halogen or cyano; or 
         R 5  and R 6  together form a (3-7C)cycloalkenyl or (2-6C)heterocycloalkenyl; each optionally substituted with (1-3C)alkyl or with one or more halogen; 
         A 5  is C or N; 
         R x  is selected from the group consisting of H, (1-6C)alkyl, (1-5C)heteroalkyl, and 
       
       
         
           
           
               
               
           
         
         n is 1 or 2; 
         A 6  is C, N or O; 
         R 1  is
 a) R 21 C(O), 
 b) R 22 NHC(O), 
 c) R 23 C(O)NH, 
 d) R 24 S(O), 
 e) R 25 SO 2 , 
 f) NH 2 , 
 g) H, 
 h) (3-7C)cycloalkyl(1-4C)alkyl, 
 i) (1-6C)alkoxycarbonyl(3-7C)cycloalkyl(1-4C)alkyl, 
 j) (6-10C)aryl(1-4C)alkyl, 
 k) (1-6C)alkyl, 
 l) (1-5C)heteroaryl(1-4C)alkyl, wherein the (1-5C)heteroaryl is optionally substituted with one or two (1-4C)alkyl, hydroxyl or halogen, 
 m) (1-5C)heterocycloalkyl(1-4C)alkyl, wherein the (1-5C)heterocycloalkyl is optionally substituted with one or two (1-4C)alkyl, hydroxyl or halogen, 
 n) cyano(1-6C)alkyl, 
 o) halo(1-6C)alkyl, 
 p) hydroxy(1-6C)alkyl, 
 q) (1-4C)alkoxy(1-6C)alkyl, or 
 r) (1-6C)alkoxyl; 
 
         R 2  is H, (1-3C)alkyl or (3-7C)cycloalkyl; 
         R 3  is H, (1-6C)alkyl or (3-7C)cycloalkyl; or 
         R 2  and R 3  may form, together with the N or C atom to which they are attached to, form a (3-7C)heterocycloalkyl or (3-7C)cycloalkyl both optionally substituted with one or two R 13 ; 
         R 2  and R 3  may form a cyclohexyl ring with the A 5 =C and A 6 =C to which they are attached, and when substituted with R 13  on the carbon one removed from the carbon adjacent to the A 5 =C, such that the R 13  and R 15  can join to form a fused (2-5C)heteroaryl ring, optionally substituted with one or two R a  selected from (1-3C)alkyl, hydroxy(1-3C)alkyl, (3-6C)cycloalkyl, or (1-3C)alkoxy(1-3C)alkyl; 
         R 2  and R 3  may form a cyclohexyl ring with the A 5 =C and A 6 =C to which they are attached, and when substituted with two R 13  groups on the carbon adjacent to the A 5 =C and the carbon one removed from the A 5 =C, such that the two R 13  groups join together to form a fused (2-5C)heteroaryl ring, optionally substituted with one or two R a  selected from (1-3C)alkyl, hydroxy(1-3C)alkyl, (3-6C)cycloalkyl, or (1-3C)alkoxy(1-3C)alkyl; 
         A 5 , R 3 , R 4  and R x  may combine to form the following ring 
       
       
         
           
           
               
               
           
         
         R 3  and R 4  may join to form a (3-6C)cycloalkyl ring with the A 5 =C and R x ═H to which they are attached said ring being substituted with a spiro-linked piperidine ring at the 4-position of the piperidine ring and the nitrogen atom of the piperidine ring being substituted with C(O)R 21 ; 
         R 4  is H, hydroxyl, (1-3C)alkyl, (1-3C)alkoxy; 
         R 13  is independently selected from the group consisting of: (1-3C)alkoxy, (2-5C)heterocycloalkyl, (1-6C)alkyl, hydroxy(1-6C)alkyl, halo(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkyl, hydrogen, hydroxyl, (1-3C)alkylcarbonyloxy, one or more halogen, halo(1-3C)alkyl, and oxo; 
         R 15  is H, (1-4C)alkyl, optionally substituted with one, two or three halogen; 
         R 16  is
 a) (1-6C)alkyl, 
 b) (3-7C)cycloalkyl, 
 c) (6-10C)aryl, 
 d) (1-9C)heteroaryl, 
 e) (1-4C)alkoxy(1-6C)alkyl, 
 f) (6-10C)aryl(1-6C)alkyl, 
 g) (1-5C)heteroaryl(1-6C)alkyl, 
 h) di[(1-6C)alkyl]amino, 
 i) (3-7C)heterocycloalkyl; 
 
         R 21  is selected from the group consisting of:
 a) H, 
 b) trifluoromethylcarbonyl, 
 c) hydroxy(1-6C)alkyl, 
 d) di[hydroxy](1-6C)alkyl, 
 e) di[(1-6C)alkyl]amino(1-6C)alkyl, 
 f) CF 3 , 
 g) CCl 3 , 
 h) amino(3-7C)cycloalkyl, 
 i) (6-10C)aryloxy, 
 j) (6-10C)arylcarbonyl(2-5C)heterocycloalkyl, 
 k) (6-10C)arylcarbonyl, 
 l) (6-10C)aryl(1-6C)alkoxy, 
 m) (3-7C)cycloalkylcarbonyl(1-5C)heterocycloalkyl, 
 n) (3-7C)cycloalkyl(1-4C)alkyl, 
 o) (3-7C)cycloalkyl, 
 p) (3-10C)cycloalkylamino, 
 q) (3-10C)cycloalkyl, 
 r) (3-10C)cycloalkylcarbonyl, 
 s) (4-10C)bicycloalkyl, 
 t) (1-6C)heterocycloalkyl, 
 u) (1-6C)alkylsulfonyl(2-5C)heterocycloalkyl, 
 v) (1-6C)alkylcarbonyl(2-5C)heterocycloalkyl, 
 w) (1-6C)alkylcarbonyl, 
 x) (1-6C)alkylaminocarbonyl, 
 y) (6-10C)arylaminocarbonyl, 
 z) (1-6C)alkylamino, 
 aa) (1-6C)alkoxycarbonyl, 
 bb) (1-6C)alkoxycarbonyl(1-4C)alkylamino(3-7C)cycloalkyl, 
 cc) (1-6C)alkoxycarbonyl(1-4C)alkyl, 
 dd) (1-6C)alkoxycarbonyl(3-7C)cycloalkyl(1-4C)alkyl, 
 ee) (1-6C)alkoxy, 
 ff) (6-10C)aryl(1-6C)alkoxy, 
 gg) (1-5C)heteroarylcarbonyl, 
 hh) (1-5C)heteroaryl(1-4C)alkyl, 
 ii) (1-5C)heteroaryl(3-7C)cycloalkyl, 
 jj) (1-5C)heterocycloalkyl, 
 kk) (1-4C)thioalkyl(1-6C)alkyl, 
 ll) di[(1-4C)alkyl]aminocarbonyl, 
 mm) (1-4C)alkylsulfonyl(1-6C)alkyl, 
 nn) (1-4C)alkylaminocarbonyl, 
 oo) (1-4C)alkoxy(1-6C)alkyl, 
 pp) (1-8C)alkoxy(1-16C)alkyl, 
 qq) cyano(1-6C)alkyl, 
 rr) amino(1-6C)alkyl, 
 ss) (6-10C)arylamino, 
 tt) (3-7C)cycloalkoxy, 
 uu) (1-6C)alkyl, 
 vv) (1-5C)heteroaryl, 
 ww) (1-4C)alkoxy[(2-4C)alkoxy] m (1-6C)alkyl, and 
 xx) amino(1-4C)alkoxy[(2-4C)alkoxy] m (1-6C)alkyl; 
 
         R 21  may optionally be substituted with one, two or three R 211  substituents; 
         m is 1-10; 
         R 22  is selected from the group consisting of:
 a) (3-7C)cycloalkyl(1-4C)alkyl, 
 b) (3-7C)cycloalkyl, 
 c) (4-10C)bicycloalkyl, 
 d) (3-7C)cycloalkoxy(1-4C)alkyl, 
 e) (3-6C)cycloalkoxy, 
 f) (1-5C)heterocycloalkyl, 
 g) (1-5C)heterocycloalkyl(1-6C)alkyl, 
 h) (6-10C)aryl, 
 i) (1-6C)alkyl, 
 j) (1-6C)alkoxy, 
 k) (1-4C)thioalkyl(1-6C)alkyl, 
 l) (1-4C)alkylsulfonyl(1-6C)alkyl, and 
 m) (1-4C)alkoxy(1-6C)alkyl; 
 
         R 22  may optionally be substituted with one, two or three R 221  substituents; 
         R 23  is selected from the group consisting of:
 a) (6-10C)aryl(1-6C)alkoxy, 
 b) (3-7C)cycloalkyl, 
 c) (3-7C)cycloalkoxy, 
 d) (1-6C)alkylamino, 
 e) (1-6C)alkyl, and 
 f) (1-4C)alkoxy(1-6C)alkyl; 
 
         R 23  may optionally be substituted with one, two or three R 231  substituents; 
         R 24  is selected from the group consisting of:
 a) (3-7C)cycloalkyl, 
 b) (1-6C)alkyl, 
 c) (6-10C)aryl, and 
 d) (2-5C)heteroaryl; 
 
         R 24  may optionally be substituted with one, two or three R 241  substituents; 
         R 25  is independently selected from the group consisting of:
 a) (3-7C)cycloalkyl, 
 b) (1-6C)alkyl, 
 c) (6-10C)aryl, and 
 d) (2-5C)heteroaryl; 
 
         R 25  may optionally be substituted with one, two or three R 251  substituents; 
         R 211 , R 221 , R 231 , R 241 , and R 251  are independently selected from the group consisting of:
 a) halogen, 
 b) CF 3 , 
 c) OCF 3 , 
 d) oxo, 
 e) hydroxyl, 
 f) cyano, 
 g) amino, 
 h) (1-6C)alkyl, 
 i) (1-4C)alkoxyl, 
 j) (3-7C)cycloalkyl, 
 k) (3-7C)cycloalkoxy, 
 l) (di[(1-6C)alkyl]amino, 
 m) (1-4C)akoxy(1-6C)alkyl, 
 n) (1-5C)heteroaryl, and 
 o) (2-5C)heterocycloalkyl; 
 
         with the proviso that:
 1) 0 to 2 atoms of X, Y, Z can simultaneously be a heteroatom; 
 2) 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; 
 3) when Z is C or N then Y is C(R 6 ) or N and X is C, N, or a bond; 
 4) when A 3  is N then A 5  is C; 
 5) in ring K, 0 to 2 atoms of B 1 , B 2 , B 3  and B 4  are N; 
 6) when A 5  is N then R 4  is absent; 
 7) when A 6  is N then R 15  is absent; 
 8) when A 6  is O then R 1  and R 15  are absent; 
 9) when X is a bond, then Y is O or S and Z is CH; and 
 10) when W is CH, then X is a bond, Y is S and Z is N. 
 
       
     
     
         2 . The compound of  claim 1 , wherein ring K is defined as:
 B 1  is C(R 7 ), B 2  is C(R 8 ), B 3  is C(R 9 ), and B 4  is C(R 10 ); or   B 1  is N, B 2  is N, B 3  is C(R 9 ), and B 4  is C(R 10 ); or   B 1  is N, B 2  is C(R 8 ), B 3  is N, and B 4  is C(R 10 ); or   B 1  is N, B 2  is C(R 8 ), B 3  is C(R 9 ), and B 4  is N; or   B 1  is C(R 7 ), B 2  is C(R 8 ), B 3  is N, and B 4  is N; or   B 1  is C(R 7 ), B 2  is N, B 3  is C(R 9 ), and B 4  is N.   
     
     
         3 . The compound of  claim 2 , wherein ring K is defined as: B 1  is C(R 7 ), B 2  is C(R 8 ), B 3  is C(R 9 ), and B 4  is C(R 10 ); and R 7 , R 8 , R 9  and R 10  each are H or halogen. 
     
     
         4 . The compound of  claim 1 , wherein ring L is selected from the group consisting of pyridyl, pyrimidyl, pyridazyl, triazinyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, thiadiazolyl, and isothiazolyl. 
     
     
         5 . The compound of  claim 4 , wherein ring L is selected from the group consisting of pyridyl, pyrimidyl, and thiazolyl. 
     
     
         6 . The compound of  claim 1 , wherein R 5  is selected from the group consisting of hydrogen, fluorine, chlorine, CN, cyclopropyl, (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 of  claim 6 , wherein R 5  is selected from the group consisting of hydrogen, fluorine, methyl, ethyl, propyl, cyclopropyl, methoxy and trifluoromethyl. 
     
     
         8 . The compound of  claim 1 , wherein R 1  is selected from the group consisting of:
 R 21 C(O), R 22 NHC(O), R 23 C(O)NH, R 25 SO 2 , (3-7C)cycloalkyl(1-4C)alkyl, (6-10C)aryl(1-4C)alkyl, (1-6C)alkyl, (1-5C)heteroaryl(1-4C)alkyl, halo(1-6C)alkyl, hydroxyl(1-6Calkyl, (1-4C)alkoxy(1-6C)alkyl, (1-4C)alkoxy(1-6C)alkyl and (1-6C)alkoxyl.   
     
     
         9 . The compound of  claim 8 , wherein R 1  is selected from the group consisting of:
 R 21 C(O), R 22 NHC(O), R 23 C(O)NH, (6-10C)aryl(1-4C)alkyl, (1-5C)heteroaryl(1-4C)alkyl, halo(1-6C)alkyl, hydroxyl(1-6C alkyl, (1-4C)alkoxy(1-6C)alkyl, (1-4C)alkoxy(1-6C)alkyl and (1-6C)alkoxyl.   
     
     
         10 . The compound of  claim 9 , wherein R 1  is selected from the group consisting of R 21 C(O), R 22 NHC(O), and R 23 C(O)NH. 
     
     
         11 . The compound of  claim 1  having Formula I wherein 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
       wherein:
 T is O, S or CH 2 ; 
 A 6  is C or N; and 
 Z is 0, 1 or 2; 
 
     
     
         12 . The compound of  claim 11 , wherein 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         13 . The compound of  claim 12 , wherein 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         14 . The compound of  claim 13 , wherein 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         15 . The compound of  claim 1 , wherein
 R 21  is selected from the group consisting of di[hydroxy](1-6C)alkyl, di[(1-6C)alkyl]amino(1-6C)alkyl, amino(3-7C)cycloalkyl, (6-10C)aryloxy, (6-10C)arylcarbonyl(2-5C)heterocycloalkyl, (3-7C)cycloalkylcarbonyl(1-5C)heterocycloalkyl, (3-7C)cycloalkyl, (3-6C)cycloalkoxy, (3-10C)cycloalkylamino, (3-10C)cycloalkyl, (1-6C)alkylsulfonyl(2-5C)heterocycloalkyl, (1-6C)alkylcarbonyl(2-5C)heterocycloalkyl, (1-6C)alkylamino, (1-6C)alkoxy, (1-5C)heteroarylcarbonyl, (1-5C)heteroaryl(1-4C)alkyl, (1-5C)heterocycloalkyl, (1-4C)thioalkyl(1-6C)alkyldi[(1-4C)alkyl]aminocarbonyl, (1-4C)alkylsulfonyl(1-6C)alkyl, (1-4C)alkylaminocarbonyl, (1-4C)alkoxy(1-6C)alkyl, (1-6C)alkoxy, amino(1-6C)alkyl, (6-10C)arylamino, (3-7C)cycloalkoxy, (2-5C)heterocycloalkyl, (1-6C)cycloalkyl, (1-6C)alkyl, (1-6C)alkoxycarbonyl(1-4C)alkyl, (1-5C)heteroaryl, and (1-4C)alkoxy[(2-4C)alkoxy] m (1-6C)alkyl; amino(1-4C)alkoxy[(2-4C)alkoxy] m (1-6C)alkyl; R 21  may optionally be substituted with R 211 ;   R 22  is selected from the group consisting of (3-7C)cycloalkyl(1-4C)alkyl, (3-7C)cycloalkyl, (3-7C)cycloalkoxy(1-4C)alkyl, (3-6C)cycloalkoxy, (1-6C)alkyl, (1-6C)alkoxy, (1-4C)thioalkyl(1-6C)alkyl, (1-4C)alkylsulfonyl(1-6C)alkyl, and (1-4C)alkoxy(1-6C)alkyl; and R 22  may optionally be substituted with R 221 ; and   R 23  is selected from the group consisting of (6-10C)aryl(1-6C)alkoxy, (3-7C)cycloalkyl, (3-7C)cycloalkoxy, (1-6C)alkylamino, (1-6C)alkyl, and (1-4C)alkoxy(1-6C)alkyl; and R 23  may optionally be substituted with R 231 .   
     
     
         16 . The compound of  claim 15 , wherein
 R 21  is selected from the group consisting of (3-7C)cycloalkylcarbonyl(1-5C)heterocycloalkyl, (3-7C)cycloalkyl, (3-6C)cycloalkoxy, (3-10C)cycloalkylamino, (3-10C)cycloalkyl, (1-6C)alkylsulfonyl(2-5C)heterocycloalkyl, (1-6C)alkylcarbonyl(2-5C)heterocycloalkyl, (1-6C)alkylamino, (1-6C)alkoxy, (1-5C)heteroarylcarbonyl, (1-5C)heteroaryl(1-4C)alkyl, (1-5C)heterocycloalkyl, (1-4C)thioalkyl(1-6C)alkyl, di[(1-4C)alkyl]aminocarbonyl, (1-4C)alkoxy[(2-4C)alkoxy] m (1-6C)alkyl, (1-4C)alkylsulfonyl(1-6C)alkyl, (1-4C)alkylaminocarbonyl, (1-4C)alkoxy(1-6C)alkyl, (1-6C)alkoxy, amino(1-6C)alkyl, (6-10C)arylamino, (3-7C)cycloalkoxy, (2-5C)heterocycloalkyl, (1-6C)cycloalkyl, (1-6C)alkyl, (1-6C)alkoxycarbonyl(1-4C)alkyl, and (1-5C)heteroaryl; R 21  may optionally be substituted with R 211 .   
     
     
         17 . The compound of  claim 16 , wherein
 R 21  is selected from the group consisting of (3-7C)cycloalkyl, (3-6C)cycloalkoxy, (1-6C)alkylsulfonyl(2-5C)heterocycloalkyl, (1-4C)thioalkyl(1-6C)alkyl, (1-4C)alkylsulfonyl(1-6C)alkyl, (1-4C)alkoxy(1-6C)alkyl, (3-7C)cycloalkoxy, (1-6C)alkyl, and (1-5C)heteroaryl; and R 21  may optionally be substituted with R 211 ;   R 22  is selected from the group consisting of (3-7C)cycloalkyl, (3-7C)cycloalkoxy(1-4C)alkyl, (3-6C)cycloalkoxy, (1-6C)alkyl, and (1-4C)alkoxy(1-6C)alkyl; and
 R 22  may optionally be substituted with R 221 ; 
   R 23  is selected from the group consisting of (3-7C)cycloalkyl, (3-7C)cycloalkoxy, and (1-4C)alkoxy(1-6C)alkyl; and R 23  may optionally be substituted with R 231 ;   R 24  is selected from the group consisting of (3-7C)cycloalkyl and (1-6C)alkyl; and
 R 24  may optionally be substituted with R 241 ; and 
   R 25  is selected from the group consisting of (3-7C)cycloalkyl and (1-6C)alkyl and
 R 25  may optionally be substituted with R 251 . 
   
     
     
         18 . The compound of  claim 1 , wherein R 11  is selected from the group consisting of H,  2 H, F, Cl, Br, Me, C 2 H 3 , ethyl, cyclopropyl and vinyl. 
     
     
         19 . The compound of  claim 18 , wherein R 11  is H. 
     
     
         20 . The compound of  claim 1 , wherein bicyclic ring system E-G is selected from to the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         21 . The compound of  claim 20 , wherein bicyclic ring system E-G is 
       
         
           
           
               
               
           
         
       
     
     
         22 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof for use in therapy. 
     
     
         23 . The compound of  claim 1  selected from the group consisting of:
 4-(8-amino-3-{(3R)-1-[(3-methyloxetan-3-yl)carbonyl]piperidin-3-yl}imidazo[1,5-a]pyrazin-1-yl)-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide; 
 4-(8-amino-3-{(3R)-1-[(3-methyloxetan-3-yl)carbonyl]piperidin-3-yl}imidazo[1,5-a]pyrazin-1-yl)-3-fluoro-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide; 
 4-(8-amino-3-{(3R)-1-[(2S)-2-hydroxypropanoyl]piperidin-3-yl}imidazo[1,5-a]pyrazin-1-yl)-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide; 
 4-(8-amino-3-{(3R)-1-[(2R)-2-hydroxypropanoyl]piperidin-3-yl}imidazo[1,5-a]pyrazin-1-yl)-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide; 
 4-(8-amino-3-{(3R)-1-[(3-methyloxetan-3-yl)carbonyl]piperidin-3-yl}imidazo[1,5-a]pyrazin-1-yl)-N-[5-(difluoromethyl)pyridin-2-yl]benzamide; 
 4-(8-amino-3-{(3R,6S)-6-methyl-1-[(3-methyloxetan-3-yl)carbonyl]piperidin-3-yl}imidazo[1,5-a]pyrazin-1-yl)-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide; 
 4-(8-amino-3-{(3R,6S)-6-methyl-1-[(3-methyloxetan-3-yl)carbonyl]piperidin-3-yl}imidazo[1,5-a]pyrazin-1-yl)-3-fluoro-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide; 
 4-{8-amino-3-[(3R,6S)-1-(cyclopropylcarbonyl)-6-methylpiperidin-3-yl]imidazo[1,5-a]pyrazin-1-yl}-3-fluoro-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide; 
 4-{8-amino-3-[(3R,6S)-1-(3-methoxypropanoyl)-6-methylpiperidin-3-yl]imidazo[1,5-a]pyrazin-1-yl}-3-fluoro-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide; 
 4-(8-amino-3-{(3R,6S)-6-methyl-1-[(3-methyloxetan-3-yl)carbonyl]piperidin-3-yl}imidazo[1,5-a]pyrazin-1-yl)-2-chloro-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide; 
 4-(8-amino-3-{(3R,6S)-6-methyl-1-[(3-methyloxetan-3-yl)carbonyl]piperidin-3-yl}imidazo[1,5-a]pyrazin-1-yl)-N-[4-(1,1-difluoroethyl)pyridin-2-yl]benzamide; 
 4-{8-amino-3-[(3R,6S)-1-(cyclopropylcarbonyl)-6-methylpiperidin-3-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(difluoromethyl)pyridin-2-yl]-3-fluorobenzamide; 
 4-[8-amino-5-(methoxymethyl)-3-{(3R)-1-[(3-methyloxetan-3-yl)carbonyl]piperidin-3-yl}imidazo[1,5-a]pyrazin-1-yl]-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide; 
 4-(8-amino-5-methyl-3-{(3R)-1-[(3-methyloxetan-3-yl)carbonyl]piperidin-3-yl}imidazo[1,5-a]pyrazin-1-yl)-N-[4-(cyclopropyloxy)pyridin-2-yl]benzamide; 
 4-(8-amino-3-{(3R,6S)-6-methyl-1-[(3-methyloxetan-3-yl)carbonyl]piperidin-3-yl}imidazo[1,5-a]pyrazin-1-yl)-2-fluoro-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide; 
 4-(8-amino-3-{(3R)-1-[(3-methyloxetan-3-yl)carbonyl]piperidin-3-yl}imidazo[1,5-a]pyrazin-1-yl)-3-methoxy-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide; 
 4-(8-amino-3-{(3R)-1-[(3-methyloxetan-3-yl)carbonyl]piperidin-3-yl}imidazo[1,5-a]pyrazin-1-yl)-N-[4-(cyclopropyloxy)pyridin-2-yl]-3-fluorobenzamide; 
 4-(8-amino-3-{(3R)-1-[(3-methyloxetan-3-yl)carbonyl]piperidin-3-yl}imidazo[1,5-a]pyrazin-1-yl)-N-(4-chloropyridin-2-yl)-3-fluorobenzamide; 
 4-{8-amino-5-chloro-3-[(2R)-4-(methoxyacetyl)morpholin-2-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide; 
 4-{8-amino-3-[(2R)-4-oxetan-3-ylmorpholin-2-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide; 
 4-{8-amino-3-[(3R)-1-(methoxyacetyl)piperidin-3-yl]imidazo[1,5-a]pyrazin-1-yl}-3-fluoro-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide; and 
 4-{8-amino-3-[(3R)-1-(3-methoxypropanoyl)piperidin-3-yl]imidazo[1,5-a]pyrazin-1-yl}-3-fluoro-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide. 
 
     
     
         24 . The compound of  claim 1  selected from the group consisting of:
 4-(8-amino-3-{(3R)-1-[(3-methyloxetan-3-yl)carbonyl]piperidin-3-yl}imidazo[1,5-a]pyrazin-1-yl)-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide; 
 4-(8-amino-3-{(3R)-1-[(3-methyloxetan-3-yl)carbonyl]piperidin-3-yl}imidazo[1,5-a]pyrazin-1-yl)-3-fluoro-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide; 
 4-(8-amino-3-{(3R,6S)-6-methyl-1-[(3-methyloxetan-3-yl)carbonyl]piperidin-3-yl}imidazo[1,5-a]pyrazin-1-yl)-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide; 
 4-(8-amino-3-{(3R,6S)-6-methyl-1-[(3-methyloxetan-3-yl)carbonyl]piperidin-3-yl}imidazo[1,5-a]pyrazin-1-yl)-3-fluoro-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide; 
 4-{8-amino-3-[(3R,6S)-1-(cyclopropylcarbonyl)-6-methylpiperidin-3-yl]imidazo[1,5-a]pyrazin-1-yl}-3-fluoro-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide; 
 4-(8-amino-3-{(3R,6S)-6-methyl-1-[(3-methyloxetan-3-yl)carbonyl]piperidin-3-yl}imidazo[1,5-a]pyrazin-1-yl)-2-chloro-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide; 
 4-[8-amino-5-(methoxymethyl)-3-{(3R)-1-[(3-methyloxetan-3-yl)carbonyl]piperidin-3-yl}imidazo[1,5-a]pyrazin-1-yl]-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide; 
 4-(8-amino-3-{(3R,6S)-6-methyl-1-[(3-methyloxetan-3-yl)carbonyl]piperidin-3-yl}imidazo[1,5-a]pyrazin-1-yl)-2-fluoro-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide; 
 4-(8-amino-3-{(3R)-1-[(3-methyloxetan-3-yl)carbonyl]piperidin-3-yl}imidazo[1,5-a]pyrazin-1-yl)-N-(4-chloropyridin-2-yl)-3-fluorobenzamide; 
 4-{8-amino-3-[(3R)-1-(methoxyacetyl)piperidin-3-yl]imidazo[1,5-a]pyrazin-1-yl}-3-fluoro-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide; and 
 4-{8-amino-3-[(3R)-1-(3-methoxypropanoyl)piperidin-3-yl]imidazo[1,5-a]pyrazin-1-yl}-3-fluoro-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide. 
 
     
     
         25 . A compound according to Formula I 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 A 1 , A 2 , A 3 , and A 4  are C, CH or N and bicyclic ring system E-G is selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
         R 11  is independently selected from the group consisting of deuterium, H, halogen, Si(CH 3 ) 3 , cyano, C 2 H 3 , COOH, COOMe, or (1-6C)alkyl, (3-7C)cycloalkyl, (6-10C)aryl, (1-5C)heteroaryl, (2-6C)alkenyl, (2-6C)alkynyl, (3-7C)heterocycloalkyl and (3-7C)heterocycloalkenyl; R 11  is optionally substituted with one or more groups selected from halogen, (1-6C)alkyl, (1-5C)alkoxy, hydroxyl, oxo or R 16 (CO); 
         wherein in aromatic ring K: 
         B 1  is N or C(R7); 
         B 2  is N or C(R8); 
         B 3  is N or C(R9); 
         B 4  is N or C(R10); 
         R 7  is H, halogen, CF 3 , (1-3C)alkyl or (1-3C)alkoxy; 
         R 8  is H, halogen, CF 3 , (1-3C)alkyl or (1-3C)alkoxy; or 
         R 7  and R 8  together with ring K they are attached to, form (6-10C)aryl or (1-9C)heteroaryl; 
         R 9  is H, halogen, (1-3C)alkyl or (1-3C)alkoxy; 
         R 10  is H, halogen, (1-3C)alkyl or (1-3C)alkoxy; 
         wherein in heteroaromatic ring L: 
         X is CH, N, O or S; 
         Y is C(R 6 ), N, O or S; 
         Z is CH, N or bond; 
         R 5  is H, halogen, cyano, (1-4C)alkyl, (1-5C)alkoxy, (3-6C)cycloalkyl; any alkyl group of R 5  may optionally be substituted with one or more halogen; or R 5  is (6-10C)aryl, (1-5C)heteroaryl or (2-6C)heterocycloalkyl; the aryl or heterocycloalkyl of which may optionally be substituted with halogen, (1-6C)alkyl, (1-3C)alkoxy; 
         R 6  is H or (1-3C)alkyl; or 
         R 5  and R 6  together form a (3-7C)cycloalkenyl or (2-6C)heterocycloalkenyl; each optionally substituted with (1-3C)alkyl or with one or more halogen; 
         and wherein 
         A 5  is C or N; 
         R x  is selected from the group consisting of H, (1-6C)alkyl, (1-5C)heteroalkyl, and 
       
       
         
           
           
               
               
           
         
         n is 1 or 2; 
         A 6  is C, N or O; 
         R 1  is R 21 C(O), R 22 NHC(O), R 23 C(O)NH, R 24 S(O), R 25 SO 2 , NH2, H, (3-7C)cycloalkyl(1-4C)alkyl, (6-10C)aryl(1-4C)alkyl, (1-6C)alkyl, (1-5C)heteroaryl(1-4C)alkyl; 
         R 2  is H, (1-3C)alkyl or (3-7C)cycloalkyl; 
         R 3  is H, (1-6C)alkyl or (3-7C)cycloalkyl); or 
         R 2  and R 3  form, together with the N or C atom they are attached to, a (3-7C)heterocycloalkyl optionally substituted with R 13 ; 
         R 4  is H, (1-3C)alkyl; 
         R 13  is independently selected from the group consisting of: (1-3C)alkoxy, (2-5C)heterocycloalkyl, (1-6C)alkyl, hydrogen, hydroxyl, (1-3C)alkylcarbonyloxy, one or more fluorine, and oxo; 
         R 15  is H, (1-4C)alkyl; 
         R 16  is (1-6C)alkyl, (3-7C)cycloalkyl, (6-10C)aryl, (1-9C)heteroaryl, (1-4C)alkoxy(1-6C)alkyl, (6-10C)aryl(1-6C)alkyl, (1-5C)heteroaryl(1-6C)alkyl, di[(1-6C)alkyl]amino, (3-7C)heterocycloalkyl; 
         R 21  is selected from the group consisting of H, trifluoromethylcarbonyl, hydroxy(1-6C)alkyl, di[hydroxy](1-6C)alkyl, di[(1-6C)alkyl]amino(1-6C)alkyl, CF 3 , CCl 3 , amino(3-7C)cycloalkyl, (6-10C)aryloxy, (6-10C)arylcarbonyl(2-5C)heterocycloalkyl, (6-10C)arylcarbonyl, (6-10C)aryl(1-6C)alkoxy, (3-7C)cycloalkylcarbonyl(1-5C)heterocycloalkyl, (3-7C)cycloalkyl(1-4C)alkyl, (3-7C)cycloalkyl, (3-6C)cycloalkoxy, (3-10C)cycloalkylamino, (3-10C)cycloalkyl, (1-6C)heterocycloalkyl, (1-6C)alkylsulfonyl(2-5C)heterocycloalkyl, (1-6C)alkylcarbonyl(2-5C)heterocycloalkyl, (1-6C)alkylcarbonyl, (1-6C)alkylaminocarbonyl, (1-6C)alkylamino, 1-6C)alkoxycarbonyl(1-4C)alkylamino(3-7C)cycloalkyl, (1-6C)alkoxycarbonyl(1-4C)alkyl, (1-6C)alkoxy, (1-5C)heteroarylcarbonyl, (1-5C)heteroaryl(1-4C)alkyl, (1-5C)heterocycloalkyl, (1-4C)thioalkyl(1-6C)alkyl, di[(1-4C)alkyl]aminocarbonyl, (1-4C)alkylsulfonyl(1-6C)alkyl, (1-4C)alkylaminocarbonyl, (1-4C)alkoxy(1-6C)alkyl, amino(1-6C)alkyl, (6-10C)arylamino, (3-7C)cycloalkoxy, (1-6C)cycloalkyl, (1-6C)alkyl, (1-5C)heteroaryl, (1-4C)alkoxy[(2-4C)alkoxy] m (1-6C)alkyl, and amino(1-4C)alkoxy[(2-4C)alkoxy] m (1-6C)alkyl; R 21  may optionally be substituted with R 211 ; 
         R 22  is selected from the group consisting of (3-7C)cycloalkyl(1-4C)alkyl, (3-7C)cycloalkyl, (3-7C)cycloalkoxy(1-4C)alkyl, (3-6C)cycloalkoxy, (1-6C)alkyl, (1-6C)alkoxy, (1-4C)thioalkyl(1-6C)alkyl, (1-4C)alkylsulfonyl(1-6C)alkyl, and (1-4C)alkoxy(1-6C)alkyl; R 22  may optionally be substituted with R 221 ; 
         R 23  is selected from the group consisting of (6-10C)aryl(1-6C)alkoxy, (3-7C)cycloalkyl, (3-7C)cycloalkoxy, (1-6C)alkylamino, (1-6C)alkyl, and (1-4C)alkoxy(1-6C)alkyl; R 23  may optionally be substituted with R 231 ; 
         R 24  is selected from the group consisting of (3-7C)cycloalkyl, (1-6C)alkyl, (6-10C)aryl, and (2-5C)heteroaryl; R 24  may optionally be substituted with R 241 ; 
         R 25  is independently selected from the group consisting of (3-7C)cycloalkyl, (1-6C)alkyl, (6-10C)aryl, and (2-5C)heteroaryl; R 25  may optionally be substituted with R 251 ; 
         R 211 , R 221 , R 231 , R 241 , and R 251  are independently selected from the group consisting of one or more halogen, CF 3 , OCF 3 , oxo, hydroxyl, cyano, (1-6C)alkyl, (1-4C)alkyl, (3-7C)cycloalkoxy, (di[(1-6C)alkyl]amino, (1-4C)akoxy(1-6C)alkyl, (1-5C)heteroaryl, and (2-5C)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 can not be O or S; 
 when Z is C or N then Y is C(R 6 ) or N and X is C or N; 
 when A 3  is N then A 5  is C; 
 in ring K, 0 to 2 atoms of B 1 , B 2 , B 3  and B 4  are N; 
 when A 5  is N then R 4  is absent; 
 when A 6  is N then R 15  is absent; 
 when A 6  is O then R 1  and R 15  are absent. 
 
       
     
     
         26 . The compound of  claim 1  having Formula Ia 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         27 . The compound of  claim 1  having Formula Ib 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         28 . The compound of  claim 1  having Formula Ic 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         29 . The compound of  claim 1  having Formula Id 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         30 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof for use in therapy. 
     
     
         31 . The compound of claim for a pharmaceutically acceptable salt thereof for use in the treatment of Bruton's Tyrosine Kinase (Btk) mediated disorders. 
     
     
         32 . Use of the compound of Formula I according to  claim 1  or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of Bruton's Tyrosine Kinase (Btk) mediated disorders. 
     
     
         33 . A pharmaceutical composition which comprises the compound of  claim 1  or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. 
     
     
         34 . The pharmaceutical composition of  claim 33 , which further comprises at least one additional therapeutically active agent. 
     
     
         35 . A method for treating a subject suffering with a Bruton's Tyrosine Kinase (Btk) mediated disorder comprising administering to the subject the compound of  claim 1  in an amount effective to treat the Btk mediated disorder, thereby treating the subject. 
     
     
         36 . The method of  claim 35 , wherein the Btk mediated disorder is selected from the group consisting of rheumatoid arthritis, psoriatic arthritis, infectious arthritis, progressive chronic arthritis, deforming arthritis, osteoarthritis, traumatic arthritis, gouty arthritis, Reiter's syndrome, polychondritis, acute synovitis and spondylitis, glomerulonephritis (with or without nephrotic syndrome), autoimmune hematologic disorders, hemolytic anemia, aplasic anemia, idiopathic thrombocytopenia, and neutropenia, autoimmune gastritis, and autoimmune inflammatory bowel diseases, ulcerative colitis, Crohn's disease, host versus graft disease, allograft rejection, chronic thyroiditis, Graves' disease, schleroderma, diabetes (type I and type II), active hepatitis (acute and chronic), pancreatitis, primary billiary cirrhosis, myasthenia gravis, multiple sclerosis, systemic lupus erythematosis, psoriasis, atopic dermatitis, contact dermatitis, eczema, skin sunburns, vasculitis (e.g. Behcet's disease) chronic renal insufficiency, Stevens-Johnson syndrome, inflammatory pain, idiopathic sprue, cachexia, sarcoidosis, Guillain-Barré syndrome, uveitis, conjunctivitis, kerato conjunctivitis, otitis media, periodontal disease, pulmonary interstitial fibrosis, asthma, bronchitis, rhinitis, sinusitis, pneumoconiosis, pulmonary insufficiency syndrome, pulmonary emphysema, pulmonary fibrosis, silicosis, chronic inflammatory pulmonary disease, and chronic obstructive pulmonary disease. 
     
     
         37 . The method of  claim 36 , wherein the Btk mediated disorder is rheumatoid arthritis, psoriatic arthritis, or osteoarthritis.