IP Library › Patent Application 14233478

Patent Application

App. No. 14/233,478

BTK INHIBITORS

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Patent No.: US None
App. No.: 14/233,478

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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.

Claims (353)

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: