2-pyrazine carboxamides as spleen tyrosine kinase inhibitors

1. A compound of the Formula (I)

or a pharmaceutically acceptable salt thereof, wherein

X is N(H) or O;

B is a 5- to 10-membered mono- or bicyclic heteroaryl optionally containing 1 heteroatom in addition to the illustrated X atom, selected from the group consisting of N, O, and S;

wherein B is unsubstituted or substituted by one to three R 3 moieties, wherein each R 3 moiety is independently selected from the group consisting of C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 fluoroalkyl, C 1 -C 3 hydroxyalkyl, di(C 1 -C 3 alkyl)sulfonium, halo, hydroxy, amino, (C 1 -C 3 alkyl)amino, di(C 1 -C 3 alkyl)amino, —N(H)SO 2 —(C 1 -C 3 alkyl), —CO 2 H, —C(O)NH 2 , —C(O)N(H)(C 1 -C 3 alkyl), —C(O)N(H)(C 1 -C 3 alkyl) 2 , —CH 2 O—(C 1 -C 4 alkylene)-OH, phenyl, methyl pyrazolyl, pyridyl, and —CH 2 CH 2 -pyrrolidon-2-yl;

or two R 3 moieties when substituted on adjacent carbon atoms of B, together with their attached carbon atoms, form a dioxanyl or dioxolanyl ring;

A is selected from the group consisting of:

wherein

Y is —CH 2 —, —S(O) 2 —, or —O—;

R 11 and R 12 are independently H or F; and

the subscript n is 1 or 2;

the subscript n′ is 0 or 1; or

wherein

R a and R b are independently H, C 1 -C 3 alkyl, or (C 1 -C 3 alkoxy)methyl;

R c is H, C 1 -C 6 alkyl, C 1 -C 3 fluoroalkyl, C 3 -C 6 cycloalkyl, —(CH 2 ) r OR 13 , —C(O)NH 2 , —C(O)N(H)(C 1 -C 3 alkyl), —C(O)N(C 1 -C 3 alkyl) 2 , —(CH 2 ) r S(O) t R 14 , —(CH 2 ) r -phenyl, or —(CH 2 ) r N(H)C(O)—(C 1 -C 3 alkyl);

R 13 is H or C 1 -C 3 alkyl; and

R 14 is C 1 -C 3 alkyl;

the subscript r is 1 or 2;

the subscript t is 0, 1, or 2;

R d is H or C 1 -C 3 alkyl.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein B is selected from the group consisting of:

wherein B is unsubstituted or substituted by one to two R 3 moieties.

3. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein B is unsubstituted or substituted by one to two R 3 moieties selected from the group consisting of chloro, fluoro, bromo, methyl, ethyl, trifluoromethyl, methoxy, phenyl, dimethylsulfonium, pyridyl, and —CH 2 CH 2 -pyrrolidon-2-yl.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:

A is

Y is —CH 2 —, —S(O) 2 —, or —O—;

R 11 and R 12 are independently H or F; and

the subscript n is 1 or 2; and

the subscript n′ is 0 or 1.

5. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of:

6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of:

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein

A is

wherein

R a and R b are independently H, C 1 -C 3 alkyl, or (C 1 -C 3 alkoxy)methyl;

R c is H, C 1 -C 6 alkyl, C 1 -C 3 fluoroalkyl, C 3 -C 6 cycloalkyl, —(CH 2 ) r OR 13 , —C(O)NH 2 , —C(O)N(H)(C 1 -C 3 alkyl), —C(O)N(C 1 -C 3 alkyl) 2 , —(CH 2 ) r S(O) t R 14 , —(CH 2 ) r -phenyl, or —(CH 2 ) r N(H)C(O)—(C 1 -C 3 alkyl);

R 13 is H or C 1 -C 3 alkyl; and

R 14 is C 1 -C 3 alkyl;

the subscript r is 1 or 2;

the subscript t is 0, 1, or 2; and

R d is H or C 1 -C 3 alkyl.

8. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein

R a is H or methoxymethyl;

R b is H;

R c is H, methyl, methoxymethyl, or —CH 2 SO 2 CH 3 ; and

R d is H.

9. The compound of claim 1 selected from the group consisting of:

(S)-5-((2-aminopropyl)amino)-3-(benzofuran-2-yl)pyrazine-2-carboxamide;

5-(((1R,2S)-2-aminocyclohexyl)amino)-3-(1H-indol-2-yl)pyrazine-2-carboxamide;

5-{[(2S)-2-aminopropyl]amino}-3-(1H-indol-2-yl)pyrazine-2-carboxamide;

5-(((3S,4S)-4-amino-1,1-dioxidotetrahydro-2H-thiopyran-3-yl)amino)-3-(1H-indol-2-yl)pyrazine-2-carboxamide;

(S)-5-((2-aminopropyl)amino)-3-(5-bromo-1H-indol-2-yl)pyrazine-2-carboxamide;

(S)-5-((2-aminopropyl)amino)-3-(5-(1-methyl-1H-pyrazol-4-yl)-1H-indol-2-yl)pyrazine-2-carboxamide;

(S)-5-((2-aminopropyl)amino)-3-(5-(2-(2-oxopyrrolidin-1-yl)ethyl)-1H-indol-2-yl)pyrazine-2-carboxamide;

5-{[(1R,2S)-2-aminocyclohexyl]amino}-3-(5-chloro-1H-indol-2-yl)pyrazine-2-carboxamide;

5-{[(2S)-2-aminopropyl]amino}-3-(4-bromo-1H-indol-2-yl)pyrazine-2-carboxamide;

5-[(3-aminotetrahydro-2H-pyran-4-yl)amino]-3-(4-chloro-1H-indol-2-yl)pyrazine-2-carboxamide;

5-[(3-aminotetrahydro-2H-pyran-4-yl)amino]-3-(4-chloro-1H-indol-2-yl)pyrazine-2-carboxamide;

5-{[(3R,4R)-3-aminotetrahydro-2H-pyran-4-yl]amino}-3-(5-methoxy-1H-indol-2-yl)pyrazine-2-carboxamide;

5-{[(3R,4R)-3-aminotetrahydro-2H-pyran-4-yl]amino}-3-(6-fluoro-1H-indol-2-yl)pyrazine-2-carboxamide;

5-{[(3S,4S)-4-amino-1,1-dioxidotetrahydro-2H-thiopyran-3-yl]amino}-3-(4-chloro-1H-indol-2-yl)pyrazine-2-carboxamide;

5-{[(3S,4S)-4-amino-1,1-dioxidotetrahydro-2H-thiopyran-3-yl]amino}-3-(5-methoxy-1H-indol-2-yl)pyrazine-2-carboxamide;

5-{[(3S,4S)-4-amino-1,1-dioxidotetrahydro-2H-thiopyran-3-yl]amino}-3-(5-fluoro-1H-indol-2-yl)pyrazine-2-carboxamide;

5-{[(3S,4S)-4-amino-1,1-dioxidotetrahydro-2H-thiopyran-3-yl]amino}-3-(5-chloro-1H-indol-2-yl)pyrazine-2-carboxamide;

(R)-5-((2-amino-3-methoxypropyl)amino)-3-(1H-indol-2-yl)pyrazine-2-carboxamide;

5-{[(3R,4R)-4-amino-1,1-dioxidotetrahydro-2H-thiopyran-3-yl]amino}-3-(1H-indol-2-yl)pyrazine-2-carboxamide;

5-{[(1R,2S)-2-aminocyclohexyl]amino}-3-(4-methyl-1H-indol-2-yl)pyrazine-2-carboxamide;

5-{[(3R,4R)-3-aminotetrahydro-2H-pyran-4-yl]amino}-3-(4-methyl-1H-indol-2-yl)pyrazine-2-carboxamide;

5-{[(3R,4R)-3-aminotetrahydro-2H-pyran-4-yl]amino}-3-(4-methoxy-1H-indol-2-yl)pyrazine-2-carboxamide;

5-{[(3R,4R)-3-aminotetrahydro-2H-pyran-4-yl]amino}-3-(1H-indol-2-yl)pyrazine-2-carboxamide;

5-{[(2R)-2-amino-3-methoxypropyl]amino}-3-(4-methoxy-1H-indol-2-yl)pyrazine-2-carboxamide;

5-[(2-aminoethyl)amino]-3-(5-fluoro-1H-indol-2-yl)pyrazine-2-carboxamide;

5-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-3-(4-methoxy-1H-pyrrolo[2,3-c]pyridin-2-yl)pyrazine-2-carboxamide;

5-(((3S,4S)-4-amino-1,1-dioxidotetrahydro-2H-thiopyran-3-yl)amino)-3-(5-(trifluoromethyl)-1H-indol-2-yl)pyrazine-2-carboxamide;

5-{[(3R,4R)-3-aminotetrahydro-2H-pyran-4-yl]amino}-3-(2,3-dihydro-7H-[1,4]dioxino[2,3-e]indol-8-yl)pyrazine-2-carboxamide;

5-{[(3R,4R)-3-aminotetrahydro-2H-pyran-4-yl]amino}-3-(4,5-dimethoxy-1H-indol-2-yl)pyrazine-2-carboxamide;

5-{[(3R,4R)-3-aminotetrahydro-2H-pyran-4-yl]amino}-3-(5-ethyl-1H-indol-2-yl)pyrazine-2-carboxamide;

5-{[(3R,4R)-3-aminotetrahydro-2H-pyran-4-yl]amino}-3-(4-ethyl-1H-indol-2-yl)pyrazine-2-carboxamide;

5-{[(3R,4R)-3-aminotetrahydro-2H-pyran-4-yl]amino}-3-(1H-pyrrolo[3,2-c]pyridin-2-yl)pyrazine-2-carboxamide;

5-{[(3R,4R)-3-aminotetrahydro-2H-pyran-4-yl]amino}-3-(1H-pyrrolo[3,2-b]pyridin-2-yl)pyrazine-2-carboxamide;

5-{[(3R,4R)-3-aminotetrahydro-2H-pyran-4-yl]amino}-3-(1H-pyrrolo[2,3-c]pyridin-2-yl)pyrazine-2-carboxamide;

5-(((3S,4S)-4-amino-1,1-dioxidotetrahydro-2H-thiopyran-3-yl)amino)-3-(3-chloro-1H-indol-2-yl)pyrazine-2-carboxamide;

(2-(6-(((3S,4S)-4-amino-1,1-dioxidotetrahydro-2H-thiopyran-3-yl)amino)-3-carbamoylpyrazin-2-yl)-1H-indol-3-yl)dimethylsulfonium;

(S)-5-((2-aminopropyl)amino)-3-(5-(pyridin-3-yl)-1H-indol-2-yl)pyrazine-2-carboxamide;

5-(2-aminoethylamino)-3-(1H-indol-2-yl)pyrazine-2-carboxamide;

5-{[2-amino-3-(methylsulfonyl)propyl]amino}-3-(1H-indol-2-yl)pyrazine-2-carboxamide;

(R)-5-((1-amino-3-methoxypropan-2-yl)amino)-3-(1H-indol-2-yl)pyrazine-2-carboxamide; and

(S)-5-((1-amino-3-methoxypropan-2-yl)amino)-3-(1H-indol-2-yl)pyrazine-2-carboxamide;

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 9 selected from the group consisting of:

5-(((3S,4S)-4-amino-1,1-dioxidotetrahydro-2H-thiopyran-3-yl)amino)-3-(1H-indol-2-yl)pyrazine-2-carboxamide;

5-{[(3R,4R)-3-aminotetrahydro-2H-pyran-4-yl]amino}-3-(5-methoxy-1H-indol-2-yl)pyrazine-2-carboxamide;

5-{[(1R,25)-2-aminocyclohexyl]amino}-3-(4-methyl-1H-indol-2-yl)pyrazine-2-carboxamide;

5-{[(3R,4R)-3-aminotetrahydro-2H-pyran-4-yl]amino}-3-(4-methoxy-1H-indol-2-yl)pyrazine-2-carboxamide; and

(S)-5-((2-aminopropyl)amino)-3-(5-(pyridin-3-yl)-1H-indol-2-yl)pyrazine-2-carboxamide;

or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

12. The compound of claim 1 , which is 5-(((3S,4S)-4-amino-1,1-dioxidotetrahydro-2H-thiopyran-3-yl)amino)-3-(1H-indol-2-yl)pyrazine-2-carboxamide, or a pharmaceutically acceptable salt thereof.