Inhibitors of Bruton's tyrosine kinase
View Patent ↗Disclosed herein are reversible and irreversible inhibitors of Bruton's tyrosine kinase (Btk). Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the Btk inhibitors are described, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, and inflammatory diseases or conditions.
1. A compound of Formula (IA) having the structure:
wherein:
ring A is substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 7 heterocycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, or substituted or unsubstituted C 1 -C 12 heteroaryl;
Y is optionally present and when present is —CH 2 O—, —OCH 2 —, —OCH 2 CH 2 O—, —O—, —N(R 3 )—, —C(O)—, —N(R 3 )C(O)—, —C(O)N(R 3 )—, —N(R 3 )C(O)N(R 3 )—, —S(O)—, —S(O) 2 —, —N(R 3 )S(O) 2 —, —S(O) 2 N(R 3 )—, —C(═NH)—, —C(═NH)N(R 3 )—, —C(═NH)N(R 3 )—, or substituted or unsubstituted C 1 -C 4 alkylene;
Z is optionally present and when present is substituted or unsubstituted C 1 -C 3 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 7 heterocycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, or substituted or unsubstituted C 1 -C 12 heteroaryl;
R 1 is —C(O)R 4 , —C(O)C(O)R 4 , —C(O)N(R 3 )(R 4 ), or —S(O) 2 R 4 ;
each R 2 is independently H, substituted or unsubstituted C 1 -C 4 alkyl, —CN, or halogen;
each R 3 is independently is H, or substituted or unsubstituted C 1 -C 4 alkyl;
each R 4 is independently H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 7 heterocycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, or substituted or unsubstituted C 1 -C 12 heteroaryl;
R 5 is H, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 7 heterocycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, or substituted or unsubstituted C 1 -C 12 heteroaryl; or R 1 and R 5 together with the nitrogen atom to which they are attached are combined to form a substituted or unsubstituted C 2 -C 9 heterocycloalkyl ring;
each R 6 is independently halogen, —CN, —OH, —NH 2 , substituted or unsubstituted C 1 -C 4 alkoxy, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 6 heterocycloalkyl, or —N(R 3 ) 2 ; or R 1 and R 6 are combined to form a substituted or unsubstituted C 2 -C 9 heterocycloalkyl ring;
each R 7 is independently halogen, —CN, —OH, —NH 2 , substituted or unsubstituted C 1 -C 4 alkoxy, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 6 heterocycloalkyl, or —N(R 3 ) 2 ;
n is 0-3;
p is 0-3; and
q is 0-3;
or a pharmaceutically acceptable solvate, or pharmaceutically acceptable salt thereof;
provided that
when n is 0; then each of p and q is independently 0, 1, or 2.
2. A compound of Formula (I) having the structure:
wherein:
ring A is substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 7 heterocycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, or substituted or unsubstituted C 1 -C 12 heteroaryl;
Y is optionally present and when present is —CH 2 O—, —OCH 2 —, —OCH 2 CH 2 O—, —O—, —N(R 3 )—, —C(O)—, —N(R 3 )C(O)—, —C(O)N(R 3 )—, —N(R 3 )C(O)N(R 3 )—, —S(O)—, —S(O) 2 —, —N(R 3 )S(O) 2 —, —S(O) 2 N(R 3 )—, —C(═NH)—, —C(═NH)N(R 3 )—, —C(═NH)N(R 3 )—, or substituted or unsubstituted C 1 -C 4 alkylene;
Z is optionally present and when present is substituted or unsubstituted C 1 -C 3 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 7 heterocycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, or substituted or unsubstituted C 1 -C 12 heteroaryl;
G is
R 1 is —C(O)(R 4 ), —C(O)N(R 3 )(R 4 ), or —S(O) 2 R 4 ;
each R 2 is independently H, —CN, or halogen;
each R 3 is independently is H, or substituted or unsubstituted C 1 -C 4 alkyl;
each R 4 is independently H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 7 heterocycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, or substituted or unsubstituted C 1 -C 12 heteroaryl;
R 5 is H, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 7 heterocycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, or substituted or unsubstituted C 1 -C 12 heteroaryl; or R 1 and R 5 together with the nitrogen atom to which they are attached are combined to form a substituted or unsubstituted C 2 -C 9 heterocycloalkyl ring;
each R 6 is independently halogen, —CN, —OH, —NH 2 , substituted or unsubstituted C 1 -C 4 alkoxy, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 6 heterocycloalkyl, or —N(R 3 ) 2 ; or R 1 and R 6 are combined to form a substituted or unsubstituted C 2 -C 9 heterocycloalkyl ring;
each R 7 is independently halogen, —CN, —OH, —NH 2 , substituted or unsubstituted C 1 -C 4 alkoxy, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 6 heterocycloalkyl, or —N(R 3 ) 2 ;
p is 0-3; and
q is 0-3;
or a pharmaceutically acceptable solvate, or pharmaceutically acceptable salt thereof.
3. The compound of claim 1 , wherein the compound is of the structure
or a pharmaceutically acceptable solvate, or pharmaceutically acceptable salt thereof.
4. The compound of claim 3 , wherein the compound is of the structure:
or a pharmaceutically acceptable solvate, or pharmaceutically acceptable salt thereof.
5. The compound according to claim 2 , wherein the compound is of Formula (IV) having the structure:
or a pharmaceutically acceptable solvate, or pharmaceutically acceptable salt thereof.
6. The compound of claim 5 , wherein R 6 is Me.
7. The compound of claim 5 , wherein ring A is phenyl.
8. The compound of claim 5 , wherein Y is absent, —CH 2 O—, —OCH 2 —, —O—, —N(R 3 )—, —C(O)—, —N(R 3 )C(O)—, —C(O)N(R 3 )—, or substituted or unsubstituted C 1 -C 4 alkylene.
9. The compound of claim 5 , wherein Z is substituted or unsubstituted C 2 -C 7 heterocycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, or substituted or unsubstituted C 1 -C 12 heteroaryl.
10. The compound of claim 5 , wherein R 1 is —C(O)R 4 .
11. The compound of claim 10 , wherein R 4 is substituted or unsubstituted C 6 -C 12 aryl, or substituted or unsubstituted C 1 -C 12 heteroaryl.
12. The compound of claim 5 , wherein ring A is substituted or unsubstituted C 1 -C 12 heteroaryl.
13. The compound of claim 12 , wherein ring A is pyridyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, or isoxazolyl.
14. The compound of claim 5 , wherein R 1 is —C(O)N(R 3 )(R 4 ).
15. The compound of claim 5 , wherein R 1 is —C(O)N(R 3 )(R 4 ) and R 4 is H, or substituted or unsubstituted C 1 -C 6 alkyl.
16. The compound of claim 5 , wherein R 1 and R 5 together with the nitrogen atom to which they are attached are combined to form a substituted or unsubstituted C 2 -C 9 heterocycloalkyl ring.
17. A compound selected from the group consisting of
5-[(3R)-3-(4-tert-butylbenzamido)piperidin-1-yl]-3-{[4-(morpholine-4-carbonyl)phenyl]amino}pyrazine-2-carboxamide;
5-[(3R)-3-(4-tert-butylbenzamido)piperidin-1-yl]-3-{[4-(1-methylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;
5-[(3R)-3-(4-tert-butylbenzamido)piperidin-1-yl]-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide;
3-{[4-(1-methylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-[(piperidine-1-carbonyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5-[(3R)-3-[(piperidine-1-carbonyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;
5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]-3-{[4-(1-propanoylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;
3-({4-[1-(cyanomethyl)piperidin-4-yl]phenyl}amino)-5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]pyrazine-2-carboxamide;
5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]-3-({4-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]phenyl}amino)pyrazine-2-carboxamide;
3-{[3-fluoro-4-(morpholin-4-yl)phenyl]amino}-5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]pyrazine-2-carboxamide;
5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]-3-{[4-(3-oxomorpholin-4-yl)phenyl]amino}pyrazine-2-carboxamide;
5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]-3-[(3-methyl-1,2-thiazol-5-yl)amino]pyrazine-2-carboxamide;
3-({4-[2-(dimethylamino)ethoxy]phenyl}amino)-5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]pyrazine-2-carboxamide;
(R)-2-(4-(3-carbamoyl-6-(3-(4-methoxybenzamido)piperidin-1-yl)pyrazin-2-ylamino)phenoxy)-N,N-dimethylethanamine oxide;
3-{[4-(dimethylcarbamoyl)phenyl]amino}-5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]pyrazine-2-carboxamide;
3-({4-[4-(dimethylcarbamoyl)piperidin-1-yl]phenyl}amino)-5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]pyrazine-2-carboxamide;
5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]-3-({4-[1-(propan-2-yl)piperidin-4-yl]phenyl}amino)pyrazine-2-carboxamide;
3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(1-formylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]pyrazine-2-carboxamide;
5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]-3-{[4-(morpholin-4-yl)phenyl]amino}pyrazine-2-carboxamide;
3-[(6-ethoxypyridin-3-yl)amino]-5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]pyrazine-2-carboxamide;
3-[(4-methanesulfonylphenyl)amino]-5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]pyrazine-2-carboxamide;
5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]-3-{[4-(2-oxo-1,2-dihydropyridin-1-yl)phenyl]amino}pyrazine-2-carboxamide;
3-{[4-(1-methanesulfonylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]pyrazine-2-carboxamide;
3-({4-[1-(2-cyanoacetyl)piperidin-4-yl]phenyl}amino)-5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]pyrazine-2-carboxamide;
3-[(4-methanesulfonylphenyl)amino]-5-[(3R)-3-[(piperidine-1-carbonyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(2-ethoxyethoxy)phenyl]amino}-5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]pyrazine-2-carboxamide;
3-[(4-ethoxyphenyl)amino]-5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]pyrazine-2-carboxamide;
5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]-3-{[4-(oxan-4-yl)phenyl]amino}pyrazine-2-carboxamide;
5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]-3-{[4-(2-oxopiperidin-1-yl)phenyl]amino}pyrazine-2-carboxamide;
3-({4-[1-(dimethylcarbamoyl)piperidin-4-yl]phenyl}amino)-5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]pyrazine-2-carboxamide;
5-[(3R)-3-[(piperidine-1-carbonyl)amino]piperidin-1-yl]-3-{[4-(1-propanoylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;
3-{[4-(1-acetylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(1-formylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-[(piperidine-1-carbonyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;
5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]-3-{[4-(1-methylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;
5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]-3-{[6-(morpholin-4-yl)pyridin-3-yl]amino}pyrazine-2-carboxamide;
5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]-3-[(quinolin-6-yl)amino]pyrazine-2-carboxamide;
3-[(1,3-benzothiazol-6-yl)amino]-5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]pyrazine-2-carboxamide;
5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]-3-[(4-methoxyphenyl)amino]pyrazine-2-carboxamide;
5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]-3-{[4-(2-methoxyethoxy)phenyl]amino}pyrazine-2-carboxamide;
3-({4-[1-(2-cyanoacetyl)piperidin-4-yl]phenyl}amino)-5-[(3R)-3-[(piperidine-1-carbonyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;
5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-[(4-methanesulfonylphenyl)amino]pyrazine-2-carboxamide;
3-({4-[1-(2-cyanoacetyl)piperidin-4-yl]phenyl}amino)-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;
5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-{[4-(piperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;
5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-{[4-(1-propanoylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;
3-{[4-(1-ethylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(1-cyclopropylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]pyrazine-2-carboxamide;
5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-{[4-(1-methylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;
5-[(3R)-3-{[ethyl(methyl)carbamoyl]amino}piperidin-1-yl]-3-{[4-(1-methylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;
5-[(3R)-3-[(diethylcarbamoyl)amino]piperidin-1-yl]-3-{[4-(1-methylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;
5-[(3R)-3-(4-fluorobenzamido)piperidin-1-yl]-3-{[4-(1-methylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;
5-[(3R)-3-(4-ethoxybenzamido)piperidin-1-yl]-3-{[4-(1-methylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;
5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]-3-{[4-(propan-2-yl)phenyl]amino}pyrazine-2-carboxamide;
3-{[4-(1,1-dioxo-1λ 6 -thiomorpholin-4-yl)phenyl]amino}-5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]pyrazine-2-carboxamide;
5-[(3R)-3-[(dimethylcarbamoyl)(methyl)amino]piperidin-1-yl]-3-{[4-(1,1-dioxo-1λ 6 -thiomorpholin-4-yl)phenyl]amino}pyrazine-2-carboxamide;
3-{[2-fluoro-4-(piperidin-4-yl)phenyl]amino}-5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]pyrazine-2-carboxamide;
3-{[3-fluoro-4-(piperidin-4-yl)phenyl]amino}-5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]pyrazine-2-carboxamide;
5-[(3R)-3-[(dimethylcarbamoyl)(methyl)amino]piperidin-1-yl]-3-{[4-(1-propanoylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;
5-[(3R)-3-[(dimethylcarbamoyl)(methyl)amino]piperidin-1-yl]-3-({4-[1-(dimethylcarbamoyl)piperidin-4-yl]phenyl}amino)pyrazine-2-carboxamide;
5-[(3R)-3-[(dimethylcarbamoyl)(methyl)amino]piperidin-1-yl]-3-{[4-(1-methanesulfonylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;
3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-[(dimethylcarbamoyl)(methyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(1,1-dioxo-1λ 6 -thiomorpholin-4-yl)phenyl]amino}-5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;
5-[(3R)-3-{imidazo[1,2-a]pyridine-6-amido}piperidin-1-yl]-3-{[4-(oxan-4-yl)phenyl]amino}pyrazine-2-carboxamide;
5-[(3R)-3-{5-hydroxyimidazo[1,2-a]pyridine-6-amido}piperidin-1-yl]-3-{[4-(oxan-4-yl)phenyl]amino}pyrazine-2-carboxamide;
5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]-3-{[4-(piperidin-1-yl)phenyl]amino}pyrazine-2-carboxamide;
3-{[4-(1-cyclopropylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;
5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-{[4-(1,1-dioxo-1λ 6 -thiomorpholin-4-yl)phenyl]amino}pyrazine-2-carboxamide;
3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(1-ethylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-{[ethyl(methyl)carbamoyl]amino}piperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-propanamidopiperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(4-fluorobenzamido)piperidin-1-yl]pyrazine-2-carboxamide;
5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-(phenylamino)pyrazine-2-carboxamide;
5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-{[4-(4-methylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;
5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-{[4-(1-ethylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;
3-{[4-(1-cyclopropylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;
3-[(4-chlorophenyl)amino]-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;
5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-({4-[1-(propan-2-yl)piperidin-4-yl]phenyl}amino)pyrazine-2-carboxamide;
4-[4-({3-carbamoyl-6-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazin-2-yl}amino)phenyl]-1-(propan-2-yl)piperidin-1-ium-1-olate;
3-[(4-chloro-3-methoxyphenyl)amino]-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;
5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-[(3-methoxy-4-methylphenyl)amino]pyrazine-2-carboxamide;
5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-{[4-(4-methyl-1-propanoylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;
3-({4-[1-(dimethylcarbamoyl)-4-methylpiperidin-4-yl]phenyl}amino)-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(1-cyclopentyl-4-methylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(4-cyclopropylpiperazin-1-yl)phenyl]amino}-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;
5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-[(4-fluorophenyl)amino]pyrazine-2-carboxamide;
3-{[4-(4-cyclopentylpiperazin-1-yl)phenyl]amino}-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;
5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-({4-[(pyridin-2-yl)carbamoyl]phenyl}amino)pyrazine-2-carboxamide;
5-[(3R)-3-{[methyl(phenyl)carbamoyl]amino}piperidin-1-yl]-3-(phenylamino)pyrazine-2-carboxamide;
3-{[2-chloro-4-(piperidin-4-yl)phenyl]amino}-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;
5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-({4-[1-(dimethylcarbamoyl)piperidin-4-yl]phenyl}amino)pyrazine-2-carboxamide;
3-{[4-(1-cyclobutylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;
5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-({4-[1-(oxan-4-yl)piperidin-4-yl]phenyl}amino)pyrazine-2-carboxamide;
5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-[(4-{1-[2-(2-hydroxyethoxy)ethyl]piperidin-4-yl}phenyl)amino]pyrazine-2-carboxamide;
3-{[4-(1-cyclopropanecarbonylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;
5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-{[4-(1-methanesulfonylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;
ethyl N-[(3R)-1-(5-carbamoyl-6-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}pyrazin-2-yl)piperidin-3-yl]carbamate;
5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-[(5-fluoro-6-methylpyridin-2-yl)amino]pyrazine-2-carboxamide;
5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-({4-[1-(pyridin-2-yl)piperidin-4-yl]phenyl}amino)pyrazine-2-carboxamide;
5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-{[4-(dimethylcarbamoyl)phenyl]amino}pyrazine-2-carboxamide;
5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-{[4-(pyrrolidine-1-carbonyl)phenyl]amino}pyrazine-2-carboxamide;
5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-{[4-(1-phenylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;
3-{[4-(1-cyclohexylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;
5-[(3R)-3-aminopiperidin-1-yl]-3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;
3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-formamidopiperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-methanesulfonamidopiperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-ethanesulfonamidopiperidin-1-yl]pyrazine-2-carboxamide;
5-[(3R)-3-benzamidopiperidin-1-yl]-3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;
3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(pyridine-3-amido)piperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(5-fluoropyridine-3-amido)piperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(2-oxopyrrolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-cyclopropaneamidopiperidin-1-yl]pyrazine-2-carboxamide;
5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-({4-[1-(oxetan-3-yl)piperidin-4-yl]phenyl}amino)pyrazine-2-carboxamide;
3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(3-ethyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(2R,3R)-3-[(dimethylcarbamoyl)amino]-2-methylpiperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(2S,3R)-3-[(dimethylcarbamoyl)amino]-2-methylpiperidin-1-yl]pyrazine-2-carboxamide;
3-({4-[4-methyl-1-(propan-2-yl)piperidin-4-yl]phenyl}amino)-5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(1-cyclopropyl-4-methylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;
3-({4-[4-methyl-1-(oxetan-3-yl)piperidin-4-yl]phenyl}amino)-5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(1-cyclobutyl-4-methylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(1-cyclopentyl-4-methylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(1-formyl-4-methylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(4-methyl-1-propanoylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(1-cyclopropanecarbonyl-4-methylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-[(dimethylsulfamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;
5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-({4-[1-(dimethylsulfamoyl)piperidin-4-yl]phenyl}amino)pyrazine-2-carboxamide;
5-[(2R,3R)-3-amino-2-methylpiperidin-1-yl]-3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;
5-[(2S,3R)-3-amino-2-methylpiperidin-1-yl]-3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;
5-[(3R)-3-aminopiperidin-1-yl]-3-{[4-(1-cyclopropylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;
3-[(4-cyclohexylphenyl)amino]-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(1-cyanocyclopentyl)phenyl]amino}-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(1-cyclopropylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-{spiro[3.3]heptane-2-amido}piperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(1-cyclopropylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(4-phenylbenzamido)piperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(1-cyclopropylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(6-phenylpyridine-3-amido)piperidin-1-yl]pyrazine-2-carboxamide;
5-[(2R,3R)-3-benzamido-2-methylpiperidin-1-yl]-3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;
5-[(2S,3R)-3-benzamido-2-methylpiperidin-1-yl]-3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;
5-[(3R)-3-(1-benzothiophene-2-amido)piperidin-1-yl]-3-{[4-(1-cyclopropylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;
5-[(3R)-3-(3-chlorobenzamido)piperidin-1-yl]-3-{[4-(1-cyclopropylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;
5-[(3R)-3-(4-chlorobenzamido)piperidin-1-yl]-3-{[4-(1-cyclopropylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;
5-[(3R)-3-(5-chlorothiophene-2-amido)piperidin-1-yl]-3-{[4-(1-cyclopropylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;
5-[(3R)-3-cyclopentaneamidopiperidin-1-yl]-3-{[4-(1-cyclopropylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;
3-{[4-(1-cyclopropylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(4,5,6,7-tetrahydro-1-benzothiophene-2-amido)piperidin-1-yl]pyrazine-2-carboxamide;
5-[(3R)-3-(5-chloropyridine-3-amido)piperidin-1-yl]-3-{[4-(1-cyclopropylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;
3-{[4-(1-cyclopropylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(naphthalene-2-amido)piperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(1-cyclopropylpiperidin-4-yl)phenyl]amino}-5-[(2R,3R)-3-[(dimethylcarbamoyl)amino]-2-methylpiperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(1-cyclobutyl-4-methylpiperidin-4-yl)phenyl]amino}-5-[(2R,3R)-3-[(dimethylcarbamoyl)amino]-2-methylpiperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(1-cyclopentyl-4-methylpiperidin-4-yl)phenyl]amino}-5-[(2R,3R)-3-[(dimethylcarbamoyl)amino]-2-methylpiperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(1-cyano-1-methylethyl)phenyl]amino}-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(1-carbamoyl-1-methylethyl)phenyl]amino}-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(1-cyanocyclopentyl)phenyl]amino}-5-[(2R,3R)-3-[(dimethylcarbamoyl)amino]-2-methylpiperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(1-carbamoylcyclopentyl)phenyl]amino}-5-[(2R,3R)-3-[(dimethylcarbamoyl)amino]-2-methylpiperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(4-cyano-1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(4-carbamoyl-1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;
5-[(3 aR,7aR)-1-(dimethylcarbamoyl)-octahydro-1H-pyrrolo[3,2-b]pyridin-4-yl]-3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;
5-[(3 aR,7aR)-1-cyclopropanecarbonyl-octahydro-1H-pyrrolo[3,2-b]pyridin-4-yl]-3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;
3-{[4-(1-cyanocyclopropyl)phenyl]amino}-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(1-carbamoylcyclopropyl)phenyl]amino}-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(4-cyano-1-cyclobutylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;
5-[(3aR,7aR)-octahydro-1H-pyrrolo[3,2-b]pyridin-4-yl]-3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;
3-{[4-(1-cyclobutylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;
5-[(3R)-3-[3-(3-chlorophenyl)-2-oxoimidazolidin-1-yl]piperidin-1-yl]-3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;
5-[(2R,3R)-2-methyl-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]-3-{[4-(4-methylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;
3-{[4-(1-cyclobutyl-4-methylpiperidin-4-yl)phenyl]amino}-5-[(2R,3R)-2-methyl-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(1-cyclopentyl-4-methylpiperidin-4-yl)phenyl]amino}-5-[(2R,3R)-2-methyl-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;
5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]-3-(phenylamino)pyrazine-2-carboxamide;
5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]-3-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)pyrazine-2-carboxamide;
5-[(3aR,7aR)-octahydro-1H-pyrrolo[2,3-c]pyridin-6-yl]-3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;
3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(3-methyl-2-oxo-1,3-diazinan-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(1-cyclopropyl-4-methylpiperidin-4-yl)phenyl]amino}-5-[(2R,3R)-3-[(dimethylcarbamoyl)amino]-2-methylpiperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(3R,4R)-3-[(dimethylcarbamoyl)amino]-4-methylpiperidin-1-yl]pyrazine-2-carboxamide;
5-[(3 aS,7aR)-1-(dimethylcarbamoyl)-octahydro-1H-pyrrolo[2,3-c]pyridin-6-yl]-3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;
5-[(3 aS,7aR)-1-cyclopropanecarbonyl-octahydro-1H-pyrrolo[2,3-c]pyridin-6-yl]-3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;
3-{[4-(1-cyclobutylpiperidin-4-yl)phenyl]amino}-5-[(2R,3R)-3-[(dimethylcarbamoyl)amino]-2-methylpiperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(4-methyl-1-propanoylpiperidin-4-yl)phenyl]amino}-5-[(2R,3R)-2-methyl-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(3-cyclopropyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;
5-[(3R)-3-(3-cyclopropyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]-3-{[4-(1-cyclopropyl-4-methylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;
3-{[4-(1-cyclobutylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(3-cyclopropyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(4-cyano-1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(2R,3R)-3-[(dimethylcarbamoyl)amino]-2-methylpiperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(4-carbamoyl-1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(2R,3R)-3-[(dimethylcarbamoyl)amino]-2-methylpiperidin-1-yl]pyrazine-2-carboxamide;
5-[(2R,3R)-3-[(dimethylcarbamoyl)amino]-2-methylpiperidin-1-yl]-3-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)pyrazine-2-carboxamide;
3-{[4-(1-cyanocyclopropyl)phenyl]amino}-5-[(2R,3R)-3-[(dimethylcarbamoyl)amino]-2-methylpiperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(1-carbamoylcyclopropyl)phenyl]amino}-5-[(2R,3R)-3-[(dimethylcarbamoyl)amino]-2-methylpiperidin-1-yl]pyrazine-2-carboxamide;
3-({4-[1-(aminomethyl)cyclopentyl]phenyl}amino)-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;
5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-({4-[1-(dimethylcarbamoyl)cyclopropyl]phenyl}amino)pyrazine-2-carboxamide;
5-[(3R)-3-({[3-chloro-5-(trifluoromethyl)phenyl](methyl)carbamoyl}amino)piperidin-1-yl]-3-[(4-fluorophenyl)amino]pyrazine-2-carboxamide;
5-[(3R)-3-({[3-chloro-5-(trifluoromethyl)phenyl](methyl)carbamoyl}amino)piperidin-1-yl]-3-{[4-(1-cyanocyclopropyl)phenyl]amino}pyrazine-2-carboxamide;
3-{[4-(1-carbamoylcyclopropyl)phenyl]amino}-5-[(3R)-3-({[3-chloro-5-(trifluoromethyl)phenyl](methyl)carbamoyl}amino)piperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(1-cyclopropylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(3-methyl-2-oxo-1,3-diazinan-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(1-cyclopropyl-4-methylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(3-methyl-2-oxo-1,3-diazinan-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;
3-[(1-cyclopropyl-1H-pyrazol-4-yl)amino]-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;
3-[(1-cyclopentyl-1H-pyrazol-4-yl)amino]-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(1-cyclopentyl-4-methylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(3-methyl-2-oxo-1,3-diazinan-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(1-cyclopropyl-4-methylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(3-ethyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(2R,3R)-2-methyl-3-(3-methyl-2-oxo-1,3-diazinan-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;
3-({4-[1-(aminomethyl)cyclopropyl]phenyl}amino)-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;
3-({4-[(dimethylamino)methyl]phenyl}amino)-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;
5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-[(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)amino]pyrazine-2-carboxamide;
3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-[(dimethylcarbamoyl)amino]azepan-1-yl]pyrazine-2-carboxamide;
3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-cyclopropaneamidoazepan-1-yl]pyrazine-2-carboxamide;
3-{[1-(1-cyclopentylazetidin-3-yl)-1H-pyrazol-4-yl]amino}-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;
3-{[1-(1-cyclopentylpiperidin-4-yl)-1H-pyrazol-4-yl]amino}-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;
3-{[1-(1-cyclopropanecarbonylpiperidin-4-yl)-1H-pyrazol-4-yl]amino}-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;
(4aR,8aR)-5-(5-carbamoyl-6-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}pyrazin-2-yl)-N,N-dimethyl-decahydro-1,5-naphthyridine-1-carboxamide;
5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-[(3-methyl-1,2-thiazol-5-yl)amino]pyrazine-2-carboxamide;
5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-[(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)amino]pyrazine-2-carboxamide;
5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-{[4-(propan-2-yloxy)phenyl]amino}pyrazine-2-carboxamide;
5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-{[4-(2-methoxyethoxy)phenyl]amino}pyrazine-2-carboxamide;
3-({4-[2-(dimethylamino)ethoxy]phenyl}amino)-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;
5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-[(4-nitrophenyl)amino]pyrazine-2-carboxamide;
3-{[4-(1-cyclobutylpiperidin-4-yl)phenyl]amino}-5-[(2R,3R)-3-[(dimethylcarbamoyl)amino]-2-ethylpiperidin-1-yl]pyrazine-2-carboxamide;
3-{[4-(cyclopentyloxy)phenyl]amino}-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;
5-[(2R,3R)-3-[(dimethylcarbamoyl)amino]-2-methylpiperidin-1-yl]-3-[(3-methyl-1,2-thiazol-5-yl)amino]pyrazine-2-carboxamide;
5-[(2R,3R)-3-[(dimethylcarbamoyl)amino]-2-methylpiperidin-1-yl]-3-{[4-(propan-2-yloxy)phenyl]amino}pyrazine-2-carboxamide;
5-[(2R,3R)-3-[(dimethylcarbamoyl)amino]-2-methylpiperidin-1-yl]-3-[(4-methanesulfonylphenyl)amino]pyrazine-2-carboxamide;
3-(4-(2-methoxyethoxy)phenylamino)-5-((R)-3-(3-((S)-1-phenylethyl)ureido)piperidin-1-yl)pyrazine-2-carboxamide;
3-(4-(2-methoxyethoxy)phenylamino)-5-((R)-3-(3-((R)-1-phenylethyl)ureido)piperidin-1-yl)pyrazine-2-carboxamide;
(R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(cyclopropanecarboxamido)-2-methylpiperidin-1-yl)pyrazine-2-carboxamide;
(R)-3-(cyclopropylamino)-5-(3-(3-methyl-3-phenylureido)piperidin-1-yl)pyrazine-2-carboxamide;
(R)-3-(cyclopentylamino)-5-(3-(3-methyl-3-phenylureido)piperidin-1-yl)pyrazine-2-carboxamide;
(R)-5-(3-(3-(3-chloro-5-(trifluoromethyl)phenyl)-3-methylureido)piperidin-1-yl)-3-(cyclopropylamino)pyrazine-2-carboxamide;
(R)-5-(3-(3-(3-chloro-5-(trifluoromethyl)phenyl)-3-methylureido)piperidin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide; and
(R)-5-(3-(3-(tetrahydro-2H-pyran-4-yl)ureido)piperidin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide;
or a pharmaceutically acceptable solvate or pharmaceutically acceptable salt thereof.
18. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , and a pharmaceutically acceptable excipient.
19. The compound of claim 1 , wherein R 1 is —C(O)R 4 , —C(O)N(R 3 )(R 4 ), or —S(O) 2 R 4 .
20. The compound of claim 2 , wherein R 1 is —C(O)R 4 or —C(O)N(R 3 )(R 4 ).