Pyrazin-2-yl-pyridin-2-yl-amine and pyrazin-2-yl-pyrimidin-4-yl-amine compounds and their use

1. A method of inhibiting CHK1 kinase function in a cell, in vitro or in vivo, comprising contacting the cell with an effective amount of a compound selected from compounds of the following formula, and pharmaceutically acceptable salts thereof:

wherein:

—X═ is —CR A5 ═;

—R A5 is -Q A5 ;

—R A3 is —H;

—R A4 is independently -Q A4N or —O-Q A4O ;

—R B3 is —H;

—R B5 is -Q B5 ;

-Q B5 is —CN; and

—R B6 is independently —H or -Q B6 ;

and wherein:

-Q A4N is independently -Q A4N1 or -Q A4N2 ;

-Q A4N1 is independently —NHR QN1 or —NR QN1 2 ;

-Q A4N2 is —NR QN2 R QN3 ;

each —R QN1 is independently:

—R I1 , —R I4 , —R I6 , —R I7 , —R I8 ,

-L I -R I4 , -L I -R I6 , -L I -R I7 , or -L I -R I8 ;

wherein:

each —R I1 is saturated aliphatic C 1-6 alkyl;

each —R I4 is saturated C 3-6 cycloalkyl;

each —R I6 is non-aromatic C 3-8 heterocyclyl;

each —R I7 is phenyl;

each —R I8 is C 5-6 heteroaryl;

each -L I - is saturated aliphatic C 1-3 alkylene;

and wherein:

each C 1-6 alkyl, C 3-6 cycloalkyl, non-aromatic C 3-8 heterocyclyl, phenyl, C 5-6 heteroaryl, and C 1-3 alkylene is optionally substituted with one or more substituents —R I9 , wherein each —R I9 is independently:

—R L1 ,

—OH, —OR L1 ,

—NH 2 , —NHR L1 , —NR L1 2 , —NR L2 R L3 ,

—C(═O)NH 2 , —C(═O)NHR L1 , —C(═O)NR L1 2 , or —C(═O)NR L2 R L3 ;

wherein:

each —NR L2 R L3 is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted with one or more groups selected from C 1-3 alkyl and —CF 3 ;

each —R L1 is independently:

—R Z1 , —R Z7 , or -L Z -R Z7 ;

wherein:

each —R Z1 is saturated aliphatic C 1-6 alkyl;

each —R Z7 is phenyl;

each -L Z - is saturated aliphatic C 1-3 alkylene;

and wherein:

each C 1-6 alkyl, C 6-10 carboaryl, and C 1-3 alkylene is optionally substituted with one or more substituents —R Z9 , wherein each —R Z9 is independently:

—F, —Cl, —Br, —I,

—R ZZ1 ,

—CF 3 , —OCF 3 ,

—OH, -L ZZ -OH,

—OR ZZ1 -L ZZ -OR ZZ1 ,

—NH 2 , —NHR ZZ1 , —NR ZZ1 2 , —NR ZZ2 R ZZ3 ,

-L ZZ -NH 2 , -L ZZ -NHR ZZ1 , -L ZZ -NR ZZ1 2 , -L ZZ -NR ZZ2 R ZZ3 ,

—C(═O)OH, —C(═O)OR ZZ1 ,

—C(═O)NH 2 , —C(═O)NHR ZZ1 , —C(═O)NR ZZ1 2 , or —C(═O)NR ZZ2 R ZZ3 ;

wherein:

each —R ZZ1 is independently saturated aliphatic C 1-4 alkyl, phenyl, or benzyl;

each -L ZZ - is saturated aliphatic C 1-5 alkylene; and

each —NR ZZ2 R ZZ3 is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted with one or more groups selected from C 1-3 alkyl and —CF 3 ;

and wherein:

—NR QN2 R QN3 is independently piperidino, piperazino, or morpholino, and is optionally substituted with one or more substituents —R QNR , wherein each —R QNR is independently:

—R AA1 ,

—NH 2 , —NHR AA1 , —NR AA1 2 , —NR AA2 R AA3 ,

-L AA -NH 2 , -L AA -NHR AA1 , -L AA -NR AA1 2 , or -L AA -NR AA2 R AA3 ;

wherein:

each -L AA - is saturated aliphatic C 1-5 alkylene;

each —NR AA2 R AA3 is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted with one or more groups selected from C 1-3 alkyl and —CF 3 ;

each —R AA1 is independently —R BB1 , —R BB7 , or -L BB -R BB7 ;

wherein:

each —R BB1 is saturated aliphatic C 1-6 alkyl;

each —R BB7 is phenyl;

each -L BB - is saturated aliphatic C 1-3 alkylene;

and wherein:

each C 1-6 alkyl, phenyl, and C 1-3 alkylene is optionally substituted with one or more substituents —R BB9 , wherein each —R BB9 is independently:

—F, —Cl, —Br, —I,

—R CC1 ,

—CF 3 , —OCF 3 ,

—OH, -L CC -OH,

—OR CC1 , -L CC -OR CC1 ,

—NH 2 , —NHR CC1 , —NR CC1 2 , —NR CC2 R CC3 ,

-L CC -NH 2 , -L CC -NHR CC1 , -L CC -NR CC1 2 , -L CC -NR CC2 R CC3 ,

—C(═O)OH, —C(═O)OR CC1 ,

—C(═O)NH 2 , —C(═O)NHR CC1 , —C(═O)NR CC1 2 , or —C(═O)NR CC2 R CC3 ;

wherein:

each —R CC1 is independently saturated aliphatic C 1-4 alkyl, phenyl, or benzyl;

each -L CC - is saturated aliphatic C 1-5 alkylene; and

each —NR CC2 R CC3 is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted with one or more groups selected from C 1-3 alkyl and —CF 3 ;

and wherein:

-Q A4O is independently —R C1 , wherein —R C1 is independently:

—R D1 , —R D6 , —R D7 , —R D8 ,

-L D -R D6 , -L D -R D7 , or -L D -R D8 ;

wherein:

each —R D1 is independently saturated aliphatic C 1-6 alkyl;

each —R D6 is non-aromatic C 3-8 heterocyclyl;

each —R D7 is phenyl;

each —R D8 is C 5-6 heteroaryl;

each -L D - is saturated aliphatic C 1-3 alkylene;

and wherein:

each C 1-6 alkyl, non-aromatic C 3-8 heterocyclyl, phenyl, C 6-10 carboaryl, C 5-6 heteroaryl, and C 1-3 alkylene is optionally substituted with one or more substituents —R D9 , wherein each —R D9 is independently:

—F, —Cl, —Br, —I,

—R E1 ,

—CF 3 , —OCF 3 ,

—OH, -L E -OH, —O-L E -OH,

—OR E1 , -L E -OR E1 , —O-L E -OR E1 ,

—NH 2 , —NHR E1 , —NR E1 2 , —NR E2 R E3 ,

-L E -NH 2 , -L E -NHR E1 , -L E -NR E1 2 , -L E -NR E2 R E3 ,

—O-L E -NH 2 , —O-L E -NHR E1 , —O-L E -NR E1 2 , —O-L E -NR E2 R E3 ,

—C(═O)OH, —C(═O)OR E1 ,

—C(═O)NH 2 , —C(═O)NHR E1 , —C(═O)NR E1 2 , or —C(═O)NR E2 R E3 ;

wherein:

each —R E1 is independently saturated aliphatic C 1-4 alkyl, phenyl, or benzyl;

each -L E - is saturated aliphatic C 1-5 alkylene; and

each —NR E2 R E3 is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted with one or more groups selected from C 1-3 alkyl and —CF 3 ;

and wherein:

-Q A5 is independently:

—F, —Cl, —Br, —I,

—R J1 ,

—CF 3 , —OCF 3 ,

—OH, -L J -OH, —O-L J -OH,

—OR J1 , -L J -OR J1 , —O-L J -OR J1 ,

—CN,

—NH 2 , —NHR J1 , —NR J1 2 , —NR J2 R J3 ,

-L J -NH 2 , -L J -NHR J1 , -L J- -NR J1 2 , -L J -NR J2 R J3 ,

—O-L J -NH 2 , —O-L J -NHR J1 , —O-L J -NR J1 2 , —O-L J -NR J2 R J3 ,

—C(═O)OH, —C(═O)OR J1 ,

—C(═O)NH 2 , —C(═O)NHR J1 , —C(═O)NR J1 2 , —C(═O)NR J2 R J3 ,

—NHC(═O)R J1 , —NR J1 C(═O)R J1 ,

—NHS(═O) 2 R J1 , —NR J1 S(═O) 2 R J1 , or

—C(═O)R J1 ;

wherein:

each -L J - is saturated aliphatic C 1-5 alkylene;

each —NR J2 R J3 is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted with one or more groups selected from C 1-3 alkyl and —CF 3 ;

each —R J1 is independently:

—R K1 , —R K2 , —R K3 , —R K4 , —R K5 , —R K6 , —R K7 , —R K8 ,

-L K -R K4 , -L K -R K5 , -L K -R K6 , -L K -R K7 , or -L K -R K8 ;

wherein:

each —R K1 is saturated aliphatic C 1-6 alkyl;

each —R K2 is aliphatic C 2-6 alkenyl;

each —R K3 is aliphatic C 2-6 alkynyl;

each —R K4 is saturated C 3-6 cycloalkyl;

each —R K5 is C 3-6 cycloalkenyl;

each —R K6 is non-aromatic C 3-8 heterocyclyl;

each —R K7 is phenyl;

each —R K8 is C 5-6 heteroaryl;

each -L K - is saturated aliphatic C 1-3 alkylene;

and wherein:

each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, non-aromatic C 3-8 heterocyclyl, phenyl, C 5-6 heteroaryl, and C 1-3 alkylene is optionally substituted with one or more substituents —R K9 , wherein each —R K9 is independently:

—F, —Cl, —Br, —I,

—R M1 ,

—CF 3 , —OCF 3 ,

—OH, -L M -OH,

—OR M1 , -L M -OR M1 , —O-L M -OR M1 ,

—NH 2 , —NHR M1 , —NR M1 2 , —NR M2 R M3 ,

-L M -NH 2 , -L M -NHR M1l , -L M -NR M1 2 , -L M -NR M2 R M3 ,

—C(═O)OH, —C(═O)OR M1 ,

—C(═O)NH 2 , —C(═O)NHR M1 , —C(═O)NR M1 2 , or —C(═O)NR M2 R M3 ;

wherein:

each —R M1 is independently saturated aliphatic C 1-4 alkyl, phenyl, or benzyl;

each -L M - is saturated aliphatic C 1-5 alkylene; and

each —NR M2 R M3 is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted with one or more groups selected from C 1-3 alkyl and —CF 3 ;

and wherein:

-Q B6 is independently:

—R W1 ,

—CF 3 , —OCF 3 ,

—OH, -L W -OH, —O-L W -OH,

—OR W1 , -L W -OR W1 , —O-L W -OR W1 ,

—CN,

—NH 2 , —NHR W1 , —NR W1 2 , —NR W2 R W3 ,

-L W -NH 2 , -L W -NHR W1 , -L W -NR W1 2 , -L W -NR W2 R W3 ,

—O-L W -NH 2 , —O-L W -NHR W1 , —O-L W -NR W1 2 , or —O-L W -NR W2 R W3 ;

wherein:

each -L W - is saturated aliphatic C 1-5 alkylene;

each —NR W2 R W3 is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted with one or more groups selected from C 1-3 alkyl and —CF 3 ;

each —R W1 is independently:

—R X1 , —R X4 , —R X6 , —R X7 , —R X8 ,

-L X -R X4 , -L X -R X6 , -L X -R X7 or -L X -R X8 ;

wherein:

each —R X1 is saturated aliphatic C 1-6 alkyl;

each —R X4 is saturated C 3-6 cycloalkyl;

each —R X6 is non-aromatic C 3-8 heterocyclyl;

each —R X7 is C 6-10 carboaryl;

each —R X8 is C 5-10 heteroaryl;

each -L X - is saturated aliphatic C 1-3 alkylene;

and wherein:

each C 1-6 alkyl, C 3-6 cycloalkyl, non-aromatic C 3-8 heterocyclyl, C 6-10 carboaryl, C 5-10 heteroaryl, and C 1-3 alkylene is optionally substituted with one or more substituents —R X9 , wherein each —R X9 is independently:

—F, —Cl, —Br, —I,

—R Y1 ,

—CF 3 , —OCF 3 ,

—OH, -L Y -OH,

—OR Y1 , -L Y -OR Y1 ,

—NH 2 , —NHR Y1 , —NR Y1 2 , —NR Y2 R Y3 ,

-L Y -NH 2 , -L Y -NHR Y1 , -L Y -NR Y1 2 , -L Y -NR Y2 R Y3 ,

—C(═O)OH, —C(═O)OR Y1 ,

—C(═O)NH 2 , —C(═O)NHR Y1 , —C(═O)NR Y1 2 , or —C(═O)NR Y2 R Y3 ;

wherein:

each —R Y1 is independently saturated aliphatic C 1-4 alkyl, phenyl, or benzyl;

each -L Y - is saturated aliphatic C 1-5 alkylene; and

each —NR Y2 R Y3 is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted with one or more groups selected from C 1-3 alkyl and —CF 3 .

2. A method according to claim 1 , wherein —R A4 is -Q A4N .

3. A method according to claim 1 , wherein —R A4 is —O-Q A4O .

4. A method according to claim 1 , wherein —R B6 is —H.

5. A method according to claim 1 , wherein —R B6 is -Q B6 .

6. A method according to claim 2 , wherein -Q A4N is -Q A4N1 .

7. A method to claim 6 , wherein:

each —R QN1 is —R I1 ; and

each —R I1 is saturated aliphatic C 1-5 alkyl.

8. A method according to claim 6 , wherein -Q A4N1 is independently selected from groups of the following formulae:

wherein:

n4 is independently 1 or 2

R NN1 is independently —H or saturated aliphatic C 1-4 alkyl; and

R NN4 is independently —H, saturated aliphatic C 1-4 alkyl, phenyl, or benzyl.

9. A method according to claim 8 , wherein -Q A4N1 is a group of formula (A4N1-J).

10. A method according to claim 9 , wherein:

n4 is 1;

—R NN1 is —H or -Me; and

—R NN4 is —H or -Me.

11. A method according to claim 1 , wherein -Q A5 is independently:

—F, —Cl, —Br, —I,

—R J1 ,

—NH 2 , —NHR J1 , —NR J1 2 , —NR J2 R J3 ,

—C(═O)OH, —C(═O)OR J1

—C(═O)NH 2 , —C(═O)NHR J1 , —C(═O)NR J1 2 , —C(═O)NR J2 R J3 ,

—NHC(═O)R J1 , —NR J1 C(═O)R J1 ,

—NHS(═O) 2 R J1 , or —NR J1 S(═O) 2 R J1 .

12. A method according to claim 1 , wherein -Q A5 is independently: —F, —Cl, —Br, —I, or —R J1 .

13. A method according to claim 1 , wherein -Q A5 is —R J1 .

14. A method according to claim 13 , wherein each —R J1 is independently:

—R K1 , —R K4 , —R K6 , —R K7 , —R K8 ,

-L K -R K4 , -L K -R K6 , -L K -R K7 , or -L K -R K8 .

15. A method according to claim 13 , wherein each —R J1 is —R K8 .

16. A method according to claim 15 , wherein each —R K8 is independently thienyl or pyrazolyl, and is optionally substituted.

17. A method according to claim 15 , wherein each —R K8 is independently selected from:

18. A method according to claim 1 , wherein each —R W1 is —R X1 ; and each —R X1 is saturated aliphatic C 1-3 alkyl.

19. A method according to claim 1 , which is a method of inhibiting CHK1 kinase function in a cell, in vitro.