2-heterocyclic compounds substituted pyrazines position 6 as inhibitors of CHK-1
2009
A compound of formula (I) ** ** Formula, wherein n is 0, 1 or 2; A is of the structure ** ** Formula and A is optionally further substituted with 1-6 R4; X1, X2, X3, X4 and X5 form a 5-membered ring heteroaryl having 1-4 nitrogen atoms in the ring; X1, X2, X3, X6 and X7 form a 5-membered ring heteroaryl having 1-4 nitrogen atoms in the ring; X1 is N or C; X2 is N, NH or CH; X3 is N; each of X4 and X5 is independently N or C; each of X6 and X7 is independently N, NH or CH; B together with X4 and X5 form a ring selected from phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl, C5-C6 cycloalkyl and C5-C6 cycloalkenyl, each of said 5-6 membered heteroaryl and heterocililo of 5-6 membered heterocycle having 1-3 heteroatoms in the ring selected from N, O and S; each of R1 and R2 is independently selected from hydrogen, fluorine, chlorine, - CN, -ORb, -N (Rb) 2 and C1-C3 alkyl optionally substituted with 1-6 groups selected from fluorine, chlorine and -CN; R3 represents 1-6 optional substituents independently selected from the group consisting of oxo- and R0; two R3 attached to the same ring atom, together with the ring atom to which they are attached, they may form a ring selected from C3-C6, C5-C6 cycloalkenyl and 3-6 membered heterocyclyl; each such C3-C6 cycloalkyl, C5-C6 cycloalkenyl and 3-6 member heterocyclyl is optionally further substituted with 1-5 groups selected from -oxo- and Rw; two R3 joined to two adjacent ring atoms, together with the ring atoms to which they are attached, may form a fused ring selected from C3-C6, C5-C6 cycloalkenyl, 3-6 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl; said C3-C6, C5-C6 cycloalkenyl, 3-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl are optionally further substituted with 1-5 groups selected from oxo and Rw; two R3 joined to two different ring atoms with one ring atom between them, form a C1-C4 alkylene, an 2-4 member heteroalkylene, or a diradical selected from the group consisting of: C1-C4 said , 2-4 member heteroalkylene diradical and, together with the azetidinyl (when n is 0), pyrrolidinyl (when n is 1) or piperidinyl (when n is 2) form a bridged bicyclic ring system, said ring system bridged bicyclic total 6-9 ring atoms with 1-3 atoms in the ring selected from O, N and S; the C1-C4 alkylene or heteroalkylene 1-4 members is optionally further substituted with 1-5 groups selected from -oxo- and Rw; each R4 is independently R0; each R0 is independently selected from the group consisting of (a) fluorine, chlorine and -CN; (B) C1-C6 alkyl, C2-C6 and C2-C6 alkynyl, each of them is further optionally substituted with 1-6 groups selected from fluorine, chlorine and CN; (C) C3-C6 cycloalkyl, -L- (C3-C6), 4-6 membered heterocyclyl, -L- (4-6 membered heterocyclyl), phenyl, -L-phenyl, 5-6 membered heteroaryl , -L- (5-6 membered heteroaryl), C5-C6 cycloalkenyl, -L- (C5-C6), wherein each C3-C6 alkyl, phenyl, 5-6 membered heteroaryl, heterocyclyl 4- 6 members and C5-C6 cycloalkenyl is optionally independently substituted with 1-6 Rx additionally; (D) -N (Ra) 2, -LN (Ra) 2; (E) -ORa, -L-ORa; (F) -OLN (Ra) 2, -N (Rb) -L-ORa, -L-OL-N (Ra) 2, -LN (Rb) -L-ORa; (G) -C (O) Ra, -C (O) ORa, -C (O) N (Ra) 2 -LC (O) Ra, -LC (O) ORa, -LC (O) N (Ra ) two; (H) N (Rb) - (L) pC (O) Ra, -N (Rb) - (L) pC (O) ORa, -N (Rb) - (L) pC (O) N (Ra) 2 , -LN (Rb) - (L) pC (O) Ra, -LN (Rb) - (L) pC (O) ORa, LN (Rb) - (L) pC (O) N (Ra) 2; (I) -O- (L) pC (O) Ra, -O- (L) pC (O) N (Ra) 2, -O- (L) pC (O) O-Ra, LO- (L ) pC (O) Ra, LO- (L) pC (O) N (Ra) 2, LO- (L) pC (O) O-Ra; (J) -S (O) 2 R, -S (O) 2OR , -S (O) 2N (Ra) 2, -LS (O) 2 R, -LS (O) 2OR , -LS (O) 2N (Ra ) two; (K) -O- (L) pS (O) 2 R, -O- (L) pS (O) 2-Ra, -O (L) pS (O) 2N (Ra) 2, LO- (L ) pS (O) 2 R, LO- (L) pS (O) 2-Ra, LO- (L) pS (O) 2N (Ra) 2; (L) -N (Rb) - (L) pS (O) 2 R, -N (Rb) - (L) pS (O) 2-Ra, -N (Rb) - (L) pS (O) 2N ( Ra) 2, -LN (Rb) - (L) pS (O) 2 R, -LN (Rb) - (L) pS (O) 2-Ra, -LN (Rb) - (L) pS (O) 2N (Ra) 2; and (m) -C (Ra) = N-CN, -LC (Ra) = N-CN; each Ra is independently selected from the group consisting of (a) hydrogen, C1-C6 perfluoroalkyl and C1-C6 alkyl; (B) C1-C6 alkyl further substituted with 1-2 groups selected from fluorine, chlorine, -CN, and -N (Rb) 2; (C) C2-C6 alkenyl and C2-C6 alkynyl, each of them is further optionally substituted with 1-3 groups selected from fluorine, chlorine, -CN, and -N (Rb) 2; (D) - (C1-C6) p (C3-C6), - (C1-C6) p-phenyl, - (C1-C6) p- (5-6 membered heteroaryl), - (alkylene C1C6) p- (4-6 membered heterocyclyl), - (C1C6 alkylene) p- (C5-C6), wherein each alkylene C1C6 is optionally further substituted with 1 to 3 groups selected from fluorine, chlorine and -CN, wherein each of said C3-C6 alkyl, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl and C5-C6 cycloalkenyl is optionally independently substituted with 1-3 Ry further; or two R attached to the same nitrogen form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl, said 3-10 member heterocyclyl and the said 5-10 member heteroaryl are optionally further substituted with 1-3 Rz; each L is independently C1-C6 alkyl, C2-C6 alkenylene or alkynylene C2-C6, and each L is optionally further substituted with 1-3 groups selected from fluorine, chlorine, OH and -CN; each R '', Rx, Ry and Rz is independently selected from the group consisting of (i) fluorine, chlorine, -CN, -OR, C1-C6 perfluoroalkyl C1-C3, C2-C6 alkynyl, C2- C6 and -N (Rb) 2; (ii) C1-C6 alkyl further substituted with 1-2 groups selected from fluorine, chlorine, -CN, and -N (Rb) 2; (iii) -C (O) -R, -C (O) OR b, -C (O) -N (Rb) 2; (iv) -N (Rb) -C (O) -R, -N (Rb) -C (O) OR b, -N (Rb) -C (O) -N (Rb) 2; (v) -OC (O) -R b, OC (O), -OC (O) -N (Rb) 2; (vi) - S (O) 2-Rb, -S (O) 2-O-Rb, -S (O) 2-N (Rb) 2; (vii) -N (Rb) -S (O) 2-Rb, - N (Rb) S (O) 2-O-Rb, -N (Rb) -S (O) 2-N (Rb) 2; and (viii) -OS (O) 2-Rb, -OS (O) 2-O-Rb, -OS (O) 2-N (Rb) 2; each Rb is independently selected from the group consisting of hydrogen, C1-C3 alkyl, C1-C3 perfluoroalkyl and C1-C3 alkyl further substituted with 1 -2 groups selected from fluorine, chlorine and CN; each p is independently 0 or 1; or a pharmaceutically acceptable salt thereof.
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