Diketohydrazine derivative compounds and drugs containing the compounds as the active ingredient

A compound of formula (I)

• [wherein R is (1) hydrogen, (2) CycA, (3) C1-8 alkyl optionally substituted with 1 to 5 groups selected from halogen, CycA, nitro, trifluoromethyl and cyano,
• (wherein CycA is a C3-15 mono-, bi- or tri-cyclic carboring or a 3-15 membered mono-, bi- or tri-cyclic heteroring comprising 1-4 of nitrogen, 1-2 of oxygen and/or 1-2 of sulfur;
• R16 is (1) C1-8 alkyl, (2) C2-8 alkenyl, (3) C2-8 alkynyl, (4) CycA or
• (5) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with 1 to 5 groups selected from halogen, nitro, trifluoromethyl, cyano, CycA, —NR18R19, —OR18, —SR18, —NHC(O)-CycA and —NHC(O)—(C1-8 alkyl);
• R17, R18 and R19 are each independently, hydrogen, C1-4 alkyl, CycA, C1-4 alkyl substituted with CycA),
• AA1 is (1) a bond, or
• (wherein R1 and R2 are each independently, (i) hydrogen, (ii) C1-8 alkyl, (iii) CycA or (iv) C1-8 alkyl substituted with 1 to 5 groups selected from the following (a) to (j):
• (a) —NR21R22, (b) —OR23, (c) —SR23, (d) —COR24, (e) —NR25C(O)NR21R22, (f) guanidino, (g) amidino, (h) CycA, and (j) —NR25SO2R21;
• or
• R1 and R2 are taken together to form C2-8 alkylene (wherein one carbon of the alkylene chain may be replaced by oxygen, sulfur or —NR20— and the alkylene may be substituted with —NR21R22, —OR23 or oxo),
• (wherein R20 is hydrogen, C1-4 alkyl, —C(O)O—(C1-4 alkyl), CycA or C1-4 alkyl substituted with CycA;
• R21, R22, R23 and R25 are each independently, hydrogen, C1-4 alkyl, CycA or C1-4 alkyl substituted with CycA;
• R24 is C1-4 alkyl, CycA, —NR21R22, —OR23, —SR23 or C1-4 alkyl substituted with CycA),
• R3 is hydrogen, C1-8 alkyl, CycA or C1-8 alkyl substituted with CycA or
• R3 may be taken together with R1 to form C2-6 alkylene (wherein one carbon of the alkylene chain may be replaced by oxygen, sulfur or —NR20— and the alkylene may be substituted with —NR21R22, —OR23, —SR23 or oxo)) or
• R and AA1 may be taken together to form
• (wherein CycB is a 5-12 membered mono- or bi-cyclic heteroring and the other symbols have the same meaning as hereinbefore),
• AA2 is (1) a bond,
• (wherein R4 and R5 are each independently, (i) hydrogen, (ii) C1-8 alkyl, (iii) CycA or (iv) C1-8 alkyl substituted with 1 to 5 groups selected from the following (a) to (h) and (j):
• (a) —NR31R32, (b) —OR33, (c) —SR33, (d) —COR34, (e) —NR35C(O)NR31R32, (f) guanidino, (g) amidino, (h) CycA, and (j) —NR35SO2R31;
• or
• R4 and R5 may be taken together to form C2-8 alkylene (wherein one carbon of the alkylene chain may be replaced by oxygen, sulfur or —NR30— and the alkylene may be substituted with —NR31R32, —OR33, —SR33 or oxo),
• (wherein R30 is hydrogen, C1-4 alkyl, —C(O)O—(C1-4 alkyl), CycA or C1-4 alkyl substituted with CycA;
• R31, R32, R33 and R35 are each independently, hydrogen, C1-4 alkyl, CycA or C1-4 alkyl substituted with CycA;
• R34 is C1-4 alkyl, CycA, —NR31R32, —OR33, —SR33 or C1-4 alkyl substituted with CycA),
• R6 is hydrogen, C1-8 alkyl, CycA or C1-8 alkyl substituted with CycA or
• R6 may be taken together with R4 or R to form C2-6 alkylene (wherein one carbon of the alkylene chain may be replaced by oxygen, sulfur or —NR30— and the alkylene may be substituted with NR31R32, OR33, SR33 or oxo),
• R38 is hydrogen, C1-4 alkyl, CycA or C1-4 alkyl substituted with CycA or
• when AA1 is a bond, R38 may be taken together with R to form C2-6 alkylene (wherein one carbon of the alkylene chain may be replaced by oxygen, sulfur or —NR37— (wherein R37 is hydrogen or C1-4 alkyl)),
• CycC is a 3-17 membered mono- or bi-cyclic heteroring,
• CycD is a C3-14 mono- or bi-cyclic carboring or a 3-14 membered mono- or bi-cyclic heteroring) or
• AA2 may be taken together with AA1 to form
• (wherein CycE is a 4-18 membered mono- or bi-cyclic heteroring, CycF is a 5-8 membered monocyclic heteroring, and the other symbols have the same meaning as hereinbefore),
• R7 and R8 are each independently (1) hydrogen, (2) C1-8 alkyl, (3) CycA or (4) C1-8 alkyl substituted with 1 to 5 groups selected from the following (i)˜(x);
• (i) —NR41R42, (ii) —OR43, (iii) —SR43, (iv) —COR44, (v) —NR45C(O)NR41R42, (vi) guanidino, (vii) amidino, (viii) CycA, (ix) —NR45SO2R41, and (x) —P(O)(OR46)(OR47), or
• R7 and R8 may be taken together to form C2-8 alkylene (wherein one carbon of the alkylene chain may be replaced by oxygen, sulfur or —NR40— and the alkylene may be substituted with —NR41R42, —OR43, —SR43 or oxo),
• R40 is hydrogen, C1-4 alkyl, —C(O)O—(C1-4 alkyl), CycA or C1-4 alkyl substituted with CycA,
• R41, R42, R43 and R45 are each independently hydrogen, C1-4 alkyl, CycA or C1-4 alkyl substituted with CycA, R44 is C1-4 alkyl, CycA, —NR41R42, —OR43, —SR43 or C1-4 alkyl substituted with CycA,
• R46 and R47 are each independently, hydrogen or C1-8 alkyl,
• R9 is hydrogen, C1-8 alkyl, CycA or C1-8 alkyl substituted with CycA or
• R9 may be taken together with R7 or R to form C2-6 alkylene (wherein one carbon of the alkylene chain may be replaced by oxygen, sulfur or —NR40— and the alkylene may be substituted with —NR41R42, —OR43, —SR43 or oxo), (wherein all symbols have the same meaning as hereinbefore),
• is a group selected from the following (1), (2) or (3);
• [wherein RA1 and RA2 are each independently, (i) hydrogen, (ii) C1-8 alkyl, (iii) C2-8 alkenyl, (iv) —NRZ1RZ2, (v) —ORZ3, (vi) —SRZ3, (vii) —CORZ4, (viii) CycP or (ix) C1-8 alkyl or C2-8 alkenyl substituted with 1 to 5 groups selected from CycP, —NRZ1RZ2, —ORZ3, —SRZ3, —CORZ4, —SO2RZ4, —COORZ3, —CONRZ1RZ2, —SO2NRZ1RZ2 and —P(O)(ORZ5)(ORZ6)
• (wherein RZ1 and RZ2 are each independently, hydrogen, C1-8 alkyl, C2-8 alkenyl, CycP, C2-8 acyl, or C1-8 alkyl substituted with CycP, C2-8 acyl, C1-8 alkoxy, C1-8 alkylthio, C1-8 monoalkylamino or di(C1-8 alkyl)amino;
• RZ3 is hydrogen, C1-8 alkyl, C2-8 alkenyl, CycP or C1-8 alkyl substituted with 1 to 5 groups selected from CycP, C1-8 alkoxy, C1-8 alkylthio, amino, C1-8 monoalkylamino, di(C1-8 alkyl)amino and C2-8 acyl;
• RZ4 is C1-8 alkyl, CycP or C1-8 alkyl substituted with 1 to 5 groups selected from CycP, C1-8 alkoxy, C1-8 alkylthio, mono(C1-8 alkyl)amino, di(C1-8 alkyl)amino or C2-8 acyl;
• RZ5 and RZ6 are each independently, hydrogen or C1-8 alkyl,
• CycP is a C4-10 carboring or 5-10 membered heteroring comprising 1-4 of nitrogen, 1-2 of oxygen and/or 1-2 of sulfur and R10 is a hydrogen atom or C1-4 alkyl) or
• RA1 and RA2 may be taken together with the adjacent carbon to represent CycH
• (wherein CycH is a C4-10 mono- or bi-cyclic carboring or 4-10 membered mono- or bi-cyclic heteroring and R10 has the same meaning as hereinbefore) or
• RA1 and R10 may be taken together with the adjacent carbon and nitrogen to represent
• (wherein CycJ is a 5-10 membered mono- or bi-cyclic heteroring and RA2 has the same meaning as hereinbefore)],
• [wherein RA3 is (i) C1-8 alkyl, (ii) C2-8 alkenyl, (iii) —NRZ1RZ2, (ix) —ORZ3, (v) —SRZ3, (vi) —CORZ4, (vii) CycP or (viii) C1-8 alkyl or C2-8 alkenyl substituted with 1 to 5 groups selected from —NRZ1RZ2, —ORZ3, —SRZ3, —CORZ4, —SO2RZ4, CycP and —P(O)(ORZ5)(ORZ6) (wherein all symbols have the same meaning as hereinbefore),
• RA4 is (i) hydrogen, (ii) C1-8 alkyl, (iii) C2-8 alkenyl, (iv) —CORZ4, (v) CycP or (vi) C1-8 alkyl or C2-8 alkenyl substituted with 1 to 5 groups selected from CycP, —NRZ1RZ2, —ORZ3, —SRZ3, —CORZ4, —SO2RZ4, —COORZ3, —CONRZ1RZ2, —SO2NRZ1RZ2 and —P(O)(ORZ5)(ORZ6) (wherein all symbols have the same meaning as hereinbefore),
• R10 has the same meaning as hereinbefore, or
• RA3 and RA4 may be taken together with the adjacent carbon and nitrogen to represent
• (wherein CycK is a 5-10 membered mono- or bi-cyclic heteroring and R10 has the same meaning as hereinbefore),
• RA3 and R10 may be taken together with the adjacent carbon and nitrogens to represent
• (wherein CycL is a 5-10 membered mono- or bi-cyclic heteroring and RA4 has the same meaning as hereinbefore)),
• [wherein n is an integer of 1 or 2, and the other symbols have the same meaning as hereinbefore, and RA3 and RA4 may be taken together with the adjacent nitrogen and sulfur to represent
• (wherein CycM is a 5-10 membered mono- or bi-cyclic heteroring and the other symbols have the same meaning as hereinbefore) or
• RA3 and R10 may be taken together with the nitrogens and sulfur to represent
• (wherein CycN is a 5-10 membered mono- or bi-cyclic heteroring and the other symbols have the same meaning as hereinbefore)],
• CycA's, CycB, CycC, CycD, CycE, CycF, CycH, CycJ, CycK, CycL, CycM, CycN and CycP may be each independently substituted with 1-5 of R27,
• R27 is (1) C1-8 alkyl, (2) halogen, (3) —NR11R12, (4) —OR13, (5) —SR13, (6) CycG, (7) nitro, (8) cyano, (9) oxo, (10) —COR14, (11) —SO2R14, (12) —P(O)(OR15)(OR16), (13) guanidino, (14) am idino or (15) C1-8 alkyl substituted with 1 to 5 groups selected from the following (i)-(xii):
• (i) halogen, (ii) —NR11R12, (iii) —OR13, (iv) —SR13, (v) CycG, (vi) nitro, (vii) cyano, (viii) —COR14, (ix) —SO2R14, (x) —P(O)(OR15)(OR16), (xi) guanidino, and (xii) amidino
• (wherein R11 and R12 are each independently, hydrogen, C1-4 alkyl, C1-4 alkoxy, —C(O)O—(C1-4 alkyl), CycG or C1-4 alkyl substituted with CycG,
• R13 is hydrogen, C1-4 alkyl, trifluoromethyl, CycG or C1-4 alkyl substituted with CycG,
• CycG's are each independently, a C4-10 mono- or bi-cyclic carboring or a 5-10 membered mono- or bi-cyclic heteroring comprising 1-4 of nitrogen, 1-2 of oxygen and/or 1-2 of sulfur,
• R14 is C1-8 alkyl, CycG, —NR11R12, —OR13, —SR13 or C1-8 alkyl substituted with CycG, —NR11R12, —OR13 or —SR13,
• R15's are each independently, hydrogen or C1-8 alkyl),
• when a saturated carbon atom exists in CycH, CycJ, CycK, CycL, CycM or CycN, the saturated carbon atom may form a spiro bond with CycQ (wherein CycQ is a C3-10 saturated or partially unsaturated mono-cyclic carboring or a 5-8 membered saturated or partially unsaturated monocyclic heteroring comprising 1 of —NRQ— (wherein RQ is C1-8 alkyl, C2-8 acyl, —SO2—(C1-8 alkyl), benzoyl, benzenesulfonyl, or toluenesulfonyl), 1 of oxygen and/or 1 of sulfur which may be oxidized)] or a pharmaceutically acceptable salt thereof.