Pyrazole compounds having therapeutic effect on multiple myeloma

A pyrazole compound of formula (1), a tautomer of the compound, or a pharmaceutically acceptable salt or solvent thereof:

• wherein
• R1 is a hydrogen atom, C1-C10 alkyl, C1-C10 alkyl substituted with R17, C1-C10 haloalkyl, C3-C10 cycloalkyl, C3-C10 halocycloalkyl, C2-C10 alkenyl, C2-C10 alkenyl substituted with a halogen atom, C2-C10 alkynyl, C2-C10 alkynyl substituted with a halogen atom, —C(O)R12, —C(O)OR12, —C(O)N(R13)R12, —C(R12)═NR13, —(R12)═NOR13, D1 to D23, cyano, phenyl, phenyl substituted with (R11)a, benzyl or benzyl having a benzene ring which may be substituted with (R11)a, in which when a is an integer of at least 2, each R11 may be identical with or different from one another, and
• when there are two neighboring R11, the two neighboring R11 may form —CH2CH2CH2—, —CH2CH2O—, —CH2OCH2—OCH2O—, —CH2CH2S—, —CH2SCH2—, —CH2CH2N(Ry)—, —CH2N(Ry)CH2—, —CH2CH2CH2CH2—, —CH2CH2CH2O—, —CH2CH2OCH2—, —CH2OCH2O—, —OCH2CH2O—, —OCH2CH2S—, —CH2CH═CH—, —OCH═CH—, —SCH═CH—, —N(Ry)CH═CH—, —OCH═N—, —SCH═N—, —N(Ry)CH═N—, —N(Ry)N═CH—, —CH═CHCH═CH—, —OCH2CH═CH—, —N═CHCH═CH—, —N═CHCH═N— or —N═CHN═CH— to form, together with the carbon atoms attached to the two R11, a 5-membered or 6-membered ring which may have a hydrogen atoms on the ring-constituting carbon atoms replaced by a Z which may be identical with or different from one another, if two or more Z's are present,
• R2 is a hydrogen atom, a halogen atom, cyano, C1-C10 alkyl, C3-C10 cycloalkyl, C2-C10 alkenyl, C2-C10 alkenyl substituted with a halogen atom, C2-C10 alkynyl, C2-C10 alkynyl substituted with a halogen atom, —C(O)R12, —C(O)OR12, —C(O)N(R13)R12, —C(R12)═NR13, —C(R12)═NOR13, D1 to D23, benzyl, benzyl having a benzene ring optionally substituted with (R21)e, phenyl or phenyl optionally substituted with (R21)e, in which when e is an integer of at least 2, each R21 may be identical with or different from one another, and
• when there are two neighboring R21, the two neighboring R21 may form —CH2CH2CH2—, —CH2CH2O—, —CH2OCH2—OCH2O—, —CH2CH2S—, —CH2SCH2—CH2CH2N(Ry)—, —CH2N(Ry)CH2—, —CH2CH2CH2CH2—, —CH2CH2CH2O—, —CH2CH2OCH2—, —CH2OCH2O—, —OCH2CH2O—, —OCH2CH2S—, —CH2CH═CH—, —OCH═CH—, —SCH═CH—, —N(Ry)CH═CH—, —OCH═N—, —SCH═N—, —N(Ry)CH═N—, —N(Ry)N═CH—, —CH═CHCH═CH—, —OCH2CH═CH—, —N═CHCH═CH—, —N═CHCH═N— or —N═CHN═CH— to form, together with the carbon atoms attached to the two R21, a 5-membered or 6-membered ring which may have a hydrogen atom on the ring-constituting carbon atoms replaced by a Z which may be identical with or different from one another, if two or more Z's are present,
• R3 is a hydrogen atom, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkenyl optionally substituted with R31, C2-C6 alkynyl, C2-C6 alkynyl optionally substituted with R31, —C(O)R12, —C(O)OR12, —C(O)N(R12)R13, —Si(R32)(R33)R34, benzyl or benzyl having a benzene ring which may be substituted with (R15)g, in which when g is an integer of at least 2, each R15 may be identical with or different from one another,
• X is a single bond or —(CR6, R7)n—
• R4 and R5 are each independently C1-C6 alkyl or C3-C6 cycloalkyl, and R4 and R5 may form —CH2CH2—, —CH2CH2CH2—, —CH2CH2CH2CH2— or —CH2CH2CH2CH2CH2— to form a 3-membered, 4-membered, 5-membered or 6-membered ring together with the carbon atoms attached to R4 and R5,
• R6 and R7 are each independently a hydrogen atom or C1-C6 alkyl,
• R8 is D1 to D23, E1 to E8, M1 to M9, C3-C10 cycloalkyl, F1, F2, C3-C10 cycloalkenyl, phenyl or phenyl optionally substituted with (R81)k, in which when k is an integer of at least 2, each R81 may be identical with or different from one another, and
• when there are two neighboring R81, the two neighboring (R81)k may form —CH2CH2CH2—, —CH2CH2O—, —CH2OCH2—, —OCH2—O, —CH2CH2S—, —CH2SCH2—, —CH2CH2N(Ry)—, —CH2N(Ry)CH2—, —CH2CH2CH2CH2—, —CH2CH2CH2O—, —CH2CH2OCH2—, —CH2OCH2O—, —OCH2CH2O—, —OCH2CH2S—, —CH2CH═CH—, —OCH═CH—, —SCH═CH—, —N(Ry)CH═CH—, —OCH═N—, —SCH═N—, —N(Ry)CH═N—, —N(Ry)N═CH—, —CH═CHCH═CH—, —OCH2CH═CH—, —N═CHCH═CH—, —N═CHCH═N— or —N═CHN═CH— to form, together with the carbon atoms attached to the two R81, a 5-membered or 6-membered ring which may have a hydrogen atom on the ring-constituting carbon atoms replaced by a Z which may be identical with or different from one another, if two or more Z's are present,
• D1 to D23 are aromatic heterocyclic rings of structural formulae, respectively,
• E1 to E8 are saturated heterocyclic rings of structural formulae, respectively,
• M1 to M9 are partially unsaturated aromatic heterocyclic rings of formulae, respectively,
• F1 and F2 are rings of formulae, respectively,
• Rx is a hydrogen atom, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, —OR82, —C(O)R12, —C(O)OR12, phenyl, phenyl which may be substituted with (R15)d, benzyl or benzyl having a benzene ring which may be substituted with (R15)d, in which when d is an integer of at least 2, each R15 may be identical with or different from one another.
• Ry is C1-C10 alkyl, C1-C10 haloalkyl, C3-C10 cycloalkyl, C3-C10 halocycloalkyl, phenyl, phenyl which may be substituted with (R15)d, benzyl or benzyl having a benzene ring which may be substituted with (R15)d, in which when d is an integer of at least 2, each R15 may be identical with or different from one another,
• RZ is a halogen atom, cyano, nitro, C1-C10 alkyl, C1-C10 haloalkyl, C1-C10 alkoxy, C1-C10 haloalkoxy, alkylsulfonyloxy, haloalkylsulfonyloxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, —C(O)NH2, —C(S)NH2, —S(O)2NH2, phenoxy, phenyl or phenyl which may be substituted with (R16)m, and when m is an integer of at least 2, each R16 may be identical with or different from one another, in which when s1, s2 or s3 is an integer of at least 2, each Rz may be identical with or different from one another, and
• when there are two neighboring Rz, the two neighboring Rz, may form —CH2CH2CH2—, —CH2CH2O—, —CH2OCH2—OCH2O—, —CH2CH2S—, —CH2SCH2—CH2CH2N(Ry)—, —CH2N(Ry)CH2—, —CH2CH2CH2CH2—, —CH2CH2CH2O—, —CH2CH2OCH2—, —CH2OCH2O—, —OCH2CH2O—, —OCH2CH2S—, —CH2CH═CH—, —OCH═CH—, —SCH═CH—, —N(Ry)CH═CH—, —OCH═N—, —SCH═N—, —N(Ry)CH═N—, —N(Ry)N═CH—, —CH═CHCH═CH—, —OCH2CH═CH—, —N═CHCH═CH—, —N═CHCH═N— or —N═CHN═CH— to form, together with the carbon atoms attached to the two neighboring Rz, a 5-membered or 6-membered ring which may have a hydrogen atom on the ring-constituting carbon atoms replaced by a Z which may be identical with or different from one another, if two or more Z's are present,
• R11 is a halogen atom, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 haloalkoxy, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, C3-C10 halocycloalkyl, C3-C10 halocycloalkoxy, C1-C6 alkoxy(C1-C6) alkyl, C1-C6 alkoxy(C1-C6) alkoxy, nitro, cyano or phenyl,
• R12 and R13 are each independently a hydrogen atom, C1-C10 alkyl, C3-C10 cycloalkyl, C1-C10 haloalkyl, C3-C10 halocycloalkyl, D1 to D23, benzyl, benzyl having a benzene ring which may optionally be substituted with (R14)b, phenyl or phenyl which may optionally be substituted with (R14)b, in which when b is an integer of at least 2, each R14 may be identical with or different from one another, and
• when there are two neighboring R14, the two neighboring R14 may form —CH2CH2CH2—, —CH2CH2O—, —CH2OCH2—OCH2O—, —CH2CH2S—, —CH2SCH2—CH2CH2N(Ry)—, —CH2N(Ry)CH2—, —CH2CH2CH2CH2—, —CH2CH2CH2O—, —CH2CH2OCH2—, —CH2OCH2O—, —OCH2CH2O—, —OCH2CH2S—, —CH2CH═CH—, —OCH═CH—, —SCH═CH—, —N(Ry)CH═CH—, —OCH═N—, —SCH═N—, —N(Ry)CH═N—, —N(Ry)N═CH—, —CH═CHCH═CH—, —OCH2CH═CH—, —N═CHCH═CH—, —N═CHCH═N— or —N═CHN═CH— to form, together with the carbon atoms attached to the two R14, a 5-membered or 6-membered ring which may have a hydrogen atom on the ring-constituting carbon atoms replaced by a Z which may be identical with or different from one another, if two or more Z's are present,
• R14 is a halogen atom, nitro, cyano, C1-C10 alkyl, C1-C10 haloalkyl, C1-C10 alkoxy, C1-C10 haloalkoxy, phenoxy or phenyl,
• R15 is a halogen atom, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, C3-C6 halocycloalkyl, C3-C6 halocycloalkoxy, nitro, cyano or phenyl,
• R16 is a halogen atom, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 haloalkoxy, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, C3-C10 halocycloalkyl, C3-C10 halocycloalkoxy, nitro, cyano or phenyl, and when there are two neighboring R16, the two neighboring R16 may form —OCH2O— to form a 5-membered ring together with the carbon atoms to the two R16,
• R17 is —C(O)OR12, phenyl or phenyl substituted with (R11)a, in which when a is an integer of at least 2, each R11 may be identical with or different from one another,
• R21 is a halogen atom, nitro, cyano, C1-C10 alkyl, C1-C10 haloalkyl, C3-C10 cycloalkyl, C3-C10 halocycloalkyl, C1-C6 alkoxy(C1-C6) alkyl, —OR23, —C(O)R24, —C(O)OR24, —NR24R25, —C(O)NR24R25, —S(O)2NR24R25, phenyl or phenyl which may be substituted with (R22)f, in which when f is an integer of at least 2, each R22 may be identical with or different from one other, and
• when there are two neighboring R22, the two neighboring R22's may form —CH2CH2CH2—, —CH2CH2O—, —CH2OCH2—, —OCH2O—, —CH2CH2S—, —CH2SCH2—, —CH2CH2N(Ry)—, —CH2N(Ry)CH2—, —CH2CH2CH2CH2—, —CH2CH2CH2O—, —CH2CH2OCH2—, —CH2OCH2O—, —OCH2CH2O—, —OCH2CH2S—, —CH2CH═CH—, —OCH═CH—, —SCH═CH—, —N(Ry)CH═CH—, —OCH═N—, —SCH═N—, —N(Ry)CH═N—, —N(Ry)N═CH—, —CH═CHCH═CH—, —OCH2CH═CH—, —N═CHCH═CH—, —N═CHCH═N— or —N═CHN═CH— to form, together with the carbon atoms attached to the two R22, a 5-membered or 6-membered ring which may have a hydrogen atom on the ring-constituting carbon atoms replaced by a Z which may be identical with or different from one another, if two or more Z's are present,
• R22 is a halogen atom, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 haloalkoxy, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, C3-C10 halocycloalkyl, C3-C10 halocycloalkoxy, nitro, cyano or phenyl,
• R23 is a hydrogen atom, C1-C10 alkyl, C1-C10 haloalkyl, C3-C10 cycloalkyl, C3-C10 halocycloalkyl, C1-C6 alkoxy(C1-C6) alkyl, phenyl, phenyl which may be substituted with (R22)f, benzyl or benzyl having a benzene ring which may be substituted with (R22)f, in which when f is an integer of at least 2, each R22 may be identical with different from one another,
• R24 and R25 are each independently a hydrogen atom, C1-C10 alkyl, C3-C10 cycloalkyl, C1-C10 haloalkyl, C3-C10 halocycloalkyl, benzyl, benzyl having a benzene ring which may optionally be substituted with (R14)b, 1-phenethyl, 1-phenethyl having a benzene ring which may optionally be substituted with (R14)b, 2-phenethyl, 2-phenethyl having a benzene ring which may optionally be substituted with (R14)b, phenyl or phenyl which may optionally be substituted with (R14)b, in which when b is an integer of at least 2, each R14 may be identical with or different from one another,
• R31 is a halogen atom or phenyl,
• R32, R33 and R34 are each independently C1-C10 alkyl, C3-C10 cycloalkyl, benzyl, benzyl having a benzene ring which may optionally be substituted with (R14)b, phenyl or phenyl which may optionally be substituted with (R14)b, in which when b is an integer of at least 2, each R14 may be identical with or different from one another,
• R81 is a halogen atom, nitro, cyano, C1-C10 alkyl, C1-C10 haloalkyl, C3-C10 cycloalkyl, C3-C10 halocycloalkyl, C1-C6 alkoxy(C1-C6) alkyl, —OR23, —C(R83)═NR84, —C(R83)═NOR84, —C(O)R24, —C(O)OR24, —S(O)cR24, —OS(O)2R24, —NR24R25, —C(O)NR24R25, —C(S)NH2, —S(O)2NR24R25, phenyl or phenyl which may be substituted with (R22)m, in which when m is an integer of at least 2, each R22 may be identical with or different from one another,
• R82 is a hydrogen atom, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C6 alkoxy(C1-C6) alkyl, phenyl, phenyl which may be substituted with (R15)d, benzyl or benzyl having a benzene ring which may be substituted with (R15)d, in which when d is an integer of at least 2, each R15 may be identical with or different from one another,
• R83 and R84 are each independently a hydrogen atom, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, phenyl, phenyl which may be substituted with (R15)d, benzyl or benzyl having a benzene ring which may be substituted with (R15)d, in which when d is an integer of at least 2, each R15′ may be identical with or different from one another,
• Z is a halogen atom, cyano, nitro, C1-C10 alkyl, C1-C10 haloalkyl, C1-C10 alkoxy, C1-C10 haloalkoxy, alkylsulfonyloxy, haloalkylsulfonyloxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, —C(O)NH2, —C(S)NH2, or —S(O)2NH2,
• a, b, d, e, f, g, k and m are each independently an integer of from 1 to 5,
• c is an integer of from 0 to 2,
• q1 is an integer of from 0 to 3,
• q2 is an integer of from 0 to 5,
• q3 is an integer of from 0 to 7,
• q4 is an integer of from 0 to 6,
• q5 is an integer of from 0 to 4,
• r is an integer of from 0 to 2,
• s1 is an integer of from 0 to 4,
• s2 is an integer of from 0 to 3,
• s3 is an integer of from 0 to 2,
• s4 is an integer of 0 or 1,
• n is an integer of 1,
• t is an integer of 0 or 1, and
• u is an integer of 0 or 1.