Compounds exhibiting thrombopoietin receptor agonism

A pharmaceutical composition exhibiting thrombopoietin receptor agonism of any one of claims I) to IX), wherein W1 is a group represented by the formula:

• 307
• wherein R13 is a hydrogen atom, lower alkyl, lower alkyloxy, lower alkylthio, or halogen atom;
• R14 and R15 are each independently a hydrogen atom, or optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl, each substituted by one or more substituent(s) selected from substituent group A;
• a broken line ( - - - ) is as defined in claim I);
• substituent group A consisits of a halogen atom, halo(lower)alkyl, optionally substituted amino, carboxy, lower alkylthio, lower alkylsilyl, or lower alkyloxy.

A pharmaceutical composition exhibiting thrombopoietin receptor agonism of any one of claims I) to IX), wherein W1 is a group represented by the formula:

• 308
• R13 is a hydrogen atom, lower alkyl, lower alkyloxy, lower alkylthio, or halogen atom;
• R26 is a hydrogen atom or lower alkyl;
• a broken line ( - - - ) is as defined in claim I);

A compound represented by the general formula (II):

• X2—Y2-Z2-W2 (II)
• wherein X2 is optionally substituted 5-member heteroaryl or optionally substituted pyridyl:
• Y2 is —NRACO—(CRCRD)0-2—, —NRACO—(CH2)0-2—V—, —NRACO—CRC═CRD—, —V—(CH2)1-5—NRACO—(CH2)0-2—, —V—(CH2)1-5—CONRA—(CH2)0-2—, —CONRA—(CH2)0-2—, —(CH2)0-2—NRA—SO2—(CH2)0-2—, —(CH2)0-2—SO2—NRA—(CH2)0-2—, —NRA—(CH2)0-2—, —NRA—CO—NRA—, —NRA—CS—NRA—, —N═C(—SRA)—NRA—, —NRACSNRACO—, —N═C(—SRA)—NRACO—, —NRA—(CH2)1-2—NRA—CO—, —NRACONRANRBCO—, or —N═C(—NRARA)—NRA—CO—,
• wherein RA is each independently a hydrogen atom or lower alkyl;
• RB is a hydrogen atom or phenyl;
• RC and RD are each independently a hydrogen atom, halogen atom, optionally substituted lower alkyl, optionally substituted lower alkyloxy, optionally substituted lower alkylthio, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted non-aromatic heterocyclic group, or optionally substituted amino;
• V is an oxygen atom or a sulfur atom;
• Z2 is optionally substituted phenylene, optionally substituted 2,5-pyridine-diyl, optionally substituted 2,5-thiophene-diyl, or optionally substituted 2,5-furan-diyl;
• W2 is a group represented by the formula:
• 309
• wherein R1, R2, R3, R4, R7, and R8 are each independently a hydrogen atom, halogen atom, optionally substituted lower alkyl, optionally substituted lower alkyloxy, optionally substituted lower alkylthio, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted non-aromatic heterocyclic group, or optionally substituted amino;
• R5, R6, and R9 are each independently a hydrogen atom, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, or optionally substituted non-aromatic heterocyclic group;
• A2 is a optionally substituted aryl or optionally substituted heteroaryl;
• a broken line ( - - - ) represents the presence or absence of a bond,
• its prodrug, or their pharmaceutically acceptable salt, or solvate thereof.

A compound described in claims XV) or XVI), wherein X2 is a group represented by the formula:

• 311
• wherein R16 is a hydrogen atom, optionally substituted lower alkyl, carboxy, lower alkyloxycarbonyl, halogen atom, or optionally substituted aminocarbonyl;
• R17, R18, R19, R20, R21, R22, and R23 are each independently a hydrogen atom, optionally substituted lower alkyl by one or more substituent(s) selected from substituent group B, cycloalkyl, optionally substituted alkyoxy by one or more substituent(s) selected from substituent group B, alkylthio, halogen atom, optionally substituted phenyl by one or more substituent(s) selected from substituent group C, optionally substituted heteroaryl by one or more substituent(s) selected from substituent group C, or optionally substituted nonaromatic heterocyclic group by one or more substituent(s) selected from substituent group C;
• substituent group B consists of hydroxy, alkyloxy, halogen atom, carboxy, lower alkyloxycarbonyl, aryloxycarbonyl, optionally substituted amino, optionally substituted phenyl by one or more substituent(s) selected from substituent group C, non-aromatic heterocyclic group, or heteroaryl;
• substituent group C consisits of hydroxy, alkyl, halogen atom, halo(lower)alkyl, carboxy, lower alkyloxycarbonyl, alkyloxy, optionally substituted amino, non-aromatic heterocyclic group, or heteroaryl;
• R16 and R17 taken together may form —CH2—, —CH2CH2—, —CH2CH2CH2—, —OCH2—, or —SCH2—;
• its prodrug, or their pharmaceutically acceptable salt, or solvate thereof.

A compound of any one of claims XV) to XXI), wherein W2 is a group represented by the formula:

• 312
• wherein, R1, R2, R3, R4, R5, R6, R7, R8 and A2 are as defined in claim XV);
• provided that R2 is not imidazolyl, triazolyl, or tetrazolyl;
• its prodrug, or their pharmaceutically acceptable salt, or solvate thereof.

A compound of any one of claims XV) to XXII), wherein W2 is a group represented by the formula:

• 313
• wherein R13 is a hydrogen atom, lower alkyl, lower alkyloxy, lower alkylthio, or halogen atom;
• R14 and R15 are each independently a hydrogen atom, or optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl, each substituted by one or more substituent(s) selected from substituent group A;
• substituent group A consists of a halogen atom, halo(lower)alkyl, optionally substituted amino, carboxy, lower alkylthio, lower alkylsilyl, or lower alkyloxy;
• its prodrug, or their pharmaceutically acceptable salt, or solvate thereof.

A compound of any one of claims XV) to XXII), wherein W2 is a group represented by the formula:

• 314
• wherein R13 is a hydrogen atom, lower alkyl, lower alkyloxy, lower alkylthio, or halogen atom;
• R26 is a hydrogen atom or lower alkyl;
• a broken line ( - - - ) as defined in claim XV);
• its prodrug, or their pharmaceutically acceptable salt, or solvate thereof.

A compound represented by the general formula (III):

• 315
• wherein R16 is a hydrogen atom, optionally substituted lower alkyl, carboxy, lower alkyloxycarbonyl, halogen atom, or optionally substituted aminocarbonyl;
• R17, R18, R19, R20, and R21 are each independently a hydrogen atom, optionally substituted lower alkyl by one or more substituent(s) selected from substituent group B, cycloalkyl, optionally substituted alkyoxy by one or more substituent(s) selected from substituent group B, alkylthio, halogen atom, optionally substituted phenyl by one or more substituent(s) selected from substituent group C, optionally substituted heteroaryl by one or more substituent(s) selected from substituent group C, or optionally substituted nonaromatic heterocyclic group by one or more substituent(s) selected from substituent group C;
• substituent group B consists of hydroxy, alkyloxy, halogen atom, carboxy, lower alkyloxycarbonyl, aryloxycarbonyl, optionally substituted amino, optionally substituted phenyl by one or more substituent(s) selected from substituent group C, non-aromatic heterocyclic group, or heteroaryl;
• substituent group C consists of hydroxy, alkyl, halogen atom, halo(lower)alkyl, carboxy, lower alkyloxycarbonyl, alkyloxy, optionally substituted amino, non-aromatic heterocyclic group, or heteroaryl;
• R16 and R17 taken together may form —CH2—, —CH2CH2—, —CH2CH2CH2—, —OCH2—, or —SCH2—;
• R31 and R32 are each independently a hydrogen atom, lower alkyl, halogen atom, halo(lower)alkyl, lower alkyloxy, halo(lower)alkyloxy, or hydroxy;
• W3 is represented by the formula:
• 316
• wherein R13 is a hydrogen atom, lower alkyl, lower alkyloxy, lower alkylthio, or halogen atom;
• R14 and R15 are each independently a hydrogen atom, or optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, or optionally substituted non-aromatic heterocyclic group, each substituted by one or more substituent(s) selected from substituent group A;
• substituent group A consists of a halogen atom, halo(lower)alkyl, optionally substituted amino, carboxy, lower alkylthio, lower alkylsilyl, or lower alkyloxy;
• R24 is a hydrogen atom or lower alkyl;
• R25 is lower alkyl, optionally substituted aryl, or optionally substituted non-aromatic heterocyclic group;
• A3 is heteroaryl;
• its prodrug, or their pharmaceutically acceptable salt, or solvate thereof.

A compound represented by the general formula (IV-A):

• 317
• wherein R27 is a hydrogen atom, C1-C3 alkyl, trifluoromethyl, or halogen atom;
• R28, R29, and R30 are independently a hydrogen atom, optionally substituted lower alkyl by one or more substituent(s) selected from substituent group B, cycloalkyl, optionally substituted alkyoxy by one or more substituent(s) selected from substituent group B, alkylthio, halogen atom, optionally substituted phenyl by one or more substituent(s) selected from substituent group C, optionally substituted heteroaryl by one or more substituent(s) selected from substituent group C, or optionally substituted nonaromatic heterocyclic group by one or more substituent(s) selected from substituent group C;
• substituent group B consists of hydroxy, alkyloxy, halogen atom, carboxy, lower alkyloxycarbonyl, aryloxycarbonyl, optionally substituted amino, optionally substituted phenyl by one or more substituent(s) selected from substituent group C, non-aromatic heterocyclic group, or heteroaryl;
• substituent group C consists of hydroxy, alkyl, halogen atom, halo(lower)alkyl, carboxy, lower alkyloxycarbonyl, alkyloxy, optionally substituted amino, non-aromatic heterocyclic group, or heteroaryl;
• R31 and R32 are each independently a hydrogen atom, lower alkyl, halogen atom, haro(lower)alkyl, lower alkyloxy, halo(lower)alkyloxy, or hydroxy;
• W4 is a group represented by the formula:
• 318
• wherein R13 is a hydrogen atom, lower alkyl, lower alkyloxy, lower alkylthio, or halogen atom;
• R14 and R15 are each independently a hydrogen atom, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, or optionally substituted non-aromatic heterocyclic group, each substituted by one or more substituent(s) selected from substituent group A;
• substituent group A consists of a halogen atom, halo(lower)alkyl, optionally substituted amino, carboxy, lower alkylthio, lower alkylsilyl, or lower alkyloxy;
• R24 is a hydrogen atom or lower alkyl;
• its prodrug, or their pharmaceutically acceptable salt, or solvate thereof.

A compound represented by the general formula (IV-B):

• 319
• wherein R28, R29, and R30 are each independently a hydrogen atom, optionally substituted lower alkyl by one or more substituent(s) selected from substituent group B, cycloalkyl, optionally substituted alkyoxy by one or more substituent(s) selected from substituent group B, alkylthio, halogen atom, optionally substituted phenyl by one or more substituent(s) selected from substituent group C, optionally substituted heteroaryl by one or more substituent(s) selected from substituent group C, or optionally substituted nonaromatic heterocyclic group by one or more substituent(s) selected from substituent group C;
• substituent group B consists of hydroxy, alkyloxy, halogen atom, carboxy, lower alkyloxycarbonyl, aryloxycarbonyl, optionally substituted amino, optionally substituted phenyl by one or more substituent(s) selected from substituent group C, non-aromatic heterocyclic group, or heteroaryl;
• substituent group C consists of hydroxy, alkyl, halogen atom, halo(lower)alkyl, carboxy, lower alkyloxycarbonyl, alkyloxy, optionally substituted amino, non-aromatic heterocyclic group, or heteroaryl;
• R31 and R32 are each independently a hydrogen atom, lower alkyl, halogen atom, haro(lower)alkyl, lower alkyloxy, halo(lower)alkyloxy, or hydroxy;
• W4 is a group represented by the formula:
• 320
• wherein R13 is a hydrogen atom, lower alkyl, lower alkyloxy, lower alkylthio, or halogen atom;
• R14 and R15 are each independently a hydrogen atom, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, or optionally substituted non-aromatic heterocyclic group, each substituted by one or more substituent(s) selected
• from substituent group A;
• substituent group A consists of a halogen atom, halo(lower)alkyl, optionally substituted amino, carboxy, lower alkylthio, lower alkylsilyl, or lower alkyloxy;
• R24 is a hydrogen atom or lower alkyl;
• T is —CH2—, —CH2CH2—, —CH2CH2CH2—, —OCH2—, or —SCH2—;
• its prodrug, or their pharmaceutically acceptable salt, or solvate thereof.

(Addition) A compound represented by the general formula (II):

• X2—Y2-Z2-W2 (II)
• wherein X2 is optionally substituted 5-membered heteroaryl or optionally substituted pyridyl;
• Y2 is —NRACO—(CRCRD)0-2—, —NRACO—(CH2)0-2—V—, —NRACO—CRC═CRD—, —V—(CH2)1-5—NRACO—(CH2)0-2—, —V—(CH2)1-5—CONRA—(CH2)0-2—, —CONRA—(CH2)0-2—, —(CH2)0-2—NRASO2—(CH2)0-2—, —(CH2)0-2—SO2—NRA—(CH2)0-2—, —NRA—(CH2)0-2—, —NRA—CO—NRA—, —NRA—CS—NRA—, —N═C(—SRA)—NRA—, —NRACSNRACO—, —N═C(—SRA)—NRACO—, —NRA—(CH2)1-2—NRA—CO—, —NRACONRANRBCO—, or —N═C(—NRARA)—NRA—CO—,
• wherein RAis each independently a hydrogen atom or lower alkyl;
• RB is a hydrogen atom or phenyl;
• RC and RD are each independently a hydrogen atom, halogen atom, optionally substituted lower alkyl, optionally substituted lower alkyloxy, optionally substituted lower alkylthio, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted non-aromatic heterocyclic group, or optionally substituted amino;
• V is an oxygen atom or a sulfur atom;
• Z2 is optionally substituted phenylene, optionally substituted 2,5-pyridine-diyl, optionally substituted 2,5-thiophene-diyl, or optionally substituted 2,5-furan-diyl;
• W2 is a group represented by the formula:
• 321
• wherein R1, R2, R3, R4, R7, and R8 are each independently a hydrogen atom, halogen atom, optionally substituted lower alkyl, optionally substituted lower alkyloxy, optionally substituted lower alkylthio, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted non-aromatic heterocyclic group, or optionally substituted amino;
• R5, R6, and R9 are each independently a hydrogen atom, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, or optionally substituted non-aromatic heterocyclic group;
• A2 is optionally substituted aryl or optionally substituted heteroaryl;
• a broken line ( - - - ) represents the presence or absence of a bond, provided that,
• 1) when X2 is thiazolyl optionally substituted with alkyl, or benzothiazolyl optionally substituted with alkoxyl or diethylamino;
• Z2 is 1,4-phenylene;
• and
• W2 is a group represented by the formula:
• 322
• R2 is not optionally substituted imidazolyl, optionally substituted triazolyl, or optionally substituted tetrazolyl,
• 2) when X2 is 2-pyridyl;
• Y2 is —NHCO—CH═CH—, or —NHCSNHCO—;
• Z2 is 1,4-phenylene;
• and W2is a group represented by the formula:
• 323
• R2 is not triazolyl,
• 3) when X2 is benzothiazolyl;
• Y2 is —NHCO—CH═CH—;
• Z2 is 1,4-phenylene;
• and
• W2 is a group represented by the formula:
• 324
• R2 is not 2-pyridyl or carboxymethyl,
• 4) when X2 is benzothiazolyl;
• Y2 is —NHCO—;
• and Z2 is 1,4-phenylene;
• W2 is not a group represented by the formula:
• 325
• 5) when X2 is thiazolyl optionally substituted with methyl, t-butyl, or unsubstituted phenyl, or benzothiazolyl optionally substituted with alkyl or diethylaminoethyl;
• Z2 is optionally substituted phenylene;
• and W2 is —CH═O, Y2 is not —NHCO—(CH2)0-2—, —NHCO—CH═CH—, —NHCO—CH2—O—, or —NHCO—CH2—NMe—,
• 6) when Y2 is —NH—CH2—;
• Z2 is 1,4-phenylene;
• W2 is optionally substituted tetrazolyl wherein 2-position is substituted phenyl, X2 is not thiadiazolyl, thiazolyl, benzothiazolyl, oxadiazazolyl, imidazolyl, or oxazolyl,
• 7) when X2 is optionally substituted benzothiazolyl;
• Z2 is 1,4-phenylene;
• and
• W2 is a group represented by the formula:
• 326
• Y2 is not —NHCO—, —NH—CH2—, —NEt—CH2—, or —NH—
• 8) when X2 is optionally substituted benzothiazolyl;
• Y2 is —NH—;
• and Z2 is 1,4-phenylene;
• W2 is not —CH2COOH or —CH2COOEt,
• 9) when X2 is optionally substituted benzothiazolyl;
• Y2 is —NH—;
• and Z2 is 2,5-pyridinediyl;
• W2 is not —COOH or —CONH2,
• 10) when X2 is optionally substituted benzothiazolyl;
• Z2 is phenylene optionally substituted with methyl or chlorine atom;
• and W2 is —COOH, —COOEt, or —CONH2, Y2 is not —NH—, —NH—CH2—, —NH—CO—, or —NH—SO2—, its prodrug, their pharmaceutically acceptable salt, or solvate thereof.

(Addition) A compound described in claim XXXIII) or XXXIV) wherein X2 is represented by the formula:

• 328
• wherein R16 is a hydrogen atom, optionally substituted lower alkyl, carboxy, lower alkyloxycarbonyl, halogen atom, or optionally substituted aminocarbonyl;
• R17, R18, R19, R20, R21, R22, and R23 are each independently a hydrogen atom, optionally substituted lower alkyl by one or more substituent(s) selected from substituent group B, cycloalkyl, optionally substituted alkyoxy by one or more substituent(s) selected from substituent group B, alkylthio, halogen atom, optionally substituted phenyl by one or more substituent(s) selected from substituent group C, optionally substituted heteroaryl by one or more substituent(s) selected from substituent group C, or optionally substituted nonaromatic heterocyclic group by one or more substituent(s) selected from substituent group C;
• substituent group B consists of hydroxy, alkyloxy, halogen atom, carboxy, lower alkyloxycarbonyl, aryloxycarbonyl, optionally substituted amino, optionally substituted phenyl by one or more substituent(s) selected from substituent group C, non-aromatic heterocyclic group, and heteroaryl;
• substituent group C consisits of hydroxy, alkyl, halogen atom, halo(lower)alkyl, carboxy, lower alkyloxycarbonyl, alkyloxy, optionally substituted amino, non-aromatic heterocyclic group, and heteroaryl;
• R16 and R17 taken together may form —CH2—, —CH2CH2—, —CH2CH2CH2—, —OCH2—, or —SCH2—;
• its prodrug, their pharmaceutically acceptable salt, or solvate thereof.

A compound of any one of claims XXXIII) to XXXIX), wherein W2 is a group represented by the formula:

• 329
• wherein, R1, R2, R3, R4, R5, R6, R7, R8 and A2 are as defined in claim XV);
• provided that R2 is not imidazolyl, triazolyl, or tetrazolyl;
• its prodrug, their pharmaceutically acceptable salt, or solvate thereof.

(Addition) A compound of any one of claims XXXIII) to XXXX), wherein W2 is a group represented by the formula:

• 330
• wherein R13 is a hydrogen atom, lower alkyl, lower alkyloxy, lower alkylthio, or halogen atom;
• R14 and R15 are each independently a hydrogen atom, or optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl, each substituted by one or more substituent(s) selected from substituent group A;
• substituent group A consists of a halogen atom, halo(lower)alkyl, optionally substituted amino, carboxy, lower alkylthio, lower alkylsilyl, or lower alkyloxy;
• its prodrug, their pharmaceutically acceptable salt, or solvate thereof.

(Addition) A compound of any one of claims XXXIII) to XXXX), wherein W2 is a group represented by the formula:

• 331
• wherein R13 is a hydrogen atom, lower alkyl, lower alkyloxy, lower alkylthio, or halogen atom;
• R26 is a hydrogen atom or lower alkyl;
• a broken line ( - - - ) is as defined in claim XV);
• its prodrug, their pharmaceutically acceptable salt, or solvate thereof.