Fused heterocyclic compounds

Abstract

[Problem] To address the problem of providing a novel condensed heterocyclic compound which has a sepiapterin reductase-inhibiting activity and is particularly useful for the treatment of a pain. [Solution] Provided are a novel condensed heterocyclic compound represented by formula (I) (wherein each substituent is as defined in detail in the description; R1 represents a hydrocarbon group or the like; R2 and R3 independently represent a hydrogen atom or the like; R4 represents a substituent as defined in the description; X represents a substituent as defined in the description; and Y represents a substituent as defined in the description), a tautomer or a pharmaceutically acceptable salt of the compound, or a solvate of the compound, the tautomer or the pharmaceutically acceptable salt.

Description

[Technical Field]

[0001] The present invention relates to novel fused heterocyclic compounds having an inhibitory activity against sepiapterin reductase (hereinafter sometimes abbreviated as "SPR"). [Background technology]

[0002] Tetrahydrobiopterin (hereinafter sometimes abbreviated as "BH4") is known to be an important cofactor for nitric oxide synthase (inducible nitric oxide synthase; iNOS, endothelial nitric oxide synthase; eNOS, neuronal nitric oxide synthase; nNOS), an enzyme cofactor for various aromatic amino acid hydroxylases, including phenylalanine, tyrosine, and tryptophan hydroxylases, as well as other enzymes such as alkylglycerol monooxygenase. Therefore, BH4 is involved in the regulation of the synthesis of various neurotransmitters (e.g., serotonin, dopamine, noradrenaline, etc.) and nitric oxide, and BH4 deficiency leads to deficiencies of neurotransmitters including serotonin and dopamine (Non-Patent Document 1). Reduced BH4 production reduces pain sensitivity (Patent Document 1).

[0003] SPR is an enzyme that catalyzes the final step in the BH4 de novo pathway, converting 6-pyruvoyltetrahydropterin into BH4, and the reduction in BH4 production associated with SPR inhibition leads to pain relief (Patent Document 2 and Non-Patent Document 2).

[0004] Compounds that inhibit SPR have been reported to include compounds having an indole ring and aromatic heterocyclic compounds (Patent Documents 1 and 2). [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Publication No. 2011 / 047156 [Patent Document 2] International Publication No. 2017 / 059191 [Non-patent literature]

[0006] [Non-Patent Document 1] Lancet Neurol 2011, 10:721-733 [Non-patent document 2] Nature Medicine, 2006, Vol. 12, No. 11: 1269-1277 Summary of the Invention [Problem to be solved by the invention]

[0007] An object of the present invention is to provide a novel pharmaceutical compound having excellent SPR inhibitory activity. [Means for solving the problem]

[0008] The present inventors have conducted extensive research to find a compound having an SPR inhibitory effect, and have found that the compound of the present invention has an excellent SPR inhibitory effect, thereby completing the present invention. That is, the present invention is characterized as follows.

[0009] (1) Formula (I) [ka] [In the formula, R 1 represents an optionally substituted hydrocarbon group; R 2 and R 3 are each independently a hydrogen atom or an optionally substituted C 1-6 represents an alkyl group; R 4 represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group; X and Y are bonded to each other and together with the carbon atoms to which X and Y are attached form an optionally substituted 5- to 7-membered ring; Or, X is a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, an optionally substituted amino group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, or Expression -CR 5 =NR 6 represents a group represented by the formula: Y is a hydrogen atom, a halogen atom, a cyano group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, or a group of the formula -CR 7 =NR 8 represents a group represented by the formula: R 5 and R 7 are each independently a hydrogen atom or C 1-6 represents an alkyl group; R 6 and R 8 each independently represents an optionally substituted hydroxy group. however, If X is a hydrogen atom, then Y is not a hydrogen atom; If Y is a hydrogen atom, then X is not a hydrogen atom. A compound represented by the formula: Figure US081202303-20130310-C00002, a tautomer of said compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. (2) X is a hydrogen atom, a halogen atom, an optionally substituted amino group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, or Expression -CR 5 =NR 6 represents a group represented by the formula: Y is a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, or a group of the formula -CR 7 =NR 8 R represents a group represented by 5 , R 6 , R 7 , R 8is the same as the definition given in (1), except that If X is a hydrogen atom, then Y is not a hydrogen atom; If Y is a hydrogen atom, X is not a hydrogen atom. The compound according to (1), a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. (3) R 2 and R 3 is a hydrogen atom, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof according to (1) or (2). (4) R 1 may be substituted C 3-10 The compound according to any one of (1) to (3), wherein the compound is a cycloalkyl group, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. (5) R 4 However, hydroxy groups, halogen atoms and C 1-6 C optionally substituted with one or more substituents independently selected from the group consisting of alkoxy groups 1-6 The compound according to any one of (1) to (4), wherein R is an alkyl group, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. (6) R 4 but, C optionally substituted with one or more substituents independently selected from the group consisting of halogen atoms and hydroxy groups 1-6 alkyl groups, C optionally substituted with one or more substituents independently selected from the group consisting of halogen atoms and hydroxy groups 1-6 alkoxy groups, halogen atoms, Hydroxy groups and C 1-6 Alkoxy-carbonyl group C, each of which may be substituted with one or more substituents independently selected from the group consisting of 3-10 Cycloalkyl groups, C 6-14The compound according to any one of (1) to (4), wherein R is an aryl group or a 3- to 14-membered non-aromatic heterocyclic group, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. (7) X is an optionally substituted amino group; The compound according to any one of (2) to (6), wherein Y is a hydrogen atom or a fluorine atom, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. (8) X is an optionally substituted heterocyclic group; The compound according to any one of (2) to (6), wherein Y is a hydrogen atom, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. (9) X is an acyl group; The compound according to any one of (2) to (6), wherein Y is a hydrogen atom or a fluorine atom, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. (10) X is a hydrogen atom; The compound according to any one of (2) to (6), wherein Y is an optionally substituted hydrocarbon group, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. (11) X is a hydrogen atom; The compound according to any one of (2) to (6), wherein Y is an optionally substituted heterocyclic group, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. (12) X is an amino group or C 1-6 is an alkylamino group; The compound according to any one of (2) to (6), wherein Y is an optionally substituted hydrocarbon group, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. (13) X is C 1-6 is an alkyl group; The compound according to any one of (2) to (6), wherein Y is an optionally substituted hydrocarbon group, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. (14) X and Y are bonded to each other and together with the carbon atoms to which X and Y are bonded form an optionally substituted 5- to 7-membered ring, and the ring is represented by the following formula (ia), (ib), (ic), (id) or (ie): [ka] (wherein α represents the carbon atom to which X is bonded, and β represents the carbon atom to which Y is bonded; Z is a single bond, -CH2-, -O-, -OCH2- (O is bonded to the carbonyl group and CH2 is bonded to the other carbon atom), or -NR 11 - indicates; R 11 may be halogenated C 1-6 Alkyl groups, optionally halogenated C 3-6 C substituted with a cycloalkyl group, a 4- to 10-membered non-aromatic heterocyclic group, or a 4- to 10-membered non-aromatic heterocyclic group 1-6 represents an alkyl group; W represents CH or a nitrogen atom; R 12 is a hydrogen atom or C 1-6 represents an alkoxy group; R 13 is a hydrogen atom, optionally halogenated C 1-6 (1) The compound according to (1), wherein R represents an alkyl group or a carbamoyl group. (15) 2-amino-N-cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide hydrochloride, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. (16) (E)-N-cyclopropyl-7-hydroxy-4-isobutyl-3-(3-morpholino-3-oxoprop-1-en-1-yl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. (17) R 1 is a cyclopropyl group; R 2 and R 3 is a hydrogen atom; R 4 is a tert-butyl group; X is a pyrimidin-4-ylamino group, a pyrazin-2-ylamino group, a 2-aminopyridin-3-yl group, a (5-(trifluoromethyl)pyrazin-2-yl)amino group, a (5-methoxypyrazin-2-yl)amino group, a (6-methoxypyrazin-2-yl)amino group, an amino group, a (5-carbamoylpyrazin-2-yl)amino group, a ureido group, or a carbamoyl group; The compound according to (2), wherein Y is a hydrogen atom, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. (18) N-cyclopropyl-7-hydroxy-4-isobutyl-5-oxo-2-(pyrazin-2-ylamino)-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. (19) (E)-2-amino-N-cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-3-(2-(tetrahydro-2H-pyran-4-yl)vinyl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide hydrochloride, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. (20) (E)-N-cyclopropyl-3-(3-(3,3-difluoropyrrolidin-1-yl)-3-oxoprop-1-en-1-yl)-7-hydroxy-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. (twenty one) N-cyclopropyl-3-((E)-3-((3S,5S)-3,5-dimethylmorpholino)-3-oxoprop-1-en-1-yl)-7-hydroxy-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. (twenty two) (S,E)-N-cyclopropyl-3-(3-(3-fluoropyrrolidin-1-yl)-3-oxoprop-1-en-1-yl)-7-hydroxy-4-isobutyl-2-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. (twenty three) N-cyclopropyl-3-((E)-3-((3S,5S)-3,5-dimethylmorpholino)-3-oxoprop-1-en-1-yl)-7-hydroxy-4-isobutyl-2-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. (twenty four) (S,E)-N-cyclopropyl-7-hydroxy-4-isobutyl-2-methyl-3-(3-(3-methylmorpholino)-3-oxoprop-1-en-1-yl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. (twenty five) N-cyclopropyl-3-((E)-3-((3R,5R)-3,5-dimethylmorpholino)-3-oxoprop-1-en-1-yl)-7-hydroxy-4-isobutyl-2-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. (26) (E)-N-cyclopropyl-3-(3-(4,4-difluoropiperidin-1-yl)-3-oxoprop-1-en-1-yl)-7-hydroxy-4-isobutyl-2-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. (27) (E)-N-cyclopropyl-3-(3-(4-(3,3-difluorocyclobutyl)piperazin-1-yl)-3-oxoprop-1-en-1-yl)-7-hydroxy-4-isobutyl-2-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. (28) A sepiapterin reductase inhibitor comprising the compound according to any one of (1) to (27), a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. (29) A drug for preventing, treating, and / or improving a disease for which sepiapterin reductase inhibitory activity is effective, comprising the compound according to any one of (1) to (27), a tautomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. (30) A pain treatment agent comprising, as an active ingredient, the compound according to any one of (1) to (27), a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. (31) A pharmaceutical composition comprising, as an active ingredient, the compound according to any one of (1) to (27), a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. [Effects of the Invention]

[0010] According to the present invention, it has become possible to provide novel fused heterocyclic compounds that have excellent SPR inhibitory activity and are particularly useful for the treatment and / or prevention of pain. DETAILED DESCRIPTION OF THE INVENTION

[0011] The definition of each substituent used in the present specification will be described in detail below. Unless otherwise specified, each substituent has the following definition. In the present invention, "n-" means normal, "s-" and "sec-" mean secondary, "t-" and "tert-" mean tertiary, "m-" means meta, "p-" means para, "cis-" means cis-isomer, "trans-" means trans-isomer, "Ph" means phenyl, and "Bu" means butyl.

[0012] "Optionally substituted" means unsubstituted or substituted with one or more substituents. The phrase "optionally substituted" means unsubstituted or substituted with one or more substituents. "Optionally halogenated" means unsubstituted or substituted with one or more halogen atoms.

[0013] C a-b Alkyl, C a-b Alkenyl, C a-b Alkynyl, C a-b Alkoxy and C a-b "C" in aralkyl a-b " are alkyl, alkenyl, The number of carbon atoms constituting alkynyl, alkoxy, and aralkyl is a to b. For example, "C a-b In "Alkyl-carbonyl group", C a-bThe number of carbon atoms constituting the alkyl group is a to b, and a-b The number of carbon atoms constituting the entire alkyl-carbonyl group is a+1 to b+1. C a-b Aryl, C a-b Cycloalkyl and C a-b "C" in cycloalkenyl a-b " means that the number of carbon atoms constituting the ring of the aryl, cycloalkyl, or cycloalkenyl is a to b, respectively.

[0014] First, the terms used to describe chemical structures in this specification will be explained.

[0015] In this specification, the term "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[0016] In this specification, "C 1-6 The term "alkyl group" means a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl.

[0017] As used herein, "optionally halogenated C 1-6 The "C alkyl group" is unsubstituted or substituted with one or more "halogen atoms". 1-6"Alkyl group" refers to an "optionally halogenated C" and examples thereof include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, propyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, and 6,6,6-trifluorohexyl. 1-6 The number of halogen atoms in the "alkyl group" is preferably 0 to 7, more preferably 0 to 5.

[0018] In this specification, "C 2-6 The term "alkenyl group" means a straight-chain or branched-chain alkenyl group having at least one double bond and 2 to 6 carbon atoms, and examples thereof include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, and 5-hexenyl.

[0019] In this specification, "C 2-6 The term "alkynyl group" means a straight-chain or branched-chain alkynyl group having at least one triple bond and 2 to 6 carbon atoms, and examples thereof include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, and 4-methyl-2-pentynyl.

[0020] In this specification, "C 3-10The term "cycloalkyl group" refers to a saturated hydrocarbon ring (C ) of which all atoms constituting the ring are carbon atoms and the ring contains 3 to 10 carbon atoms, and which is a monocyclic, fused, bridged or spirocyclic ring. 3-10 It means a group obtained by removing one hydrogen atom from any position of a cycloalkane, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, and adamantyl.

[0021] In this specification, "C 3-6 The "cycloalkyl group" is defined as the "C 3-10 Among "cycloalkyl groups," the term "cycloalkyl group" refers to a group having 3 to 6 carbon atoms constituting the ring.

[0022] In this specification, "C 3-10 The term "cycloalkenyl group" refers to a monocyclic, fused, bridged or spirocyclic ring (C) in which all atoms constituting the ring are carbon atoms, the number of carbon atoms constituting the ring is 3 to 10, and at least one double bond is present within the ring. 3-10 It means a group in which one hydrogen atom has been removed from any position of a cycloalkene, and examples thereof include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0023] In this specification, "C 3-6 The "cycloalkenyl group" is defined as the "C 3-10 Among "cycloalkenyl groups," the term "cycloalkenyl group" refers to a group having 3 to 6 carbon atoms constituting the ring.

[0024] In this specification, "C 6-14 The term "aryl group" refers to a monovalent substituent obtained by removing one hydrogen atom from any position of a monocyclic or fused-ring aromatic hydrocarbon ring, in which all atoms constituting the ring are carbon atoms and the number of carbon atoms constituting the ring is 6 to 14. Examples of such groups include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, and 9-anthryl.

[0025] In this specification, "C 7-16 The "aralkyl group" is defined as the "C 6-14 The "aryl group" is the "C 1-6 Among the groups bonded to an "alkyl group," it means a group having 7 to 16 carbon atoms, and examples thereof include benzyl, phenethyl, naphthylmethyl, and phenylpropyl.

[0026] In this specification, "C 1-6 The "alkoxy group" is defined as "C 1-6 "Alkyl group" means a group in which an oxy group is bonded to an oxy group, and examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, and hexyloxy.

[0027] As used herein, "optionally halogenated C 1-6 The "alkoxy group" is an unsubstituted or C substituted with one or more of the "halogen atoms". 1-6 It means an alkoxy group, and specific examples thereof include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, and hexyloxy. 1-6 The number of halogen atoms contained in the "alkoxy group" is preferably 0 to 7, and more preferably 0 to 5.

[0028] In this specification, "C 3-10 "Cycloalkyloxy group" is "C 3-10 "Cycloalkyl group" means a group in which the group is bonded to an oxy group, and examples thereof include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy.

[0029] "C 2-6 alkenyloxy group," "C 6-14 aryloxy group" and "C 7-16Aralkyloxy group" are "C 2-6 alkenyl group," "C 6-14 aryl group" and "C 7-16 An "aralkyl group" refers to a group in which an aralkyl group is bonded to an oxy group.

[0030] In this specification, "C 1-6 "Alkylthio group" is "C 1-6 "Alkyl group" means a group in which the "alkyl group" is bonded to a thio group, and examples thereof include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio, and hexylthio.

[0031] In this specification, "C 1-6 "Alkyl-carbonyl group" is "C 1-6 "Alkyl group" means a group in which an "alkyl group" is bonded to a carbonyl group, and examples thereof include acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl, hexanoyl, and heptanoyl.

[0032] As used herein, "optionally halogenated C 1-6 The "alkyl-carbonyl group" is an unsubstituted or C substituted with one or more of the "halogen atoms". 1-6 It means an alkyl-carbonyl group, and specific examples thereof include acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl, and hexanoyl. 1-6 The number of halogen atoms in the alkyl-carbonyl group is preferably 0 to 7, more preferably 0 to 5.

[0033] In this specification, "C 1-6 "Alkoxy-carbonyl group" is "C 1-6An "alkoxy group" refers to a group bonded to a carbonyl group, and examples thereof include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, and hexyloxycarbonyl.

[0034] In this specification, "C 6-14 "Aryl-carbonyl group" is "C 6-14 "Aryl group" means a group bonded to a carbonyl group, and examples include benzoyl, 1-naphthoyl, and 2-naphthoyl.

[0035] In this specification, "C 7-16 "Aralkyl-carbonyl group" is "C 7-16 An "aralkyl group" refers to a group in which an aralkyl group is bonded to a carbonyl group, and examples thereof include phenylacetyl and phenylpropionyl.

[0036] As used herein, the term "5- to 14-membered aromatic heterocyclic carbonyl group" means a group in which a "5- to 14-membered aromatic heterocyclic group" described later is bonded to a carbonyl group, and examples thereof include nicotinoyl, isonicotinoyl, thenoyl, and furoyl.

[0037] As used herein, the term "3- to 14-membered non-aromatic heterocyclic carbonyl group" means a group in which a "3- to 14-membered non-aromatic heterocyclic group" described later is bonded to a carbonyl group, and examples thereof include morpholinylcarbonyl, piperidinylcarbonyl, and pyrrolidinylcarbonyl.

[0038] In this specification, "C 3-10 Cycloalkylcarbonyl group" and "C 3-10 "Cycloalkenylcarbonyl group" is "C 3-10 Cycloalkyl groups" and "C 3-10 "Cycloalkenyl group" means a group bonded to a carbonyl group.

[0039] "C 6-14 Aryloxy-carbonyl group" and "C7-16 "Aralkyloxy-carbonyl group" is "C 6-14 aryl group" and "C 7-16 "Aralkyl group" refers to a group bonded to the oxy group of an oxy-carbonyl group (-OC(=O)-), respectively.

[0040] "C 1-6 alkyl-carbonyloxy group, "C 6-14 aryl-carbonyloxy group"; "C 1-6 alkoxy-carbonyloxy group, "5- to 14-membered aromatic heterocyclic carbonyloxy group" and The "3- to 14-membered non-aromatic heterocyclic carbonyloxy group" is defined as "C 1-6 alkyl group," "C 6-14 aryl group," "C 1-6 "alkoxy group," "5- to 14-membered aromatic heterocyclic group," and "3- to 14-membered non-aromatic heterocyclic group" refer to groups bonded to the carbonyl group of a carbonyloxy group (-C(=O)O-).

[0041] As used herein, "mono- or di-C 1-6 The "mono- or di-C alkyl-carbamoyl group" is defined as follows: 1-6 "Alkylamino group" means a group in which an "alkylamino group" is bonded to a carbonyl group, and examples thereof include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, and N-ethyl-N-methylcarbamoyl.

[0042] As used herein, "mono- or di-C 7-16 The "aralkyl-carbamoyl group" is a "mono- or di-C 7-16 An "aralkylamino group" refers to a group in which an "aralkylamino group" is bonded to a carbonyl group, and examples thereof include benzylcarbamoyl and phenethylcarbamoyl.

[0043] "Mono- or di-C 3-10 cycloalkyl-carbamoyl group" and "Mono- or di-C 6-14The "aryl-carbamoyl group" means, , "Mono- or di-C 3-10 Cycloalkylamino group" and "mono- or di-C 6-14 "Arylamino group" means a group bonded to a carbonyl group.

[0044] "C 1-6 alkyl-carbamoyl group, "C 3-10 cycloalkyl-carbamoyl group, "C 3-10 cycloalkenyl-carbamoyl group, "C 6-14 aryl-carbamoyl group"; "5- to 14-membered aromatic heterocyclic carbamoyl group" and The "3- to 14-membered non-aromatic heterocyclic carbamoyl group" refers to a group in which one hydrogen atom of the carbamoyl group is substituted with one "C 1-6 alkyl group," "C 3-10 cycloalkyl group, "C 3-10 cycloalkenyl group," "C 6-14 "aryl group," "5- to 14-membered aromatic heterocyclic group," and "3- to 14-membered non-aromatic heterocyclic group."

[0045] "(Hydroxy)(C 1-6 "(alkyl)-carbamoyl group" refers to a group in which the two hydrogen atoms of the carbamoyl group are substituted with one hydroxyl group and one C 1-6 It means a group substituted with an alkyl group. "(C 1-6 Alkoxy)(C 1-6 "Carbamoyl group" refers to a group in which two hydrogen atoms of the carbamoyl group are bonded to one C 1-6 Alkoxy groups and one C 1-6 It means a group substituted with an alkyl group.

[0046] "C 1-6 An alkoxy-carbamoyl group is one in which one hydrogen atom of the carbamoyl group is substituted with one C 1-6 It means a group substituted with an alkoxy group.

[0047] "Mono- or di-C 1-6 The "mono- or di-C alkyl-carbamoyloxy group" is 1-6 "Alkyl-carbamoyl group" means a group in which an "alkyl-carbamoyl group" is bonded to an oxy group, and specific examples include methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, and diethylcarbamoyloxy. "C 6-14 "Aryl-carbamoyloxy group" means "C 6-14 "Aryl group" means a group bonded to the nitrogen atom of a carbamoyloxy group (-NH-C(=O)-O-).

[0048] "C 1-6 alkyl-carbamoyloxy group" and "C 7-16 Each "aralkyl-carbamoyloxy group" has one "C 1-6 alkyl group" and "C 7-16 An "aralkyl group" refers to a group attached to the nitrogen atom of a carbamoyloxy group (-NH-C(=O)-O-). "C 1-6 alkylsulfonyloxy group" and "C 6-14 Each "arylsulfonyloxy group" has one "C 1-6 alkyl group" and "C 7-16 An "aralkyl group" refers to a group bonded to the sulfonyl group of a sulfonyloxy group (-SO2-O-).

[0049] "Mono- or di-C 1-6 An "alkylamino group" is a group in which one hydrogen atom of the amino group is substituted with one "C 1-6 A group in which two hydrogen atoms of an amino group are replaced by "C alkyl groups" or two hydrogen atoms of an amino group are replaced by the same or different "C 1-6 and examples thereof include methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, and N-ethyl-N-methylamino.

[0050] "Mono- or di-C 6-14 arylamino group, "Mono- or di-C 3-10 cycloalkylamino group, "Mono- or di-C 7-16 aralkylamino group, "Mono- or di-C 6-14 aryl-carbonylamino group" and "Mono- or di-C 7-16 "Aralkyl-carbonylamino group" means "mono- or di-C 1-6 The nitrogen atom of each group is defined as having two substituents (C 6-14 Aryl group, C 3-10 Cycloalkyl groups, C 7-16 Aralkyl group, C 6-14 Aryl-carbonyl groups, and C 7-16 When the aryl group has an aralkyl-carbonyl group, the two substituents may be the same or different.

[0051] "(Mono- or di-C 1-6 The "mono- or di-C alkyl-carbamoyl)amino group" is 1-6 "Alkyl-carbamoyl group" means a group attached to an amino group. "(Mono- or di-C 7-16 The "mono- or di-C (aralkyl-carbamoyl) amino group" is 7-16 "Aralkyl-carbamoyl group" means a group attached to an amino group.

[0052] "C 1-6 The "alkylamino group" is a group consisting of one "C 1-6 "Alkyl group" means a group in which an amino group is bonded to the alkyl group. "5- to 14-membered aromatic heterocyclic amino group", "5- to 10-membered aromatic heterocyclic amino group", "3- to 14-membered non-aromatic heterocyclic amino group", "4- to 10-membered non-aromatic heterocyclic amino group", "C 3-10 cycloalkylamino group" and "C 3-10The "cycloalkenylamino group" is a group consisting of one of "5- to 14-membered aromatic heterocyclic group", "5- to 10-membered aromatic heterocyclic group", "3- to 14-membered non-aromatic heterocyclic group", "4- to 10-membered non-aromatic heterocyclic group", "C 3-10 Cycloalkyl groups" and "C 3-10 "Cycloalkenyl group" means a group bonded to an amino group.

[0053] The terms "5- to 14-membered aromatic heterocyclic oxy group," "3- to 14-membered non-aromatic heterocyclic oxy group," and "4- to 10-membered non-aromatic heterocyclic oxy group" mean groups in which one "5- to 14-membered aromatic heterocyclic group," "3- to 14-membered non-aromatic heterocyclic group," and "4- to 10-membered non-aromatic heterocyclic group" is bonded to an oxy group, respectively.

[0054] "C 1-6 alkyl-carbonylamino group, "C 6-14 aryl-carbonylamino group"; "C 1-6 Alkoxy-carbonylamino group" and "C 7-16 Aralkyloxy-carbonylamino group" has one "C 1-6 alkyl group," "C 6-14 aryl group," "C 1-6 Alkoxy group" and "C 7-16 An "aralkyloxy group" refers to a group bonded to the carbonyl group of a carbonylamino group (-C(=O)-NH-). "(C 1-6 Alkyl)(C 1-6 The "C alkyl-carbonyl) amino group" is a group in which one hydrogen atom of the amino group is substituted with one "C 1-6 alkyl group" and one hydrogen atom of the amino group is replaced by one "C 1-6 It means a group substituted with an "alkyl-carbonyl group."

[0055] In this specification, "C 1-6 "Alkylsulfonyl group" is "C 1-6"Alkyl group" means a group in which the "alkyl group" is bonded to a sulfonyl group, and examples thereof include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl, and tert-butylsulfonyl.

[0056] As used herein, "optionally halogenated C 1-6 The "alkylsulfonyl group" is an unsubstituted or C substituted with one or more of the "halogen atoms". 1-6 It means an alkylsulfonyl group, and specific examples thereof include methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl, pentylsulfonyl, and hexylsulfonyl. 1-6 The number of halogen atoms in the alkylsulfonyl group is preferably 0 to 7, and more preferably 0 to 5.

[0057] In this specification, "C 6-14 "Arylsulfonyl group" is "C 6-14 "Aryl group" means a group bonded to a sulfonyl group, and examples include phenylsulfonyl, 1-naphthylsulfonyl, and 2-naphthylsulfonyl.

[0058] In the present specification, the term "hydrocarbon group" means a linear, branched or cyclic saturated or unsaturated group composed only of carbon atoms and hydrogen atoms, such as C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-10 Cycloalkyl groups, C 3-10 Cycloalkenyl group, C 6-14 Aryl group, C 7-16 Examples include aralkyl groups.

[0059] In the present specification, examples of the "optionally substituted hydrocarbon group" include the above-mentioned hydrocarbon groups which may have one or more substituents independently selected from the following Substituent Group A1. Here, among the following (1) to (67), 5- to 14-membered aromatic heterocycles, 3- to 14-membered non-aromatic heterocycles, C 3-10 Cycloalkanes and C 3-10 The group having a cycloalkene may be substituted with one or more substituents independently selected from the following substituent group D1. [Substituent group A1] (1) a halogen atom, (2) a nitro group, (3) a cyano group, (4) an oxo group, (5) a hydroxy group, (6) C optionally substituted with one or more substituents independently selected from the following substituent group C1: 1-6 alkoxy groups, (7) C 6-14 aryloxy groups (e.g., phenoxy, naphthoxy); (8) C 7-16 aralkyloxy groups (e.g., benzyloxy), (9) 5- to 14-membered aromatic heterocyclic oxy group (e.g., pyridyloxy), (10) 3- to 14-membered non-aromatic heterocyclic oxy group (e.g., morpholinyloxy, piperidinyloxy), (11) C optionally substituted with one or more substituents independently selected from the following substituent group C1: 1-6 alkyl-carbonyloxy groups (e.g., acetoxy, propanoyloxy); (12)C 6-14 aryl-carbonyloxy groups (e.g., benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy); (13) C optionally substituted with one or more substituents independently selected from the following substituent group C1: 1-6 alkoxy-carbonyloxy groups (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy), (14) Mono- or di-C optionally substituted with one or more substituents independently selected from the following substituent group C1: 1-6 alkyl-carbamoyloxy groups (e.g., methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy); (15)C 6-14 aryl-carbamoyloxy groups (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy); (16) 5- to 14-membered aromatic heterocyclylcarbonyloxy group (e.g., nicotinoyloxy), (17) 3- to 14-membered non-aromatic heterocyclylcarbonyloxy groups (e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy), (18) C optionally substituted with one or more substituents independently selected from the following substituent group C1: 1-6 alkylsulfonyloxy groups (e.g., methylsulfonyloxy, trifluoromethylsulfonyloxy); (19)C 6-14 arylsulfonyloxy groups (e.g., phenylsulfonyloxy, toluenesulfonyloxy); (20) C optionally substituted with one or more substituents independently selected from the following substituent group C1: 1-6 alkylthio groups, (21) a 5- to 14-membered aromatic heterocyclic group, (22) a 3- to 14-membered non-aromatic heterocyclic group, (23) a formyl group, (24) a carboxy group, (25) C optionally substituted with one or more substituents independently selected from the following substituent group C1: 1-6 alkyl-carbonyl groups, (26)C 6-14 aryl-carbonyl groups, (27) a 5- to 14-membered aromatic heterocyclic carbonyl group, (28) a 3- to 14-membered non-aromatic heterocyclic carbonyl group, (29)C 3-10 a cycloalkylcarbonyl group, (30)C 3-10a cycloalkenylcarbonyl group, (31) C optionally substituted with one or more substituents independently selected from the following substituent group C1: 1-6 alkoxy-carbonyl groups, (32)C 6-14 aryloxy-carbonyl groups (e.g., phenyloxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl); (33)C 7-16 aralkyloxy-carbonyl groups (e.g., benzyloxycarbonyl, phenethyloxycarbonyl), (34) a carbamoyl group, (35) a thiocarbamoyl group, (36) Mono- or di-C optionally substituted with one or more substituents independently selected from the following substituent group C1: 1-6 alkyl-carbamoyl groups, (37)C 6-14 aryl-carbamoyl groups (e.g., phenylcarbamoyl); (38) 5- to 14-membered aromatic heterocyclic carbamoyl group (e.g., pyridylcarbamoyl, thienylcarbamoyl), (39) 3- to 14-membered non-aromatic heterocyclic carbamoyl groups (e.g., morpholinylcarbamoyl, piperidinylcarbamoyl, tetrahydropyranylcarbamoyl), (40)(hydroxy)(C 1-6 alkyl)-carbamoyl group (e.g., N-hydroxy-N-methyl-carbamoyl group), (41)(C 1-6 Alkoxy)(C 1-6 alkyl)-carbamoyl group (e.g., N-methoxy-N-methyl-carbamoyl group), (42) C optionally substituted with one or more substituents independently selected from the following substituent group C1 1-6 alkylsulfonyl groups, (43)C 6-14 arylsulfonyl groups, (44) 5- to 14-membered aromatic heterocyclic sulfonyl group (e.g., pyridylsulfonyl, thienylsulfonyl), (45) C optionally substituted with one or more substituents independently selected from the following substituent group C1 1-6 alkylsulfinyl groups, (46)C 6-14 arylsulfinyl groups (e.g., phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl); (47) a 5- to 14-membered aromatic heterocyclylsulfinyl group (e.g., pyridylsulfinyl, thienylsulfinyl), (48) amino group, (49) Mono- or di-C optionally substituted with one or more substituents independently selected from the following substituent group C1: 1-6 alkylamino groups, (50) Mono- or di-C 6-14 arylamino groups (e.g., phenylamino); (51) 5- to 14-membered aromatic heterocyclic amino group (e.g., pyridylamino), (52)C 7-16 aralkylamino groups (e.g., benzylamino), (53) formylamino group, (54) C optionally substituted with one or more substituents independently selected from the following substituent group C1 1-6 alkyl-carbonylamino groups (e.g., acetylamino, propanoylamino, butanoylamino); (55)(C 1-6 Alkyl)(C 1-6 alkyl-carbonyl)amino groups (e.g., N-acetyl-N-methylamino), (56)C 6-14 arylcarbonylamino groups (e.g., phenylcarbonylamino, naphthylcarbonylamino); (57) C optionally substituted with one or more substituents independently selected from the following substituent group C1 1-6 alkoxycarbonylamino groups (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino), (58)C 7-16aralkyloxy-carbonylamino group (e.g., benzyloxycarbonylamino), (59) C optionally substituted with one or more substituents independently selected from the following substituent group C1 1-6 alkylsulfonylamino groups (e.g., methylsulfonylamino, ethylsulfonylamino), (60)C 6-14 arylsulfonylamino groups (e.g., phenylsulfonylamino, toluenesulfonylamino); (61) a carbamoylamino group, (62) C optionally substituted with one or more substituents independently selected from the following substituent group C1: 1-6 alkyl groups, (63) C optionally substituted with one or more substituents independently selected from the following substituent group C1 2-6 alkenyl groups, (64)C 2-6 alkynyl groups, (65)C 3-10 cycloalkyl groups, (66)C 3-10 cycloalkenyl groups, and (67)C 6-14 Aryl groups.

[0060] In the present specification, examples of the "optionally substituted hydrocarbon group" include the above-mentioned hydrocarbon groups which may have one or more substituents independently selected from the above-mentioned Substituent Group A1, as well as, for example, the following Substituent Group A2. Here, among the following (1) to (75), 5- to 14-membered aromatic heterocycles, 3- to 14-membered non-aromatic heterocycles, C 3-10 Cycloalkanes and C 3-10 The group having a cycloalkene may be substituted with one or more substituents independently selected from the following substituent group D2. [Substituent group A2] the substituents described in (1) to (67) in Substituent Group A1, (68)NC 1-6 Alkyl-NC 3-10 a cycloalkylcarbamoyl group (e.g., N-methyl-N-cyclopropylcarbamoyl); (69)NC1-6 alkyl-N-3 to 14-membered non-aromatic heterocyclic carbamoyl group, (70)N,N-di-C 3-10 a cycloalkylcarbamoyl group, (71) N,N-di-C optionally substituted with one or more substituents independently selected from the following substituent group C2 1-6 alkylcarbamoyl groups, (72) NC optionally substituted with one or more substituents independently selected from the following substituent group C2 1-6 alkylcarbamoyl groups, (73) C substituted with one or more substituents independently selected from the following substituent group C2 6-14 aryl-carbonyl groups, (74) 3- to 14-membered non-aromatic heterocyclic carbonylamino group and (75)C 3-10 Cycloalkylcarbonylamino group. In addition, in the substituent group A2, among the substituents described in (1) to (67) in the substituent group A1, 5- to 14-membered aromatic heterocycles, 3- to 14-membered non-aromatic heterocycles, C 3-10 Cycloalkanes and C 3-10 The group having a cycloalkene may be substituted with one or more substituents independently selected from the following substituent group D2.

[0061] Substituent group B is halogen atoms, nitro group, cyano group, hydroxy groups, formyl group, carboxyl group, carbamoyl group, thiocarbamoyl group, amino group, Formylamino group and Carbamoylamino group It is a group of substituents consisting of:

[0062] The substituent group C1 is Substituents constituting the above-mentioned Substituent Group B: C 1-6alkyl-carbonyloxy groups, C 1-6 alkoxy-carbonyloxy groups, Mono- or di-C 1-6 alkyl-carbamoyloxy groups, Optionally halogenated C 1-6 alkylsulfonyloxy groups, Optionally halogenated C 1-6 alkyl-carbonyl groups, C 1-6 alkoxy-carbonyl groups, Optionally halogenated C 1-6 alkylsulfonyl groups, Mono- or di-C 1-6 alkylamino groups, C 1-6 alkyl-carbonylamino groups, (C 1-6 Alkyl)(C 1-6 alkyl-carbonyl)amino group, C 1-6 Alkoxy-carbonylamino groups and C 1-6 Alkylsulfonylamino group It is a group of substituents consisting of:

[0063] The substituent group C2 is Substituents constituting the above-mentioned substituent group C1: C 7-16 aralkyloxy groups, Optionally halogenated C 1-6 alkoxy groups, Optionally halogenated C 3-10 cycloalkyl groups, a 4- to 10-membered non-aromatic heterocyclic group, a 4- to 10-membered non-aromatic heterocyclic oxy group, C 6-14 aryl groups and C 1-6 5- to 10-membered aromatic heterocyclic group optionally substituted by alkyl group It is a group of substituents consisting of:

[0064] The substituent group D1 is Substituents constituting the above-mentioned substituent group C1: Optionally halogenated C 1-6 Alkyl groups and C 2-6 Alkenyl group It is a group of substituents consisting of:

[0065] The substituent group D2 is Substituents constituting the above-mentioned substituent group C2: Optionally halogenated C 1-6 alkyl groups, C 2-6 alkenyl groups, C 1-6 Alkoxy-substituted C 1-6 alkyl groups, Hydroxy-substituted C 1-6 alkyl groups, N,N-di-C 1-6 Alkylcarbamoyl groups and Optionally halogenated C 3-10 C substituted with cycloalkyl groups 1-6 Alkyl group It is a group of substituents consisting of:

[0066] The number of the above-mentioned substituents in the "optionally substituted hydrocarbon group" is preferably 0 to 5, more preferably 0 to 3. When the number of substituents is 2 or more, the respective substituents may be the same or different.

[0067] C substituted with a 3- to 14-membered non-aromatic heterocyclic group 1-6 The alkyl group is a C substituted with one or more 3- to 14-membered non-aromatic heterocyclic groups. 1-6 means an alkyl group, C 1-6 It includes groups in which one carbon atom of the alkyl group forms a double bond with a 3- to 14-membered non-aromatic heterocycle (exo-olefin structure). Similarly, C 3-10 C substituted with cycloalkyl groups 1-6 Alkyl groups and C 3-10 C substituted with cycloalkenyl groups 1-6The alkyl groups each contain one or more C 3-10 Cycloalkyl group, or C 3-10 C substituted with cycloalkenyl groups 1-6 means an alkyl group, C 1-6 Each carbon atom in the alkyl group is C 3-10 Cycloalkanes and C 3-10 Contains a group that forms a double bond with the cycloalkene (exo-olefin structure).

[0068] In the present specification, the term "heterocyclic group" includes (i) a 5- to 14-membered aromatic heterocyclic group and (ii) a 3- to 14-membered non-aromatic heterocyclic group, each of which contains, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms independently selected from a nitrogen atom, a sulfur atom, and an oxygen atom.

[0069] In the present specification, the term "5- to 14-membered aromatic heterocyclic group" refers to a group obtained by removing one hydrogen atom at any position from a 5- to 14-membered monocyclic or fused-ring aromatic heterocycle (5- to 14-membered aromatic heterocycle) containing, in addition to carbon atoms as ring-constituting atoms, 1 to 4 heteroatoms independently selected from a nitrogen atom, a sulfur atom, and an oxygen atom. Preferable examples of the above-mentioned "5- to 14-membered aromatic heterocyclic group" include 5- or 6-membered monocyclic aromatic heterocyclic groups such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, and triazinyl; Benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thia and 8- to 14-membered fused polycyclic (preferably bi- or tricyclic) aromatic heterocyclic groups such as pyrazolopyrimidinyl, pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl, isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl.

[0070] Of the "5- to 14-membered aromatic heterocyclic groups", preferably "5- to 10-membered aromatic heterocyclic groups", more preferably "5- or 6-membered aromatic heterocyclic groups" are used. The "5- to 10-membered aromatic heterocyclic group" means a 5- to 10-membered aromatic heterocyclic group among the above-mentioned "5- to 14-membered aromatic heterocyclic groups". The "5- or 6-membered aromatic heterocyclic group" means a 5- or 6-membered aromatic heterocyclic group among the above-mentioned "5- to 14-membered aromatic heterocyclic groups".

[0071] In the present specification, the term "3- to 14-membered non-aromatic heterocyclic group" refers to a group obtained by removing one hydrogen atom from any position of a 3- to 14-membered monocyclic, fused ring (a fused ring system may be formed by fusion of non-aromatic rings with each other, or by fusion of an aromatic ring with one non-aromatic ring with an aromatic ring), bridged ring, or spiro ring system non-aromatic heterocyclic ring (3- to 14-membered non-aromatic heterocyclic ring), which contains, in addition to carbon atoms as ring-constituting atoms, one to four heteroatoms independently selected from nitrogen, sulfur, and oxygen atoms, and which may contain a carbon-oxygen double bond (C=O) or a sulfur-oxygen double bond (S=O or S(=O)2). The bonding position(s) is not particularly limited, and may be bonded at any desired position; however, in the case of a fused ring system in which an aromatic ring is fused to a non-aromatic ring, the substitution occurs on the non-aromatic ring. Preferable examples of the above-mentioned "non-aromatic heterocyclic group" include aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, oxopyrrolidinyl, imidazolinyl, oxoimidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisothiazolyl ... 3- to 8-membered monocyclic non-aromatic heterocyclic groups such as tetrahydroisoxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydro-2H-pyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, and diazocanyl; Dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolidinyl, indolinyl, isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl, tetrahydroquinoxalinyl, tetrahydrophenanthridinyl 9- to 14-membered fused polycyclic (preferably bi- or tricyclic) non-aromatic heterocyclic groups such as hexahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl, tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl, tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacridinyl, tetrahydrophenazinyl, tetrahydrothioxanthenyl, and octahydroisoquinolyl; 7- to 10-membered heterobridged ring groups such as quinuclidinyl, 7-azabicyclo[2.2.1]heptanyl, etc.; Examples include 7- to 11-membered heterospirocyclic groups such as 1-oxa-8-azaspiro[4.5]decanyl, 1-oxa-8-azaspiro[4.5]dec-3-enyl, and 1,9-diazaspiro[5.5]undecanyl.

[0072] Of the "3- to 14-membered non-aromatic heterocyclic groups", preferably "4- to 10-membered non-aromatic heterocyclic groups", more preferably "4- to 7-membered non-aromatic heterocyclic groups", and even more preferably "5- or 6-membered non-aromatic heterocyclic groups" are used.

[0073] The "4- to 10-membered non-aromatic heterocyclic group" means a 4- to 10-membered non-aromatic heterocyclic ring among the above-mentioned "3- to 14-membered non-aromatic heterocyclic groups". The "4- to 7-membered non-aromatic heterocyclic group" means a 4- to 7-membered non-aromatic heterocyclic ring among the above-mentioned "3- to 14-membered non-aromatic heterocyclic groups". The "5- or 6-membered non-aromatic heterocyclic group" means a 5- or 6-membered non-aromatic heterocyclic ring among the above-mentioned "3- to 14-membered non-aromatic heterocyclic groups".

[0074] In the present specification, the term "nitrogen-containing heterocyclic group" refers to a "heterocyclic group" that contains one or more nitrogen atoms as ring-constituting atoms. "5- to 14-membered nitrogen-containing aromatic heterocyclic group", "5- to 10-membered nitrogen-containing aromatic heterocyclic group" and The "5- or 6-membered nitrogen-containing aromatic heterocyclic group" means a group containing one or more nitrogen atoms among "5- to 14-membered aromatic heterocyclic groups," "5- to 10-membered aromatic heterocyclic groups," and "5- or 6-membered aromatic heterocyclic groups," respectively.

[0075] In the present specification, examples of the "optionally substituted heterocyclic group" include a heterocyclic group which may have a substituent selected from the above-mentioned Substituent Group A (Substituent Group A1 or Substituent Group A2). The number of substituents in the "optionally substituted heterocyclic group" is, for example, 0 to 3. When the number of substituents is 2 or more, the respective substituents may be the same or different.

[0076] In the present specification, the term "acyl group" means, for example, C may each have one or more substituents independently selected from the substituent group A (substituent group A1 or substituent group A2). 1-6 Alkyl group, C 2-6 Alkenyl group, C 1-6 Alkoxy group, C 3-10 Cycloalkyl groups, C 3-10 Cycloalkenyl group, C 6-14 Aryl group, C 7-16 aralkyl groups, 5- to 14-membered aromatic heterocyclic groups, and 3- to 14-membered non-aromatic heterocyclic groups; hydroxy groups; amino group; (hereinafter referred to as Substituent Group G) each independently represents a group bonded to a carbonyl group, an oxygen atom of an oxycarbonyl group (-OC(=O)-), a thiocarbonyl group, an oxygen atom of an oxy-thiocarbonyl group (-OC(=S)-), a sulfonyl group, or a sulfinyl group; One or two substituents independently selected from the substituent group G are each bonded to the nitrogen atom of an amino-carbonyl group (-NC(=O)-) or the nitrogen atom of an amino-thiocarbonyl group (-NC(=S)-).

[0077] In the present specification, the term "acyl group" means Formula -C(=O)-NR a R b (In the formula, R a and R b are each independently hydrogen atoms; C may each have one or more substituents independently selected from the substituent group A (substituent group A1 or substituent group A2). 1-6 Alkyl group, C 2-6 Alkenyl groups and C 1-6 Alkoxy group, C 3-10 Cycloalkyl groups, C 3-10 Cycloalkenyl group, C 6-14 Aryl group, C 7-16 aralkyl groups, 5- to 14-membered aromatic heterocyclic groups, and 3- to 14-membered non-aromatic heterocyclic groups; a hydroxy group; or an amino group, or R a and R b together with the nitrogen atom to which they are bonded form a 5- to 14-membered aromatic heterocycle or a 3- to 14-membered non-aromatic heterocycle, each of which optionally has one or more substituents independently selected from Substituent Group A (Substituent Group A1 or Substituent Group A2). The present invention includes groups represented by the following formula:

[0078] Suitable examples of the "acyl group" include: Formyl group; carboxyl group; Carbamoyl group; a 5- to 14-membered aromatic heterocyclic group, a 3- to 14-membered non-aromatic heterocyclic group, each of which may be substituted with one or more substituents independently selected from the substituent group F described below; 6-14 Aryl group, C 3-10Cycloalkyl groups and C 3-10 C may be substituted with one or more substituents independently selected from the group consisting of a cycloalkenyl group and the substituents constituting the substituent group E described below; 1-6 Alkoxy-carbonyl group, C 1-6 Alkyl-carbonyl group or mono- or di-C 1-6 Alkyl-carbamoyl group; (hydroxy)(C 1-6 (alkyl)-carbamoyl group; (C 1-6 Alkoxy)(C 1-6 (alkyl)-carbamoyl group; C 1-6 Alkoxy-carbamoyl group; mono- or di-C, each of which may be substituted with one or more substituents independently selected from the substituent group F described below; 7-16 Aralkyl-carbamoyl group, mono- or di-C 6-14 Aryl-carbamoyl group, mono- or di-C 3-10 Cycloalkyl-carbamoyl group, 5- to 14-membered aromatic heterocyclic carbamoyl group, 3- to 14-membered non-aromatic heterocyclic carbamoyl group, C 6-14 Aryl-carbonyl group, C 3-10 Cycloalkylcarbonyl group, C 3-10 Cycloalkenylcarbonyl group, C 7-16 Examples include an aralkyl-carbonyl group, a 5- to 10-membered aromatic heterocyclylcarbonyl group, and a 3- to 10-membered non-aromatic heterocyclylcarbonyl group. Here, the substituent group E is a halogen atom, optionally halogenated C 1-6 Alkoxy group, carbamoyl group, carboxy group, hydroxy group, amino group, carbamoylamino group, C 1-6 Alkyl-carbonyl group, C 1-6 Alkoxy-carbonyl groups and C 7-16 This is a group of substituents consisting of aralkyloxy groups. Here, the substituent group F includes the substituents constituting the substituent group E, a 4- to 7-membered non-aromatic heterocyclic group, and an optionally halogenated C 1-6 It is a group of substituents consisting of alkyl groups.

[0079] In the present specification, examples of the "optionally substituted amino group" include "amino groups each having one or more substituents independently selected from the substituent group A (substituent group A1 or substituent group A2), C 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 aralkyl group, 5- to 14-membered aromatic heterocyclic group, 3- to 14-membered non-aromatic heterocyclic group, C 1-6 Alkyl-carbonyl group, C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl group, carbamoyl group, sulfamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group, mono- or di-C 7-16 Aralkyl-carbamoyl group, C 1-6 Alkylsulfonyl group, C 6-14 Arylsulfonyl groups and (di-C 1-6 and an amino group which may have one or two substituents independently selected from the group consisting of alkylamino and methylene groups.

[0080] In the present specification, the term "optionally substituted amino group" means Formula -N(H)-C(=O)-Z 1 -R d1 (In the formula, Z 1 is C 1-6 a methylene group optionally substituted with an alkyl group, -N-, or -O-; Z 1 But C 1-6 When it is a methylene group optionally substituted by an alkyl group, R d1 may each have one or more substituents independently selected from the substituent group A (the substituent group A1 or the substituent group A2), C 1-6 Alkyl group, C 6-14Aryl group, C 7-16 an aralkyl group, a 5- to 14-membered aromatic heterocyclic group, or a 3- to 14-membered non-aromatic heterocyclic group; Z 1 When is -O-, R d1 may have one or more substituents independently selected from Substituent Group A (Substituent Group A1 or Substituent Group A2), C 1-6 is an alkyl group; Z 1 When is -N-, -Z 1 -R d1 may, together with each other, each have one or more substituents independently selected from Substituent Group A (Substituent Group A1 or Substituent Group A2), a carbamoyl group, (mono- or di-C 1-6 alkyl-carbamoyl)amino group, or (mono- or di-C 7-16 aralkyl-carbamoyl)amino group The present invention includes groups represented by the following formula:

[0081] The "optionally substituted amino group" is Formula -N(H)-S(=O)2-Z 2 -R d2 (In the formula, Z 2 is C 1-6 a methylene group optionally substituted with an alkyl group, or an amino group; Z 2 But C 1-6 When it is a methylene group optionally substituted by an alkyl group, R d2 may each have one or more substituents independently selected from the substituent group A (the substituent group A1 or the substituent group A2), C 1-6 Alkyl group or C 6-14 is an aryl group; Z 2 is an amino group, -Z 2 -R d2are taken together to represent a sulfamoyl group which may have one or more substituents independently selected from Substituent Group A (Substituent Group A1 or Substituent Group A2). The present invention includes groups represented by the following formula:

[0082] Preferable examples of the optionally substituted amino group include: amino group; Carbamoylamino group; sulfamoylamino group; C 1-6 Alkoxy-carbonylamino group; C 1-6 Alkyl-carbonylamino group; C 6-14 Aralkyl-carbonylamino group; C 6-14 Aralkyloxy-carbonylamino group; C, each of which may be substituted with one or more substituents independently selected from the substituent group F; 6-14 Aryl group, C 3-10 Cycloalkyl groups, C 3-10 optionally substituted with a cycloalkenyl group, a 3- to 14-membered non-aromatic heterocyclic group or a 5- to 14-membered aromatic heterocyclic group, C 1-6 alkylamino groups; C, each of which may be substituted with one or more substituents independently selected from the substituent group F; 6-14 Arylamino group, C 3-10 Cycloalkylamino group, C 3-10 Examples thereof include a cycloalkenylamino group, a 3- to 14-membered non-aromatic heterocyclic amino group, and a 5- to 14-membered aromatic heterocyclic amino group.

[0083] In the present specification, examples of the "optionally substituted hydroxy group" include "a hydroxy group which may have one or more substituents independently selected from the substituent group A (the substituent group A1 or the substituent group A2), C 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 3-10 Cycloalkenyl group, C 6-14 Aryl group, C 7-16aralkyl group, 5- to 14-membered aromatic heterocyclic group, 3- to 14-membered non-aromatic heterocyclic group, C 1-6 Alkyl-carbonyl group, C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group, mono- or di-C 7-16 Aralkyl-carbamoyl group, C 1-6 Alkylsulfonyl group and C 6-14 and a hydroxy group which may have a substituent selected from the group consisting of arylsulfonyl groups. Suitable examples of the optionally substituted hydroxy group include: a hydroxy group, or Halogen atoms, C 1-6 Alkoxy group, carboxy group, carbamoyl group, hydroxy group, amino group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, 5- to 14-membered non-aromatic heterocyclic carbonyl group, C 6-14 aryl-carbonyl group, 3- to 14-membered non-aromatic heterocyclic group, 5- to 14-membered non-aromatic heterocyclic group, C 6-14 C, each of which may be substituted with one or two substituents independently selected from the group consisting of aryl groups; 1-6 Alkoxy groups and C 2-6 An example is an alkenyloxy group. More preferred examples of the optionally substituted hydroxy group include: a hydroxy group, or C 1-6 C optionally substituted by one or two substituents independently selected from the group consisting of an alkoxy group, a carboxy group, a carbamoyl group, a 4- to 7-membered non-aromatic heterocyclic carbonyl group, and a phenyl group 1-6 Examples include alkoxy groups.

[0084] In this specification, "C 1-3The term "alkylene group" means a methylene group, a 1,2-ethane-diyl group, a 1,1-ethane-diyl group, a 1,3-propane-diyl group, a 1,2-propane-diyl group, a 1,1-propane-diyl group, or a 2,2-propane-diyl group.

[0085] In this specification, "C 1-6 The "alkylene group" is defined as the "C 1-6 It means a divalent group obtained by removing one hydrogen atom from an alkyl group at any position.

[0086] In this specification, "C 2-6 The "alkenylene group" is defined as the "C 2-6 It means a divalent group obtained by removing one hydrogen atom from an alkenyl group at any position.

[0087] In this specification, "C 2-6 The "alkynylene group" is defined as the "C 2-6 It means a divalent group obtained by removing one hydrogen atom from an "alkynyl group" at any position.

[0088] In this specification, "C 6-14 The "arylene group" is defined as the "C 6-14 It means a divalent group obtained by removing one hydrogen atom from an "aryl group" at any position.

[0089] In the present specification, the term "heterocyclic-diyl group" refers to a divalent group obtained by removing one hydrogen atom at any position from the above-mentioned "heterocyclic group".

[0090] In the present specification, a compound represented by "X and Y bond to each other and form an optionally substituted 5- to 7-membered ring together with the carbon atoms to which X and Y are bonded" refers to a compound represented by the formula (IA) as a whole molecule, where X and Y bond to each other and form a ring together with the carbon atoms to which X and Y are bonded. [ka] [In the formula, R 1 , R 2 , R 3 and R 4is the same as formula (I), Ring A is an optionally substituted 5- to 7-membered non-aromatic heterocycle, or an optionally substituted 5- or 6-membered nitrogen-containing aromatic heterocycle. The compound represented by the formula: Here, the "5- to 7-membered non-aromatic heterocycle" in ring A means a 5- to 7-membered monocyclic non-aromatic heterocycle containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms independently selected from a nitrogen atom, a sulfur atom, and an oxygen atom, and optionally containing a carbon-oxygen double bond (C=O) or a sulfur-oxygen double bond (S=O, or S(=O)2). Preferred examples include pyrrolidine, pyrrolidinone, piperidine, piperidinone, 1,3-oxazinan-2-one, 5,6-dihydropyridin-2(1H)-one, tetrahydropyrimidin-2(1H)-one, and 1,3-oxazepan-2-one. Examples of the substituent in the "optionally substituted 5- to 7-membered non-aromatic heterocycle" include: C, each of which may be substituted with one or more substituents independently selected from the substituent group F; 1-6 Alkyl group, C 3-6 Examples include cycloalkyl groups and 4- to 10-membered non-aromatic heterocyclic groups. Here, the term "5- or 6-membered nitrogen-containing aromatic heterocycle" refers to a 5- or 6-membered aromatic heterocycle containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms independently selected from nitrogen atoms, sulfur atoms, and oxygen atoms, and containing at least one nitrogen atom. Suitable examples include pyrrole, pyrazole, pyridine, pyrimidine, pyridazine, and pyrazine. Examples of the substituent in the "optionally substituted 5- or 6-membered nitrogen-containing aromatic heterocycle" include the substituents that make up the substituent group E.

[0091] When X and Y are bonded to each other to form an optionally substituted 5- to 7-membered ring together with the carbon atoms to which X and Y are bonded, X and Y are preferably represented by the following formula (ia), (ib), (ic), (id) or (ie): [ka] (wherein α represents the carbon atom to which X is bonded, and β represents the carbon atom to which Y is bonded; Z is a single bond, -CH2-, -O-, -OCH2- (O is bonded to the carbonyl group and CH2 is bonded to the other carbon atom), or -NR 11 - indicates; R 11 each optionally substituted with one or more substituents independently selected from the substituent group F; C 1-6 Alkyl group, C 3-6 represents a cycloalkyl group and a 4- to 10-membered non-aromatic heterocyclic group; W represents CH or a nitrogen atom; R 12 and R 13 represents a hydrogen atom or a substituent independently selected from the substituent group E. It is a group represented by the following formula: When X and Y are groups represented by the formula (ia), (ib), (ic), (id) or (ie), The overall compound may be represented by the following formula (Ia), (Ib), (Ic), (Id) or (Ie): [ka] (wherein each symbol is the same as defined in formula (ia), formula (ib), formula (ic), formula (id) or formula (ie) above).

[0092] Preferred structures of each substituent in the present invention are listed below. In this specification, preferred examples of each substituent include, among the substituents defined above or in addition to the substituents defined above, the substituents shown below in particular.

[0093] R 2 and R 3 is preferably a hydrogen atom or C 1-6 It is an alkyl group, and more preferably a hydrogen atom.

[0094] R1 is preferably a halogen atom and optionally halogenated C 1-6 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl groups 3-10 It is a cycloalkyl group. R 1 is preferably C 3-6 It is a cycloalkyl group. R 1 is more preferably a cyclopropyl group or a cyclobutyl group.

[0095] R 4 The optionally substituted hydrocarbon group represented by the formula (I) is preferably one of the following (i) to (iii): (i) a halogen atom, (ii) a hydroxy group, and (iii)C 1-6 alkoxy group C optionally substituted by 1 to 3 substituents independently selected from 1-6 It is an alkyl group. R 4 The optionally substituted hydrocarbon group represented by the formula: is more preferably a C 1-6 It is an alkyl group, more preferably a tert-butyl group or an isopropyl group, or a tert-butyl group substituted with one hydroxy group, and particularly preferably a tert-butyl group or an isopropyl group.

[0096] In other embodiments, R 4 The optionally substituted hydrocarbon group represented by the formula (I), (II), (IV) to (VI) below is preferably selected from the group consisting of: (i) a halogen atom, (ii) a hydroxy group, (iv) C optionally substituted with 1 to 3 substituents selected from a halogen atom and a hydroxy group 1-6 alkyl groups, (v) C optionally substituted with 1 to 3 substituents selected from a halogen atom and a hydroxy group 1-6 Alkoxy groups and (vi) C 1-6 Alkoxy-carbonyl group C optionally substituted with one or more substituents independently selected from 3-10 It is a cycloalkyl group. R 4 The optionally substituted hydrocarbon group represented by the formula (I) is more preferably an optionally halogenated hydrocarbon group represented by the formula (I). 3-6 It is a cycloalkyl group, more preferably a cyclohexyl group optionally substituted with 1 to 3 halogen atoms.

[0097] In other embodiments, R 4 The optionally substituted hydrocarbon group represented by the formula (I) is preferably a C 6-14 It is an aryl group. R 4 The optionally substituted hydrocarbon group represented by the formula: is more preferably a C 1-6 C optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl groups and halogen atoms 6-14 It is an aryl group. R 4 is more preferably a phenyl group optionally substituted with 1 to 3 substituents independently selected from the group consisting of a fluorine atom, a chlorine atom, and a hydroxymethyl group.

[0098] R 4 The optionally substituted heterocyclic group represented by the formula (I) is preferably a 4- to 10-membered non-aromatic heterocyclic group optionally substituted with one or more substituents independently selected from the group consisting of (i), (ii), (iv) to (vi). R 4 The optionally substituted heterocyclic group represented by the formula (I) is more preferably a heterocyclic group containing a halogen atom and C 1-6 and a 4- to 7-membered non-aromatic heterocyclic group optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl groups. R 4The optionally substituted heterocyclic group represented by the formula (I) is more preferably a tetrahydropyran-4-yl group optionally substituted by 1 or 2 substituents independently selected from the group consisting of a fluorine atom and a methyl group. R 4 The optionally substituted heterocyclic group represented by the formula: is particularly preferably a tetrahydropyran-4-yl group or a 4-methyltetrahydropyran-4-yl group.

[0099] When Y is a hydrogen atom, The optionally substituted amino group represented by X is preferably an amino group substituted by a heterocyclic group optionally substituted by one or more substituents independently selected from Substituent Group F; C which is also substituted with a heterocyclic group which may be substituted with one or more substituents independently selected from the substituent group F 1-6 an alkylamino group; amino group, a carbamoylamino group, sulfamoylamino group, C 1-6 alkyl-carbonylamino group or C 1-6 It is an alkoxy-carbonylamino group. The optionally substituted amino group represented by X is more preferably C 1-6 Alkoxy group, carbamoyl group, carboxy group, optionally halogenated C 1-6 Alkyl groups and C 1-6 an amino group substituted with a 5- to 10-membered aromatic heterocyclic group optionally substituted with 1 to 2 substituents independently selected from the group consisting of alkoxy-carbonyl groups, or a C substituted with a 4- to 10-membered non-aromatic heterocyclic group; 1-6 It is an alkylamino group, an amino group, or a carbamoylamino group. The optionally substituted amino group represented by X is more preferably C 1-6 Alkoxy group, carbamoyl group, carboxy group, optionally halogenated C 1-6 Alkyl groups and C 1-6It is an amino group which is also substituted with a 5- or 6-membered nitrogen-containing aromatic heterocyclic group which may be substituted with 1 or 2 substituents independently selected from the group consisting of alkoxy-carbonyl groups, or it is an amino group or a carbamoylamino group. The optionally substituted amino group represented by X is even more preferably a pyrimidin-4-ylamino group or a pyrazin-2-ylamino group, each of which is substituted with one or more substituents independently selected from the group consisting of a methoxy group, a carbamoyl group, a carboxy group, a trifluoromethyl group, and a methoxycarbonyl group; Amino group or It is a carbamoylamino group.

[0100] When Y is a hydrogen atom, The optionally substituted heterocyclic group represented by X is preferably a 5- to 14-membered aromatic heterocyclic group or a 3- to 14-membered non-aromatic heterocyclic group optionally substituted with one or more substituents independently selected from the aforementioned substituent group F. The optionally substituted heterocyclic group represented by X is more preferably a halogen atom, a hydroxy group, a carbamoyl group, an amino group, a carbamoylamino group, an optionally halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Independently from the group consisting of alkoxy-carbonyl groups and 4- to 7-membered non-aromatic heterocyclic groups Selection and the like. The nitrogen-containing aromatic heterocyclic group is a 5- to 14-membered nitrogen-containing aromatic heterocyclic group which may be substituted with one or more substituents such as aryl, aryl, aryls ... The optionally substituted heterocyclic group represented by X is even more preferably a 5- or 6-membered nitrogen-containing aromatic heterocyclic group substituted with an amino group.

[0101] When Y is a hydrogen atom, The acyl group represented by X is preferably carboxyl group; Carbamoyl group; sulfamoyl group; one or more substituents independently selected from the substituent group F each may be substituted Phenyl group, C 3-10 cycloalkyl basis , a 5- to 10-membered aromatic heterocyclic group, a 4- to 10-membered non-aromatic heterocyclic group, and a mono- or di-C 1-6 a alkyl-carbamoyl group or C 1-6 an alkoxy-carbonyl group; or one or more substituents independently selected from the substituent group F each optionally substituted benzoyl group, C 3-10 It is a cycloalkylcarbonyl group, a 5- to 10-membered aromatic heterocyclylcarbonyl group, or a 4- to 10-membered non-aromatic heterocyclylcarbonyl group. The acyl group represented by X is more preferably carboxyl group; Carbamoyl group; sulfamoyl group; Optionally halogenated C 1-6 mono- or di-C, each of which may be substituted by one or two substituents independently selected from the group consisting of an alkoxy group, a hydroxy group, a halogen atom, a 5- or 6-membered aromatic heterocyclic group, and a 4- to 7-membered non-aromatic heterocyclic group; 1-6 Alkyl-carbamoyl group; C 1-6 Alkoxy-carbonyl groups; 5- or 6-membered aromatic heterocyclic carbonyl group; a 4- to 7-membered non-aromatic heterocyclic carbonyl group; or C 1-6 It is an alkoxy-carbamoyl group. The acyl group represented by X is more preferably a carbamoyl group or a sulfamoyl group. The acyl group represented by X is particularly preferably a carbamoyl group.

[0102] When Y is a hydrogen atom, The optionally substituted hydrocarbon group represented by X is preferably an optionally halogenated C 1-6Alkoxy group, hydroxy group, halogen atom, C 1-6 C, each of which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of an alkoxy-carbonyl group, a carbamoyl group, an amino group, and a carboxy group; 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl group or C 6-14 It is an aryl group. The optionally substituted hydrocarbon group represented by X is more preferably C 1-6 Alkoxy group, hydroxy group, C 1-6 each optionally substituted with 1 or 2 substituents independently selected from the group consisting of an alkoxy-carbonyl group, a carbamoyl group, and an amino group; C 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-6 It is a cycloalkyl group or a phenyl group.

[0103] When X is a hydrogen atom, The acyl group represented by Y is preferably carboxyl group, formyl group, sulfamoyl group, a carbamoyl group, or C 1-6 an alkoxy-carbonyl group, or Mono- or di-C optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen atoms and hydroxy groups 1-6 an alkyl-carbamoyl group, or C 1-6 C, each of which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of an alkyl group, a halogen atom, and a hydroxy group; 3-10 It is a cycloalkyl-carbamoyl group, a 5- to 10-membered aromatic heterocyclylcarbonyl group, or a 4- to 10-membered non-aromatic heterocyclylcarbonyl group. The acyl group represented by Y is more preferably carboxyl group, formyl group, C1-6 alkoxy-carbonyl groups, Mono- or di-C 1-6 alkyl-carbamoyl groups, Optionally halogenated mono- or di-C 3-10 a cycloalkyl-carbamoyl group, or 1 to 3 Cs 1-6 It is a 4- to 7-membered non-aromatic heterocyclic carbonyl group optionally substituted by an alkyl group.

[0104] When X is a hydrogen atom, The optionally substituted hydrocarbon group represented by Y is preferably Hydroxy group, C 1-6 Alkoxy group, C 7-16 Aralkyloxy group, mono- or di-C 1-6 Alkyl-carbamoyl group, C 1-6 each optionally substituted with one or more substituents independently selected from the group consisting of alkoxy-carbonylamino groups, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 6-14 Aryl group, C 3-10 Cycloalkyl group or C 3-10 It is a cycloalkenyl group.

[0105] In other embodiments, When X is a hydrogen atom, The optionally substituted hydrocarbon group represented by Y is more preferably a 3- to 14-membered non-aromatic heterocyclic carbonyl group, a 5- to 14-membered aromatic heterocyclic carbonyl group, C 6-14 Aryl-carbonyl group or C 3-10 C, each substituted with one or more substituents selected from the group consisting of cycloalkylcarbonyl groups 1-6 Alkyl group or C 2-6 It is an alkenyl group. The optionally substituted hydrocarbon group represented by Y is more preferably a halogen atom, a hydroxy group, a carbamoyl group, an amino group, an optionally halogenated C 1-6 Alkyl group, C 1-6 Alkoxy groups and C 1-6 C substituted with a 4- to 10-membered non-aromatic heterocyclic carbonyl group optionally substituted with one or more substituents independently selected from the group consisting of alkoxy-carbonyl groups 2-6 It is an alkenyl group. The optionally substituted hydrocarbon group represented by Y is more preferably a halogen atom, an optionally halogenated C 1-6 an ethenyl group substituted by a 4- to 7-membered non-aromatic heterocyclic carbonyl group optionally substituted by 1 or 2 substituents independently selected from the group consisting of an alkyl group and a hydroxy group; Here, the ethenyl group is particularly preferably in a trans form.

[0106] When X is a hydrogen atom, The optionally substituted heterocyclic group represented by Y is preferably a halogen atom, a hydroxy group, a carbamoyl group, an amino group, a carbamoylamino group, an optionally halogenated C 1-6 Alkyl group, C 1-6 Alkoxy groups and C 1-6 and a 4- to 14-membered non-aromatic heterocyclic group or a 5- to 14-membered aromatic heterocyclic group, each of which may be substituted with one or more substituents independently selected from the group consisting of alkoxy-carbonyl groups. The optionally substituted heterocyclic group represented by Y is more preferably a heterocyclic group containing a halogen atom and C 1-6 It is a 4- to 7-membered non-aromatic heterocyclic group containing an oxygen atom, which may be substituted with 1 to 4 substituents independently selected from the group consisting of alkyl groups. The optionally substituted heterocyclic group represented by Y is more preferably a dihydropyranyl group.

[0107] When Y is a halogen atom, X is preferably a hydrogen atom, an amino group, a carbamoylamino group, a carbamoyl group or C 1-6 It is an alkoxy-carbonyl group. When X is a halogen atom, Y is preferably a hydrogen atom, an amino group, a carbamoylamino group, a carbamoyl group or C 1-6 It is an alkoxy-carbonyl group, more preferably a hydrogen atom.

[0108] When X is an amino group, Y is preferably a hydrogen atom; a halogen atom; 1-6 Alkoxy-carbonyl substituted C 2-6 alkenyl group; or C 1-6 Alkyl group or C 1-6 It is a 4- to 7-membered non-aromatic heterocyclic group optionally substituted with an alkoxy-carbonyl group.

[0109] In other embodiments, When X is an amino group, The optionally substituted hydrocarbon group represented by Y is preferably a halogen atom, an optionally halogenated C 1-6 and an ethenyl group substituted by a 4- to 10-membered non-aromatic heterocyclic carbonyl group optionally substituted by 1 to 2 substituents independently selected from the group consisting of alkyl groups. The optionally substituted hydrocarbon group represented by Y is more preferably a group containing a halogen atom and C 1-6 and an ethenyl group substituted by a 5- or 6-membered non-aromatic heterocyclic carbonyl group which may be substituted by 1 or 2 substituents independently selected from the group consisting of alkyl groups. Here, the ethenyl group is particularly preferably in a trans form.

[0110] In other embodiments, When X is an amino group, The optionally substituted hydrocarbon group represented by Y is preferably C 1-6 Alkyl group, C 2-6It is an ethenyl group substituted with an alkenyl group or a 5- or 6-membered non-aromatic heterocyclic group. Here, the ethenyl group is particularly preferably in a trans form.

[0111] When X is a methylamino group, The optionally substituted hydrocarbon group represented by Y is preferably a halogen atom, an optionally halogenated C 1-6 and an ethenyl group substituted by a 4- to 10-membered non-aromatic heterocyclic carbonyl group optionally substituted by 1 to 2 substituents independently selected from the group consisting of alkyl groups. The optionally substituted hydrocarbon group represented by Y is more preferably a group containing a halogen atom and C 1-6 and an ethenyl group substituted by a 5- or 6-membered non-aromatic heterocyclic carbonyl group which may be substituted by 1 or 2 substituents independently selected from the group consisting of alkyl groups. Here, the ethenyl group is particularly preferably in a trans form.

[0112] X is C 1-6 When it is an alkyl group, The optionally substituted hydrocarbon group represented by Y is preferably a halogen atom, an optionally halogenated C 1-6 Alkyl groups, optionally halogenated C 3-6 Cycloalkyl groups and C 1-6 and an ethenyl group substituted by a 4- to 10-membered non-aromatic heterocyclic carbonyl group optionally substituted by 1 or 2 substituents independently selected from the group consisting of alkoxy groups. The optionally substituted hydrocarbon group represented by Y is more preferably a group containing a halogen atom and C 1-6 and an ethenyl group substituted by a 5- or 6-membered non-aromatic heterocyclic carbonyl group which may be substituted by 1 or 2 substituents independently selected from the group consisting of alkyl groups. Here, X is preferably a methyl group or an ethyl group, and particularly preferably a methyl group. The ethenyl group is particularly preferably in the trans form.

[0113] When X and Y are bonded to each other and together with the carbon atoms to which X and Y are bonded form an optionally substituted 5- to 7-membered ring, X and Y are preferably represented by the following formula (ia) or formula (ib): [ka] (wherein α represents the carbon atom to which X is bonded, and β represents the carbon atom to which Y is bonded; Z is -CH2-, -O- or -NR 11 - indicates; R 11 represents a methyl group, a cyclopropyl group, a tetrahydropyran-4-yl group, a 3,3-difluorocyclobutyl group, or a tetrahydropyran-4-ylmethyl group; W represents CH. X and Y are more preferably groups of formula (ia) in which Z is -CH2-.

[0114] Next, preferred compounds in the present invention will be listed. (1) Formula (I) [ka] [In the formula, R 1 is C 3-6 represents a cycloalkyl group; R 2 and R 3 indicates a hydrogen atom; R 4 teeth, hydroxy groups, Halogen atoms and C 1-6 C optionally substituted with one or more substituents independently selected from the group consisting of alkoxy groups 1-6 alkyl groups; Or, C optionally substituted with one or more substituents independently selected from the group consisting of halogen atoms and hydroxy groups 1-6 alkyl groups, C optionally substituted with one or more substituents independently selected from the group consisting of halogen atoms and hydroxy groups 1-6 alkoxy groups, halogen atoms, Hydroxy groups and C 1-6 Alkoxy-carbonyl group C, each of which may be substituted with one or more substituents independently selected from the group consisting of 3-6 a cycloalkyl group, a phenyl group, or a 4- to 7-membered non-aromatic heterocyclic group indicates; X is hydrogen atoms, halogen atoms, an optionally substituted amino group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, acyl groups, Or, the expression -CR 5 =NR 6 represents a group represented by the formula: The optionally substituted amino group is phenyl, each of which may be substituted with one or more substituents independently selected from substituent group F; amino group, C 3-10 cycloalkyl amino a 5- to 10-membered aromatic heterocyclic amino group or a 4- to 10-membered non-aromatic heterocyclic amino group, a phenyl group, each of which may be substituted with one or more substituents independently selected from the substituent group F; 3-10 Mono- or di-C optionally substituted with a cycloalkyl group, a 5- to 10-membered aromatic heterocyclic group, or a 4- to 10-membered non-aromatic heterocyclic group 1-6 alkylamino groups, amino group, a carbamoylamino group, sulfamoylamino group, C 1-6 alkyl-carbonylamino group or C 1-6 an alkoxy-carbonylamino group, The optionally substituted hydrocarbon group for X is Optionally halogenated C 1-6 Alkoxy group, hydroxy group, halogen atom, C 1-6 C, each of which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of an alkoxy-carbonyl group, a carbamoyl group, an amino group, and a carboxy group; 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 a cycloalkyl group or a phenyl group; The optionally substituted heterocyclic group for X is a 5- to 10-membered aromatic heterocyclic group or a 4- to 10-membered non-aromatic heterocyclic group optionally substituted by one or more substituents independently selected from substituent group F; The acyl group represented by X is carboxyl group, carbamoyl group, a sulfamoyl group, or a phenyl group, each of which may be substituted with one or more substituents independently selected from the substituent group F; C 3-10 mono- or di-C, each of which may be substituted by one or more substituents independently selected from the group consisting of a cycloalkyl group, a 5- to 10-membered aromatic heterocyclic group, a 4- to 10-membered non-aromatic heterocyclic group, and the substituents constituting the substituent group E; 1-6 Alkyl-carbamoyl group or C 1-6 an alkoxy-carbonyl group, or each of which may be substituted with one or more substituents independently selected from the substituent group F phenylcarbonyl group, C 3-10 cycloalkyl carbonyl a 5- or 6-membered aromatic heterocyclic carbonyl group or a 4- to 7-membered non-aromatic heterocyclic carbonyl group, or C 1-6 is an alkoxy-carbamoyl group; Y is hydrogen atoms, halogen atoms, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, acyl groups, Or, the expression -CR 7 =NR 8 represents a group represented by the formula: The optionally substituted hydrocarbon group for Y is Substituents constituting the substituent group F, optionally halogenated C 3-6 Cycloalkyl groups, 4- to 10-membered non-aromatic heterocyclic groups, C 6-14 C substituted with aryl or hydroxy groups 1-6 Alkyl groups, and C 1-6 Alkoxy-substituted C 1-6 each optionally substituted with one or more substituents independently selected from the group consisting of alkyl groups; a 3- to 10-membered non-aromatic heterocyclic carbonyl group, a 5- to 10-membered aromatic heterocyclic carbonyl group, a phenylcarbonyl group, or C 3-10 cycloalkylcarbonyl group C each substituted with one substituent selected from the group consisting of 1-6 Alkyl group or C 2-6 an alkenyl group, or Hydroxy group, C 1-6 Alkoxy group, C 7-16 Aralkyloxy group, mono- or di-C 1-6 Alkyl-carbamoyl groups, and C 1-6 each optionally substituted with one or more substituents independently selected from the group consisting of alkoxy-carbonylamino groups, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 6-14 Aryl group, C 3-10 Cycloalkyl group or C 3-10 represents a cycloalkenyl group; The optionally substituted heterocyclic group represented by Y is Halogen atom, hydroxy group, carbamoyl group, amino group, carbamoylamino group, optionally halogenated C 1-6 Alkyl group, C 1-6 Alkoxy groups and C 1-6a 4- to 10-membered non-aromatic heterocyclic group or a 5- to 10-membered aromatic heterocyclic group, each of which may be substituted with one or more substituents independently selected from the group consisting of alkoxy-carbonyl groups; The acyl group represented by Y is carboxyl group, carbamoyl group, sulfamoyl group, Mono- or di-C, each of which may be substituted with one or more substituents independently selected from the substituent group E; 1-6 Alkyl-carbamoyl group or C 1-6 alkoxy-carbonyl groups, each of which may be substituted with one or more substituents independently selected from the substituent group F 、 Benzoyl group, C 3-10 Cycloalkylcarbonyl group, C 3-10 a cycloalkenylcarbonyl group, a 5- to 10-membered aromatic heterocyclylcarbonyl group, or a 4- to 10-membered non-aromatic heterocyclylcarbonyl group, or a phenylcarbamoyl group, each of which may be substituted with one or more substituents independently selected from the substituent group F; 3-10 Cycloalkyl-carbamoyl group, C 3-10 a cycloalkenyl-carbamoyl group, a 4- to 10-membered non-aromatic heterocyclic carbamoyl group, or a 5- to 10-membered aromatic heterocyclic carbamoyl group, or C 1-6 represents an alkoxy-carbamoyl group; R 5 and R 7 are each independently a hydrogen atom or C 1-6 represents an alkyl group; R 6 and R 8 are each independently a hydroxy group, or C 1-6 C optionally substituted with one substituent selected from the group consisting of an alkoxy group, a carboxy group, a carbamoyl group, a 4- to 7-membered non-aromatic heterocyclic carbonyl group, and a phenyl group 1-6 represents an alkoxy group. however, If X is a hydrogen atom, then Y is not a hydrogen atom; If Y is a hydrogen atom, then X is not a hydrogen atom. a compound represented by the formula: et al. solvates.

[0115] (2) Formula (I) [ka] [In the formula, R 1 is C 3-6 represents a cycloalkyl group; R 2 and R 3 indicates a hydrogen atom; R 4 teeth, hydroxy groups, Halogen atoms and C 1-6 C optionally substituted with one or more substituents independently selected from the group consisting of alkoxy groups 1-6 alkyl groups; Or, C optionally substituted with one or more substituents independently selected from the group consisting of halogen atoms and hydroxy groups 1-6 alkyl groups, C optionally substituted with one or more substituents independently selected from the group consisting of halogen atoms and hydroxy groups 1-6 alkoxy groups, halogen atoms, Hydroxy groups and C 1-6 Alkoxy-carbonyl group C, each of which may be substituted with one or more substituents independently selected from the group consisting of 3-6 a cycloalkyl group, a phenyl group, or a 4- to 7-membered non-aromatic heterocyclic group indicates; X is hydrogen atoms, halogen atoms, an optionally substituted amino group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, acyl groups, Or, the expression -CR 5 =NR 6 represents a group represented by the formula: The optionally substituted amino group is phenyl, each of which may be substituted with one or more substituents independently selected from substituent group F; amino group, C 3-10 cycloalkyl amino a 5- to 10-membered aromatic heterocyclic amino group or a 4- to 10-membered non-aromatic heterocyclic amino group, a phenyl group, each of which may be substituted with one or more substituents independently selected from the substituent group F; 3-10 a cycloalkyl group, a 5- to 10-membered aromatic heterocyclic group, or a 4- to 10-membered aromatic heterocyclic group Mono- or di-C optionally substituted with a 10-membered non-aromatic heterocyclic group 1-6 alkylamino groups, amino group, a carbamoylamino group, sulfamoylamino group, C 1-6 alkyl-carbonylamino group or C 1-6 an alkoxy-carbonylamino group, The optionally substituted hydrocarbon group for X is Optionally halogenated C 1-6 Alkoxy group, hydroxy group, halogen atom, C 1-6 C, each of which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of an alkoxy-carbonyl group, a carbamoyl group, an amino group, and a carboxy group; 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 a cycloalkyl group or a phenyl group; The optionally substituted heterocyclic group for X is a 5- to 10-membered aromatic heterocyclic group or a 4- to 10-membered non-aromatic heterocyclic group optionally substituted by one or more substituents independently selected from substituent group F; The acyl group represented by X is carboxyl group, carbamoyl group, a sulfamoyl group, or a phenyl group, each of which may be substituted with one or more substituents independently selected from the substituent group F; C 3-10 mono- or di-C, each of which may be substituted by one or more substituents independently selected from the group consisting of a cycloalkyl group, a 5- to 10-membered aromatic heterocyclic group, a 4- to 10-membered non-aromatic heterocyclic group, and the substituents constituting the substituent group E; 1-6 Alkyl-carbamoyl group or C 1-6 an alkoxy-carbonyl group, or each of which may be substituted with one or more substituents independently selected from the substituent group F phenylcarbonyl group, C 3-10 cycloalkyl carbonyl a 5- or 6-membered aromatic heterocyclic carbonyl group or a 4- to 7-membered non-aromatic heterocyclic carbonyl group, or C 1-6 is an alkoxy-carbamoyl group; Y is hydrogen atoms, halogen atoms, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, acyl groups, Or, the expression -CR 7 =NR 8 represents a group represented by the formula: The optionally substituted hydrocarbon group for Y is a 3- to 10-membered non-aromatic heterocyclylcarbonyl group, a 5- to 10-membered aromatic heterocyclylcarbonyl group, a phenylcarbonyl group or C, each of which may be substituted by one or more substituents independently selected from substituent group F; 3-10 C each substituted with one substituent selected from the group consisting of cycloalkylcarbonyl groups 1-6Alkyl group or C 2-6 an alkenyl group, or Hydroxy group, C 1-6 Alkoxy group, C 7-16 Aralkyloxy group, mono- or di-C 1-6 Alkyl-carbamoyl groups, and C 1-6 each optionally substituted with one or more substituents independently selected from the group consisting of alkoxy-carbonylamino groups, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 6-14 Aryl group, C 3-10 Cycloalkyl group or C 3-10 represents a cycloalkenyl group; The optionally substituted heterocyclic group represented by Y is Halogen atom, hydroxy group, carbamoyl group, amino group, carbamoylamino group, optionally halogenated C 1-6 Alkyl group, C 1-6 Alkoxy groups and C 1-6 Al a 4- to 10-membered non-aromatic heterocyclic group or a 5- to 10-membered aromatic heterocyclic group, each of which may be substituted by one or more substituents independently selected from the group consisting of alkoxy-carbonyl groups; The acyl group represented by Y is carboxyl group, carbamoyl group, sulfamoyl group, Mono- or di-C, each of which may be substituted with one or more substituents independently selected from the substituent group E; 1-6 Alkyl-carbamoyl group or C 1-6 alkoxy-carbonyl groups, each of which may be substituted with one or more substituents independently selected from the substituent group F 、 Benzoyl group, C 3-10 Cycloalkylcarbonyl group, C 3-10 a cycloalkenylcarbonyl group, a 5- to 10-membered aromatic heterocyclylcarbonyl group, or a 4- to 10-membered non-aromatic heterocyclylcarbonyl group, or a phenylcarbamoyl group, each of which may be substituted with one or more substituents independently selected from the substituent group F; 3-10 Cycloalkyl-carbamoyl group, C 3-10 a cycloalkenyl-carbamoyl group, a 4- to 10-membered non-aromatic heterocyclic carbamoyl group, or a 5- to 10-membered aromatic heterocyclic carbamoyl group, or C 1-6 represents an alkoxy-carbamoyl group; R 5 and R 7 are each independently a hydrogen atom or C 1-6 represents an alkyl group; R 6 and R 8 are each independently a hydroxy group, or C 1-6 C optionally substituted with one substituent selected from the group consisting of an alkoxy group, a carboxy group, a carbamoyl group, a 4- to 7-membered non-aromatic heterocyclic carbonyl group, and a phenyl group 1-6 represents an alkoxy group. however, If X is a hydrogen atom, then Y is not a hydrogen atom; If Y is a hydrogen atom, then X is not a hydrogen atom. A compound represented by the formula: Figure US081202303-20130310-C00002, a tautomer of said compound, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0116] (3) R 1 is a cyclopropyl group or a cyclobutyl group, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof according to (1) or (2).

[0117] (4) R 4 is a tert-butyl group, an isopropyl group, a 3-pentyl group, a 2,2-dimethylpropan-1-yl group, or a tert-butyl group substituted with one hydroxy group, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof according to (1), (2), or (3). (5) R 4 but, halogen atoms, C optionally substituted with hydroxy 1-6 Alkyl group C 1-6 Alkoxy-carbonyl group The compound according to (1), (2), or (3), wherein each of the groups is a cyclohexyl group, a phenyl group, or a tetrahydropyranyl group, each of which may be substituted by 1 to 3 substituents independently selected from the group consisting of:

[0118] (6) The compound according to any one of (1) to (5), wherein either X or Y is a hydrogen atom, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0119] (7) X is a group of the formula -L X -R X (In the formula, R X is a phenyl group, each of which may be substituted with one or more substituents independently selected from the substituent group F, 3-10 a cycloalkyl group, a 4- to 10-membered non-aromatic heterocyclic group, or a 5- to 10-membered aromatic heterocyclic group, L X represents a single bond, -N(H)-, a carbonyl group, -N(R 9 )-R 10 -* or -C(=O)-N(R 9 )-R 10 -* and R 9 is a hydrogen atom or an optionally halogenated C 1-6 is an alkyl group, R 10 is C 1-6 is an alkylene group, * indicates R X (meaning the bonding position with The compound according to any one of (1) to (6), wherein the compound is a group represented by the following formula:

[0120] (8) R 9 is a hydrogen atom, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof according to (7). (9) R X but, Halogen atoms, carboxy groups, carbamoyl groups, hydroxy groups, amino groups, carbamoylamino groups, optionally halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 a phenyl group, C, each of which is optionally substituted by 1 to 3 substituents independently selected from the group consisting of an alkoxy-carbonyl group, and a 4- to 7-membered non-aromatic heterocyclic group; 3-6 The compound according to (7) or (8), wherein the compound is a cycloalkyl group, a 4- to 7-membered non-aromatic heterocyclic group, or a 5- to 10-membered aromatic heterocyclic group, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0121] (10) X is a halogen atom, a carbamoyl group, a hydroxy group, an amino group, a carbamoylamino group, or C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 a phenyl group, C, each of which may be substituted by one or two substituents independently selected from the group consisting of an alkoxy-carbonyl group and a 4- to 7-membered non-aromatic heterocyclic group; 3-6 The compound according to any one of (1) to (6), wherein the cycloalkyl group is a 4- to 7-membered non-aromatic heterocyclic group, or a 5- to 10-membered aromatic heterocyclic group, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. (11) X is a halogen atom, a carbamoyl group, a hydroxy group, an amino group, a carbamoylamino group, or C 1-6Alkoxy group, C 1-6 The compound according to any one of (1) to (6), which is a 4- to 7-membered non-aromatic heterocyclic group or a 5- to 10-membered aromatic heterocyclic group, each of which is optionally substituted by one or two substituents independently selected from the group consisting of an alkoxy-carbonyl group and a 4- to 7-membered non-aromatic heterocyclic group, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. (12) X is a carbamoyl group, a carbamoylamino group, a hydroxy group, an amino group, or C 1-6 The compound according to any one of (1) to (6), which is a 5- to 10-membered aromatic heterocyclic group optionally substituted by 1 or 2 substituents independently selected from the group consisting of an alkoxy group and a 4- to 7-membered non-aromatic heterocyclic group, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. (13) The compound according to any one of (1) to (6), wherein X is a 5- to 10-membered aromatic heterocyclic group substituted with an amino group, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. (14) The compound according to any one of (1) to (6), wherein X is a pyridyl group, a pyrimidyl group, a pyrazolyl group, a pyrazyl group, or a benzimidazolyl group, each of which is substituted with an amino group, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0122] (15) R X represents a 4- to 10-membered non-aromatic heterocyclic group or a 5- to 10-membered aromatic heterocyclic group, each of which may be substituted with one or more substituents independently selected from substituent group F, L X is -N(H)-, a carbonyl group, -N(H)-R 10 -* or -C(=O)-N(H)-R 10 -* and R 10 is C 1-6 is an alkylene group, * indicates R X The compound according to (7) or (8), a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the bonding position of (16) R X may be halogenated C 1-6 Alkyl groups, optionally halogenated C 1-6 Alkoxy group, C 1-6 The compound according to (7), (8), or (15), which is a 4- to 7-membered non-aromatic heterocyclic group or a 5- or 6-membered aromatic heterocyclic group, each of which may be substituted with 1 or 2 substituents independently selected from the group consisting of an alkoxy-carbonyl group, a carboxy group, and a carbamoyl group, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. (17) R 10 is C 1-3 The compound according to any one of (7), (8), (15) and (16), wherein the alkylene group is an alkylene group, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. (18) R X may be halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 a 5- or 6-membered aromatic heterocyclic group optionally substituted with one substituent selected from the group consisting of an alkoxy-carbonyl group, a carboxy group, and a carbamoyl group; L X is —N(H)—, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof according to any one of (7), (8), (15) to (17). (19) R Xis a pyrimidinyl group or a pyrazinyl group optionally substituted with one substituent selected from the group consisting of a trifluoromethyl group, a methoxy group, a methoxy-carbonyl group, a carboxy group, and a carbamoyl group, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof according to any one of (7), (8), (15) to (18).

[0123] (20) X is an amino group, a carbamoylamino group, a sulfamoylamino group, or C 1-6 Alkyl-carbonylamino group, C 1-6 alkoxy-carbonylamino groups, C 1-6 Alkoxy-carbamoyl group, carbamoyl group, carboxy group, C 1-6 alkoxy-carbonyl groups, Optionally halogenated C 1-6 mono- or di-C optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkoxy groups, hydroxy groups, and halogen atoms; 1-6 alkyl-carbamoyl groups, C 1-6 C, each of which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of an alkoxy-carbonyl group, a carbamoyl group, and a hydroxy group; 1-6 Alkyl group or C 2-6 an alkenyl group, or Expression -CR 5 =NR 6 represents a group represented by the formula: R 5 is a hydrogen atom or C 1-6 represents an alkyl group; R 6 is a hydroxy group, or C 1-6 C optionally substituted with one substituent independently selected from the group consisting of an alkoxy group, a carboxy group, a carbamoyl group, and a phenyl group 1-6 The compound according to any one of (1) to (6), wherein R is an alkoxy group, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. (twenty one) The compound according to any one of (1) to (6), wherein X is an amino group, a carbamoylamino group, or a carbamoyl group, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. (twenty two) X is C 1-6 Alkylamino group or C 1-6 The compound according to any one of (1) to (6), which is an alkyl group, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0124] (twenty three) Y is a group of the formula -L Y -L Yy -R Y (In the formula, R Y is a phenyl group, each of which may be substituted with one or more substituents independently selected from the substituent group F, 3-10 Cycloalkyl groups, C 3-10 a cycloalkenyl group, a 4- to 10-membered non-aromatic heterocyclic group, a 5- to 10-membered aromatic heterocyclic group, a phenylamino group, C 3-10 a cycloalkylamino group, a 4- to 10-membered non-aromatic heterocyclic amino group, a 5- to 10-membered aromatic heterocyclic amino group, or Mono- or di-C 1-6 Alkylamino group, C 1-6 an alkoxy group, a hydroxy group, an amino group, or a hydrogen atom; L Y is a single bond, C 1-6 Alkylene group or C 2-6 is an alkenylene group, L Yy is a single bond or a carbonyl group, L Y and L Yy is a single bond, R Y is not a hydrogen atom) The compound according to any one of (2) to (22), wherein the compound is a group represented by the following formula (1), a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. (twenty four) Y is a phenyl group, each of which may be substituted with one or more substituents independently selected from the substituent group F, 3-6 Cycloalkyl groups, C 3-6 The compound according to any one of (2) to (23), wherein the compound is a cycloalkenyl group, a 4- to 7-membered non-aromatic heterocyclic group, or a 5- or 6-membered aromatic heterocyclic group, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. (twenty five) Y is optionally halogenated C 1-6 Alkyl group, C 1-6 Alkoxy-carbonyl group, C 1-6 Alkoxy-carbonylamino group, C 7-14 a phenyl group, C 3-6 Cycloalkyl groups, C 3-6 The compound according to any one of (2) to (24), wherein the cycloalkenyl group is a 4- to 7-membered non-aromatic heterocyclic group, or a 5- or 6-membered aromatic heterocyclic group, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. (26) Y is optionally halogenated C 1-6 Alkyl groups, and C 1-6 The compound according to any one of (2) to (25), which is a 4- to 7-membered non-aromatic heterocyclic group or a 5- or 6-membered aromatic heterocyclic group, each of which is optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkoxy-carbonyl groups, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. (27) The compound according to any one of (2) to (26), wherein Y is a tetrahydropyranyl group optionally substituted with 1 to 4 methyl groups, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0125] (28) Y is a group of the formula -L Y -L Yy -RY (In the formula, R Y may be halogenated C 1-6 Alkyl groups, optionally halogenated C 3-6 Cycloalkyl groups, C 1-6 Alkoxy-carbonyl group, hydroxy group, 4- to 10-membered non-aromatic heterocyclic group, C 6-14 C substituted with aryl or hydroxy groups 1-6 Alkyl group, C 1-6 Alkoxy-substituted C 1-6 C, each of which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl groups and halogen atoms; 3-6 Cycloalkyl groups, 4- to 10-membered non-aromatic heterocyclic groups, C 3-6 a cycloalkylamino group, a 4- to 7-membered non-aromatic heterocyclic amino group, or Mono- or di-C 1-6 Alkylamino group, C 1-6 an alkoxy group, a hydroxy group, or an amino group; L Y is C 1-6 Alkylene group or C 2-6 is an alkenylene group, L Yy is a carbonyl group.), a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof according to any one of (1) to (22), (29) L Y is a 1,2-ethane-diyl group or a 1,2-ethene-diyl group, R Y may be halogenated C 1-6 Alkyl groups, optionally halogenated C 3-6 Cycloalkyl groups, C 1-6 a 4- to 7-membered non-aromatic heterocyclic group, each of which may be substituted by 1 to 3 substituents independently selected from an alkoxy-carbonyl group, a hydroxy group, and a halogen atom; 3-6 a cycloalkylamino group, a 4- to 7-membered non-aromatic heterocyclic amino group, or Mono- or di-C1-6 Alkylamino group, C 1-6 The compound according to (28), wherein R is an alkoxy group, a hydroxy group, or an amino group, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. (30) R Y may be halogenated C 1-6 Alkyl groups, optionally halogenated C 3-6 Cycloalkyl groups, C 1-6 The compound according to (29), a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the compound is a morpholino group, a pyrrolidin-1-yl group, a piperazinyl group, a piperidino group, a tetrahydropyranylamino group, or a cyclobutylamino group, each of which is optionally substituted by 1 or 2 substituents independently selected from an alkoxy-carbonyl group, a hydroxy group, and a halogen atom.

[0126] (31) R Y may be halogenated C 1-6 Alkyl group, C 1-6 C, each of which may be substituted with 1 to 3 substituents independently selected from an alkoxy-carbonyl group, a hydroxy group, and a halogen atom; 3-6 Cycloalkyl groups, 4- to 7-membered non-aromatic heterocyclic groups, C 3-6 a cycloalkylamino group, a 4- to 7-membered non-aromatic heterocyclic amino group, or Mono- or di-C 1-6 Alkylamino group, C 1-6 an alkoxy group, a hydroxy group, or an amino group; L Y is C 1-6 Alkylene group or C 2-6 is an alkenylene group, L Yy is a carbonyl group, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof according to (23). (32) L Yis a 1,2-ethane-diyl group or a 1,2-ethene-diyl group, R Y may be halogenated C 1-6 Alkyl group, C 1-6 a 4- to 7-membered non-aromatic heterocyclic group, each of which may be substituted by 1 to 3 substituents independently selected from an alkoxy-carbonyl group, a hydroxy group, and a halogen atom; 3-6 a cycloalkylamino group, a 4- to 7-membered non-aromatic heterocyclic amino group, or Mono- or di-C 1-6 Alkylamino group, C 1-6 The compound according to (31), wherein R is an alkoxy group, a hydroxy group, or an amino group, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. (33) R Y may be halogenated C 1-6 Alkyl group, C 1-6 The compound according to (32), a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the compound is a morpholino group, a piperazinyl group, a piperidino group, a tetrahydropyranylamino group, or a cyclobutylamino group, each of which is optionally substituted by 1 or 2 substituents independently selected from an alkoxy-carbonyl group, a hydroxy group, and a halogen atom.

[0127] (34) R 4 is a tert-butyl group, an isopropyl group, a tetrahydropyran-4-yl group, or a 4-methyl-tetrahydropyran-4-yl group; X is an amino group, a carbamoylamino group, or a carbamoyl group; or Optionally halogenated C 1-6 Alkyl group, C 1-6 a pyrazinylamino group or a pyrimidinylamino group substituted with an alkoxy group or a carbamoyl group, or a pyridyl group substituted with an amino group, The compound according to (2), wherein Y is a hydrogen atom, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. (35) R 4 is a tert-butyl group, an isopropyl group, or a 4-methyl-tetrahydropyran-4-yl group; X is a hydrogen atom, The compound according to (2), wherein Y is a dihydro-2H-pyran-4-yl group or an ethenyl group substituted with a morpholinocarbonyl group, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. (36) R 4 is tetrahydropyran-4-yl or 4-methyl-tetrahydropyran-4-yl, X is a hydrogen atom, The compound according to (2), wherein Y is a dihydro-2H-pyran-4-yl group, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0128] (37) R 1 is a cyclopropyl group, R 4 is a tert-butyl group or an isopropyl group, X is an amino group, a methylamino group, an ethyl group, or a methyl group; Y is a group of the formula -L Y -L Yy -R Y (In the formula, R Y may be halogenated C 1-6 Alkyl groups, optionally halogenated C 3-6 Cycloalkyl groups, C 1-6 a morpholino group, a pyrrolidin-1-yl group, a piperazin-1-yl group, a piperidin-1-yl group, or a dihydro-2H-pyran-4-yl group, each of which is optionally substituted by 1 or 2 substituents independently selected from an alkoxy group and a halogen atom; L Yis a 1,2-ethene-diyl group, L Yy is a single bond or a carbonyl group. The compound according to (1), a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the compound is a group represented by the formula:

[0129] (38) In formula (I), X and Y are bonded to each other and together with the carbon atoms to which X and Y are bonded form an optionally substituted 5- to 7-membered ring, and the ring is represented by the following formula (Ia), formula (Ib), formula (Ic), formula (Id), or formula (Ie): [ka] [In the formula, R 1 is C 3-6 represents a cycloalkyl group; R 2 and R 3 indicates a hydrogen atom; R 4 teeth, hydroxy groups, Halogen atoms and C 1-6 C optionally substituted with one or more substituents independently selected from the group consisting of alkoxy groups 1-6 alkyl groups; Or, C optionally substituted with one or more substituents independently selected from the group consisting of halogen atoms and hydroxy groups 1-6 alkyl groups, C optionally substituted with one or more substituents independently selected from the group consisting of halogen atoms and hydroxy groups 1-6 alkoxy groups, halogen atoms, Hydroxy groups and C 1-6 Alkoxy-carbonyl group C, each of which may be substituted with one or more substituents independently selected from the group consisting of 3-6 a cycloalkyl group, a phenyl group, or a 4- to 7-membered non-aromatic heterocyclic group indicates; Z is a single bond, -CH2-, -O-, -OCH2- (O is bonded to the carbonyl group and CH2 is bonded to the other carbon atom), or -NR 11 - indicates; R 11 each optionally substituted with one or more substituents independently selected from the substituent group F; C 1-6 Alkyl group, C 3-6 represents a cycloalkyl group and a 4- to 10-membered non-aromatic heterocyclic group; W represents CH or a nitrogen atom; R 12 and R 13 represents a hydrogen atom or a substituent independently selected from the substituent group E] A compound represented by the formula: Figure US081202303-20130310-C00002, a tautomer of said compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. (39) R 1 is a cyclopropyl group or a cyclobutyl group, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof according to (38). (40) R 4 is a tert-butyl group, an isopropyl group, a tetrahydro-2H-pyran-4-yl group, or a 4-methyltetrahydro-2H-pyran-4-yl group, a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof according to (38) or (39). (41) In formula (I), X and Y are bonded to each other to form an optionally substituted 5- to 7-membered ring together with the carbon atoms to which X and Y are bonded, and the ring is represented by the following formula (Ia) or (Ib): [ka] (Wherein, Z is —CH—, —O—, or —NR 11 - indicates; R 11represents a methyl group, a cyclopropyl group, a tetrahydropyran-4-yl group, a 3,3-difluorocyclobutyl group, or a tetrahydropyran-4-ylmethyl group; W represents CH.), a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof according to (38), (39), or (40),

[0130] (42) A sepiapterin reductase inhibitor comprising, as an active ingredient, the compound according to any one of (1) to (41), a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. (43) A drug for preventing, treating, and / or improving a disease for which sepiapterin reductase inhibitory activity is effective, comprising the compound according to any one of (1) to (41), a tautomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. (44) A pain treatment agent comprising, as an active ingredient, the compound according to any one of (1) to (41), a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. (45) A pharmaceutical composition comprising, as an active ingredient, the compound according to any one of (1) to (41), a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. (46) A pharmaceutical having a sepiapterin reductase inhibitory effect, comprising the compound according to any one of (1) to (41), a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. (47) A drug for preventing, treating, and / or ameliorating a disease, which has a sepiapterin reductase inhibitory activity and contains, as an active ingredient, the compound according to any one of (1) to (41), a tautomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0131] Specific examples of the compound represented by formula (I) include the compounds of Synthesis Examples 1 to 40 described below, more preferably the compounds of Synthesis Examples 4 and 10 to 33, and particularly preferably the compounds of Synthesis Examples 4, 10, 12, 18, 21, 23, 32 and 33.

[0132] Specific examples of the compound represented by formula (I) include the compounds of Synthesis Examples 215 to 756 described below, more preferably the compounds of Synthesis Examples 390, 403, 433, 452 to 458, 511, 534, 544, 551, 563 to 586, 602 to 635, 639 to 642, 644 to 659, 662 to 669, 671 to 677, 679 to 694, 697 to 698, 701 to 723, 741, and 749 to 756, and particularly preferably the compounds of Synthesis Examples 433, 453, 457, 511, 534, 544, 551, 563, 564, 565, 566, 567, 568, 569, 570, 574, 576, 579, 582, 586, 602, 603, 606, 615, 628, 641, 644, 645, 646, 647, 648, 656, 657, 658, 659, 671, 681, 682, 683, 685, 697, 701, 702, 706, 708, 713, 716, 717, 718, 722, 723, 741, 749, 750, 751, 753, 754, 755 and 756 compounds.

[0133] The present invention includes compounds of formula (I) of the present invention that exist via their tautomerism and geometric isomerism, whether endocyclic or exocyclic, as well as mixtures thereof or mixtures of individual isomers. Furthermore, when an asymmetric center is present or an asymmetric center is generated as a result of isomerization, the present invention also includes the existence of individual optical isomers and mixtures of these isomers in any ratio. Furthermore, in the case of compounds having two or more asymmetric centers, diastereomers resulting from the respective optical isomers also exist. The compounds of the present invention also include compounds containing all of these forms in any ratio. For example, diastereomers can be separated by methods well known to those skilled in the art, such as fractional crystallization, and optically active forms can be obtained by well-known organic chemistry techniques for this purpose.

[0134] The compounds of formula (I) of the present invention or pharmaceutically acceptable salts thereof may exist in any crystalline form or any hydrate depending on the production conditions, and these crystalline forms, hydrates, and mixtures thereof are also included in the scope of the present invention. They may also exist as solvates containing organic solvents such as acetone, ethanol, 1-propanol, and 2-propanol, and all of these forms are included in the scope of the present invention.

[0135] The present invention also includes pharmaceutically acceptable salts of the compounds of formula (I) of the present invention. The compound of the present invention represented by formula (I) can be converted into a pharmaceutically acceptable salt, or can be liberated from the resulting salt, as necessary. Examples of the pharmaceutically acceptable salt of the present invention include: Alkali metals (lithium, sodium, potassium, etc.), Alkaline earth metals (magnesium, calcium, etc.), ammonium, organic bases, amino acid, Inorganic acids (hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, etc.) or Examples of the salts include salts with organic acids (acetic acid, citric acid, maleic acid, fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, etc.).

[0136] The present invention also includes prodrugs of the compounds of formula (I) of the present invention. A prodrug is a derivative of a pharmaceutical compound having a chemically or metabolically decomposable group, which is decomposed by solvolysis or in vivo under physiological conditions to yield a pharmacologically active pharmaceutical compound. Methods for selecting and preparing suitable prodrug derivatives are described, for example, in Design of Prodrugs (Elsevier, Amsterdam 1985). In the present invention, when a compound has a hydroxy group, examples of prodrugs include acyloxy derivatives prepared by reacting the compound with an appropriate acyl halide, an appropriate acid anhydride, or an appropriate haloalkoxycarbonyl compound. Particularly preferred structures for prodrugs include -O-COC2H5, -O-CO(t-Bu), -O-COC 15 H 31 , -O-CO(m-CO2Na-Ph), -O-COCH2CH2CO2Na, -OCOCH(NH2)CH3, -O-COCH2N(CH3)2 or -O-CH2OC(=O)CH3. When the compound forming the present invention has an -NH- group, examples include prodrugs produced by reacting a compound having an -NH- group with an appropriate acid halide, an appropriate mixed acid anhydride or an appropriate haloalkoxycarbonyl compound. A particularly preferred structure for a prodrug is -N-CO(CH2) 20 Examples include -OCH3, -N-COCH(NH2)CH3, -N-CH2O(C=O)CH3, etc.

[0137] Specific examples of methods for administering a drug containing the compound of the present invention as an active ingredient include oral administration, rectal administration, transdermal absorption, and injection. Specific examples of the dosage form of the pharmaceutical containing the compound of the present invention as an active ingredient include tablets, capsules, powders, granules, pills, and syrups. The agents can be administered as single therapeutic agents or as mixtures with other therapeutic agents. They may be administered alone, but are generally administered in the form of a pharmaceutical composition. These preparations can be prepared by conventional methods with the addition of pharmacologically and pharmaceutically acceptable additives. That is, oral preparations can contain conventional additives such as excipients, lubricants, binders, disintegrants, wetting agents, plasticizers, and coating agents. Oral liquid preparations may be in the form of aqueous or oily suspensions, solutions, emulsions, syrups, elixirs, etc., or may be provided as dry syrups to be reconstituted with water or other suitable solvents before use. The liquid preparations may contain conventional additives such as suspending agents, flavorings, diluents, or emulsifiers. For rectal administration, the drug can be administered as a suppository, which may be made from a suitable base such as cacao butter, laurin butter, macrogol, glycerogelatin, witepsol, sodium stearate, or a mixture thereof, to which an emulsifier, suspending agent, preservative, etc. may be added as needed. Injections contain formulation components such as distilled water for injection, physiological saline, 5% glucose solution, propylene glycol, and other solubilizers or solubilizing agents, pH adjusters, isotonicity agents, and stabilizers, which can be used to form aqueous or ready-to-use dosage forms.

[0138] When the drug of the present invention is administered to humans, the dosage is determined depending on the age and condition of the patient, but for adults, the dosage is usually about 0.1 mg to 1000 mg / person / day for oral or rectal administration, and about 0.05 mg to 500 mg / person / day for injection. These figures are merely examples, and the dosage is determined according to the patient's symptoms.

[0139] In addition to primates, such as humans, a variety of other mammals can be treated by the methods of the present invention. For example, but not limited to, mammals can be treated, including cows, sheep, goats, horses, dogs, cats, guinea pigs, or other bovine, ovine, equine, canine, feline, and rodent species, such as mice. The methods can also be practiced in other species, such as birds (e.g., chickens).

[0140] The present invention provides a novel method for preventing and treating sepiapterin reductase (SPR)-associated diseases. The SPR-associated diseases of the present invention include pain. Specific examples of pain include inflammatory pain, nociceptive pain, functional pain, and neuropathic pain, regardless of whether acute or chronic. Further, more specific examples of the above pain include: (1) musculoskeletal pain (after trauma, infection, and exercise), (2) neuropathic pain due to spinal cord injury, tumor, compression, inflammation, toothache, episiotomy pain, (3) deep and visceral pain (e.g., cardiac pain, bladder pain, or pelvic viscera pain), (4) muscular pain, (5) ocular pain, (6) orofacial pain (e.g., toothache, trigeminal neuralgia, glossopharyngeal neuralgia), (7) abdominal pain, (8) gynecological pain (e.g., dysmenorrhea and labor pain), (9) nerve-related pain due to trauma, compression, inflammation, toxic chemicals, metabolic disorders, genetic conditions, infection, vasculitis, or autoimmune disease, (10) pain associated with nerve root injury, (11) central nervous system pain such as pain due to spinal cord injury, brainstem injury, cerebrovascular incidents, tumor, infection, or demyelinating disease (including multiple sclerosis), (12) low back pain, (13) sciatica, and (14) postoperative pain. Further examples of SPR-related diseases in the present invention include (15) pain due to disease or injury in soft tissues, joints (e.g., acute trauma, osteoarthritis, or rheumatoid arthritis), (16) myofacial pain syndrome (fibromyalgia), (17) headache (including cluster headache, migraine, and tension-type headache), (18) myocardial infarction, angina, ischemic cardiovascular disease, post-stroke pain, (19) sickle cell anemia, peripheral vascular occlusive disease, cancer, inflammatory conditions of the skin or joints, (20) diabetic neuropathy, and acute tissue damage due to surgery or traumatic injury (e.g., burns, lacerations, or fractures). The present invention can be used in the prevention, treatment, and diagnosis of the above-mentioned sepiapterin reductase (SPR)-related diseases. The concept of treatment also includes symptomatic relief. Among the above, the present invention is more preferably used in the prevention or treatment, and even more preferably in the treatment. The applications of the present invention are envisioned as described above, but are not limited to these.

[0141] (combination therapy) The compounds of the invention, or tautomers, salts, solvates, prodrugs, or pharmaceutical compositions thereof, can be administered alone or in combination with one or more additional therapeutic agents, such as analgesics used in the treatment of nociceptive, inflammatory, functional, or neuropathic pain. In the present invention, the second therapeutic agent may or may not provide a therapeutic effect when administered independently, but provides such an effect (e.g., pain relief) when administered with a composition of the invention.

[0142] The compounds of the present invention can be used alone or in combination with one or more of the agents listed below. Drugs that can be combined include, but are not limited to, nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., rofecoxib, celecoxib, valdecoxib, parecoxib, salicylic acid, acetaminophen, diclofenac, piroxicam, indomethacin, ibuprofen, and naproxen), opioid analgesics (e.g., propoxyphene, meperidine, hydromorphone, hydrocodone, oxycodone, morphine, ane, codeine and tramadol), NMDA antagonist analgesics (e.g., 2-piperidino-1-alkanol derivatives, ketamine, dextromethorphan, eliprodil or ifenprodil), anesthetics (e.g., nitrous oxide, halothane, fluothane), local anesthetics (lidocaine, etidocaine, ropivacaine, chloroprocaine, sarapin and bupivacaine), benzodiazepines (diazepam, chlordiazepoxide, alfa), prazolam and lorazepam), capsaicin, tricyclic antidepressants (e.g., amitriptyline, perphenazine, protriptyline, tranylcypromine, imipramine, desipramine, and clomipramine), skeletal muscle relaxant analgesics (e.g., flexeril, carisoprodol, robaxil, norgesic, and dantrium), antimigraine medications (e.g., eletriptan, sumatriptan, rizatriptan, zolmitriptan, and naratriptan), anticonvulsants (e.g., phenytoin, lamotrigine, pregabalin, carbamazepine, oxcarbazepine, topiramate, valproic acid, and gabapentin), baclofen, clonidine, mexiliten, diphenylhydramine, hydroxyzine, caffeine, prednisone, methylprednisone, decadron, paroxetine, sertraline, fluoxetine, tramadol, ziconotide, and levodopa.

[0143] The compounds of the present invention can be synthesized by the methods shown below, but the following production methods are examples of general production methods and are not intended to limit the production methods.

[0144] The raw materials and reagents used in each step of the following production methods, as well as the resulting compounds, may each form a salt. Examples of such salts include the same salts as those of the compounds of the present invention described above.

[0145] When the compound obtained in each step is a free compound, it can be converted into the desired salt by a method known per se. Conversely, when the compound obtained in each step is a salt, it can be converted into the free form or another desired type of salt by a method known per se.

[0146] The compound obtained in each step can be used in the next reaction either as a reaction solution or as a crude product, or the compound obtained in each step can be isolated and / or purified from the reaction mixture by a separation means such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractional distillation, chromatography, etc., according to a conventional method.

[0147] The compound of the present invention can usually be purified by column chromatography, thin-layer chromatography, high-performance liquid chromatography (HPLC), high-performance liquid chromatography / mass spectrometry (LC / MS), supercritical fluid chromatography (SFC), or the like, and if necessary, a highly pure product can be obtained by recrystallization or washing with a solvent.

[0148] When the raw materials and reagent compounds for each step are commercially available, the commercially available products can be used as they are.

[0149] In the reaction of each step, the reaction time may vary depending on the reagents and solvent used, but unless otherwise specified, it is usually 1 minute to 48 hours, preferably 10 minutes to 8 hours.

[0150] In the reactions of each step, the reaction temperature may vary depending on the reagents and solvents used, but is usually from -78°C to 300°C, preferably from -78°C to 150°C, unless otherwise specified.

[0151] In the reactions of each step, the pressure may vary depending on the reagents and solvents used, but unless otherwise specified, it is usually 1 atm to 20 atm, preferably 1 atm to 3 atm.

[0152] In the reactions of each step, a microwave synthesis apparatus such as Biotage's Initiator may be used. The reaction temperature may vary depending on the reagents and solvent used, but unless otherwise specified, it is usually room temperature to 300°C, preferably 50°C to 250°C. The reaction time may vary depending on the reagents and solvent used, but unless otherwise specified, it is usually 1 minute to 48 hours, preferably 1 minute to 8 hours.

[0153] In the reactions of each step, unless otherwise specified, the reagent is used in an amount of 0.5 to 20 equivalents, preferably 0.8 to 5 equivalents, relative to the substrate. When a reagent is used as a catalyst, the reagent is used in an amount of 0.001 to 1 equivalent, preferably 0.01 to 0.2 equivalents, relative to the substrate. When a reagent also serves as a reaction solvent, the reagent is used in the amount of the solvent.

[0154] Unless otherwise specified, the reactions in each step are carried out without solvent or by dissolving or suspending in a suitable solvent. Specific examples of the solvent include those described in the Examples and the following. Alcohols: methanol, ethanol, tert-butyl alcohol, 1-propanol, 2-propanol, 2-methoxyethanol, ethylene glycol, etc.; Ethers: diethyl ether, diphenyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, cyclopentyl methyl ether, etc.; Aromatic hydrocarbons: benzene, chlorobenzene, toluene, xylene, etc.; Saturated hydrocarbons: cyclohexane, hexane, heptane, etc.; Amides: N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide, etc.; Halogenated hydrocarbons: dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride, etc.; Nitriles: acetonitrile, propionitrile, etc.; Sulfoxides: dimethyl sulfoxide, etc.; Aromatic organic bases: pyridine, etc.; Acid anhydrides: acetic anhydride, etc.; Organic acids: formic acid, acetic acid, trifluoroacetic acid, etc.; Inorganic acids: hydrochloric acid, sulfuric acid, etc.; Esters: ethyl acetate, etc.; Ketones: acetone, methyl ethyl ketone, etc.; water. The reaction can also be carried out using any of the above solvents or without solvent.

[0155] When a base is used in the reaction of each step, for example, the bases shown below or the bases described in the Examples are used. Inorganic bases: sodium hydroxide, potassium hydroxide, magnesium hydroxide, etc.; Basic salts: sodium carbonate, calcium carbonate, sodium bicarbonate, potassium carbonate, tripotassium phosphate, cesium carbonate, etc.; Organic bases: triethylamine, N,N-diisopropylethylamine, diethylamine, pyridine, 4-dimethylaminopyridine, N,N-dimethylaniline, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-7-undecene, imidazole, piperidine, etc.; Metal alkoxides: sodium ethoxide, sodium methoxide, potassium tert-butoxide, sodium tert-butoxide, etc.; Alkali metal hydrides: sodium hydride, etc.; Metal amides: sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, etc.; Organolithium compounds: n-butyllithium, s-butyllithium, lithium diisopropylamide, isopropylmagnesium bromide, etc.

[0156] When an acid or an acid catalyst is used in the reaction of each step, for example, the acids and acid catalysts shown below or the acids and acid catalysts described in the Examples are used. Inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc.; Organic acids: acetic acid, trifluoroacetic acid, citric acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc.; Lewis acids: boron trifluoride diethyl ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous iron chloride, etc.

[0157] Unless otherwise specified, the reactions in each step are carried out by a method known per se, for example, in Experimental Chemistry Lectures, 5th Edition, Vol. 13-19 (edited by the Chemical Society of Japan); New Experimental Chemistry Lectures, Vol. 14-15 (edited by the Chemical Society of Japan); Precision Organic Chemistry, Revised 2nd Edition (L.F. Tietze, Th. Eicher, Nankodo); Revised Organic Named Reactions: Their Mechanisms and Key Points (by Hideo Togo, Kodansha); Organic Syntheses Collective Volumes I-VII (John Wiley & Sons Inc.); Modern Organic Synthesis in the Laboratory: A Collection of Standard Experimental Procedures (by Jie Jack Li, Oxford University Press); Comprehensive Heterocyclic Chemistry III, Vol. 1-14 (Elsevier Japan Co., Ltd.); Organic Synthesis Strategies Learned from Named Reactions (translated and supervised by Kiyoshi Tomioka, published by Kagaku Dojin); Comprehensive Organic Transformations (VCH Publishers Inc., 1989, or in accordance with the method described in the Examples.

[0158] In the general production method of the compound of the present invention shown below, the general formulae of the intermediates and final products in each step are shown, but the concepts of the general formulae of these intermediates and final products also include derivatives protected with protecting groups. Here, the term "derivatives protected with protecting groups" means compounds that can be derived into the target product by hydrolysis, reduction, oxidation, alkylation, etc., as necessary, and includes, for example, compounds protected with protecting groups acceptable in organic synthetic chemistry.

[0159] In each step, the protection or deprotection reaction of a functional group is carried out according to a method known per se, for example, the method described in "Protective Groups in Organic Synthesis, 4th Ed." (Theodora W. Greene, Peter G.M.Wuts), published by Wiley-Interscience, 2007; "Protecting Groups, 3rd Ed." (P.J. Kocienski), published by Thieme, 2004, or the method described in the Examples. Examples of protecting groups for hydroxy groups such as alcohols and phenolic hydroxy groups include ether-type protecting groups such as methoxymethyl ether, benzyl ether, tert-butyldimethylsilyl ether, and tetrahydropyranyl ether; carboxylic acid ester-type protecting groups such as acetate ester; sulfonic acid ester-type protecting groups such as methanesulfonate ester; and carbonate-type protecting groups such as tert-butyl carbonate. Examples of the protecting group for the carbonyl group of an aldehyde include acetal-type protecting groups such as dimethyl acetal; and cyclic acetal-type protecting groups such as cyclic 1,3-dioxane. Examples of protecting groups for the carbonyl group of ketones include ketal-type protecting groups such as dimethyl ketal; cyclic ketal-type protecting groups such as cyclic 1,3-dioxane; oxime-type protecting groups such as O-methyloxime; and hydrazone-type protecting groups such as N,N-dimethylhydrazone. Examples of the carboxyl-protecting group include ester-type protecting groups such as methyl ester; and amide-type protecting groups such as N,N-dimethylamide. Examples of the thiol-protecting group include ether-type protecting groups such as benzylthioether; and ester-type protecting groups such as thioacetate, thiocarbonate, and thiocarbamate. Examples of protecting groups for amino groups and aromatic heterocycles such as imidazole, pyrrole, and indole include carbamate-type protecting groups such as benzylcarbamate; amide-type protecting groups such as acetamide; alkylamine-type protecting groups such as N-triphenylmethylamine; and sulfonamide-type protecting groups such as methanesulfonamide. The protecting group can be removed by a method known per se, for example, a method using an acid, a base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, or a trialkylsilyl halide (e.g., trimethylsilyl iodide, trimethylsilyl bromide), or a reduction method.

[0160] In each step, when a reduction reaction is carried out, examples of the reducing agent to be used include metal hydrides such as lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), sodium borohydride, and tetramethylammonium triacetoxyborohydride; boranes such as borane tetrahydrofuran complex; Raney nickel; Raney cobalt; hydrogen; formic acid; triethylsilane; etc. When a carbon-carbon double bond or triple bond is reduced, a catalyst such as palladium-carbon or Lindlar's catalyst may be used.

[0161] In the oxidation reactions carried out in each step, examples of oxidizing agents that can be used include peracids such as m-chloroperbenzoic acid (mCPBA), hydrogen peroxide, and tert-butyl hydroperoxide; perchlorates such as tetrabutylammonium perchlorate; chlorates such as sodium chlorate; chlorites such as sodium chlorite; periodates such as sodium periodate; high-valent iodine reagents such as iodosylbenzene; manganese-containing reagents such as manganese dioxide and potassium permanganate; lead compounds such as lead tetraacetate; chromium-containing reagents such as pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), and Jones reagent; halogen compounds such as N-bromosuccinimide (NBS); oxygen; ozone; sulfur trioxide-pyridine complex; osmium tetroxide; selenium dioxide; and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).

[0162] When a radical cyclization reaction is carried out in each step, examples of the radical initiator used include azo compounds such as azobisisobutyronitrile (AIBN), water-soluble radical initiators such as 4-4-azobis-4-cyanopentanoic acid (ACPA), triethylboron in the presence of air or oxygen, benzoyl peroxide, etc. Examples of the radical reaction reagent used include tributylstannane, tristrimethylsilylsilane, 1,1,2,2-tetraphenyldisilane, diphenylsilane, samarium iodide, etc.

[0163] When a Wittig reaction is carried out in each step, examples of the Wittig reagent used include alkylidenephosphoranes, etc. The alkylidenephosphoranes can be prepared by a method known per se, for example, by reacting a phosphonium salt with a strong base.

[0164] When Horner-Emmons reaction is carried out in each step, examples of the reagent to be used include phosphonoacetates such as methyl dimethylphosphonoacetate and ethyl diethylphosphonoacetate; and bases such as alkali metal hydrides and organolithium compounds.

[0165] When a Friedel-Crafts reaction is carried out in each step, the reagent used may be a combination of a Lewis acid and an acid chloride, or a combination of a Lewis acid and an alkylating agent (e.g., alkyl halides, alcohols, olefins, etc.). Alternatively, an organic acid or an inorganic acid may be used instead of the Lewis acid, and an acid anhydride such as acetic anhydride may be used instead of the acid chloride.

[0166] In each step, when an aromatic nucleophilic substitution reaction is carried out, a nucleophile (eg, amines, imidazole, etc.) and a base (eg, basic salts, organic bases, etc.) are used as reagents.

[0167] In each step, when a nucleophilic addition reaction by a carbanion, a nucleophilic 1,4-addition reaction (Michael addition reaction) by a carbanion, or a nucleophilic substitution reaction by a carbanion is carried out, examples of the base used to generate the carbanion include organolithiums, metal alkoxides, inorganic bases, and organic bases.

[0168] When a Grignard reaction is carried out in each step, examples of the Grignard reagent include arylmagnesium halides such as phenylmagnesium bromide and alkylmagnesium halides such as methylmagnesium bromide. The Grignard reagent can be prepared by a method known per se, for example, by reacting an alkyl halide or aryl halide with metallic magnesium using ether or tetrahydrofuran as a solvent.

[0169] In each step, when a Knoevenagel condensation reaction is carried out, an active methylene compound sandwiched between two electron-withdrawing groups (e.g., malonic acid, diethyl malonate, malononitrile etc.) and a base (e.g., organic bases, metal alkoxides, inorganic bases) are used as reagents.

[0170] In each step, when the Vilsmeier-Haack reaction is carried out, phosphoryl chloride and an amide derivative (eg, N,N-dimethylformamide, etc.) are used as reagents.

[0171] In each step, when an azidation reaction of alcohols, alkyl halides, or sulfonate esters is carried out, examples of the azidation agent used include diphenylphosphoryl azide (DPPA), trimethylsilyl azide, sodium azide, etc. For example, when azidating alcohols, there are methods using diphenylphosphoryl azide and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and methods using trimethylsilyl azide and a Lewis acid.

[0172] When a reductive amination reaction is carried out in each step, examples of the reducing agent used include sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, hydrogen, formic acid, etc. When the substrate is an amine compound, examples of the carbonyl compound used include paraformaldehyde, aldehydes such as acetaldehyde, and ketones such as cyclohexanone. When the substrate is a carbonyl compound, examples of the amine used include ammonia, primary amines such as methylamine, and secondary amines such as dimethylamine.

[0173] When Mitsunobu reaction is carried out in each step, azodicarboxylic acid esters (eg, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), etc.) and triphenylphosphine are used as reagents.

[0174] In each step, when an esterification reaction, an amidation reaction, or a urea reaction is carried out, examples of the reagent to be used include acyl halides such as acid chlorides and acid bromides; and activated carboxylic acids such as acid anhydrides, activated esters, and sulfate esters. Examples of activating agents for carboxylic acids include carbodiimide-based condensing agents such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD); triazine-based condensing agents such as 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride-n-hydrate (DMT-MM); carbonate-based condensing agents such as 1,1-carbonyldiimidazole (CDI); diphenylphosphoric acid azide (DPPA); benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent); 2-chloro-1-methyl-pyridinium iodide (Mukaiyama reagent); thionyl chloride; lower alkyl haloformates such as ethyl chloroformate; O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (HATU); sulfuric acid; or combinations thereof. When a carbodiimide-based condensing agent is used, an additive such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), or dimethylaminopyridine (DMAP) may be further added to the reaction.

[0175] In each step, when a coupling reaction is carried out, examples of the metal catalyst to be used include palladium compounds such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), dichlorobis(triethylphosphine)palladium(II), tris(dibenzylideneacetone)dipalladium(0), 1,1-bis(diphenylphosphino)ferrocenepalladium(II) chloride, and palladium(II) acetate; nickel compounds such as tetrakis(triphenylphosphine)nickel(0); rhodium compounds such as tris(triphenylphosphine)rhodium(III) chloride; cobalt compounds; copper compounds such as copper oxide and copper(I) iodide; and platinum compounds. A base may also be added to the reaction, and examples of such bases include inorganic bases and basic salts.

[0176] When a thiocarbonylation reaction is carried out in each step, diphosphorus pentasulfide is typically used as the thiocarbonylating agent. However, in addition to diphosphorus pentasulfide, a reagent having a 1,3,2,4-dithiadiphosphetane-2,4-disulfide structure, such as 2,4-bis(4-methoxyphenyl-1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawesson's reagent) may also be used.

[0177] When performing the Wohl-Ziegler reaction in each step, examples of halogenating agents that can be used include N-iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, sulfuryl chloride, etc. Furthermore, the reaction can be accelerated by adding a radical initiator such as heat, light, benzoyl peroxide, or azobisisobutyronitrile to the reaction.

[0178] When a halogenation reaction of a hydroxy group is carried out in each step, the halogenating agent used may be a hydrohalic acid or an acid halide of an inorganic acid, specifically, for chlorination, hydrochloric acid, thionyl chloride, phosphorus oxychloride, etc., or for bromination, 48% hydrobromic acid, etc. Alternatively, a method may be used in which an alkyl halide is obtained from an alcohol by the reaction of triphenylphosphine with carbon tetrachloride or carbon tetrabromide, etc. Alternatively, a method may be used in which an alkyl halide is synthesized via a two-step reaction, in which the alcohol is converted to a sulfonic acid ester and then reacted with lithium bromide, lithium chloride, or sodium iodide.

[0179] When Arbuzov reaction is carried out in each step, examples of the reagent to be used include alkyl halides such as ethyl bromoacetate and the like; and phosphites such as triethyl phosphite and tri(isopropyl) phosphite and the like.

[0180] When a sulfonate esterification reaction is carried out in each step, examples of the sulfonylating agent to be used include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonic anhydride, and the like.

[0181] In each step, when a hydrolysis reaction is performed, an acid or a base is used as a reagent. When an acid hydrolysis reaction of a tert-butyl ester is performed, formic acid or triethylsilane may be added to reductively trap the by-product tert-butyl cation.

[0182] When a dehydration reaction is carried out in each step, examples of the dehydrating agent to be used include sulfuric acid, diphosphorus pentoxide, phosphorus oxychloride, N,N-dicyclohexylcarbodiimide, alumina, polyphosphoric acid, and the like.

[0183] In each step, when a nitration reaction is carried out, examples of the nitrating agent to be used include nitric acid, fuming nitric acid, and copper nitrate, and the nitration reaction is carried out after activation with concentrated sulfuric acid, acetic anhydride, or the like.

[0184] When a halogenation reaction is carried out in each step, examples of the halogenating agent to be used include N-iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), iodine monochloride, iodine, bromine, sulfuryl chloride, etc. In this reaction, an additive such as trifluoroacetic acid may be used for the purpose of activating the halogenating agent.

[0185] In each step, when an acylation reaction is carried out, an amidation reaction, a urea reaction, a carbamate reaction, a thiocarbamate reaction, etc. are carried out. When a carbamate reaction or a thiocarbamate reaction is carried out, examples of the reagent used include a carbonate ester-based condensing agent such as triphosgene or 1,1-carbonyldiimidazole (CDI), a chlorocarbonate, a chlorocarbonate thioester, an isothiocyanate, etc.

[0186] In each step, when a cyclization reaction is carried out, it is carried out by Mitsunobu reaction or alkylation reaction. When an alkylation reaction is carried out, a base is used as a reagent.

[0187] Compounds (4), (5), (6) and (7) can be produced from compound (1) by the following method. [ka] Compound (2) can be produced by reductive amination of compound (1), an aldehyde, acetic acid, and a reducing agent such as sodium triacetoxyborohydride, sodium cyanoborohydride, or sodium borohydride, using a solvent such as tetrahydrofuran. Compound (1) may be a commercially available product or may be produced by a known method or a method analogous thereto. Compound (3) can be produced by a ring-forming reaction between compound (2), triethyl methanetricarboxylate, and a base, using, for example, triethylamine as the base and toluene as the solvent. Compound (4) can be produced by amidation of compound (3) with an amine, using N,N-dimethylacetamide as the solvent. Compound (5) can be produced by hydrolysis of compound (4) with a base, such as potassium trimethylsilanolate, sodium hydroxide, potassium hydroxide, or lithium hydroxide, and solvents such as tetrahydrofuran, water, or ethanol. Compound (6) can be prepared by an intramolecular rearrangement reaction of compound (5), diphenylphosphoryl azide, a base, and tert-butanol. The base used may be triethylamine or the like. Compound (7) can be prepared by deprotecting compound (6) with an acid, such as hydrochloric acid or trifluoroacetic acid, and using 1,4-dioxane or ethyl acetate as a solvent.

[0188] Compound (11) and compound (7) can be produced from compound (8) by the following method. [ka] Compound (9) can be produced by reductive amination of compound (8) with an aldehyde, acetic acid, and a reducing agent such as sodium triacetoxyborohydride, sodium cyanoborohydride, or sodium borohydride, using a solvent such as tetrahydrofuran or 1,2-dichloroethane. Compound (8) may be a commercially available product or may be produced by a known method or a method analogous thereto. Compound (10) can be produced by a ring-forming reaction between compound (9), triethyl methanetricarboxylate, and a base, such as triethylamine, and a solvent such as toluene. Compound (11) can be produced by amidation of compound (10) with an amine, using N,N-dimethylacetamide as the solvent. Compound (7) can be produced by amination of compound (11), (2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid carboxamide, copper(I) iodide, potassium carbonate, and aqueous ammonia in a solvent such as dimethyl sulfoxide.

[0189] Compounds (15), (16), (17), (18), (19), (20) and (21) can be produced from compound (12) by the following method. (Wherein, R h and R i The combination of R h is a hydrogen atom or a C which may be substituted with one or more substituents independently selected from the substituent group C (substituent group C1 or substituent group C2). 1-6 is an alkyl group, R i is a hydrogen atom, a C which may be substituted with one or more substituents independently selected from the substituent group C (substituent group C1 or substituent group C2). 1-6 alkyl groups, C 6-14 aryl groups, a 5- to 14-membered aromatic heterocyclic group or a 3- to 14-membered non-aromatic heterocyclic group, each of which may have one or more substituents independently selected from the substituent group D (D1 or D2), or R h is C 1-6 is an alkyl group R i is a hydroxy group or C 1-6 an alkoxy group, or R h and R i together with the nitrogen atom to which they are bonded, form a 5- to 14-membered aromatic heterocycle or a 3- to 14-membered non-aromatic heterocycle, each of which optionally has one or more substituents independently selected from Substituent Group D (Substituent Group D1 or Substituent Group D2). [ka] Compound (13) can be produced by reductive amination of compound (12) with an aldehyde, acetic acid, and a reducing agent such as sodium triacetoxyborohydride, sodium cyanoborohydride, or sodium borohydride, using a solvent such as tetrahydrofuran or 1,2-dichloroethane. Compound (12) may be a commercially available product or may be produced by a known method or a method analogous thereto. Compound (14) can be produced by a ring-forming reaction between compound (13), triethyl methanetricarboxylate, and a base, such as triethylamine, and a solvent such as toluene. Compound (15) can be produced by amidation of compound (14) with an amine, using N,N-dimethylacetamide as the solvent. Compound (16) can be produced by reduction of compound (15) with a reducing agent such as lithium aluminum hydride, and a solvent such as tetrahydrofuran. Compound (17) can be produced by oxidation of compound (16) with an oxidizing agent such as 2-iodoxybenzoic acid, and a solvent such as dimethyl sulfoxide. Compound (18) can be prepared by the Horner-Emmons reaction of compound (17), sodium hydride, and trimethyl phosphonoacetate in a solvent such as tetrahydrofuran. Compound (19) can be prepared by hydrolysis of compound (18) with a base, such as potassium trimethylsilanolate, sodium hydroxide, potassium hydroxide, or lithium hydroxide, and solvents such as tetrahydrofuran, 1,4-dioxane, water, or ethanol. Compound (20) can be prepared by amidation of compound (19), an amine, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and 1-hydroxybenzotriazole monohydrate in a solvent such as N,N-dimethylacetamide. Compound (21) can be produced by reducing compound (20) with hydrogen and palladium-carbon in a solvent such as methanol.

[0190] Compound (22) can be produced from compound (11) by the following method. (Wherein, R c represents a hydrogen atom or a substituent in an optionally substituted amino group (an optionally substituted C 1-6 alkyl groups, optionally substituted heterocyclic groups, etc.) [ka] Compound (22) can be prepared by coupling reaction of compound (11), an amine, a palladium catalyst, a ligand, and a base. Examples of the palladium catalyst include tris(dibenzylideneacetone)dipalladium(0), ligands include 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, bases include sodium tert-butoxide, and solvents include 1,4-dioxane.

[0191] Compound (23) can be produced from compound (11) by the following method. [ka] Compound (23) (a compound in which X is an optionally substituted heterocyclic group, a hydrocarbon group, or an acyl group) can be produced by a coupling reaction using compound (11), a coupling reagent, a metal catalyst, a ligand, and a base. Coupling reagents used include boronic acid, boronic acid esters, acrylic acid esters, imidazole, pyrazole, N1,N2-dimethylethane-1,2-diamine, and pyrrolidone. Metal catalysts include [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II), palladium(II) acetate, tris(dibenzylideneacetone)dipalladium(0), and copper(I) iodide. Ligands include 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, N1,N2-dimethylethane-1,2-diamine, 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl, and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene. Bases include potassium carbonate, cesium carbonate, and sodium. tert-butoxide, triethylamine, etc., and solvents such as 1,4-dioxane, water, N,N-dimethylformamide, dimethyl sulfoxide, and N-methylpyrrolidone.

[0192] Compounds (24), (25), (26), and (27) can be produced from compound (11) by the following method. (In the formula, n represents an integer of 1 to 3, and Z 1 , R d1 Other symbols are the same as defined above. For example, Z 1 represents an optionally substituted methylene group, -N- or -O-; R d1 is optionally substituted C 1-6 It indicates an alkyl group, etc.) [ka] Compound (24) can be prepared by coupling compound (11), acyl amide, copper(I) iodide, a ligand, and a base. The ligand used can be (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine, the base can be potassium carbonate, and the solvent can be 1,4-dioxane. Compound (24) can be prepared by acylation of compound (7) with an acylating agent, pyridine, and N,N-dimethyl-4-aminopyridine. The base used may be triethylamine, and the solvent may be toluene or tetrahydrofuran. Compound (24) can be produced by urea reaction of compound (7) with isocyanate, using a solvent such as toluene or tetrahydrofuran. Compound (24) can be produced by a carbamate reaction of compound (7), a chloroformate, and a base, using a base such as triethylamine and a solvent such as pyridine, toluene, or tetrahydrofuran. Compound (25) can be prepared by a coupling reaction of compound (11), a saturated cyclic amide, copper(I) iodide, a ligand, and a base. teeth pyrrolidone, etc.; a ligand such as N1,N2-dimethylethane-1,2-diamine, etc.; a base such as potassium carbonate, etc.; a solvent such as N-methylpyrrolidone, etc. Compound (26) can be produced by urea formation using compound (7), trichloroacetyl isocyanate, and a base. The base used may be potassium carbonate, and the solvent may be tetrahydrofuran, methanol, or the like. Compound (27) can be prepared by acylation of compound (7) with an acylating agent, pyridine, and N,N-dimethyl-4-aminopyridine. The base used may be triethylamine, and the solvent may be toluene or tetrahydrofuran. Compound (27) is produced by a urea reaction of compound (7) with an isocyanate. The solvent used may be tetrahydrofuran or the like. Compound (27) can be produced by carbamate reaction of compound (7), chloroformate, and a base, using a base such as triethylamine and a solvent such as pyridine, toluene, or tetrahydrofuran. Compound (25) can be prepared by intramolecular cyclization of compound (27) with a base, such as potassium tert-butoxide, in a solvent such as tetrahydrofuran.

[0193] Compound (28) can be produced from compound (5) by the following method. (Wherein, R a and R b is the same as defined above in "acyl group.") [ka] Compound (28) can be prepared by amidation of compound (5), an amine, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and 1-hydroxybenzotriazole monohydrate in a solvent such as N,N-dimethylacetamide.

[0194] Compound (32) and compound (33) can be produced from compound (29) by the following method. [ka] Compound (30) can be prepared by reductive amination of compound (29), an aldehyde, acetic acid, and a reducing agent such as sodium triacetoxyborohydride, sodium cyanoborohydride, or sodium borohydride, using a solvent such as tetrahydrofuran or 1,2-dichloroethane. Compound (29) may be a commercially available product or may be produced by a known method or a method analogous thereto. Compound (31) can be produced by a ring-forming reaction between compound (30), triethyl methanetricarboxylate, and a base, such as triethylamine, and a solvent such as toluene. Compound (32) can be produced by amidation of compound (31) with an amine, using N,N-dimethylacetamide or the like as the solvent. Compound (33) (a compound in which Y is an optionally substituted heterocyclic group, a hydrocarbon group, or an acyl group) can be produced by a coupling reaction using compound (32), a coupling reagent, a metal catalyst, a ligand, and a base. Coupling reagents used include boronic acid, boronic acid esters, acrylic acid esters, imidazole, pyrazole, N1,N2-dimethylethane-1,2-diamine, pyrrolidone, and amines. Metal catalysts include [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II), palladium(II) acetate, tris(dibenzylideneacetone)dipalladium(0), and copper(I) iodide. Ligands include 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, N1,N2-dimethylethane-1,2-diamine, 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl, and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene. Bases include potassium carbonate, cesium carbonate, and sodium. tert-butoxide, triethylamine, etc., and solvents such as 1,4-dioxane, water, N,N-dimethylformamide, dimethyl sulfoxide, and N-methylpyrrolidone.

[0195] Compound (34) and compound (35) can be produced from compound (15) by the following method. (Wherein, R a and R b is the same as defined above in "acyl group.") [ka] Compound (34) can be prepared by hydrolysis of compound (15) with a base, such as potassium trimethylsilanolate, sodium hydroxide, potassium hydroxide, or lithium hydroxide, and solvents such as tetrahydrofuran, 1,4-dioxane, water, or ethanol. Compound (35) can be prepared by amidation of compound (34), an amine, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, and a base, such as N,N-diisopropylethylamine, and a solvent such as N,N-dimethylformamide.

[0196] Compounds (36), (37) and (38) can be produced from compound (7) by the following method. 1 represents a protecting group that can be removed by catalytic reduction, hydrolysis, etc., and Z 2 , R d2 Other symbols such as are defined above. For example, Z 2 represents an optionally substituted methylene group or -N-, and R d2 is optionally substituted C 1-6 It indicates an alkyl group, etc.) [ka] Compound (36) can be prepared by sulfonylation of compound (7) with sulfonyl chloride and a base. Examples of the base used include triethylamine, and examples of the solvent include pyridine, toluene, and tetrahydrofuran. Compound (36) can be prepared by sulfamation of compound (7) with a chlorosulfonic acid ester and a base, using a base such as triethylamine and a solvent such as pyridine, toluene, or tetrahydrofuran. Compound (37) can be prepared by sulfamoylation of compound (7) with tert-butyl (chlorosulfonyl)carbamate and a base, such as triethylamine, in a solvent such as dichloromethane. Compound (38) can be prepared by deprotecting compound (37) with an acid, such as trifluoroacetic acid.

[0197] Compound (39), compound (40) and compound (41) can be produced from compound (4) by the following method. [ka] Compound (39) can be produced by reduction of compound (4) with a reducing agent such as lithium aluminum hydride, and a solvent such as tetrahydrofuran. Compound (40) can be produced by oxidation of compound (39) with an oxidizing agent such as 2-iodoxybenzoic acid, and a solvent such as dimethyl sulfoxide. Compound (41) can be produced by subjecting compound (40) to an oximation reaction with an amine, such as hydroxylamine hydrochloride or an alkoxyamine, and using methanol as a solvent.

[0198] Compound (42) and compound (43) can be produced from compound (11) by the following method. [ka] Compound (42) can be prepared by coupling reaction of compound (11) with a tin reagent and a palladium catalyst. Examples of the tin reagent used include tributyl(1-ethoxyvinyl)tin, examples of the palladium catalyst include tetrakis(triphenylphosphine)palladium(0), and examples of the solvent include toluene. Compound (43) can be produced by subjecting compound (42) to an oximation reaction with an amine, such as hydroxylamine hydrochloride or an alkoxyamine, and using methanol as a solvent.

[0199] Compound (44) and compound (45) can be produced from compound (7) by the following method. [ka] Compound (44) can be produced by halogenating compound (7) with N-bromosuccinimide in a solvent such as N,N-dimethylformamide or acetonitrile. Compound (45) can be prepared by a coupling reaction using compound (44), a coupling reagent, a palladium catalyst, a ligand, and a base. Examples of the coupling reagent include boronic acid, a boronate ester, and an acrylate ester. Examples of the palladium catalyst include [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) and palladium(II) acetate. Examples of the ligand include 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl. Examples of the base include potassium carbonate and triethylamine. Examples of the solvent include 1,4-dioxane, water, and N,N-dimethylformamide.

[0200] Compounds (45), (48), (49), (50) and (51) can be produced from compound (2) by the following method. (Wherein, R a and R b is the same as defined above in "acyl group.") [ka] Compound (46) can be prepared by halogenating compound (2) with a halogenating reagent such as N-fluorobenzenesulfonimide or N-bromosuccinimide, and using N,N-dimethylformamide or acetonitrile as the solvent. Compound (47) can be produced by a ring-forming reaction between compound (46), triethyl methanetricarboxylate, and a base, such as triethylamine, and a solvent such as toluene. Compound (48) can be produced by amidation of compound (47) with an amine, using N,N-dimethylacetamide as the solvent. Compound (49) can be prepared by hydrolysis of compound (48) with a base. Examples of the base used include potassium trimethylsilanolate, sodium hydroxide, potassium hydroxide, and lithium hydroxide. Examples of the solvent used include 1,4-dioxane, tetrahydrofuran, water, and ethanol. Compound (50) can be prepared by an intramolecular rearrangement reaction of compound (49), diphenylphosphoryl azide, a base, and tert-butanol. The base used may be triethylamine or the like. Compound (51) can be prepared by amidation of compound (49), an amine, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and 1-hydroxybenzotriazole monohydrate in a solvent such as N,N-dimethylacetamide. Compound (45) can be prepared by deprotecting compound (50) with an acid, such as hydrochloric acid or trifluoroacetic acid, and using 1,4-dioxane or ethyl acetate as a solvent.

[0201] Compounds (52), (53), (54) and (55) can be produced from compound (45) by the following method. (In the formula, n represents an integer of 1 to 3, and Z 1 , R d1is the same as defined above. For example, Z 1 represents an optionally substituted methylene group, -N- or -O-; R d1 is optionally substituted C 1-6 It indicates an alkyl group, etc.) [ka] Compound (52) can be prepared by acylation of compound (45) with an acylating agent, pyridine, and N,N-dimethyl-4-aminopyridine. The base used may be triethylamine, and the solvent may be toluene or tetrahydrofuran. Compound (52) can be produced by urea reaction of compound (45) with an isocyanate in a solvent such as toluene or tetrahydrofuran. Compound (52) can be produced by a carbamate reaction of compound (45), a chloroformate, and a base, using triethylamine as the base and pyridine, toluene, tetrahydrofuran, or the like as the solvent. Compound (53) can be produced by urea formation using compound (45), trichloroacetyl isocyanate, and a base. The base used may be potassium carbonate, and the solvent may be tetrahydrofuran, methanol, or the like. Compound (54) can be prepared by acylation of compound (45) with pyridine and N,N-dimethyl-4-aminopyridine as an acylating agent. The base used may be triethylamine, and the solvent may be toluene or tetrahydrofuran. Compound (54) can be produced by urea reaction of compound (45) with an isocyanate, using tetrahydrofuran or the like as the solvent. Compound (54) can be produced by a carbamate reaction of compound (45), a chloroformate, and a base, using triethylamine as the base and pyridine, toluene, tetrahydrofuran, or the like as the solvent. Compound (55) can be prepared by intramolecular cyclization of compound (54) with a base, such as potassium tert-butoxide, in a solvent such as tetrahydrofuran.

[0202] Compounds (56), (57), (58), (59), (60), and (61) can be produced from compound (44) by the following method. (In the formula, m represents an integer of 1 to 3, n represents an integer of 1 to 3, and R d represents a substituent in an optionally substituted heterocyclic group (optionally halogenated C 1-6 alkyl group, etc.), and P 1 indicates a protecting group that can be removed by catalytic reduction, hydrolysis, etc. [ka] Compound (56) can be prepared by coupling reaction of compound (44) with a boric acid reagent, a palladium catalyst, and a base. Examples of the boric acid reagent include boronic acid and boronate esters, examples of the palladium catalyst include [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II), examples of the base include potassium carbonate, and examples of the solvent include 1,4-dioxane and water. Compound (57) can be prepared from compound (56) by catalytic reduction or acid-mediated deprotection. Deprotection reagents include palladium-carbon, hydrogen, hydrochloric acid, trifluoroacetic acid, etc., and solvents include 1,4-dioxane, ethyl acetate, etc. Compound (58) can be prepared by reductive amination of compound (57) with an aldehyde, acetic acid, and a reducing agent such as sodium triacetoxyborohydride, sodium cyanoborohydride, or sodium borohydride, using a solvent such as tetrahydrofuran or 1,2-dichloroethane. Compound (59) can be produced by reducing compound (56) with hydrogen and palladium-carbon in a solvent such as methanol. Compound (60) can be prepared from compound (59) by catalytic reduction or acid deprotection. Deprotection reagents include palladium-carbon, hydrogen, hydrochloric acid, trifluoroacetic acid, etc., and solvents include 1,4-dioxane, ethyl acetate, etc. Compound (61) can be prepared by reductive amination of compound (60) with an aldehyde, acetic acid, and a reducing agent such as sodium triacetoxyborohydride, sodium cyanoborohydride, or sodium borohydride, using a solvent such as tetrahydrofuran or 1,2-dichloroethane.

[0203] Compounds (62), (63), (64), (65), (66), and (67) can be produced from compound (11) by the following method. (In the formula, m represents an integer of 1 to 3, n represents an integer of 1 to 3, and R d represents a substituent in an optionally substituted heterocyclic group (optionally halogenated C 1-6 alkyl group, etc.), and P 1 indicates a protecting group that can be removed by catalytic reduction, hydrolysis, etc. [ka] Compound (62) can be prepared by coupling reaction of compound (11) with a boric acid reagent, a palladium catalyst, and a base. Examples of the boric acid reagent include boronic acid and boronate esters, examples of the palladium catalyst include [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II), examples of the base include potassium carbonate, and examples of the solvent include 1,4-dioxane and water. Compound (63) can be prepared from compound (62) by catalytic reduction or acid-mediated deprotection. Deprotection reagents include palladium-carbon, hydrogen, hydrochloric acid, trifluoroacetic acid, etc., and solvents include 1,4-dioxane, ethyl acetate, etc. Compound (64) can be prepared by reductive amination of compound (63) with an aldehyde, acetic acid, and a reducing agent such as sodium triacetoxyborohydride, sodium cyanoborohydride, or sodium borohydride, using a solvent such as tetrahydrofuran or 1,2-dichloroethane. Compound (65) can be produced by reducing compound (62) with hydrogen and palladium-carbon in a solvent such as methanol. Compound (66) can be prepared from compound (65) by catalytic reduction or acid-mediated deprotection. Deprotection reagents include palladium-carbon, hydrogen, hydrochloric acid, trifluoroacetic acid, etc., and solvents include 1,4-dioxane, ethyl acetate, etc. Compound (67) can be prepared by reductive amination of compound (66) with an aldehyde, acetic acid, and a reducing agent such as sodium triacetoxyborohydride, sodium cyanoborohydride, or sodium borohydride, using a solvent such as tetrahydrofuran or 1,2-dichloroethane.

[0204] Compound (23) and compound (68) can be produced from compound (11) by the following method. [ka] Compound (68) can be prepared by the stannylation of compound (11) with bis(trimethyltin) and a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0), in a solvent such as toluene. Compound (23) can be prepared by coupling compound (68), an aryl halide, and a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0), in a solvent such as toluene.

[0205] Compounds (69), (70), (71) and (72) can be produced from compound (11) by the following method. (Wherein, R h and R i The combinations are as defined above.) [ka] Compound (69) can be prepared by a coupling reaction of compound (11), an ethyl acetoacetate palladium catalyst, a ligand, and a base. The palladium catalyst used may be palladium(II) acetate, the ligand may be 2-di-tert-butylphosphino-2'-methylbiphenyl, the base may be tripotassium phosphate, and the solvent may be toluene. Compound (70) can be prepared by hydrolysis of compound (69) with a base, such as potassium trimethylsilanolate, sodium hydroxide, potassium hydroxide, or lithium hydroxide, and solvents such as 1,4-dioxane, tetrahydrofuran, water, or ethanol. Compound (71) can be produced by reduction of compound (69) with a reducing agent such as lithium aluminum hydride, and a solvent such as tetrahydrofuran. Compound (72) can be prepared by amidation of compound (70), an amine, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and 1-hydroxybenzotriazole monohydrate in a solvent such as N,N-dimethylacetamide.

[0206] Compounds (73), (74), (75), (76), (77), and (78) can be produced from compound (32) by the following method. (In the formula, m represents an integer of 1 to 3, n represents an integer of 1 to 3, and R d represents a substituent in an optionally substituted heterocyclic group (an optionally substituted C 1-6 alkyl group, etc.), and P 1 indicates a protecting group that can be removed by catalytic reduction, hydrolysis, etc. [ka] Compound (73) can be prepared by coupling reaction of compound (32) with a boric acid reagent, a palladium catalyst, and a base. Examples of the boric acid reagent include boronic acid and boronate esters, examples of the palladium catalyst include [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II), examples of the base include potassium carbonate, and examples of the solvent include 1,4-dioxane and water. Compound (74) can be prepared from compound (73) by catalytic reduction or acid-mediated deprotection. Deprotection reagents include palladium-carbon, hydrogen, hydrochloric acid, trifluoroacetic acid, etc., and solvents include 1,4-dioxane, ethyl acetate, etc. Compound (75) can be prepared by reductive amination of compound (74) with an aldehyde, acetic acid, and a reducing agent such as sodium triacetoxyborohydride, sodium cyanoborohydride, or sodium borohydride, using a solvent such as tetrahydrofuran or 1,2-dichloroethane. Compound (75) can be produced by the Eschweiler-Clarke reaction of compound (74), formaldehyde, and formic acid. The solvent used may be water. Compound (76) can be produced by reducing compound (73) with hydrogen and palladium-carbon in a solvent such as methanol. Compound (77) can be prepared from compound (76) by catalytic reduction or acid-mediated deprotection. Deprotection reagents include palladium-carbon, hydrogen, hydrochloric acid, trifluoroacetic acid, etc., and solvents include 1,4-dioxane, ethyl acetate, etc. Compound (78) can be prepared by reductive amination of compound (77) with an aldehyde, acetic acid, and a reducing agent such as sodium triacetoxyborohydride, sodium cyanoborohydride, or sodium borohydride, using a solvent such as tetrahydrofuran or 1,2-dichloroethane. Compound (78) can be produced by the Eschweiler-Clarke reaction of compound (77), formaldehyde, and formic acid. The solvent used may be water.

[0207] Compounds (81), (82), (83) and (84) can be produced from compound (8) by the following method. (Wherein, R c represents a hydrogen atom or a substituent in an optionally substituted amino group (optionally substituted C 1-6 alkyl group, optionally substituted heterocyclic group, etc.), and R d each optionally substituted, C 1-6 Alkyl group, C 6-14 Aryl group or C 7-16 R indicates an aralkyl group, etc. e are optionally substituted C 1-6 Alkylene group, C 2-6 Alkenylene group, C 2-6 Alkynylene group, C 6-14 an arylene group, a heterocycle-diyl group, or the like. [ka] Compound (79) can be prepared by reductive amination of compound (8) with an aldehyde, acetic acid, and a reducing agent such as sodium triacetoxyborohydride, sodium cyanoborohydride, or sodium borohydride, using a solvent such as tetrahydrofuran or 1,2-dichloroethane. Compound (80) can be produced by a ring-forming reaction between compound (79), triethyl methanetricarboxylate, and a base, such as triethylamine, and a solvent such as toluene. Compound (81) can be produced by amidation of compound (80) with an amine. Examples of the solvent used include N,N-dimethylacetamide. Compound (82) can be produced by reduction of compound (81) with a reducing agent such as lithium aluminum hydride, and a solvent such as tetrahydrofuran. Compound (83) can be prepared by coupling compound (82) with an amine, a palladium catalyst, a ligand, and a base. Examples of the palladium catalyst include tris(dibenzylideneacetone)dipalladium(0), ligands include 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, bases include sodium tert-butoxide, and solvents include 1,4-dioxane. Compound (84) can be produced by a coupling reaction using compound (82), a coupling reagent, a metal catalyst, a ligand and a base. Coupling reagents used include boronic acid, boronic acid esters, acrylic acid esters, imidazole, pyrazole, N1,N2-dimethylethane-1,2-diamine, and pyrrolidone. Metal catalysts include [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II), palladium(II) acetate, tris(dibenzylideneacetone)dipalladium(0), and copper(I) iodide. Ligands include 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, N1,N2-dimethylethane-1,2-diamine, 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl, and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene. Bases include potassium carbonate, cesium carbonate, and sodium. tert-butoxide, triethylamine, etc., and solvents such as 1,4-dioxane, water, N,N-dimethylformamide, dimethyl sulfoxide, and N-methylpyrrolidone.

[0208] Compound (85) can be produced from compound (17) by the following method. [ka] Compound (85) can be produced by subjecting compound (17) to an oximation reaction with an amine, such as hydroxylamine hydrochloride or an alkoxyamine, and using methanol as a solvent.

[0209] Compound (23) can be produced from compound (86) by the following method. [ka] Compound (87) can be prepared by reductive amination of compound (86) with an aldehyde, acetic acid, and a reducing agent such as sodium triacetoxyborohydride, sodium cyanoborohydride, or sodium borohydride, using a solvent such as tetrahydrofuran or 1,2-dichloroethane. Compound (86) can be produced by using a commercially available product as is, or by a known method or a method equivalent thereto, or by appropriately combining a protection / deprotection reaction, an oxidation-reduction reaction, a hydrolysis reaction, or a condensation reaction such as acylation / amidation / urea formation. Compound (88) can be produced by a ring-forming reaction between compound (87), triethyl methanetricarboxylate, and a base, such as triethylamine, and a solvent such as toluene. Compound (23) can be produced by amidation of compound (88) with an amine in a solvent such as N,N-dimethylacetamide.

[0210] Compound (33) can be produced from compound (89) by the following method. [ka] Compound (90) can be prepared by reductive amination of compound (89), an aldehyde, acetic acid, and a reducing agent such as sodium triacetoxyborohydride, sodium cyanoborohydride, or sodium borohydride, using a solvent such as tetrahydrofuran or 1,2-dichloroethane. Compound (89) can be produced by using a commercially available product as is, by a known method or a method equivalent thereto, or by appropriately combining a protection / deprotection reaction, a redox reaction, a hydrolysis reaction, or a condensation reaction such as acylation / amidation / urea formation. Compound (91) can be produced by a ring-forming reaction between compound (90), triethyl methanetricarboxylate, and a base, such as triethylamine, and a solvent such as toluene. Compound (33) can be produced by amidation of compound (91) with an amine, using N,N-dimethylacetamide as the solvent.

[0211] Compound (95) can be produced from compound (92) by the following method. (wherein ring A is an optionally substituted 5- to 7-membered non-aromatic heterocycle or an optionally substituted 5- or 6-membered nitrogen-containing aromatic heterocycle.) [ka] Compound (93) can be prepared by reductive amination of compound (92) with an aldehyde, acetic acid, and a reducing agent such as sodium triacetoxyborohydride, sodium cyanoborohydride, or sodium borohydride, using a solvent such as tetrahydrofuran or dichloromethane. Compound (92) may be a commercially available product or may be produced by a known method or a method analogous thereto. Compound (94) can be produced by a ring-forming reaction between compound (93), triethyl methanetricarboxylate, and a base, such as triethylamine, and a solvent such as toluene. Compound (95) can be produced by amidation of compound (94) with an amine. Examples of the solvent used include N,N-dimethylacetamide.

[0212] Compound (100) can be produced from compound (6) by the following method. [ka] Compound (96) can be produced by halogenating compound (6) with N-bromosuccinimide in a solvent such as N,N-dimethylformamide or dichloromethane. Compound (97) can be prepared by a coupling reaction using compound (96), a coupling reagent, a palladium catalyst, and a base. Examples of the coupling reagent include boronic acid, a boronate ester, and an acrylate ester. Examples of the palladium catalyst include [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II). Examples of the base include potassium carbonate and sodium carbonate. Examples of the solvent include 1,4-dioxane and water. Compound (98) can be produced by reducing compound (97) with hydrogen and palladium-carbon in a solvent such as ethyl acetate or methanol. Compound (99) can be prepared by deprotecting compound (98) with an acid, such as hydrochloric acid or trifluoroacetic acid, and using 1,4-dioxane as a solvent. Compound (100) can be prepared by intramolecular cyclization of compound (99) with a base, such as potassium carbonate or sodium hydride, and a solvent such as 1,4-dioxane.

[0213] Compounds (102), (103) and (104) can be produced from compound (96) by the following method. (Wherein, R 13 may be halogenated 1-6 It indicates an alkyl group, a carbamoyl group, etc.) [ka] Compound (101) can be prepared by a coupling reaction using compound (96), a coupling reagent, a palladium catalyst, and a base. Examples of the coupling reagent include boronic acid, a boronate ester, and ethyl vinyl ether. Examples of the metal catalyst include [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II). Examples of the base include potassium carbonate and sodium carbonate. Examples of the solvent include 1,4-dioxane and water. Compound (102) can be prepared by deprotecting compound (101) with an acid, such as hydrochloric acid or trifluoroacetic acid, and using dichloromethane as a solvent. Compound (103) can be produced by reduction of compound (102) with a reducing agent such as sodium cyanoborohydride, and a solvent such as acetic acid. Compound (104)(R 13 may be halogenated C 1-6 The compound (103) can be produced by alkylation using an alkylating agent and a base. Examples of the alkylating agent include alkyl halides and trifluoromethanesulfonate esters, examples of the base include N,N-diisopropylethylamine, and examples of the solvent include dimethyl sulfoxide. Compound (104)(R 13 The compound (103) can be produced by urea formation using compound (103) and an isocyanate. The isocyanate used can be trimethylsilyl isocyanate, and the solvent can be dichloromethane.

[0214] Compound (108) can be produced from compound (96) by the following method. [ka] Compound (105) can be prepared by a coupling reaction using compound (96), a coupling reagent, a palladium catalyst, and a base. Examples of the coupling reagent include vinylboronic acid and potassium vinyltrifluoroborate. Examples of the palladium catalyst include [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II). Examples of the base include potassium carbonate and sodium carbonate. Examples of the solvent include 1,4-dioxane and water. Compound (106) can be prepared by oxidative cleavage of compound (105) using a metal catalyst and an oxidizing agent, such as osmium tetroxide or potassium osmate(VI) dihydrate. Examples of the metal catalyst used include osmium tetroxide, potassium osmate(VI) dihydrate, etc.; examples of the oxidizing agent include 4-methylmorpholine N-oxide and sodium periodate, etc.; and examples of the solvent include tert-butanol and water. Compound (107) can be produced by reduction of compound (106) with a reducing agent such as sodium borohydride, and solvents such as tetrahydrofuran and methanol. Compound (108) can be produced by intramolecular cyclization of compound (107) with a base, such as sodium hydride, in a solvent such as tetrahydrofuran.

[0215] Compound (110) can be produced from compound (105) by the following method. [ka] Compound (109) can be prepared by hydroboration / oxidation using compound (105), a borane reagent, an oxidizing agent, and a base. Examples of the borane reagent include borane-tetrahydrofuran complex, etc.; examples of the oxidizing agent include hydrogen peroxide and sodium peroxoborate tetrahydrate, etc.; examples of the base include sodium hydroxide, etc.; and examples of the solvent include tetrahydrofuran and water. Compound (110) can be produced by intramolecular cyclization of compound (109) with a base, such as sodium hydride, in a solvent such as N,N-dimethylformamide.

[0216] Compound (112) can be produced from compound (106) by the following method. (Wherein, R 11 is the same as defined above.) [ka] Compound (111) can be produced by reductive amination of compound (106), a carbonyl compound such as an aldehyde or ketone, an acid, and a reducing agent. Examples of the acid used include acetic acid and tetraethyl orthotitanate, examples of the reducing agent include sodium triacetoxyborohydride, and examples of the solvent include toluene and tetrahydrofuran. Compound (112) can be produced by intramolecular cyclization of compound (111) with a base. Examples of the base used include sodium hydride and sodium hydroxide, and examples of the solvent include 1,4-dioxane and dimethyl sulfoxide.

[0217] Compound (45) and compound (50) can be produced from compound (96) by the following method. [ka] Compound (50) (a compound in which Y is an optionally substituted hydrocarbon group) can be produced by a coupling reaction using compound (96), a coupling reagent, a palladium catalyst, and a base. Examples of the coupling reagent used include boronic acid, a boronate ester, and an acrylic ester. Examples of the palladium catalyst include [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II). Examples of the base include potassium carbonate and sodium carbonate. Examples of the solvent include 1,4-dioxane and water. Compound (45) (a compound in which Y is an optionally substituted hydrocarbon group) can be prepared by deprotecting compound (50) with an acid. Examples of the acid used include hydrochloric acid and trifluoroacetic acid, and examples of the solvent include 1,4-dioxane.

[0218] Compound (114) (a compound in which Y is an optionally substituted hydrocarbon group) can be produced from compound (44) by the following method. c is a substituent (C 1-6 It indicates an alkyl group, etc. [ka] Compound (113) can be produced by mono-alkylation of compound (44), an orthoester, and a reducing agent, such as triethyl orthoformate or triethyl orthoacetate, sodium borohydride, or methanol. Compound (114) can be produced by a coupling reaction using compound (113), a coupling reagent, a palladium catalyst, a ligand, and a base. Examples of the coupling reagent include boronic acid, a boronate ester, and an acrylate ester. Examples of the palladium catalyst include [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II). Examples of the base include potassium carbonate and sodium carbonate. Examples of the solvent include 1,4-dioxane and water.

[0219] Compound (120) (a compound in which X is an optionally substituted heterocyclic group, hydrocarbon group, or acyl group) can be produced from compound (87) by the following method. (In the formula, R h and R i The combination of R h is a hydrogen atom or a C which may be substituted with one or more substituents independently selected from the substituent group C2. 1-6 is an alkyl group, R iis a hydrogen atom, a C which may be substituted with one or more substituents independently selected from the substituent group C2 1-6 alkyl groups, C 6-14 aryl groups, a 5- to 14-membered aromatic heterocyclic group or a 3- to 14-membered non-aromatic heterocyclic group, each of which optionally has one or more substituents independently selected from substituent group D2, or R h and R i together with the nitrogen atom to which they are attached form a 3- to 14-membered non-aromatic heterocycle, each of which may have one or more substituents independently selected from substituent group D2). [ka] Compound (115) can be produced by halogenating compound (87) with N-bromosuccinimide in a solvent such as N,N-dimethylformamide or dichloromethane. Compound (116) can be produced by a ring-forming reaction between compound (115), triethyl methanetricarboxylate, and a base. Examples of the base used include N,N-diisopropylethylamine and triethylamine, and examples of the solvent include toluene. Compound (117) can be produced by amidation of compound (116) with an amine. Examples of the solvent used include N,N-dimethylacetamide. Compound (118) can be prepared by a coupling reaction using compound (117), a coupling reagent, a palladium catalyst, and a base. Examples of the coupling reagent include boronic acid, a boronate ester, and an acrylate ester. Examples of the palladium catalyst include [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II). Examples of the base include potassium carbonate and sodium carbonate. Examples of the solvent include 1,4-dioxane and water. Compound (119) can be prepared by hydrolysis of compound (118) with a base. Examples of the base used include potassium trimethylsilanolate, sodium hydroxide, potassium hydroxide, and lithium hydroxide. Examples of the solvent used include tetrahydrofuran, 1,4-dioxane, water, and ethanol. Compound (120) can be produced by an amidation reaction using compound (119), an amine, a condensing agent, and an additive. Examples of the condensing agent include 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate. Examples of the additive include 1-hydroxybenzotriazole monohydrate and 4-dimethylaminopyridine. Examples of the solvent include dichloromethane and N,N-dimethylacetamide.

[0220] Compound (121) (a compound in which X is a heterocyclic group, a hydrocarbon group, or an acyl group, each of which may be substituted, and Y is a hydrocarbon group, each of which may be substituted) can be produced from compound (117) by the following method. [ka] Compound (121) can be prepared by a coupling reaction using compound (117), a coupling reagent, a palladium catalyst, and a base. Examples of the coupling reagent include boronic acid and boronic acid esters, palladium catalysts include [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II), bases include potassium carbonate and sodium carbonate, and solvents include 1,4-dioxane and water.

[0221] Depending on the type of substituent of the starting compound, starting compounds having different substituents can be produced using the compounds produced by the above production methods as starting materials by applying means known per se.

[0222] The compound of formula (I), which is the product of this reaction, may be produced as a single compound or as a mixture.

[0223] When the compound represented by formula (I) has isomers such as optical isomers, stereoisomers, positional isomers, and rotational isomers, any one of the isomers and a mixture thereof are included in the compound represented by formula (I).

[0224] For example, when the compound represented by formula (I) has optical isomers, the optical isomers resolved from the racemate are also encompassed in the compound represented by formula (I). These isomers can be obtained as single products by known synthetic and separation techniques (e.g., concentration, solvent extraction, column chromatography, recrystallization).

[0225] Furthermore, when the compound represented by formula (I) has stereoisomers, the present invention includes both the isomers alone and mixtures thereof.

[0226] The compound represented by formula (I) may be crystalline, and both a single crystalline form and a mixture of crystalline forms are encompassed by the compound represented by formula (I). Crystals can be produced by crystallization using a crystallization method known per se. Examples of crystallization methods include crystallization from a solution, crystallization from vapor, and crystallization from a melt. Crystal analysis by powder X-ray diffraction is a common method for analyzing the obtained crystals. Furthermore, methods for determining the crystal orientation include mechanical and optical methods.

[0227] The compound represented by formula (I) may also be a pharmaceutically acceptable cocrystal or cocrystal salt. Here, a cocrystal or cocrystal salt refers to a crystalline substance composed of two or more distinct solids at room temperature, each having different physical properties (e.g., structure, melting point, heat of fusion, hygroscopicity, and stability). A cocrystal or cocrystal salt can be prepared by a cocrystallization method known per se. [Example]

[0228] The present invention will be explained in more detail below by showing synthesis examples, evaluation examples and formulation examples, but the present invention is not limited to these examples. Those skilled in the art of organic chemical synthesis can appropriately set detailed reaction conditions. Examples of detailed conditions include setting reagent equivalents, solvent amounts, reaction temperatures, etc., determining the reaction end point, and selecting post-treatment and purification methods and conditions. Therefore, when a term "substantially similar reaction" is used in this specification, it is understood to mean, for example, that a reaction based on the same basic principle is carried out with supplementary conditions that can be appropriately set by a person skilled in the art. In the examples, "NMR" means nuclear magnetic resonance, "LC / MS" means high performance liquid chromatography / mass spectrometry, and "(v / v)" means (volume / volume). In addition, in the table, "Ex" means a synthesis example, "Data" means physical data, "condition" means measurement conditions, "R.time" means LC / MS retention time, and "min" means minutes. 1 H-NMR data, when provided, were measured at 300 MHz (JNM-ECP300; JEOL, or JNM-ECX300; JEOL, respectively) and represent the chemical shifts δ (unit: ppm) of the signals (splitting pattern, integration value) using tetramethylsilane as the internal standard. "s" denotes singlet, "d" denotes doublet, "t" denotes triplet, "dd" denotes doublet of doublets, "m" denotes multiplet, "br" denotes broad, "br s" denotes broad singlet, "J" denotes coupling constant, "CDCl3" denotes deuterated chloroform, and "DMSO-D6" denotes deuterated dimethyl sulfoxide. Unless otherwise specified, purification by silica gel column chromatography was carried out using either a Yamazen Hi-Flash column, Merck Silica Gel 60, Fuji Silysia Chemical PSQ60B or Biotage SNAP column. For purification by silica gel reverse phase column chromatography, unless otherwise specified, either Xbridge PREP C18 5 μm 19×100 mm or Xselect CSH Prep C18 5 μm 19×100 mm was used. For purification by thin-layer silica gel chromatography, Merck PLC plates were used unless otherwise specified. The microwave reactor used was Initiator sixty manufactured by Biotage. LC / MS was performed using ESI (electrospray ionization) under the following conditions, where "ESI+" indicates ESI positive ion mode and "ESI-" indicates ESI negative ion mode. In each chromatography and experimental procedure, "number / number" indicates the volume ratio of each solvent unless otherwise specified.

[0229] LC / MS Condition 1: Instrument: Waters ACQUITY UPLC / SQ Detector Column: Waters ACQUITY UPLC BEH C18 (1.7 μm, 2.1 × 50 mm) Column temperature: 40℃ solvent: Solution A: 0.1% formic acid solution Solution B: 0.1% formic acid-acetonitrile solution Gradient conditions: Measurement was started at a flow rate of 0.6 mL / min with a mixture ratio of A and B of 90 / 10, after which the mixture ratio of A and B was changed linearly to 10 / 90 over a period of 0.5 minutes to 1.5 minutes. Thereafter, the mixture ratio of solution A and solution B was fixed at 10 / 90 for 0.8 minutes. Then, over 0.1 minutes, the mixture ratio of solution A and solution B was changed linearly to 90 / 10 and the flow rate to 0.8 mL / min. Thereafter, the mixture ratio of solution A and solution B was fixed at 90 / 10 for 1 minute. Detection wavelength: UV (254 nm)

[0230] LC / MS Condition 2: Instrument: Waters ACQUITY UPLC H CLASS / SQ Detector 2 Column: Waters ACQUITY UPLC BEH C18 (1.7 μm, 2.1 × 50 mm) Column temperature: 40℃ solvent: Solution A: 0.1% formic acid solution Solution B: 0.1% formic acid-acetonitrile solution Gradient conditions: Measurement was started at a flow rate of 0.6 mL / min with a mixture ratio of A and B of 90 / 10, after which the mixture ratio of A and B was changed linearly to 10 / 90 over a period of 3 minutes. Thereafter, the mixture ratio of solution A and solution B was fixed at 10 / 90 for 0.7 minutes. Then, over 0.1 minutes, the mixture ratio of solution A and solution B was changed linearly to 90 / 10 and the flow rate to 0.8 mL / min. Thereafter, the mixture ratio of solution A and solution B was fixed at 90 / 10 for 1 minute. Detection wavelength: PDA (190-500nm)

[0231] LC / MS Condition 3: Instrument: Waters ACQUITY UPLC / Thermo LTQ XL Column: Waters ACQUITY UPLC BEH C18 (1.7 μm, 2.1 × 50 mm) Column temperature: 40℃ solvent Solution A: 0.1% formic acid solution Solution B: 0.1% formic acid-acetonitrile solution Gradient conditions: Measurement was started at a flow rate of 0.6 mL / min with a mixture ratio of A and B of 90 / 10. After 0.5 minutes, the mixture ratio of A and B was changed linearly to 10 / 90 over a period of 2.5 minutes. Thereafter, the mixture ratio of solution A and solution B was fixed at 10 / 90 for 0.7 minutes. Then, over 0.1 minutes, the mixture ratio of solution A and solution B was changed linearly to 90 / 10 and the flow rate to 0.8 mL / min. Thereafter, the mixture ratio of solution A and solution B was fixed at 90 / 10 for 1 minute. Detection wavelength: PDA (190-399 nm)

[0232] LC / MS Condition 4: Equipment:Waters ACQUITY UPLC I CLASS / SQ Detector 2 Column: Waters ACQUITY UPLC BEH C18 (1.7 μm, 2.1 × 50 mm) Column temperature: 40℃ solvent: Solution A: 0.1% formic acid solution Solution B: 0.1% formic acid-acetonitrile solution Gradient conditions: Measurement was started at a flow rate of 0.6 mL / min with a mixture ratio of A and B of 90 / 10. After 0.5 minutes, the mixture ratio of A and B was changed linearly to 10 / 90 over a period of 3.0 minutes. Thereafter, the mixture ratio of solution A and solution B was fixed at 10 / 90 for 0.8 minutes. Then, over 0.1 minutes, the mixture ratio of solution A and solution B was changed linearly to 90 / 10 and the flow rate to 0.8 mL / min. Thereafter, the mixture ratio of solution A and solution B was fixed at 90 / 10 for 1 minute. Detection wavelength: PDA (190-400nm)

[0233] LC / MS Condition 5: Instrument: Waters ACQUITY UPLC / SQ Detector Column: Waters ACQUITY UPLC BEH C18 (1.7 μm, 2.1 × 50 mm) Column temperature: 40℃ solvent: Solution A: 0.1% formic acid solution Solution B: 0.1% formic acid-acetonitrile solution Gradient conditions: Measurements were started at a flow rate of 0.6 mL / min with a mixture ratio of A and B of 95 / 5. Over 0.5 minutes, the mixture ratio of A and B was linearly changed to 90 / 10. From 0.5 minutes later, the mixture ratio of A and B was linearly changed to 40 / 60 over the next 1.5 minutes. Thereafter, the mixture ratio of solution A and solution B was fixed at 40 / 60 for 0.8 minutes. Then, over 0.1 minutes, the mixture ratio of solution A and solution B was changed linearly to 90 / 10 and the flow rate to 0.8 mL / min. Thereafter, the mixture ratio of solution A and solution B was fixed at 90 / 10 for 1 minute. Detection wavelength: UV (254 nm)

[0234] LC / MS Condition 6: Instrument: Waters ACQUITY UPLC / SQ Detector Column: Waters ACQUITY UPLC BEH C18 (1.7 μm, 2.1 × 50 mm) Column temperature: 40℃ solvent: Solution A: 10mmol ammonium acetate aqueous solution Solution B: 1 mol / L ammonium acetate aqueous solution - water - acetonitrile (mixing ratio = 1 / 1 / 9) Gradient conditions: Measurement was started at a flow rate of 0.6 mL / min with a mixture ratio of A and B of 90 / 10, after which the mixture ratio of A and B was changed linearly to 10 / 90 over a period of 0.5 minutes to 1.5 minutes. Thereafter, the mixture ratio of solution A and solution B was fixed at 10 / 90 for 0.8 minutes. Then, over 0.1 minutes, the mixture ratio of solution A and solution B was changed linearly to 90 / 10 and the flow rate to 0.8 mL / min. Thereafter, the mixture ratio of solution A and solution B was fixed at 90 / 10 for 1 minute. Detection wavelength: UV (254 nm)

[0235] LC / MS Condition 7: Equipment:Waters ACQUITY UPLC H CLASS / QDa Detector Column: Waters ACQUITY UPLC BEH C18 (1.7 μm, 2.1 × 50 mm) Column temperature: 40℃ solvent: Solution A: 0.1% formic acid solution Solution B: 0.1% formic acid-acetonitrile solution Gradient conditions: Measurement was started at a flow rate of 0.6 mL / min with a mixture ratio of A and B of 90 / 10, after which the mixture ratio of A and B was changed linearly to 10 / 90 over a period of 3 minutes. Thereafter, the mixture ratio of solution A and solution B was fixed at 10 / 90 for 0.7 minutes. Then, over 0.1 minutes, the mixture ratio of solution A and solution B was changed linearly to 90 / 10 and the flow rate to 0.8 mL / min. Thereafter, the mixture ratio of solution A and solution B was fixed at 90 / 10 for 1 minute. Detection wavelength: PDA (190-400nm)

[0236] When an asterisk (*) is written in the structural formula of the examples, the absolute configuration is undetermined, but it means that the stereochemistry of the corresponding asymmetric carbon is single, and it is an optically active substance. Also, the notation of Isomer A and Isomer B means that they are different stereoisomers. Compounds without an asterisk written at the asymmetric carbon atom mean that they are racemic. Furthermore, in the case of cyclic compounds in which the asymmetric carbon center is exactly on two rings and the cis / trans configuration is determined, it is also possible to write "cis" or "trans" in the name and structural formula.

[0237] Synthesis Example 1 6-(Cyclopropylcarbamoyl)-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-2-carboxylate ethyl ester (Step A) Ethyl 5-(neopentylamino)-1H-pyrazole-3-carboxylate [ka] Acetic acid (2.43 mL) was added to a mixture of ethyl 5-amino-1H-pyrazole-3-carboxylate (5 g), pivalaldehyde (4.62 mL), and tetrahydrofuran (50 mL) at room temperature, followed by stirring for 17 hours. The reaction mixture was cooled to 0°C, and sodium borohydride (1.61 g) was added. The mixture was stirred at room temperature for 4 hours. After cooling to 0°C, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform / methanol = 100 / 0 → 95 / 5 (v / v)) to give the title compound (6.0 g) as a white solid. LC / MS: Condition 2, retention time = 2.06 minutes LC / MS(ESI+) m / z: 226.3 [M+H] + (Step B) Diethyl 7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-2,6-dicarboxylate [ka] A mixture of ethyl 5-(neopentylamino)-1H-pyrazole-3-carboxylate (6.0 g) obtained in Step A of Synthesis Example 1, triethyl methanetricarboxylate (6.79 mL), triethylamine (11.1 mL), and toluene (30 mL) was stirred for 16 hours at 120° C. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform / methanol = 100 / 0 → 95 / 5 → 90 / 10 (v / v)) to give the title compound (7.6 g) as a white solid. LC / MS: Condition 2, retention time = 1.93 minutes LC / MS(ESI+) m / z: 366.3 [M+H] + (Step C) Ethyl 6-(cyclopropylcarbamoyl)-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-2-carboxylate A mixture of diethyl 7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-2,6-dicarboxylate (7.5 g) obtained in Step B of Synthesis Example 1, cyclopropylamine (2.35 g), and N,N-dimethylacetamide (75 mL) was stirred at 120° C. for 4 hours. The reaction mixture was cooled to room temperature, and 1M aqueous hydrochloric acid was added, followed by stirring at room temperature for 2 hours. The resulting solid was collected by filtration and dried under reduced pressure to obtain the title compound (7.0 g) as a white solid.

[0238] Synthesis Example 2 6-(Cyclopropylcarbamoyl)-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-2-carboxylic acid A mixture of ethyl 6-(cyclopropylcarbamoyl)-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-2-carboxylate (3.76 g) obtained in Step C of Synthesis Example 1, potassium trimethylsilanolate (2.57 g), and tetrahydrofuran (150 mL) was stirred at room temperature for 14 hours. The reaction mixture was cooled to room temperature, and 1M aqueous hydrochloric acid was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (3.3 g) as a white solid.

[0239] Synthesis Example 3 tert-Butyl (6-(cyclopropylcarbamoyl)-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)carbamate A mixture of 6-(cyclopropylcarbamoyl)-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-2-carboxylic acid (9.0 g) obtained in Synthesis Example 2, diphenylphosphoryl azide (8.3 mL), triethylamine (7.19 mL), and tert-butanol (180 mL) was stirred for 3 hours at 100° C. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform / methanol = 100 / 0 → 95 / 5 → 90 / 10 (v / v)) to give the title compound (7.0 g) as a white solid.

[0240] Synthesis Example 4 2-Amino-N-cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide hydrochloride A mixture of tert-butyl (6-(cyclopropylcarbamoyl)-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)carbamate (1.1 g) obtained in Synthesis Example 3, 4 M hydrogen chloride ethyl acetate solution (20 mL), and ethyl acetate (20 mL) was stirred at room temperature for 63 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (0.921 g) as a white solid.

[0241] Synthesis Example 5 6-(Cyclopropylcarbamoyl)-7-hydroxy-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylate ethyl ester (Step A) Ethyl 5-(isobutylamino)-1H-pyrazole-4-carboxylate [ka] Acetic acid (1.11 mL) was added to a mixture of ethyl 5-amino-1H-pyrazole-4-carboxylate (10 g), isobutyraldehyde (5.58 g), and 1,2-dichloroethane (200 mL) at room temperature, followed by stirring for 2 hours. Sodium triacetoxyborohydride (27.3 g) was added to the reaction mixture at room temperature, followed by stirring for 16 hours. Aqueous sodium carbonate was added to the reaction mixture until the pH changed to 8-9, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (13.8 g) as a colorless oil. LC / MS: Condition 4, retention time = 1.95 minutes LC / MS(ESI+) m / z: 212.0 [M+H] + (Step B) Diethyl 7-hydroxy-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-3,6-dicarboxylate [ka] A mixture of ethyl 5-(isobutylamino)-1H-pyrazole-4-carboxylate (13.8 g) obtained in Step A of Synthesis Example 5, triethyl methanetricarboxylate (25 g), triethylamine (26.9 mL), and toluene (70 mL) was stirred for 87 hours at 120° C. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform / methanol = 100 / 0 → 95 / 5 → 90 / 10 (v / v)) to give the title compound (22.6 g) as a brown oil. LC / MS: Condition 4, retention time = 2.52 minutes LC / MS(ESI+) m / z: 352.0 [M+H] + (Step C) Ethyl 6-(cyclopropylcarbamoyl)-7-hydroxy-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylate A mixture of diethyl 7-hydroxy-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-3,6-dicarboxylate (22.6 g) obtained in Step B of Synthesis Example 5, cyclopropylamine (9.2 g), and N,N-dimethylacetamide (65 mL) was stirred for 3 hours at 120° C. The reaction mixture was cooled to room temperature, and 1 M aqueous hydrochloric acid was added. The resulting solid was collected by filtration and dried under reduced pressure to obtain the title compound (14.1 g) as a white solid.

[0242] Synthesis Example 6 N-Cyclopropyl-7-hydroxy-3-(hydroxymethyl)-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide Lithium aluminum hydride (45 mL, 2.0 M tetrahydrofuran solution) was added to a mixture of ethyl 6-(cyclopropylcarbamoyl)-7-hydroxy-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylate (10.87 g) obtained in Step C of Synthesis Example 5 and tetrahydrofuran (100 mL) at 0° C., followed by stirring for 4 hours at 0° C. Sodium sulfate decahydrate was added to the reaction mixture at 0° C., followed by addition of chloroform. After filtration, the mixture was concentrated under reduced pressure to obtain the title compound (7.9 g) as a yellow amorphous substance.

[0243] Synthesis Example 7 N-Cyclopropyl-3-formyl-7-hydroxy-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide To a mixture of N-cyclopropyl-7-hydroxy-3-(hydroxymethyl)-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide (7.9 g) obtained in Synthesis Example 6 and dimethyl sulfoxide (79 mL), 2-iodoxybenzoic acid (53.1 g, >39.0% purity, containing benzoic acid and isophthalic acid as stabilizers) was added at room temperature, and the mixture was stirred at room temperature for 4 hours and 40 minutes. The reaction mixture was cooled to 0°C, and saturated aqueous sodium thiosulfate solution was added. Saturated aqueous sodium bicarbonate solution was added until the pH changed to 6-7, and then water was added. The resulting solid was collected by filtration, washed with water, and dried under reduced pressure to obtain the title compound (6.1 g) as a brown solid.

[0244] Synthesis Example 8 Methyl (E)-3-(6-(cyclopropylcarbamoyl)-7-hydroxy-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-3-yl)acrylate A mixture of trimethyl phosphonoacetate (4.48 mL) and tetrahydrofuran (35 mL) was added to a mixture of sodium hydride (1.13 g, >55.0% purity, containing paraffin liquid) and tetrahydrofuran (35 mL) at -4°C. Subsequently, a mixture of N-cyclopropyl-3-formyl-7-hydroxy-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide (3.52 g) obtained in Synthesis Example 7 and tetrahydrofuran (70 mL) was added at -4°C, and the mixture was stirred at -4°C for 30 minutes. The mixture was then stirred at 0°C for 1 hour and then at room temperature for 1 hour and 30 minutes. The reaction mixture was cooled to 0°C, water was added, and then 1M aqueous hydrochloric acid was added until the pH changed to 2-3, followed by extraction with chloroform. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (6.5732 g) as a brown solid.

[0245] Synthesis Example 9 (E)-3-(6-(cyclopropylcarbamoyl)-7-hydroxy-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-3-yl)acrylic acid To a mixture of methyl (E)-3-(6-(cyclopropylcarbamoyl)-7-hydroxy-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-3-yl)acrylate (6.6 g) obtained in Synthesis Example 8, 1,4-dioxane (40 mL), and water (40 mL), lithium hydroxide monohydrate (1.4 g) was added at room temperature, and the mixture was stirred at 80°C for 8 hours. The reaction mixture was concentrated under reduced pressure (30 mL of solvent was distilled off), and then 1 M aqueous hydrochloric acid was added until the pH changed to 2, and the resulting solid was collected by filtration. Ethanol was added to the resulting solid, and the solid was collected by filtration and dried under reduced pressure to obtain the title compound (2.1793 g) as a brown solid.

[0246] Synthesis Example 10 (E)-N-Cyclopropyl-7-hydroxy-4-isobutyl-3-(3-morpholino-3-oxoprop-1-en-1-yl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide To a mixture of (E)-3-(6-(cyclopropylcarbamoyl)-7-hydroxy-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-3-yl)acrylic acid (167.9 mg) obtained in Synthesis Example 9 and N,N-dimethylacetamide (1.7 mL), triethylamine (96.9 μL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (107.2 mg), 1-hydroxybenzotriazole monohydrate (85.6 mg), and morpholine (48.7 μL) were added at room temperature, and the mixture was stirred at room temperature for 14 hours and 30 minutes. To the reaction mixture, 2M aqueous hydrochloric acid was added, followed by water, and the mixture was stirred at room temperature for 30 minutes. The resulting solid was collected by filtration, washed with water, and dried under reduced pressure. The obtained solid was suspended in ethanol, and the solid was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (148.5 mg) as a white solid.

[0247] Synthesis Example 11 2-Bromo-N-cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide (Step A) 3-Bromo-N-neopentyl-1H-pyrazol-5-amine [ka] To a mixture of 3-bromo-1H-pyrazol-5-amine (1 g), pivalaldehyde (689 mg), and tetrahydrofuran (20 mL) was added acetic acid (480 mg) at room temperature and stirred for 17 hours. The reaction mixture was cooled to 0°C, and sodium borohydride (303 mg) was added. The mixture was stirred at room temperature for 4 hours. After cooling to 0°C, water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform / methanol = 100 / 0 → 95 / 5 (v / v)) to give the title compound (1.43 g) as a white solid. LC / MS: Condition 4, retention time = 2.18 minutes LC / MS(ESI+) m / z: 234.2 [M+H] + (Step B) Ethyl 2-bromo-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxylate [ka] A mixture of 3-bromo-N-neopentyl-1H-pyrazol-5-amine (1.43 g) obtained in Step A of Synthesis Example 11, triethyl methanetricarboxylate (1.51 mL), triethylamine (2.58 mL), and toluene (7 mL) was stirred for 16 hours at 120° C. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform / methanol = 100 / 0 → 95 / 5 → 90 / 10 (v / v)) to give the title compound (1.39 g) as a light brown solid. LC / MS: Condition 2, retention time = 2.03 minutes LC / MS(ESI+) m / z: 372.3 [M+H] + (Step C) 2-Bromo-N-cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide A mixture of ethyl 2-bromo-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxylate (5.0 g) obtained in Step B of Synthesis Example 11, cyclopropylamine (1.54 g), and N,N-dimethylacetamide (50 mL) was stirred at 120°C for 3 hours. The reaction mixture was cooled to room temperature, and 1M aqueous hydrochloric acid was added, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (3.83 g) as a light brown solid.

[0248] Synthesis Example 12 N-Cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-2-(pyrimidin-4-ylamino)-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide A mixture of 2-bromo-N-cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide (76.6 mg) obtained in Step C of Synthesis Example 11, pyrimidin-4-amine (38.0 mg), tris(dibenzylideneacetone)dipalladium(0) (18.3 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (23.1 mg), sodium tert-butoxide (57.7 mg), and 1,4-dioxane (1.6 mL) was stirred overnight at 100° C. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 99 / 1 → 97 / 3 (v / v)) and then by silica gel reverse-phase column chromatography (0.1% formic acid-acetonitrile / 0.1% formic acid aqueous solution = 40 / 60 → 60 / 40 (v / v)) to give the title compound (5.65 mg) as a pale brown solid.

[0249] Synthesis Example 13 N-Cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-2-(pyrazin-2-ylamino)-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide A mixture of 2-bromo-N-cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide (100 mg) obtained in Step C of Synthesis Example 11, pyrazin-2-amine (24.7 mg), tris(dibenzylideneacetone)dipalladium(0) (11.9 mg), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (11.0 mg), sodium tert-butoxide (37.5 mg), and 1,4-dioxane (1 mL) was stirred under microwave irradiation at 120°C for 1 hour. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate=95 / 5→60 / 40→chloroform / methanol=95 / 5 (v / v)) to give the title compound (5.37 mg) as a yellow solid.

[0250] Synthesis Example 14 2-(2-aminopyridin-3-yl)-N-cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide A mixture of 2-bromo-N-cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide (76.6 mg) obtained in Step C of Synthesis Example 11, 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (88.0 mg), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (13.0 mg), potassium carbonate (82.9 mg), water (0.77 mL), and 1,4-dioxane (0.77 mL) was stirred overnight at 110° C. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel reverse-phase column chromatography (0.1% formic acid-acetonitrile / 0.1% aqueous formic acid solution=30 / 70→60 / 40 (v / v)) to give the title compound (15.3 mg) as a pale brown solid.

[0251] Synthesis Example 15 N-Cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide A mixture of 2-bromo-N-cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide (100 mg) obtained in Step C of Synthesis Example 11, 5-(trifluoromethyl)pyrazin-2-amine (92.97 mg), tris(dibenzylideneacetone)dipalladium(0) (23.8 mg), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (22.1 mg), sodium tert-butoxide (59.4 mg), and 1,4-dioxane (1 mL) was stirred under microwave irradiation at 120°C for 1 hour. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel reverse-phase column chromatography (0.1% formic acid-acetonitrile / 0.1% aqueous formic acid solution=40 / 60→70 / 30 (v / v)) to give the title compound (18.39 mg) as a yellow solid.

[0252] Synthesis Example 16 N-Cyclopropyl-7-hydroxy-2-((5-methoxypyrazin-2-yl)amino)-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide A mixture of 2-bromo-N-cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide (50 mg) obtained in Step C of Synthesis Example 11, 5-methoxypyrazin-2-amine (32.5 mg), tris(dibenzylideneacetone)dipalladium(0) (11.9 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (15.0 mg), sodium tert-butoxide (37.5 mg), and 1,4-dioxane (1 mL) was stirred overnight at 110° C. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel reverse-phase column chromatography (0.1% formic acid-acetonitrile / 0.1% aqueous formic acid solution=60 / 40→70 / 30 (v / v)) to give the title compound (9.12 mg) as a yellow solid.

[0253] Synthesis Example 17 N-Cyclopropyl-7-hydroxy-2-((6-methoxypyrazin-2-yl)amino)-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide A mixture of 2-bromo-N-cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide (100 mg) obtained in Step C of Synthesis Example 11, 6-methoxypyrazin-2-amine (100 mg), tris(dibenzylideneacetone)dipalladium(0) (23.8 mg), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (22.1 mg), sodium tert-butoxide (59.4 mg), and 1,4-dioxane (1 mL) was stirred under microwave irradiation at 120°C for 1 hour. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel reverse-phase column chromatography (0.1% formic acid-acetonitrile / 0.1% aqueous formic acid solution=60 / 40→80 / 20 (v / v)) to give the title compound (42.1 mg) as a yellow solid.

[0254] Synthesis Example 18 2-Amino-N-cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide A mixture of 2-bromo-N-cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide (516 mg) obtained in Step C of Synthesis Example 11, (2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid carboxamide (177 mg), copper(I) iodide (128.6 mg), potassium carbonate (1.87 g), 28% aqueous ammonia (2.5 mL), and dimethyl sulfoxide (8 mL) was stirred under an argon atmosphere under microwave irradiation at 130° C. for 1 hour. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel reverse-phase column chromatography (0.1% formic acid-acetonitrile / 0.1% aqueous formic acid solution=50 / 50→70 / 30 (v / v)) to give the title compound (10.63 mg) as a yellow solid.

[0255] Synthesis Example 19 5-((6-(cyclopropylcarbamoyl)-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)amino)pyrazine-2-carboxylate methyl ester A mixture of 2-amino-N-cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide (95.8 mg) obtained in Synthesis Example 18, methyl 5-chloropyrazine-2-carboxylate (103.6 mg), tris(dibenzylideneacetone)dipalladium(0) (27.5 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (34.7 mg), sodium carbonate (95.4 mg), and 1,4-dioxane (1 mL) was stirred overnight at 100°C under an argon atmosphere. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 99 / 1 → 97 / 3 (v / v)) to afford the title compound (71.7 mg) as a brown amorphous solid.

[0256] Synthesis Example 20 5-((6-(cyclopropylcarbamoyl)-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)amino)pyrazine-2-carboxylic acid To a mixture of methyl 5-((6-(cyclopropylcarbamoyl)-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)amino)pyrazine-2-carboxylate (70 mg) obtained in Synthesis Example 19, 1,4-dioxane (0.7 mL), and water (0.7 mL), lithium hydroxide monohydrate (13 mg) was added at room temperature, followed by stirring at 80° C. for 3 hours. The reaction mixture was cooled to room temperature, and 1 M aqueous hydrochloric acid was added until the pH changed to 2. The resulting solid was collected by filtration and dried under reduced pressure to give the title compound (60.2 mg) as a gray solid.

[0257] Synthesis Example 21 2-((5-carbamoylpyrazin-2-yl)amino)-N-cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide To a mixture of 5-((6-(cyclopropylcarbamoyl)-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)amino)pyrazine-2-carboxylic acid (31 mg) obtained in Synthesis Example 20 and N,N-dimethylacetamide (0.6 mL), 1-hydroxy-1H-benzotriazole, ammonium salt (26.7 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (26.9 mg) were added at 0°C, and the mixture was stirred at room temperature overnight. 1M aqueous hydrochloric acid was added to the reaction mixture, and the resulting solid was collected by filtration. The resulting solid was purified by silica gel reverse-phase column chromatography (acetonitrile / 10 mM aqueous ammonium bicarbonate solution = 18 / 82 → 27 / 73 (v / v)) to give the title compound (18.58 mg) as a white solid.

[0258] Synthesis Example 22 2-Bromo-N-cyclopropyl-7-hydroxy-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide (Step A) 3-Bromo-N-isobutyl-1H-pyrazol-5-amine [ka] To a mixture of 3-bromo-1H-pyrazol-5-amine (1 g), isobutyraldehyde (534 mg), and 1,2-dichloroethane (30 mL) was added acetic acid (37 mg) at room temperature and stirred for 2 hours. Sodium triacetoxyborohydride (2.62 g) was added to the reaction mixture at room temperature and stirred for 16 hours. Aqueous sodium carbonate was added to the reaction mixture until the pH changed to 8-9, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (1.35 g) as a colorless oil. LC / MS: Condition 4, retention time = 1.98 minutes LC / MS(ESI+) m / z: 218.2 [M+H] + (Step B) Ethyl 2-bromo-7-hydroxy-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxylate [ka] A mixture of 3-bromo-N-isobutyl-1H-pyrazol-5-amine (1.35 g) obtained in Step A of Synthesis Example 22, triethyl methanetricarboxylate (1.51 mL), triethylamine (2.58 mL), and toluene (7 mL) was stirred for 16 hours at 120° C. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform / methanol = 100 / 0 → 95 / 5 → 90 / 10 (v / v)) to give the title compound (912 mg) as a light brown solid. LC / MS: Condition 2, retention time = 1.83 minutes LC / MS(ESI+) m / z: 360.3 [M+H] + (Step C) 2-Bromo-N-cyclopropyl-7-hydroxy-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide A mixture of ethyl 2-bromo-7-hydroxy-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxylate (2.5 g) obtained in Step B of Synthesis Example 22, cyclopropylamine (13.96 mL), and N,N-dimethylacetamide (12 mL) was stirred at 150° C. for 1 hour under microwave irradiation. The reaction mixture was cooled to room temperature, and 2 M aqueous hydrochloric acid was added. The resulting solid was collected by filtration, washed with water, and dried under reduced pressure to obtain the title compound (2.51 g) as a light brown solid.

[0259] Synthesis Example 23 N-Cyclopropyl-7-hydroxy-4-isobutyl-5-oxo-2-(pyrazin-2-ylamino)-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide A mixture of 2-bromo-N-cyclopropyl-7-hydroxy-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide (88.37 mg) obtained in Step C of Synthesis Example 22, pyrazin-2-amine (95.11 mg), tris(dibenzylideneacetone)dipalladium(0) (21.6 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (27.3 mg), sodium tert-butoxide (68 mg), and 1,4-dioxane (1 mL) was stirred overnight at 110° C. under an argon atmosphere. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel reverse-phase column chromatography (0.1% formic acid-acetonitrile / 0.1% aqueous formic acid solution=50 / 50→60 / 40 (v / v)) to give the title compound (16.76 mg) as a white solid.

[0260] Synthesis Example 24 2-(2-aminopyridin-3-yl)-N-cyclopropyl-7-hydroxy-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide A mixture of 2-bromo-N-cyclopropyl-7-hydroxy-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide (73.8 mg) obtained in Step C of Synthesis Example 22, 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (88.0 mg), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (13.0 mg), potassium carbonate (82.9 mg), water (0.74 mL), and 1,4-dioxane (0.74 mL) was stirred overnight at 110° C. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel reverse-phase column chromatography (0.1% formic acid-acetonitrile / 0.1% aqueous formic acid solution=30 / 70→40 / 60 (v / v)) to give the title compound (28.9 mg) as a pale brown solid.

[0261] Synthesis Example 25 2-Bromo-N-cyclobutyl-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide A mixture of ethyl 2-bromo-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxylate (2.0 g) obtained in Step B of Synthesis Example 11, cyclobutanamine (764 mg), and N,N-dimethylacetamide (20 mL) was stirred at 120°C for 4 hours. The reaction mixture was cooled to room temperature, and 1M aqueous hydrochloric acid was added and stirred for 2 hours. The resulting precipitate was collected by filtration, washed with water, and dried under reduced pressure to obtain the title compound (2.0 g) as a flesh-colored solid.

[0262] Synthesis Example 26 N-Cyclobutyl-7-hydroxy-4-neopentyl-5-oxo-2-(pyrazin-2-ylamino)-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide A mixture of 2-bromo-N-cyclobutyl-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide (79.5 mg) obtained in Synthesis Example 25, pyrazin-2-amine (38.0 mg), tris(dibenzylideneacetone)dipalladium(0) (18.3 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (23.1 mg), sodium tert-butoxide (57.7 mg), and 1,4-dioxane (3 mL) was stirred under an argon atmosphere at 110° C. for 15 hours. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel reverse-phase column chromatography (0.1% formic acid-acetonitrile / 0.1% aqueous formic acid solution=60 / 40→70 / 30 (v / v)) to give the title compound (49.5 mg) as a brown solid.

[0263] Synthesis Example 27 2-Bromo-N-cyclopropyl-7-hydroxy-4-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide (Step A) 3-Bromo-N-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-5-amine [ka] To a mixture of 3-bromo-1H-pyrazol-5-amine (1 g), 4-methyltetrahydro-2H-pyran-4-carbaldehyde (950 mg), and 1,2-dichloroethane (30 mL), acetic acid (37 mg) was added at room temperature and stirred for 2 hours. Sodium triacetoxyborohydride (2.62 g) was added to the reaction mixture at room temperature and stirred for 16 hours. Aqueous sodium carbonate was added to the reaction mixture until the pH changed to 8-9, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (1.69 g) as a white solid. LC / MS: Condition 4, retention time = 1.76 minutes LC / MS(ESI+) m / z: 276.3 [M+H] + (Step B) Ethyl 2-bromo-7-hydroxy-4-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxylate [ka] A mixture of 3-bromo-N-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-5-amine (1.69 g) obtained in Step A of Synthesis Example 27, triethyl methanetricarboxylate (1.51 mL), triethylamine (2.58 mL), and toluene (7 mL) was stirred at 120° C. for 16 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform / methanol = 100 / 0 → 95 / 5 → 90 / 10 (v / v)) to give the title compound (1.49 g) as a white solid. LC / MS: Condition 4, retention time = 1.62 minutes LC / MS(ESI+) m / z: 416.4 [M+H] + (Step C) 2-Bromo-N-cyclopropyl-7-hydroxy-4-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide A mixture of ethyl 2-bromo-7-hydroxy-4-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxylate (1.5 g) obtained in Step B of Synthesis Example 27, cyclopropylamine (756 μL), and N,N-dimethylacetamide (15 mL) was stirred at 130° C. for 1 hour under microwave irradiation. The reaction mixture was cooled to room temperature, and 2 M aqueous hydrochloric acid was added. The resulting solid was collected by filtration, washed with water, and dried under reduced pressure to obtain the title compound (1.2 g) as a pale pink solid.

[0264] Synthesis Example 28 N-Cyclopropyl-7-hydroxy-4-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-5-oxo-2-(pyrazin-2-ylamino)-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide A mixture of 2-bromo-N-cyclopropyl-7-hydroxy-4-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide (200 mg) obtained in Step C of Synthesis Example 27, pyrazin-2-amine (67.1 mg), tris(dibenzylideneacetone)dipalladium(0) (43 mg), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (54.3 mg), sodium tert-butoxide (135.5 mg), and 1,4-dioxane (2 mL) was stirred at 120°C for 1 hour under microwave irradiation. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol=95 / 5→50 / 50 (v / v)) to give the title compound (10.28 mg) as a yellow solid.

[0265] Synthesis Example 29 2-(2-aminopyridin-3-yl)-N-cyclopropyl-7-hydroxy-4-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide A mixture of 2-bromo-N-cyclopropyl-7-hydroxy-4-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide (85.1 mg) obtained in Step C of Synthesis Example 27, 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (88.0 mg), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (13.0 mg), potassium carbonate (82.9 mg), water (0.85 mL), and 1,4-dioxane (0.85 mL) was stirred at 100° C. overnight. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 99 / 1 → 97 / 3 → 93 / 7 → 90 / 10 (v / v)). Ethanol was added to the resulting solid, and the resulting solid was collected by filtration and dried under reduced pressure to give the title compound (58.8 mg) as a white solid.

[0266] Synthesis Example 30 2-Bromo-N-cyclobutyl-7-hydroxy-4-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide A mixture of ethyl 2-bromo-7-hydroxy-4-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxylate (2.0 g) obtained in Step B of Synthesis Example 27, cyclobutanamine (687 mg), and N,N-dimethylacetamide (20 mL) was stirred at 120° C. for 2 hours. The reaction mixture was cooled to room temperature, and 1 M aqueous hydrochloric acid was added, followed by stirring at room temperature for 2 hours. The resulting solid was collected by filtration and dried under reduced pressure to obtain the title compound (2.07 g) as a white solid.

[0267] Synthesis Example 31 N-Cyclobutyl-7-hydroxy-4-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-5-oxo-2-(pyrazin-2-ylamino)-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide A mixture of 2-bromo-N-cyclobutyl-7-hydroxy-4-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide (87.9 mg) obtained in Synthesis Example 30, pyrazin-2-amine (38.0 mg), tris(dibenzylideneacetone)dipalladium(0) (18.3 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (23.1 mg), sodium tert-butoxide (57.7 mg), and 1,4-dioxane (3 mL) was stirred under an argon atmosphere at 110° C. for 14 hours. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel reverse-phase column chromatography (0.1% formic acid-acetonitrile / 0.1% aqueous formic acid solution=40 / 60→70 / 30 (v / v)) to give the title compound (78.3 mg) as a pale brown solid.

[0268] Synthesis Example 32 N-Cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-2-ureido-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide To a mixture of 2-amino-N-cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide (64 mg) obtained in Synthesis Example 18 and tetrahydrofuran (1.2 mL), trichloroacetyl isocyanate (47.4 μL) was added and stirred at room temperature for 3 hours. Methanol (1.2 mL) and potassium carbonate (138.2 mg) were added to the reaction mixture, and the mixture was stirred at room temperature overnight. After adding water, 1M aqueous hydrochloric acid was added until the pH changed to 2. The resulting solid was collected by filtration and dried under reduced pressure to obtain the title compound (70.1 mg) as a white solid.

[0269] Synthesis Example 33 N6-Cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-2,6-dicarboxamide To a mixture of 6-(cyclopropylcarbamoyl)-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-2-carboxylic acid (69.7 mg) obtained in Synthesis Example 2 and N,N-dimethylacetamide (1.4 mL), 1-hydroxy-1H-benzotriazole, ammonium salt (73.0 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (46.0 mg) were added at 0°C and stirred overnight at room temperature. 1M aqueous hydrochloric acid was added to the reaction mixture, and the resulting solid was collected by filtration and dried under reduced pressure to give the title compound (60.0 mg) as a white solid.

[0270] Synthesis Example 34 3-Bromo-N-cyclopropyl-7-hydroxy-5-oxo-4-((tetrahydro-2H-pyran-4-yl)methyl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide (Step A) 4-Bromo-N-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-5-amine [ka] Acetic acid (1.37 mL) was added to a mixture of 4-bromo-1H-pyrazol-5-amine (3.24 g), tetrahydro-2H-pyran-4-carbaldehyde (2.51 g), and tetrahydrofuran (32 mL) at room temperature, followed by stirring for 8 hours. The reaction mixture was cooled to 0°C, and sodium borohydride (908 mg) was added. The mixture was stirred at room temperature for 15 hours and 30 minutes. 2M aqueous hydrochloric acid was added to the reaction mixture, and the aqueous layer was washed with diethyl ether. Saturated aqueous sodium bicarbonate was added to the aqueous layer until the pH changed to 8, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (3.1 g) as a colorless oil. LC / MS: Condition 3, retention time = 1.45 minutes LC / MS(ESI+) m / z: 260.06 [M+H] + (Step B) Ethyl 3-bromo-7-hydroxy-5-oxo-4-((tetrahydro-2H-pyran-4-yl)methyl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxylate [ka] A mixture of 4-bromo-N-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-5-amine (3.1 g) obtained in Step A of Synthesis Example 34, triethyl methanetricarboxylate (3.03 mL), triethylamine (4.96 mL), and toluene (31 mL) was refluxed for 6 hours and 15 minutes. The reaction mixture was cooled to room temperature, and ethyl acetate and chloroform were added. 2M aqueous hydrochloric acid was added, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Ethyl acetate was added to the resulting residue, and the solid was collected by filtration and dried under reduced pressure to obtain the title compound (1.5988 g) as a brown solid. LC / MS: Condition 2, retention time = 1.33 minutes LC / MS(ESI+) m / z: 400.39 [M+H] + (Step C) 3-Bromo-N-cyclopropyl-7-hydroxy-5-oxo-4-((tetrahydro-2H-pyran-4-yl)methyl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide A mixture of ethyl 3-bromo-7-hydroxy-5-oxo-4-((tetrahydro-2H-pyran-4-yl)methyl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxylate (1 g) obtained in Step B of Synthesis Example 34, cyclopropylamine (0.522 mL), and N,N-dimethylformamide (7 mL) was stirred at 120° C. for 30 minutes under microwave irradiation. The reaction mixture was cooled to room temperature, and 2 M aqueous hydrochloric acid was added. The resulting solid was collected by filtration, washed with water, and dried under reduced pressure to obtain the title compound (750.9 mg) as a light brown solid.

[0271] Synthesis Example 35 N-Cyclopropyl-3-(3,6-dihydro-2H-pyran-4-yl)-7-hydroxy-5-oxo-4-((tetrahydro-2H-pyran-4-yl)methyl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide A mixture of 3-bromo-N-cyclopropyl-7-hydroxy-5-oxo-4-((tetrahydro-2H-pyran-4-yl)methyl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide (41.2 mg) obtained in Step C of Synthesis Example 34, 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (31.5 mg), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (3.3 mg), potassium carbonate (41.5 mg), water (0.42 mL), and 1,4-dioxane (0.412 mL) was refluxed overnight. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel reverse-phase column chromatography (0.1% formic acid-acetonitrile / 0.1% aqueous formic acid solution=40 / 60→50 / 50 (v / v)) to give the title compound (17.91 mg) as a pale brown amorphous substance.

[0272] Synthesis Example 36 N6-Cyclopropyl-7-hydroxy-N2-methoxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-2,6-dicarboxamide To a mixture of 6-(cyclopropylcarbamoyl)-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-2-carboxylic acid (69.7 mg) obtained in Synthesis Example 2 and N,N-dimethylacetamide (1 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (76.7 mg), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (152.1 mg), triethylamine (139 μL), and O-methylhydroxylamine hydrochloride (33.4 mg) were added and stirred at room temperature for 15 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel reverse-phase column chromatography (0.1% formic acid-acetonitrile / 0.1% aqueous formic acid solution=50 / 50→70 / 30 (v / v)) to give the title compound (67.3 mg) as a white solid.

[0273] Synthesis Example 37 N6-Cyclopropyl-7-hydroxy-N2-(3-methoxypropyl)-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-2,6-dicarboxamide To a mixture of 6-(cyclopropylcarbamoyl)-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-2-carboxylic acid (69.7 mg) obtained in Synthesis Example 2 and N,N-dimethylacetamide (1 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (76.7 mg), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (152.1 mg), and 3-methoxypropan-1-amine (35.7 mg) were added and stirred at room temperature for 14 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel reverse-phase column chromatography (0.1% formic acid-acetonitrile / 0.1% aqueous formic acid solution=50 / 50→80 / 20 (v / v)) to give the title compound (54.4 mg) as a white solid.

[0274] The compounds of Synthesis Examples 38 to 50 were produced according to the methods shown in the above Synthesis Examples or methods similar thereto.

[0275] Synthesis Example 38 N6-Cyclopropyl-N2-ethyl-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-2,6-dicarboxamide Yield: 3.09 mg, white solid

[0276] Synthesis Example 39 N6-Cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-N2-(pyrazin-2-ylmethyl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-2,6-dicarboxamide Yield: 2.51 mg, white solid

[0277] Synthesis Example 40 N6-Cyclopropyl-7-hydroxy-N2-(2-morpholinoethyl)-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-2,6-dicarboxamide Yield: 88.7 mg, white solid

[0278] Synthesis Example 41 N6-Cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-N2-(pyridin-2-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-2,6-dicarboxamide Yield: 41.32 mg, white solid

[0279] Synthesis Example 42 N6-Cyclopropyl-7-hydroxy-N2-(2-hydroxy-2-methylpropyl)-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-2,6-dicarboxamide Yield: 49.1 mg, white solid

[0280] Synthesis Example 43 N6-Cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-N2-(2,2,2-trifluoroethyl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-2,6-dicarboxamide Yield: 66.6 mg, white solid

[0281] Synthesis Example 44 N6-Cyclopropyl-7-hydroxy-N2-(3-morpholinopropyl)-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-2,6-dicarboxamide Yield: 69.5 mg, white solid

[0282] Synthesis Example 45 N6-Cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-N2-(2-(trifluoromethoxy)ethyl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-2,6-dicarboxamide Yield: 71.2 mg, white solid

[0283] Synthesis Example 46 N6-Cyclopropyl-7-hydroxy-N2-(3-methoxy-3-methylbutyl)-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-2,6-dicarboxamide Yield: 82.9 mg, white solid

[0284] Synthesis Example 47 N6-Cyclopropyl-7-hydroxy-N2,N2-dimethyl-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-2,6-dicarboxamide Yield: 2.32 mg, white solid

[0285] Synthesis Example 48 N6-Cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-N2-(2-(pyrazin-2-yl)ethyl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-2,6-dicarboxamide Yield: 8.82 mg, yellow solid

[0286] Synthesis Example 49 N6-Cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-N2-(pyridin-2-ylmethyl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-2,6-dicarboxamide Yield: 44.01 mg, yellow solid

[0287] Synthesis Example 50 N6-Cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-N2-(pyrazin-2-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-2,6-dicarboxamide Yield 2.21 mg, yellow oil

[0288] Synthesis Example 51 6-(Cyclopropylcarbamoyl)-7-hydroxy-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid To a mixture of ethyl 6-(cyclopropylcarbamoyl)-7-hydroxy-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylate (100 mg) obtained in Step C of Synthesis Example 5 and 1,4-dioxane (1 mL), 1M aqueous sodium hydroxide solution (1 mL) was added at room temperature and stirred at 60°C for 7.5 hours. 1M aqueous hydrochloric acid was added to the reaction mixture, and the resulting solid was collected by filtration. The resulting solid was washed with water and dried under reduced pressure to give the title compound (56.7 mg) as a white solid.

[0289] Synthesis Example 52 N6-Cyclopropyl-7-hydroxy-4-isobutyl-N3-isopropyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-3,6-dicarboxamide To a mixture of 6-(cyclopropylcarbamoyl)-7-hydroxy-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid (50 mg) obtained in Synthesis Example 51, isopropylamine (19.3 μL), and N,N-dimethylformamide (0.5 mL), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (85.2 mg) and N,N-diisopropylethylamine (53.7 μL) were added at 0°C and stirred for 3 hours. Water was added to the reaction mixture, which was then extracted with chloroform and concentrated under reduced pressure. The residue was purified by silica gel reverse-phase column chromatography (0.1% formic acid-acetonitrile / 0.1% aqueous formic acid solution=40 / 60→60 / 40 (v / v)) to give the title compound (2.58 mg) as a white solid.

[0290] The compounds of Synthesis Examples 53 to 56 were produced according to the methods shown in the above Synthesis Examples or methods similar thereto.

[0291] Synthesis Example 53 N6-Cyclopropyl-N3-(3,3-difluorocyclobutyl)-7-hydroxy-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-3,6-dicarboxamide Yield: 3.20 mg, yellow solid

[0292] Synthesis Example 54 N-Cyclopropyl-7-hydroxy-4-isobutyl-3-(4-methylpiperazine-1-carbonyl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide Yield: 54.59 mg, white solid

[0293] Synthesis Example 55 N6-Cyclobutyl-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-2,6-dicarboxamide Yield: 88.7 mg, white solid

[0294] Synthesis Example 56 2-Amino-N-cyclobutyl-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide hydrochloride Yield: 161.5 mg, white solid

[0295] Synthesis Example 57 N-Cyclobutyl-7-hydroxy-4-neopentyl-5-oxo-2-(sulfamoylamino)-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide To a mixture of 2-amino-N-cyclobutyl-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide hydrochloride (90 mg) obtained in Synthesis Example 56, triethylamine (70 μL), and dichloromethane (2 mL) was added tert-butyl (chlorosulfonyl)carbamate (88 mg) and stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and trifluoroacetic acid (2 mL) was added to the resulting solid and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel reverse-phase column chromatography (acetonitrile / 10 mM ammonium bicarbonate aqueous solution = 18 / 82 → 27 / 73 (v / v)) to afford the title compound (25.2 mg) as a white solid.

[0296] Synthesis Example 58 N-Cyclopropyl-7-hydroxy-2-(hydroxymethyl)-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide Ethyl 6-(cyclopropylcarbamoyl)-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-2-carboxylate (570 mg) obtained in Step C of Synthesis Example 1 was added to a mixture of lithium aluminum hydride (149 mg) and tetrahydrofuran (14 mL) at 0°C, followed by stirring for 2 hours. Sodium sulfate decahydrate was added to the reaction mixture at 0°C, followed by extraction with chloroform. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (550 mg) as a white solid.

[0297] Synthesis Example 59 N-Cyclopropyl-2-formyl-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide To a mixture of N-cyclopropyl-7-hydroxy-2-(hydroxymethyl)-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide (136 mg) obtained in Synthesis Example 58 and dimethyl sulfoxide (1 mL), 2-iodoxybenzoic acid (341.7 mg, >39.0% purity, containing benzoic acid and isophthalic acid as stabilizers) was added at room temperature and stirred for 3 hours. The reaction mixture was cooled to 0°C, and saturated aqueous sodium thiosulfate was added, followed by saturated aqueous sodium bicarbonate until the pH changed to 6-7. The mixture was stirred for 10 minutes and then extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (120 mg) as a yellow solid.

[0298] Synthesis Example 60 (E)-N-Cyclopropyl-2-((ethoxyimino)methyl)-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide A mixture of N-cyclopropyl-2-formyl-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide (30 mg) obtained in Synthesis Example 59, O-ethylhydroxylamine hydrochloride (22 mg), and methanol (0.6 mL) was stirred at 80°C for 3 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel reverse-phase column chromatography (0.1% formic acid-acetonitrile / 0.1% formic acid aqueous solution = 70 / 30 → 90 / 10 (v / v)) to give the title compound (10.55 mg) as a yellow oil.

[0299] Synthesis Example 61 2-Acetyl-N-cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide A mixture of 2-bromo-N-cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide (100 mg) obtained in Step C of Synthesis Example 11, tributyl(1-ethoxyvinyl)tin (157 mg), tetrakis(triphenylphosphine)palladium(0) (7.32 mg), and toluene (1 mL) was stirred overnight at 110°C under an argon atmosphere. The reaction mixture was cooled to room temperature, and 1M aqueous hydrochloric acid was added. The mixture was stirred for 5 hours and 30 minutes. Water was added, followed by extraction with ethyl acetate and concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform / methanol = 100 / 0 → 70 / 30 (v / v)) to afford the title compound (51 mg) as a white solid.

[0300] Synthesis Example 62 (E)-N-Cyclopropyl-2-(1-(ethoxyimino)ethyl)-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide A mixture of 2-acetyl-N-cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide (100 mg) obtained in Synthesis Example 61, O-ethylhydroxylamine hydrochloride (28.7 mg), and methanol (1 mL) was stirred at 80°C for 1 hour. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 100 / 0 → 30 / 70 (v / v)) to afford the title compound (26.17 mg) as a yellow solid.

[0301] The compounds of Synthesis Examples 63 to 68 were produced according to the methods shown in the above Synthesis Examples or methods similar thereto.

[0302] Synthesis Example 63 (E)-N-Cyclopropyl-7-hydroxy-2-((hydroxyimino)methyl)-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide Yield: 3.29 mg, yellow solid

[0303] Synthesis Example 64 (E)-N-Cyclopropyl-7-hydroxy-2-(((2-methoxyethoxy)imino)methyl)-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide Yield 15.94 mg, yellow oil

[0304] Synthesis Example 65 (E)-2-((((6-(cyclopropylcarbamoyl)-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)methylene)amino)oxy)acetic acid Yield: 2.09 mg, white solid

[0305] Synthesis Example 66 (E)-2-(((2-amino-2-oxoethoxy)imino)methyl)-N-cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide Yield: 5.56 mg, white solid

[0306] Synthesis Example 67 (E)-2-(((benzyloxy)imino)methyl)-N-cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide Yield 26.69 mg, yellow oil

[0307] Synthesis Example 68 (E)-N-Cyclopropyl-7-hydroxy-2-((methoxyimino)methyl)-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide Yield: 8.11 mg, yellow solid

[0308] Synthesis Example 69 2-Amino-N-cyclopropyl-7-hydroxy-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide A mixture of 2-bromo-N-cyclopropyl-7-hydroxy-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide (300 mg) obtained in Step C of Synthesis Example 22, (2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid (106.5 mg), copper(I) iodide (77.4 mg), potassium carbonate (1.69 g), 28% aqueous ammonia (1.5 mL), and dimethyl sulfoxide (1.5 mL) was stirred at 140°C under argon atmosphere and microwave irradiation for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. To the residue, methanol (20 mL), chloroform (10 mL), and diatomaceous earth were added, stirred, and filtered. The obtained filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel reverse-phase column chromatography (acetonitrile / water = 5 / 95 → 100 / 0 (v / v)) to obtain the title compound (98.2 mg) as a pale green amorphous substance.

[0309] Synthesis Example 70 2-Amino-N-cyclopropyl-7-hydroxy-4-isobutyl-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide A mixture of 2-amino-N-cyclopropyl-7-hydroxy-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide (80.6 mg) obtained in Synthesis Example 69, N-bromosuccinimide (56.4 mg), and acetonitrile (2 mL) was stirred at 0°C for 3.5 hours. The reaction mixture was warmed to room temperature and then divided into two portions. Each portion was concentrated under reduced pressure to give a brown solid. One portion was used crude in the next step. A mixture of the resulting crude product, 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (44.2 mg), palladium chloride 1,1'-bis(di-teat-butylphosphino)ferrocene complex (8.6 mg), potassium carbonate (54.7 mg), 1,4-dioxane (0.5 mL), and water (0.5 mL) was stirred at 100°C for 14 hours under an argon atmosphere. The reaction mixture was cooled to room temperature, and chloroform (4.0 mL) and diatomaceous earth were added and stirred. The filtered solution was concentrated under reduced pressure. The residue was purified by silica gel reverse-phase column chromatography (0.1% formic acid-acetonitrile / 0.1% formic acid aqueous solution = 30 / 70 → 60 / 40 (v / v)) to give the title compound (2.9 mg) as a black amorphous solid.

[0310] The compound of Synthesis Example 71 was prepared according to the method shown in the above Synthesis Example or a method similar thereto.

[0311] Synthesis Example 71 2-Amino-N-cyclopropyl-3-(3,6-dihydro-2H-pyran-4-yl)-7-hydroxy-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide Yield: 1.4 mg, colorless solid

[0312] Synthesis Example 72 2-Amino-3-bromo-N-cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide A mixture of 2-amino-N-cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide hydrochloride (200 mg) obtained in Synthesis Example 4, N-bromosuccinimide (100.4 mg), and N,N-dimethylformamide (3 mL) was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the resulting solid was collected by filtration, washed with water, and dried to give the title compound (137 mg) as a yellow solid.

[0313] Synthesis Example 73 (E)-3-(2-amino-6-(cyclopropylcarbamoyl)-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-3-yl)acrylic acid tert-butyl ester A mixture of 2-amino-3-bromo-N-cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide (90 mg) obtained in Synthesis Example 72, tert-butyl acrylate (98.3 μL), palladium(II) acetate (5.05 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (31.5 mg), triethylamine (125 μL), and N,N-dimethylformamide (1 mL) was stirred under microwave irradiation at 130°C for 1 hour. The reaction mixture was cooled to room temperature, and the filtered solution was concentrated under reduced pressure. The residue was purified by silica gel reverse-phase column chromatography (0.1% formic acid-acetonitrile / 0.1% aqueous formic acid solution=40 / 60→60 / 40 (v / v)) to give the title compound (0.76 mg) as a red oil.

[0314] Synthesis Example 74 6-(Cyclopropylcarbamoyl)-3-fluoro-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-2-carboxylate ethyl ester (Step A) Ethyl 4-fluoro-5-(neopentylamino)-1H-pyrazole-3-carboxylate [ka] To a mixture of ethyl 5-(neopentylamino)-1H-pyrazole-3-carboxylate (1.5 g) obtained in Step A of Synthesis Example 1 and acetonitrile (60 mL), N-fluorobenzenesulfonimide (4.2 g) was added at 0°C and stirred for 3 hours and 40 minutes. After adding water, the mixture was extracted with chloroform and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / ethyl acetate = 100 / 0 → 55 / 45 (v / v)) to give the title compound (800.2 mg) as a yellow oil. LC / MS: Condition 2, retention time = 2.27 minutes LC / MS(ESI+) m / z: 244.0 [M+H] + (Step B) Ethyl 6-(cyclopropylcarbamoyl)-3-fluoro-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-2-carboxylate Substantially the same reactions as in Steps B and C of Synthesis Example 1 were carried out using 4-fluoro-5-(neopentylamino)-1H-pyrazole-3-carboxylate ethyl obtained in Step A of Synthesis Example 74 instead of 5-(neopentylamino)-1H-pyrazole-3-carboxylate ethyl obtained in Step A of Synthesis Example 1 to give the title compound (109.28 mg) as a red solid.

[0315] The compounds of Synthesis Examples 75 to 79 were produced according to the methods shown in the above Synthesis Examples or methods similar thereto.

[0316] Synthesis Example 75 N6-Cyclopropyl-3-fluoro-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-2,6-dicarboxamide Yield: 22.29 mg, white solid

[0317] Synthesis Example 76 2-Amino-N-cyclopropyl-3-fluoro-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide Yield: 220 mg, white solid

[0318] Synthesis Example 77 N-Cyclopropyl-3-fluoro-7-hydroxy-4-neopentyl-5-oxo-2-ureido-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide Yield: 1.99 mg, yellow solid

[0319] Synthesis Example 78 2-Amino-N-cyclopropyl-7-hydroxy-4-isobutyl-5-oxo-3-(1,2,3,6-tetrahydropyridin-4-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide dihydrochloride Yield: 2.49 mg, white solid

[0320] Synthesis Example 79 2-Amino-N-cyclopropyl-3-(3,6-dihydro-2H-pyran-4-yl)-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide Yield: 1.99 mg, white solid

[0321] Synthesis Example 80 tert-Butyl 4-(6-(cyclopropylcarbamoyl)-7-hydroxy-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate A reaction essentially similar to that in Synthesis example 24 was carried out using tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine to obtain the title compound (66.03 mg) as a brown solid.

[0322] Synthesis Example 81 N-Cyclopropyl-7-hydroxy-4-isobutyl-5-oxo-2-(1,2,3,6-tetrahydropyridin-4-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide hydrochloride A mixture of tert-butyl 4-(6-(cyclopropylcarbamoyl)-7-hydroxy-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (20 mg) obtained in Synthesis Example 80 and 4 M hydrogen chloride in 1,4-dioxane (0.4 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and washed with ethyl acetate to give the title compound (2.93 mg) as a yellow solid.

[0323] Synthesis Example 82 tert-Butyl 4-(6-(cyclopropylcarbamoyl)-7-hydroxy-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)piperidine-1-carboxylate A mixture of tert-butyl 4-(6-(cyclopropylcarbamoyl)-7-hydroxy-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (38 mg) obtained in Synthesis Example 80, 10% palladium on carbon (19 mg, approximately 55% wet with water), and methanol (0.7 mL) was stirred under a hydrogen atmosphere at room temperature for 3 hours. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound (20 mg) as a green solid.

[0324] The compounds of Synthesis Examples 83 to 87 were produced according to the methods shown in the above Synthesis Examples or methods similar thereto.

[0325] Synthesis Example 83 N-Cyclopropyl-7-hydroxy-4-isobutyl-5-oxo-2-(piperidin-4-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide hydrochloride Yield: 11.22 mg, white solid

[0326] Synthesis Example 84 tert-Butyl 5-(6-(cyclopropylcarbamoyl)-7-hydroxy-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate Yield: 29.85 mg, yellow solid

[0327] Synthesis Example 85 N-Cyclopropyl-7-hydroxy-4-isobutyl-5-oxo-2-(1,2,5,6-tetrahydropyridin-3-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide hydrochloride Yield: 3.16 mg, white solid

[0328] Synthesis Example 86 N-Cyclopropyl-7-hydroxy-4-isobutyl-5-oxo-2-(piperidin-3-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide hydrochloride (racemic mixture) Yield: 9.82 mg, white solid

[0329] Synthesis Example 87 (S)-N-Cyclopropyl-7-hydroxy-2-(3-hydroxypyrrolidin-1-yl)-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide Yield: 2.5 mg, brown solid

[0330] Synthesis Example 88 N-Cyclopropyl-7-hydroxy-2-(4-isopropoxypyridin-3-yl)-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide (Step A) N-cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-2-(trimethylstannyl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide [ka] A mixture of 2-bromo-N-cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide (8.43 g) obtained in Step C of Synthesis Example 11, tetrakis(triphenylphosphine)palladium(0) (2.54 g), bis(trimethyltin) (12.25 g), and toluene (200 mL) was stirred at 110°C for 1 hour under a nitrogen atmosphere. A saturated aqueous solution of potassium fluoride was added to the reaction mixture, and after filtration, the filtrate was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of potassium fluoride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 0 → 80 / 20 (v / v)) to give a yellow solid (3.8 g). In a separate batch, a mixture of 2-bromo-N-cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide (36.2 g), tetrakis(triphenylphosphine)palladium(0) (10.92 g), bis(trimethyltin) (57.25 g), and toluene (600 mL) was stirred at 110 °C for 1 hour under a nitrogen atmosphere. Saturated aqueous potassium fluoride was added to the reaction mixture, which was then filtered. The filtrate was extracted with ethyl acetate. The organic layer was washed with saturated aqueous potassium fluoride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 0 → 80 / 20 (v / v)) to give the pure compound (3.1 g) and a yellow solid containing impurities (10.3 g). A mixture of the impure yellow solid (10.3 g) and the previously obtained yellow solid (3.8 g) was washed with tert-butyl methyl ether, collected by filtration, and lyophilized together with the previously obtained pure compound (3.1 g) to obtain the title compound (13.81 g) as a yellow solid. LC / MS: Condition 4, retention time = 3.40 minutes LC / MS(ESI+) m / z: 469.4 [M+H] + (Step B) N-cyclopropyl-7-hydroxy-2-(4-isopropoxypyridin-3-yl)-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide A mixture of N-cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-2-(trimethylstannyl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide (200 mg) obtained in Step A of Synthesis Example 88, 3-bromo-4-isopropoxypyridine (186 mg), tetrakis(triphenylphosphine)palladium(0) (30.2 mg), and toluene (2 mL) was stirred overnight at 110°C under an argon atmosphere. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel reverse-phase column chromatography (acetonitrile / 10 mM aqueous ammonium bicarbonate = 36 / 64 → 63 / 37 (v / v)) to afford the title compound (34.35 mg) as an orange oil.

[0331] Synthesis Example 89 2-(6-(cyclopropylcarbamoyl)-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetic acid ethyl ester A mixture of 2-bromo-N-cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide (191.6 mg) obtained in Step C of Synthesis Example 11, ethyl acetoacetate (126 mg), palladium(II) acetate (11.22 mg), 2-di-tert-butylphosphino-2'-methylbiphenyl (31.24 mg), tripotassium phosphate (424.5 mg), and toluene (2 mL) was stirred overnight at 110°C under an argon atmosphere. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 95 / 5 → 70 / 30 (v / v)) to afford the title compound (135 mg) as a brown solid.

[0332] Synthesis Example 90 2-(2-amino-2-oxoethyl)-N-cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide A mixture of ethyl 2-(6-(cyclopropylcarbamoyl)-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetate (50 mg) obtained in Synthesis Example 89, lithium hydroxide monohydrate (10.7 mg), 1,4-dioxane (1 mL), and water (1 mL) was stirred at 60°C for 1.5 hours. The reaction mixture was cooled to room temperature, and 2 M aqueous hydrochloric acid was added. The resulting white solid was collected by filtration and dried under reduced pressure. A mixture of the resulting white solid (30 mg), 1-hydroxy-1H-benzotriazole ammonium salt (31.6 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (39.9 mg), and N,N-dimethylacetamide (0.6 mL) was stirred at room temperature overnight. Water was added to the reaction mixture, which was then extracted with chloroform and concentrated under reduced pressure. The residue was purified by silica gel reverse-phase column chromatography (0.1% formic acid-acetonitrile / 0.1% aqueous formic acid solution=40 / 60→70 / 30 (v / v)) to give the title compound (2.1 mg) as a yellow oil.

[0333] Synthesis Example 91 N-Cyclopropyl-7-hydroxy-2-(2-hydroxyethyl)-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide To a mixture of lithium aluminum hydride (14.6 mg) and tetrahydrofuran (1 mL), ethyl 2-(6-(cyclopropylcarbamoyl)-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetate (50 mg) obtained in Synthesis Example 89 was added at 0°C, followed by stirring for 1 hour. Sodium sulfate decahydrate was added carefully at room temperature, followed by stirring at room temperature. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound (3.26 mg) as a yellow oil.

[0334] Synthesis Example 92 tert-Butyl 5-(6-(cyclopropylcarbamoyl)-7-hydroxy-5-oxo-4-((tetrahydro-2H-pyran-4-yl)methyl)-4,5-dihydropyrazolo[1,5-a]pyrimidin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate A mixture of 3-bromo-N-cyclopropyl-7-hydroxy-5-oxo-4-((tetrahydro-2H-pyran-4-yl)methyl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide (100 mg) obtained in Step C of Synthesis Example 34, tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (112.8 mg), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (7.9 mg), potassium carbonate (100.8 mg), water (1 mL), and 1,4-dioxane (1 mL) was refluxed overnight under an argon atmosphere. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel reverse-phase column chromatography (0.1% formic acid-acetonitrile / 0.1% aqueous formic acid solution=50 / 50→80 / 20 (v / v)) to give the title compound (53.4 mg) as a brown amorphous substance.

[0335] Synthesis Example 93 N-Cyclopropyl-7-hydroxy-5-oxo-4-((tetrahydro-2H-pyran-4-yl)methyl)-3-(1,2,5,6-tetrahydropyridin-3-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide hydrochloride A mixture of tert-butyl 5-(6-(cyclopropylcarbamoyl)-7-hydroxy-5-oxo-4-((tetrahydro-2H-pyran-4-yl)methyl)-4,5-dihydropyrazolo[1,5-a]pyrimidin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate (47.3 mg) obtained in Synthesis Example 92 and 4 M hydrogen chloride in 1,4-dioxane (0.5 mL) was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (43.7 mg) as a brown amorphous substance.

[0336] Synthesis Example 94 N-Cyclopropyl-7-hydroxy-3-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-5-oxo-4-((tetrahydro-2H-pyran-4-yl)methyl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide A mixture of N-cyclopropyl-7-hydroxy-5-oxo-4-((tetrahydro-2H-pyran-4-yl)methyl)-3-(1,2,5,6-tetrahydropyridin-3-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide hydrochloride (31.9 mg) obtained in Synthesis Example 93, formic acid (0.076 mL), and 37% aqueous formaldehyde solution (0.163 mL) was stirred at 80° C. for 3 hours. The reaction mixture was cooled to room temperature, and chloroform was added, followed by saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. To the residue were added formic acid (0.076 mL) and 37% aqueous formaldehyde solution (0.163 mL), and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was cooled to room temperature, and chloroform was added, followed by saturated aqueous sodium bicarbonate solution. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel reverse-phase column chromatography (0.1% formic acid-acetonitrile / 0.1% formic acid aqueous solution = 10 / 90 → 30 / 70 (v / v)) to give the title compound (8.68 mg) as a pale yellow amorphous solid.

[0337] Synthesis Example 95 4-((2-bromo-6-(cyclopropylcarbamoyl)-7-hydroxy-5-oxopyrazolo[1,5-a]pyrimidin-4(5H)-yl)methyl)-3,5-dichlorobenzoate Reactions were carried out in essentially the same manner as in Step A, Step B, and Step C of Synthesis example 11, except that methyl 3,5-dichloro-4-formylbenzoate was used instead of pivalaldehyde, to give the title compound (890 mg) as a brown solid.

[0338] Synthesis Example 96 2-Bromo-N-cyclopropyl-4-(2,6-dichloro-4-(hydroxymethyl)benzyl)-7-hydroxy-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide A mixture of methyl 4-((2-bromo-6-(cyclopropylcarbamoyl)-7-hydroxy-5-oxopyrazolo[1,5-a]pyrimidin-4(5H)-yl)methyl)-3,5-dichlorobenzoate (890 mg) obtained in Synthesis Example 95 and tetrahydrofuran (9 mL) was stirred at 0° C. for 30 minutes, and then lithium aluminum hydride (95.6 mg) was added at 0° C. and stirred for 3 hours until the temperature reached room temperature. Sodium sulfate decahydrate was added carefully at room temperature, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound (648.3 mg) as an orange solid.

[0339] Synthesis Example 97 2-(2-aminopyridin-3-yl)-N-cyclopropyl-4-(2,6-dichloro-4-(hydroxymethyl)benzyl)-7-hydroxy-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide A mixture of 2-bromo-N-cyclopropyl-4-(2,6-dichloro-4-(hydroxymethyl)benzyl)-7-hydroxy-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide (100.4 mg) obtained in Synthesis Example 96, 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (88.0 mg), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (13.0 mg), potassium carbonate (82.9 mg), water (3 mL), and 1,4-dioxane (3 mL) was stirred under an argon atmosphere at 110° C. for 12 hours and 45 minutes. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel reverse-phase column chromatography (0.1% formic acid-acetonitrile / 0.1% aqueous formic acid solution=30 / 70→40 / 60 (v / v)) to give the title compound (9.4 mg) as a pale brown solid.

[0340] Synthesis Example 98 2-Acetamido-N-cyclopropyl-7-hydroxy-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide A mixture of 2-bromo-N-cyclopropyl-7-hydroxy-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide (50 mg) obtained in Step C of Synthesis Example 22, (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (1.9 mg), copper(I) iodide (2.6 mg), potassium carbonate (74.6 mg), acetic acid (8.3 μL), and 1,4-dioxane (1 mL) was stirred at 110°C for 15 hours under an argon atmosphere. The reaction mixture was cooled to room temperature, water (0.2 mL) was added, and the mixture was stirred. Then, diatomaceous earth (200 mg) and ethyl acetate (3 mL) were added and stirred. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel reverse-phase column chromatography (0.1% formic acid-acetonitrile / 0.1% aqueous formic acid solution=50 / 50→70 / 30 (v / v)) to give the title compound (10.5 mg) as a colorless solid.

[0341] Synthesis Example 99 N-Cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-2-(2-oxoimidazolidin-1-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide A mixture of 2-bromo-N-cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide (76.7 mg) obtained in Step C of Synthesis Example 11, N1,N2-dimethylethane-1,2-diamine (52.9 mg), copper(I) iodide (38.1 mg), potassium carbonate (138.2 mg), imidazolidin-2-one (86.1 mg), and N-methylpyrrolidone (2 mL) was stirred under an argon atmosphere with microwave irradiation at 130° C. for 3 hours. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel reverse-phase column chromatography (0.1% formic acid-acetonitrile / 0.1% aqueous formic acid solution=40 / 60→70 / 30 (v / v)) to give the title compound (6.9 mg) as a pale brown solid.

[0342] Synthesis Example 100 2-(2-amino-1H-benzo[d]imidazol-1-yl)-N-cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide A mixture of 2-bromo-N-cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide (76.7 mg) obtained in Step C of Synthesis Example 11, N1,N2-dimethylethane-1,2-diamine (52.9 mg), copper(I) iodide (38.1 mg), potassium carbonate (138.2 mg), 1H-benzo[d]imidazol-2-amine (79.9 mg), and dimethyl sulfoxide (2 mL) was stirred under an argon atmosphere with microwave irradiation at 130° C. for 3 hours. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel reverse-phase column chromatography (0.1% formic acid-acetonitrile / 0.1% aqueous formic acid solution=40 / 60→70 / 30 (v / v)) to give the title compound (5.1 mg) as a brown solid.

[0343] Synthesis Example 101 2-Acetamido-N-cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide To a mixture of 2-amino-N-cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide (20 mg) obtained in Synthesis Example 18, pyridine (25 μL), N,N-dimethyl-4-aminopyridine (1.53 mg), and toluene (0.4 mL), acetic anhydride (11.8 μL) was added at room temperature and stirred for 1 hour. After adding 2M aqueous hydrochloric acid, the reaction mixture was extracted with chloroform and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 95 / 5 → 70 / 30 (v / v)) to obtain the title compound (14.69 mg) as a white solid.

[0344] Synthesis Example 102 2-Amino-N-cyclopropyl-7-hydroxy-4-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide A reaction in substantially the same manner as in Synthesis Example 18 was carried out using 2-bromo-N-cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide obtained in Step C of Synthesis Example 27 instead of 2-bromo-N-cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide obtained in Step C of Synthesis Example 11, to give the title compound (320 mg) as a brown solid.

[0345] Synthesis Example 103 N-Cyclopropyl-7-hydroxy-4-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-5-oxo-2-(2-oxoimidazolidin-1-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide To a mixture of 2-amino-N-cyclopropyl-7-hydroxy-4-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide (40 mg) obtained in Synthesis Example 102 and tetrahydrofuran (0.8 mL), 2-chloroethyl isocyanate (53.5 μL) was added at room temperature and stirred at 80°C overnight. Potassium tert-butoxide (52.0 mg) was then added to the reaction mixture, and the mixture was stirred at 80°C for 2 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with chloroform and concentrated under reduced pressure. The residue was purified by silica gel reverse-phase column chromatography (0.1% formic acid-acetonitrile / 0.1% formic acid aqueous solution = 30 / 70 → 60 / 40 (v / v)) to give the title compound (6.66 mg) as a white solid.

[0346] Synthesis Example 104 3-Bromo-N-cyclopropyl-7-hydroxy-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide Substantially the same reactions as in Steps A, B, and C of Synthesis Example 22 were carried out using 4-bromo-1H-pyrazol-5-amine instead of 3-bromo-1H-pyrazol-5-amine to give the title compound (400 mg) as a yellow solid.

[0347] Synthesis Example 105 N-Cyclopropyl-7-hydroxy-4-isobutyl-5-oxo-3-((tetrahydro-4H-pyran-4-ylidene)methyl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide To a mixture of 2,2,6,6-tetramethylpiperidine (136.2 μL) and tetrahydrofuran (0.8 mL), n-butyllithium hexane solution (532 μL, 1.55 M hexane solution) was added at 0°C. After stirring for 10 minutes, bis[(pinacolato)boryl]methane (80 mg) was added and stirred at 0°C for 30 minutes. The reaction mixture was cooled to -78°C, and tetrahydro-4H-pyran-4-one (36.74 μL) was added. The mixture was stirred at -78°C for 1 hour. The reaction mixture was warmed to room temperature and concentrated under reduced pressure. To the residue was added 3-bromo-N-cyclopropyl-7-hydroxy-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide (73.6 mg) prepared in Synthesis Example 104, [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (13 mg), potassium carbonate (82.9 mg), 1,4-dioxane (0.8 mL), and water (0.8 mL), followed by stirring at 110°C overnight. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel reverse-phase column chromatography (0.1% formic acid-acetonitrile / 0.1% formic acid aqueous solution = 60 / 30 → 70 / 30 (v / v)) to afford the title compound (1.85 mg) as a colorless oil.

[0348] Synthesis Example 106 N-Cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-2-(1H-pyrazol-1-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide A mixture of 2-bromo-N-cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide (76.7 mg) obtained in Step C of Synthesis Example 11, 1H-pyrazole (40.8 mg), copper(I) iodide (38.1 mg), potassium carbonate (110.6 mg), and N-methylpyrrolidone (2 mL) was stirred at 160°C for 3 hours under argon atmosphere with microwave irradiation. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel reverse-phase column chromatography (0.1% formic acid-acetonitrile / 0.1% formic acid aqueous solution = 60 / 40 → 70 / 30 (v / v)) to give the title compound (7.0 mg) as a light brown solid.

[0349] The compounds of Synthesis Examples 107 to 214 were produced according to the methods shown in the above Synthesis Examples or methods similar thereto.

[0350] Synthesis Example 107 N-Cyclopropyl-3-(3,6-dihydro-2H-pyran-4-yl)-7-hydroxy-4-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide Yield: 4.67 mg, brown amorphous

[0351] Synthesis Example 108 N-Cyclopropyl-7-hydroxy-5-oxo-4-((tetrahydro-2H-pyran-4-yl)methyl)-3-(2,2,6,6-tetramethyl-3,6-dihydro-2H-pyran-4-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide Yield: 50.4 mg, light brown solid

[0352] Synthesis Example 109 N-Cyclopropyl-3-(3,6-dihydro-2H-pyran-4-yl)-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide Yield: 47.6 mg, brown amorphous

[0353] Synthesis Example 110 N-Cyclopropyl-4-((4,4-difluorocyclohexyl)methyl)-3-(3,6-dihydro-2H-pyran-4-yl)-7-hydroxy-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide Yield: 49.0 mg, light brown solid

[0354] Synthesis Example 111 N-Cyclopropyl-4-(2,6-dichlorobenzyl)-3-(3,6-dihydro-2H-pyran-4-yl)-7-hydroxy-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide Yield: 28.8 mg, light brown solid

[0355] Synthesis Example 112 N-Cyclopropyl-3-(3,6-dihydro-2H-pyran-4-yl)-7-hydroxy-5-oxo-4-(2,4,6-trifluorobenzyl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide Yield: 78.0 mg, white solid

[0356] Synthesis Example 113 N-Cyclopropyl-3-(3,6-dihydro-2H-pyran-4-yl)-4-(4-fluorobenzyl)-7-hydroxy-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide Yield: 48.0 mg, white solid

[0357] Synthesis Example 114 N-Cyclopropyl-3-(3,6-dihydro-2H-pyran-4-yl)-4-(3,3-dimethylbutyl)-7-hydroxy-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide Yield: 26.6 mg, brown solid

[0358] Synthesis Example 115 tert-Butyl 4-(6-(cyclopropylcarbamoyl)-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate Yield: 20.82 mg, yellow solid

[0359] Synthesis Example 116 N-Cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-3-(1,2,3,6-tetrahydropyridin-4-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide hydrochloride Yield: 3.48 mg, yellow solid

[0360] Synthesis Example 117 (R)-N-Cyclopropyl-7-hydroxy-2-(3-hydroxypyrrolidin-1-yl)-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide Yield: 4.5 mg, brown solid

[0361] Synthesis Example 118 tert-Butyl 4-(6-(cyclopropylcarbamoyl)-7-hydroxy-5-oxo-4-((tetrahydro-2H-pyran-4-yl)methyl)-4,5-dihydropyrazolo[1,5-a]pyrimidin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate Yield: 62.15 mg, brown amorphous

[0362] Synthesis Example 119 (E)-N-Cyclopropyl-3-((ethoxyimino)methyl)-7-hydroxy-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide Yield: 8.03 mg, yellow solid

[0363] Synthesis Example 120 3-(Cyclohex-1-en-1-yl)-N-cyclopropyl-7-hydroxy-5-oxo-4-((tetrahydro-2H-pyran-4-yl)methyl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide Yield: 21.8 mg, brown solid

[0364] Synthesis Example 121 N-Cyclopropyl-3-(3,6-dihydro-2H-pyran-4-yl)-7-hydroxy-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide Yield: 23.9 mg, pale yellow amorphous

[0365] Synthesis Example 122 N-Cyclopropyl-7-hydroxy-4-isobutyl-5-oxo-3-(1,2,3,6-tetrahydropyridin-4-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide hydrochloride Yield: 1.43 mg, brown amorphous

[0366] Synthesis Example 123 N-Cyclopropyl-7-hydroxy-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide Yield: 3.4 mg, white solid

[0367] Synthesis Example 124 4-(Cyclohexylmethyl)-N-cyclopropyl-3-(3,6-dihydro-2H-pyran-4-yl)-7-hydroxy-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide Yield: 54.9 mg, light brown amorphous

[0368] Synthesis Example 125 N-Cyclopropyl-7-hydroxy-4-isobutyl-5-oxo-3-(pyridin-2-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide Yield: 45.02 mg, brown solid

[0369] Synthesis Example 126 N-Cyclopropyl-3-(3,6-dihydro-2H-pyran-4-yl)-4-(2-ethylbutyl)-7-hydroxy-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide Yield: 42.5 mg, light brown amorphous

[0370] Synthesis Example 127 N-Cyclopropyl-7-hydroxy-5-oxo-3-(pyridin-2-yl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide Yield: 65.11 mg, brown solid

[0371] Synthesis Example 128 N-Cyclopropyl-7-hydroxy-4-isobutyl-5-oxo-3-(6-(trifluoromethyl)pyridin-3-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide Yield: 2.71 mg, brown amorphous

[0372] Synthesis Example 129 N-Cyclopropyl-7-hydroxy-4-isobutyl-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide Yield: 5.9 mg, pale yellow amorphous

[0373] Synthesis Example 130 N-Cyclopropyl-7-hydroxy-4-isobutyl-5-oxo-3-(piperidin-4-ylidenemethyl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide hydrochloride Yield: 5.73 mg, yellow solid

[0374] Synthesis Example 131 N-Cyclopropyl-7-hydroxy-5-oxo-3-phenyl-4-((tetrahydro-2H-pyran-4-yl)methyl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide Yield: 26.24 mg, brown amorphous

[0375] Synthesis Example 132 (E)-N-Cyclopropyl-7-hydroxy-4-isobutyl-3-(((2-morpholino-2-oxoethoxy)imino)methyl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide Yield: 27.27 mg, white solid

[0376] Synthesis Example 133 3-(Cyclohex-1-en-1-yl)-N-cyclopropyl-7-hydroxy-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide Yield: 1.1 mg, pale yellow amorphous

[0377] Synthesis Example 134 N-Cyclopropyl-7-hydroxy-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-oxo-4-((tetrahydro-2H-pyran-4-yl)methyl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide Yield: 9.13 mg, pale yellow solid

[0378] Synthesis Example 135 N,2-Dicyclopropyl-7-hydroxy-5-oxo-4-((tetrahydro-2H-pyran-4-yl)methyl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide Yield: 1900.1 mg, light brown solid

[0379] Synthesis Example 136 4-(6-(cyclopropylcarbamoyl)-7-hydroxy-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-3-yl)benzoic acid methyl ester Yield: 12.32 mg, brown amorphous

[0380] Synthesis Example 137 tert-Butyl 4-(6-(cyclopropylcarbamoyl)-7-hydroxy-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate Yield: 14.51 mg, brown amorphous

[0381] Synthesis Example 138 N-Cyclopropyl-4-(2,6-dichlorobenzyl)-7-hydroxy-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide Yield: 10.7 mg, brown solid

[0382] Synthesis Example 139 N-Cyclopropyl-4-(4-fluorobenzyl)-7-hydroxy-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide Yield: 37.7 mg, light brown solid

[0383] Synthesis Example 140 N-Cyclopropyl-7-hydroxy-5-oxo-4-((tetrahydro-2H-pyran-4-yl)methyl)-3-(1,2,3,6-tetrahydropyridin-4-yl...

Claims

1. Formula (I) 【Chemistry 1】 [In the formula, R １ represents an optionally substituted hydrocarbon group; R ２ and R ３ each independently represents a hydrogen atom or an optionally substituted C １－６ represents an alkyl group; R ４ represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group; X and Y are bonded to each other and together with the respective carbon atoms to which X and Y are attached form an optionally substituted 5- to 7-membered ring; Or, X is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, an optionally substituted amino group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, or Formula -CR ５ =NR ６ represents a group represented by Y is a hydrogen atom, a halogen atom, a cyano group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, or a group of the formula -CR ７ =NR ８ represents a group represented by R ５ and R ７ are each independently a hydrogen atom or C １－６ represents an alkyl group; R ６ and R ８ each independently represents an optionally substituted hydroxy group. however, When X is a hydrogen atom, Y is not a hydrogen atom; When Y is a hydrogen atom, X is not a hydrogen atom. A compound represented by the following formula (1): a tautomer of said compound, or a pharma- ceutically acceptable salt thereof, or a solvate thereof.

2. X is a hydrogen atom, a halogen atom, an optionally substituted amino group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, or Formula -CR ５ =NR ６ represents a group represented by Y is a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, or a group represented by the formula -CR ７ =NR ８ R represents a group represented by ５ , R ６ , R ７ , R ８ is as defined in claim 1, with the proviso that When X is a hydrogen atom, Y is not a hydrogen atom; When Y is a hydrogen atom, X is not a hydrogen atom.

2. The compound according to claim 1, a tautomer of the compound, or a pharma- ceutically acceptable salt thereof, or a solvate thereof.

3. R ２ and R ３ is a hydrogen atom, a tautomer of the compound, or a medicamentically acceptable salt or solvate thereof according to claim 1 or 2.

4. R １ is optionally substituted C ３－１０ The compound according to any one of claims 1 to 3, which is a cycloalkyl group, a tautomer of the compound, or a medicamentically acceptable salt thereof, or a solvate thereof.

5. R ４ is a hydroxy group, a halogen atom and C １－６ C which may be substituted with one or more substituents independently selected from the group consisting of alkoxy groups １－６ The compound according to any one of claims 1 to 4, which is an alkyl group, a tautomer of the compound, or a medicamentically acceptable salt or solvate thereof.

6. R ４ but, C which may be substituted with one or more substituents independently selected from the group consisting of halogen atoms and hydroxy groups; １－６ Alkyl groups, C which may be substituted with one or more substituents independently selected from the group consisting of halogen atoms and hydroxy groups; １－６ Alkoxy groups, Halogen atoms, Hydroxy groups and C １－６ Alkoxy-carbonyl group C, each of which may be substituted with one or more substituents independently selected from the group consisting of ３－１０ Cycloalkyl group, C ６－１４ The compound according to any one of claims 1 to 4, which is an aryl group or a 3- to 14-membered non-aromatic heterocyclic group, a tautomer of the compound, a medicamentarily acceptable salt thereof, or a solvate thereof.

7. X is an optionally substituted amino group; 7. The compound according to any one of claims 2 to 6, wherein Y is a hydrogen atom or a fluorine atom, a tautomer of the compound, a medicamentically acceptable salt thereof, or a solvate thereof.

8. X is an optionally substituted heterocyclic group; 7. The compound according to any one of claims 2 to 6, wherein Y is a hydrogen atom, a tautomer of the compound, a medicamentically acceptable salt thereof, or a solvate thereof.

9. X is an acyl group; 7. The compound according to any one of claims 2 to 6, wherein Y is a hydrogen atom or a fluorine atom, a tautomer of the compound, a medicamentically acceptable salt thereof, or a solvate thereof.

10. X is a hydrogen atom; 7. The compound according to claim 2, wherein Y is an optionally substituted hydrocarbon group, a tautomer of the compound, or a medicamentically acceptable salt or solvate thereof.

11. X is a hydrogen atom; 7. The compound according to claim 2, wherein Y is an optionally substituted heterocyclic group, a tautomer of the compound, or a medicamentically acceptable salt or solvate thereof.

12. X is an amino group or C １－６ an alkylamino group; 7. The compound according to claim 2, wherein Y is an optionally substituted hydrocarbon group, a tautomer of the compound, or a medicamentically acceptable salt or solvate thereof.

13. X is C １－６ is an alkyl group; 7. The compound according to claim 2, wherein Y is an optionally substituted hydrocarbon group, a tautomer of the compound, or a medicamentically acceptable salt or solvate thereof.

14. X and Y are bonded to each other and together with the carbon atoms to which X and Y are bonded form an optionally substituted 5- to 7-membered ring, and are represented by the following formula (ia), (ib), (ic), (id) or (ie): 【Chemistry 2】 (wherein α represents the carbon atom to which X is bonded, and β represents the carbon atom to which Y is bonded; Z is a single bond, -CH ２ -, -O-, -OCH ２ -(O is bonded to a carbonyl group, CH ２ is bonded to the other carbon atom.) or -NR 11 - indicates; R 11 is optionally halogenated C １－６ Alkyl group, optionally halogenated C ３－６ a cycloalkyl group, a 4- to 10-membered non-aromatic heterocyclic group, or a C substituted with a 4- to 10-membered non-aromatic heterocyclic group; １－６ represents an alkyl group; W represents CH or a nitrogen atom; R 1２ is a hydrogen atom or C １－６ represents an alkoxy group; R 1３ is a hydrogen atom, an optionally halogenated C １－６ 2. The compound according to claim 1, wherein R is a tautomer of said compound, a medicamentically acceptable salt thereof, or a solvate thereof.

15. 2-amino-N-cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide hydrochloride, a tautomer of the compound, or a medicamentously acceptable salt thereof, or a solvate thereof.

16. (E)-N-cyclopropyl-7-hydroxy-4-isobutyl-3-(3-morpholino-3-oxoprop-1-en-1-yl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide, a tautomer of the compound, a medicamentously acceptable salt thereof, or a solvate thereof.

17. R １ is a cyclopropyl group; R ２ and R ３ is a hydrogen atom; R ４ is a tert-butyl group; X is a pyrimidin-4-ylamino group, a pyrazin-2-ylamino group, a 2-aminopyridin-3-yl group, a (5-(trifluoromethyl)pyrazin-2-yl)amino group, a (5-methoxypyrazin-2-yl)amino group, a (6-methoxypyrazin-2-yl)amino group, an amino group, a (5-carbamoylpyrazin-2-yl)amino group, a ureido group, or a carbamoyl group; The compound according to claim 2, wherein Y is a hydrogen atom, a tautomer of the compound, a medicamentically acceptable salt thereof, or a solvate thereof.

18. N-cyclopropyl-7-hydroxy-4-isobutyl-5-oxo-2-(pyrazin-2-ylamino)-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide, a tautomer of the compound, a medicamentously acceptable salt thereof, or a solvate thereof.

19. (E)-2-amino-N-cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-3-(2-(tetrahydro-2H-pyran-4-yl)vinyl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide hydrochloride, a tautomer of the compound, or a medicamentously acceptable salt thereof, or a solvate thereof.

20. (E)-N-cyclopropyl-3-(3-(3,3-difluoropyrrolidin-1-yl)-3-oxoprop-1-en-1-yl)-7-hydroxy-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide, a tautomer of the compound, or a medicamentously acceptable salt thereof, or a solvate thereof.

21. N-cyclopropyl-3-((E)-3-((3S,5S)-3,5-dimethylmorpholino)-3-oxoprop-1-en-1-yl)-7-hydroxy-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide, a tautomer of the compound, a medicamentously acceptable salt thereof, or a solvate thereof.

22. (S,E)-N-cyclopropyl-3-(3-(3-fluoropyrrolidin-1-yl)-3-oxoprop-1-en-1-yl)-7-hydroxy-4-isobutyl-2-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide, a tautomer of the compound, or a medicamentously acceptable salt thereof, or a solvate thereof.

23. N-cyclopropyl-3-((E)-3-((3S,5S)-3,5-dimethylmorpholino)-3-oxoprop-1-en-1-yl)-7-hydroxy-4-isobutyl-2-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide, a tautomer of the compound, a medicamentously acceptable salt thereof, or a solvate thereof.

24. (S,E)-N-cyclopropyl-7-hydroxy-4-isobutyl-2-methyl-3-(3-(3-methylmorpholino)-3-oxoprop-1-en-1-yl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide, a tautomer of the compound, a medicamentously acceptable salt thereof, or a solvate thereof.

25. N-cyclopropyl-3-((E)-3-((3R,5R)-3,5-dimethylmorpholino)-3-oxoprop-1-en-1-yl)-7-hydroxy-4-isobutyl-2-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide, a tautomer of the compound, a medicamentarily acceptable salt thereof, or a solvate thereof.

26. (E)-N-cyclopropyl-3-(3-(4,4-difluoropiperidin-1-yl)-3-oxoprop-1-en-1-yl)-7-hydroxy-4-isobutyl-2-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide, a tautomer of the compound, or a medicamentously acceptable salt thereof, or a solvate thereof.

27. (E)-N-cyclopropyl-3-(3-(4-(3,3-difluorocyclobutyl)piperazin-1-yl)-3-oxoprop-1-en-1-yl)-7-hydroxy-4-isobutyl-2-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide, a tautomer of the compound, or a medicamentously acceptable salt thereof, or a solvate thereof.

28. 28. A sepiapterin reductase inhibitor comprising the compound according to any one of claims 1 to 27, a tautomer of the compound, or a pharma- ceutical acceptable salt or solvate thereof as an active ingredient.

29. A drug for preventing, treating and / or improving a disease for which sepiapterin reductase inhibitory activity is effective, comprising as an active ingredient a compound according to any one of claims 1 to 27, a tautomer of the compound, or a pharma- ceutical acceptable salt or solvate thereof.

30. 28. A therapeutic agent for pain comprising the compound according to any one of claims 1 to 27, a tautomer of said compound, or a pharma- ceutical acceptable salt or solvate thereof as an active ingredient.

31. 28. A medicine comprising the compound according to any one of claims 1 to 27, a tautomer of said compound, or a pharma- ceutically acceptable salt or solvate thereof as an active ingredient.

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