TW201345908A - A pyrazolo [1,5-a] pyrimidine compound - Google Patents

Abstract

The present invention provides a pyrazolo [1, 5-a] pyrimidine compound, having CB1 receptor-antagonizing activity, of the following formula [I]: in which R1 and R2 are the same or different and each an optionally substituted aryl group etc, R0 is hydrogen atom, an alkyl group etc, E is a group of the formula: -C(=O)- or -SO2-, R is a group of the following formula [i], [ii] or [iii] etc: Ring A is (a) a C3-8 cycloalkyl group optionally fused to a benzene ring or (b) a benzene ring, Q is a single bond or a methylene group, Ring B is a 4- to 7-membered aliphatic heterocyclic group, said cyclic group binding via its ring-carbon atom to the adjacent nitrogen atom, X is sulfur atom etc, R3 is an alkyl group optionally substituted by an alkylthio group, R4 is hydrogen atom, an alkyl group etc, one of RA and RB is an alkyl group etc, and the other is hydrogen atom, an alkyl group etc, or a pharmaceutically acceptable salt thereof.

Description

Pyrazolo[1,5-a]pyrimidine compound

The present invention relates to a novel pyrazolo[1,5-a]pyrimidine compound or a pharmaceutically acceptable salt thereof which has potent central cannabinoid receptor (CB1) antagonistic activity and is therefore useful as a medicament.

It is well known that by ingesting marijuana, a variety of mental reactions or neurological reactions such as a sense of time or spatial dissonance, euphoria, memory changes, analgesia, hallucinations, and the like may occur. Compounds commonly known as "marijuana" include delta 9-tetrahydro-cannabinol (delta 9-THC) responsible for a variety of such reactions. The role of cannabis is thought to result from the interaction between the compound and its endogenous specific/high affinity receptor. Two cannabinoid receptor subtypes (CB1 and CB2) have been identified and transferred. The CB1 receptor system is distributed in various regions of the central nervous system (CNS) including the brain (Nature, vol. 346, 1990, pp561-564), while the CB2 receptor system is distributed in the immune system including the spleen (Nature, Vol. 365, 1993, pp61). -65).

Substances that have affinity for such cannabinoid receptors (agonists, antagonists or anti-agonists) can produce a variety of pharmacological effects similar to cannabis. In particular, substances having affinity for the central CB1 receptor can be used to treat CNS diseases such as psychiatric disorders, neurological disorders and the like.

A variety of compounds are known to include pyrazol-3-carboxamide compounds such as SR141716 (Life Science, Vol. 63, 1998, PL 113-117), 4, 5- Dihydro-pyrazole compounds such as SLV-319 (Journal of Medicinal Chemistry, Vol. 47 (3), 2004, p. 627-643), dihydropyrazolo[3,4-c]pyridine-7-one compounds 2H-pyrazolo[4,3-d]-pyrimidin-7(6H)-one compound (WO2004/094417), 1-[2- and/or 3-(substituted aryl)-pyrazole A [1,5-a]pyrimidin-7-yl]piperidine compound (WO2004/069838) or the like is a substance having affinity for such a cannabinoid receptor. At the same time, the applicant of the present application filed a patent application for pyrazol [1,5-a] pyrimidine-3-carboxamide or sulfonamide compound. Case (WO2007/046548). Among them, at least SR141716 and SLV-319 were used as clinical studies for the efficacy of anorexigenics (anti-obesity agents).

It is an object of the present invention to provide a novel pyrazolo[1,5-a]pyrimidine compound which has potent CB1 receptor antagonistic activity and thus can be used as a medicament.

The present invention relates to a novel pyrazolo[1,5-a]pyrimidine compound of the formula [I] or a pharmaceutically acceptable salt thereof: Wherein R ¹ and R ² are the same or different, each of which is optionally substituted aryl or optionally substituted saturated or unsaturated heterocyclic group, and R ⁰ is (a) a hydrogen atom; (b) An alkyl group substituted with 1 to 3 halogen atoms; (c) an alkyloxyalkyl group; (d) a group of the formula: -CON(R ^e )(R ^f ); (e) an alkane a group, the amine moiety of the group being optionally substituted with 1 to 2 alkyl groups; (f) an amine group optionally substituted with a group selected from the group consisting of an alkyl group, an alkylcarbonyl group and an alkylsulfonyl group; (g) 4 to 6 membered nitrogen-containing aliphatic heterocyclic groups; (h) a group of the formula: -SO ₂ N(R ⁰¹ )(R ⁰² ); (i) a group of the formula :-NHCONHR ⁰³ ; (j) alkoxy group substituted by a hydroxyl group as required; (k) hydroxyalkyl group; or (l) carboxyl group, R ^e and R ^f are the same or different and each is a hydrogen atom, an alkyl group or a dialkylamino group, R ⁰¹ and R ⁰² are the same or different and each is a hydrogen atom, an alkyl group or a carbamoylalkyl group, R ⁰³ is a hydrogen atom or an alkyl group, and E is a group of the formula :-C(=O)- or -SO ₂ -, R is (A) a group of the following formula [i], [ii] or [iii]: At this time, R ⁰ is (a) a hydrogen atom; (b) an alkyl group substituted with 1 to 3 halogen atoms as needed; (c) an alkoxyalkyl group; (e) an aminoalkyl group, an amine of the group The base moiety is optionally substituted with 1 to 2 alkyl groups; (f) an amine group optionally substituted with a group selected from an alkyl group, an alkylcarbonyl group and an alkylsulfonyl group; (g) 4 to 6 a nitrogen-containing aliphatic heterocyclic group; or (j) an alkoxy group optionally substituted by a hydroxyl group, and (B) (a) an alkoxy group or (b) a group of the formula: -N(R ⁵ )(R ⁶ And, at this time, R ⁰ is a group of the formula: -SO ₂ N(R ⁰¹ )(R ⁰² ); a group of the formula: -NHCONHR ⁰³ ; a group of the formula: -CON(R ^e )(R ^f ); Carboxy or hydroxyalkyl, ring A is (a) optionally fused to the C _3-8 cycloalkyl group of the phenyl ring or (b) benzene ring, Q is a single bond or methylene, ring B is 4 To 7 members of an aliphatic heterocyclic group, the ring system is bonded to an adjacent nitrogen atom through its ring carbon atom, X is a sulfur atom, a group of the formula: -SO-, a group of the formula:- SO ₂ -, an oxygen atom or a group of the formula: -NR ^k -, R ^k is alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, optionally substituted by 1 or 2 alkyl groups Amine sulfonate, or as needed Or two of the alkyl amine substituted acyl (carbamoyl), R ³ is (a) an optionally selected from hydroxy, amino, acyl group (acylamino), carbamoyl dialkyl acyl - group a (dialkylcarbamoyl-amino group), an alkylsulfonyl-amino group, and a substituted alkyl group in a dialkylsulfamoyl-amino group; (b) a cyano group; (c) a carboxyl group; (d) an alkoxycarbonyl group; (e) a group of the formula: -N(R ^a )(R ^b ); (f) a group of the formula: -CON(R ^a )( R ^b ); (g) a group of the formula: or (h) a hydroxyl group, R ^a and R ^b are the same or different and each is a hydrogen atom, a hydroxyl group, a cyano group, an alkyl group, a cyanoalkyl group, a trihalogenoalkyl group, a hydroxyalkyl group, an alkoxyalkyl group. a group, a cycloalkyl group, a decyl group, an alkylsulfonyl group or an aminoalkyl group (the amine moiety of the group is optionally substituted by 1 or 2 alkyl groups), or both R ^a and R ^b are The terminal is bonded to form a saturated or unsaturated nitrogen-containing heterocyclic group which is selected from a sulfur atom and a hetero atom other than the nitrogen atom, and R ⁴ is (a) hydrogen. (b) alkyl; (c) cyano; (d) carboxy; (e) alkylcarbonyl; (f) alkoxycarbonyl; (g) group of the formula: -CON(R ^c ) (R ^d ); (h) phenyl; (i) benzyl; or (j) mercaptoamine, R ^c and R ^d are the same or different and each is a hydrogen atom or an alkyl group, in R ^A and R ^B One is (a) an alkyl group substituted with a hydroxyl group, an alkoxy group, an amine group, an alkylamino group or a dialkylamino group, if necessary; (b) one to two, if necessary, selected from a halogen atom, the substituted alkoxy and trihalomethyl group of a phenyl group; (c) benzyl; (d) heteroaryl; or (e) cycloalkyl and R ^A and R ^B The other is (a) hydrogen; or (b) is optionally substituted by hydroxyl, alkoxy, amino, alkyl or dialkyl substituted amino group of the alkyl group, R ⁵ and R ⁶ are as follows: (A) one of R ⁵ and R ⁶ is a hydrogen atom or an alkyl group, and the other is (a) an alkyl group which is optionally substituted with 1 to 3 groups selected from the group consisting of a halogen atom and a hydroxyl group. , cyano group, alkoxy group, cycloalkyl group, amine group optionally substituted by 1 or 2 alkyl groups, alkylthio group, alkylsulfinyl group, alkylsulfonyl group, fluorenyl group , optionally substituted aryl and optionally substituted saturated or unsaturated heterocyclic groups; (b) optionally substituted cycloalkyl; (c) group of the formula: -N(R ⁸ )(R ⁹ ); (d) an optionally substituted aryl group; or (e) optionally substituted saturated or unsaturated heterocyclic group, or (B) both R ⁵ and R ⁶ are bonded to each other at their ends The ortho nitrogen atoms together form a saturated or unsaturated nitrogen-containing heterocyclic group, one of R ⁸ and R ⁹ is a hydrogen atom or an alkyl group, and the other is (a) optionally 1 to 3 selected from An alkyl group substituted with a halogen atom, a cyano group, and an aryl group; (b) a ring which is optionally substituted (c) an optionally substituted aryl group; (d) a fluorenyl group; or (e) a substituted or unsaturated heterocyclic group, if desired, but excluding 6-phenyl-7-(4-chlorobenzene 3-(N-isopropylaminecarbamimido)-pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3 -(N-isopropylaminemethanyl)-pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[N- (4-cyano-4-tetrahydrothiopyranyl)amine-carbamoyl]pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorophenyl -3-[N-(α-dimethylbenzyl)amine-carbamoyl]pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorobenzene 3-[N-(α-methylbenzyl)amine-carbamoyl]pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorobenzene 3-[N-[1-(2-pyridyl)ethyl]amine-carbamoyl]pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-( 4-trifluoromethylphenyl)-3-[N-[1-(2-pyridyl)ethyl]aminemethanyl]pyrazolo[1,5-a]pyrimidine; 6-(2-chloro Phenyl)-7-(4-chlorophenyl)-3-[N-(4-cyanobenzyl)aminemethanyl]pyrazolo[1,5-a]pyrimidine; and 6-(2- Chlorophenyl)-7-(4-chlorophenyl)-3-[N-(1,1-dionetetrahydro-thiophen-3-yl)aminemethanyl]pyrazolo[1,5- a] pyrimidine.

As an example, the invention includes a compound of formula [II] or a pharmaceutically acceptable salt thereof: Wherein R ^0A is (a) a hydrogen atom; (b) an alkyl group substituted with 1 to 3 halogen atoms as required; (c) an alkoxyalkyl group; (d) an aminoalkyl group, an amine group of the group Partially substituted with 1 to 2 alkyl groups; (e) an amine group optionally substituted with a group selected from an alkyl group, an alkylcarbonyl group and an alkylsulfonyl group; (f) 4 to 6 members a nitrogen-containing aliphatic heterocyclic group; or (g) an alkoxy group optionally substituted by a hydroxyl group, and R' is a group of the following formula [i], [ii] or [iii]: And other symbols are the same as defined above, but exclude 6-phenyl-7-(4-chlorophenyl)-3-(N-isopropylaminemethanyl)-pyrazolo[1,5-a] Pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-(N-isopropylaminecarbamimido)-pyrazolo[1,5-a]pyrimidine; 6- (2-Chlorophenyl)-7-(4-chlorophenyl)-3-[N-(4-cyano-4-tetrahydrothiopiperidyl)aminecarboxylidene]pyrazolo[1,5 -a]pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[N-(α-dimethylbenzyl)aminemethanyl]pyrazolo[1, 5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[N-(α-methylbenzyl)aminemethanyl]pyrazolo[1, 5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[N-[1-(2-pyridyl)ethyl]aminemethylmercapto]pyrazole And [1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-trifluoromethylphenyl)-3-[N-[1-(2-pyridyl)ethyl] Aminomethyl]pyrazolo[1,5-a]pyrimidine; and 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[N-(4-cyanobenzyl) Aminomethylpyrazine]pyrazolo[1,5-a]pyrimidine.

Further, as another embodiment, the present invention also includes a compound of the formula [I-II] or a pharmaceutically acceptable salt thereof: Wherein R ^0B is a group of the formula: -SO ₂ N(R ⁰¹ )(R ⁰² ); a group of the formula: -NHCONHR ⁰³ ; a group of the formula: -CON(R ^e )(R ^f ); a carboxyl group; A hydroxyalkyl group, R ⁰¹ and R ⁰² are the same or different and each are a hydrogen atom, an alkyl group or an aminomethylalkyl group, R ⁰³ is a hydrogen atom or an alkyl group, and R ^e and R ^f are the same or different and Each is a hydrogen atom, an alkyl group or a dialkylamine group, R" is an alkoxy group or a group of the formula: -N(R ⁵ )(R ⁶ ) and other symbolic systems are as defined above, but excluding 6-( 2-Chlorophenyl)-7-(4-chlorophenyl)-3-[N-(1,1-dionetetrahydrothiophen-3-yl)aminecarbenyl]-2-(hydroxymethyl) Pyrazolo[1,5-a]pyrimidine.

In the case where R ¹ and/or R ² in the compound [I] of the present invention is an aryl group, examples of the aryl group include a 6- to 10-membered monocyclic or bicyclic aryl group such as a phenyl group or a naphthyl group, wherein Phenyl is preferred.

In the case where R ¹ and/or R ² in the compound [I] of the present invention is a saturated or unsaturated heterocyclic group, examples of the heterocyclic group include one selected from the group consisting of a sulfur atom, an oxygen atom and a nitrogen atom. Saturated or unsaturated to 3 heteroatoms from 5 to 7 membered heteromonocyclic groups. More specific examples of the heterocyclic group may be a 5- to 6-membered oxygen-containing heterocyclic group such as a furyl group, a tetrahydrofuranyl group, a piperidyl group or a tetrahydropyranyl group; a 5- to 6-membered sulfur-containing heterocyclic group such as a thienyl group; , tetrahydrothiophenyl, thiopyranyl or tetrahydrothiopyranyl; or a 5- to 7-membered nitrogen-containing heterocyclic group such as pyrrolidinyl, imidazolyl, pyrazolyl, Azolyl, different Azyl, thiazolyl, isothiazolyl, pyridyl, piperidinyl, pyrimidinyl, pyridyl Pyrazinyl group, 嗒 Pyridazinyl group, morpholinyl group, thiomorpholinyl, or azacycloheptyl group. Among them, a 5- to 6-membered sulfur- or nitrogen-containing heteromonocyclic group such as a thienyl group, a pyrrolidinyl group, a piperidinyl group or a pyridyl group is preferred.

The aryl group in R ¹ and/or R ² may be substituted with one or three groups selected from the same or different ones selected from the group consisting of a halogen atom, a cyano group, and optionally an alkyl group substituted with 1 to 3 halogen atoms. An alkoxy group optionally substituted with 1 to 3 halogen atoms, an amine group substituted with 1 to 2 alkyl groups as needed, an alkylthio group, an alkylsulfinyl group, and an alkylsulfonyl group.

The saturated or unsaturated heterocyclic group in R ¹ and/or R ² may be substituted with 1 to 3 groups selected from the same or different ones selected from the group consisting of a halogen atom, a cyano group, a ketone group, and optionally 1 to 3 halogen-substituted alkyl groups, alkoxyalkyl groups, alkoxy groups optionally substituted with 1 to 3 halogen atoms, alkoxyalkoxy groups, optionally substituted with 1 to 2 alkyl groups Amino, alkylthio, alkylsulfinyl, and alkylsulfonyl.

In the case where R ⁰ or R ^0A in the compound [I] of the present invention is a 4- to 6-membered nitrogen-containing aliphatic heterocyclic group, examples of the aliphatic heterocyclic group include an azetidyl group and a pyrrolidinyl group. Imidazolidinyl, piperidinyl, piperidine Piperazinyl group and morpholinyl.

Examples of the saturated or unsaturated nitrogen-containing heterocyclic group in R ³ [the group of the formula: -N(R ^a )(R ^b ) or a group of the formula: -CON(R ^a )(R ^b )] include 5 to 6 members of a nitrogen-containing heteromonocyclic group such as pyrrolyl, pyrrolidinyl, piperidinyl, and piperidin Base, morpholinyl or thiomorpholinyl. Among them, pyrrolidinyl or morpholinyl is preferred.

In the case where R ^A or R ^B is a heteroaryl group, examples of such heteroaryl groups include 5- to 6-membered nitrogen-containing monocyclic heteroaryl groups such as pyridyl.

In the case where R ⁵ , R ⁶ , R ⁸ or R ⁹ of the compound [I] is a cycloalkyl group, the cycloalkyl group may be substituted with 1 to 2 groups selected from the group consisting of: (a) a cyano group. , (b) an alkyl group, (c) a carboxyl group, (d) an alkyloxycarbonyl group, (e) an amine group optionally substituted with 1 or 2 alkyl groups, and (f) 1 or 2 as needed Alkyl substituted amine carbenyl.

Examples of the aryl group in R ⁵ , R ⁶ , R ⁸ or R ⁹ include a 6- to 10-membered monocyclic aryl group or a bicyclic aryl group such as a phenyl group or a naphthyl group, of which a phenyl group is preferred. The aryl group may be substituted with one or two halogen atoms.

In the case where R ⁵ , R ⁶ , R ⁸ or R ⁹ is a saturated or unsaturated heterocyclic group, examples of the heterocyclic group include (a) a saturated or unsaturated 4 to 7 membered heteromonocyclic group, which is hetero The monocyclic group contains 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom; (b) is selected from the above-mentioned heteromonocyclic group and selected from a C _3-8 cycloalkyl group, 5 to 6 members. A saturated or unsaturated 8- to 15-membered nitrogen-containing bicyclic heterocyclic group formed by condensing one or two other ring-based groups of a cycloaryl group and a saturated or unsaturated 4- to 7-membered heterocyclic group. Or a tricyclic heterocyclic group containing 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom; and (c) a saturated or unsaturated 8 to 11 member nitrogen-containing spiro Spiro-heterocyclic group.

Examples of the saturated or unsaturated heterocyclic group in R ⁵ , R ⁶ , R ⁸ or R ⁹ include: (A) a saturated or unsaturated oxygen-containing or sulfur-containing heterocyclic group selected from the group consisting of furanyl and tetrahydrofuran. Base, piperidyl, tetrahydropyranyl, thiacyclobutyl group, thienyl, tetrahydrothiophenyl, thiopyranyl, tetrahydrothiopyranyl, benzofuranyl group, Dihydrobenzofuranyl, isobenzofuranyl, Chromyl group Isochromanyl group, Ethyl (chromenyl group), different An alkenyl group, a benzothienyl group, and a dihydrobenzothiophenyl group; or (B) a saturated or unsaturated nitrogen-containing heterocyclic group selected from the group consisting of an anthracenyl group, a pyrrolidinyl group, a pyrrololinyl group, Imidazolidinyl, imidazolinyl group, pyrazolidinyl, pyrazolinyl, pyrrolyl, 2H-pyrrolyl, imidazolyl, pyrazolyl, dihydropyrazolyl, thiazolidinyl, thiazolyl, Isothiazolyl, different Isozolyl group, Oxazolidinyl group, pyridyl, dihydropyridyl, tetrahydropyridyl, piperidinyl, pyridyl Base Base, pyrimidinyl, tetrahydropyrimidinyl, anthracene Base, morpholinyl, anthracene Azocinyl group, anthracycline, anthraquinone Benzoimidazolyl, benzotriazolyl, fluorenyl, isodecyl, 3H-indenyl, porphyrinyl, isoindolyl, 1H-indazolyl group , pyrrolopyridyl, pyrrolopyrimidinyl, tetrazolyl, indolyl, pteridinyl group, 4H-quine 4H-quinolizinyl group, quinolyl group, dihydroquinolyl, tetrahydroquinolyl, isoquinolyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, anthracene (phthalazinyl group), dihydroanthracene base, Naphthyridinyl group, dihydrogen Pyridyl, tetrahydrogen Pyridyl, quinoxalinyl group, quinazolinyl group, dihydrobenzothiazide Dihydrobenzoyl base, Cinnolinyl group, acridinyl group, Xanthenyl group, carbazolyl group, beta-carbolinyl group, phenanthridinyl group, acridinyl group, 5H-dihydrodibenzo 5H-dihydro-dibenzazepinyl group, and the following spiro heterocyclic group: Wherein R ^G and R ^H are the same or different and each is a hydrogen atom or an alkyl group and q and r are integers of 1 or 2.

Among the saturated or unsaturated heterocyclic groups in R ⁵ , R ⁶ , R ⁸ or R ⁹ , a preferred heterocyclic group includes a tetrahydrofuranyl group, a pyrrolyl group, a pyrrolidinyl group, a piperidinyl group, an anthranyl group, a tetrahydro group. Piperidyl, piperazine Base, morpholinyl, thiomorpholinyl, thicyclobutyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, thiazolyl, pyridyl, pyrimidinyl, porphyrinyl, pyrrolopyridinyl or tetrahydrogen Pyridyl.

Examples of the saturated or unsaturated heterocyclic group formed by the combination of R ⁵ and R ⁶ include (a) a saturated or unsaturated 4 to 7 membered heteromonocyclic group, which may contain two or more as needed. a nitrogen atom and one to two hetero atoms other than a nitrogen atom selected from an oxygen atom and a sulfur atom; (b) a saturated or unsaturated 8 to 15 membered nitrogen-containing bicyclic heterocyclic group or a tricyclic heterocyclic ring a group, which is one or two selected from the group consisting of a C _3-8 cycloalkyl group, a 5- to 6-membered monocyclic aryl group, and a saturated or unsaturated 4 to 7 membered heteromonocyclic group via the aforementioned heteromonocyclic group. Formed by condensing other ring-based groups containing from 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen; and (c) saturated or unsaturated from 8 to 11 members A nitrogen-containing spiro heterocyclic group.

Examples of the above saturated or unsaturated nitrogen-containing heterocyclic group formed by a combination of R ⁵ and R ⁶ are a saturated or unsaturated nitrogen-containing heterocyclic group selected from the group consisting of an anthracenyl group, a pyrrolidinyl group, and a pyrroline. Base, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, pyrrolyl, imidazolyl, pyrazolyl, dihydropyrazolyl, thiazolidinyl, Zyridinyl, dihydropyridyl, tetrahydropyridyl, piperidinyl, piperid , tetrahydropyrimidinyl, morpholinyl, anthracenyl heptyl, benzimidazolyl, benzotriazolyl, indolyl, isodecyl, porphyrin, isoindolyl, 1H-indole Azyl, tetrazolyl, fluorenyl, dihydroquinolyl, tetrahydroquinolyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, indoline Base, dihydroquinazolinyl, dihydrobenzothiazide Dihydrobenzoyl a group, a carbazolyl group, a beta-carboline group, a 5H-dihydrodibenzofluorenyl group, and a spiroheterocyclic group: Wherein R ^G and R ^H are the same or different and each is a hydrogen atom or an alkyl group, and q and r are integers of 1 or 2. Preferred examples of the saturated or unsaturated nitrogen-containing heterocyclic group include a saturated or unsaturated 5- to 7-membered nitrogen-containing heterocyclic group such as morpholinyl, thiomorpholinyl, piperidinyl, and piperidin. Base or anthracene ring heptyl.

Further, the saturated or unsaturated heterocyclic group in R ⁵ , R ⁶ , R ⁸ or R ⁹ or the heterocyclic group formed by combining R ⁵ and R ⁶ may be selected from the group consisting of 1 to 4 which are the same Or a different group substituted: a halogen atom, a hydroxyl group, a cyano group, a ketone group, an alkyl group, an alkyl group substituted with 1 to 3 halogen atoms, an alkoxyalkyl group, an aminoalkyl group, a cycloalkyl group, Arylalkyl, alkoxy, alkoxy substituted with 1 to 3 halogen atoms, fluorenyl group, optionally substituted with 1 to 2 alkyl groups, mercaptoamine group, alkylsulfonyl group An arylsulfonyl group substituted with 1 to 2 alkyl groups, an aryl group substituted with 1 to 2 halogen atoms as needed, and a saturated or unsaturated 5- to 6-membered nitrogen-containing heterocyclic group.

The fluorenyl group in R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ or R ⁹ may be a fluorenyl group of the formula: R ^x CO-, which is formed by removing a hydroxyl group from a carboxylic acid of the formula: R ^x -COOH [Ac-1] wherein R ^x is (a) a hydrogen atom, and (b) is optionally substituted with 1 to 3 groups selected from a halogen atom, a cyano group, an alkylsulfonyl group and a pyridyl group. An alkyl group, (c) an alkoxy group optionally substituted with an aryl group, (d) a cycloalkyl group, (e) optionally selected from a halogen atom, a cyano group, an alkyl group, a trihaloalkyl group, and an alkoxy group. An aryl group substituted with 1 to 2 groups in the group, (f) an amine group substituted with 1 or 2 alkyl groups as needed or (g) optionally selected from a halogen atom, a cyano group, an alkyl group, and One to two of the trihaloalkyl groups are substituted with a saturated or unsaturated 5- to 7-membered heterocyclic group. Examples of the mercapto group include (a1) a mercapto group, (b1) a C _1-6 alkylcarbonyl group such as an ethyl fluorenyl group or a propyl fluorenyl group, a trihalogen-C _1-6 alkylcarbonyl group such as a trifluoroethyl fluorenyl group, Cyano-C _1-6 alkylcarbonyl such as cyanoethyl or pyridyl-C _1-6 alkylcarbonyl such as pyridylethyl, (c1)C _1-6 alkoxycarbonyl such as methoxycarbonyl , ethoxycarbonyl, or a third butoxycarbonyl or aryl-C _1-6 alkoxycarbonyl group such as benzyloxycarbonyl, (d1)C _3-8 cycloalkylcarbonyl such as cyclopropylcarbonyl or cyclopentylcarbonyl , (e1) arylcarbonyl such as benzylidene, monohaloarylcarbonyl or dihaloarylcarbonyl such as chlorobenzylidene, fluorobenzhydryl or difluorobenzylidene; cyanoaryl-carbonyl Such as cyanobenzylidene; trihalo-C _1-6 alkylarylcarbonyl such as trifluoromethyl benzhydryl; or C _1-6 alkoxyarylcarbonyl such as methoxybenzimidyl, (f1) an amine carbaryl group, an NC _1-6 alkylamine carbhydryl group or (g1) a 5- to 6-membered heteroarylcarbonyl group (the heteroaryl group of the group is optionally selected from a halogen atom, a cyano group) , one or two of the alkyl and trihaloalkyl groups are substituted) such as furanyl, thiophenemethyl, bromothiophene Mercapto, cyanothiophenemethyl, pyridylcarbonyl, chloropyridylcarbonyl, cyanopyridylcarbonyl, trifluoromethylpyridylcarbonyl, or pyridyl Alkylcarbonyl.

As a more specific embodiment, the invention includes a compound of the formula [IIA] or a pharmaceutically acceptable salt thereof: Wherein R ¹⁰ is a group of 6 to 10 membered monocyclic aryl or bicyclic aryl groups wherein R ²⁰ are the same or different and each is (i) optionally substituted with 1 to 3 groups selected from the group consisting of halogen atoms, a cyano group, an alkyl group substituted with 1 to 3 halogen atoms, an alkoxy group optionally substituted with 1 to 3 halogen atoms, an amine group substituted with 1 to 2 alkyl groups, an alkylthio group, Alkylsulfinyl and alkylsulfonyl or (ii) 4 to 7 member saturated or unsaturated sulfur-containing, oxygen-containing or nitrogen-containing impurities, optionally substituted with 1 to 3 groups selected from the group consisting of Monocyclic group: a halogen atom, a cyano group, a ketone group, an alkyl group optionally substituted with 1 to 3 halogen atoms, an alkoxy group optionally substituted with 1 to 3 halogen atoms, optionally 1 to 2 alkyl groups a substituted amino group, an alkylthio group, an alkylsulfinyl group, and an alkylsulfonyl group, and R ^S is a group of the following formula [ia], [ii-a] or [iii-a]: R ³⁰ is (a) optionally selected from the group consisting of a hydroxyl group, an amine group, a mercaptoamine group, a dialkylamine formamylamine group, an alkylsulfonylamino group, and a dialkylaminesulfonylamino group. a group substituted with an alkyl group; (b) a cyano group; (c) a carboxyl group; (d) an alkoxycarbonyl group; (e) a group of the formula: -N(R ^aa )(R ^bb ); a group of the formula: -CON(R ^aa )(R ^bb ); (g) a group of the formula: (h) a hydroxyl group, R ^aa and R ^bb may be the same or different and each is a hydrogen atom, a hydroxyl group, a cyano group, an alkyl group, a cyanoalkyl group, a trihaloalkyl group, a hydroxyalkyl group, an alkoxyalkyl group, or a ring. An alkyl group, a group of the formula: R ^xa CO-, an alkylsulfonyl group or an aminoalkyl group substituted with 1 or 2 alkyl groups as required for the amine moiety; or both R ^aa and R ^bb are The terminal group is bonded to form a saturated or unsaturated nitrogen-containing heterocyclic group which optionally contains an additional hetero atom selected from the group consisting of an oxygen atom and a sulfur atom other than a nitrogen atom; R ^xa is (a) a hydrogen atom, b) an alkyl group substituted with 1 to 3 groups selected from a halogen atom, a cyano group, an alkylsulfonyl group and a pyridyl group, if necessary, (c) 6 to 10 membered monocyclic aryl groups or a bicyclic aryl-substituted alkoxy group, (d) a cycloalkyl group, (e) optionally having 1 or 2 selected from the group consisting of a halogen atom, a cyano group, an alkyl group, a trihaloalkyl group, and an alkoxy group. a 6- to 10-membered monocyclic aryl or bicyclic aryl group substituted by a group, (f) an amine group substituted with 1 or 2 alkyl groups as needed or (g) optionally 1 to 2 selected from a halogen atom, Saturation of groups in cyano, alkyl, and trihaloalkyl groups Unsaturated 4-7 sulfur, or oxygen-containing heteromonocyclic group, R ⁴⁰ is (a) hydrogen atom; (b) alkyl; (c) cyano; (d) a carboxyl group; (e) alkoxy (f) alkoxycarbonyl; (g) a group of the formula: -CON(R ^cc )(R ^dd ); (h) phenyl; (i) benzyl; or (j) a group of the formula : R ^xa CONH-, R ^cc and R ^dd are the same or different and each is a hydrogen atom or an alkyl group, and one of R ^Aa and R ^Bb is: (a) optionally via a hydroxyl group, an alkoxy group, an amine group An alkyl group substituted with an alkylamino group or a dialkylamino group; (b) a phenyl group optionally substituted with one or two groups selected from a halogen atom, an alkoxy group and a trihaloalkyl group; (c) benzyl; (d) 5 to 6 membered nitrogen-containing heteroaryl; or (e) cycloalkyl; and the other of R ^Aa and R ^Bb is (a) hydrogen or (b) The alkyl group and other symbolic groups which need to be substituted by a hydroxyl group, an alkoxy group, an amine group, an alkylamino group or a dialkylamino group are the same as defined above, but exclude 6-(2-chlorophenyl)-7-(4) -Chlorophenyl)-3-[N-(4-cyanobenzyl)aminemethanyl]pyrazolo[1,5-a]pyrimidine;6-(2-chlorophenyl)-7-(4 -Chlorophenyl)-3-[N-(4-cyano-4-tetrahydrothiopiperidyl)aminecarboxylidene]pyrazolo[1,5-a]pyrimidine; 6-phenyl-7 -(4-chlorophenyl)-3-(N-isopropylaminemethanyl)-pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4- Chlorophenyl)-3-(N-isopropylaminemethanyl)-pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorophenyl) -3-[N-( α -dimethylbenzyl)aminemethanyl]pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorophenyl --3-[N-( α -methylbenzyl)aminemethanyl]pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorophenyl) -3-[N-[1-(2-pyridyl)ethyl]amine-carbamoyl]pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4 -trifluoromethylphenyl)-3-[N-[1-(2-pyridyl)ethyl]aminemethanyl]pyrazolo[1,5-a]pyrimidine; and 6-(2-chloro Phenyl)-7-(4-chlorophenyl)-3-[N-(4-cyanobenzyl)aminecarboxylidene]pyrazolo[1,5-a]pyrimidine.

As a further specific embodiment, the aforementioned compound [IIA] of the present invention includes a compound of the following formula [IIa] or a pharmaceutically acceptable salt thereof: Wherein R ^1A is (a) a phenyl group substituted with 1 to 2 groups selected from a halogen atom, a difluoroalkyl group, a trifluoroalkyl group, and a dialkylamino group, or (b) as needed a saturated or unsaturated 5- to 6-membered nitrogen-containing heterocyclic group substituted with a group selected from an alkyl group, a trifluoroalkyl group and an alkoxy group, and R ^2A is optionally selected from 1 to 2 a phenyl group substituted with a halogen atom and a group of a cyano group, and R ^S1 is a group of the formula [ib], [ic], [id], [ii-b], [iii-b] or [iii-c] : Ring A ^a is (a) C _3-8 cycloalkyl or (b) C _5-6 cycloalkyl fused to benzene ring, Q is a single bond or methylene group, and ring B ^a is through its ring carbon atom Bonded to a 4- to 7-membered aliphatic heteromonocyclic group of an adjacent nitrogen atom, R ³¹ is a cyano group, an alkyl group, a hydroxyalkyl group, optionally an alkylcarbonyl group or a dialkylamine sulfonate. Alkyl, alkylsulfonyl or dialkylaminecarbamyl substituted aminoalkyl, carboxyalkyl, carboxyl, alkoxycarbonyl, optionally 1 to 2 selected from alkyl and dialkyl Amineyl group substituted by a group of an aminoalkyl group, or a group of the formula: R ⁴¹ is a hydrogen atom, an amine group or a group of the formula: R ^xa CONH-, R ³² is a hydroxyl group, a carboxyl group, an alkoxycarbonyl group, an amine group or a group of the formula: R ^xa CONH-, and R ³³ is a carboxyl group or an alkane Oxycarbonyl, R ³⁴ is cyano, alkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, carboxy, alkoxycarbonyl, optionally 1 to 2 selected from alkyl, hydroxyalkyl, Aminomethyl group substituted by a group of a cyanoalkyl group, a trihaloalkyl group, an alkoxyalkyl group, a cycloalkyl group, an alkylsulfonyl group and a dialkylaminoalkyl group, a group of the formula: Or a group of the formula: Ring J is a saturated or unsaturated nitrogen-containing 4- to 7-membered heteromonocyclic group which may contain an oxygen atom as a hetero atom other than a nitrogen atom, and R ³⁵ is a hydroxyalkyl group, a carboxyl group, an alkoxycarbonyl group or optionally 1 or 2 alkyl-substituted amine mercapto groups, R ^A1 being an alkyl group, a cycloalkyl group, optionally substituted by 1 to 2 groups selected from a halogen atom, an alkoxy group and a trihaloalkyl group Phenyl or benzyl, R ^B1 is a hydrogen atom or an alkyl group, R ³⁶ is an alkyl group or an amine carbenyl group, R ^B2 is a hydrogen atom or an alkyl group, and other symbols are the same as defined above, but 6-( 2-Chlorophenyl)-7-(4-chlorophenyl)-3-[N-(4-cyano-4-tetrahydrothiopiperidyl)aminemethanyl]pyrazolo[1,5- a]pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[N-[1-(2-pyridyl)ethyl]aminemethanyl]pyrazolo[ 1,5-a]pyrimidine; and 6-(2-chlorophenyl)-7-(4-trifluoromethylphenyl)-3-[N-[1-(2-pyridyl)ethyl]amine Mercapto]pyrazolo[1,5-a]pyrimidine.

As another more specific embodiment, the present invention includes (1) a compound of the following formula [I-II-i] or a pharmaceutically acceptable salt thereof: Wherein R ^5A is a hydrogen atom or an alkyl group, and R ^6A is (A) optionally substituted with 1 to 3 alkyl groups selected from the group consisting of: (a) a halogen atom, (b) a hydroxyl group, (c) a cyano group. , (d) alkoxy group, (e) carboxyl group, (f) amine carbenyl group substituted by 1 or 2 alkyl groups, (g) alkylthio group, (h) alkylsulfonyl group, (i) a cycloalkyl group substituted with 1 to 2 groups selected from an alkyl group and a hydroxyl group, (j) an amine group optionally substituted with 1 or 2 alkyl groups, and (k) saturated or unsaturated 4 To 10 members of a monocyclic or bicyclic nitrogen-containing, sulfur-containing or oxygen-containing heterocyclic group; or (B) a cycloalkane fused to a benzene ring and optionally substituted with 1 to 2 groups selected from the group consisting of Base: (a) an alkyl group substituted with a hydroxyl group, a carboxyl group, and an amine group as needed; (b) a cyano group; (c) a carboxyl group; (d) a group of the formula: R ^xa CO-; (e) a group of the formula :-N(R ^a1 )(R ^b1 ); (f) a group of the formula: -CON(R ^a1 )(R ^b1 ); (g) 6 to 10 membered monocyclic or bicyclic aryl; (h) An alkyl group substituted with 6 to 10 membered monocyclic or bicyclic aryl groups; and (i) a saturated or unsaturated 4 to 7 membered aza-containing monocyclic group substituted with 1 or 2 keto groups as needed, R ^a1 and R ^b1 are the same or different and each is a hydrogen atom, a hydroxyl , Cyano, alkyl, a group of the formula: R ^xa CO-, alkylsulfonyl group, amino group, mono alkylamino group or a dialkylamino group; or (C) as needed a 6- to 10-membered monocyclic aryl or bicyclic aryl group substituted with 1 to 2 groups selected from the group consisting of a cyano group, a trihaloalkyl group, an alkoxy group and a carboxyl group; or (D) containing at least one selected from the group consisting of a saturated or unsaturated 4 to 10 membered nitrogen-containing monocyclic heterocyclic group or a bicyclic ring which is substituted with 1 to 4 groups selected from the group consisting of a sulfur atom, an oxygen atom and a nitrogen atom, if necessary. Heterocyclic group: (a) a halogen atom, (b) a hydroxyl group, (c) a ketone group, (d) a cyano group, an (e) alkyl group, (f) a trihaloalkyl group, (g) a hydroxyalkyl group, (h) Alkoxyalkyl, (i) alkoxy, (j) group of the formula: R ^xa CO-, (k) cycloalkyl, (l) alkylsulfonyl, (m) optionally 1 Or 2 alkyl-substituted amine sulfonyl groups, (n) phenyl sulfonyl, (o) amine groups, (p) groups of the formula: R ^xa CONH-, (q) 1 or 2 as needed An alkyl-substituted amine carbenyl group, (r) a 6- to 10-membered monocyclic aryl or bicyclic aryl group substituted by a halogen atom, and (s) optionally 1 to 2 selected from an alkyl group and Among trihaloalkyl groups The group substituted saturated or unsaturated 4-7 sulfur, oxygen-containing or nitrogen-containing monocyclic group; or (E) a group of the ^{formula: -N (R 81) (R} 91), R 81 is a hydrogen atom Or an alkyl group, R ⁹¹ is (a) an alkyl group which is optionally substituted with 1 to 3 groups selected from a halogen atom, a cyano group, and a 6- to 10-membered monocyclic aryl group or a bicyclic aryl group; b) a cycloalkyl group; (c) optionally selected from the group consisting of a halogen atom, a cyano group, an alkyl group, a trihaloalkyl group, an alkoxy group, a trihaloalkoxy group, an alkylthio group, an alkylsulfonyl group and group of the formula: the substituents R ^xa CO- group of 6-10 monocyclic aryl or bicyclic aryl group; (d) group of the formula: R ^xa CO-; or (e) an optionally selected from a saturated or unsaturated 4 to 7 membered sulfur-, oxygen- or nitrogen-containing heteromonocyclic group substituted with a halogen atom, an alkyl group, a trihaloalkyl group, and an alkoxy group; or (F)R ^5A and R ^{6A is} bonded to each other and forms together with an adjacent nitrogen atom, optionally containing one or two hetero atoms selected from the sulfur atom and the oxygen atom, and optionally one or two selected from a halogen atom. , ketone group, an alkyl group, a group of the formula: R ^xa CO- and sulfo dialkyl amine in the acyl group substituted by the And or unsaturated 4- to 10-membered nitrogen-containing monocyclic or bicyclic heterocyclic groups, and other symbolic systems are as defined above, excluding 6-(2-chlorophenyl)-7-(4-chlorophenyl) )-3-[N-(1,1-diketyltetrahydrothiophen-3-yl)amine-carbamoyl]-2-(hydroxymethyl)pyrazolo[1,5-a]pyrimidine, and 2) A compound of the following formula [I-II-ii] or a pharmaceutically acceptable salt thereof: Wherein R ⁿ is an alkyl group and the other symbol systems are as defined above.

As still another specific embodiment, the present invention includes (1) the compound [I-II-i] wherein R ¹⁰ is (a) optionally 1 to 2 selected from a halogen atom, an alkyl group, a difluoroalkyl group. a phenyl group substituted with a group of a trifluoroalkyl group and a dialkylamino group or (b) a saturated or unsaturated group which is optionally substituted with a group selected from the group consisting of an alkyl group, a trifluoroalkyl group and an alkoxy group. To 6 members of the nitrogen-containing heterocyclic group, R ²⁰ is a phenyl group optionally substituted with 1 to 2 groups selected from a halogen atom and a cyano group, and R ^{6A is} (A) optionally selected from 1 to 1 An alkyl group substituted with a group of three halogen atoms, a hydroxyl group, a cyano group, a carboxyl group, and an alkoxycarbonyl group; or (B) a group of the formula: Wherein Ring A ^b is (A) C _3-8 cycloalkyl or (b) a benzene ring fused to the C _3-8 cycloalkyl group; R ³⁷ is a hydrogen atom, a cyano group, an alkyl, hydroxyalkyl, amine An alkyl group, a carboxyalkyl group, a carboxyl group, an alkoxycarbonyl group, an amine carbenyl group substituted with 1 to 2 groups selected from an alkyl group and a dialkylaminoalkyl group, or a group of the formula : R ⁴³ is a hydrogen atom, an amine group, an alkoxycarbonylamino group or a benzyloxycarbonylamino group; or (C) optionally 1 to 2 selected from a halogen atom, an alkoxy group, a trihaloalkylcarboxy group and an alkane a phenyl group substituted with a group in the oxycarbonyl group; or (D) a ring group of the formula: Wherein ring B ^b is a 4- to 7-membered aliphatic heterocyclic group which is bonded to an adjacent nitrogen atom through its ring carbon atom; ring B ^c is a 4 to 7 member nitrogen-containing aliphatic group a heteromonocyclic group, X ¹ is a sulfur atom, a group of the formula: -SO-, a group of the formula: -SO ₂ -, an oxygen atom, or a group of the formula: -NR ^m -, R ^m is an alkyl group, An alkylcarbonyl group, an alkoxycarbonyl group, an alkylsulfonyl group, an aminesulfonyl group optionally substituted by 1 or 2 alkyl groups or an amine carbenyl group optionally substituted by 1 or 2 alkyl groups; R ³⁸ is a hydrogen atom, a cyano group, an alkyl group, a hydroxyalkyl group, an aminoalkyl group, a carboxyalkyl group, a carboxyl group, an alkoxycarbonyl group, optionally 1 to 2 selected from an alkyl group and a dialkylaminoalkyl group. a group substituted with an amine carbenyl group or a group of the formula: (E) a group of the formula: -N(R ^8a )(R ^9a ), wherein R ^8a is a hydrogen atom or an alkyl group; R ^9a is an alkyl group, a trihaloalkyl group, a cyanoalkyl group, a benzyl group, a cycloalkane And optionally selected from the group consisting of a halogen atom, a cyano group, an alkyl group, a trihaloalkyl group, an alkoxy group, a trihaloalkoxy group, an alkylthio group, an alkylsulfonyl group, an alkoxycarbonyl group, and a benzyloxycarbonyl group. a group substituted with a phenyl group, an alkoxycarbonyl group, a benzyloxycarbonyl group or a 5- to 6-membered nitrogen-containing heteroaryl group; or (F) a group of the formula: Wherein ring A ^c is a C _3-8 cycloalkyl group optionally fused to a benzene ring; ring B ^d is (a) optionally substituted by a halogen atom, a cyano group, an alkoxy group, a trihaloalkyl group or a carboxyl group. Phenyl or (b) pyridyl; R ^S11 is a hydrogen atom or an alkyl group; R ^S12 is a hydrogen atom, an alkyl group, a carboxyl group, an amine methyl sulfhydryl group or a monoalkylamine methyl fluorenyl group or a dialkylamine fluorenyl group; R ³⁹ is a hydrogen atom, a halogen atom, a cyano group, an alkyl group, a hydroxyalkyl group, a trihaloalkyl group, an aminoalkyl group, an alkoxy group, a carboxyalkyl group, a carboxyl group, and optionally one to two selected from a group of an alkyl group and a dialkylaminoalkyl group substituted with an aminomethyl group, an amine group, an alkoxycarbonylamino group or a benzyloxycarbonylamino group; and k is an integer from 0 to 2; and (2) a compound [I-II-ii], wherein R ¹⁰ is (a) benzene which is optionally substituted with 1 to 2 groups selected from a halogen atom, a difluoroalkyl group, a trifluoroalkyl group and a dialkylamino group. Or (b) a saturated or unsaturated 5- to 6-membered nitrogen-containing heterocyclic group substituted with a group selected from the group consisting of an alkyl group, a trifluoroalkyl group and an alkoxy group; and R ²⁰ is optionally One to two phenyl groups selected from the group consisting of a halogen atom and a cyano group.

In the compound [I] of the present invention, examples of preferred compounds include the compound [II] wherein R ¹ and R ² are the same or different and each is (a) optionally selected from a halogen atom, a cyano group, or the like. a phenyl group substituted with one to three halogen atoms and one to three groups substituted with one or two alkyl groups as desired; or (b) optionally selected from a saturated or unsaturated 5- to 7-membered nitrogen-containing heterocyclic group substituted with a group substituted with 1 to 3 halogen atoms and an alkoxy group, and A1)R' is a group of the formula [i] And R ³ is (a) an alkyl group optionally substituted with a group selected from a hydroxyl group and an amine group, (b) a cyano group, (c) a carboxyl group, (d) an alkoxycarbonyl group, (e) a group: -CON(R ^e )(R ^f ) or (f) amidino group, R ^e and R ^f are the same or different and each is a hydrogen atom, an alkyl group or a dialkylaminoalkyl group; R ⁴ Is a hydrogen atom or a mercaptoamine group; or A2) R' is a group of the formula [ii]; X is a sulfur atom, a group of the formula: -SO ₂ -, an oxygen atom or a group of the formula: -NR ^k -, R ^k is an alkoxycarbonyl group, an alkylsulfonyl group, an alkylcarbonyl group or a sulfo dialkyl amines acyl; R ³ is (a) an optionally substituted a hydroxyalkyl , (B) carboxy, (c) alkoxycarbonyl or (d) a group of the ^{formula: -CON (R e) (R} f), R e , and R ^f is the same or different and each is a hydrogen atom, an alkoxy Or a trihaloalkyl group; R ⁴ is a hydrogen atom; or A3) R' is a group of the formula [iii], and R ^A is an alkyl group optionally substituted by a hydroxyl group, optionally substituted by a halogen atom or a trihaloalkyl group. Phenyl or 5- to 6-membered nitrogen-containing heteroaryl; R ^B is a hydrogen atom or an alkyl group; R ³ is an alkyl group, a carboxyl group or a group of the formula: -CON(R ^a )(R ^b ), R ^a and R ^b is the same or different and each is a hydrogen atom or an alkyl group; and R ^0A is a hydrogen atom, an alkyl group optionally substituted with 1 to 3 halogen atoms, an alkoxy group optionally substituted by a hydroxyl group, a hydroxyalkyl group An amine group substituted with 1 to 2 groups selected from an alkyl group, an alkylcarbonyl group and an alkylsulfonyl group, or a 4 to 6 membered nitrogen-containing aliphatic heterocyclic group.

In the preferred compound [II] of the present invention, examples of the more preferable compound include: A1) the compound [II] wherein R' is a group of the formula [i]; and R ³ is (a) a C _1-6 alkyl group. (b) hydroxy-C _1-6 alkyl, (c) amino-C _1-6 alkyl, (d) cyano, (e) carboxy, (f) C _1-6 alkoxycarbonyl, (g Aminomethyl sulfhydryl, (h) mono- or di(C _1-6 alkyl)amine mercapto, (i) di(C _1-6 alkyl)amino-C _1-6 alkylamine formazan Or (j)C _1-6 alkoxycarbonylamino group; and R ⁴ is a hydrogen atom or a phenyl-C _1-6 alkoxycarbonylamino group; A2) a compound [II] wherein R' is a formula [ Ii] a group, X is a sulfur atom, a group of the formula: -SO ₂ -, an oxygen atom or a group of the formula: -NR ^k -, R ^k is a C _1-6 alkoxycarbonyl group, a C _1-6 alkane a sulfonyl group, a C _1-6 alkylcarbonyl group or a di(C _1-6 alkyl)amine sulfonyl group; R ³ is (a) an amine carbenyl group, (b) a mono- or a di-(C _1-6 Alkyl)-aminocarbazinyl, (c) mono(trihalo-C _1-6 alkyl)aminecarbamyl, (d)C _1-6 alkoxycarbonyl, (e)C _1-6 alkyl Or (f) hydroxy-C _1-6 alkyl; and R ⁴ is a hydrogen atom; or A3) compound [II], wherein R' is a group of the formula [iii]; R ^A is a C _1-6 alkyl group, a hydroxyl group -C _1-6 alkyl, phenyl, halophenyl, trihalo (C _1-6 alkyl) - phenyl Pyridyl; R ^B is a hydrogen atom or C _1-6 alkyl; and R ³ is C _1-6 alkyl, carboxy, C _1-6 alkoxycarbonyl, carbamoyl or acyl group.

In the above compound [II] of the group A ¹ to A ³ , examples of further preferred compounds include the compounds wherein R ¹ is selected from a halogen atom, a dihalo-C _1-6 alkyl group, a trihalogen- a phenyl group substituted with 1 to 2 groups of a C _1-6 alkyl group and a di(C _1-6 alkyl)amino group, a C _1-6 alkoxypyrrolidinyl group, a C _1-6 alkyl group- Piperidinyl or C _1-6 alkoxy-piperidinyl; R ² is (a) phenyl substituted with 1 or 2 halogen atoms, (b) cyanophenyl or (c) trihalide (C _1-6 alkyl)-pyridyl; and R ^0A is a hydrogen atom, a C _1-6 alkyl group, a dihalo-C _1-6 alkyl group, a trihalo-C _1-6 alkyl group, a C _1-6 alkoxy group a hydroxy-C _1-6 alkoxy group, an amine group, a C _1-6 alkylcarbonylamino group, a mono(C _1-6 alkyl)amine carbenyl group or a 4- to 6-membered nitrogen-containing aliphatic heterocyclic ring base.

In the compound [II], the particularly preferred compound may be a compound selected from the group consisting of 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[N- (1-cyanocyclohexyl)amine-carbamoyl]pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[N- (1-cyanocyclopentyl)amine-carbamoyl]pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[N -(1-methylcyclohexyl)aminecarboxylidene]pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[N -(1-methylcyclopropyl)aminemethanyl]pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-3-[N-(1-cyanocyclopentyl) Aminomethyl]-7-(4-trifluoromethylphenyl)-2-methylpyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-3-[N -(1-cyanocyclohexyl)amine-carbamoyl]-7-(4-trifluoromethylphenyl)-2-methylpyrazolo[1,5-a]pyrimidine; 3-[N-( 4-Aminomercapto-1,1-dione-tetrahydrothiopyran-4-yl)amine-mercapto]-6-(2-chlorophenyl)-7-(4-chlorophenyl) -pyrazolo[1,5-a]pyrimidine; 2-acetamido-6-(2-chlorophenyl)-7-(4-trifluoromethylphenyl)-3-[N-[1 -(2-pyridyl)ethyl]aminemethanyl]pyrazolo[1,5-a]pyrimidine; 6-(2-Chlorophenyl)-7-(4-chloro-2-fluorophenyl)-3-[N-[1-(2-pyridyl)ethyl]aminemethanyl]pyrazolo[ 1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-trifluoromethylphenyl)-3-[N-[1-(2-pyridyl)ethyl]amine A Mercapto]-2-(1-pyrrolidinyl)-pyrazolo[1,5-a]pyrimidine; 3-[N-[1-(aminocarboxycyclohexyl)aminecarbamyl]-6- (2-chlorophenyl)-7-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3 -[N-[1-methyl-1-(2-pyridyl)ethyl]aminemethanyl]pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7- (4-Trifluoromethylphenyl)-3-[N-[1-methyl-1-(2-pyridyl)ethyl]aminemethanyl]pyrazolo[1,5-a]pyrimidine; 3-[N-(4-Aminomethyl decyl-1,1-dione-tetrahydrothiopyran-4-yl)amine-carbamoyl]-6-(2-chlorophenyl)-7-( 4-trifluoromethylphenyl)-pyrazolo[1,5-a]pyrimidine; 3-[N-[1-(carboxycyclohexyl)aminecarbamyl]-6-(2-chlorophenyl) -7-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[[1-[N -[2-(N,N-dimethylamino)ethyl]aminemethylmercapto]cyclohexyl]aminecarboxylidene]pyrazolo[1,5-a]pyrimidine; 6-(2-chlorobenzene -7-(4-Chlorophenyl)-3-[N-[1-(N-methylamine-methyl)cyclohexyl]amine A Pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[N-[1-(N,N-dimethyl Aminomethyl)cyclohexyl]amine-carbamoyl]pyrazolo[1,5-a]pyrimidine; (S)-3-[N-(1-carboxy-2-methylpropyl)aminecarboxamide -6-(2-chlorophenyl)-7-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidine; (S)-3-[N-(1-carboxy-2-benzene Ethylethyl)amine-mercapto]-6-(2-chlorophenyl)-7-(4-trifluoromethylphenyl)pyrazolo[1,5-a]pyrimidine; (S)-3-[N-(1-carboxy-2-methylpropyl)aminemethanyl]-6-(2-chlorophenyl)-7-(4-trifluoromethylphenyl)pyrene Zizo[1,5-a]pyrimidine; (s)-3-[N-(α-carboxybenzyl)aminemethanyl]-6-(2-chlorophenyl)-7-(4-trifluoro Methylphenyl)pyrazolo[1,5-a]pyrimidine; (S)-3-[N-(1-carboxy-2-methylpropyl)aminemethanyl]-6-(2-chloro Phenyl)-7-(4-chlorophenyl)-2-methylpyrazolo[1,5-a]pyrimidine; 3-[N-(1-carboxy-1-methylethyl)amine formazan -6-(2-chlorophenyl)-7-(4-chlorophenyl)-2-methylpyrazolo[1,5-a]pyrimidine; 3-[N-(α-carboxybenzyl Aminomethyl]]-6-(2-chlorophenyl)-7-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidine; 3-[N-(1-carboxy-1- Methylethyl)amine-mercapto]-6-(2-chlorophenyl)-7-(4-trifluoromethylphenyl)pyrazolo[1,5-a]pyrimidine; 3-[N- (1-carboxy-2-phenylethyl)amine-mercapto]-6-(2-chlorophenyl)-7-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidine; -[N-(4-carboxy-1-cyclohexyl)aminecarbamyl]-6-(2-chlorophenyl)-7-(4-trifluoromethylphenyl)pyrazolo[1,5- a]pyrimidine; 3-[N-(4-carboxybenzyl)aminemethanyl]-6-(2-chlorophenyl)-7-(4-trifluoromethylphenyl)pyrazolo[1, 5-a]pyrimidine; 3-[N-(3-carboxybenzyl)aminecarbamyl]-6-(2-chlorophenyl)-7- (4-trifluoromethylphenyl)pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[N-[1- (2-pyridyl)ethyl]amine-methylmethyl]pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-3-[N-(1-cyanocyclohexyl)amine Mercapto]-7-(4-trifluoromethylphenyl)pyrazolo[1,5-a]pyrimidine; 6-(2-Chlorophenyl)-7-(4-chlorophenyl)-3-[N-(1-methoxycarbonylcyclohexyl)aminecarboxylidene]pyrazolo[1,5-a] Pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorophenyl)-2-(methylsulfonylamino)-3-[N-[1-(2-pyridyl)ethyl Aminomethyl]pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorophenyl)-2-[N-methyl-N-(A) Alkylsulfonyl)amino]-3-[N-[1-(2-pyridyl)ethyl]aminemethylmercapto]pyrazolo[1,5-a]pyrimidine; 6-(2-chlorobenzene -7-(4-Methylpiperidin-1-yl)-3-[N-[1-methyl-1-(2-pyridyl)ethyl]aminemethanyl]pyrazolo[1 ,5-a]pyrimidine;6-(2-chlorophenyl)-7-(4-methoxypiperidin-1-yl)-3-[N-[1-methyl-1-(2-pyridine) Ethyl]aminomethane]pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(3-methoxypyrrolidin-1-yl)-3- [N-[1-methyl-1-(2-pyridyl)ethyl]amine-methylmethyl]pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-( 4-trifluoromethylphenyl)-3-[N-(1-methoxycarbonylcyclohexyl)amine sulfonyl]-2-methylpyrazolo[1,5-a]pyrimidine; 3-[ N-(1-carboxycyclohexyl)amine sulfonyl]-6-(2-chlorophenyl)-7-(4-trifluoromethylphenyl)-2-methylpyrazolo[1,5- a]pyrimidine; 6-(2-chlorophenyl)-7-(4-trifluoromethylphenyl)-3-[N- (4-methoxycarbonyl-1,1-dione-tetrahydrothiopyran-4-yl)aminecarbenyl]pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl) -7-(4-Trifluoromethylphenyl)-3-[N-(4-methyl-1,1-dione-tetrahydrothiopyran-4-yl)aminecarboxylidene]pyridinium Zizo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorophenyl)-2-methyl-3-[N-(4-methyl-1,1 -diketo-tetrahydrothiopyran-4-yl)aminecarboxylidene]pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-trifluoromethyl Phenyl)-2-methyl-3-[N-(4-methyl-1,1-dione-tetrahydrothiopyran-4-yl)aminecarbenyl]pyrazolo[1, 5-a]pyrimidine; 6-(2-Chlorophenyl)-7-(4-chlorophenyl)-3-[N-(3-hydroxy-2-methylpropan-2-yl)aminemethanyl]-2-methyl -pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-trifluoromethylphenyl)-3-[N-(4-hydroxymethyl-1, 1-diketo-tetrahydrothiopyran-4-yl)amine-methylmethyl]pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorobenzene 2-trifluoromethyl-3-[N-(4-methyl-1,1-dione-tetrahydrothiopyran-4-yl)aminecarboxylidene]pyrazolo[1, 5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorophenyl)-2-ethoxy-3-[N-(4-methyl-1,1-dione -tetrahydrothiopyran-4-yl)amine-methylmethyl]pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(2-fluoro-4-trifluoromethyl) Phenyl)-3-[N-(4-methyl-1,1-dione-tetrahydrothiopyran-4-yl)aminecarboxylidene]pyrazolo[1,5-a]pyrimidine 6-(2-chlorophenyl)-7-(4-trifluoromethylphenyl)-3-[N-(3-methoxycarbonyl-1,1-dionethiolane- 3-(amino)pyrido[1,5-a]pyrimidine(6-(2-chlorophenyl)-7-(4-trifluoromethylphenyl)-3-[N-(3-methoxycarobonyl-1,1 -dioxothietan-3-yl)carbamoyl]-pyrazolo[1,5-a]pyrimidine); 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[N-(1-cyanide) Aminomethyl sulfhydryl]-2-methyl Pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorophenyl)-2-(2-hydroxyethoxy)-3-[N-(3 -methyl-1,1-dione-tetrahydrothiophen-3-yl)amine,carboxylidene]pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-( 4-trifluoromethylphenyl)-2-(2-hydroxyethoxy)-3-[N-(3-methyl-1,1-dionetetrahydrothiophen-3-yl)aminecaramidine Pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-trifluoromethylphenyl)-3-[N-(3-methyl-1, 1-diketo-tetrahydrothiophen-3-yl)amine-methylmethyl]pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-2-(difluoromethyl)-7 -(4-Trifluoromethylphenyl)-3-[N-(3-methyl-1,1-dionetetrahydrothiophen-3-yl)aminemethanyl]pyrazolo[1,5 -a]pyrimidine; 6-(2-Chlorophenyl)-7-(4-chlorophenyl)-2-(trifluoromethyl)-3-[N-(3-methyl-1,1-dionetetrahydrothiophene 3-yl)amine-mercapto]pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-trifluoromethylphenyl)-3-[N- [4-(N-Methylaminocarbamimidyl)-1,1-dione-tetrahydrothiopyran-4-yl]aminecarboxylidene]pyrazolo[1,5-a]pyrimidine; -(2-chlorophenyl)-3-[N-[4-[N-(2,2,2-trifluoroethyl)aminemethanyl]-1,1-dionetetrahydrothiopyran 4-yl]amine-mercapto]-7-(4-trifluoromethylphenyl)pyrazolo[1,5-a]pyrimidine; and 6-(2-chlorophenyl)-3-[N -[4-[N-(2,2,2-trifluoroethyl)amine-carbamoyl]-1,1-dionetetrahydrothiopyran-4-yl]aminecarboxylidene-7-7- (4-Trifluoromethylphenyl)-2-methylpyrazolo[1,5-a]pyrimidine or a pharmaceutically acceptable salt thereof.

Another example of a preferred compound of the present invention comprises: B1) a compound [I-II] wherein R ¹ and R ² are the same or different and each is optionally 1 to 2 selected from a halogen atom and a cyano group. a phenyl group substituted with a group in an alkyl group, a dihaloalkyl group, and a trihaloalkyl group; R" is a group of the formula: -N(R ⁵ )(R ⁶ ), and R ⁵ is a hydrogen atom or an alkyl group And R ⁶ is (a) an alkyl group substituted with 1 to 3 groups selected from the group consisting of a halogen atom, a hydroxyl group, a cyano group, an alkoxy group, a C _3-8 cycloalkyl group, a hydroxy group -C _{3 -8} cycloalkyl, amino-C _3-8 cycloalkyl, C _3-8 cycloalkyl substituted with 1 or 2 halogen atoms, dialkylamino group, carboxyl group, optionally 1 or 2 alkane a substituted phenylamino group, optionally substituted with 2 or 2 halogen atoms, a phenyl group, a trihaloalkylphenyl group, an alkoxyphenyl group, a carboxyphenyl group, and a saturated or unsaturated 5 to 6 member nitrogen. Or an oxygen-containing heterocyclic group, (b) a C _3-8 cycloalkyl group which may be fused to the benzene ring as needed and optionally substituted with 1 to 2 groups selected from the group consisting of: cyano group , alkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl, alkylcarbonylamino-alkyl, dialkylamine -Amino-alkyl, alkylsulfonylamino-alkyl, dialkylamine sulfonylamino-alkyl, carboxyl, alkoxycarbonyl, phenylalkoxycarbonyl, group of the formula :-CON(R ^a1 )(R ^b1 ) and tetrazolyl, R ^a1 and R ^b1 are the same or different and each is a hydrogen atom, an alkyl group or a dialkylaminoalkyl group, (c) as needed a saturated or unsaturated 4- to 6-membered nitrogen-containing, sulfur-containing or oxygen-containing heterocyclic group substituted with a group selected from the group consisting of a keto group, a hydroxyl group, a cyano group, an alkyl group, a hydroxyalkyl group, a carboxyl group, Alkoxycarbonyl, alkylsulfonyl, a group of the formula: -CON(R ^a2 )(R ^b2 ), pyrrolidinylcarbonyl or N-morpholinylcarbonyl, R ^a2 and R ^b2 are the same or different and each Is a hydrogen atom, an alkyl group, a trihaloalkyl group, a cyanoalkyl group, a hydroxyalkyl group, an alkoxyalkyl group, an alkylsulfonyl group or a C _3-8 cycloalkyl group or (d) optionally selected from An amine group substituted with one to two groups of an alkyl group and a pyridyl group, but excluding 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[N-(1,1) -diketo-tetrahydrothiophen-3-yl)amine carbaryl]-2-(hydroxymethyl)pyrazolo[1,5-a]pyrimidine; and B2) compound [I-II], wherein R ¹ and R ² are the same or Different and each is an optionally 1-2 selected from a halogen atom, the cyano-substituted, di-haloalkyl, trihaloalkyl and in the phenyl group; R ^0B is a group of the formula: -SO ₂ N(R ⁰¹ )(R ⁰² ) and R" are alkoxy groups.

In the compound [I-II], a more preferable compound may be a compound wherein E is a group of the formula: -C(=O)-.

In the compound [I-II], examples of further preferred compounds include: B1-1) a compound wherein R ¹ and R ² are the same or different, and each is optionally one to two selected from a halogen atom, a phenyl group substituted with a group of a cyano group, an alkyl group, a dihaloalkyl group and a trihaloalkyl group; R ^0B is a group of the formula: -NHCONHR ⁰³ ; E is a group of the formula: -C(=O)- ;R" is a group of the formula: -N(R ⁵ )(R ⁶ ), R ⁵ is a hydrogen atom and R ⁶ is (a)alkyl, (b) trihaloalkyl, (c) C _3-8 a cycloalkyl group, (d) a dialkylamino group or (e) a saturated or unsaturated 5 member substituted with one to three groups selected from the group consisting of a keto group, an alkyl group and an amine carbaryl group. a 6-membered sulfur-containing heterocyclic group; B1-2) a compound wherein R ¹ and R ² are the same or different, and each is (i) optionally 1 to 2 selected from a halogen atom, a cyano group, or an alkane. a phenyl group substituted with a group in a dihaloalkyl group, a trihaloalkyl group and an alkoxy group or (ii) a saturated or unsaturated 5- to 6-membered aza-monocyclic group; R ^0B is a group of the formula :-SO ₂ N(R ⁰¹ )(R ⁰² ); R ⁰¹ is a hydrogen atom or an alkyl group; R ⁰² is a hydrogen atom, an alkyl group or an aminomethylalkyl group; E is a group of the formula: -C(= O)-;R" Group of the ^{formula: -N (R 5) (R} 6), R 5 is a hydrogen atom or an alkyl group and R ⁶ is (a) an optionally with 1 to 3 substituents selected from the group consisting of an alkyl group: halo An atom, a hydroxyl group, a cyano group, an alkoxy group, a C _3-8 cycloalkyl group optionally substituted with 1 to 2 halogen atoms, an amine group optionally substituted with 1 to 2 alkyl groups, and a pyridyl group, (b) a C _3-8 cycloalkyl group substituted with a group selected from an alkyl group and an aminomethyl sulfonyl group, and (c) optionally substituted with 1 to 2 groups selected from the group consisting of an alkyl group and a pyridyl group. Amine or (d) a saturated or unsaturated 5- to 6-membered nitrogen or sulfur-containing heterocyclic group substituted with 1 to 3 groups selected from the group consisting of a keto group, an alkyl group and an amine carbaryl group. B1-3) a compound wherein R ¹ and R ² are the same or different and each is a phenyl group optionally substituted with 1 to 2 groups selected from a halogen atom and a trihaloalkyl group; R ^0B Is a group of the formula: -CON(R ^e )(R ^f ), R ^e is a hydrogen atom or an alkyl group; R ^f is a hydrogen atom, an alkyl group or a dialkylamine group; and E is a group of the formula: -C (= O) -; R "is a group of the formula: optionally substituted with 1 to 3 substituents of halogen atoms ^{-N (R 5) (R 6} ), R 5 is a hydrogen atom and R ⁶ is (a) (b) C _3-8 cycloalkyl, or (c) optionally substituted with 1 to 3 substituents selected from substituted alkyl and the keto group with 1 to 3 groups of a saturated or unsaturated 4-6 sulfur a heterocyclic group; B1-4) a compound wherein R ¹ and R ² are the same or different, and each is a phenyl group optionally substituted with 1 to 2 groups selected from a halogen atom and a trihaloalkyl group, if necessary. R ^0B is a hydroxyalkyl group; E is a group of the formula: -C(=O)-; R" is a group of the formula: -N(R ⁵ )(R ⁶ ), R ⁵ is a hydrogen atom and R ⁶ (a) an alkyl group substituted with 1 to 3 halogen atoms as needed, (b) an alkyl group substituted with a pyridyl group, (c) optionally substituted with a group selected from a cyano group and an aminomethyl group a C _3-8 cycloalkyl group or (d) optionally substituted with 1 to 3 groups of 1 to 3 groups selected from a keto group and an alkyl group, saturated or unsaturated, 4 to 6 members containing nitrogen or containing Thioheterocyclyl, but excluding 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[N-(1,1-dionetetrahydrothiophen-3-yl)amine A Methyl]-2-(hydroxymethyl)pyrazolo[1,5-a]pyrimidine; B1-5) a compound wherein R ¹ and R ² are the same or different and each is selected from a phenyl group substituted with one or two groups of a halogen atom and a trihaloalkyl group R ^0B is a carboxyl group; E is a group of the formula: -C (= O) -, R " is a group of the ^{formula: -N (R 5) (R} 6), R 5 is a hydrogen atom and R ⁶ is optionally a saturated or unsaturated 5- to 6-membered sulfur-containing heterocyclic group substituted with one to three groups selected from a keto group and an alkyl group; and B2-1) a compound wherein R ¹ and R ² are the same Or different and each is a halophenyl group; R ^0B is an aminesulfonyl group substituted by 1 to 2 alkyl groups as needed; E is a group of the formula: -C(=O)- and R" is an alkoxy group .

In the aforementioned compound [I-II], an example of a particularly preferred compound is: B1-a) a compound wherein R ¹ is (i) optionally selected from a halogen atom, a C _1-6 alkyl group, a dihalogen- a phenyl group substituted with 1 to 2 groups of C _1-6 alkyl and trihalo-C _1-6 alkyl or (ii) piperidinyl; R ² is optionally selected from a halogen atom and cyanide a phenyl group substituted with 1 to 2 groups in the group; R ^0B is a group of the formula: -SO ₂ N(R ⁰¹ )(R ⁰² ); R ⁰¹ is a hydrogen atom or a C _1-6 alkyl group; R ⁰² Is a hydrogen atom, a C _1-6 alkyl group or an amine carbenyl-C _1-6 alkyl group; R ⁵ is a hydrogen atom; and R ⁶ is (a) optionally selected from a halogen atom, a C _1-6 alkoxy group. a C _1-6 alkyl group substituted with 1 to 3 groups of a C _3-8 cycloalkyl group and a pyridyl group, (b) a C _3-8 cycloalkyl group substituted with a C _1-6 alkyl group as needed , (c) an amine group substituted with 1 to 2 groups selected from a C _1-6 alkyl group and a pyridyl group, or (d) a saturated or unsaturated group substituted with 1 to 2 keto groups as necessary 5 to 6 member nitrogen-containing or sulfur-containing heterocyclic groups; or B1-b) a compound wherein R ¹ is a trihalo-C _1-6 alkylphenyl group; R ² is a halogen phenyl group; R ^0B is as follows ^{group: -CON (R e) (R} f); R e is a hydrogen atom or C _1-6 alkyl R ^f is a hydrogen atom or C _1-6 alkyl; R ⁵ is a hydrogen atom; R ⁶ is (a) optionally substituted with 1 to 3 substituents of halogen atoms, C _1-6 alkyl or (b) optionally substituted with 1 a saturated or unsaturated 5- to 6-membered sulfur-containing heterocyclic group substituted with a group selected from a keto group and a C _1-6 alkyl group; or B1-c) a compound wherein R ¹ is a trihalogen -C _1-6 alkylphenyl; R ² is halophenyl; R ^0B is hydroxy-C _1-6 alkyl; R ⁵ is a hydrogen atom; R ⁶ is (a) trihalo-C _1-6 alkyl , (b) -C _1-6 alkyl-pyridyl, (c) is selected from an optionally substituted carbamoyl and cyano group of the acyl group of C _5-7 cycloalkyl, or (d) an optionally 1 to 3 saturated or unsaturated 5- to 6-membered sulfur-containing heterocyclic groups substituted with a group selected from a keto group and a C _1-6 alkyl group, but excluding 6-(2-chlorophenyl)-7 -(4-chlorophenyl)-3-[N-(1,1-dione-tetrahydrothiophen-3-yl)amine-carbazyl]-2-(hydroxymethyl)pyrazolo[1, 5-a]pyrimidine; or B2-a) a compound wherein R ¹ and R ² are the same or different and each is halophenyl, R ^0B is C _1-6 alkyl-amine sulfonyl and R" is C _1-6 alkoxy.

Examples of the above-mentioned particularly preferred compound [I-II] include a compound selected from the group consisting of 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-ethoxycarbonyl. -2-(N-methylamine sulfonyl)pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-ethoxy Carbonyl-2-(N,N-dimethylaminesulfonyl)pyrazolo[1,5-a]pyrimidine; (R)-6-(2-chlorophenyl)-7-(4-chlorobenzene 2-(N-methylamine sulfonyl)-3-[N-(1,1-dione) Tetrahydrothiophen-3-yl)amine,carboxylidene]pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[N -(cyclopentyl)amine-mercapto]-2-(N-methylaminesulfonyl)pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4 -Chlorophenyl)-3-[[N'-methyl-N'-(2-pyridyl)indolyl]carbonyl]-2-(N-methylaminesulfonyl)pyrazolo[1,5 -a]pyrimidine; (R)-6-(2-chlorophenyl)-7-(4-chlorophenyl)-2-(N,N-dimethylaminesulfonyl)-3-[N- (1,1-diketyltetrahydrothiophen-3-yl)aminecarboxylidene]pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorobenzene Benzyl-3-(N-(cyclopentyl)aminecarbamyl]-2-(N,N-dimethylaminesulfonyl)pyrazolo[1,5-a]pyrimidine; 6-(2 -Chlorophenyl)-7-(4-chlorophenyl)-2-(N,N-dimethylaminesulfonyl)-3-[N-(1-pyrrolidinyl)aminecarboxylidene]pyridinium Zizo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[[N'-methyl-N'-(2-pyridyl) Mercapto]carbonyl]-2-(N,N-dimethylaminesulfonyl)pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorobenzene 2-(N-methylaminesulfonyl)-3-[N-(1-pyrrolidinyl)aminecarboxylidene]pyrazolo[1,5-a]pyrimidine; (R)-6 -(2-chlorophenyl)-7-(4-chlorophenyl)-3-[N-(1,1-dionethiol-3 -yl)aminomethane]-2-aminesulfonylpyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[ N-(1-pyrrolidinyl)amine-carbamoyl]-2-aminesulfonylpyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorobenzene -3-[[N'-methyl-N'-(2-pyridyl)indolyl]carbonyl]-2-aminesulfonylpyrazolo[1,5-a]pyrimidine; (S)- 6-(2-Chlorophenyl)-7-(4-chlorophenyl)-3-[N-(1,1-dionetetrahydrothiophen-3-yl)aminecarboxylidene-2-amine Sulfosylpyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[N-(cyclopentyl)aminecarbamyl] 2-amine sulfonylpyridinium Zizo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[N-(1,1-dionetetrahydrothiopyran- 4-yl)amine-mercapto]-2-aminesulfonylpyrazolo[1,5-a]pyrimidine; (R)-6-(2-chlorophenyl)-7-(4-trifluoromethyl) Phenyl))-3-[N-(1,1-dionetetrahydrothiophen-3-yl)amine-carbamoyl]-2-aminesulfonylpyrazolo[1,5-a]pyrimidine; (S)-6-(2-Chlorophenyl)-7-(4-trifluoromethylphenyl)-3-[N-(1,1-dionetetrahydrothiophen-3-yl)amine A Mercapto]-2-aminesulfonylpyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-3-[N-(cyclopentyl)aminecarbamyl]-7- (4-trifluoromethylphenyl)-2-aminesulfonylpyrazolo[1,5-a]pyrimidine; (R)-7-(4-chlorophenyl)-6-(2-cyano Phenyl)-3-[N-(1,1-diketyltetrahydrothiophen-3-yl)aminecarboxylidene-2-aminesulfonylpyrazolo[1,5-a]pyrimidine; -(4-chlorophenyl)-6-(2-cyanophenyl)-3-[N-(cyclopentyl)aminecarbamimidyl]-2-aminesulfonylpyrazolo[1,5- a]pyrimidine; 7-(4-chlorophenyl)-6-(2-cyanophenyl)-3-[[N'-methyl-N'-(2-pyridyl)indenyl]carbonyl]- 2-Aminesulfonylpyrazolo[1,5-a]pyrimidine; (R)-2-[N-(Aminomethylmethyl)aminesulfonyl]-6-(2-chlorophenyl) -7-(4-chlorophenyl)-3-[N-(1,1-dionetetrahydrothiophen-3-yl) Aminomethyl]pyrazolo[1,5-a]pyrimidine; 2-[N-(aminomethylmethyl)amine sulfonyl]-6-(2-chlorophenyl)-7-(4 -Chlorophenyl)-3-[N-(cyclopentyl)aminecarbamyl]pyrazolo[1,5-a]pyrimidine; 2-[N-(aminomethylmethyl)amine sulfonyl -6-(2-Chlorophenyl)-7-(4-chlorophenyl)-3-[[N'-methyl-N'-(2-pyridyl)indolyl]carbonyl]pyrazolo[ 1,5-a]pyrimidine; 2-[N-(aminomethylmethylmethyl)amine sulfonyl]-6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[ N-(1-pyrrolidinyl)amine-carbamoyl]pyrazolo[1,5-a]pyrimidine; 3-[N-(1-carboxycyclohexyl)aminecarbamyl]-6-(2-chloro Phenyl)-7-(4-chlorophenyl)-2-(N-A Thiasulfonyl)pyrazolo[1,5-a]pyrimidine; 3-[N-(1-aminoformylcyclohexyl)aminecarbamyl]-6-(2-chlorophenyl)-7 -(4-chlorophenyl)-2-aminesulfonylpyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-trifluoromethylphenyl)- 2-hydroxymethyl-3-[N-[1-methyl-1-(2-pyridyl)ethyl]aminemethanyl]pyrazolo[1,5-a]pyrimidine; 6-(2- Chlorophenyl)-7-(4-trifluoromethylphenyl)-2-hydroxymethyl-3-[N-(3-methyl-1,1-dionetetrahydrothiophen-3-yl) Aminomethyl]pyrazolo[1,5-a]pyrimidine;6-(2-chlorophenyl)-3-[N-(1-cyanocyclohexyl)aminecarbamyl]-7-(4 -trifluoromethylphenyl)-2-(hydroxymethyl)pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-trifluoromethylphenyl) -2-hydroxymethyl-3-[N-(4-methyl-1,1-dionetetrahydrothiopyran-4-yl)aminemethanyl]pyrazolo[1,5-a] Pyrimidine; 2-aminoformamido-6-(2-chlorophenyl)-7-(4-trifluoromethylphenyl)-3-[N-(4-methyl-1,1-dione Tetrathiathiopyran-4-yl)amine-methylmethyl]pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-trifluoromethylphenyl)- 2-(N-methylamine-mercapto)-3-[N-(4-methyl-1,1-dionetetrahydrothiopyran-4-yl)aminecarboxylidene]pyrazolo[ 1,5-a]pyrimidine; 6-(2-chloro -7-(4-chlorophenyl)-3-[N-(2,2-dimethylpropyl)aminemethanyl]-2-aminesulfonylpyrazolo[1,5-a Pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[N-(cyclohexylmethyl)aminecarbamyl]-2-aminesulfonylpyrazolo[ 1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[N-(2,2,2-trifluoroethyl)aminecarbamyl] 2-aminosulfonylpyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[N-(3-methylpropane) Aminomethyl hydrazino]-2-amine sulfonyl pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[N -(2,2-difluoroethyl)aminemethanyl]-2-amine sulfonate Mercaptopyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[N-(cyclopropylmethyl)aminecarbamyl ]-2-aminesulfonylpyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[N-(1-methyl) Cyclopropyl)amine-mercapto]-2-aminesulfonylpyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-3-[N-(2,2,2- Trifluoroethyl)amine-mercapto]-7-(4-trifluoromethylphenyl)-2-(hydroxymethyl)pyrazolo[1,5-a]pyrimidine; 6-(2-chlorobenzene -7-(4-Difluoromethylphenyl)-3-[N-(isobutyl)aminemethanyl]-2-aminesulfonylpyrazolo[1,5-a]pyrimidine; 2-Aminomethylmercapto-6-(2-chlorophenyl)-3-[N-(2,2,2-trifluoroethyl)aminemethylmercapto]-7-(4-trifluoromethylbenzene Pyrazolo[1,5-a]pyrimidine;6-(2-chlorophenyl)-7-(4-chloro-2-fluorophenyl)-3-[N-(2,2,2- Trifluoroethyl)amine-mercapto]-2-aminesulfonylpyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-difluoromethylphenyl )-3-[N-(2,2,2-trifluoroethyl)amine-methylmethyl]-2-aminesulfonylpyrazolo[1,5-a]pyrimidine; 6-(2-chlorobenzene -7-(4-Trifluoromethylphenyl)-3-[N-(n-propyl)aminemethanyl-2-aminesulfonylpyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-trifluoromethylphenyl)-3-[N-(isobutyl) Methiol]-2-amine sulfonyl pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-trifluoromethylphenyl)-3-[N -(1-methylpropyl)aminemethanyl]-2-aminesulfonylpyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-trifluoro Methylphenyl)-3-[N-(3-methoxyprop-2-yl)aminemethanyl]-2-aminesulfonylpyrazolo[1,5-a]pyrimidine; 6-( 2-chlorophenyl)-7-(4-trifluoromethylphenyl)-3-[N-(1-methylcyclopropyl)aminecaramidine 2-aminosulfonylpyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-3-[N-(2,2,2-trifluoroethyl)amine A N-based]-7-(4-fluorophenyl)-2-amine sulfonylpyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-trifluoromethyl Phenyl)-3-[[N'-methyl-N'-(2-pyridyl)indolyl]carbonyl]-2-aminesulfonylpyrazolo[1,5-a]pyrimidine; 6- (2-Chlorophenyl)-7-(4-trifluoromethylphenyl)-3-[N-(2,2,2-trifluoroethyl)aminecarbenyl]-2-(dimethyl Aminomethylpyridyl)pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-trifluoromethylphenyl)-3-[N-[1-methyl 1-(2-pyridyl)ethyl]amine-methylmethyl]-2-aminesulfonylpyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-3-[N -(3-methoxypropan-2-yl)aminemethylmercapto]-7-(4-methylpropyl)-2-aminesulfonylpyrazolo[1,5-a]pyrimidine; 6- (2-Chlorophenyl)-3-[N-(2,2,2-trifluoroethyl)aminemethylmercapto]-7-(4-methylphenyl)-2-aminesulfonylpyrazole And [1,5-a]pyrimidine; 6-(2-chlorophenyl)-3-[N-(isobutyl)aminecarbamyl]-7-(4-methylphenyl)-2-amine Sulfosylpyrazolo[1,5-a]pyrimidine; and 6-(2-chlorophenyl)-3-[N-(cyclopentyl)aminecarbamyl]-7-(4-methylbenzene 2-aminosulfonylpyrazolo[1,5-a]pyrimidine; or its medicinal Acceptance of salt.

When the compound [I] of the present invention has an asymmetric carbon atom in its molecule, the compound [I] may exist as a stereoisomer (diastereomer, optical isomer) due to the asymmetric carbon atom. And the invention also encompasses one of the stereoisomers and mixtures thereof.

The compound [I] of the present invention exhibits a high affinity for the CB1 receptor, and thus can be used as a CB1 receptor ligand, and is particularly useful as a CB1 receptor. Antagonist. Based on the antagonistic activity, the compounds are also useful as prophylactic and/or therapeutic agents for CB1 receptor-mediated diseases such as psychosis including schizophrenia, anxiety, stress, depression, epilepsy, neurodegenerative disorders, spinal cord Spinocerebellar disorder, cognitive impairment, craniocerebral trauma, panic attack, peripheral neuropathy, glaucoma, migraine, Parkinson's disease, Alzheimer's disease, Huntington's disease, Renault Syndrome, tremor, obsessive-compulsive disorder, amnesia, senile dementia, thymic disorder, Tourette's symdrome, delayed onset dyskinesia, bipolar disorder, cancer, drug-induced motor difficulty, dystonia, Septic shock, hemorrhagic shock, hypotension, insomnia, immune diseases including inflammation, multiple sclerosis, vomiting, diarrhea, asthma, appetite disorders such as bulimexia, anorexia, obesity, non-insulin Dependent Diabetes (NIDDM), memory disorder, urinary disorder, cardiovascular disease Disease, infertility, infection, demyelinating diseases, neuroinflammation, viral encephalitis, cerebral vascular incidents, cirrhosis or gastrointestinal disorders include intestinal transit disorders.

Further, the compound [I] of the present invention can be used as a long-term treatment, alcohol dependence or drug abuse (for example, opiates, barbiturates, marijuana, cocaine, amphetamine, phencyclidine) , hallucinogenic agents, benzodiazepine compounds, etc.) withdrawal agents.

Further, the compound [I] of the present invention can be used as an analgesic activity enhancer for an analgesic or narcotic drug or the like; a smoking cessation agent (by smoking or nicotine-dependent withdrawal).

Further, the compound [I] of the present invention can be used for the treatment of diseases associated with metabolic diseases, including obesity, diabetes, impaired glucose tolerance, hyperinsulinemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, Fat metabolism, atherosclerosis Chemotherapy, hypertension, cardiovascular disease, coronary heart disease, depression, anxiety, drug addiction, and substance addiction.

Further, the compound [I] of the present invention can be excellently used as a drug because of its low toxicity.

Meanwhile, from the viewpoint of low brain penetration of the compound [I] of the present invention, the compound [I] contains a compound which can be used as a selective antagonist to the peripheral CB1 receptor.

The compound [I] of the present invention can be used clinically in the form of a free form or a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable salt of the compound [I] comprises a salt formed with a mineral acid such as a hydrochloride, a sulfate, a phosphate or a hydrobromide salt; or a salt formed with an organic acid such as an acetate or a butene Diacid salts, oxalates, citrates, methanesulfonates, besylate, tosylate or maleate. Further, when the compound [I] of the present invention has a carboxyl group or the like in its molecule, examples of the pharmaceutically acceptable salt include a salt formed with a base such as a salt formed with an alkali metal (for example, a sodium salt or a potassium salt). Or a salt formed with an alkaline earth metal (for example, a calcium salt).

The compound [I] or a pharmaceutically acceptable salt thereof contains an intramolecular salt or an additive thereof and a solvate compound or hydrate thereof.

The present compound [I] or a pharmaceutically acceptable salt thereof can be administered orally or parenterally, and can be formulated into a conventional pharmaceutical preparation such as a tablet, a granule, a capsule, a powder, an injection or an inhalant. .

The dose of the compound [I] of the present invention or a pharmaceutically acceptable salt thereof may vary depending on the administration route and the age, weight and condition of the patient. For example, when administered in an injection preparation, the usual dosage is in the range of about 0.0001 to 1.0 mg/kg/day, preferably in the range of about 0.001 to 0.1 mg/kg/day. When administered in an oral formulation, the usual dosage is in the range of about 0.001 to 100 mg/kg/day, preferably 0.01. Up to 10 mg / kg / day.

The compound [I] of the present invention can also be used as adjunctive therapy, augmentation therapy or a supplementary therapy for the aforementioned diseases or conditions. Auxiliary, elevated, or complementary treatment refers to one or more additional therapeutic agents that the patient has received, is receiving, or will receive for treatment of the indication, such as one or more known antidepressants, antipsychotics, or anti-anxiety agents. The compound of the invention is administered to the patient simultaneously or sequentially.

The compound [I] of the present invention can be produced by the following method, but is not limited to the following methods.

(Method A)

In the compound [I] of the present invention, a compound having the following formula [IA]: Wherein R ^M is a group of the formula: or Or a group of the formula: -N(R ⁵ )(R ⁶ ) and other symbols are as defined above, and the compound is produced by a compound of the following formula [II-A]: Wherein R ^a is a hydrogen atom, an alkyl group or a benzyl group, which is reacted with or reacted with an amine compound of the formula [III]: HR ^M [III] wherein R ^M is as defined above.

When R ^a is a hydrogen atom, the aforementioned reaction can be carried out in a solvent in the presence of a condensing agent and in the presence or absence of an activator and a base. Examples of the solvent include any solvent which does not interfere with the reaction, such as dichloromethane, chloroform, dimethylformamide, dimethylacetamide, tetrahydrofuran, (dioxane), toluene, benzene, 1,2-dichloroethane, 1-methylpyrrolidone, 1,2-dimethoxyethane, and the like. The condensing agent may be dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC HCl), azide Diphenylphosphoryl azide (DPPA), carbonyl diimidazole (CDI), diethylcyanophosphonate (DEPC), diisopropylcarbodiimide (DIPCI), benzotriazole Benzyltriazol-1-yloxytrispyrrolidinophosphonium hexafluorophosphate (PyBOP), carbonyl di-triazole, N-cyclohexylcarbodiimide-N'-propoxymethylpoly Styrene (PS-carbodiimide), N-ethoxycarbonyl 2ethoxy-1,2-dihydroquinoline (EEDQ), 2-(7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium-1,1,3,3-tetramethyluronium hexafluorophosphate, HATU, 2-(1H- Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, 2-(1H-benzotriazol-1-yl-1,1,3,3-tetramethyluronium hexafluorophosphate, HBTU), bromotripyyrrolidinophosphonium hexaflurophosphate, Py BroP), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (2-(1H-benzotriazol-1-yl)-1,1 , 3,3-tetramethyluronium, TBTU), chloro-1,1,3,3-tetramethyl-uronium hexachloroantimonate (ACTU), and the like. Examples of activators include 1-hydroxybenzotriazole (HOBt), 1-hydroxybutylimine (HOSu), dimethylaminopyridine (DMAP), 1-hydroxy-7-azabenzotriazole (1-hydroxy-7-azabenzotriazole, HOAt), hydroxyphthalic acid imide (HOPht), pentafluorophenol (Pfp-OH), 1-hydroxybenzotriazole-6-sulfonylaminomethyl polymerization Styrene (PS-HOBt) and the like. The base includes, for example, pyridine, triethylamine, diisopropylethylamine, 4-methylmorpholine, 1,8-diazabicyclo[5,4,0]-7-undecene (1,8). -diazabicyclo[5,4,0]-7-undecene, DBU), etc.

In the above method, the compound [II-A] may be used in an amount of from 0.33 to 1.5 mol, preferably from 0.5 to 1.2 mol, per mol of the compound [III]. The amount of the condensing agent may be 1.0 to 3.0 moles, preferably 1.0 to 1.2 moles per 1 mole of the compound [II-A] or the compound [III]. The amount of the base may be 1.0 to 3.0 moles, preferably 1.0 to 1.2 moles per 1 mole of the compound [II-A] or the compound [III]. The activator may be used in an amount of 0.01 to 2.0 moles, preferably 0.1 to 1.0 moles per 1 mole of the compound [II-A] or the compound [III]. The reaction can be carried out at from 0 ° C to 150 ° C, preferably from 20 ° C to 80 ° C.

When R ^a in the compound [II-A] is ^a hydrogen atom, the compound [IA] can be produced by converting the compound [II-A] into a corresponding reactive derivative (for example, an acid halide or a mixed acid anhydride). And then reacting the reactive derivative with the compound [III] in the presence or absence of a solvent in the presence or absence of a solvent.

When R ^a in the compound [II-A] is an alkyl group or a benzyl group, the method of the present method A can also be carried out by a known method such as hydrolysis, acid hydrolysis or hydrogenation using hydrochloric acid, formic acid, trifluoroacetic acid or the like. The ester compound is converted into a corresponding carboxylic acid compound of the formula [II-Aa]: Wherein the symbols are as defined above, and then the carboxylic acid compound [II-Aa] is reacted with the compound [III] in the same manner as described above.

(Method B)

In the compound [I] of the present invention, a compound having a group of the formula: -SO ₂ - (the compound [IB] can be via, for example, the formula [II-B] sulfonylhalide and an amine compound [III] The reaction is made: Wherein W ⁰⁰ is a halogen atom and the other symbol systems are the same as defined above. This reaction can be carried out in a solvent in the presence of a base. Examples of the solvent include any solvent which does not interfere with the reaction, such as chloroform, dichloromethane, tetrahydrofuran, and the like. Examples of the base include pyridine, triethylamine, diisopropylethylamine, and the like. The amine compound [III] may be used in an amount of from 0.5 to 5.0 mols, preferably from 0.8 to 1.5 mols per 1 mol of the compound [II-B]. The amount of the base may be 1.0 to 5.0 moles, preferably 1.0 to 1.5 moles per 1 mole of the compound [II-B]. The reaction can be carried out at from -10 ° C to 100 ° C, and preferably from 0 ° C to 40 ° C.

(Method C)

In the compound [I] of the present invention, the compound of the following formula [IC]: Wherein each symbol is as defined above, for example via a compound of the formula [II-C]: Each symbol is as defined above, and is prepared by reacting with an alkyl isocyanate compound: R ⁰³ NCO wherein each symbol is as defined above, in the absence of a solvent. An excess of a mole number of an isocyanate compound can be used per 1 mole of the compound [II-C] to function as a solvent. The reaction can be carried out at 20 ° C to 120 ° C, preferably 50 ° C to 90 ° C. Meanwhile, other solvents such as chloroform, dichloromethane, tetrahydrofuran and the like can also be used for the reaction.

The object compound [I] of the present invention can also be produced, for example, by converting a substituent of R ¹ , R ² or the like in the compound [I] as defined above into another desired substituent. The intramolecular conversion procedure can be selected depending on the kind of the substituent of interest, and can be carried out, for example, by the following methods (a) to (h).

Process (a): The compound [I] having a cyano group (or a cyano group-containing group) as a substituent may have a halogen atom or an alkylsulfonyl group (or a halogen atom-containing group or an alkylsulfonyl group-containing group) a corresponding compound [I] as a substituent and a cyanide (for example, zinc cyanide, copper cyanide, trimethylsilyl cyanide, potassium cyanide, etc.) It can be obtained by reacting without the presence of a catalyst, a base and an additive. Examples of the base include triethylamine, N-methylpiperidine, diisopropylethylamine, and the like. Examples of the catalyst include a palladium catalyst such as palladium acetate, bis(dibenzylideneacetone)dipalladium, trans-dichloroindole-(tricyclohexylphosphine)palladium, ruthenium (triphenylphosphine)palladium or the like; and a nickel catalyst such as dibromofluorene - (triphenylphosphine) nickel or the like. Examples of the additive include phosphine compounds such as 1,1'-bis-(diphenylphosphino)ferrocene, racemic 2,2'-fluorene-(diphenyl) -phosphinyl)-1,1'-binaphthyl, 2-(di-t-butylphosphino)biphenyl, 2-(dicyclohexylphosphino)biphenyl, 2-dicyclohexylphosphino-2' -(N,N'-dimethylamino)biphenyl, tri-tert-butylphosphine, and the like.

Process (b): the compound [I] having an alkylamino group or a cycloalkylamino group (or an alkylamino group-containing group or a cycloalkylamino group-containing group) as a substituent may have a halogen The corresponding compound [I] having an atom (or a halogen-containing group) as a substituent is obtained by reacting a monoalkylamine or a dialkylamine or a cycloalkylamine in a suitable solvent in the presence of a catalyst, an additive and a base. An example of the catalyst may be a palladium compound or a copper compound used in the method (a). An example of the additive may be the phosphine compound used in the method (a). Examples of the base include potassium acetate, potassium carbonate, cesium carbonate, potassium third potassium hydride, and the like.

Process (c): A method of obtaining a compound [I] having an alkoxy group (or an alkoxy group-containing group) as a substituent, for example, (i) a corresponding one having a hydroxyl group (or a hydroxyl group-containing group) as a substituent Compound [I] is reacted with an alkyl halide in a solvent; or (ii) a corresponding compound [I] having a hydroxyl group (or a hydroxyl group-containing group) as a substituent and an alkanol in a solvent, such as potassium carbonate , cesium carbonate, sodium hydride, etc.) or an activator (such as diethyl azodicarboxylate), and in the presence of a trisubstituted phosphine; or (iii) will have an alkylsulfonyl group The compound [I] as a substituent (or an alkylsulfonyl group) is reacted with an alkali metal alkoxide in a suitable solvent.

Process (d): a compound [I] having an alkylsulfinyl group or an alkylsulfonyl group (or an alkylsulfinyl group or an alkylsulfonyl group) as a substituent can be A corresponding compound [I] having an alkylthio group (or an alkylthio group-containing group) as a substituent is obtained by reacting an oxidizing agent such as 3-chloroperbenzoic acid in a suitable solvent.

Process (e): The compound [I] having a mercaptoamine group such as an alkylcarbonylamino group (or a group containing a mercaptoamine group) as a substituent can be obtained by having an amine group (or an amine group-containing group) The corresponding compound [I] of the substituent is obtained by reacting with a carboxylic acid compound of the formula: R ^x -COOH [Ac-1] wherein R ^x is as defined above or a reactive derivative thereof (for example, corresponding anhydride or corresponding) Acid halide). The reaction can be carried out in a solvent in the presence of a base such as triethylamine or the like or a condensing agent such as a water-soluble carbodiimide, and in the presence or absence of an activator such as 1-hydroxybenzotriazole. Further, depending on the type of mercapto group, such mercapto groups can be removed by conventional methods such as acid treatment or catalytic hydrogenation.

Process (f): having a substituted or unsubstituted amine carbenyl group: -CON(R ^e )(R ^f ) (or a group containing a substituted or unsubstituted amine carbenyl group) as a substituent The compound [I] may be a corresponding compound [I] having a carboxyl group or an alkoxycarbonyl group (or a carboxyl group-containing or alkoxycarbonyl group-containing group) as a substituent and an amine compound of the formula: HN ( R ^e )(R ^f ) such as ammonia, monoalkylamine or dialkylamine is obtained by reaction in a suitable solvent.

Process (g): The compound [I] having an alkylamine-methylamino group (or a group containing an alkylamine-methylamino group) as a substituent may have an amine group (or an amine group-containing group) The corresponding compound [I] as a substituent is obtained by reacting an alkyl isocyanate in a suitable solvent.

Method (h): a compound having a group of the formula [I]: Wherein the ring A ¹ is a 5- to 7-membered nitrogen-containing aliphatic heteromonocyclic group as a substituent, and the compound [I] can be via a corresponding compound [I] having an amine group as a substituent and a compound of the formula: X ⁰¹ -Alk ¹ -X ⁰² wherein X ⁰¹ and X ⁰² are a halogen atom and Alk ¹ is an alkylene group in a solvent such as acetonitrile, in the presence of a base such as potassium carbonate, and in the presence or absence of an additive such as sodium iodide, Examples of such a nitrogen-containing aliphatic heterocyclic group include a 1-pyrrolidinyl group, a 1-piperidinyl group and the like.

Process (i): The compound [I] having a carboxyl group (or a carboxyl group-containing group) as a substituent can be treated with a hydroxymethyl group (or a hydroxymethyl group) via a suitable solvent and an oxidizing agent such as pyridinium dichromate. The group) is obtained as the corresponding compound [I] of the substituent.

The compound [I] of the present invention obtained by the above method can be converted into a pharmaceutically acceptable salt thereof in a conventional manner, if necessary.

[Preparation of intermediate compounds]

(i) In the intermediate compound [II-A] of the present invention, the compound of the formula [II-A1]: Wherein each symbol is as defined above, the compound of the formula [II-A1] can be produced in the manner as shown in the following Reaction Schemes A1 to A3.

In the above Reaction Schemes A1 to A3, R ⁰⁰¹ is an alkyl group; each of R ¹¹ and R ²¹ is an optionally substituted aryl group, an optionally substituted heteroaryl group or an optionally substituted nitrogen-containing aliphatic heterocyclic ring. R ¹² and R ²² are each an optionally substituted aryl group or an optionally substituted heteroaryl group; R ¹³ and R ²³ are each independently substituted nitrogen-containing aliphatic heterocyclic group; R ⁰⁰² And R ⁰⁰³ are the same or different, and each is a hydrogen atom or an alkyl group or a combination of the two to form an alkylene group; t-Bu is a third butyl group; W ⁰¹ and W ⁰² are each a halogen atom and other symbol systems Same as the previous definition.

Examples of the aryl group in R ¹¹ , R ¹² , R ²¹ or R ²² include a 6- to 10-membered monocyclic aryl group or a bicyclic aryl group such as a phenyl group or a naphthyl group. Among them, phenyl is preferred.

Examples of the heteroaryl group in R ¹¹ , R ¹² , R ²¹ or R ²² include a 5- to 10-membered monocyclic heteroaryl group having 1 to 3 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom. Or a bicyclic heteroaryl group. Among them, a furyl group, a thienyl group or a pyridyl group is preferred.

Examples of the nitrogen-containing aliphatic heterocyclic group in R ¹¹ , R ¹² , R ²¹ or R ²² may additionally have one or two hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, as needed. 5 to 7 members of aliphatic heteromonocyclic groups. Among them, a 1-pyrrolidinyl group, a 1-piperidinyl group, a morpholinyl group or a thiomorpholin group is preferred.

Each of the aryl, heteroaryl or nitrogen-containing aliphatic heterocyclic group in R ¹¹ , R ¹² , R ²¹ or R ²² may be substituted with one to three groups selected from the group consisting of a halogen atom, a cyano group, An alkyl group substituted with 1 to 3 halogen atoms, an alkoxy group substituted with 1 to 3 halogen atoms as necessary, and an alkylsulfonyl group.

The alkylene group formed by the combination of R ⁰⁰² and R ⁰⁰³ may be a linear or branched C _2-6 alkylene group such as an ethylidene group, a trimethylene group or a 1,1,2,2-tetramethyl group. base. Examples of the alkylene substituent include an alkyl group such as a methyl group.

The respective reactions described in the above Reaction Chart A1 to Reaction Diagram A3 can be carried out, for example, in the manner described later.

Step A1-1:

The reaction of the compound [VI] with the compound [VII] can be carried out under heating in a suitable solvent. Examples of the solvent include any solvent which does not interfere with the reaction, such as dimethylformamide, dimethylacetamide, and two 1,2-dichloroethane, toluene, xylene, and the like. The compound [VII] may be used in an amount of 1.0 to 10 moles, preferably 1.0 to 3.0 moles per 1 mole of the compound [VI]. The reaction can be carried out at 50 ° C to 200 ° C, preferably 80 ° C to 150 ° C.

Step A1-2:

The reaction of the compound [VIII] with the compound [i] can be carried out in a suitable solvent in the presence or absence of a base. Examples of the base include piperidine, morpholine, and N-methylpiperidone. , diethylamine, etc. Examples of the solvent include any solvent that does not interfere with the reaction, such as acetic acid, methanol, ethanol, isopropanol, ethylene glycol, and the like. The compound [i] may be used in an amount of from 0.5 to 2.0 mols, preferably from 0.8 to 1.2 mols per 1 mol of the compound [VIII]. The base may be used in an amount of from 0.01 to 2.0 moles, preferably from 0.1 to 1.0 moles per 1 mole of the compound [VIII]. The reaction can be carried out at 50 ° C to 150 ° C, preferably 70 ° C to 100 ° C.

Further, the reaction can be carried out in a solvent in the presence or absence of an acid. Examples of the acid include hydrobromic acid, hydrochloric acid, acetic acid, and the like. Examples of the solvent include any solvent that does not interfere with the reaction, such as acetic acid, methanol, ethanol, isopropanol, ethylene glycol, and the like. The compound [i] may be used in an amount of from 0.5 to 2.0 mols, preferably from 0.8 to 1.2 mols per 1 mol of the compound [VIII]. The acid may be used in an amount of 0.1 to 3.0 moles, preferably 0.3 to 1.0 moles per 1 mole of the compound [VIII]. The reaction can be carried out at from 0 ° C to 150 ° C, preferably from 60 ° C to 100 ° C.

Step A2-1:

The reaction of the compound [VI-a] with the compound [VII] can be carried out in the same manner as described in the step A1-1.

Step A2-2:

The reaction of the compound [VII-a] with the compound [i] can be carried out in the same manner as described in the step A1-2. Further, when the present reaction is carried out in the presence of acetic acid, the compound [X-a] can be obtained without performing the next step A2-3.

Step A2-3:

The intramolecular cyclization reaction of the compound [IX-a] can be carried out in a solvent in the presence of a base. Examples of the solvent include any solvent which does not interfere with the reaction such as ethanol, acetonitrile, chloroform, tetrahydrofuran, , toluene, N,N-dimethylformamide, and the like. Examples of the base include sodium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, dimethylaminopyridine, and the like. The base may be used in an amount of from 0.1 to 10.0 mol, preferably from 1.2 to 3.0 mol, per 1 mol of the compound [IX-a]. The reaction can be carried out at 30 ° C to 150 ° C, preferably 60 ° C to 100 ° C.

Step A2-4:

Conversion of the compound [Xa] to the compound [XII-a] can be carried out in a solvent in the presence of a halogenating agent and in the presence or absence of a base. Examples of the solvent include any solvent which does not interfere with the reaction such as acetonitrile, chloroform, tetrahydrofuran, , toluene, N,N-dimethylformamide, and the like. Examples of the halogenating agent include phosphorus oxychloride, sulfinium chloride, phosphorus pentachloride, grass chloroform, and the like. Examples of the base include N,N-dimethylaniline, diisopropylethylamine, N-methylmorpholine and the like. The halogenating agent may be used in an amount of 1.1 to 5.0 moles, preferably 1.2 to 1.5 moles per 1 mole of the compound [Xa]. The base may be used in an amount of from 1.2 to 10.0 mol, preferably from 1.5 to 2.0 mol, per 1 mol of the compound [Xa]. The reaction can be carried out at 50 ° C to 200 ° C, preferably at 80 ° C to 150 ° C.

Step A2-5:

(1) The reaction of the compound [XII-a] with the boric acid compound [XIII-a] can be carried out in a solvent in the presence of a catalyst and a base. Examples of the boric acid compound [XIII-a] include wherein R ⁰⁰² and R ⁰⁰³ are each a hydrogen atom or an alkyl group such as a methyl group, an ethyl group, an isopropyl group or the like, or R ⁰⁰² and R ⁰⁰³ are combined with each other to form an alkylene group such as a stretching group. A compound such as ethyl, propyl, 1,1,2,2-tetramethylethyl or the like. Among them, preferred examples include the compound [XIII-a] wherein R ⁰⁰² and R ⁰⁰³ are each a hydrogen atom or a corresponding boroxin compound of the following formula: Each symbol is defined as before. Examples of the solvent include any solvent that does not interfere with the reaction such as two , toluene, dimethoxyethane, ethanol, N,N-dimethylformamide, tetrahydrofuran, water, and the like. Examples of the catalyst include a palladium catalyst such as ruthenium (triphenylphosphine)palladium(0), palladium(II) acetate, ruthenium (dibenzylideneacetone)palladium(0), ruthenium (triphenylphosphine)palladium dichloride ( II), hydrazine (tri-o-tolylphosphine) palladium (II) dichloride, ruthenium (tricyclohexylphosphine) palladium (II) dichloride, or [1,1'-fluorene (diphenylphosphino) iron莘] palladium (II) dichloride; a nickel catalyst such as 1,3-bis(diphenylphosphino)propane nickel (II) chloride or ruthenium (triphenylphosphine) nickel (II) chloride. Examples of the base include potassium phosphate, sodium carbonate, cesium carbonate, sodium hydrogencarbonate, potassium fluoride, triethylamine, lithium chloride, and the like. The compound [XIII-a] may be used in an amount of 1.0 to 5.0 moles, preferably 1.1 to 2.0 moles per 1 mole of the compound [XII-a]. The catalyst may be used in an amount of from 0.001 to 0.5 mol, preferably from 0.01 to 0.05 mol, per 1 mol of the compound [XII-a]. The base may be used in an amount of from 1.0 to 10.0 mol, preferably from 2.0 to 5.0 mol, per 1 mol of the compound [XII-a]. The reaction can be carried out at 20 ° C to 150 ° C, preferably 60 ° C to 120 ° C.

(2) The reaction of the compound [XII-a] with the nitrogen-containing heterocyclic compound [XIII-b] can be carried out in a solvent in the presence of a base. Examples of the solvent include any solvent that does not interfere with the reaction, such as N,N-dimethylformamide, toluene, and , tetrahydrofuran, and the like. Examples of the base include potassium carbonate, sodium carbonate, cesium carbonate, sodium hydrogencarbonate, potassium fluoride, triethylamine, diisopropylethylamine, dimethylaminopyridine, and the like. The compound [XIII-b] may be used in an amount of from 0.8 to 5.0 mols, preferably from 1.0 to 1.5 mols, per 1 mol of the compound [XII-a]. The base may be used in an amount of from 1.0 to 10.0 mol, preferably from 2.0 to 5.0 mol, per 1 mol of the compound [XII-a]. The reaction can be carried out at 80 ° C to 200 ° C, preferably 120 ° C to 180 ° C.

Step A3-1:

The reaction of the compound [VI-b] with the compound [VII-b] can be carried out in a solvent or without any solvent. Examples of the solvent include any solvent which does not interfere with the reaction, such as dimethylformamide, toluene, and , tetrahydrofuran, dimethoxyethane, and the like. The compound [VII-b] may be used in an amount of 0.5 to 5.0 moles, preferably 0.9 to 1.5 moles per 1 mole of the compound [VI-b]. The reaction can be carried out at from 0 ° C to 150 ° C, preferably from 50 ° C to 80 ° C.

Step A3-2:

The halogenation of the compound [VIII-b] can be carried out in a solvent in the presence of a halogenating agent and in the presence or absence of a base. Examples of the solvent include any solvent which does not interfere with the reaction, such as dichloromethane, carbon tetrachloride, chloroform, acetic acid, tetrahydrofuran, and the like. Examples of the halogenating agent include bromine, N-bromosuccinimide, N-chlorobutaneimine, and the like. Examples of the base include triethylamine, diisopropylethylamine, potassium carbonate, sodium carbonate, and the like. The halogenating agent may be used in an amount of from 0.5 to 10.0 mol, preferably from 1.0 to 3.0 mol, per 1 mol of the compound [VIII-b]. The reaction can be carried out at from -40 ° C to 100 ° C, preferably from -5 ° C to 20 ° C.

Step A3-3:

The reaction of the compound [IX-b] with the compound [i] can be carried out in the same manner as described in the step A1-2.

Step A3-4:

The reaction of the compound [X-b] with the boronic acid compound [XIII-c] or the nitrogen-containing heterocyclic compound [XIII-d] can be carried out in the same manner as described in the step A2-5(1) or A2-5(2), respectively.

(ii) In the intermediate compound [II-A], a compound of the following formula [II-A3]: Wherein each symbol is as defined above, the compound of the formula [II-A3] can be produced according to the following reaction scheme A4.

(Reaction diagram A4)

In the above reaction scheme, Bzl is a benzyl group and other symbol systems are the same as defined above.

The reaction described in the above Reaction Chart A4 can be carried out, for example, in the manner exemplified below.

Step A4-1:

This reaction can be carried out in the same manner as described in the step A1-2.

Step A4-2:

The reaction of the compound [II-A5] with sodium chlorite can be carried out in a solvent in the presence of an acid such as concentrated hydrochloric acid. Examples of the solvent include any solvent which does not interfere with the reaction, such as dichloromethane, chloroform or the like. The amount of sodium chlorite may be from 0.5 to 10.0 mol, preferably from 1.0 to 3.0 mol, per 1 mol of the compound [II-A5]. The reaction can be carried out at from -40 ° C to 100 ° C, preferably from -5 ° C to 20 ° C.

Step A4-3:

The reaction of the compound [II-A6] with the compound [III-C] can be carried out in the same manner as described in the method B.

(iii) in the intermediate compound [II-A], wherein a compound wherein R ⁰ is a hydroxyalkyl group is prepared, for example, by using a brominating agent such as N-bromosuccinimide in a solvent such as carbon tetrachloride. Treating a corresponding compound having R ⁰ as an alkyl group; and then reacting the product thus obtained with an acetate compound such as potassium acetate in a solvent such as dimethylformamide; and further a base such as an alkali metal alkoxide Sodium ethoxide) is prepared by treating the reaction product in a solvent such as a mixture of ethanol and tetrahydrofuran.

(iv) the aforementioned intermediate compound [II-B] can be, for example, via a compound of the following formula [II-C]: [wherein each symbol is as defined above] and a halogenated sulfonic acid compound of the formula [XIV]: Hal-SO ₃ H [XIV] [wherein Hal is a halogen atom] is reacted in a solvent such as chloroform; and then a halogenating agent such as sulfin The reaction product is prepared by treating a reaction product with a thionyl halide such as sulfinium chloride.

In the present specification and the entire scope of the patent application, "halogen atom" means a fluorine, chlorine, iodine or bromine atom. "Alkyl" means a straight or branched alkyl group having 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms. "Cycloalkyl" means a cycloalkyl group having 3 to 8 carbon atoms and preferably 5 to 7 carbon atoms. "Alkylene" means a straight or branched alkyl group having 1 to 8 carbon atoms and preferably 1 to 6 carbon atoms.

Instance

Further details of the compounds of the present invention are illustrated by the following examples, but are not to be construed as limited to the following examples.

Example A1

3-carboxy-6-(2-chlorophenyl)-7-(4-chlorophenyl)pyrazolo-[1,5-a]pyrimidine (Compound 1-(4) compound; 58 mg ( Mg)) and 1-cyanocyclohexylamine hydrochloride (25 m g) In a solution of chloroform (1.0 ml (mL) containing pentene), add 1-hydroxybenzotriazole monohydrate to chloroform (0.45 ml of pentene) in 0.5 M solution, 1-(3-dimethyl Aminomethyl-propyl)-3-ethylcarbodiimide hydrochloride in 0.5 M solution of N,N-dimethylformamide (0.45 ml) and triethylamine (63 μL (μL) The mixture was stirred overnight at room temperature. Aqueous saturated sodium bicarbonate solution (2 ml), water (2 ml) and chloroform (4 ml). The organic layer was separated and the aqueous layer was extracted with chloroform (3 ml). The combined organic layers were washed with EtOAc EtOAc m. The obtained crude product was purified by liquid chromatography-mass spectrometry (LCMS, column; XTerra MS C18, solvent; 10 mM ammonium carbonate/methanol = 40/60 to 10/90) and lyophilized to obtain 6 -(2-chlorophenyl)-7-(4-chlorophenyl)-3-[N-(1-cyanocyclohexyl)aminecarboxylidene]pyrazolo[1,5-a]pyrimidine (15.6 Mg; yield: 21%) in powder.

MS (ESI) m/z; 490 [M+H] ⁺

Example A2

To a solution of the compound (70 mg), m. m. Aqueous saturated sodium bicarbonate solution and dichloromethane were added sequentially to the reaction mixture. After stirring, the organic layer was separated and concentrated in vacuo. The obtained crude product was purified by column chromatography on a silica gel (solvent; chloroform/methanol = 100/0 to 95/5) to obtain 3-[N-(1-amine-carbamoylcyclohexyl)amine. Indoleyl-6-(2-chlorophenyl)-7-(4-chlorophenyl)-pyrazolo[1,5-a]pyrimidine (18 mg; yield: 25%), as a pale yellow solid .

MS (APCI) m/z; 508/510 [M+H] ⁺

Example A3

(1) The compound obtained in Reference Example 1-(4) (77 mg) and 4-amino-4-cyanotetrahydrothiopyran hydrochloride were treated in the same manner as described in Example A1 (Reference Example A3-(1) ) the obtained compound; 34 mg) to give 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[N-(4-cyanotetrahydrothiopyran-4-yl) Aminomethylmercapto]pyrazolo[1,5-a]pyrimidine (50.8 mg; yield: 50%) was obtained as a powder.

MS (APCI) m/z; 508/510 [M+H] ⁺

(2) The compound obtained in the above step (1) (yield: 47 mg) was dissolved in dichloromethane/methanesulfonic acid (1 ml / 18 μl), and m-chloroperbenzoic acid (75%, 53 mg) was added thereto. The mixture was stirred at room temperature for 3 hours. An aqueous saturated sodium bicarbonate solution was added to the reaction mixture. After stirring, the organic layer was separated and concentrated in vacuo. The obtained crude product was purified by column chromatography on a silica gel (solvent; chloroform/methanol = 98/2 to 95/5) to obtain 3-[N-(4-amine-carbazin-1, 1- Diketo-tetrahydrothiopyran-4-yl)amine-mercapto]-6-(2-chlorophenyl)-7-(4-chlorophenyl)-pyrazolo[1,5-a] Pyrimidine (18 mg; yield: 35%) as a solid.

MS (APCI) m/z; 558/560 [M+H] ⁺

Example A4

(1) In a solution of the compound obtained in Reference Example 1-(4) (300 mg) and 1-methoxycarbonylcyclohexylamine hydrochloride (181 mg) in dichloromethane (4 ml) Benzotriazole monohydrate (179 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (224 mg) and triethylamine (328 μl) The mixture was stirred overnight at room temperature. Dichloromethane and an aqueous saturated sodium bicarbonate solution were added to the reaction mixture. After vigorous stirring for 10 minutes, the organic layer was separated and concentrated in vacuo. The obtained crude product was purified by NH-hydroxy gel by column chromatography (Chromatorex NH Oxygen Gel, Fuji Silicia Chem., solvent; hexane/acetic acid) Ethyl ester = 70/30 to 50/50) to give 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[N-(1-methoxycarbonylcyclohexyl)amine Methylidene]pyrazolo[1,5-a]pyrimidine (380 mg; yield: 93%).

MS (APCI) m/z; 523/525 [M+H] ⁺

(2) To a solution of the compound (200 mg) obtained in the above step (1) in ethanol (2 ml), aqueous 2N sodium hydroxide solution (0.38 ml), and the mixture was stirred at room temperature overnight and stirred at 50 ° C 5 hour. After cooling to room temperature, aqueous 2N hydrochloric acid solution (0.38 mL), brine and dichloromethane were then applied to the mixture. The organic layer was separated and concentrated under vacuum. The obtained crude product was purified by column chromatography on a silica gel (solvent; chloroform/methanol = 99/1 to 92/8) to give 3-[N-(1-carboxycyclohexyl)amine carbhydryl] -6-(2-Chlorophenyl)-7-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidine (180 mg; Yield: 92%), as a powder.

MS (APCI) m/z; 509/511 [M+H] ⁺

Example A5

Add 1-hydroxybenzotriazole monohydrate (23 mg), 1- in a solution of the compound (50 mg) and m. (3-Dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (29 mg) and triethylamine (21 mL). Dichloromethane and an aqueous saturated sodium bicarbonate solution were added to the reaction mixture. After vigorous stirring for 10 minutes, the organic layer was separated and concentrated in vacuo. The obtained crude product was purified by column chromatography on a silica gel (solvent; chloroform/methanol = 100/0 to 95/5), and triturated to obtain 6-(2-chlorophenyl)-7- ( 4-chlorophenyl)-3-[N-[1-(N-methylaminecarbamimidyl)cyclohexyl]pyrazolo[1,5-a]pyrimidine (25 mg; yield: 61%).

MS (APCI) m/z; 522/524 [M+H] ⁺

Example A6

(1) The compound obtained in Reference Example A6 (2-amino-6-(2-chloro-phenyl)-3-ethoxycarbonyl-7-(4-) was treated in the same manner as described in Reference Example A1-(4). Trifluoromethylphenyl)pyrazolo[1,5-a]pyrimidine, 3.0 g), (2-amino-3-carboxy-6-(2-chloro-phenyl)-7-(4) -Trifluoromethylphenyl)pyrazolo[1,5-a]pyrimidine, 3.0 g), as a powder.

(2) The compound obtained in the above step (1) (200 mg) and 1-(2-pyridyl)ethylamine (73 mg) were treated in the same manner as described in Example A1 to obtain 2-amino-6-(2). -Chlorophenyl)-7-(4-trifluoromethylphenyl)-3-[N-[1-(2-pyridyl)ethyl]aminemethanyl]pyrazolo[1,5-a Pyrimidine (112 mg; yield: 45%) in powder.

(3) A mixture of the compound (59 mg), ethyl acetate (156 m), triethylamine (304 liters) and tetrahydrofuran (5 ml) obtained in the above step (2) was stirred overnight at 60 °C. Aqueous saturated sodium bicarbonate solution was added to the reaction mixture at 0 °C. After stirring, the mixture was extracted with chloroform, and the extract was dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum, and the obtained crude product was purified by column chromatography on NH-H.sub.O.O. (K. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 70), and 2-acetamido-6-(2-chlorophenyl)-7-(4-trifluoromethylphenyl)-3-[N-[1-(2-pyridyl)-ethyl Aminomethylpyrazine]pyrazolo[1,5-a]pyrimidine (50.8 mg; yield: 80%) was obtained as a pale yellow powder.

MS (APCI) m/z; 579/581 [M+H] ⁺

Example A7

(1) 1,4-dichlorobutane (2.9 g), potassium carbonate (3.2 g) and iodine were added to a solution of the compound (2.1 g) obtained in the title compound A6 in water / acetonitrile (21 ml / 84 ml). Sodium (2.7 g) was added and the mixture was refluxed for 5 days. After cooling to room temperature, ethyl acetate and water were added to the reaction mixture. After stirring, the organic layer was separated, dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum, and the obtained crude product was purified on a silica gel column chromatography. Hexane/ethyl acetate = 85/15 to 70/30) to obtain 6-(2-chlorophenyl)-3-ethoxycarbonyl-7-(4-trifluoromethylphenyl)- 2-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine (0.61 g; yield: 26%) as a yellow oil.

MS (APCI) m/z; 515/517 [M+H] ⁺

(2) The compound obtained in the above step (1) (610 mg) was obtained in the same manner as the the the Methylphenyl)-2-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine (449 mg), then the compound (70 mg) was obtained in the same manner as described in Example A1 to give 6 -(2-chlorophenyl)-7-(4-trifluoromethylphenyl)-3-[N-[1-(2-pyridyl)ethyl]aminemethanyl]-2-(pyrrolidine) -1-yl)pyrazolo[1,5-a]pyrimidine (15.2 mg).

MS (APCI) m/z; 591/593 [M+H] ⁺

Example A8

(1) The compound obtained in Reference A11 (3-carboxy-7-(4-chloro-2-fluorophenyl)-6-(2-chlorophenyl)pyrazolo[1,5) was treated in the same manner as described in Example A1. -a]pyrimidine; 39 mg) and methyl 4-amino-1,1-dionetetrahydrothiopyran-4-carboxylate (20 mg) to give 7-(4-chloro-2-fluoro Phenyl)-6-(2-chlorophenyl)-3-[N-(4-methoxycarbonyl-1,1-dionetetrahydrothiopyran-4-yl)aminemethanyl]pyridinium Zyrazolo[1,5-a]pyrimidine (45 mg; yield: 79%), as a gray-yellow powder.

MS (APCI) m/z; 591/593 [M+H] ⁺

(2) The compound obtained in the above step (1) (352 mg) was obtained in the same manner as described in Example A4-(2) to obtain 3-[N-(4-carboxy-1,1-dione-tetrahydrothiophene).喃-4-yl)amine-mercapto]-7-(4-chloro-2-fluorophenyl)-6-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidine (301 mg; Yield: 88%), a grayish yellow powder.

MS (APCI) m/z; 577/579 [M+H] ⁺

(3) The compound obtained in the above step (2) (70 mg) and ammonium chloride (32 mg) were obtained in the same manner as described in Example 1 to obtain 3-[N-(4-amine-carbazin-1, 1- Diketotetrahydrothiopyran-4-yl)amine-mercapto]-7-(4-chloro-2-fluorophenyl)-6-(2-chlorophenyl)pyrazolo[1,5- a] Pyrimidine (40 mg; yield: 57%), as a grayish yellow powder.

MS (APCI) m/z;576/578[M+H] ⁺

Examples A9 to A15

The corresponding starting materials were treated in the same manner as described in Example A1 to give the compound shown in Table 1 below.

Examples A16 to A18

The corresponding starting materials were treated in the same manner as described in Example A5, and the compound shown in Table 2 below was obtained.

Examples A19 to A30

The corresponding starting materials were treated in the same manner as described in Example A4, and the compound shown in Table 3 below was obtained.

Examples A31 to A32

The corresponding starting materials were treated in the same manner as described in Example A1 to give the compound shown in Table 4 below.

Example A34

(1) The corresponding starting materials were treated in the same manner as described in Reference Example 6, to obtain 2-amino-6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-ethoxy Alkylcarbonylpyrazolo[1,5-a]pyrimidine in the form of a yellow powder.

MS (APCI) m/z; 427/429 [M+H] ⁺

(2) A solution of the compound obtained in the above step (1) (2.64 g) in tetrahydrofuran (50 ml) was added triethylamine (5.17 ml) and methanesulfonyl chloride (2.83 g) at 0 ° C Stir for 5 minutes and stir at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and water was added at 0 °C. After stirring, the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer was combined by dehydration with magnesium sulfate and filtration. The filtrate was concentrated under vacuum, and the obtained crude product was purified by column chromatography on EtOAc (H.sub. - 7-(4-chlorophenyl)-3-ethoxycarbonyl-2-[indolyl(methylsulfonyl)-amino]pyrazolo[1,5-a]pyrimidine (2.91 g, produced) Rate: 81%), grayish yellow solid.

MS (APCI) m/z; 583/585.[M+H] ⁺

(3) To a solution of the compound (2.91 g) obtained in the above step (2) in tetrahydrofuran (60 ml), tetrabutylammonium fluoride trihydrate (3.15 g) was added, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was stirred. The organic layer was separated and the aqueous layer was extracted with chloroform. The combined organic layers were concentrated under vacuum, and the obtained crude product was purified by column chromatography (solvent; hexane/ethyl acetate = 70/30 to 50/50) to obtain 6-(2-chloro Phenyl)-7-(4-chlorophenyl)-3-ethoxycarbonyl-2-(methylsulfonyl-amino)pyrazolo[1,5-a]pyrimidine (2.20 g, yield: 87%), grayish yellow solid.

MS (APCI) m/z; 505/507.[M+H] ⁺

(4) In a solution of the compound obtained in the above step (3) (0.8 g) in ethanol / THF (10 ml / 20 ml), aqueous 2 N sodium hydroxide solution (4.8 ml), and the mixture was stirred overnight at 40 ° C . The precipitate was collected by filtration to give 3-carboxy-6-(2-chlorophenyl)-7-(4-chlorophenyl)-2-(methylsulfonylamino)pyrazolo[1,5-a] Pyrimidine (0.86 g) as a crude product.

MS (APCI) m/z; 477/479.[M+H] ⁺

(5) The compound obtained in the above step (4) (70 mg) and 1-(2-pyridyl)-ethylamine (23 mg) were treated in the same manner as described in Example A1 to give 6-(2-chlorophenyl). - 7-(4-Chlorophenyl)-2-(methylsulfonylamino)-3-[N-[1-(2-pyridyl)ethyl]aminemethanyl]pyrazolo[1] , 5-a]pyrimidine (27 mg; yield: 32%), as a colorless powder.

MS (APCI) m/z; 581/583. [M+H] ⁺

Example A35

(1) A mixture of the obtained compound (1.0 g), sodium oxychloride (1.35 g) and ethanol (40 ml) was stirred at 80 ° C for 10 min. Methyl iodide (2.5 ml) was added dropwise thereto, and the mixture was stirred for 3 days. The reaction mixture was concentrated under vacuum and added to residue Water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer was combined by dehydration with magnesium sulfate and filtration. The filtrate was concentrated under vacuum, and the obtained crude product was purified by column chromatography on NH-H.sub.O.O. (K. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 60), to obtain 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-ethoxycarbonyl-2-[N-methyl-N-(methylsulfonyl)amine Pyrazolo[1,5-a]pyrimidine (1.06 g, yield: 100%) as a colorless powder.

MS (APCI) m/z;519/521.[M+H] ⁺

(2) A solution of the compound obtained in the above step (1) (1.06 g) in ethanol / THF (15 ml / 15 ml) . The reaction mixture was acidified with aqueous EtOAc (EtOAc)EtOAc. Dehydrate with magnesium sulfate and filter the organic layer. The filtrate was concentrated in vacuo and the residue was crystallised from diethyl ether to afford 3-carboxy-6-(2-chlorophenyl)-7-(4-chlorophenyl)-2-[N-methyl-N- ( Methylsulfonyl)amino]pyrazolo[1,5-a]pyrimidine (0.75 g, yield: 75%) was obtained as a pale yellow powder.

MS (APCI) m/z; 491/493.[M+H] ⁺

(3) The compound obtained in the above step (2) (60 mg) and 1-(2-pyridyl)-ethylamine (19 mg) were treated in the same manner as described in Example A1 to give 6-(2-chlorophenyl). )-7-(4-chlorophenyl)-2-[N-methyl-N-(methylsulfonyl)amino]-3-[N-[1-(2-pyridyl)ethyl] Aminomethylidene]pyrazolo[1,5-a]pyrimidine (57 mg, yield: 79%) was obtained as a colorless powder.

MS (APCI) m/z; 595/597.[M+H] ⁺

Examples A36 to A38

The corresponding starting materials were treated in the same manner as described in Example A1 to obtain the compound shown in Table 5 below.

Example A39

The compound obtained in Reference Example A9 (159 mg) and pyridine (83 ml) was obtained from chloroform (5 ml). The solution was stirred at room temperature for 17 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was concentrated under vacuum, and the obtained crude product was purified by column chromatography (solvent; hexane/ethyl acetate = 80/20 to 65/35) to obtain 6-(2-chlorobenzene). -7-(4-Trifluoromethylphenyl)-3-[N-(1-methoxycarbonylcyclohexyl)amine sulfonyl]-2-methylpyrazolo[1,5-a Pyrimidine (205 mg, yield: 82%) in powder.

MS (APCI) m/z; 607/609 [M+H] ⁺

Example 40

A solution of the compound (190 mg) obtained from m. After cooling to room temperature, aqueous 2 N hydrochloric acid (400 μl) was added to the reaction mixture. Dilute the mixture with water. The precipitate was collected by filtration to give 3-[N-(1-carboxycyclohexyl)aminesulfonyl]-6-(2-chlorophenyl)-7-(4-trifluoromethylphenyl)-2-methyl Pyrazolo[1,5-a]pyrimidine (150 mg, yield: 81%) was obtained as a powder.

MS (APCI) m/z; 593/595 [M+H] ⁺

Example A41

(1) The compound obtained in Reference Example A10 (200 mg) and the compound obtained in Reference Example B15 (63 mg) were obtained in the same manner as described in Example A1 to obtain 6-(2-chlorophenyl)-7-(4-trifluoromethyl). Phenyl)-3-[N-(4-methyl-tetrahydrothiopyran-4-yl)aminecarboxylidene]pyrazolo[1,5-a]pyrimidine (153 mg, yield: 48 %), in powder.

MS (APCI) m/z; 531/533 [M+H] ⁺

(2) To a solution of the compound (95 mg) obtained from m. Stir for 21 hours. Aqueous saturated sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was concentrated under vacuum, and the obtained crude product was purified by column chromatography (solvent; hexane/ethyl acetate = 80/20 to 60/40) to obtain 6-(2-chlorobenzene). -7-(4-Trifluoromethylphenyl)-3-[N-(4-methyl-1,1-dionetetrahydrothiopyran-4-yl)aminecarboxyl]- Pyrazolo[1,5-a]pyrimidine (68 mg; yield: 68%) as a powder.

MS (APCI) m/z; 563/565 [M+H] ⁺

Examples A42 to A49

The corresponding starting materials were treated in the same manner as described in Example A41 to give the compound shown in Table 6 below.

Examples A50 to A64

The corresponding starting materials were treated in the same manner as described in Example A1, and obtained as follows The compounds shown in Table 7.

Example A65

(1) In a solution of 1-(t-butoxycarbonylamino)-cyclopentanoic acid (2.29 g) in methanol (10 ml), 2 M trimethyldecyl group was added dropwise with ice cooling The diazomethane solution was taken in hexane (11.9 mL). The reaction mixture was concentrated and hexane was added to the residue. The precipitated crystals were collected by filtration, and the filtrate was purified on a silica gel column chromatography (solvent; hexane/ethyl acetate 9/1 to 7/3). The product and crystals obtained above were combined to obtain methyl 1-(t-butoxycarbonyl)-cyclopentanecarboxylate (2.49 g).

MS (ESI) m/z; 244 [M+H] ⁺

(2) In a solution of the compound obtained in the above step (1) (2.49 g) in tetrahydrofuran (12 ml), 3 M methylmagnesium bromide was added dropwise under ice cooling under a nitrogen atmosphere. The solution was taken in diethyl ether (13.3 mL). The mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dehydrated with magnesium sulfate and purified by column chromatography on silica gel (solvent; hexane/ethyl acetate 8/1) to give [1-(1-hydroxy-1-methyl-ethyl). A mixture (0.57 g) of cyclopentyl]aminocarbamic acid tert-butyl ester and methyl 1-(t-butoxycarbonylamino)cyclopentacarboxylate (0.57 g) was obtained as a powder.

(3) A solution of the compound (0.56 g, m. The reaction mixture was concentrated in vacuo and crystall Concentrated hydrochloric acid (0.6 ml) was added thereto, and the mixture was stirred for 1 minute. The reaction mixture was concentrated under vacuum and the residue was dissolved in ethanol. The solution was concentrated and ethanol/diethyl ether was added to the residue. The mixture was stirred overnight, and the crystals which precipitated were collected by filtration, washed with diethyl ether and dehydrated to give 1-(1-hydroxy-1-methylethyl)-cyclopentylamine hydrochloride and 1-aminocyclopentanecarboxylate. A mixture of acid methyl ester hydrochloride (376 mg) was obtained as a powder.

(4) The compound obtained in the above step (3) (56 mg) and 3-carboxy-6-(2-chlorophenyl)-7-(4-chlorophenyl) were treated in the same manner as described in Example A4-(1). Pyrazolo[1,5-a]pyrimidine (100 mg), the reaction product was dissolved in ethanol (2 mL). An aqueous 2 N sodium hydroxide solution (0.2 ml) was added thereto, and the mixture was stirred at 60 ° C for 2.5 hours. After cooling to room temperature, the reaction mixture was neutralized with aqueous 2N hydrochloric acid and extracted with dichloromethane. The organic layer was concentrated under vacuum, and the obtained crude product was purified by column chromatography (solvent; hexane/ethyl acetate=70/30 to 50/50→chloroform/methanol=90/10) Obtaining 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[N-[1-(1-hydroxy-1-methylethyl)cyclopentyl]aminecarbamyl] Pyrazolo[1,5-a]pyrimidine (65 mg; yield: 49%, compound a) as a powder, and 3-[N-(1-carboxycyclopentyl)aminecarbamyl]-6- (2-Chlorophenyl)-7-(4-chlorophenyl)-pyrazolo[1,5-a]pyrimidine (24 mg; Yield: 19%, Compound b) as a powder.

Compound a: MS (APCI) m/z; 509/511 [M+H] ⁺

Compound b: MS (APCI) m/z; 495/497 [M+H] ⁺

Examples A66 to A72

The corresponding starting materials were treated in the same manner as described in Example A4-(1) to give the compound shown in Table 8 below.

Examples A73 to A74

The corresponding starting materials were treated in the same manner as described in Example A41-(2) to obtain the compound shown in Table 9 below.

Example A75 to A78

The corresponding starting materials were treated in the same manner as described in Example A4-(2) to give the compound shown in Table 10 below.

Examples A79 to A106

The corresponding starting materials were treated in the same manner as described in Examples A4-(1) to A4-(2) to obtain the compound shown in Table 11 below.

Example 107

(1) The compound obtained in Example A64 (805 mg) in two (10 ml) solution, add 4 N hydrochloric acid to two A solution of (10 ml) was stirred at room temperature for 4 hours. The reaction mixture was diluted with diisopropyl ether, and the precipitate was collected by filtration to give 4-amine-carboyl-4-[6-(2-chlorophenyl)-7-(4-trifluoromethylphenyl)pyrazole. And [1,5-a]pyrimidine-3-carboxylamido]piperidine hydrochloride (784 mg; yield: 100%) was obtained as a powder.

MS (APCI) m/z; 543/545 [M+H] ⁺

(2) Potassium carbonate (30 mg) and isopropyl iodide (13 μL) were added to a solution of the compound obtained in the above step (1) (50 mg) in dimethylformamide (1 ml). The mixture was stirred at ° C for 20 hours. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under vacuum, and the obtained crude product was purified on a silica gel column chromatography (solvent; chloroform/methanol=99/1 to 87/13) to afford 4-amine-carbazin-4-[ 6-(2-Chlorophenyl)-7-(4-trifluoromethylphenyl)pyrazolo[1,5-a]pyrimidin-3-carboxyindoleamino]-1-isopropylpiperidine ( 27 mg; yield: 55%), in powder.

MS (APCI) m/z; 585/587 [M+H] ⁺

Example A108

To a solution of the compound (45 mg) obtained from m. m. The mixture was allowed to stand for 15 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was concentrated under vacuum, and the obtained crude product was purified on a silica gel column chromatography (solvent; hexane/ethyl acetate = 30/70 to 0/100) 4-[6-(2-Chlorophenyl)-7-(4-trifluoromethylphenyl)pyrazolo[1,5-a]pyrimidin-3-carboxyindoleamino]-1-methylsulfonate Mercaptopidine (36 mg; yield: 75%) was in the form of a powder.

MS (APCI) m/z; 621/623 [M+H] ⁺

Examples A109 to A121

The corresponding starting materials were treated in the same manner as described in Example A5 to give the compound shown in Table 12 below.

Examples A122 to A123

The corresponding starting materials were treated in the same manner as described in Example A108 to give the compound shown in Table 13 below.

Examples A124 to A138

The corresponding starting materials were treated in the same manner as described in Example A5 to give the compound shown in Table 14 below.

Examples A139 to A142

The corresponding starting materials were treated in the same manner as described in Example A1 to give the compound shown in Table 15 below.

Example A143

The compound obtained in Example A142 (175 mg) was obtained in the same manner as described in Example 4-(2) to give 3-[N-(1-carboxycyclohexyl)aminecarbamoyl]-6-(2-chlorobenzene). 7-(4-Chlorophenyl)-2-(2-hydroxyethoxy)pyrazolo[1,5-a]pyrimidine (131 mg; Yield: 77%) as a powder.

MS (APCI) m/z; 569/571 [M+H] ⁺

Example A144

The compound obtained in Reference Example A18 (6-(2-bromophenyl)-3-carboxy-7-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidine; 500 was treated in the same manner as described in Example A1. (mg) and the compound obtained in Reference Example A9 (293 mg), and then the reaction product was treated in the same manner as described in Example A4-(2) to obtain 6-(2-bromophenyl)-3-[N-(1) -carboxycyclohexyl)amine formazan 7-(4-Chlorophenyl)pyrazolo[1,5-a]pyrimidine (648 mg) as a powder.

MS (APCI) m/z; 553/555 [M+H] ⁺

Example A145

(1) The compound obtained in Example A144 (100 mg) and ammonium chloride (19 mg) were obtained in the same manner as described in Example A5 to give 6-(2-bromophenyl)-3-[N-(1-amine). Methyl decylcyclohexyl)amine carbaryl]-7-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidine (84 mg) as a powder.

MS (APCI) m/z; 552/554 [M+H] ⁺

(2) a solution of the compound obtained in the above step (1) (83 mg), zinc cyanide (20 mg) and bismuth(triphenylphosphine)palladium (17 mg) in dimethylformamide (1 ml) The mixture was stirred at 110 ° C for 13 hours under a nitrogen atmosphere. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under vacuum, and the crude material was purified eluted eluted eluted elution elution 1-amine-mercaptocyclohexyl)amine-mercapto]-7-(4-chlorophenyl)-6-(2-cyanophenyl)pyrazolo[1,5-a]pyrimidine (22 mg; Yield: 30%), in powder.

MS (APCI) m/z; 499/501 [M+H] ⁺

Examples A146 to A147

The corresponding starting materials were treated in the same manner as described in Example A1, and then the reaction product was treated in the same manner as described in Example A145 to obtain the compound shown in Table 16 below.

Examples A148 to A149

The corresponding starting materials were treated in the same manner as described in Example A6 to give the compound shown in Table 17 below.

Example A150

The compound obtained in Example A1 (106 mg) in toluene (4 ml) To a solution of the amine (1.5 ml), sodium azide (86 mg) and triethylamine hydrochloride (183 mg) were added, and the mixture was stirred at 120 ° C for 24 hours. Further, sodium azide (90 mg) and triethylamine hydrochloride (183 mg) were added to the reaction mixture, and the mixture was stirred for 21 hr. After cooling to room temperature, the reaction mixture was filtered through Celite to remove the precipitate and the filtrate was concentrated in vacuo. The obtained crude product was purified by column chromatography on a silica gel (solvent; chloroform/methanol = 100/0 to 95/5) and by gel permeation chromatography (solvent; chloroform) to obtain 6-( 2-Chlorophenyl)-7-(4-chlorophenyl)-3-[N-[1-(1,2,3,4-tetrazol-5-yl)cyclohexyl]aminecarbenyl]pyridinium Zoxao[1,5-a]pyrimidine (95 mg; yield: 83%) as a powder.

MS (APCI) m/z; 533/535 [M+H] ⁺

Example A151

To a solution of the compound (195 mg), m. Aqueous sodium thiosulfate solution and dichloromethane were added to the reaction mixture. The organic layer was separated and concentrated under vacuum. The obtained crude product was purified by column chromatography on a NH-hydroxy gel (Kemator NH oxime gel, solvent; hexane/ethyl acetate = 50/50 to 30/70) to obtain 6 -(2-chlorophenyl)-7-(4-trifluoromethylphenyl)-3-[N-(4-hydroxymethyl-1,1-dionetetrahydrothiopyran-4-yl Aminomethylmercapto]pyrazolo[1,5-a]pyrimidine (169 mg; yield: 82%), as a grayish yellow powder.

MS (APCI) m/z; 579/581 [M+H] ⁺

Example A152

To a solution of the compound obtained in Example A62 (50 mg) in THF (1 mL / 1 mL), EtOAc (EtOAc) day. The reaction mixture is filtered, The filtrate was concentrated under vacuum. The obtained crude product was purified by NH-hydroxy gel column chromatography (Kemator NH oxime gel, solvent; chloroform) to give 3-[N-[1-(aminomethyl)- Cyclohexyl]amine-mercapto]-6-(2-chlorophenyl)-7-(4-chlorophenyl)-2-methylpyrazolo[1,5-a]pyrimidine (35 mg; yield : 69%), grayish yellow powder.

MS (APCI) m/z; 508/510 [M+H] ⁺

Example A153

A solution of the compound (35 mg), m. Aqueous saturated sodium bicarbonate solution was added to the reaction mixture, and the mixture was stirred for 5 minutes. The mixture was extracted with dichloromethane and the org. The obtained crude product was purified by column chromatography on a NH-[theta][theta][[[[[[[[[[ [N-[(1-Aminocyclopentyl)methyl]aminemethylmercapto]-6-(2-chlorophenyl)-7-(4-chlorophenyl)-2-methylpyrazolo[ 1,5-aI]pyrimidine (14 mg; yield: 48%) as a powder.

MS (APCI) m/z; 494/496 [M+H] ⁺

Example A154

To a solution of the compound (51 mg) obtained from m. Water and dichloromethane were added to the reaction mixture, the organic layer was separated and concentrated in vacuo. The obtained crude product was purified by column chromatography on a silica gel (solvent; chloroform/methanol = 100/0 to 95/5) to obtain 3-[N-[1-(ethylaminomethyl)- Cyclohexyl]amine-mercapto]-6-(2-chlorophenyl)-7-(4-chlorophenyl)-2-methylpyrazolo[1,5-a]pyrimidine (36.5 mg; Yield : 66%), in powder.

MS (APCI) m/z; 550/552 [M+H] ⁺

Example A155

The compound obtained in Example A152 (51 mg) and dimethylaminemethane chloride (11 μL) were treated in the same manner as described in Example A154 to give 6-(2-chlorophenyl)-7-(4-chlorobenzene. 2-methyl-3-[N-[1-[(3,3-dimethylureido)methyl]cyclohexyl]aminecarboxylidene]pyrazolo[1,5-a]pyrimidine (25.3 mg; yield: 44%) in powder.

MS (APCI) m/z; 579/581 [M+H] ⁺

Example A156

The compound obtained in Example A152 (51 mg) and methanesulfonium chloride (9 μL) were treated in the same manner as described in Example A154 to give 6-(2-chlorophenyl)-7-(4-chlorophenyl)- 3-[N-[1-(Methanesulfonylaminomethyl)cyclohexyl]amine-carbamoyl]-2-methyl-pyrazolo[1,5-a]pyrimidine (39.2 mg; Yield: 67%), in powder.

MS (APCI) m/z; 586/588 [M+H] ⁺

Example A157

The compound obtained in Example A152 (51 mg) and dimethylaminosulfonyl chloride (13 μL) were treated in the same manner as described in Example A154 to give 6-(2-chlorophenyl)-7-(4-chloro Phenyl)-2-methyl-3-[N-[1-[[(dimethylaminesulfonyl)amino]methyl]cyclohexyl]aminecarboxylidene]pyrazolo[1,5- a] Pyrimidine (12.3 mg; yield: 20%) in powder.

MS (APCI) m/z; 615/617 [M+H] ⁺

Examples A158 to A159

The corresponding starting materials were treated in the same manner as described in Example A1 to give the compound shown in Table 18 below.

Examples A160 to A161

The corresponding starting materials were treated in the same manner as described in Example A1 to give the compound shown in Table 19 below.

Examples A162 to A163

The compound obtained in Example A143 and the relatives were treated in the same manner as described in Example A5. The amine compound was obtained, and the compound shown in the following Table 20 was obtained.

Examples A164 to A174

The compound obtained in Example A75 and the corresponding amine compound were treated in the same manner as described in Example A5 to give the compound shown in Table 21 below.

Examples A175 to A184

The corresponding starting materials were treated in the same manner as described in Example A1, and the reaction product was treated in the same manner as described in Example A4-(2), and then the reaction product was treated in the same manner as described in Example A5 to obtain the compound shown in Table 22 below. .

Example B1

A solution of the compound (70 mg) obtained from EtOAc (EtOAc m. Concentrate the reaction mixture under vacuum and add aqueous saturated hydrogen carbonate The sodium solution is in the residue. The mixture was extracted with chloroform and the organic layer was evaporated. The obtained crude product was purified by column chromatography on a NH-hydroxy gel (Kemator NH oxime gel, solvent; hexane/ethyl acetate = 80/20 to 30/70) to obtain 6- (2-Chlorophenyl)-7-(4-chlorophenyl)-3-ethoxycarbonyl-2-(N-methylaminesulfonyl)pyrazolo[1,5-a]pyrimidine (75 Mg; yield: 100%), as a colorless powder.

MS (APCI) m/z; 505/507 [M+H] ⁺

Example B2

(1) To a solution of EtOAc (EtOAc m. The reaction mixture was weakly acidified with aqueous 2N hydrochloric acid. The mixture was concentrated in vacuo and extracted with EtOAc. Dehydrate with magnesium sulfate and filter the organic layer. The filtrate was concentrated under vacuum to give 3-carboxy-6-(2-chlorophenyl)-7-(4-chlorophenyl)-2-(N-methylaminesulfonyl)pyrazolo[1, 5-a]pyrimidine (543 mg) as a crude product.

(2) The compound obtained in the above step (1) was treated in the same manner as described in Example A1 to obtain 6-(2-chlorophenyl)-7-(4-chlorophenyl)-2-(N-methylamine sulfonate. Indyl)-3-[N-(1-pyrrolidinyl)aminemethanyl]pyrazolo[1,5-a]pyrimidine (29 mg) was obtained as a pale yellow powder.

MS (APCI) m/z; 545/547 [M+H] ⁺

Example B3

A solution of the compound (600 mg) obtained from m. m. The reaction mixture was concentrated in vacuo and aq. The mixture was extracted with chloroform and the organic layer was evaporated. The obtained crude product was purified by column chromatography on a NH-hydroxyl gel (Kemator NH oxime gel, solvent; hexane/ethyl acetate = 80/20 to 0/100) to obtain 6- (2-chlorobenzene -7-(4-chlorophenyl)-3-ethoxycarbonyl-2-(N,N-dimethylaminesulfonyl)pyrazolo[1,5-a]pyrimidine (566 mg; Yield: 93%) as a colorless powder.

MS (APCI) m/z; 519/521 [M+H] ⁺

Example B4

In a solution of the compound obtained in Reference Example B3 (300 mg) in tetrahydrofuran (10 ml), A solution of (7 ml) was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum, THF (EtOAc) was evaporated. The filtrate was concentrated under vacuum, and the obtained crude product was purified by column chromatography (solvent; hexane/ethyl acetate = 80/20 to 50/50) to give 6-(2-chlorophenyl). - 7-(4-chlorophenyl)-3-ethoxycarbonyl-2-aminesulfonylpyrazolo[1,5-a]pyrimidine (242 mg; yield: 84%) as a colorless powder .

MS (APCI) m/z; 491/493 [M+H] ⁺

Example B5

To a solution of the title compound (40 mg), m. After cooling to room temperature, aqueous sodium hydrogencarbonate solution and chloroform were added to the reaction mixture. After stirring, the organic layer was separated and concentrated in vacuo. The obtained crude product was purified by column chromatography on a silica gel (solvent; hexane/ethyl acetate = 80/20 to 60/40) to obtain 6-(2-chlorophenyl)-7-(4) -Chlorophenyl)-3-(N-cyclopentylaminecarbamimidoyl)-2-(3-ethylureido)pyrazolo[1,5-a]pyrimidine (33.3 mg; Yield: 72% ), a grayish yellow solid.

MS (APCI) m/z; 537/539 [M+H] ⁺

Examples B6 to B24

The corresponding starting materials were treated in the same manner as described in Example B2-(2) to obtain the compound shown in Table 23 below.

Example B25 to B28

The corresponding starting materials were treated in the same manner as described in Example B2 to give the compound shown in Table 24 below.

Example B29

(1) The corresponding starting materials were treated in the same manner as described in Example B2-(2) to obtain 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[N-( 1-Methoxycarbonylcyclohexyl)amine indolyl]-2-(N-methylaminesulfonyl)pyrazolo[1,5-a]pyrimidine (185 mg) was obtained as a pale yellow powder.

MS (APCI) m/z; 616/618 [M+H] ⁺

(2) The compound obtained in the above step (1) (182 mg) was obtained in the same manner as described in the Example A4-(2) to obtain 3-[N-(1-carboxycyclohexyl)aminecarbazinyl]-6- ( 2-chlorophenyl)-7-(4-chlorophenyl)-2-(N-methylaminesulfonyl)pyrazolo[1,5-a]pyrimidine (5.6 m g), in powder.

MS (APCI) m/z; 602/604 [M+H] ⁺

Example B30

The compound obtained in Reference Example B5 (35 mg) and the compound obtained in Reference Example B10 (17.5 mg) were treated in the same manner as described in Example A1 to give 3-[N-(1-amine-carbamoylcyclohexyl)aminecarbazinyl] -6-(2-chlorophenyl)-7-(4-chlorophenyl)-2-aminesulfonylpyrazolo[1,5-a]pyrimidine (3.6 mg; yield: 8%), Colorless powder.

MS (APCI) m/z; 587/589 [M+H] ⁺

Example B31

(1) The compound obtained in Example A6-(1) (200 mg) and the compound obtained in Reference Example B11 (137 mg) were treated in the same manner as described in Example A1 to obtain 2-amino-3-[N-(4-amine). Mercapto-1,1-dionetetrahydrothiopyran-4-yl)amine-mercapto]-6-(2-chlorophenyl)-7-(4-trifluoromethylphenyl)pyrene Zyrazolo[1,5-a]pyrimidine (82 mg; yield: 29%), as a gray-yellow powder.

MS (APCI) m/z; 607/609 [M+H] ⁺

(2) The compound obtained in the above step (1) (39 mg) was obtained in the same manner as described in Example B5 to obtain 3-[N-(4-aminocarbazin-1,1-dione-tetrahydrothiopyran. 4-yl)amine-mercapto]-6-(2-chlorophenyl)-2-(3-ethylureido)-7-(4-trifluoromethylphenyl)pyrazolo[1, 5-a]pyrimidine (15 mg; yield: 34%), as a gray-yellow powder.

MS (APCI) m/z; 678/680 [M+H] ⁺

Example B32

The compound obtained in Reference Example B17 (500 mg) was treated in the same manner as described in Example A1, and then the reaction product was treated in the same manner as described in Example A41-(2) to obtain 6-(2-chlorophenyl)-7-(4- Trifluoromethylphenyl)-2-hydroxymethyl-3-[N-(4-methyl-1,1-dione Tetrathiathiopyran-4-yl)amine-methylpyridyl]pyrazolo[1,5-a]pyrimidine (498 mg) was obtained as a gray-yellow powder.

MS (APCI) m/z; 593/595 [M+H] ⁺

Example B33

A solution of the compound obtained in Example B32 (335 mg) eluted eluted elute The reaction mixture was filtered through a pad of silica gel and washed with chloroform/methanol (9/1). The mother liquor was concentrated under vacuum. The residue was diluted with ethyl acetate and water was added. The organic layer was separated, washed sequentially with water and brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum, and the obtained crude product was purified on a silica gel column chromatography (solvent; chloroform/methanol = 100/0 to 85/15) to obtain 2-carboxy-6-(2-chlorobenzene). -7-(4-Trifluoromethylphenyl)-3-[N-(4-methyl-1,1-dionetetrahydrothiopyran-4-yl)aminecarbenyl]pyridinium Zoxao[1,5-a]pyrimidine (245 mg; yield: 71%) as a colorless solid.

MS (APCI) m/z; 607/609 [M+H] ⁺

Example B34

The compound obtained in Reference Example B17 (45 mg) was obtained in the same manner as described in Example A1 to give 3-[N-(1-amine-carbamoylcyclohexyl)aminecarbazinyl]-6-(2-chlorophenyl). -7-(4-Trifluoromethylphenyl)-2-(hydroxymethyl)pyrazolo[1,5-a]pyrimidine (29 mg; yield: 50%) as a colorless powder.

MS (APCI) m/z; 572/574 [M+H] ⁺

Examples B35 to B38

The compound obtained in Example B33 and the corresponding amine compound material were treated in the same manner as described in Example A5 to obtain the compound shown in Table 25 below.

Examples B39 to B51

The corresponding starting materials were treated in the same manner as described in Example A1 to give the compound shown in Table 26 below.

Examples B52 to B53

The corresponding starting materials were treated in the same manner as described in Example A41 to give the compound below.

Example B52:

2-Aminomercapto-6-(2-chlorophenyl)-7-(4-trifluoromethylphenyl)-3-[N-(1,1-dione-thiolan-3- Aminomethylmercapto]pyrazolo[1,5-a]pyrimidine (powder)

MS (APCI) m/z; 564/566 [M+H] ⁺

Example B53:

6-(2-Chlorophenyl)-7-(4-trifluoromethylphenyl)-2-hydroxymethyl-3-[N-(1,1-dione-thiolan-3-yl) Aminomethyl]pyrazolo[1,5-a]pyrimidine (powder)

MS (APCI) m/z; 551/553 [M+H] ⁺

Example B54 to B120

The corresponding starting materials were treated in the same manner as described in Example A1 to give the compound shown in Table 27 below.

Example B121

Under a nitrogen atmosphere, a solution of 2 M trimethylaluminum in toluene (0.15 ml) was added to a solution of cyclopentylamine (30 μL) in toluene (1.5 mL). The compound was 15 minutes. The compound obtained in Reference Example B21 (76 mg) was added, and the mixture was stirred at room temperature for 1 hour and the mixture was stirred at 100 ° C for 17 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, and aqueous 20% Rochell salt solution was added. The mixture was extracted with chloroform and the organic layer was evaporated. The obtained crude product was purified by column chromatography on a silica gel (solvent; chloroform/methanol = 100/0 to 96/4) to obtain 6-(2-chlorophenyl)-3-[N-( Amyl-aminomethylamino-7-(4-trifluoromethylphenyl)-2-ureidopyrazolo[1,5-a]pyrimidine (48 mg; yield: 59%) in powder .

MS (APCI) m/z; 543/545 [M+H] ⁺

Example B122 to B125

The corresponding starting materials were treated in the same manner as described in Example B121 to give the compound shown in Table 28 below.

Reference example A1

(1) Magnesium (6.04 g) and a catalytic amount of iodine were added to diethyl ether (250 ml), and the mixture was stirred. 2-Chlorobenzyl chloride (20.0 g) was slowly added dropwise thereto, whereby the temperature of the mixture began to rise, and the mixture was stirred for 1 hour. A solution of 4-chlorobenzonitrile (18.8 g) in tetrahydrofuran / diethyl ether (20 ml / 50 ml) was added and the mixture was stirred for 3 hr. An aqueous 2 N hydrochloric acid solution (150 ml) was added to the mixture and the mixture was stirred at room temperature for 2 hr. The reaction mixture was extracted with EtOAc. EtOAc was evaporated. The filtrate was concentrated under vacuum, and the obtained crude product was purified eluted eluted eluted elute 4-chlorophenyl)methanone (24.40 g; yield: 74%) as a powder.

MS (APCI) m/z; 265/267 [M+H] ⁺

(2) The compound obtained in the above step (1) (6.4 g) and N,N-dimethylformamide dimethylacetal (6.4 ml) in N,N-dimethylformamide (24 ml) The solution was stirred at 150 ° C for 4 hours. After the reaction mixture was cooled to room temperature, water was added thereto, and the mixture was extracted with a mixture of ethyl acetate and hexane (3 times). The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum to give 1-(4-chlorophenyl)-2-(2-chlorophenyl)-3-(N,N-dimethylamino)-2propan-1-one as Oily.

(3) The compound obtained in the above step (2) was dissolved in acetic acid (8 ml), and 3-amino-4-ethoxycarbonyl-1H-pyrazole (3.75 g) and piperidine (0.48 ml) were added thereto. The mixture was heated at 80 ° C for 16 hours. After cooling to room temperature, water and ethyl acetate were added to the mixture. After stirring, the organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum, and the obtained crude product was purified on a silica gel column chromatography (solvent; hexane/ethyl acetate = 17/3 to 67/33) to obtain 6-(2-chlorophenyl). )-7-(4-chloro Phenyl)-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine (5.02 g, combined yield of steps (2) and (3): 50%) was obtained as a powder.

MS (APCI) m/z; 412/414 [M+H] ⁺

(4) To a solution of the title compound (m. An aqueous 2 N hydrochloric acid solution was added to the reaction mixture, and the mixture was stirred and concentrated in vacuo. The residue was extracted with EtOAc. The filtrate was concentrated under vacuum to give 3-carboxy-6-(2-chlorophenyl)-7-(4-chlorophenyl)-pyrazolo[1,5-a]pyrimidine (2.1 g, yield 90 %), in powder.

MS (APCI) m/z; 384/386 [M+H] ⁺

Reference example A2

(1) 4-Dichlorobenzyl bromide (4.1 g), 4-chlorobenzhydryl chloride (2.56 ml), hydrazine (triphenylphosphine) palladium dichloride (diphenylphosphine) 702 mg) and zinc powder (2.6 g), and the mixture was stirred under a nitrogen atmosphere for 2 hours. The reaction mixture was filtered. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the obtained crude product was purified by column chromatography (solvent; hexane/ethyl acetate=49/1 to 9/1) to obtain (2-chlorobenzyl). (4-Chlorophenyl)methanone (4.85 g, yield: 91%) as a powder.

MS (GC-EI) m/z; 264 [M] ⁺

(2) The compound obtained in the above step (1) is treated in the same manner as described in Reference Example 1 (2) to Reference Example 1 (4) to obtain 3-carboxy-6-(2-chlorophenyl)-7-(4) -Chlorophenyl)pyrazolo[1,5-a]pyrimidine.

Reference example A3

(1) A solution of potassium cyanide (5.6 g) and ammonium chloride (5.06 g) in water (17 ml) A solution of tetrahydro-4H-thiazolidine-4-one (10 g) in MeOH (22 mL). After cooling to room temperature, an aqueous 1 N sodium hydroxide solution was added to the mixture and the mixture was extracted with diethyl ether. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. EtOAc m. The precipitate was collected by filtration to give 4-amino-tetrahydrothiopyran-4-carbonitrile (13.6 g, yield: 88%) as a colourless solid.

MS (APCI) m/z; 143 [M+H] ⁺

(2) A solution of the compound obtained in the above step (1) (10.5 g). After cooling to room temperature, the reaction mixture was evaporated. mjjjjjjjj

MS (APCI) m/z; 162 [M+H] ⁺

(3) To a solution of the compound (10.6 g) obtained in the above step (2) in methanol (70 ml), sulfonium chloride (5.7 ml) was slowly added dropwise, and the mixture was refluxed and heated overnight. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The residue was washed with ethyl acetate / diethyl ether. The mixture was extracted with chloroform and the organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give ethyl 4-amino-tetrahydrothiopyran-4-carboxylate (3.83 g, yield: 39%).

MS (APCI) m/z; 176 [M+H] ⁺

(4) To a solution of the compound (100 mg. Methanol (4 ml) was added to the reaction mixture, and PL-HCO ₃ MP resin (0.9 g, Polymer Labs.) was slowly added thereto. The mixture was stirred overnight. The reaction mixture was filtered and the filtrate evaporated. The obtained crude product was purified by column chromatography on a silica gel (solvent; hexane/ethyl acetate = 30/70 to 0/100) to obtain 4-amino-1,1-dione-tetrahydrogen. Methyl thiopyran-4-carboxylate (38 mg, yield: 32%) as a colourless solid.

MS (ESI) m/z; 208 [M+H] ⁺

Reference example A4

A solution of ethyl 2-cyano-3,3-indenylthioacrylate (40.0 g), hydrazine hydrate (12.6 g) and sodium acetate (22.6 g) in ethanol (700 ml) was stirred at 90 ° C for 2 h. . After cooling to room temperature, the reaction mixture was evaporated. The organic layer was separated, dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum and ethyl acetate and hexane were added to the residue. The precipitate was collected by filtration and dried to give 3-amino-4-ethoxycarbonyl-5-methylthiopyrazole (17.4 g, yield: 47%) as a colourless solid.

MS (APCI) m/z; 202 [M+H] ⁺

Reference example A5

(1) 2-Chlorobenzyl chloride (50 g) and 4-trifluoromethylbenzonitrile (53.1 g) were treated in the same manner as described in Reference Example A1-(1) to obtain (2-chlorobenzyl) (4). -Trifluoromethylphenyl)methanone (42.5 g, yield: 46%) as a powder.

(2) The compound obtained in the above step (1) (15.1 g) and N,N-dimethylformamide dimethyl acetal (12.1 g) were treated in the same manner as described in Reference Example A1 - (2) to obtain 2 -(2-Chlorophenyl)-1-(4-trifluoromethylphenyl)-3-(N,N-dimethylamino)-2-propen-1-one (17.7 g), crude Product oil.

(3) The compound obtained in the above step (2) (17.7 g) and the compound obtained in Reference Example A4 (10.2 g) were treated in the same manner as described in Reference Example A1 - (3) to obtain 6-(2-chlorophenyl)- 3-ethoxycarbonyl-7-(4-trifluoromethylphenyl)-2-methylthiopyrazolo[1,5-a]pyrimidine (12.2 Gram, yield: 46%), in powder.

MS (APCI) m/z; 492/494 [M+H] ⁺

Reference example A6

(1) 6-(2-Chlorophenyl)-3-ethoxycarbonyl-7-(4-trifluoromethylphenyl)-2-methylthiopyrazolo[1,5-a]pyrimidine (Compound Example A5; 11.0 g) mp. Aqueous sodium thiosulfate solution was added dropwise to the reaction mixture at 0 ° C under stirring, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum, and the obtained crude product was washed with ethanol to give 6-(2-chlorophenyl)-3-ethoxycarbonyl-7-(4-trifluoromethylphenyl)-2-methylsulfonate. Mercaptopyrazolo[1,5-a]pyrimidine (10.7 g, yield: 91%) was obtained as a powder.

(2) To a solution of the compound (10.7 g) obtained in the above step (1) in dimethylformamide (120 ml), sodium azide (5.3 g) was added, and the mixture was stirred at 110 ° C for 3 hours. After cooling to room temperature, water was added to the reaction mixture. After stirring, the mixture was extracted with EtOAc. The obtained crude product was purified by column chromatography on a silica gel (solvent; hexane/ethyl acetate = 80/20 to 65/35) to give 2-azido-6-(2-chlorophenyl). 3-ethoxycarbonyl-7-(4-trifluoromethylphenyl)pyrazolo[1,5-a]pyrimidine (9.7 g, yield: 98%), m.

(3) To a solution of the compound (9.7 g), m. After cooling to room temperature, the reaction mixture was concentrated in vacuo. EtOAc m. -(2-chlorophenyl)-3-ethoxycarbonyl-7-(4-trifluoromethylphenyl)-2-(N-triphenylphosphazinylamino)pyrazolo[1, 5-a]pyrimidine (6-(2-chlorophenyl)-3-ethoxycarbonyl-7-(4-trifluoromethylphenyl)-2-(N-triphenylphosphoranylidenamino)pyrazolo[1,5-a]pyrimidine) (11.1 g, yield: 77%) Yellow solid.

(4) A solution of the compound obtained in the step (3) (11.1 g) in THF (28 ml), EtOAc (EtOAc) After cooling to room temperature, the reaction mixture was concentrated in vacuo, and the obtained crude product was purified on EtOAc EtOAc EtOAc EtOAc 2-amino-6-(2-chlorophenyl)-3-ethoxycarbonyl-7-(4-trifluoromethylphenyl)pyrazolo[1,5-a]pyrimidine (5.2 g, produced Rate: 73%), grayish yellow solid.

MS (APCI) m/z; 461/463 [M+H] ⁺

Reference example A7

(1) In a solution of 1-methylcyclopropanecarboxylic acid (3.52 g) in tert-butanol (50 ml), diphenylphosphoryl azide (7.58 ml) and triethylamine (diethylamine) 4.90 ml), the mixture was stirred at 80 ° C for 15 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo. Water and aqueous saturated sodium bicarbonate solution were added to the residue and the mixture was evaporated. The organic layer was dried over magnesium sulfate and filtered. The residue was concentrated in vacuo, and the obtained crude material was purified eluted eluted elute -[N-(Tertidinoxycarbonyl)amino]-cyclopropane (4.66 g, yield: 77%) as a colourless solid.

MS (APCI) m/z; 172 [M+H] ⁺

(2) The compound obtained in the above step (1) (4.66 g) in 1,4-di (10 ml) solution, add 4 N hydrochloric acid to two The solution (10 mL) was stirred at rt overnight. Diisopropyl ether was added to the reaction mixture, and the crystals precipitated were collected by filtration to give 1-methylcyclopropylamine hydrochloride (2.69 g, yield: 92%) as a colorless solid.

MS (APCI) m/z; 72 [M+H] ⁺

Reference example A8

A solution of anhydrous ruthenium chloride (5.0 g) in tetrahydrofuran (40 ml) was stirred at room temperature overnight. A solution of 1.04 M methyllithium in diethyl ether (19 mL) was added dropwise over a period of 20 min. The mixture was stirred at the same temperature for 30 minutes, and a solution of 2-cyanopyridine (685 mg) in tetrahydrofuran (1 ml) was added dropwise. After warming to room temperature over a period of 5 hours, an aqueous 28% ammonia solution (12.5 ml) was added to the reaction mixture under ice cooling. The mixture was filtered through Celite to remove the precipitate. The filtrate was dehydrated with sodium sulfate and filtered. The filtrate was concentrated in vacuo to give 1-methyl-l-(2-pyridyl)ethylamine (863 mg).

MS (APCI) m/z; 137 [M+H] ⁺

Reference example A9

To a solution of 1-aminocyclohexanecarboxylic acid (600 mg) in tetrahydrofuran-methanol, trimethyldecyldinitromethane (4.2 ml) was added dropwise with ice-cooling and stirring, and the mixture was stirred overnight. The reaction mixture was concentrated with EtOAc EtOAc (EtOAc) The precipitate was collected by suction and dried to give ethyl 1-amino-cyclohexanecarboxylate (423 mg; yield: 52%) as white powder.

MS (APCI) m/z; 158 [M+H] ⁺

Reference example A10 to A13

The corresponding starting materials were treated in the same manner as described in Reference Example A1 to give the compound shown in Table 29 below.

Reference example A14

(1) Methyl 2-chlorophenylacetate (10 g) in dimethylformamide (150 ml) was added N,N-dimethylformamide dimethylacetal (14.4 ml). The mixture was stirred at 85 ° C overnight. After cooling to room temperature, ethyl acetate and water were added to the reaction mixture. After stirring, the organic layer was separated, dried over sodium sulfate and filtered and evaporated. The residue was diluted with acetic acid (18 mL), and then 3-amino-4-ethoxycarbonyl-1H-pyrazole (8.4 g) and piperidine (1.1 ml). The mixture was stirred at 80 ° C for 3.5 hours. After cooling to room temperature, ethyl acetate and water were added to the reaction mixture. The mixture was stirred and filtered, and the obtained precipitate was dried to give 3-[2-(2-chlorophenyl)-2-methoxycarbonyl-vinylamino]-4-ethoxycarbonyl-1H-pyrazole. (11.8 g, yield: 62%), in powder.

MS (APCI) m/z; 350/352 [M+H] ⁺

(2) To a solution of the compound (10.7 g) obtained in the above step (1) in ethanol (250 ml), sodium carbonate (3.24 g) was added, and the mixture was heated under reflux for 4 days. After cooling to room temperature, the reaction mixture was filtered and evaporated. Water was added to the residue, and the mixture was stirred and filtered (this filtration procedure was repeated 5 times). The resulting precipitate was dried to give 6-(2-chlorophenyl)-3-ethoxycarbonyl-7-keto-4,7-dihydropyrazolo[1,5-a]pyrimidine (8.5 g, Yield: 87%), in powder.

MS (APCI) m/z; 318/320 [M+H] ⁺

(3) Add N,N-dimethylaniline (319 μl) and phosphorous oxychloride (270 μm) to a solution of the compound obtained in the above step (2) (300 mg) in acetonitrile (2 ml). l), the mixture was heated under reflux for 1 day. After cooling to room temperature, the reaction mixture was poured into ice water and the mixture was extracted with dichloromethane. The extract was dehydrated with magnesium sulfate and filtered. The filtrate was concentrated under vacuum, and the obtained crude product was purified by column chromatography (solvent; hexane/ethyl acetate = 80/20 to 60/40) to afford 7-chloro-6- (2) -Chlorophenyl)-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine (108 mg; yield: 34%) as a powder.

MS (APCI) m/z; 336/338 [M+H] ⁺

(4) In a solution of the compound obtained in the above step (3) (500 mg) in dimethylformamide (6 ml), 4-methylpiperidine (210 μl) and potassium carbonate were added. (412 mg), the mixture was stirred at 80 ° C for 2.5 hours. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water and brine, dried over sodium sulfate and filtered. The filtrate was concentrated under vacuum, and the obtained crude material was purified on a silica gel column chromatography (solvent; hexane / ethyl acetate = 80 / 20 50/50) to obtain 6-(2-chlorophenyl)-3-ethoxycarbonyl-7-(4-methylpiperidin-1-yl)pyrazolo[1,5-a]pyrimidine ( 593 mg; yield: 99%), in oil.

MS (APCI) m/z; 399/401 [M+H] ⁺

(5) The compound obtained in the above step (4) (593 mg) was treated in the same manner as described in Reference Example 1-(4) to obtain 3-carboxy-6-(2-chlorophenyl)-7-(4- Methylpiperidin-1-yl)pyrazolo[1,5-a]pyrimidine (500 mg; yield: 91%) as a colourless solid.

MS (APCI) m/z; 371/373 [M+H] ⁺

Reference example A14B

Add N,N-dimethylformamide dimethyl acetal (36 ml) to a solution of methyl 2-chlorophenylacetate (25 g) in dimethylformamide (400 ml). Stir at 90 ° C overnight. After cooling to room temperature, ethyl acetate and water were added to the reaction mixture. After stirring, the organic layer was separated, dried over magnesium sulfate and filtered. The residue was diluted with acetic acid (60 ml), and 3-amino-4-ethoxycarbonyl-5-methyl-1H-pyrazole (19.7 g) was added. The mixture was stirred at 120 ° C overnight. After cooling the reaction mixture to room temperature, the precipitate was collected by filtration, washed with ethyl acetate /diisopropyl ether (1/1) and dried to give 6-(2-chlorophenyl)-3-ethoxy. Carbonyl-2-methyl-7-keto-4,7-dihydropyrazolo[1,5-a]pyrimidine (26.0 g) was obtained as a powder.

MS (APCI) m/z; 332/334 [M+H] ⁺

Reference examples A15 to A16

The corresponding starting materials were treated in the same manner as described in Reference Example A14 or A14B, and then the reaction products were each treated in the same manner as described in Reference Examples A14-(3) to A14-(4), and the results shown in Table 30 below were obtained. Compound.

Reference example A17

(1) The corresponding starting materials were treated in the same manner as described in Reference Example A1-(1) to obtain (2-chlorobenzyl)(4-trifluoromethyl-phenyl)methanone.

(2) The compound obtained in the above step (1) (3.0 g) and N,N-dimethylformamide dimethyl acetal are treated in the same manner as described in Reference Example A1 - (2), and then the reaction product and 3-Amino-5-methyl-1H-pyrazole (977 mg) was treated in the same manner as described in Reference Example A1-(3) to give 6-(2-chlorophenyl)-7-(4- Fluoromethylphenyl)-2-methylpyrazolo[1,5-a]pyrimidine (2.63 g, yield: 67%) was obtained as a brown oil.

MS (APCI) m/z; 388/390 [M+H] ⁺

(3) To a solution of the compound (2.27 g) obtained in the above step (3) in chloroform (50 ml), chlorosulfonic acid (1.35 ml) was added dropwise, and the mixture was stirred at 70 ° C for 3.5 hours. The reaction mixture was concentrated in vacuo and EtOAc (EtOAc) The mixture was heated under reflux for 2 hours. The reaction mixture was concentrated in vacuo and ice water was evaporated. The mixture was extracted with chloroform and the organic layer was taken with sodium sulfate Water and filtration. The filtrate was concentrated under vacuum, and the obtained crude product was purified by column chromatography (solvent; hexane/ethyl acetate = 85/15 to 60/40) to obtain 6-(2-chlorophenyl). )-3-chlorosulfonyl-7-(4-trifluoromethylphenyl)-2-methylpyrazolo[1,5-a]pyrimidine (2.71 g, yield: 95%), gray Yellow solid.

MS (APCI) m/z; 486/488 [M+H] ⁺

Reference example A18 to A20

The corresponding starting materials were treated in the same manner as described in Reference Example A1 to obtain the compound shown in Table 31 below.

Reference Examples A21 to A22

The corresponding starting materials were treated in the same manner as described in Reference Example A2 to give the compound shown in Table 32 below.

Reference example A23

(1) In a solution of methyl 2-chlorophenylacetate (7.4 g) in dimethylformamide (110 ml), N,N-dimethylformamide dimethyl acetal (10.6 ml) The mixture was stirred overnight at 90 °C. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate /hexane (4/1, 20 ml, and 100 ml). The combined organic layers were washed sequentially with water and brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was diluted with acetic acid (18 ml), and 3-amino-4-ethoxycarbonyl-1H-pyrazole (6.2 g) was added. The mixture was stirred at 110 ° C overnight. After cooling the reaction mixture to room temperature, the precipitate was collected by filtration, washed with ethyl acetate and diisopropyl ether and dried to give 6-(2-chlorophenyl)-3-ethoxycarbonyl-7- Ketopropyl-4,7-dihydropyrazolo[1,5-a]pyrimidine (9.9 g, yield: 78%) was obtained as a powder.

MS (APCI) m/z; 318/320 [M+H] ⁺

(2) The compound obtained in the above step (1) (4.8 g) was treated in the same manner as described in Reference Example A14-(3) to obtain 7-chloro-6-(2-chlorophenyl)-3-ethoxy. Carbonylpyrazolo[1,5-a] Pyrimidine (4.2 g, yield: 85%) in powder.

MS (APCI) m/z; 336/338 [M+H] ⁺

(3) the compound obtained in the above step (2) (840 mg), [1,1-indole (diphenylphosphino)pyrene]dichloropalladium(II)-dichloromethane complex (61 mg), Potassium phosphate (1.6 g) and 2-fluoro-4-methylphenylphenylboronic acid (462 mg) in 1,4-two A solution of (25 ml) was stirred at 80 ° C overnight under a nitrogen atmosphere. After cooling to room temperature, ethyl acetate and aqueous saturated sodium bicarbonate solution were added to the mixture. The organic layer was separated, washed sequentially with water and brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum, and the obtained crude product was purified on a silica gel column chromatography (solvent; hexane/ethyl acetate = 70/30 to 50/50) to give 6-(2-chlorophenyl). 3-ethoxycarbonyl-7-(2-fluoro-4-methylindenylphenyl)pyrazolo[1,5-a]pyrimidine (665 mg; yield: 63%) as a powder.

MS (APCI) m/z; 424/426 [M+H] ⁺

(4) In a solution of the compound obtained in the above step (3) (660 mg) in methylene chloride (0.7 ml), s(2-methoxyethyl)aminosulfur trifluoride (783 μl, Name: Deoxo-Fluor, Scott Inc., and the mixture was stirred at room temperature for 1 day. To the reaction mixture, an aqueous saturated sodium hydrogencarbonate solution was added under ice cooling, and the mixture was stirred for 10 minutes. The mixture was extracted with dichloromethane, and the organic layer was evaporatedjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Obtained 6-(2-chlorophenyl)-3-ethoxycarbonyl-7-(2-fluoro-4-difluoromethylphenyl)pyrazolo[1,5-a]pyrimidine (295 mg; Rate: 42%), in powder.

MS (APCI) m/z; 446/448 [M+H] ⁺

(5) The compound obtained in the above step (4) (290 mg) was treated in the same manner as described in Reference Example A1-(4) to obtain 3-carboxy-6-(2-chlorophenyl)-7-(2- Fluoro-4-difluoromethylphenyl) Pyrazolo[1,5-a]pyrimidine (208 mg; yield: 77%) as a solid.

MS (APCI) m/z; 418/420 [M+H] ⁺

Reference example A24

The corresponding starting materials were treated in the same manner as described in Reference Examples A23-(1) to (3), and then the reaction product was treated in the same manner as described in Reference Example A23-(5) to obtain 3-carboxy- 6-(2-Chlorophenyl)-2-methyl-7-phenylpyrazolo[1,5-a]pyrimidine (250 mg; Yield: 94%).

MS (APCI) m/z; 364/366 [M+H] ⁺

Reference example A25

(1) To a solution of sodium sulphate (14.32 g) in ethanol (20 ml), EtOAc. To the reaction mixture, difluoroacetic acid (4.85 ml) was added, and the mixture was stirred at room temperature for 4 hours and at 60 ° C (external temperature) for 17 hours. The reaction mixture was concentrated under vacuum and toluene (10 mL) The mixture was stirred at 45 ° C for 1 hour. Further, phosphorus chloride (1.9 g) was added to the reaction mixture, and the mixture was stirred at 55 ° C for 2 hours. The reaction mixture was cooled in an ice-bath, filtered and filtered and evaporated. Ethyl alcohol (20 ml) of hydrazine monohydrate (0.8 ml) and triethylamine (3.0 ml) were added to the residue, and the mixture was stirred at 60 ° C for 2 hours. After cooling to room temperature, aqueous saturated sodium bicarbonate solution and water were added, and the mixture was extracted with chloroform (4 times). The combined organic layers were dried over sodium sulfate and filtered. The filtrate was concentrated under vacuum, and the obtained crude product was purified by column chromatography (solvent; chloroform/methanol = 100/0 to 94/6) and washed with chloroform to afford 3-amino-4 Ethoxycarbonyl-5-difluoromethyl-1H-pyrazole (1.26 g; Yield: 41%) as a colorless solid.

MS (APCI) m/z; 206 [M+H] ⁺

(2) The compound obtained in the above step (1) (400 mg) was treated in the same manner as described in Reference Example A1-(2) to (3) to obtain 3-carboxy-6-(2-chlorophenyl)-7. -(4-Chlorophenyl)-2-difluoromethylpyrazolo[1,5-a]pyrimidine (405 mg; Yield: 48%) as a powder.

MS (APCI) m/z; 434/436 [M+H] ⁺

Reference example A26

(1) To a solution of methyl cyanoacetate (14.6 g) in dichloromethane (260 ml), trifluoroacetic acid (37.2 g) was added and the mixture was stirred at room temperature. Triethylamine (51.7 ml) was slowly added dropwise at 0 ° C, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum to give methyl 2-cyano-2-(2-trifluoroethyl)acetate (Compound 2a) and 2-cyano-4,4,4-trifluoro-3-trifluoromethyl A mixture of methyl oxycarbonyl-2-butenoate (compound 2b) (55.3 g).

Compound 2a: MS (APCI) m/z; 196 [M+H] ⁺

Compound 2b: MS (APCI) m/z; 292 [M+H] ⁺

(2) a mixture of the compounds 2a and 2b obtained in the above step (1) (27.6 g) in dichloromethane (200 ml), slowly added dropwise oxalyl chloride (31.6 ml) and a few drops of pyridine, The mixture was heated under reflux for 4 hours. The reaction mixture was slowly poured into water, and the mixture was extracted with dichloromethane. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum to give methyl 3-chloro-2-cyano-4,4,4-trifluoro-2-butenoate as a crude product.

(3) To the compound obtained in the above step (2), water (20 ml) was added, and hydrazine monohydrate (80%, 6.74 g) was slowly added dropwise at 0 °C. Triethylamine (2 ml) was added to the mixture at room temperature, and the mixture was stirred for 1 hour. Add water to the reaction mixture to The mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum and chloroform was added to the residue. The precipitate was collected by filtration to give 3-amino-5-trifluoromethyl-4-methoxycarbonyl-1H-pyrazole (3.96 g) as an orange solid.

MS (APCI) m/z; 210 [M+H] ⁺

(4) The compound obtained in the above step (3) (2.37 g) was treated in the same manner as described in Reference Example A1-(2) to (3) to obtain 3-carboxy-6-(2-chlorophenyl)-7. -(4-Chlorophenyl)-2-trifluoromethylpyrazolo[1,5-a]pyrimidine (1.81 g) as a crude product (powder).

MS (APCI) m/z; 452/454 [M+H] ⁺

Reference example A27 to A28

The corresponding starting materials were treated in the same manner as described in Reference Example A25 or A26 to obtain the compound shown in Table 33 below.

Reference Examples A29 to A30

The corresponding starting materials were treated in the same manner as described in Reference Example A6, and then the reaction products were treated in the same manner as described in Reference Example A1-(4) to obtain the following Table 34. Show compound.

Reference example A31

(1) in 2-[(cyano)(ethoxycarbonyl)vinyl]-1,3-di (2-[(cyano)(ethoxycarbonyl)vinyl]-1,3-dioxolane) (2.0 g) in a solution of ethanol (20 ml), hydrazine hydrochloride (748 mg) and sodium acetate (1.34 g), The mixture was stirred at 80 ° C (external temperature) for 1 hour. After cooling to room temperature, the reaction mixture was filtered with celite and filtered. The obtained crude product was purified by column chromatography on a silica gel (solvent; chloroform/methanol = 100/0 to 85/15) to obtain 3-amino-4-ethoxycarbonyl-5-[2- (Hydroxy)ethoxy]-1H-pyrazole (2.01 g, yield: 86%), as a grayish solid.

MS (APCI) m/z; 216 [M+H] ⁺

(2) The compound obtained in the above step (1) (2.65 g) was treated in the same manner as described in Reference Example A1-(2) to (4) to obtain 3-carboxy-6-(2-chlorophenyl)-7. -(4-Chlorophenyl)-2-(2-hydroxyethoxy)pyrazolo[1,5-a]pyrimidine as a powder.

MS (ESI) m/z; 444/446 [M+H] ⁺

Reference example A32

(1) To a solution of methyl 2-pyridylacetate (3.78 g) in acetic acid (15 ml), aq. Stir at room temperature for 30 minutes. The reaction mixture was neutralized with aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum, and the obtained crude product was purified by column chromatography (solvent; hexane/ethyl acetate=75/25 to 25/75) to obtain (hydroxyimino) (2) Methyl-pyridyl)acetate (3.72 g, yield: 83%) as a colourless solid.

MS (APCI) m/z; 181 [M+H] ⁺

(2) To a solution of the compound obtained in the above step (1) (1.64 g) in methanol (32 ml), 10% palladium-carbon (200 mg), and the mixture was shaken under a hydrogen atmosphere / 50 Pa (Parr) 6 hours. The reaction mixture was filtered, and the filtrate was evaporated,jjjjjjjj

MS (APCI) m/z; 167 [M+H] ⁺

(3) A solution of the compound (659 mg) obtained in the above step (2) in chloroform (10 ml) was added to a solution of dibutyl succinate (908 mg) in chloroform (10 ml). Stir for 1.5 hours. An aqueous saturated sodium bicarbonate solution was added to the reaction mixture. The organic layer was separated and concentrated under vacuum, and the obtained crude product was purified by column chromatography (solvent; hexane/ethyl acetate = 85/15 to 60/40). Methyl (2-pyridyl)acetate (123 mg, yield: 12%) as a yellow oil.

MS (APCI) m/z; 267 [M+H] ⁺

(4) a solution of the compound (122 mg) obtained in the above step (3) in methanol (3 ml) Aqueous 2 N sodium hydroxide solution (460 μl) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and EtOAc m. The obtained reaction product was further treated in the same manner as described in Reference Example A7-(2) to obtain 2-amino-2-(2-pyridyl)acetamide (92 mg, yield: 89%). powder.

MS (APCI) m/z; 152 [M+H] ⁺

Reference example A33

The corresponding starting materials were treated in the same manner as described in Reference Examples A23-(1) to (3), and then the reaction product was treated in the same manner as described in Reference Example A23-(5) to obtain 3-carboxy- 6-(2-Chlorophenyl)-7-(4-dimethylaminophenyl)pyrazolo[1,5-a]pyrimidine (230 mg; Yield: 86%).

MS (APCI) m/z; 393/395 [M+H] ⁺

Reference example B1

(1) Sodium hydride (60%, 6.77 g) was added to dimethylformamide (75 ml) under a nitrogen atmosphere. A solution of ethyl cyanoacetate (9.57 g) in dimethylformamide (15 ml) was added dropwise under reduced pressure (internal temperature: about 10 ° C) over 15 min. minute. In which it is cooled (internal temperature A solution of carbon disulfide (5.09 ml) in dimethylformamide (12 ml) was added dropwise over a period of 20 min. The mixture was stirred overnight at room temperature where it was cooled (internal temperature) A solution of benzyl bromide (20.1 ml) in dimethylformamide (23 ml) was added dropwise. The mixture was stirred at 70 ° C for 7 hours and stirred at room temperature overnight. The reaction mixture was poured into ice water and the mixture was stirred. The precipitate was collected by filtration and recrystallized from hot ethanol. The crystals obtained were washed with cold ethanol to give ethyl 2-cyano-3,3-indole (benzylthio)acrylate (25.63 g, yield: 82%) as a colorless solid.

MS (APCI) m/z; 370 [M+H] ⁺

(2) To a solution of the compound obtained in the above step (1) (15.0 g) in tetrahydrofuran (16 ml) and ethanol (41 ml), hexanes monohydrate (2.04 g) in ethanol (18 ml) The solution was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo andqqqqqqqqq The obtained crystal was washed with hexane/diisopropyl ether (4/1) to give 5-amino-3-benzylthio-4-ethoxycarbonyl-1H-pyrazole (9.45 g, yield: 84%), a colorless solid.

MS (APCI) m/z; 278 [M+H] ⁺

Reference example B2

The compound obtained in Reference Example B1 (8.15 g) and (2-chlorobenzyl)(4-chlorophenyl)methanone (the compound obtained in Reference Example A1-(1), 9.78 g) were used in Reference Example A1-(3). Treated in the same manner to obtain 2-benzylthio-6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine (8.24 g, yield: 51%) was obtained as a pale yellow solid.

MS (APCI) m/z; 534/536 [M+H] ⁺

Reference example B3

To a solution of the title compound (100 mg), m. A 4% sodium hypochlorite solution (Antiformine, 0.4 ml) was added thereto, and the mixture was stirred for 2 hours. The reaction mixture was extracted with dichloromethane. The organic layer was concentrated under vacuum, and the obtained crude product was purified by column chromatography (solvent: hexane/ethyl acetate = 80/20 to 65/35) to obtain 6-(2-chlorobenzene). -7-(4-Chlorophenyl)-2-chlorosulfonyl-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine (78 mg, yield: 82%), colorless solid.

MS (APCI) m/z; 510/512 [M+H] ⁺

Reference example B4

The compound obtained in Reference Example B3 (546 mg) was treated in the same manner as described in the title of the compound of the formula B2-(1) to obtain 3-carboxy-6-(2-chlorophenyl)-7-(4-chlorophenyl)- 2-(N,N-Dimethylaminesulfonyl)pyrazolo[1,5-a]pyrimidine (558 mg) as a crude product.

Reference example B5

The compound obtained in Reference Example B4 (240 mg) was treated in the same manner as described in Reference Example B2-(1) to obtain 3-carboxy-6-(2-chlorophenyl)-7-(4-chlorophenyl)- 2-Aminesulfonylpyrazolo[1,5-a]pyrimidine (239 mg) as a crude product.

Reference example B6

A solution of ethyl 2-cyano-3,3-indole (methylthio)acrylate (40 g), hydrazine hydrochloride (12.6 g) and sodium acetate (22.6 g) in ethanol was stirred at 90 ° C for 2 hr. After cooling to room temperature, the reaction mixture was evaporated mjjjjjjjjj The organic layer was separated, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and ethyl acetate and hexane was evaporated. The precipitate was collected by suction and dried to give 5-amino-4-ethoxycarbonyl-3-methylthio-1H-pyrazole (17.4 g, yield: 47%) as a colorless solid.

Reference example B7

(1) The compound obtained in Reference Example B6 (5-amino-4-ethoxycarbonyl-3-methylthio-1H-pyrazole; 6.8 g), 1-(4-chlorophenyl)-2-( A solution of 2-chlorophenyl)-3-(dimethylamino)-2-propen-1-one (10.9 g) and piperidine (578 mg) in acetic acid (13 mL) was stirred overnight. After cooling to room temperature, water and ethyl acetate were added to the mixture. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum, and the obtained crude product was purified by column chromatography (solvent: hexane/ethyl acetate=85/15 to 70/30) to give 6-(2-chlorophenyl). )-7-(4-chlorophenyl)-3-ethoxycarbonyl-2- Methylthiopyrazolo[1,5-a]pyrimidine (5.88 g, yield: 38%) was obtained as a pale yellow solid.

(2) The compound obtained in the above step (1) (600 mg) was treated in the same manner as described in Reference Example A1-(4) to obtain 3-carboxy-6-(2-chlorophenyl)-7-(4) -Chlorophenyl)-2-methylthiopyrazolo[1,5-a]pyrimidine (502 mg) as a grayish yellow powder.

MS (APCI) m/z; 430/432 [M+H] ⁺

(3) In a solution of the compound obtained in the above step (2) (1.0 g) in chloroform (20 ml), cyclopentylamine (260 mg), water-soluble dimethylimine hydrochloride (620 mg) and 1-Hydroxybenzotriazole (540 mg), and the mixture was stirred overnight at room temperature. An aqueous sodium hydrogencarbonate solution and chloroform were added to the reaction mixture. After stirring, the organic layer was concentrated under vacuum and the obtained crude product was purified by column chromatography (solvent: hexane/ethyl acetate = 82/18 to 67/33) to obtain 6-(2) -Chlorophenyl)-7-(4-chlorophenyl)-3-(N-cyclopentylaminemethanyl)-2-methylthiopyrazolo[1,5-a]pyrimidine (940 mg, Yield: 81%), as a yellow solid.

MS (APCI) m/z; 497/499 [M+H] ⁺

(4) To a solution of the compound (940 mg. hour. An aqueous sodium thiosulfate solution was added to the reaction mixture. The mixture was stirred and extracted with EtOAc. The obtained crude product was purified by column chromatography on a NH-hydrazine gel (Kemator NH oxime gel, solvent: hexane/ethyl acetate = 50/50 to 0/100) to obtain 6 -(2-chlorophenyl)-7-(4-chlorophenyl)-3-(N-cyclopentylaminecarboxylidene)-2-methylsulfonylpyrazolo[1,5-a] Pyrimidine (1.0 g, yield: 100%) as a colorless solid.

MS (APCI) m/z; 529/531 [M+H] ⁺

(5) Compound (1.5 g) obtained in the above step (4) in dimethylformamide (20 ml) A solution of sodium azide (1.11 g) was added to the solution, and the mixture was stirred at 110 ° C overnight. After cooling to room temperature, brine was added to the reaction mixture, and the mixture was stirred and evaporated. The organic layer was washed with water and concentrated under vacuum, and the obtained crude product was purified on a silica gel column chromatography (solvent: hexane/ethyl acetate = 80/20 to 30/70) to obtain 2- Azido-6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-(N-cyclopentylaminecarbamimido)pyrazolo[1,5-a]pyrimidine (1.15 g), a yellow solid. Triphenylphosphine (869 mg) was added to a solution of this compound (870 mg) in THF (16 ml), and the mixture was stirred at 40 ° C for one hour. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the obtained crude product was purified by column chromatography (solvent: chloroform/methanol = 100/0 to 97/3) to obtain 6- (2-Chlorophenyl)-7-(4-chlorophenyl)-3-(N-cyclopentylaminecarboxylidene)-2-triphenylphosphazinylaminopyrazole [1,5 -a]pyrimidine (942 mg, yield: 58%), as a yellow solid.

MS (APCI) m/z; 726/728 [M+H] ⁺

(6) To a solution of the compound obtained in the above step (5) (1.1 g) in THF (EtOAc (EtOAc) After cooling to room temperature, an aqueous 2 N sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was dehydrated with magnesium sulfate and filtered. The filtrate was concentrated under vacuum, and the obtained crude product was purified by column chromatography (solvent: hexane/ethyl acetate = 80/20 to 60/40) to afford 2-amino-6-( 2-chlorophenyl)-7-(4-chlorophenyl)-3-(N-cyclopentylaminecarbamimido)pyrazolo[1,5-a]pyrimidine (529 mg, yield: 75%) ), a yellow solid.

MS (APCI) m/z; 466/468 [M+H] ⁺

Reference example B8

(1) treating the corresponding starting materials in the same manner as described in Reference Example B2, The reaction product was further treated in the same manner as described in Reference Example B3 to obtain 6-(2-chlorophenyl)-2-chlorosulfonyl-3-ethoxycarbonyl-7-(4-trifluoromethylbenzene. Pyrazolo[1,5-a]pyrimidine is a colorless powder.

MS (APCI) m/z; 544/546 [M+H] ⁺

(2) The compound obtained in the above step (1) (2.2 g) was treated in the same manner as described in Reference Example B4, and the reaction product was further treated in the same manner as described in Reference Example B2-(1) to obtain 3-carboxy- 6-(2-Chlorophenyl)-7-(4-trifluoromethylphenyl)-2-aminesulfonylpyrazolo[1,5-a]pyrimidine (0.45 g), as a pale yellow powder.

MS (APCI) m/z; 497/499 [M+H] ⁺

Reference example B9

(1) The corresponding starting material is treated in the same manner as described in Example B2-(1) to obtain 6-(2-bromophenyl)-3-carboxy-7-(4-chlorophenyl)- 2-Aminosulfonylpyrazolo[1,5-a]pyrimidine (897 mg) as a grayish yellow powder.

MS (APCI) m/z; 507/509 [M+H] ⁺

(2) The compound obtained in the above step (1) (150 mg) and cyclopentylamine (33 mg) were treated in the same manner as described in Example A1 to obtain 6-(2-bromophenyl)-7-(4). -Chlorophenyl)-3-(N-cyclopentylaminecarbamimidyl)-2-aminesulfonylpyrazolo[1,5-a]pyrimidine (170 mg, yield: 100%), gray Yellow powder.

MS (APCI) m/z; 574/576 [M+H] ⁺

(3) The compound obtained in the above step (2) (166 mg) was added with zinc cyanide (37 mg) and hydrazine (triphenylphosphine) palladium (0) in dimethylformamide (2 ml) (tetrakis (triphenylphosphin) Palladium (0)) (33 mg), and the mixture was stirred overnight at 110 ° C under a nitrogen atmosphere. After cooling to room temperature, water and ethyl acetate were added to the reaction mixture. The mixture was stirred and the organic layer was separated and concentrated in vacuo. The obtained crude product was purified by column chromatography on a silica gel (solvent: hexane/ethyl acetate = 60/40 to 50/50) to obtain 7-(4-chlorophenyl)-6-(2) -cyanophenyl)-3-(N-cyclopentylaminemethylhydrazino)-2-amine sulfonylpyrazolo[1,5-a]pyrimidine (24 mg, yield: 16%), Gray-yellow powder.

MS (APCI) m/z;521/523[M+H] ⁺

Reference example B10

(1) in 1-aminocyclohexanecarboxylic acid (5 g) in two A solution of (70 ml) was added aqueous sodium hydroxide solution (4.19 g in 70 ml of water), and dibutyl succinate (16.7 g) was added thereto. The mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo and water and ethyl acetate. The mixture was weakly acidified with aqueous 2N aqueous solution and extracted with ethyl acetate. The combined organic layers were washed sequentially with water and brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo. EtOAc m. .

MS (APCI) m/z; 244 [M+H] ⁺

(2) The compound obtained in the above step (1) and ammonium chloride (6.4 g) were treated in the same manner as in Example A1 to obtain 1-(t-butoxycarbonylamino)cyclohexan-1-carboxamide (1) - (tert-butoxycarbonylamino)cyclohexan-1-carboxamide) (5.4 g, yield: 92%) as a colorless solid.

MS (APCI) m/z; 243 [M+H] ⁺

(3) the compound obtained in the above step (2) is in the second (80 ml), add 4 N hydrochloric acid to two The solution (22.1 mL) was stirred at rt overnight. Diethyl ether was added to the reaction mixture, and the mixture was stirred. The precipitate was collected by filtration to give 1-aminocyclohexan-1-carboxamide (3.35 g, yield: 85%) as a colorless powder.

MS (APCI) m/z; 143 [M+H] ⁺

Reference example B11

(1) The compound (8 g) obtained in Reference Example A3-(2) was treated in the same manner as described in Reference Example B10-(1) to obtain 4-(t-butoxycarbonylamino)-tetrahydrothiophene. M- 4-carboxylic acid (10.8 g, yield: 69%) was obtained as a pale yellow solid.

MS (APCI) m/z; 262 [M+H] ⁺

(2) The compound obtained in the above step (1) and ammonium chloride (11.1 g) were treated in the same manner as in Example A1 to obtain 4-(t-butoxycarbonylamino)-tetrahydrothiopyran-4-carboxylate. Guanidine (3.3 g, yield: 30%) was obtained as a colorless solid.

MS (APCI) m/z; 261 [M+H] ⁺

(3) To a solution of the compound (3. The reaction mixture was extracted with chloroform and the organic layer was washed with aqueous saturated sodium hydrogen carbonate. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum, and the obtained crude product was purified by column chromatography (solvent: chloroform/methanol = 98/2 to 90/10) to give 4-(t-butoxycarbonylamino). -1,1-dionetetrahydrothiopyran-4-carboxyguanamine (3.3 g, yield: 90%) as a colorless powder.

MS (APCI) m/z; 293 [M+H] ⁺

(4) The compound obtained in the above step (3) (3.3 g) was treated in the same manner as described in Reference Example B10-(3) to obtain 4-amino-1,1-dione-tetrahydrothiopyran-4 Carboxylamidine (2.0 g, yield: 77%) as a colorless powder.

MS (APCI) m/z; 193 [M+H] ⁺

Reference example B12

(1) A mixture of (R)-methionine (R)-methioninol (4.95 g), benzonitrile (8.3 ml) and zinc bromide (250 mg) was stirred at 120 ° C for 90 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered, washed with water and brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum, and the obtained crude product was purified on a silica gel column chromatography (solvent; hexane/ethyl acetate = 5/1 to 3/1) to obtain (R)-4-(2) -methylthioethyl)-2-phenyl-4,5-dihydro Azole (3.94 g, yield: 48.6%) as a colorless oil.

MS (APCI) m/z; 222 [M+H] ⁺

(2) Concentrated hydrochloric acid (7.7 ml) was added to a solution of the compound (3. After cooling to room temperature, the reaction mixture was concentrated in vacuo. Aqueous sodium hydroxide solution (50 ml) and chloroform (100 ml) were added to the residue and the mixture was stirred. Magnesium sulfate and a hydrazine gel were added to the organic layer, and the mixture was stirred and filtered. The filtrate was concentrated under reduced pressure, and the obtained crude product was washed with diethyl ether and dried to give (R)-N-(tetrahydrothiophen-3-yl)benzylamine (2.80 g, yield: 76%). It is a colorless solid.

MS (APCI) m/z; 208 [M+H] ⁺

(3) In a solution of the compound obtained in the above step (2) (3.59 g) in methylene chloride (70 ml), m-chloroperbenzoic acid (75%, 10 g) Stir overnight at room temperature. Water (35 ml), sodium sulfite (3.5 g) and aqueous saturated sodium hydrogen carbonate solution (100 ml) were added to the mixture, and the mixture was stirred for 30 minutes and extracted with chloroform. The extract was washed with an aqueous saturated sodium bicarbonate solution and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under vacuum, and the obtained solid was washed ethyl acetate to give (R)-N-(1,1-dione-tetrahydrothiophen-3-yl) benzamide (3.5 g, yield: 85%) as a colorless solid.

MS (APCI) m/z; 240 [M+H] ⁺

(4) To a solution of the compound (3. After cooling to room temperature the aqueous layer was washed with EtOAc EtOAc. The precipitated solid material was washed with ethanol/diethyl ether, and collected by filtration and washed with diethyl ether to give (R)-N-(1,1-dione-tetrahydrothiophen-3-yl)amine hydrochloride (2.52) Gram, yield: 100%), as a colorless solid.

MS (APCI) m/z; 136 [M+H] ⁺

Reference example B13

(S)-Ethylamine alcohol (4.83 g) was treated in the same manner as described in Reference Example B12 to obtain (S)-N-(1,1-dione-tetrahydrothiophen-3-yl)amine hydrochloride. Salt (3.86 g) as a colorless solid.

MS (APCI) m/z; 136 [M+H] ⁺

Reference example B14

In a solution of 4-amino-4-carboxy-tetrahydropyran hydrochloride (2 g) in methanol, 2 M trimethylsilyldiazomethane-diethylether was added dropwise with ice cooling. The solution (33 ml) was stirred at room temperature for 4 days. The reaction mixture was concentrated under EtOAc (EtOAc)EtOAc. The precipitate was collected by filtration to give 4-amino-4-methoxycarbonyl-tetrahydropyran (2.13 g, yield: 99%) as white crystals.

MS (ESI) m/z; 160 [M+H] ⁺

Reference example B15

(1) Under a argon atmosphere, in a solution of tetrahydro-4H-thiazolidine-4-one (25.0 g) in diethyl ether (500 ml), 3 M methyl bromide was added dropwise at 0 ° C A solution of diethyl ether was stirred at the same temperature for 30 minutes. Aqueous saturated ammonium chloride solution (200 ml) was added to the mixture and the mixture was evaporated. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum, and the obtained crude product was purified by column chromatography (solvent; hexane/ethyl acetate = 9/1 to 6/1) to obtain 4-methyltetrahydrogen. Piperan-4-ol (14.7 g, yield: 52%) was obtained as a solid.

(2) To a solution of the compound obtained in the above step (1) (13.7 g) in toluene (100 ml), trimethylsulfonyl azide (14.3 g) and boron trifluoride etherate complex (17.6 g) The mixture was stirred overnight at room temperature. The reaction mixture was poured into water, and the organic layer was separated and washed sequentially with aqueous saturated sodium hydrogen carbonate solution, water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum, and the obtained crude product was purified eluted eluted elute Hydrothiazepine (6.84 g, yield: 42%), as an oil.

MS (APCI) m/z; 130 [M+HN ₂ ] ⁺

(3) To a solution of the compound (370 mg. Water (442 μl), aqueous 15% sodium hydroxide solution (442 μL) and water (884 μL) were added to the reaction mixture, and the mixture was stirred. The mixture was filtered through a Hillite filter to remove the resulting precipitate. The filtrate was concentrated in vacuo to give 1-methyl-tetrahydrothiophenylamine (221 mg, yield: 72%) as oil.

MS (APCI) m/z; 132 [M+H] ⁺

Reference example B16

(1) 1,3-dibromo-2,2-dimethoxypropane (26.45 g) in dimethyl hydrazine (sodium) Sodium sulfide (9.46 g) was added to a solution of sulfide (200 ml), and the mixture was stirred at 110 ° C to 140 ° C (external temperature) for 30 minutes. The reaction mixture was diluted with diethyl ether under ice cooling, and aqueous saturated sodium hydrogen carbonate solution and water were added. The mixture was extracted with diethyl ether (twice). The filtrate was concentrated under vacuum, and the obtained crude product was purified on a silica gel column chromatography (solvent; hexane/diethyl ether = 100/0 to 15/1) to obtain 3,3-dimethoxythiophene. Cyclobutane (10.55 g, yield: 78%) was a yellow liquid.

MS (APCI) m/z; 103 [M+H-MeOH] ⁺

(2) In a solution of the compound obtained in the above step (1) (9.0 g) in acetone (70 ml), an iron exchange resin (Amberlyst 15E, 3.5 g) was added, and the mixture was stirred at room temperature 21 hour. The reaction mixture was filtered through celite and the residue was washed with acetone. The filtrate and washings were combined and concentrated under vacuum. The precipitate was collected by filtration and washed with cold acetone to give 3- syloxythiocyclobutane (1.58 g, yield: 27%) as colorless crystals.

(3) In a solution of potassium cyanide (0.80 g) and ammonium chloride (0.62 g) in water (10 ml), ammonium carbonate (3.59 g) and the compound obtained in the above step (2) (1.0 g) in methanol A solution of (10 ml) was stirred at 60 ° C overnight. An aqueous 1 N sodium hydroxide solution (5 ml) and water (50 ml) were added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and filtered. The filtrate was concentrated under vacuum, and the obtained crude product was washed with diisopropyl ether to give 2-thia-5,7-dioxaspiro[3,4]oct-6,8-dione (2-thia-5) , 7-diazaspiro [3, 4] octan-6, 8-dione) (0.79 g, yield: 44%), as a powder.

MS (ESI) m/z; 157 [MH] ^-

(4) The compound obtained in the above step (3) (0.75 g) was dissolved in aqueous 1 N sodium hydroxide. The solution of the liquid (10 ml) was heated under reflux for 15 hours. After cooling to room temperature, concentrated hydrochloric acid (3 ml) was added to the mixture, and the mixture was concentrated in vacuo to give 3-aminothietan-3-carboxylic acid ( 1.54 g), solid.

MS (APCI) m/z; 134 [M+H] ⁺

(5) To a suspension of the compound (1.54 g. The reaction mixture was neutralized with ice water and aqueous sodium hydrogen carbonate, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo. EtOAc (EtOAc m. Methyl thiazide-3-carboxylate (0.53 g, yield: 61%) was obtained as a powder.

MS (APCI) m/z; 148 [M+H] ⁺

Reference example B17

(1) 6-(2-Chlorophenyl)-3-ethoxycarbonyl-7-(4-trifluoro-methylphenyl)-2-methylpyrazolo[1,5-a]pyrimidine (corresponding to the ethyl ester of the compound obtained in Reference Example A12; 5.35 g) in a solution of carbon tetrachloride (73 ml), N-bromosuccinimide (6.21 g) and 2, 2'-Azobisisobutylonitrile (96 mg), and the mixture was stirred at 85 ° C (external temperature) for 18 hours. After cooling to room temperature, the reaction mixture was filtered with EtOAc EtOAc. The obtained crude product was purified by column chromatography on a silica gel (solvent; hexane/ethyl acetate = 80/20 to 65/35) to obtain 2-bromomethyl-6-(2-chlorophenyl). 3-ethoxycarbonyl-7-(4-trifluoro-methylphenyl)pyrazolo[1,5-a]pyrimidine (4.72 g, yield: 75%) as a pale yellow solid.

MS (APCI) m/z; 538/540 [M+H] ⁺

(2) To a solution of the compound (4.72 g) obtained in the above step (1) in dimethylformamide (50 ml), potassium acetate (2.58 g) was added, and the mixture was stirred at 60 ° C for 1.5 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and water was evaporated. The organic layer was separated, washed sequentially with water and brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum, and the obtained crude product was purified on a silica gel column chromatography (solvent; hexane/ethyl acetate = 80/20 to 60/40) 5-(2-chlorophenyl)-3-ethoxycarbonyl-7-(4-trifluoromethylphenyl)pyrazolo[1,5-a]pyrimidine (1.86 g, yield: 41 %), a colorless powder.

MS (APCI) m/z; 518/520 [M+H] ⁺

(3) In a solution of the compound obtained in the above step (2) (1.86 g) in ethanol (30 ml / 30 ml), 21% sodium hydroxide in ethanol (2.5 ml), and the mixture was stirred at 60 ° C 30 minute. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, and aqueous diluted hydrochloric acid solution was added. The organic layer was separated and washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum, and the obtained crude product was purified by column chromatography (solvent; hexane/ethyl acetate = 85/15 to 55/45) to obtain 6-(2-chlorobenzene). 3-ethoxycarbonyl-7-(4-trifluoromethylphenyl)-2-hydroxymethyl-pyrazolo[1,5-a]pyrimidine (1.05 g, yield: 62%) It is a colorless solid.

MS (APCI) m/z; 476/478 [M+H] ⁺

(4) The compound obtained in the above step (3) (1.03 g) was treated in the same manner as described in Reference Example A1-(4) to obtain 3-carboxy-6-(2-chlorophenyl)-7-(4) -Trifluoromethylphenyl)-2-hydroxymethyl-pyrazolo[1,5-a]pyrimidine (894 mg, yield: 92%).

MS (APCI) m/z; 448/450 [M+H] ⁺

Reference example B18 to B20

The compound obtained in Reference Examples B17-(3) was treated in the same manner as described in Example B33, and the reaction product and the corresponding amine were treated in the same manner as described in Example A5, and then the reaction product was referred to Reference Example A1-(4). The treatment was carried out in the same manner to obtain the compound shown in Table 35 below.

Reference example B21

A solution of the compound (1.00 g) and triethylamine (1.33 ml) in methylene chloride (20 ml) was added to the mixture. Stir for 1.5 hours. Add 0.5 M ammonia to the reaction mixture The solution (20 mL) was stirred at room temperature for 30 min. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum, and the obtained crude product was purified eluting from EtOAc EtOAc EtOAc EtOAc EtOAc 6-(2-Chlorophenyl)-7-(4-trifluoromethylphenyl)-2-ureidopyrazolo[1,5-a]pyrimidine (0.70 g, yield: 64%), Colorless powder.

MS (APCI) m/z; 504/506 [M+H] ⁺

Reference example B22

(1) In a solution of the compound (100 mg) obtained in the title compound (16 mg) in ethanol (3 ml), hydroxyamine hydrochloride (236 mg) and sodium carbonate (360 mg) were added, and the mixture was heated under reflux. hour. After cooling to room temperature, an aqueous saturated sodium hydrogencarbonate solution and water were added to the mixture, and the mixture was extracted with chloroform. The organic layer was concentrated under vacuum, and the obtained crude product was purified by column chromatography (solvent; hexane/ethyl acetate = 90/10 to 50/50) to obtain 3-hydroxyimido group. Thiocyclobutane (93 mg, yield: 80%) as a colorless solid.

(2) To a solution of the above-mentioned step (1) (93 mg) in tetrahydrofuran (1.5 ml) was added dropwise to a solution of lithium hydride (58 mg) in tetrahydrofuran (2 ml). The solution was stirred at room temperature for 1 hour. Water (60 μl), an aqueous 15% sodium hydroxide solution (60 μL) and water (120 μl) were added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature. The reaction mixture was filtered through celite, and the filtrate was concentrated in vacuo to give 3-aminothiocyclobutane as a crude product.

Reference example B23

(1) The compound obtained in Reference Example B1 was treated in the same manner as described in Reference Example A14B, and then the reaction product was treated in the same manner as described in Reference Example A14-(3) to obtain 2-benzylthio-7-chloro- 6-(2-Chlorophenyl)-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine in powder.

MS (APCI) m/z; 458/460 [M+H] ⁺

(2) The compound obtained in the above step (1) (1.0 g), [1,1'-indole (diphenylphosphino)ferrium]palladium(II) chloride-dichloromethane complex (63 mg) ), potassium phosphate (1.4 g) and 4-fluorophenyl dihydroxyboric acid (339 mg) in 1,4-two The solution (25 ml) was stirred at 80 ° C for 16 hours. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum, and the obtained crude product was purified by column chromatography (solvent; hexane/ethyl acetate = 2/1 to 1/1) to afford 2-benzylthio-6. -(2-Chlorophenyl)-3-ethoxycarbonyl-7-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidine (865 mg, yield: 76%) as a powder.

MS (APCI) m/z; 518/520 [M+H] ⁺

(3) The compound obtained in the above step (2) ( 854 mg) was treated in the same manner as described in the titled Example B3, and then the reaction product was treated in the same manner as described in Example B4 to obtain 6-(2-chlorophenyl). 3-Ethoxycarbonyl-7-(4-fluorophenyl)-2-aminesulfonylpyrazolo[1,5-a]pyrimidine (670 mg, yield: 78%) was obtained as a powder.

MS (APCI) m/z; 475/477 [M+H] ⁺

(4) The compound obtained in the above step (3) (660 mg) was treated in the same manner as described in Example B2-(1) to obtain 3-carboxy-6-(2-chlorophenyl)-7-(4-fluoro Phenyl)-2-aminesulfonylpyrazolo[1,5-a]pyrimidine (318 mg, yield: 56%) as a powder.

MS (APCI) m/z; 447/449 [M+H] ⁺

Reference example B24 to B28

1) Reference Examples B24 to B25: The corresponding starting materials were sequentially treated in the same manner as described in Reference Examples B1 to B3, Example B4 and Example B2-(1) to obtain the compound shown in Table 36 below.

2) Reference Examples B26 to B27: The corresponding starting materials were treated in the same manner as described in Reference Example B23 to obtain the compound shown in Table 36 below.

3) Reference Example B28: The corresponding starting materials are as in Reference Example B23-(1) and The compounds shown in Table 36 below were obtained in the same manner as described in Tests A14-(4) to (5).

Experimental example 1 [Human CB1 receptor binding assay]

(1) Preparation of human CB1 receptor (membrane part):

material)

Human CB1-expressing cell line: hCB1/CHO (#ES-100-C, Eulock)

Medium: F-12 (GIBCO #11765-062), 10% fetal bovine serum, 400 μg/ ML Geneticin (GIBCO #11811-031), 100 units/ml penicillin (Penicillin), 100 μg/ml Streptomycin (GIBCO #15140-122)

Buffer A: 50 mM tris-HCl (pH 7.5) containing exoethyldiaminetetraacetic acid (2.5 mM), MgGl ₂ (5 mM) and sucrose (200 mM)

Method) The receptor-expressing cells cultured in the aforementioned medium are washed with phosphate buffer (twice), and added with buffer A (2 ml) under ice cooling or 4 ° C (the following procedure is also performed at the same temperature). ). Cells were harvested using a cell scraper and treated with a microtip-type ultrasonic oscillator for 20 seconds (pulse on: 2 seconds, pulse off: 1 second) and centrifugation (500 x g, 15 minutes). The supernatant was separated and centrifuged (43000 x g, 60 minutes). The pellet obtained was suspended in buffer A and homogenized using a potter type homogenizer. An equal amount of 80% glycerol was added to the homogenate and stored at -80 °C.

(2) Procedure for CB1 receptor binding assay analysis:

material)

Buffer B: 50 mM tris-HCl (pH 7.5) containing exoethyldiaminetetraacetic acid (2.5 mM), MgGl _{2 (} 5 mM) and bovine serum albumin (2 mg/ml, free of fatty acids, Sigma) (SIGMA)-A7030)

Buffer C: 50 mM tris-HCl (pH 7.5) containing exoethyldiaminetetraacetic acid (2.5 mM), MgGl _{2 (} 5 mM) and bovine serum albumin (2 mg/ml, Sigma-A7906)

Coating solution: 0.3% ethyl imino polymer

Radioligand: [ ³ H]-CP55940 (30 nM, 7992 dpm/μl, PerkinElmer, # NET-1051) prepared by diluting 8.3 μM radioligand solution with buffer B

Method) Assay Analytical well plates (96 wells, Corning Costar, code #3371) were filled with buffer B (140 μl), each test compound in dimethyl sulfoxide solution (20 μm) L, final concentration: 0.1%), radioligand (20 μl) and membrane preparation (20 μl, 0.5 to 8.0 μg / 20 μl), and the mixture was incubated at room temperature for 90 minutes to carry out a binding reaction. The reaction mixture was collected by filtration through Unifilter GF/B (Packard #6005177) pre-soaked with the aforementioned coating solution. The well plates were washed with buffer C (200 μl x 10 times), dried at 50 ° C for 1 hour, and a microscintimeter (Microscinti) 40 (40 μl/well) was added to each well. The combined radioactive label was quantified by a scintillation counter (Top Count NXT, Parker). Use Microsoft (Microsoft) Excel 2000 (Microsoft Corporation) based on the quantization radiolabel activity, calculated for each test compound IC ₅₀ value for binding of radioactive ligand to the receptor CB1.

(3) Results:

The IC ₅₀ values of the respective test compounds are shown in Table 37 below. At the same time, the symbols (++ and +++) are defined as follows:

++: 10 nM<IC ₅₀ <100 nM

+++: 10 nM>IC ₅₀

Experimental example 2 [Selectivity of test compound for human CB1 receptor]

(1) Materials and methods

a) Human CB1 receptor binding assay analysis: Binding assay analysis was performed in the same manner as described in Experimental Example 1.

b) Human CB2 receptor binding assay analysis: Binding assay analysis was performed in the same manner as described in Experimental Example 1, except that the CHO cell line (hCB2/CHO) expressing human CB2 was used in place of the hCB1 cell line. Each test compound radioligand system in the same manner of Experimental Example 1 binding to calculate _IC50 values IC CB2 receptor. In addition, / selectivity ratio in the evaluation based on CB1 receptor CB2 of the IC ₅₀ values for the IC ₅₀ values of CB1.

(2) Results: The selectivity of each test compound is shown in Table 38 below. Meanwhile, the symbols (++ and +++) in the table are the same as those in Experimental Example 1.

Industrial applicability

The compound [I] of the present invention can be used for the treatment and/or prevention of diseases of various CB1 receptor vectors, such as psychosis including schizophrenia. The compound [I] of the present invention can also be used in the ring Chronic treatment, alcohol addiction or substance abuse. Further, the compound [I] of the present invention can be used as an analgesic activity enhancer or a smoking cessation agent.

Claims (12)

A compound of the formula [I-II-i] or a pharmaceutically acceptable salt thereof: Wherein R ¹⁰ is (i) optionally 1 to 2 selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a difluoro-C _1-6 alkyl group, a trifluoro-C _1-6 alkyl group and two a phenyl group substituted with a C _1-6 alkyl)amino group or (ii) optionally selected from a C _1-6 alkyl group, a trifluoro-C _1-6 alkyl group, and a C _1-6 alkoxy group. a saturated or unsaturated 5- to 6-membered nitrogen-containing monocyclic group substituted by a group in which R ^{20 is} optionally substituted by 1 to 2 groups selected from a halogen atom and a cyano group, R ^0B Is a group of the formula: -SO ₂ N(R ⁰¹ )(R ⁰² ); a group of the formula: -NHCONHR ⁰³ ; a group of the formula: -CON(R ^e )(R ^f ); a carboxyl group; or a hydroxy group-C _1-6 alkyl; R ⁰¹ and R ⁰² are the same or different and each are a hydrogen atom, a C _1-6 alkyl group or an aminomethyl group -C _1-6 alkyl group, and R ⁰³ is a hydrogen atom or C _{1- 6} alkyl, R ^e and R ^f are the same or different and each is a hydrogen atom, a C _1-6 alkyl group or a di(C _1-6 alkyl)amino group, and E is a group of the formula: -C (= O)- or -SO ₂ -, R ^5A is a hydrogen atom or a C _1-6 alkyl group, and R ^6A is (A) optionally selected from 1 to 3 halogen atoms, a hydroxyl group, a cyano group, a carboxyl group, and C. _a C _1-6 alkyl group substituted with a group of alkoxycarbonyl group; or (B) a group of the formula: Wherein Ring A ^b is (A) C _3-8 cycloalkyl or (b) a benzene ring fused to the C _3-8 cycloalkyl group; R ³⁷ is a hydrogen atom, a cyano group, C _1-6 alkyl, hydroxy-C _1-6 alkyl, amino-C _1-6 alkyl, carboxy-C _1-6 alkyl, carboxy, C _1-6 alkoxycarbonyl, optionally 1 to 2 selected from C Aminomethyl group substituted by a group in a _1-6 alkyl group and a di(C _1-6 alkyl)amino group-C _1-6 alkyl group or a group of the formula: R ⁴³ is a hydrogen atom, an amine group, a C _1-6 alkoxycarbonylamino group or a benzyloxycarbonylamino group; or (C) optionally 1 to 2 selected from a halogen atom and a C _1-6 alkoxy group; , -C _1-6 alkyl trihalomethyl, carboxy and C _1-6 alkoxycarbonyl group in the substituent of the phenyl group; or (D) the ring system radical of formula: Wherein, ring B ^b is a 4- to 7-membered aliphatic heteromonocyclic group which is bonded to an adjacent nitrogen atom through its ring carbon atom; ring B ^c is from 4 to 7 members of nitrogen-containing fat. a heterocyclic monocyclic group; X ¹ is a sulfur atom, a group of the formula: -SO-, a group of the formula: -SO ₂ -, an oxygen atom, or a group of the formula: -NR ^m -, R ^m is C _{1 -6} alkyl, C _1-6 alkylcarbonyl, C _1-6 alkoxycarbonyl, C _1-6 alkylsulfonyl, amide sulfonium substituted with 1 or 2 C _1-6 alkyl groups as needed a group or an amine carbenyl group optionally substituted by 1 or 2 C _1-6 alkyl groups; R ³⁸ is (a) a hydrogen atom, (b) a cyano group, (c) a C _1-6 alkyl group, (d) Hydroxy-C _1-6 alkyl, (e) amino-C _1-6 alkyl, (f) carboxy-C _1-6 alkyl, (g) carboxyl, (h) C _1-6 alkoxycarbonyl And (i) an amine carbenyl group substituted by 1 to 2 groups selected from a C _1-6 alkyl group and a di(C _1-6 alkyl)aminoalkyl group, or (j) Group: (E) a group of the formula: -N(R ^8a )(R ^9a ), wherein R ^8a is a hydrogen atom or a C _1-6 alkyl group; R ^9a is a C _1-6 alkyl group, a trihalo-C _1-6 An alkyl group, a cyano-C _1-6 alkyl group, a benzyl group, a C _3-8 cycloalkyl group, optionally selected from a halogen atom, a cyano group, a C _1-6 alkyl group, a trihalogen-C _1-6 Alkyl, C _1-6 alkoxy, trihalo-C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylsulfonyl, C _1-6 alkoxycarbonyl and benzyl a phenyl group substituted with a group in the oxycarbonyl group, a C _1-6 alkoxycarbonyl group, a benzyloxycarbonyl group or a 5- to 6-membered nitrogen-containing heteroaryl group; or (F) a group of the formula: Wherein ring A ^c is a C _3-8 cycloalkyl group fused to the benzene ring as needed; ring B ^d is (a) optionally through a halogen atom, a cyano group, a C _1-6 alkoxy group, a trihalogen-C _{a 1-6} alkyl or carboxy substituted phenyl group or (b) pyridyl group; R ^S11 is a hydrogen atom or a C _1-6 alkyl group; R ^S12 is a hydrogen atom, a C _1-6 alkyl group, a carboxyl group, an amine carbenyl group Or a mono(C _1-6 alkyl)amine carbenyl or a di(C _1-6 alkyl)amine carbenyl group; R ³⁹ is a hydrogen atom, a halogen atom, a cyano group, a C _1-6 alkyl group, a hydroxyl group - C _1-6 alkyl, trihalo-C _1-6 alkyl, amino-C _1-6 alkyl, C _1-6 alkoxy, carboxy-C _1-6 alkyl, carboxy, optionally 1 Up to 2 amine-methyl hydrazino groups, amine groups, C _1-6 alkoxy groups substituted with a group selected from a C _1-6 alkyl group and a di(C _1-6 alkyl)amino group-C _1-6 alkyl group a carbonylamino group or a benzyloxycarbonylamino group; and k is an integer from 0 to 2, but excluding 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[N-(1, 1-Diketotetrahydrothiophen-3-yl)amine-mercapto]-2-(hydroxymethyl)pyrazolo[1,5-a]pyrimidine. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of 6-(2-chlorophenyl)-7-(4-chlorophenyl) --3-ethoxycarbonyl-2-(N-methylaminesulfonyl)pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorobenzene (3-)oxycarbonyl-2-(N,N-dimethylaminesulfonyl)pyrazolo[1,5-a]pyrimidine; (R)-6-(2-chlorophenyl) -7-(4-chlorophenyl)-2-(N-methylaminesulfonyl)-3-[N-(1,1-dionetetrahydrothiophen-3-yl)aminecarbamyl] Pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[N-(cyclopentyl)aminecarbamyl]-2- (N-methylamine sulfonyl)pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[[N'-A -N'-(2-pyridyl)indenyl]carbonyl]-2-(N-methylaminesulfonyl)pyrazolo[1,5-a]pyrimidine; (R)-6-(2- Chlorophenyl)-7-(4-chlorophenyl)-2-(N,N-dimethylaminesulfonyl)-3-[N-(1,1-dionetetrahydrothiophene-3- Aminomethyl]pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[N-(cyclopentyl)amine Mercapto]-2-(N,N-dimethylaminesulfonyl)pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorophenyl )-2- (N,N-dimethylaminesulfonyl)-3-[N-(1-pyrrolidinyl)aminecarboxylidene]pyrazolo[1,5-a]pyrimidine; 6-(2-chlorobenzene -7-(4-chlorophenyl)-3-[[N'-methyl-N'-(2-pyridyl)indolyl]carbonyl]-2-(N,N-dimethylamine sulfonate Mercapto)pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorophenyl)-2-(N-methylaminesulfonyl)-3- [N-(1-pyrrolidinyl)aminemethanyl]pyrazolo[1,5-a]pyrimidine; (R)-6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[N-(1,1-dionetetrahydrothiophen-3-yl)aminemethanyl] 2-aminosulfonylpyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[N-(1-pyrrolidinyl) Aminomethyl hydrazino]-2-amine sulfonyl pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[[N '-Methyl-N'-(2-pyridyl)indenyl]carbonyl]-2-aminesulfonylpyrazolo[1,5-a]pyrimidine; (S)-6-(2-chlorophenyl) - 7-(4-Chlorophenyl)-3-[N-(1,1-dionetetrahydrothiophen-3-yl)amine-carbamoyl]-2-aminesulfonylpyrazolo[1] ,5-a]pyrimidine;6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[N-(cyclopentyl)aminemethylmercapto]-2-amine sulfonylpyridinium Zizo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[N-(1,1-dionetetrahydrothiopyran- 4-yl)amine-mercapto]-2-aminesulfonylpyrazolo[1,5-a]pyrimidine; (R)-6-(2-chlorophenyl)-7-(4-trifluoromethyl) Phenyl))-3-[N-(1,1-dionetetrahydrothiophen-3-yl)amine-carbamoyl]-2-aminesulfonylpyrazolo[1,5-a]pyrimidine; (S)-6-(2-Chlorophenyl)-7-(4-trifluoromethylphenyl)-3-[N-(1,1-dionetetrahydrothiophen-3-yl)amine A Mercapto]-2-aminesulfonylpyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-3-[N- (cyclopentyl)amine-mercapto]-7-(4-trifluoromethylphenyl)-2-aminesulfonylpyrazolo[1,5-a]pyrimidine; (R)-7-(4 -Chlorophenyl)-6-(2-cyanophenyl)-3-[N-(1,1-dionetetrahydrothiophen-3-yl)amine-carbenyl]-2-amine sulfonyl Pyrazolo[1,5-a]pyrimidine; 7-(4-chlorophenyl)-6-(2-cyanophenyl)-3-[N-(cyclopentyl)aminecarbamyl]-2 - amidoxime pyrazolo[1,5-a]pyrimidine; 7-(4-chlorophenyl)-6-(2-cyanophenyl)-3-[[N'-methyl-N' -(2-pyridyl)indolyl]carbonyl]-2-aminesulfonylpyrazolo[1,5-a]pyrimidine; (R)-2-[N-(Aminomethylmethyl)amine sulfonyl]-6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[N-(1 ,1-diketotetrahydrothiophen-3-yl)amine,carboxylidene]pyrazolo[1,5-a]pyrimidine; 2-[N-(aminomethylmethyl)aminesulfonyl]- 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[N-(cyclopentyl)aminecarboxylidene]pyrazolo[1,5-a]pyrimidine; 2-[ N-(Aminomethylmethyl)amine sulfonyl]-6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[[N'-methyl-N'-( 2-pyridyl)indenyl]carbonyl]pyrazolo[1,5-a]pyrimidine; 2-[N-(aminomethylmethylmethyl)amine sulfonyl]-6-(2-chlorophenyl) -7-(4-chlorophenyl)-3-[N-(1-pyrrolidinyl)aminecarboxylidene]pyrazolo[1,5-a]pyrimidine; 3-[N-(1-carboxyl ring) Hexyl)aminomethane]-6-(2-chlorophenyl)-7-(4-chlorophenyl)-2-(N-methylaminesulfonyl)pyrazolo[1,5-a] Pyrimidine; 3-[N-(1-amine-mercaptocyclohexyl)amine-carbamoyl]-6-(2-chlorophenyl)-7-(4-chlorophenyl)-2-amine sulfonylpyridinium Azolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-trifluoromethylphenyl)-2-hydroxymethyl-3-[N-[1-methyl 1-(2-pyridyl)ethyl]amine-methylmethyl]pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-trifluoromethylphenyl )-2-hydroxymethyl-3-[N-(3-methyl-1,1-dione) Hydrothiophen-3-yl)amine-methylmethyl]pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-3-[N-(1-cyanocyclohexyl)aminecarboxamide 7-(4-trifluoromethylphenyl)-2-(hydroxymethyl)pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4- Trifluoromethylphenyl)-2-hydroxymethyl-3-[N-(4-methyl-1,1-dionetetrahydrothiopyran-4-yl)aminemethanyl]pyrazole [1,5-a]pyrimidine; 2-aminoformamido-6-(2-chlorophenyl)-7-(4-trifluoromethylphenyl)-3-[N-(4-methyl- 1,1-diketotetrahydrothiopyran-4-yl)aminecarboxylidene]pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-tri Fluoromethylphenyl)-2-(N-methylaminemethanyl)-3-[N-(4- Methyl-1,1-dionetetrahydrothiopyran-4-yl)aminecarboxylidene]pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-( 4-chlorophenyl)-3-[N-(2,2-dimethylpropyl)aminemethanyl]-2-aminesulfonylpyrazolo[1,5-a]pyrimidine; 6-( 2-Chlorophenyl)-7-(4-chlorophenyl)-3-[N-(cyclohexylmethyl)aminemethanyl]-2-aminesulfonylpyrazolo[1,5-a] Pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[N-(2,2,2-trifluoroethyl)aminecarboxylidene-2-aminesulfonate Pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[N-(3-methylpropyl)aminecarboxamido ]-2-aminesulfonylpyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[N-(2,2- Difluoroethyl)amine-mercapto]-2-aminesulfonylpyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3 -[N-(cyclopropylmethyl)aminemethanyl]-2-aminesulfonylpyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4- Chlorophenyl)-3-[N-(1-methylcyclopropyl)aminemethanyl]-2-aminesulfonylpyrazolo[1,5-a]pyrimidine; 6-(2-chlorobenzene -3[N-(2,2,2-trifluoroethyl)amine-mercapto]-7-(4-trifluoromethylphenyl)-2-(hydroxymethyl)pyrazolo[ 1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-difluoromethylphenyl)- 3-[N-(isobutyl)aminemethanyl]-2-aminesulfonylpyrazolo[1,5-a]pyrimidine; 2-aminoformamido-6-(2-chlorophenyl) -3-[N-(2,2,2-trifluoroethyl)aminemethanyl]-7-(4-trifluoromethylphenyl)pyrazolo[1,5-a]pyrimidine; 6- (2-Chlorophenyl)-7-(4-chloro-2-fluorophenyl)-3-[N-(2,2,2-trifluoroethyl)aminemethanyl]-2-aminesulfonate Pyrazolo[1,5-a]pyrimidine; 6-(2-Chlorophenyl)-7-(4-difluoromethylphenyl)-3-[N-(2,2,2-trifluoroethyl)aminemethylmercapto]-2-aminesulfonate Mercaptopyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-trifluoromethylphenyl)-3-[N-(n-propyl)aminecarboxamide 2-aminosulfonylpyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-trifluoromethylphenyl)-3-[N-( Isobutyl)amine-mercapto]-2-aminesulfonylpyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-trifluoromethylphenyl) -3-[N-(1-methylpropyl)aminemethanyl]-2-aminesulfonylpyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7- (4-Trifluoromethylphenyl)-3-[N-(3-methoxypropan-2-yl)aminemethanyl]-2-aminesulfonylpyrazolo[1,5-a] Pyrimidine; 6-(2-chlorophenyl)-7-(4-trifluoromethylphenyl)-3-[N-(1-methylcyclopropyl)aminemethanyl]-2-aminesulfonate Pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-3-[N-(2,2,2-trifluoroethyl)aminecarbamyl]-7-(4 -fluorophenyl)-2-aminesulfonylpyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-trifluoromethylphenyl)-3-[ [N'-Methyl-N'-(2-pyridyl)indenyl]carbonyl]-2-aminesulfonylpyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)- 7-(4-Trifluoromethylphenyl)-3-[N-(2,2,2-trifluoroethyl) Methyl]-2-(dimethylaminocarbamimido)pyrazolo[1,5-a]pyrimidine; 6-(2-chlorophenyl)-7-(4-trifluoromethylphenyl) -3-[N-[1-methyl-1-(2-pyridyl)ethyl]aminemethanyl]-2-aminesulfonylpyrazolo[1,5-a]pyrimidine; 6-( 2-Chlorophenyl)-3-[N-(2,2,2-trifluoroethyl)aminemethylmercapto]-7-(4-methylphenyl)-2-aminesulfonylpyrazole [1,5-a]pyrimidine;6-(2-chlorophenyl)-3-[N-(isobutyl)aminemethanyl]-7-(4-methylphenyl)-2-amine sulfonate Mercaptopyrazolo[1,5-a]pyrimidine; 6-(2-Chlorophenyl)-3-[N-(cyclopentyl)aminemethylmercapto]-7-(4-methylphenyl)-2-aminesulfonylpyrazolo[1,5 -a] pyrimidine; or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising, as an active ingredient, a compound of the formula [I-II-i] or a pharmaceutically acceptable salt thereof: Wherein R ¹⁰ is (i) optionally 1 to 2 selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a difluoro-C _1-6 alkyl group, a trifluoro-C _1-6 alkyl group and two a phenyl group substituted with a C _1-6 alkyl)amino group or (ii) optionally selected from a C _1-6 alkyl group, a trifluoro-C _1-6 alkyl group, and a C _1-6 alkoxy group. a saturated or unsaturated 5- to 6-membered nitrogen-containing monocyclic group substituted by a group in which R ²⁰ is a phenyl group optionally substituted with 1 to 2 groups selected from a halogen atom and a cyano group, R ^0B Is a group of the formula: -SO ₂ N(R ⁰¹ )(R ⁰² ); a group of the formula: -NHCONHR ⁰³ ; a group of the formula: -CON(R ^e )(R ^f ); a carboxyl group; or a hydroxy group-C _1-6 alkyl; R ⁰¹ and R ⁰² are the same or different and each are a hydrogen atom, a C _1-6 alkyl group or an aminomethyl group -C _1-6 alkyl group, and R ⁰³ is a hydrogen atom or C _{1- 6} alkyl, R ^e and R ^f are the same or different and each is a hydrogen atom, a C _1-6 alkyl group or a di(C _1-6 alkyl)amino group, and E is a group of the formula: -C (= O)- or -SO ₂ -, R ^5A is a hydrogen atom or a C _1-6 alkyl group, and R ^6A is (A) optionally selected from 1 to 3 halogen atoms, a hydroxyl group, a cyano group, a carboxyl group, and C. _a C _1-6 alkyl group substituted with a group of alkoxycarbonyl group; or (B) a group of the formula: Wherein Ring A ^b is (A) C _3-8 cycloalkyl or (b) a benzene ring fused to the C _3-8 cycloalkyl group; R ³⁷ is a hydrogen atom, a cyano group, C _1-6 alkyl, hydroxy-C _1-6 alkyl, amino-C _1-6 alkyl, carboxy-C _1-6 alkyl, carboxy, C _1-6 alkoxycarbonyl, optionally 1 to 2 selected from C Aminomethyl group substituted by a group in a _1-6 alkyl group and a di(C _1-6 alkyl)amino group C _1-6 alkyl group or a group of the formula: R ⁴³ is a hydrogen atom, an amine group, a C _1-6 alkoxycarbonylamino group or a benzyloxycarbonylamino group; or (C) optionally 1 to 2 selected from a halogen atom and a C _1-6 alkoxy group; , -C _1-6 alkyl trihalomethyl, carboxy and C _1-6 alkoxycarbonyl group in the substituent of the phenyl group; or (D) the ring system radical of formula: Wherein, ring B ^b is a 4- to 7-membered aliphatic heteromonocyclic group which is bonded to an adjacent nitrogen atom through its ring carbon atom; ring B ^c is from 4 to 7 members of nitrogen-containing fat. a heterocyclic monocyclic group; X ¹ is a sulfur atom, a group of the formula: -SO-, a group of the formula: -SO ₂ -, an oxygen atom, or a group of the formula: -NR ^m -, R ^m is C _{1 -6} alkyl, C _1-6 alkylcarbonyl, C _1-6 alkoxycarbonyl, C _1-6 alkylsulfonyl, amide sulfonium substituted with 1 or 2 C _1-6 alkyl groups as needed Or an amine carbenyl group substituted by 1 or 2 C _1-6 alkyl groups; R ³⁸ is (a) a hydrogen atom, (b) a cyano group, (c) a C _1-6 alkyl group, (d) a hydroxyl group - C _1-6 alkyl, (e) amino-C _1-6 alkyl, (f) carboxy-C _1-6 alkyl, (g) carboxyl, (h) C _1-6 alkoxycarbonyl, ( i) an amine formazan group substituted with 1 to 2 groups selected from a C _1-6 alkyl group and a di(C _1-6 alkyl)aminoalkyl group, or (j) a group of the formula : (E) a group of the formula: -N(R ^8a )(R ^9a ), wherein R ^8a is a hydrogen atom or a C _1-6 alkyl group; R ^9a is a C _1-6 alkyl group, a trihalo-C _1-6 An alkyl group, a cyano-C _1-6 alkyl group, a benzyl group, a C _3-8 cycloalkyl group, optionally selected from a halogen atom, a cyano group, a C _1-6 alkyl group, a trihalogen-C _1-6 Alkyl, C _1-6 alkoxy, trihalo-C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylsulfonyl, C _1-6 alkoxycarbonyl and benzyl a phenyl group substituted with a group in the oxycarbonyl group, a C _1-6 alkoxycarbonyl group, a benzyloxycarbonyl group or a 5- to 6-membered nitrogen-containing heteroaryl group; or (F) a group of the formula: Wherein ring A ^c is a C _3-8 cycloalkyl group fused to the benzene ring as needed; ring B ^d is (a) optionally through a halogen atom, a cyano group, a C _1-6 alkoxy group, a trihalogen-C _{a 1-6} alkyl or carboxy substituted phenyl group or (b) pyridyl group; R ^S11 is a hydrogen atom or a C _1-6 alkyl group; R ^S12 is a hydrogen atom, a C _1-6 alkyl group, a carboxyl group, an amine carbenyl group Or a mono(C _1-6 alkyl)amine carbenyl or a di(C _1-6 alkyl)amine carbenyl group; R ³⁹ is a hydrogen atom, a halogen atom, a cyano group, a C _1-6 alkyl group, a hydroxyl group - C _1-6 alkyl, trihalo-C _1-6 alkyl, amino-C _1-6 alkyl, C _1-6 alkoxy, carboxy-C _1-6 alkyl, carboxy, optionally 1 Up to 2 amine-methyl hydrazino groups, amine groups, C _1-6 alkoxy groups substituted with a group selected from a C _1-6 alkyl group and a di(C _1-6 alkyl)amino group-C _1-6 alkyl group a carbonylamino group or a benzyloxycarbonylamino group; and k is an integer from 0 to 2, but excluding 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[N-(1, 1-Diketotetrahydrothiophen-3-yl)amine-mercapto]-2-(hydroxymethyl)pyrazolo[1,5-a]pyrimidine. The pharmaceutical composition of claim 3, which is a preventive and/or therapeutic agent for a disease of the CB1 receptor vector. The pharmaceutical composition of claim 4, wherein the CB1 receptor vector is a mental illness including schizophrenia, anxiety, stress, depression, epilepsy, neurodegenerative disorder, spinal cerebellar bundle disease, cognitive impairment, cranial Brain trauma, panic attacks, peripheral neuropathy, glaucoma, migraine, Parkinson's disease, Alzheimer's disease, Huntington's disease, Raynaud's Syndrome), tremor, obsessive-compulsive disorder, amnesia, senile dementia, thymic disorder, Tourette's syndrome, delayed dyskinesia, bipolar disorder, cancer, drug-induced motor difficulty, dystonia, septic shock Hemorrhagic shock, hypotension, insomnia, immune diseases including inflammation, multiple sclerosis, vomiting, diarrhea, asthma, appetite disorders such as bulimia-anorexia, anorexia, obesity, non-insulin dependent diabetes (NIDDM), Memory impairment, urinary system disorders, cardiovascular disorders, infertility, infection, demyelinating diseases , neuroinflammation, viral encephalitis, cerebrovascular attacks, cirrhosis or gastrointestinal disorders including intestinal passage disorders. For example, the pharmaceutical composition of the third application patent scope is chronic treatment and alcohol formation. Addiction agents for addiction or drug abuse. For example, the pharmaceutical composition of claim 3, the analgesic activity enhancer of the painkiller or anesthetic. For example, the pharmaceutical composition of claim 3, which is a smoking cessation agent (quit smoking addiction or nicotine addiction). A use of a compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease, condition or condition modulated by a CB1 receptor antagonist. A compound of claim 1 or a pharmaceutically acceptable salt thereof, which is 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[[N'-A -N'-(2-pyridyl)indenyl]carbonyl]-2-(N-methylaminesulfonyl)pyrazolo[1,5-a]pyrimidine. A compound of claim 1 or a pharmaceutically acceptable salt thereof, which is 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[N-(1- Pyrrrolidinyl)aminomethane]-2-aminesulfonylpyrazolo[1,5-a]pyrimidine. A compound of claim 1 or a pharmaceutically acceptable salt thereof, which is 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[[N'-A -N'-(2-pyridyl)indenyl]carbonyl]-2-aminesulfonylpyrazolo[1,5-a]pyrimidine.