BRPI0617659A2 - pyrazolo [1,5-a] pyrimidine compound and pharmaceutical composition containing it - Google Patents

Abstract

<B> PIRAZOLO COMPOUND [1,5-a] PYRIMIDIN AND PHARMACEUTICAL COMPOSITION THAT CONTAINS <D> The present invention relates to a new compound of pyrazole [1, 5-a] pyrimidine of the formula [1]: wherein Ring A is a substituted pyrazole ring fused to the adjacent pyrimidine ring having the following formula (A), (B) or (O), or a pharmaceutically acceptable salt thereof.

Description

Patent Descriptive Report for "COMPOSTODE PIRAZ0L0 [1,5-a] PYRIMIDINE AND THE PHARMACEUTICAL COMPOSITION IT CONTAINS".

TECHNICAL FIELD

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

BACKGROUND ART

It is well known that the use of cannabis would produce various psychiatric or neurological reactions such as temporal or spatial confusion, euphoria, memory impairment, analgesia, hallucination and the like. The compounds generally referred to as "cannabinoids" including A9-tetrahydrocannabinol (A9-THC) are responsible for many of these? reactions. The effect of cannabinoids is considered to be produced by an interaction between the compound and its specific / high affinity endogenous receptors. Two cannabinoid receptor subtypes (CB1 and CB2) have been identified and cloned. Receptor CB1 is distributed in central nervous system (CNS) regions including the brain (Nature, Vol. 346,1990, pp. 561-564), while CB2 receptor is distributed in the immune system including the spleen (Nature, Vol. 365, 1993, pp 61-65).

Substances having affinity for said cannabinoid receptors (agonists, antagonists or inverse agonists) may produce various pharmacological effects such as cannabis. In particular, affinity for central receptor CB1 may be useful for treating a central nervous system disorder such as a psychotic disorder, a neurological disorder and the like.

Various compounds are known, including pyrazol-3-carboxamide compounds such as SR141716 (Life Science, Vol. 63, 1998, PL113-PL117), 4,5-dihydropyrazole compounds such as SLV-319 (Journal of Medical Chemistry, Vol. 47 (3), 2004, pp.627-643), dihydropyrazolo [3,4-c] pyridin-7-one, 2H-pyrazolo [4,3-d] pyrimidin-7 (6H) compounds -ona (W02004 / 094417) 2

and the like as substances having affinity for said cannabinoid receptors. Among these, at least SR141716 and SLV-319 are under clinical studies on their efficacy as anorectic agents (antiobesity agent).

DISCOVERY OF THE INVENTION

The object of the present invention is to provide a novel pyrazolo [1,5-a] pyrimidine compound which has potent CB1 receptor antagonizing activity and is therefore useful as a medicament.

The present invention relates to a pyrazolo [1,5-a] pyrimidine compound of formula [I]:

<formula> formula see original document page 3 </formula>

on what

R1 and R2 are the same or different and an optionally substituted aryl group or an optionally substituted saturated or unsaturated heterocyclic group,

Q is a single bond, a methylene group or a group of the formula:

-N (Rq) -,

Rq is an alkyl group,

Ring A is a substituted pyrazole ring fused to the pyrimidine ring

adjacent formula having the following formula (A), (B) or (C),

<formula> formula see original document page 3 </formula>

R3 and R4 are the same or different and (a) a hydrogen atom, (b) a cyano group, (c) an alkyl group optionally substituted by one to three halogen atoms, (d) an alkyloxy group (the portion said alkyl group being optionally substituted by one to three groups selected from a halogen atom, a hydroxyl group, an amino group optionally substituted by one or two alkyl groups, an alkyloxy group and an alkylsulfonyl group), (e) an alkylthio group, (f) an alkylsulfinyl group, (g) an alkylsulfonyl group or (h) a group of the formula: -N (R ') (R "),

R 'and R "are the same or different and (a) a hydrogen atom, (b) an alkyl group optionally substituted by one to three groups selected from a halogen atom, an amino group optionally substituted by one or two groups alkyl and an alkyloxy group, (c) an acyl group, (d) an alkylsulfonyl group or (e) an amino sulfonyl group optionally substituted by one to two alkyl groups, or both R 'and R "combine with each other. another at its termini to form together with an adjacent denitrogen atom an optionally substituted saturated or unsaturated nitrogen-containing heterocyclic group,

And is one of the following groups (i) to (v):

<formula> formula see original document page 4 </formula>

R00 is an alkyl group,

Q1 is a single bond, an alkylene group or a group of the formula: -N (R7) -, R7 is a hydrogen atom or an alkyl group,

Q2 is a single bond or an alkylene group,

one of R5 and R6 is a hydrogen atom or an alkyl group and the other is (a) an alkyl group optionally substituted by one to three groups selected from a halogen atom, a cyano group, an alkyloxy group, an optionally cycloalkyl group substituted, an amino optionally substituted by one or two alkyl groups, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group, an acyl group, an optionally substituted aryl group and optionally substituted saturated or unsaturated heterocyclic group, (b) an optionally substituted cycloalkyl group (c) a group of the formula: -N (R 8) (R 9) 1 (d) an optionally substituted aryl group or (e) an optionally substituted saturated or unsaturated heterocyclic group, or both R 5 and R 6 combine with one another. another to form together with an adjacent nitrogen atom a heterocyclic group containing optionally substituted saturated or unsaturated nitrogen,

one of R8 and R9 is a hydrogen atom or an alkyl group and the other is (a) an alkyl group optionally substituted by one to three groups selected between a halogen atom, a cyano group and an aryl group, (b) a cycloalkyl group (c) an optionally substituted aryl group or (d) an acyl group or (e) an optionally substituted saturated or unsaturated heterocyclic group,

one of R50 and R60 is a hydrogen atom or an alkyl group and the other is a hydrogen atom, an alkyl group or an acyl group, or both combine together with the adjacent nitrogen atom to form a group cyclic of the following formula:

<formula> formula see original document page 5 </formula>

wherein Ring A1 is a 5- to 7-membered aliphatic nitrogen-containing heterocyclic group optionally substituted by an oxo group,

R51 is an alkyl group or an optionally substituted arylsulfonyl group,

R61 is an alkylamino group or an azido group, or a pharmaceutically acceptable salt thereof.

BEST MODE FOR CARRYING OUT THE INVENTION

With respect to the compound [I] of the present invention, where each of R 1 and R 2 is an aryl group, examples of such an aryl group include a 6 to 10 membered monocyclic or bicyclic aryl group such as a phenyl group or a naphthyl group. Among these, preferred examples of such aryl group is a phenyl group.

With respect to the compound [I] of the present invention, where R1, R2, R3 or R4 is a saturated or unsaturated heterocyclic group, examples of such a heterocyclic group include a 5-7 membered heteromono-cyclic group including one to three heteroatoms selected from one sulfur atom, one oxygen atom and one nitrogen atom. More specifically, said heterocyclic group may be a saturated or unsaturated 5 to 6 membered heterocyclic oxygen containing group such as a furyl group, a tetrahydrofuranoyl group, a pyranyl group or a tetrahydropyranyl group, a 5-6 membered sulfur-containing heterocyclic group or unsaturated group such as thienyl group, tetrahydrothienyl group, thiopyranyl group or tetrahydrothiopyranyl group or a saturated or unsaturated 5- to 7-membered nitrogen heterocyclic group such as pyrrolidinyl group, imidazolyl group, pyrazolyl group, oxazole group isoxazolyl, a thiazolyl group, an isothiazolyl group, a group pyridyl, a piperidyl group, a pyrimidinyl group, a pyrazinyl group, a pyridazinyl group, a morpholinyl group, a thiomorpholinyl group or a azacycloheptyl group. Among these, a preferred example of R1 or R2 is a saturated or unsaturated 5- or 6-membered sulfur or nitrogen-containing heterocyclic group such as a thienyl group, a pyrrolidinyl group, a piperidyl group or a pyridyl group, and a preferred example of R3 or R4 is a group unsaturated 5- or 6-membered sulfur, oxygen or nitrogen heterocyclic heterocyclic groups such as a pyrrolidinyl group, a piperidyl group, a morpholino group or a thiomorpholine group.

The aryl group and / or the saturated or unsaturated heterocyclic group in R 1, R 21 R 3 or R 4 mentioned above may be substituted by one to three groups selected from a halogen atom, a cyano group, an alkyl group optionally substituted by one to three halogen atoms, an alkyloxy group optionally substituted by one to three halogen atoms, an amino group optionally substituted by one to two alkyl groups, an alkylthio group, an alkylsulfinyl group and an alkylsulfonyl group.

In the case where R5, R6, R8 or R9 is a cycloalkyl group, said group cycloalkyl may be substituted by one to two groups selected from a cyano group and an alkyl group.

The aryl group in R 5, R 6, R 8 or R 9 mentioned above may be a 6 to 10 membered monocyclic or bicyclic aryl group such as a groupophenyl, a naphthyl group and the like, preferably a phenyl group. The aryl group may be substituted by one to two halogen atoms.

Where R5, R61, R8 or R9 is a saturated or unsaturated heterocyclic group, examples of such a heterocyclic group include (a) a 4-7 membered saturated or unsaturated heteromonocyclic group, or a hetero-cyclic group containing one to four heteroatoms. selected from oxygen atom, sulfur atom and nitrogen atom; (b) a saturated or unsaturated 8 to 15-membered nitrogen-containing bicyclic or tricyclic heterocyclic group formed by fusing the above-mentioned heteromonocyclic group with one or two other cyclic groups selected from a C 3-8 cycloalkyl group, a monocyclic aryl group of 5 to 6 is a 4 to 7 membered saturated or unsaturated heteromonocyclic group, said heteromonocyclic group containing one to four heteroatoms selected from one oxygen atom, one sulfur atom and one denitrogen atom; or (c) a saturated or unsaturated 8 to 11 membered nitrogen-containing spiroheterocyclic group.

Examples of the saturated or unsaturated heterocyclic group at R 5, R 6, R 8 or R 9 is (A) a heterocyclic group containing oxygen or sulfur selected from a furyl group, a tetrahydrofuranoyl group, a pyranyl group, a tetrahydropyranyl group, a thiaciclobutyl group, a thienyl group, a groupotetrahydrothienyl, a thiopyranyl group, a tetrahydrothiopyranyl group, a groupobenzofuranyl, a dihydrobenzofuranyl group, an isobenzofuranyl group, a chromanyl group, an isochromanil group, an iso-chromioyl group and a iso-benzothenyl group ; or (B) a nitrogen-containing heterocyclic group selected from an azetidyl group, a pyrrolidinyl group, a pyrrolinyl group, an imidazolidinyl group, an imidazolidinyl group, a pyrazolidinyl group, a pyrazolinyl group, a 2H-pyrrolyl group, an imidazolyl group , a pyrazolyl group, a group dihydropyrazolyl, a thiazolidinyl group, a thiazolyl group, an isothiazolyl group, an isoxazolyl group, an oxazolidinyl group, a pyridyl group, a tetrahydropyridyl group, a piperidyl group, a pyrazinyl group piperazinyl group, pyrimidinyl group, tetrahydropyrimidinyl group, pyridazinyl group, morpholinyl group, azocinyl group, azacycloheptyl group, indolizinyl group, benzimidazolyl group, grupobenzotriazolyl group, indolyl group, isoindolyl group , an indolinyl group, an isoindolinyl group, an 1 H-indazolyl group, a group pyrrolopyridyl, a pyrrolopyrimidinyl group, a purinyl group, a pteri-dinyl group, a 4H-quinolizinyl group, a quinolyl group, a dihydroquinolyl group, a tetrahydroquinolyl group, an isoquinolyl group, a dihydroisoquinolyl group, a phthalazinyl group, a dihydrophthalazinyl group, a , a dihydronaphthyridinyl group, a tetrahydronaphthyridyl · nila group, a quinoxalinyl group, a quinazolinyl group, a dihydroquinazolinyl group, a dihydrobenzothiazinyl group, a dihydrobenzoxazinyl group, a grupokinolinyl group, a xanthenyl group, a carbazolyl group, a beta-carbazolyl group a phenanthridinyl group, an acridinyl group, a 5H-dihydro-dibenza zepinyl group and a spiroheterocyclic group of the formula:

<formula> formula see original document page 8 </formula>

wherein Ra and Rb are the same or different and a hydrogen atom or an alkyl group, and q and r are an integer of 1 or 2.

Among these, preferred examples of the saturated or unsaturated heterocyclic group include a tetrahydrofuranoyl group, a pyrrolyl group, a pyrrolidinyl group, a piperidyl group, an azacycloheptyl group, a groupupetrahydropyranyl group, a piperazinyl group, a morpholinyl group, a thio morpholine group, a thiaciclobutyl group, a tetrahydrothienyl group, a tetrahydrothiopyranyl group, a thiazolyl group, a pyridyl group, a pyrimidinyl group, an indolyl group, a pyrrolopyridyl group or a tetrahydronaphthyridinyl group.

Where R5 and R6 combine to form a saturated or unsaturated nitrogen-containing heterocyclic group, examples of such a nitrogen-containing heterocyclic group include (a) a 4- to 7-membered saturated or unsaturated nitrogen-containing heterocyclic group, said hetero-monocyclic group optionally containing two or more nitrogen atoms and optionally containing one to two heteroatoms different from said nitrogen atoms selected from deoxy oxygen and sulfur atom; (b) a saturated or unsaturated 8 to 15 membered bicyclic or tricyclic nitrogen containing heterocyclic group is formed by fusion of the above hetero-monocyclic group with one or two different cyclic groups selected from a C 3-8 cycloalkyl group, a 5- to 6-monocyclic aryl group members and a saturated or unsaturated 4- to 7-membered heteromonocyclic group, said heteromonocyclic group having one to four heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom; or (c) a saturated or unsaturated 8 to 11 membered spiroheterocyclic nitrogen containing group.

Examples of the saturated or unsaturated nitrogen-containing heterocyclic group mentioned above include a nitrogen-containing heterocyclic group selected from an azetidyl group, a pyrrolidinyl group, a grupopyrrolinyl, an imidazolidinyl group, a pyrazo-lidinyl group, a pyrazolinyl group, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a dihydropyrazolyl group, a thiazolidinyl group, an oxazolidinyl group, a dihydropyridyl group, a tetrahydropyridyl group, a piperazinyl group, a tetrahydropyrimidinyl group, a grupomorazyl group, a azole group and a group , a groupobenzotriazolyl, an indolyl group, an isoindolyl group, an indolinyl group, an isoindolinyl group, a 1H-indazolyl group, a purinyl group, a dihydroquinolyl group, a tetrahydroquinolyl group, a dihydroisoquinolyl group, a tetrahydroisoquinol group, dihydrophthalazinyl, a dihydroquine zolinyl group, a group dihydrobenzothiazinyl, a dihydrobenzoxazinyl group, a carbazolyl group, a beta-carbolinyl group, a 5H-dihydro-dibenzazepinyl group and a spiroheterocyclic group of the formula:

<formula> formula see original document page 9 </formula>

wherein Ra and Rb are the same or different and a hydrogen atom or an alkyl group, and q and r are an integer Ne of 1 or 2.

Among these, preferred examples of the saturated or unsaturated heterocyclic group include a saturated 5- to 7-membered nitrogen-containing hetero-monocyclic group, such as a morpholino group, a thiomorphino group, a piperidino group, a piperazine group or an azacycloheptyl group. .

In addition, the saturated or unsaturated heterocyclic group at R 5, R 6, R 8 or R 9 (and the saturated or unsaturated nitrogen-containing heterocyclic group formed by combining R 5 with R 6) may be substituted by one to four groups selected from a halogen atom, a hydroxyl group, a cyano group, an oxo group, an alkyl group, an alkyl group substituted by one to three halogen atoms, an alkyloxyalkyl group, an aminoalkyl group, a cycloalkyl group, an arylalkyl group, an alkyloxy group, a substituted alkyloxy group one to three halogen atoms, one acyl group, one amino group optionally substituted by one to two alkyl groups, one acylamino group, one alkylsulfonyl group, one aminosulfonyl group optionally substituted by one to two alkyl groups, one optionally substituted aryl group. substituted by one to two halogen atoms and a saturated or unsaturated 5 to 6 membered heterocyclic nitrogen containing group.

Examples of the acyl group in R4, R51, R6, R8 or R9 include a group formed by removing a hydroxyl group from a carboxylic acid having the following formula [Ac-I]:

Rx-COOH [Ac-I], that is, a group of the formula: Rx-CO-, where Rx is (a) a hydrogen atom, (b) an alkyl group optionally substituted by one to three groups selected from one atom halogen, a cyano group, an alkylsulfonyl group and a pyridyl group, (c) an alkyloxy group optionally substituted by an aryl group, (d) a cycloalkyl group, (e) an aryl group optionally substituted by a halogen atom, a cyano group, an alkyl group, a trihalogenoalkyl group and an alkyloxy group, (f) an amino group optionally substituted by one to two alkyl groups or (g) a saturated or unsaturated heterocyclic group. Concrete examples of such an acyl group include (a1) a formyl group, (b1) a C1-6 alkylcarbonyl group such as an acetyl group, a propionyl group and the like, a C1-6 alkylcarbonyl trihalogen group such as a trifluoro-roacetyl group and the like, a cyano-C1-6 alkylcarbonyl group such as groupocyanacetyl and the like, a pyridyl-C1-6 alkylcarbonyl group such as a pyridylacetyl group and the like, (c1) a C1- Alkyloxycarbonyl such as a methoxycarbonyl group, an ethoxycarbonyl group, a group tert-butoxycarbonyl and the like, an aryl-C1-6 alkyloxycarbonyl group such as a benzyloxycarbonyl group, (d1) a C3.8 cycloalkylcarbonyl group such as a cyclopropylcarbonyl group a cyclopentylcarbonyl and the like group, (e1) an arylcarbonyl group such as a benzoyl and the like group, a mono- or dihalogenaryl carbonyl group such as a group chlorobenzoyl, a fluorobenzoyl group, a difluorobenzoyl and the like, u a cyanoarylcarbonyl group such as a cyanobenzoyl group, a trihalogen-C 1-6 alkylaryl carbonyl group such as a trifluoromethyl benzoyl group and the like, a C1-6 alkyloxy aryl carbonyl group such as a methoxybenzoyl group and the like , (f) a carbamoyl group, an N- (C 1-6 alkyl) carbamoyl group, or (g1) a furoyl group, a thenoyl group, a groupobromothenoyl, a cyanothenoyl group, a pyridylcarbonyl group, a groupupyropyridylcarbonyl group, a cyanopyridylcarbonyl group trifluoromethyl-pyridylcarbonyl group or a pyrazinylcarbonyl group.

Where E is a group of formula (ii) in the compound [I] of the present invention, examples of group (ii) include a group of the following formula:

(a) -C (= 0) -N (R 5) (R 6),

(b) -C (= 0) -Alk-N (R 5) (R 6),

(C) -Alk-C (= 0) -N (R 5) (R 6), or

(d) -N (R7) -C (= 0) -N (R5) (R6)

wherein Alk is a straight or branched chain C1-6 alkylene group and other symbols are the same as defined above.

Among the compounds [I] of the present invention, preferred decomposed examples include a compound of the following Group AaE.

Group A: Compound [I] in which

R1 and R2 are the same or different and (a) a phenyl group optionally substituted by one to two groups selected from a dehalogen atom to a trihalogenoalkyl group,

Q is a single bond,

Ring A is a substituted pyrazole ring of formula (A), E is a group of the following formula: -C (= O) O-R00 (i)

R4 is (a) an amino group optionally substituted by one to two groups selected from an alkyl group and an alkylsulfonyl group or (b) an aminosulfonyl group optionally substituted by one to two alkyl groups or a pharmaceutically acceptable salt thereof.

Among Group A compounds, preferred examples include a compound wherein R1 is a chlorophenyl group or a trifluoro-C1-4 alkylphenyl group, R2 is a chlorophenyl group, Ra is a C1-4 alkyl group and R4 is an amino group substituted by one to two groups selected from a C1-4 alkyl group and a C1-4 alkylsulfonyl group or a pharmaceutically acceptable salt thereof.

Group B: Compound [I] in which

R 1 and R 2 are the same or different and (a) a phenyl group optionally substituted by one to three groups selected from a halogen atom, a cyano group, an alkyl group optionally substituted by a three halogen atoms, an optionally alkyloxy group substituted by one to three halogen atoms, an amino group optionally substituted by one to two alkyl groups and one alkylsulfonyl group or (b) a saturated or unsaturated 5 to 7 membered heterocyclic group optionally substituted by one to three groups selected from a halogen atom, an oxo group, an alkyl group optionally substituted by one to three halogen atoms, an alkyloxy group, an alkyloxyalkyl group and an alkyloxyalkyloxy group,

Ring A is a substituted pyrazole ring of formula (A) or (B),

E is one of the groups of the following formula (a) to (e):

a) -C (= O) -N (R 5) (R 6),

b) -C (= 0) -Alk-N (R 5) (R 6),

c) -Alk-C (= 0) -N (R 5) (R 6),

d) -N (R 7) -C (= 0) N (R 5) (R 6),

e) -C (= NR51) -R61,

R3 is a hydrogen atom, a cyano group or an alkoxy group, R4 is (a) a hydrogen atom, (b) a cyano group, (c) an alkyl group optionally substituted by one to three groups selected from a hydrogen atom. halogen and a hydroxyl group, (d) an alkyloxy group optionally substituted by one to three groups selected from a halogen atom, a hydroxyl group, an amino group optionally substituted by one to two alkyl groups, an alkyloxy group and an alkylsulfonyl group, (and ) an alkylthio group, (f) an alkylsulphinyl group, (g) an alkylsulphonyl group or (h) a group of the formula: -N (R1) (Rn),

R 'and R "are the same or different and (a) a hydrogen atom, (b) an alkyl group optionally substituted by one to three groups selected from a halogen atom, an amino group optionally substituted by one to two groups alkyl and an alkyloxy group, (c) an acyl group, (d) an alkylsulfonyl group or (e) an aminosulfonyl group optionally substituted by one to two alkyl groups, or (f) both combine together with the adjacent nitrogen atom to form a 5-6 membered saturated or unsaturated nitrogen-containing hetero-monocyclic group optionally substituted by a hydroxyl group or an alkyloxy group,

one of R5 and R6 is a hydrogen atom or an alkyl group and the other is

(1) an alkyl group optionally substituted by one to three groups selected from a halogen atom, an alkyloxy group, a cycloalkyl group, an alkylthio group, an alkylsulfonyl group, an amino group optionally substituted by one or two alkyl groups, a morpholinocarbonyl group a phenyl group optionally substituted by a cyano group and a saturated or unsaturated 5-6 membered nitrogen containing hetero-monocyclic group, said hetero-monocyclic group being optionally substituted by a group selected from a halogen atom, an alkyl group and a trihalogenoalkyl group;

(2) a cycloalkyl group optionally substituted by a groupocyan or an alkyl group;

(3) a group of the formula: -N (R 8) (R 9); or

(4) a phenyl group; or (5) a 4- to 10-membered saturated or unsaturated monocyclic or bicyclic heterocyclic group optionally substituted by one to four groups selected from a halogen atom, a cyano group, a hydroxyl group, an oxo group, an alkyl group optionally substituted by one to three atoms halogen, a cycloalkyl group, an alkylcarbonyl group, an alkyloxycarbonyl group, an alkylsulfonyl group, an aminosulfonyl group optionally substituted by one or two alkyl groups, a carbamoyl group optionally substituted by one to two alkyl groups, an alkyloxycarbonylamino group phenyl group optionally substituted by one to two halogen atoms and a saturated or unsaturated 5 to 6 membered hetero-monocyclic group; or

(6) Both R5 and R6 combine together with the adjacent nitrogen atom to form a 4- to 7-membered saturated or unsaturated heterocyclic group containing optionally substituted by one to two groups selected between a halogen atom and an oxo group. ,

R8 is hydrogen atom or an alkyl group,

R 9 is (a) an alkyl group optionally substituted by one to three groups selected from a halogen atom, a cyano group and a phenyl group; (b) a phenyl group optionally substituted by a group selected from a halogen atom, a cyano group, an alkyl group, a trihalogenoalkyl group, a cycloalkyl group, a trihalogenoalkyloxy group, an alkyloxy group, an alkylthio group and an alkylsulfonyl group ; (c) an alkyloxycarbonyl group; or (d) a saturated or unsaturated 5-6 membered hetero-monocyclic group optionally substituted by a group selected from a halogen atom, a cyano group, an alkyl group, an alkyloxy group and a trihalogenoalkyl group,

R7 is a hydrogen atom,

R51 is an alkyl group or a phenylsulfonyl group optionally substituted by one to two halogen atoms and R61 is an alkylamino group or an azido group or a pharmaceutically acceptable salt thereof.

Among the Group B compounds, examples of the most preferred compound include a compound wherein R1 is (a) a phenyl group optionally substituted by one or two groups selected from a dehalogen atom, a cyano group, a dihalogenoalkyl group, a trihalo group. -genoalkyl, an alkyloxy group, an alkyloxyalkyl group and a (alkyl) amino group or (b) a saturated or unsaturated 5 to 7 membered heterocyclic group optionally substituted by one to two groups selected from an oxo group, an alkyl group, a trihalogenoalkyl group an alkylalkoxy group, an alkyloxyalkyl group, an alkyloxyalkyloxy group and a (alkyl) amino group,

R 2 is (a) a phenyl group optionally substituted by one or two groups selected from a halogen atom and a cyano group or (b) a saturated or unsaturated 5- to 6-membered heterocyclic group optionally substituted by a halogen atom,

R3 is a hydrogen atom,

R 4 is a hydrogen atom, an alkyl group, a diha logenoalkyl group, a hydroxyalkyl group, a trihalogenoalkyl group, an alkyloxyalkyl group, a hydroxyalkyloxy group, an alkyloxyalkyloxy group, an alkylsulfonylalkyl group or a group of the formula: -N (R ') (R "),

one of R 'and R1 "is a hydrogen atom or an alkyl group and the other is an acyl group an alkylsulfonyl group,

E is one of the groups of the following formula (a), (b) and (e):

(a) -C (= O) -N (R 5) (R 6),

(b) -C (= O) -Alk-N (R 5) (R 6),

(e) -C (= NR51) -R61,

one of R5 and R6 is a hydrogen atom or an alkyl group, the other is (a) an alkyl group, (b) a cycloalkyl group, (c) a phenyl group, (d) a mono- or bicyclic heterocyclic group of 4 saturated or unsaturated 10-membered group optionally substituted by one to four groups selected from a halogen atom, an oxo group, a cyano group, a hydroxyl group, an alkyl group, a trihalogenoalkyl group, an alkyloxy group, an alkyloxyalkyl group, an alkylcarbonyl group a di (alkyl) carbamoyl group, an alkylsulfonyl group, a di (alkyl) aminosulfonyl group, a phenyl group, a halogenophenyl group and a pyridyl group or (e) a group of the formula: -N (R8) (R9) 1 or (f) both combine together with the adjacent nitrogen atom to form a saturated or unsaturated 5- to 6-membered hetero-monocyclic group optionally substituted by one to two groups selected between a halogen atom and an oxo group, R 8 is an alkyl group,

R 9 is (a) an alkyl group, (b) a phenyl group optionally substituted by a halogen atom, (c) an alkyl group optionally substituted by a pyridyl group or (d) a 4-6 membered saturated or optionally unsaturated hetero-monocyclic group substituted by a group selected from a halogen atom, an alkyl group, a triha-iogenoalkyl group and an alkyloxy group,

R51 is an alkyl group or a halogenphenyl sulfonyl group, and R61 is an alkylamino group or an azido group.

Among the Group B compounds, examples of additional preferred compound include a compound wherein R 1 is (a) a phenyl group optionally substituted by a group selected from a chlorine atom, a fluorine atom, a cyano group, a C1-4 alkyl difluoro group and a C1-4 alkyl groupuprifluoro or (b) a pyridyl group optionally substituted by a C1-4 alkyl trifluoro group,

R 2 is a phenyl group optionally substituted by one to two groups selected from a chlorine atom, a fluorine atom, a bromine atom and a cyano group,

R3 is a hydrogen atom,

R4 is a hydrogen atom, a Ch alkyl group, a

difluoro-C1-4 alkyl, a trifluoro-C1-4 alkyl group, a C1.4 alkyloxy-C1-4alkyl group or a C1-4 alkylcarbonylamino group,

E is one of the groups of the following formula (a) and (b) :( a) -C (= 0) -N (R5) (R6), (b) -C (= 0) -Alk-N (R5) (R6),

one of R5 and R6 is a hydrogen atom and the other is a C1-4alkyl group, a pyridyl-C1-4 alkyl group, a C5.7 cycloalkyl group, a grupochlorophenyl, a saturated 4-6 membered hetero-monocyclic group or unsaturated optionally substituted by one to two groups selected from a halogen atom, an oxo group and a C1.4 alkyloxy-C1-4 alkyl group or a group of the formula: -N (R8) (R9) 1 or both together with the adjacent denitrogen atom to form a 5- to 6-membered saturated or unsaturated hetero-monocyclic group optionally substituted by one to two oxo groups,

R 8 is a C 1-4 alkyl group and R 9 is a C 1-4 alkyl group, a group chlorophenyl, a pyridyl group or a C 1-4 alkyloxy pyridyl group.

Group C: A compound [I] wherein R1 and R2 are the same or different and a phenyl group optionally substituted by one to two groups selected between a halogen atom and a trihaloalkyl group, Q is a single bond, Ring A is a substituted pyrazole ring of formula (A), R3 is a hydrogen atom, R4 is a hydrogen atom or an alkyl group, and E is a group of formula (iii):

<formula> formula see original document page 17 </formula>

one of R5 and R6 is a hydrogen atom or an alkyl group and the other is (a) an alkyl group, (b) a cycloalkyl group or (c) a saturated or unsaturated 5-6 membered sulfur or nitrogen hetero-monocyclic group or (d) both combine together with the adjacent nitrogen atom to form a saturated or unsaturated 5- to 6-membered nitrogen-containing heterocyclic group optionally substituted by one or two oxo groups or a pharmaceutically acceptable group thereof.

Among the Group C compounds, examples of the most preferred compound include a compound wherein R1 is a trihalogenoalkylphenyl group, R2 is a halogenophenyl group,

R4 is an alkyl group,

one of R5 and R6 is a hydrogen atom or an alkyl group, the other is (a) an alkyl group, (b) a cycloalkyl group, (c) a 5-6 membered sulfur or nitrogen containing hetero-monocyclic group saturated or unsaturated optionally substituted by one to two oxo groups, or (d) both combine together with the adjacent nitrogen atom to form a saturated or unsaturated 5 to 6 membered hetero-monocyclic group optionally substituted by one to two oxo groups.

Group D: A compound [I] wherein R1 and R2 are the same or different and a phenyl group optionally substituted by one to two groups selected between a halogen atom and a trihaloalkyl group, Q is a single bond, Ring A is a substituted pyrazole ring of formula (A), R3 is a hydrogen atom, R4 is a hydrogen atom or an alkyl group, and E is a group of formula (iv):

<formula> formula see original document page 18 </formula>

one of R50 and R60 is a hydrogen atom or an alkyl group and the other is an alkyl group or an acyl group, or both combine together with the adjacent denitrogen atom to form an optionally substituted nitrogen-containing 5- to 6-membered unsaturated or unsaturated heterocyclic group by one or two oxo groups or a pharmaceutically acceptable salt thereof.

Group E: A compound [I] wherein R1 and R2 are the same or different and a phenyl group optionally substituted by one to two groups selected between a halogen atom and a trihaloalkyl group, Q is a single bond, Ring A is a substituted pyrazole ring of formula (C), R3 is a hydrogen atom, R4 is a group of the formula -N (R ') (R "), R' and R" are the same or different and a hydrogen atom or an alkyl group, or both combine together with the adjacent nitrogen atom to form a saturated or unsaturated 5 to 6 membered nitrogen containing heterocyclic group or a pharmaceutically acceptable salt thereof.

Among the compounds [I] of the present invention, particularly preferred decomposed examples include a compound selected from the group consisting of:

6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- (N-piperidinocarbamoyl) pyrazolo [1,5-a] pyrimidine;

6- (2-chlorophenyl) -7- (4-chlorophenyl) -3 - [(N'-methyl-N'-phenylhydrazino) carbonyl] pyrazo [1,5-a] pyrimidine; 6- (2- chlorophenyl) -7- (4-chlorophenyl) -3- (N-cyclohexylcarbamoyl) pyrazolo [1,5-a] pyrimidine;

6- (2-chlorophenyl) -7- (4-chlorophenyl) -3 - [(N 'N'-dimethylhydrazino) carbonyl] pyrazolo [1,5-a] pyrimidine;

6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- (N-pyrrolidinocarbamoyl) pyrazolo [1,5-a] pyrimidine;

6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- (N-cyclopentylcarbamoyl) pyrazolo [1,5-a] pyrimidine;

6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- [N- (4-tetrahydropyranyl) carbamoyl] pyrazolo [1,5-a] pyrimidine;

6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- [N- (1,1-dioxo-tetrahydrothiophen-3-yl) -carbamoyl] pyrazolo [1,5-a] pyrimidine;

(R) -6- (2-chlorophenyl) -7- (4-difluoromethylphenyl) -3- [N- (1H-dioxo-tetrahydro-thiophen-3-yl) carbamoyl] pyrazolo [1,5-a] pyrimidine ;

(R) -6- (2-chlorophenyl) -7- (4-trifluoromethylphenyl) -2-methyl-3- [N- (1,1-dioxo-tetrahydro-thiophen-3-yl) carbamoyl] pyrazolo [1, 5-a] pyrimidine;

(S) -6- (2-chlorophenyl) -7- (4-trifluoromethylphenyl) -2-methyl-3- [N- (1,1-dioxo-tetrahydrothiophen-3-yl) carbamoyl] pyrazolo [1, 5-a] pyrimidine;

6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- [N- [2- (2-pyridyl) ethyl] carbamoyl] pyrazolo [1,5-a] pyrimidine;

6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- (N-cyclopentylcarbamoyl) -2-methoxypyrazolo [1,5-a] pyrimidine;

(R) -6- (2-chlorophenyl) -7- (4-chlorophenyl) -2-methyl-3- [N- (1,1-dioxo-tetrahydro-thiophen-3-yl) carbamoyl] pyrazolo [1, 5-a] pyrimidine;

(S) -6- (2-chlorophenyl) -7- (4-chlorophenyl) -2-methyl-3- [N- (1,1-dioxo-tetrahydro-thiophen-3-yl) carbamoyl] pyrazolo [1, 5-a] pyrimidine;

6- (2-bromophenyl) -7- (4-chlorophenyl) -3- (N-cyclopentylcarbamoyl) pyrazolo [1,5-a] pyrimidine;

(R, S) -6- (2-bromophenyl) -7- (4-chlorophenyl) -3- [N- (1,1-dioxo-tetrahydrothiophen-3-yl) carbamoyl] pyrazolo [1,5- a] pyrimidine;

(S) -6- (2-chlorophenyl) -7- (4-trifluoromethylphenyl) -3- [N- (1,1-dioxo-tetrahydro-thiophen-3-yl) carbamoyl] pyrazolo [1,5- a] pyrmidine (R) -6- (2-chlorophenyl) -7- (4-trifluoromethylphenyl) -3- [N- (1,1-dioxo-tetrahydro-thiophen-3-yl) carbamoyl] pyrazolo [1,5 -a] pyrimidine;

6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- [N- [N- (3-chlorophenyl) -N-methylamino] carbamoyl] pyrazolo [1,5-a] pyrimidine; 2-cyanophenyl) -7- (4-chlorophenyl) -3- [N- [N-methyl · N- (2-pyriclyl) amino] carbamoyl] pyrazolo [1,5-a] pyrimidine;

6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- (N-isobutylcarbamoyl) pyrazolo [1,5-a] pyrimidine;

6- (2-chlorophenyl) -7- (4-trifluoromethylphenyl) -3- [N- (1,1-dioxo-tetrahydro-thiophen-3-yl) carbamoyl] pyrazolo [1,5-a] pyrimidine;

6- (2H: chlorophenyl) -7- (4-trifluoromethylphenyl] pyrimidine;

6- (2-chlorophenyl) -7- (4-trifluoromethylphenyl) -3- [N- [N-methyl-N- (2-pyridyl) amino] phenyl] pyrazolo [1,5-a] pyrimidine; R) -6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- [N- (1,1-dioxo-tetrahydrothiophen-3-yl) carbamoyl] pyrazolo [1,5-a] pyrimidine;

6- (2-chlorophenyl) -7- (4-cyanophenyl) -3- (N-cyclopentylcarbamoyl) pyrazolo [1,5- a] pyrimidine;

(R, S) -6- (2-chlorophenyl) -7- (4-chlorophenyl) -2-methyl-3- [N- (1,1-dioxo-tetrahydro-phen-3-yl] carbamoyl] pyrazolo [1,5-a] pyrimidine;

6- (2-chlorophenyl) -7- (4-fluorophenyl) -3- (N-cyclopentylcarbamoyl) pyrazolo [1,5-a] pyrimidine;

6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- [N- [N-methyl-N- (2-pyridyl) amino] carbamoyl] pyrazolo [1,5-a] pyrimidine; ) -6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- [N- (1,1-dioxo-tetrahydrothiophen-3-yl] carbamoyl] pyrazolo [1,5-a] pyrimidine;

6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- (N-ethylcarbamoyl) pyrazolo [1,5-a] pyrimidine;

6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- (N-cyclopropylcarbamoyl) pyrazolo [1,5-a] pyrimidine;

(S) -6- (2-chlorophenyl) -7- (4-chloro-2-fluorophenyl) -3- [N- (1,1-dioxothetrahydro-thiophen-3-yl) carbamoyl] pyrazolo [1,5- a] pyrimidine;

(S) -6- (2-chlorophenyl) -7- (4-difluoromethylphenyl) -3- [N- (1,1-dioxothetrahydro-thiophen-3-yl) carbamoyl] pyrazolo [1,5-a] pyrimidine;

(R) -6- (2-cyanophenyl) -7- (4-trifluoromethylphenyl) -3- [N- (1,1-dioxotetrahydro-thiophen-3-yl) carbamoyl] -2-methylpyrazolo [1,5-a ] pyrimidine;

(S) -6- (2-cyanophenyl) -7- (4-trifluoromethylphenyl) -3- [N- (1,1-dioxotetrahydro-thiophen-3-yl) carbamoyl] -2-methylpyrazolo [1,5-a ] pyrimidine;

6- (2-chlorophenyl) -7- (4-chlorophenyl) -3 - [[N'-methyl-N '- (2-methoxypyridin-5-yl) hydrazino] carbonyl] pyrazolo [1,5-a] pyrimidine;

6- (2-cyanophenyl) -7- (4-chlorophenyl) -3- [N- (1-pyrrolidinyl) carbamoyl] pyrazolo [1,5-a] pyrimidine;

6- (2-chlorophenyl) -7- (2-trifluoromethylpyridin-5-yl) -3- (N-cyclopentylcarbamoyl) -pyrazo-1- [1,5-a] pyrimidine;

(R) -6- (2-cyanophenyl) -7- (4-chlorophenyl) -3- [N- (1,1-dioxotetrahydro-thiophen-3-yl) carbamoyl] -2-methylpyrazolo [1,5 -a] pyrimidine;

6- (2-cyanophenyl) -7- (4-chlorophenyl) -3 - [[N'-methyl-N '- (2-pyridyl) hydrazino] carbonyl] -2-methylpyrazolo [1,5-a ] pyrimidine;

(R) -6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- [N- (1,1-dioxotetrahydro-thiophen-3-yl) carbamoyl] -2-trifluoromethylpyrazolo [1,5 -a] pyrimidine;

6- (2-chlorophenyl) -7- (4-trifluoromethylphenyl) -3 - [(N ', N'-dimethylhydrazino) carbonyl] -2-acetylaminopyrazolo [1,5-a] pyrimidine;

6- (2-chlorophenyl) -7- (4-chlorophenyl) -3 - [[N'-methyl-N '- (2-pyridyl) hydrazino] carbonyl] -2-acetylaminopyrazolo [1,5-a ] pyrimidine;

6- (2-chlorophenyl) -7- (4-chlorophenyl) -3 - [[N'-methyl-N '- (2-pyridyl) hydrazino] carbonyl] -2- (trifluoromethyl) pyrazolo [1, 5-a] pyrimidine;

6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- [N- (1-pyrrolidinyl) carbamoyl] -2-difluoromethylpyrazolo [1,5-a] pyrimidine;

(R) -6- (2-chlorophenyl) -7- (4-trifluoromethylphenyl) -3- [N- (1,1-dioxotetrahydro-thiophen-3-yl) carbamoyl] -2-difluoromethylpyrazolo [1,5-a ] pyrimidine;

(S) -6- (2-chlorophenyl) -7- (4-trifluoromethylphenyl) -3- [N- (1,1-dioxothetrahydro-thiophen-3-yl) carbamoyl] -2-difluoromethylpyrazolo [1,5-a ] pyrimidine;

6- (2-cyanophenyl) -7- (4-chlorophenyl) -3- (N-piperidinocarbamoyl) -2-difluoromethylpyrazolo [1,5-a] pyrimidine;

6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- [N- (1,1-dioxothiaciclobutan-3-yl) carbamoyl] pyrazolo [1,5-a] pyrimidine;

7- (4-chlorophenyl) -6- (2-cyano-4-fluorophenyl) -3- [N- (1-pyrrolidinyl) carbamoyl] pyrazolo [1,5-a] pyrimidine;

7- (4-chlorophenyl) -6- (2-cyanophenyl) -3- (N-piperidinocarbamoyl) -2-methylpyrazolo [1,5-a] pyrimidine;

7- (4-chlorophenyl) -6- (2-cyanophenyl) -3- [N- (1'-irrolidinyl) carbamoyl] -2-methylpyrazo [1,5-a] pyrimidine;

(S) -6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- [N- (2-methoxymethyl-1-pyrrolidinyl) carbamoyl] pyrazolo [1,5-a] pyrimidine; 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- [N- (4-fluoropiperidino) carbamoyl] -pyrazo [1,5-a] pyrimidine;

(R) -7- (4-chloro-2-fluorophenyl) -6- (2-cyanophenyl) -3- [N- (1,1-dioxotetrahydro-phen-3-yl) carbamoyl] -2-methylpyrazole [1,5-a] pyrimidine; 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3 - [[N'-methyl-N, - (2-ethoxypyridin-5-yl) hydrazine ] carbonyl] pyrazolo [1,5-a] pyrimidine;

(R) -6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- [N- (1,1-dioxotetrahydro-thiophen-3-yl) carbamoyl] -2-methoxymethylpyrazolo [1,5 -a] pyrimidine;

(S) -6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- [N- (1,1-dioxothetrahydro-thiophen-3-yl) carbamoyl] -2-methoxymethylpyrazolo [1,5 -a] pyrimidine; 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3 - [[N'-methyl-N '- (2-pyridyl) hydrazino] carbonyl] -2-methoxymethylpyrazolo [1,5-a ] pyrimidine;

6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- [N- (1-pyrrolidinyl) carbamoyl] -2-methoxymethylpiperolo [1,5-a] pyrimidine;

7- (4-chloro-2-fluorophenyl) -6- (2-cyanophenyl) -3- [N- (1-pyrrolidinyl) carbamoyl] -2-methylpyrazolo [1,5-a] pyrimidine;

6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- [2- (1,1-dioxothiomorpholino) acetyl] -2-methylpyrazolo [1,5-a] pyrimidine;

6- (2-cyanophenyl) -7- (4-chlorophenyl) -3- [N- (4-fluoropiperidino) carbamoyl] -2-methylpyrazolo [1,5-a] pyrimidine; and 6- (2-chlorophenyl) -7- (4-trifluoromethylphenyl) -3- [N- (tetrahydrothiophen-3-yl) carbamoyl] piperolo [1,5-a] pyrimidine

or a pharmaceutically acceptable salt thereof. When compound [I] of the present invention has one or more asymmetric carbon atoms in its molecule, it may exist as a stereoisomer thereof (diastereoisomers, optical isomers) due to one or more carbon atoms. said asymmetric embodiments thereof, and the present invention also includes one of the stereoisomers and a mixture thereof.

A compound [I] of the present invention exhibits antagonistic potent reactivity against receptor CB1 and may be useful as an agent for prevention and / or treatment of some CB1 receptor mediated diseases such as psychosis including schizophrenia, anxiety disorders, stress, depression, epilepsy, disorders neurodegenerative disorders, cerebellar disorders, cognitive disorders, head trauma, depanic attack, peripheral neuropathy, glaucoma, migraine, Parkinson's disease, Alzheimer's disease, Huntington's disease, Raynaud's syndrome, tremor, obsessive-compulsive disorders, amnesia, geriatric dementia, disorders, Tourette's syndrome, tardive dyskinesia, bipolar disorder, cancer, drug-induced dyskinesia, dystonia, septic shock, hemorrhagic shock, hypotension, insomnia, immune disorders including inflammation, multiple sclerosis, vomiting, diarrhea, asthma, appetite disorders such as buli marexia, anorex ia and the like, obesity, non-insulin dependent diabetes mellitus (NIDDM), memory disorders, urinary disorders, cardiovascular disorders, infertility disorders, infections, demyelination-related diseases, neuroinflammation, viral encephalitis, stroke, hepatic cirrhosis or gastrointestinal disorders including intestinal transit.

In addition, a compound [I] of the present invention may be useful as an agent for chronic treatment withdrawal, alcohol dependence or drug abuse (e.g., an opioid, barbiturate, marijuana, cocaine, amphetamine, phencyclidine, a hallucinogen agent, a debenzodiazepine compound and the like).

In addition, a compound [I] of the present invention may be useful as an agent for enhancing the analgesic activity of analgesic or narcotic drugs and the like; or an agent to stop smoking (smoking cessation or nicotine addiction).

In addition, a compound [I] of the present invention may be useful for treating a condition related to metabolic disorders including obesity, diabetes, glucose intolerance, hyperinsulinemia, hyperlipidaemia, hypercholesterolemia, hypertriglyceridemia, lipid metabolism disorder, atherosclerosis, hypertension, cardiovascular disease, coronary heart disease, depression, anxiety, drug addiction, and substance addiction.

In addition, the compound [I] of the present invention may be advantageous as a medicament due to its low toxicity.

The compound [I] of the present invention may be used clinically either in free form or in the form of a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable salt of compound [I] includes a common inorganic acid salt such as hydrochloride, sulfate, phosphate or hydrobromide, or a salt with an organic acid such as acetate, fumarate, oxalate, citrate, methanesulfonate, benzenesulfonate, tosylate or maleate . In addition, when the compound [I] of the present invention has one or more similar carboxyl groups in its molecule, examples of the pharmaceutically acceptable salt include salts with a base such as alkali metal (e.g. sodium salt, potassium salt) or alkaline earth metal (e.g., calcium salt).

Compound [I] or a pharmaceutically acceptable salt thereof includes or intramolecular salt or an additive thereof, and solvates or hydrates thereof.

The present compound [I] or a pharmaceutically acceptable salt thereof may be either orally or parenterally, and may be formulated in a conventional pharmaceutical preparation such as tablets, granules, capsules, powders, injections or inhalants.

The dose of the compound [I] of the present invention or a pharmaceutically acceptable salt thereof may vary according to the various routes of administration, and the ages, weights and conditions of the patients. For example, when administered in an injection preparation, generally 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 preparation, it is generally in the range of about 0.001 to 100 mg / kg / day, preferably in the range of 0.01 to 10 mg / kg / day.

A compound [I] of the present invention may also be useful as adjunctive, additional (add-ori) or supplemental therapy for the treatment of the diseases / disorders mentioned above. Said adjunctive, additional or supplemental therapy means concomitant or sequential administration of a compound of the present invention to a patient who has already received administration of, is receiving administration of, or will receive administration of one or more administration of additional therapeutic agents for the treatment of the indicated conditions, for example one or more known antidepressant, antipsychotic or anxiolytic agents.

The compound [I] of the present invention may be prepared by the following methods but should not be considered limited thereto.

(1) Among the compound of the present invention, a compound [I] in which Ring A is a substituted pyrazole ring of formula (A) and E is a group of the following formula (ii):

<formula> formula see original document page 25 </formula>

may be prepared according to, for example, the following methods AaD.

(Method A)

A compound [I] wherein Q2 is a single bond, that is having the following formula [1-A]:

<formula> formula see original document page 25 </formula>

wherein the symbols are the same as defined above can be prepared by reacting a compound of formula [II-A]: <formula> formula see original document page 26 </formula>

wherein Ra is a hydrogen atom, an alkyl group or a benzyl group and the other symbols are the same as defined above with an amine compound of the following formula [III]:

<formula> formula see original document page 26 </formula>

wherein the symbols are the same as defined above or a salt thereof.

When Ra is a hydrogen atom, the above reaction may be carried out in a solvent in the presence of a condensing agent, and in the presence or absence of an activating agent and base. Examples of the solvent include any solvent which does not disturb aeration, such as methylene chloride, chloroform, dimethylformamide, dimethyl lacetamide, tetrahydrofuran, dioxane, toluene, benzene, 1,2-dichloroethane, 1-methylpyrrolidinone, 1,2-dimethoxyethane and similar. The damping agent may be dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylamino-propyl) carbodiimide hydrochloride (WSC HCI), diphenylphosphoryl azide (DPPA), carbonyldiimidazole (CDI), diethyl cyanophosphonate (DEPC), diisopropylcarbodiimide (DIPCI), benzotriazol-1-yloxytrispyrrolidinophosphonium hexafluorophosphate (Py-BOP), carbonylditriazole, N-cyclohexylcarbodiimide-N'-propyloxymethylpolystyrene-2-carbodioxy-1,2-carbodioxycarbide dihydroquinoline (EEDQ), 2- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium (HATU) hexafluorophosphate, 2- (1H-benzotriazol-1-yl-1,1-hexafluorophosphate) 3,3-tetramethyluronium (HBTU), bromotrispyrrolidinophosphonium hexafluorophosphate (PyBroP), 2- (1H-benzotriazol-1-yl) tetrafluoroborate -1,1,3> 3-tetramethyluronium (TBTU), chlorohexane-1-monate , 1,3,3-tetramethyl uronium (ACTU) and the like Examples of the activating agent include 1-hydroxybenzotriazole (HOBt), 1-hydroxysuccinimide (HOSu), dimethylaminopyridine (DMAP), 1-hydroxy Azabenzo-triazole (HOAt), hydroxyphthalimide (HOPht), pentafluorophenol (Pfp-OH), 1-hydroxybenzotriazole-6-sulfonamidomethylpolystyrene (PS-HOBt) and the like. The base includes, for example, pyridine, triethylamine, diisopropylethylamine, 4-methylmorpholine, 1,8-diazabicyclo [5,4,0] -7-undecene (DBU) and the like.

In the process mentioned above, compound [II-A] may be used in an amount of 0.33 to 1.5 mol, preferably 0.5 to 1.2 mol per one mol of compound [III]. The condensing agent may be used in an amount of from 1.0 to 3.0 moles, preferably from 1.0 to 1.2 moles, for a compound consisting of [11a] or [III]. The base may be used in an amount of 1.0 to 3.0 moles, preferably 1.0 to 1.2 moles for one mol of compound [11a] or [III]. The activating agent may be used in an amount from 0.01 to 2.0 moles, preferably from 0.1 to 1.0 moles per one mol of compound [11a] or [III]. The reaction may be carried out at 0 to 150 ° C, preferably at 20 to 80 ° C.

When Ra in compound [II-A] is hydrogen atom, compound [1A] may be prepared by converting compound [II-A] into a corresponding reactive derivative (e.g., an acid halide, a mixed acid anhydride). and reacting said reactive derivative with compound [III] in the presence of the base in or without the solvent.

When Ra in compound [II-A] is an alkyl group or a groupobenzyl, the present process A may also be carried out by converting the ester compound into a corresponding carboxylic acid compound of the following formula [II-Aa]:

<formula> formula see original document page 27 </formula>

wherein the symbols are the same as defined above by a conventional manner such as hydrolysis, hydrochloric acid acidolysis, formic acid, trifluoroacetic acid and the like or hydrogenation and thereafter reacting the carboxylic acid compound [11a-Aa] with the compound [ III] names in the same manner as described above.

Meanwhile, a compound [I] in which Ring A is a group of the following formula (C): <formula> formula see original document page 28 </formula>

wherein the symbol is the same as defined above, may be obtained as a byproduct in the reaction of compound [II-Aa] and compound [III] (Method B).

A compound [I] wherein Q 2 is an alkylene group, that is a compound of the following formula [1-B]:

<formula> formula see original document page 28 </formula>

wherein Q21 is an alkylene group and the other symbols are the same as defined above may be prepared by reacting a compound of the following formula [II-B]:

<formula> formula see original document page 28 </formula>

wherein X is a halogen atom and the other symbols are the same as defined above with compound [III] or a salt thereof.

in a solvent in the presence or absence of a base. Examples of the solvent include any solvent which does not disturb the reaction, such as methylene chloride, chloroform, dimethylformamide, dimethylacetamide, dimethylsulfoxide, tetrahydrofuran, dioxane, toluene, benzene, 1,2-dichloroethane, 1-methylpyrrolidinone, 1,2 dimethoxyethane and the like. The base includes, for example, sodium hydride, potassium carbonate, pyridine, triethylamine, diisopropylethylamine, 4-methylmorpholine, 1,8-diazabicyclo [5,4,0] -7-undecene (DBU) and the like.

The reaction of compound [II-B] with compound [III] may be carried out. In the process mentioned above, compound [III] may be used in an amount of 1.0 to 20 moles, preferably 1.0 to 3.0. mole per mole of compound [II-B]. The base may be used in an amount of 0 to 20 moles, preferably 1.0 to 3.0 moles per one mol of compound [III] or [II-B]. The reaction may be carried out at -20 to 100 ° C, preferably at 0 to 50 ° C.

(Method C)

Among the compounds [I] of the present invention, a compound wherein Q1 is a group of the formula: -N (R7) -and Q2 is a single bond, that is, a compound of the following formula [I-C]:

<formula> formula see original document page 29 </formula>

wherein the symbols are the same as defined above may be prepared by reacting a compound of the following formula [II-C]:

<formula> formula see original document page 29 </formula>

wherein the symbols are the same as defined above with compound [III] in the presence of a compound of formula [a]:

W1-CO-W2 [a]

wherein W1 and W2 are the same or different and a removal group.

In compound [a], examples of W1 and W2 include an imidazoline group, a halogen atom, a phenoxy group and the like. Concrete examples of similar compounds include 1,1'-carbonyldiimidazole, phosgene, triphosgene and the like. Examples of the solvent include any solvent which does not disturb the reaction, such as acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, dioxane, benzene, toluene, dimethylformamide and the like. Compound [III] may be used in an amount of 1.0 to 5.0 moles, preferably 1.0 to 1.2 moles per one mol of compound [11 -C]. Compound [a] may be used in an amount of from 0.33 to 5.0 moles, preferably from 1.0 to 2.0 moles per one mol of compound [II-O] or [III]. Sanding can be performed at -20 to 100 ° C, preferably at 0 to 50 ° C.

In addition, compound [1-C] may also be prepared by reacting compound [11-C] with compound [a] to obtain a compound of formula [IV]:

<formula> formula see original document page 30 </formula>

wherein the symbols are the same as defined above and reacting the product or a reactive derivative thereof with compound [III], or by reacting compound [III] with compound [a] to obtain a compound of formula [V]:

<formula> formula see original document page 30 </formula>

wherein the symbols are the same as defined above and reacting the product or a reactive derivative thereof with compound [II-C].

Examples of the reactive derivative of compound [IV] or [V] include those in which W2 is converted to a group of the formula:

<formula> formula see original document page 30 </formula>

and said reactive derivative may be obtained by reacting a compound [IV] or [V] wherein W2 is an imidazolyl group with methyl iodide.

The reaction of compound [II-C] or compound [III] with compound [a] may be carried out in a solvent. Examples of the solvent include any solvent which does not disturb the reaction, such as acetonitrile, dichloromethane, 1,2-dichloroethane, benzene, toluene, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, dimethylformamide and the like. Compound [a] may be used in an amount of 1.0 to 3.0 moles, preferably 1.0 to 2.0 moles per mole of compound [II-C] or compound [III]. The present reaction may be performed at 0 to 150 ° C, preferably at 20 to 80 ° C reactive derivative of compound [IV] or [V] may be prepared, for example, by treating said compound [IV] or [V] with a alkylatal halide as methyl iodide in a solvent. The present reaction may be carried out at 0 to 150 ° C, preferably at 20 to 80 ° C.

The reaction of compound [IV] (or its reactive derivative) with compound [III] or the reaction of compound [V] (or its reactive derivative) with compound [II-C] may be conducted in a solvent in the presence of a base. Examples of the solvent include any solvent which does not disturb the reaction, such as methylene chloride, chloroform, dimethylformamide, dimethylacetamide, dimethylsulfoxide, tetrahydrofuran, dioxane, toluene, benzene, 1,2-dichloroethane, 1-methylpyrrolidinone, 1,2- dimethoxyethane and the like. Examples of the base include pyridine, triethylamine, diisopropylethylamine, 4-methylmorpholine, 1,8-diaza-bicyclo [5,4,0] undecene and the like. Said reactive derivative may be used in an amount of from 0.33 to 3.0 mol, preferably from 0.5 to 1.2 mol per one mol of compound [III] or [II-C]. The present reaction may be conducted at -30 to 100 ° C, preferably at 0 to 50 ° C.

(Method D)

A compound of the following formula [1-D]:

<formula> formula see original document page 31 </formula>

wherein the symbols are the same as defined above may be prepared by a compound of the following formula [II-D]:

<formula> formula see original document page 31 </formula>

wherein the symbols are the same as defined above with divinyl sulfone in an appropriate solvent in the presence of a base. Examples of the solvent include any solvent which does not disturb the reaction, such as ethanol, isopropyl alcohol, dioxane, toluene, β, β-dimethylformamide, dimethyl sulfoxide and the like. Examples of the base include triethylamine, diisopropyllethylamine, N-methylmorpholine, dimethylaminopyridine and the like. Divinyl sulfone may be used in an amount from 1.0 to 3.0 moles, preferably 1.2 to 1.5 moles per one mol of compound [II-D]. The present reaction may be conducted at 60 to 200 ° C, preferably at 80 to 150 ° C.

(2) Among the compound of the present invention, a compound [I] in which Ring A is a substituted pyrazole ring of formula (B) and E is a group of the following formula (ii):

<formula> formula see original document page 32 </formula>

may be prepared according to, for example,

a) treating a compound [II-A01]:

<formula> formula see original document page 32 </formula>

wherein the symbols are the same as defined above in the same manner as described in Method A mentioned above, or b) treating a compound [II-B01]:

<formula> formula see original document page 32 </formula>

wherein the symbols are the same as defined above in the same manner as described in Method B mentioned above, or c) treating a compound [II-O01]:

<formula> formula see original document page 32 </formula> wherein the symbols are the same as defined above in the same manner as described in Method C mentioned above, or

d) treating a compound [II-D01]:

<formula> formula see original document page 33 </formula>

wherein the symbols are the same as defined above in the same manner as described in Method D mentioned above.

In addition, a compound [I] in which R 50 and R 60 in the group of formula (iv) is an alkyl group may be prepared, for example, by reacting a compound [II-C] or a compound [II-C01] in the group. which R7 is a hydrogen atom (compound [11a-Ca] or compound [11a-Ca01]) with an aldehyde compound of the formula [a-1]:

Ry-CHO [a-1]

wherein Ry is a hydrogen atom or an alkyl group in the presence of a reducing agent in the presence or absence of a base (Method E). Examples of the base include sodium triacetoxyborohydride, sodium boride, sodium cyanoborohydride and the like. Examples of the reducing agent include triethylamine, diisopropylethylamine, N-methylmorpholine, dimethylaminopyridine and the like. Compound [a-1] can be used in an amount of 1.0 to 3.0 moles, preferably 1.2 to 1.5 moles per one mol of compound [11-Ca]. 1.2 to 5.0 moles, preferably 1.5 to 2.0 moles per one mol of the compound [II-Ca]. The present reaction may be conducted at -50 to 100 ° C, preferably at -10 to 40 ° C.

In addition, a compound [I] wherein R 50 and R 60 in the group of formula (iv) is a cyclic group of the following formula:

<formula> formula see original document page 33 </formula>

wherein Ring A1 is a 5- to 7-membered aliphatic nitrogen-containing hetero-monocyclic group optionally substituted by an oxo group may be prepared, for example,

a) reacting a [II-C] compound or a [II-O01] compound in which R7 is a hydrogen atom (a [II-Ca] compound or a [II-Ca01] compound) with a compound of the following formula:

X01-Alk1-X02

wherein X01 and X02 are a halogen atom and Alk1 is a C4-alkylene group in a solvent such as acetonitrile and the like in the presence of a basetal such as potassium carbonate and in the presence or absence of an additive such as sodium iodide and the like, or

b) reacting a [II-Ca] compound or a [II-Ca01] compound with divinyl sulfone. The reaction of compound [II-Ca] or compound [II-Ca01] with divinyl sulfone may be conducted in the same manner as described in Method D mentioned above.

(3) Among the compounds [I] of the present invention, a compound in which Ring A is a substituted pyrazole ring of formula (A) or (B) and E is the group of formula (v) may be prepared, for example, by reacting compound [II-Aa] or the [II-Da] compound with an alkylamine such as methylamine and the like in a solvent such as methanol and the like in the presence of a condensing agent such as water soluble carbodiimide and the like and an activating agent such as 1-hydroxybenzotriazole and the like , and then treating the resulting product with Lawesson's reagent, and further reacting the reaction product with a sulfonaazide compound of the following formula:

Ar-SO2-N3

wherein Ar is an aryl group optionally substituted in a solvent such as pyridine and the like. Meanwhile, examples of the substituent on Arinclude a halogen atom.

The target compound [I] of the present invention may also be prepared, for example, by intramolecularly converting one or more substituents into R1, R2 and the like of a similar compound [I] as obtained above into one or more other desired substituents. The intramolecular conversion processes may be selected according to the types of the target substituents, and may be carried out, for example, by the following methods (a) to (h).

Method (a): A compound [I] having a cyano group (or a group containing a cyano group) as a substituent may be obtained by reacting a corresponding compound [I] having a halogen atom or an alkylsulfonyl group (or a group containing halogen or alkylsulfonyl) as a cyanide compound substitute (e.g., zinc cyanide, copper cyanide, trimethylsilyl cyanide, potassium cyanide and the like) in the presence or absence of a catalyst, a base and an additive. Examples of the base include triethylamine, N-methylpiperidine, diisopropylethylamine and the like. Examples of said catalyst include a palladium catalyst such as palladium acetate, tris (dibenzylideneacetone) dipaladium, trans-dichlorobis- (tricyclohexylphosphine) palladium (3) palladium and the like or a nickel catalyst such as dibromobis (triphenylphosphine) nickel and the like. Examples of the additive include a phosphine compound such as 1,1'-bis- (diphenylphosphino) ferrocene, 2,2'-bis- (diphenylphosphine) ) Racemic -1,1'-binaphthyl, 2- (di-tert-butylphosphino) biphenyl, 2- (dicyclohexylphosphino) biphenyl, 2-dicyclohexylphosphino-2 '- (N, N'-dimethylamino) biphenyl, tri -tert-butylphosphine and the like.

Method (b): A compound [I] having an alkylamino group or a cycloalkylamino group as a substituent (or a group containing alkylamino or cycloalkylamino) may be obtained by reacting a corresponding compound [I] having a halogen atom with a mono- or di-alkylamine or a cycloalkylamine in a suitable solvent in the presence of a catalyst, an additive and a base. Examples of the catalyst may be the palladium compounds or copper compounds used in Method (a). Examples of the additive may be the phosphine compounds used in Method (a). Examples of the base include potassium acetate, potassium carbonate, decesium carbonate, potassium tert-butoxide and the like.

Method (c): A compound [I] having an alkyloxy group as a substituent (or an alkyloxy containing group) may be obtained, for example, by (i) reacting a corresponding compound [I] having a hydroxyl group as a substituent (or a containing hydroxy) with an alkyl halide in a solvent, or (ii) by reacting a corresponding compound [I] having a hydroxyl group as a substituent (or a hydroxy containing group) with an alkanol in a solvent in the presence of a base (eg carbonate potassium cesium carbonate, sodium hydride and the like) or a reactivating agent (e.g. diethyl azodicarboxylate and the like) and in the presence of a trisubstituted phosphine or (iii) by reacting a compound [I] corresponding to an alkylsulfonyl group (or an alkylsulfonyl-containing group) with an alkali metal alkoxide in an appropriate solvent. Method (d): A compound [I] having an alkylsulfinyl group or an alkylsulfonyl group as a substituent (or a group containing alkylsulfinyl or alkylsulfonyl) may be obtained by reacting a corresponding compound [I] having an alkylthio group as a substituent. (or an alkylthio-containing group) with an oxidizing agent such as 3-chloroperbenzoic acid in an appropriate solvent.

Method (e): A compound [I] having an acylamino group such as an alkylcarbonylamino group as a substituent (or an acylamino containing group) may be obtained by reacting a corresponding compound [I] having an amino group (or an amino containing group) with an acid carboxylic acid compound of the following formula:

Rx-COOH [Ac-1] wherein Rx is an alkyl group optionally substituted by an aryl group or an optionally substituted aryl group or a reactive derivative thereof (e.g. a corresponding acid anhydride or a corresponding acid halide). The present reaction may be carried out in a solvent in the presence of a base such as triethylamine and the like or a damping agent such as water soluble carbodiimide and in the presence or absence of an activating agent such as 1-hydroxybenzotriazole. In addition, said acyl group may be removed, according to the type of said acyl group, in a conventional manner such as treatment with cationic acid or hydrogenation.

Method (f): A compound [I] having a carbamoyl group as a substituent (or a carbamoyl containing group) may be obtained by reacting a corresponding compound [I] having a alkyloxycarbonyl group as a substituent (or a alkyloxycarbonyl containing group) with an ammonia. water in an appropriate solvent.

Method (g): A compound [I] having an alkylcarbamoyl-mino group as a substituent (or an alkylcarbamoylamino containing group) may be obtained by reacting a corresponding compound [I] having an amino group as a substituent (or an amino containing group) with an alkyl isocyanate in an appropriate solvent.

Method (h): A compound [I] having a group of the formula:

<formula> formula see original document page 37 </formula>

wherein Ring A1 is a 5- to 7-membered nitrogen-containing aliphatic heterocyclic group may be obtained by reacting a corresponding compound [I] having an amino group with a compound of the formula:

X01-Alk1-X02

wherein the symbols are the same as defined above in a solventetal such as acetonitrile in the presence of a base such as potassium carbonate in the presence or absence of an additive such as sodium iodide. Examples of a similar aliphatic nitrogen-containing heterocyclic group include 1-pyrrolidinyl group, 1-piperidyl group and the like.

If necessary, the compounds [I] of the present invention obtained in the above processes may be converted to a pharmaceutically acceptable salt thereof in a conventional manner.

[Preparation of Intermediate Compound]

i) For example, a compound [II-A] in which Q1 is a single bond or an alkylene group may be prepared in a manner as described in the following reaction schemes A1 to A4 (Reaction Scheme A1).

<formula> formula see original document page 38 </formula> (Reaction Scheme A3)

<formula> formula see original document page 39 </formula>

In the reaction scheme mentioned above A1 to A4, Raa is hydrogen atom or an alkyl group, Rc is an alkyl group, W3 and W4 are a reactive residue, R01 is an alkyl group, R11 and R21 are an optionally substituted aryl group, optionally substituted heteroaryl group or optionally substituted nitrogen-containing aliphatic heterocyclic group, R12 and R22 are an optionally substituted aryl group or optionally substituted heteroaryl group, R13 and R23 are an optionally substituted nitrogen-containing aliphatic heterocyclic group, R14 is an opioid aryl group -substituted or an optionally substituted heteroaryl group, R02 and R03 are the same or different and a hydrogen atom or an alkyl group or both combine to form an alkylene group, t-Bu is a tert-butyl group, W01 and W02 is a halogen atom and the other symbols are the same as defined above.

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

Examples of the R11, R121, R21 or R22 heteroaryl group include a 5- to 10-membered mono- or bicyclic heteroaryl group having one to three heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom. Of these, 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 include a 5- to 10-membered mono- or bicyclic heterocyclic aliphatic group having additionally one or two heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom. Of these, a furyl group, a 1-pyrrolidinyl group, 1-piperidyl group, a group-morpholino or a thiomorpholine group is preferred.

Each of the aryl group, heteroaryl group or aliphatic group containing nitrogen at R11, R12, R21 or R22 may be substituted by one to three groups selected from a halogen atom, a cyano group, an alkyl group optionally substituted by one to three halogen atoms, an alkyloxy group optionally substituted by one to three halogen atoms and an alkylsulfonyl group.

The alkylene group formed by combining R02 with R03 may be a straight or branched C2-6 alkylene group such as ethylene, groupotrimethylene group or 1,1,2,2-tetramethylethylene group. Exemplary substituents of said alkylene group include an alkyl group such as methyl group.

Each reaction described in scheme A1 to A4 mentioned above may be performed, for example, in the manner as illustrated below.

Step A1-1:

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

StepAI-2:

Reaction of compound [VIII] with compound [i] may be conducted in an appropriate solvent in the presence or absence of a base. Examples of the base include piperidine, morpholine, N-methylpiperazine, diethylamine and the like. Examples of the solvent include any solvent which does not disturb the reaction, such as acetic acid, methanol, ethanol, isopropanol, ethylene glycol and the like. Compound [i] may be used in an amount of 0.5 to 2.0 moles, preferably 0.8 to 1.2 moles per one compound mol [VIII]. The base may be used in an amount of 0.01 to 2.0 moles, preferably 0.1 to 1.0 mol per one mol of compound [VIII]. The reaction may be performed at 50 to 150 ° C, preferably at 70 to 100 ° C.

In addition, the present reaction may be performed 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 which does not disturb the reaction, such as acetic acid, methanol, ethanol, isopropanol, ethylene glycol and the like. Compound [i] may be used in an amount of from 0.5 to 2.0 moles, preferably from 0.8 to 1.2 moles per one mol of compound [VIII]. The acid may be used in an amount from 0.1 to 3.0 moles, preferably 0.3 to 1.0 moles per one mol of compound [VIII]. The reaction may be carried out at 0 to 150 ° C, preferably at 60 to 100 ° C.

Step A2-1:

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

Step A2-2:

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

Step A2-3:

Intramolecular cyclization of compound [IX-a] may be performed in a solvent in the presence of a base. Examples of the solvent include any solvent which does not disturb the reaction, such as ethanol, acetonitrile, chloroform, tetrahydrofuran, dioxane, toluene, α, β-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 from 0.1 to 10.0 moles, preferably from 1.2 to 3.0 moles per one mol of compound [IX-a]. The reaction may be carried out at 30 to 150 ° C, preferably at 60 to 100 ° C.

Step A2-4:

The conversion of compound [X-a] to compound [X11-a] may 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 disturb the reaction, such as acetonitrile, chloroform, tetrahydrofuran, dioxane, toluene, α, β-dimethylformamide and the like. Examples of the halogenating agent include phosphorus oxychloride, chlorethodethionyl, phosphorus pentachloride, oxalyl chloride and the like. Examples of the base include α, β-dimethylaniline, diisopropylethylamine, N-methylmorpholine and the like. The halogenating agent may be used in an amount of from 1.1 to 5.0 moles, preferably from 1.2 to 1.5 moles for one mol of compound [X-a]. The base may be used in an amount of 1.2 to 10.0 moles, preferably 1.5 to 2.0 moles per one mol of compound [X-a]. The reaction may be carried out at 50 to 200 ° C, preferably at 80 to 150 ° C.

Step A2-5:

(1) The reaction of compound [X11-a] with boronate compound [X11-a] may be carried out in a solvent in the presence of a catalyst and a base.

Examples of the boronate compound [X111-a] include a compound in which R02 and R03 are a hydrogen atom or an alkyl group such as methyl group, ethyl group, isopropyl group and the like, or both R02 and R03 combine with one another to form a compound. alkylene group such as ethylene group, group propylene group, 1,1,2,2-tetramethylethylene group and the like. Among these, a preferred example includes a compound [X111-a] wherein R02 and R03 are hydrogen atom or a corresponding boroxin compound of the formula: [R12-BOfe]. Solvent examples include any solvent which does not disturb the reaction, such as dioxane. toluene, dimethoxyethane, ethanol, N, N-dimethylformamide, tetrahydrofuran, water and the like. Examples of the catalyst include a palladium catalyst such as tetracis (triphenylphosphine) palladium (0), depalladium acetate (II), bis (dibenzylidene acetone) palladium (0), bis (triphenylphosphine) palladium (II) dichloride bis (tri-tolylphosphine) palladium (II) dichloride, debis (tricyclohexylphosphine) palladium (II) dichloride or [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride, a nickel catalyst such as 1,3-bis (diphenylphosphine) propane nickel (II) dichloride or similar bis (triphenylphosphine) nickel (II) dichloride. Examples of the base include potassium phosphate, disodium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium fluoride, triethylamine, lithium chloride and the like. Compound [X111-a] may be used in an amount of 1.0 to 5.0 moles, preferably 1.1 to 2.0 moles per one mol of compound [X11-a]. The catalyst may be used in an amount of 0.001 to 0.5 mol, preferably 0.01 to 0.05 mol for a compound [X11-a]. The base may be used in an amount from 1.0 to 10.0 moles, preferably from 2.0 to 5.0 moles per one mol of compound [X11-a]. Sanding can be performed at 20 to 150 ° C, preferably at 60 to 120 ° C.

(2) The reaction of the compound [X11-a] with the heterocyclic nitrogen-containing compound [X11-b] may be carried out in a solvent in the presence of a base. Examples of the solvent include any solvent which does not disrupt the reaction, such as N, N-dimethylformamide, toluene, dioxane, tetrahydrofuran and the like. Examples of the base include potassium carbonate, sodium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium fluoride, triethylamine, diisopropylethylamine, dimethylaminopyridine and the like. Compound [X111-b] may be used in an amount of 0.8 to 5.0 moles, preferably 1.0 to 1.5 moles per mole of compound [X11-a]. 1.0 to 10.0 moles, preferably from 2.0 to 5.0 moles per one mol of compound [X11-a]. The reaction may be carried out at 80 to 200 ° C, preferably at 120 to 180 ° C.

Step A2-6:

The reaction of compound [X11-a] and compound [X11-c] may be carried out in a solvent in the presence of a base. Examples of the solvent include any solvent which does not disturb the reaction, such as N, N-dimethylformamide, dimethyl sulfoxide, dimethoxyethane, tetrahydrofuran and the like. Examples of the base include sodium hydride, potassium hydride, sodium ethoxide, potassium tert-butoxide and the like. Compound [X111-c] may be used in an amount of 0.5 to 5.0 moles, preferably 1.0 to 3.0 moles per one mol of compound [X11-a]. The base may be used in an amount of from 0.5 to 10.0 moles, preferably from 1.2 to 6.0 moles per one mol of compound [X11-a]. The reaction may be carried out at 40 to 200 ° C, preferably at 60 to 120 ° C.

Step A2-7:

The reaction of compound [X11-a] with compound [X11-d] may be carried out in a solvent in the presence of a catalyst and zinc. Examples of the solvent include any solvent which does not disturb the reaction, such as dimethoxyethane, tetrahydrofuran, N, N-dimethylformamide and the like. Examples of the catalyst include a palladium catalyst such as debis (triphenylphosphine) palladium (II) dichloride, tetracis (triphenylphosphine) palladium (0), palladium (II) acetate, bis (dibenzylidene acetone) palladium (0) dichloride, bis (tri-o-to-lylphosphine) palladium (II), bis (tricyclohexylphosphine) palladium (II) dichloride or dichlorode [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) and the like. Compound [X111-d] may be used in an amount of 0.5 to 5.0 moles, preferably 1.0 to 3.0 moles per one mol of compound [X11-a]. The catalyst may be used in an amount of 0.001 to 1.0 mol, preferably 0.01 to 0.3 mol per one mol of the compound [X11 -a]. Zinc may be used in an amount of 1.0 to 5.0 moles, preferably 1.5 to 3.0 moles per one mol of compound [X11-a]. The reaction may be carried out at 40 to 200 ° C, preferably at 60 to 120 ° C.

Step A3-1:

The reaction of compound [V1-b] with compound [V11-b] may be carried out in a solvent or without any solvent. Examples of the solvent include any solvent which does not disturb the reaction, such as dimethylformamide, toluene, dioxane, tetrahydrofuran, dimethoxyethane and the like. Compound [VII-b] may be used in an amount of 0.5 to 5.0 moles, preferably 0.9 to 1.5 moles per one mol of compound [VII-b]. The reaction may be carried out at 0 to 150 ° C, preferably at 50 to 80 ° C.

Step A3-2:

The halogenation of the compound [VIIll-b] may 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 disturb the reaction, such as methylene chloride, decarbon tetrachloride, chloroform, acetic acid, tetrahydrofuran and the like. Examples of the halogenating agent include bromine, N-bromosuccinimide, N-chlorosuccinimide and the like. Examples of the base include triethylamine, diisopropylethylamine, potassium carbonate, sodium carbonate and the like. The halogenation agent may be used in an amount of from 0.5 to 10.0 moles, preferably from 1.0 to 3.0 moles per one mol of the compound [V111-b]. The reaction may be performed at -40 to 100 °. C, preferably at -5 to 20 ° C.

Step A3-3:

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

Step A3-4:

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

Step A4-1:

The conversion of compound [II-A11] to a corresponding reactive derivative (compound [IX]) may be accomplished in a conventional manner. Examples of such a reactive derivative include a corresponding acid halide (a compound [IX] in which W3 is a halogen atom) or a corresponding mixed acid anhydride (a compound [IX] in which W3 is an alkyloxycarbonyloxy group and the like). The corresponding acid halide may be prepared, for example, by reacting compound [II-A11] with a halogenating moiety (e.g. thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride and the like) in or without a solvent in the presence or absence of a catalytic amount of dimethyl formamide. Examples of the solvent include any solvent which does not disturb the reaction, such as methylene chloride, chloroform, tetrahydrofuran, benzene, toluene and the like. The present reaction may be conducted at -20 to 150 ° C, preferably at 0 to 120 ° C. In addition, the corresponding acid mixed anhydride may be prepared, for example, by reacting compound [II-A11] with an alkyl chloroformate (e.g., similar ethyl chloroformate) in a solvent in the presence of a base (e.g. tilamine, diisopropylethylamine and the like). Examples of the solvent include any solvent which does not disturb the reaction, such as methylene chloride, chloroform, tetrahydrofuran, benzene, toluene and the like. The presenteration may be conducted at -60 to 100 ° C, preferably at -40 to 80 ° C.

Step A4-2:

Conversion of compound [IX] to compound [X] may be performed in a solvent in the presence of a diazomethane compound (e.g. diazomethane, trimethylsilyl diazomethane and the like). Examples of the solvent include any solvent which does not disturb the reaction, such as diethyl ether, dioxane, benzene, toluene and the like. The diazomethane compound may be used in an amount from 1.0 to 10 moles, preferably from 1.0 to 3.0 moles per one mol of compound [IX]. The reaction may be performed at -50 to 80 ° C, preferably at -10 to 50 ° C. Step A4-3:

The conversion of compound [X] to compound [II-A12] may be carried out in a solvent in the presence or absence of a silver salt under heating. Examples of the solvent include any solvent which does not disturb the reaction, such as water, an alkanol (e.g. methanol, ethanol), or the like. Examples of the silver salt include silver oxide, deprato benzoate and the like. The silver salt may be used in an amount from 1.0 to 20 moles, preferably from 1.0 to 5.0 moles per one mol of compound [X]. The reaction may be carried out at 50 to 200 ° C, preferably at 80 to 150 ° C.

Step A4-4:

The reaction to obtain compound [XI] by reducing compound [II-Al 1] may be carried out in a solvent in the presence of a reducing agent (e.g. lithium aluminum hydride and the like). Examples of the solvent include any solvent which does not disturb the reaction, such as diethylethyl, tetrahydrofuran and the like. The reducing agent may be used in a quantity of 0.25 to 20 moles, preferably 2.0 to 5.0 moles per one mol of compound [II-A11]. The reaction may be carried out at -50 to 100 ° C, preferably at -10 to 40 ° C.

Meanwhile, compound [XI] can also be prepared by reducing a compound [II-A1] in which Ra is an alkyl group. The present reaction may be conducted in a solvent in the presence of a reducing agent such as sodium borohydride and the like. Examples of the solvent include any solvent which does not disturb the reaction, such as a mixture of tetrahydrofuran and methanol and the like. The reducing agent may be used in an amount from 1.0 to 20 mol, preferably from 2.0 to 5.0 mol per one mol of compound [II-A1]. The reaction may be carried out at 30 to 100 ° C, preferably at 50 to 80 ° C.

Step A4-5:

Conversion of compound [XI] into a corresponding reactive derivative (compound [XII]) may be carried out in a conventional manner. For example, a compound [XII] in which W4 is a halogen atom or an alkylsulfonyloxy group may be prepared. treating compound [XI] with a thionyl halide such as thionyl chloride or an alkylsulfonyl halide such as methanesulfonyl chloride, respectively.

Step A4-6:

The reaction of compound [XII] with compound [d] or a similar salt may be carried out in a solvent in the presence of a base. Examples of the salt of compound [d] include a metal salt such as potassium salt. Examples of the solvent include any solvent which does not disturb the reaction, such as diethyl ether, tetrahydrofuran, benzene, dimethylformamide, dimethylacetamide, methanol, ethanol and the like. Examples of the base include sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, lithium diisopropylamide, lithium hexamethyl disilazane and the like. The compound [d] or a salt thereof may be used in an amount from 1.0 to 10.0 moles, preferably from 1.5 to 3.0 moles per one mol of compound [XII]. The base may be used in an amount from 1.0 to 10.0 moles, preferably from 1.5 to 3.0 moles per one mol of compound [XII]. The reaction may be performed at -20 to 200 ° C, preferably at 20 to 100 ° C.

A compound [II-A] wherein Q1 is an alkylene group having 3 or more carbon atoms may be obtained, for example, by converting a target compound obtained from Step A4-3 above (or Step A4-6) into a carboxylic acid compound. deesterification, if necessary, and then subjecting the said carboxylic acid compound to a serial reaction process of Step A4-1, A4-2 and A4-3 (or Step A4-4, A4-5 and A4- 6) repeatedly at desired times.

In addition, a compound [II-A] wherein Q 1 is a group of the formula: -N (R 7) -can be obtained, for example, by subjecting compound [II-Ae] or compound [II-Af] (cf. , Reaction Step C1-4 described below) to a conventional esterification enhancement.

ii) Compound [II-B] may be prepared, for example, in the manner described below (Reaction Scheme B1) using a compound [II-Aa] or a corresponding amide compound (e.g. a corresponding dimethyl amide, corresponding N-alkyl-N-alkyloxyamide compound and the like) (Reaction Scheme B1)

<formula> formula see original document page 49 </formula>

In scheme B1 above, Rc is an alkyl group, Y is a halogen atom and the other symbols are the same as defined above.

Each reaction described in Scheme B1 may be performed, for example, in a manner as illustrated below.

Step B1-1:

The reaction of compound [II-Aa] or a corresponding amide compound with compound [b1] or compound [b2] may be carried out in a solvent. Examples of the solvent include any solvent which does not disturb the reaction, such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, benzene, toluene and the like. Compound [b1] or compound [b2] may be used in an amount of 1.0 to 3.0 moles, preferably 1.0 to 2.2moles for one mol of compound [11a] or a corresponding amide compound. The reaction may be carried out at -78 to 50 ° C, preferably at -40 to 30 ° C.

Step B1-2:

Halogenation of compound [XIV] may be performed in a solvent. Examples of the halogenating agent include bromine, N-bromosuccinimide, bis (N, N-dimethylacetamide) hydrogen dibromobromate and the like. Examples of the solvent include any solvent which does not disturb the reaction, such as diethyl ether, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride and the like. The halogenating agent may be used in an amount from 1.0 to 3.0 moles, preferably from 1.0 to 2.0 moles per one mol of compound [XIV]. The reaction may be carried out at -10 to 50 ° C, preferably at 0 to 30 ° C.

iii) Compound [II-C] may be prepared, for example, using a compound [II-Aa] wherein Q1 is a single bond (compound [IIa]) and in a manner as described in the following Reaction Scheme C1. Reaction Scheme C1)

<formula> formula see original document page 50 </formula>

In the above Reaction Scheme R71 is an alkyl group, and tBu is a tert-butyl group and the other symbols are the same as defined above.

Each reaction described in Scheme C1 may be performed, for example, in a manner as illustrated below.

Step C1-1:

The reaction of compound [IIa] with an acidifying agent may be carried out in a solvent in the presence or absence of a base. Examples of the solvent include any solvent which does not disturb the reaction, such as acetone, benzene, toluene, tetrahydrofuran, diethyl ether and the like.

Examples of the azidating agent include diphenyl phosphoryl azide, sodium azide and the like. Examples of the base include pyridine, triethylamine, diisopropylethylamine, 4-methylmorpholine, 1,8-diazabicyclo-5,4,0] undecene (DBU) and the like. The azidating agent may be used in an amount of 1.1 to 5.0 moles, preferably 1.2 to 1.5 moles per one mol of compound [IIa]. The base may be used in an amount from 1.2 to 10.0 moles, preferably from 1.5 to 3.0 moles per one mol of compound [IIa]. The reaction may be carried out at -30 to 50 ° C, preferably at -10 to 10 ° C.

Step C1-2:

Preparation of compound [XVI-a] by Crutius recombination reaction may be carried out in a solvent under heating. Examples of the solvent include any solvent which does not disturb the reaction, such as benzene, toluene, dioxane, chloroform and the like. The reaction may be carried out at 40 to 200 ° C, preferably at 60 to 20 ° C. In addition, compound [XVI-b] can be obtained by performing the present reaction on tert-butanol.

Stage CI-3:

Treatment of compound [XVI-a] or [XVI-b] with an acid may be carried out in or without a solvent. Examples of the solvent include water, ethyl acetate, tetrahydrofuran, dioxane, methylene chloride, chloroform, toluene and the like. Examples of the acid include a strong acid such as sulfuric acid, hydrochloric acid, nitric acid, trifluoroacetic acid, hydrobromic acid and the like. The acid may be used in an amount from 1.0 to 50.0 mol, preferably from 5.0 to 10.0 mol per one mol of compound [XVI-a] or [XVI-b]. The reaction may be carried out at -20 to 200 ° C, preferably at 20 to 120 ° C.

Step C1-4:

Alkylation of the compound [11a-Ca] may be carried out in a solvent, for example 1) in the presence of a base (e.g., sodium hydride, potassium carbonate, pyridine, triethylamine, diisopropylethylamine, 4-methylmorpholine, 1 , 8-diazabicyclo- [5,4,0] undecene and the like) and an alkylalkyl of the formula [XVIII]:

<formula> formula see original document page 51 </formula>

wherein R72 is an alkyl group and X4 is a halogen atom; or 2) in the presence of a reducing agent (e.g. lithium aluminum hydride, sodium borohydride, sodium cyanoboride, sodium triacetoxyborohydride and the like), an acid (e.g. acetic acid, formic acid and the like) and an aldehyde compound [XIX]:

R73-CHO [XIX]

wherein R73 is an alkyl group; or 3) in the presence of an activating agent (e.g. diethyl azodicarboxylate and the like), a trisubstituted phosphine (e.g. triphenylphosphine, tributylphosphine and the like) and an alkanol compound of the formula [XX]:

R74-OH [XX]

wherein R74 is an alkyl group. Examples of the solvent include methylene chloride, chloroform, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, dioxane, toluene, benzene, 1,2-dichloroethane, 1-methylpyrrolidinone, 1,2-dimethoxyethane and the like. The reaction may be carried out at -20 to 100 ° C, preferably at 0 to 40 ° C.

Meanwhile, if required, an appropriate protecting group (e.g. an alkyloxycarbonyl group such as tert-butoxycarbonyl group, an arylalkyloxycarbonyl group such as benzyloxycarbonyl group and the like) may be introduced into the 3-amino group in compound [II-Ca] prior to alkylation. same. Said protecting group may be introduced or removed in a conventional manner depending on the type of said protecting group.

Compound [II-Cb] may also be prepared by conducting Crutius recombination gaseous above into an alkanol of the formula [e]:

Re-OH [e]

wherein Re is tert-butyl group or benzyl group to obtain a compound of the following formula [II-Ae]:

<formula> formula see original document page 52 </formula>

and reacting said compound [II-Ae] with the above-mentioned alkylalkyl compound [XVIII] or the alkanol compound [XX] to give a compound [II-Af]:

<formula> formula see original document page 53 </formula>

wherein the symbols are the same as defined above, and then moving the acyl group represented by the group of the formula: ReOCO-. Removal of said acyl group may be conducted (1) by treating the product [11a-Af] with an acid such as hydrochloric acid, trifluoroacetic acid, hydrobromic acid and the like; or (2) heating said product to about 150 ° C; or (3) subjecting said product to catalytic hydrogenation.

iv) Compound [11-D] may be prepared by reacting compound [11-Aa] with hydrazine compound of the following formula [c]:

H2N-NHZ

wherein Z is an acyl group or a salt thereof according to the same manner as described in Method A mentioned above, and then moving the acyl group (Z) of the reaction product in a conventional manner.

Intermediate compound [II-A01], [II-B01] or [II-C01] may be prepared, for example, by treating the corresponding starting compound having a desired substituent at the 2-position of the pyrazolo [1,5-a] portion thereof. ] pyrimidine in the same manner as illustrated in Reaction Scheme A1, B1 or C1.

In addition, compound [II-D01] may be prepared, for example, by reacting a compound of the following formula [II-Da]:

<formula> formula see original document page 53 </formula>

wherein the symbols are the same as defined above with a hydrazine compound [c] in the same manner as described in Method A, and then removing the acyl group (Z) by a conventional method.

Among the intermediates mentioned above, each of compound [i], compound [VI], compound [Vl-a], compound [Vl-b], compound [VII], compound [Xlll-a ], the compound [Xlll-b], the compound [Xlll-c] and the compound [Xlll-d] is a known compound or a compound obtainable from a known compound using a conventional process in synthetic chemistry.

From the beginning to the end of the present description and claims, the "halogen atom" means fluorine, chlorine, iodine or bromine atom. "Alkyl group" means a straight or branched chain alkyl group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. "Cycloalkyl group" means a cycloalkyl group having 3 to 8 carbon atoms, preferably 5 to 7 carbon atoms. "Alkylene group" means a straight or branched chain alkylene group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms.

EXAMPLES

The compounds of the present invention are further illustrated by the following Examples, but should not be considered limited to the same.

Example 1

To a suspension of 3-carboxyl-6- (2-chlorophenyl) -7- (4-chlorophenyl) pyrazolo [1,5-a] pyrimidine (200 mg, compound obtained in Reference Example 1) in Toluene (1.5 mL) was added thionyl chloride (114 µL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and the resulting crude product was dissolved in methylene chloride (1.5 mL). To a solution was added triethylamine (217 μί) and 1-aminopiperidine (56 μί) and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated in vacuo and the resulting product was purified by silica gel column chromatography (solvent: chloroform / methanol = 100/0 to 19/5 and hexane / ethyl acetate = 67/3 to 2/3 ) to obtain 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- (N-piperidinocarbamoyl) pyrazolo [1,5-a] pyrimidine (162 mg; yield: 67%) as a powder.MS ( APCI) m / z; 466/468 [M + H] +

Example 2

To a suspension of the compound obtained in Reference Example 1 (200 mg) in toluene (2 mL) was added oxalyl chloride (136 µL), and the mixture was stirred at 60 ° C for 1 hour. The reaction mixture was concentrated in vacuo and the resulting crude product was dissolved in methylene chloride (2 mL). To a solution was added triethylamine (217 µL) and 1-methyl-1-phenylhydrazine (61 µL) and the mixture was stirred. at room temperature for 2 hours. To the mixed reaction was added water and methylene chloride and the organic layer was washed with saturated brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resulting crude product was purified by column chromatography over silica gel (solvent: hexane / ethyl acetate = 4/1 to 7/3) to obtain 6- (2-chlorophenyl) -7- (4 -chlorophenyl) -3 - [(N'-methyl-N'-phenylhydrazine) carbonyl] pyrazolo [1,5-a] pyrimidine (204 mg; yield: 80%) as a powder.

MS (APCI) m / z; 488/490 [M + H] +

Example 3

To a solution of the compound obtained in Reference Example 1 (57.6 mg) and 1-aminopyrrolidine HCl (24.5 mg) in chloroform (1.0 mL containing amylene) was added 1-hydroxybenzotriazole monohydrate (0.23 mL). 0.5 M solution of chloroform containing amylene), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide HCl (0.23 mL, 0.5 M N solution of N-dimethylformamide) and triethylamine (63 μί) and the mixture was stirred at room temperature overnight. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (2 mL), water (2 mL) and chloroform (5 mL) and the mixture was stirred vigorously for 15 minutes. After separating the organic layer, the aqueous layer was separated. extracted with chloroform (3 mL). The combined organic layer was washed successively with a saturated aqueous sodium hydrogen carbonate solution (3 mL) and saturated brine (3 mL) and concentrated in vacuo. The resulting crude product was purified by liquid chromatography-mass spectrometer (LCMS) (column; XTerra MS C18, solvent; 10 mM ammonium carbonate / methanol = 40/60 to 10/90). The eluted fraction was concentrated and the residue was dissolved in tert-butanol and lyophilized to give 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- (N-pyrroli-dinocarbamoyl) pyrazolo [1,5-a] pyrimidine (47.2 mg; yield: 70%) as a powder.

MS (APCI) m / z; 452 [M + H] +

Examples 4 to 27

Corresponding raw materials were treated in the same manner as described in any of Examples 1 to 3 to obtain the compounds as shown in the following Table 1.

Table 1 (No. 1)

<table> table see original document page 56 </column> </row> <table> Table 1 (Ns 2)

<table> table see original document page 57 </column> </row> <table> Table 1 (# 3)

<table> table see original document page 58 </column> </row> <table> <table> table see original document page 59 </column> </row> <table>

Example 28

To a solution of 3-carboxy-6- (2-chlorophenyl) -7- (4-chlorophenyl) pyrazolo [1,5-a] pyrimidine (compound obtained in Reference Example 1 (4), 165 mg) In chloroform (1.0 mL containing amylene) was added the compound obtained in Reference Example 13 (2), water-soluble carbodiimide HCl (123 mg), 1-hydroxybenzotriazole monohydrate (97 mg), and triethylamine (178 μl) and a The mixture was stirred at room temperature overnight. To the mixture was added a saturated aqueous sodium hydrogen carbonate solution (2 mL) and the mixture was stirred and extracted with chloroform. The extract was concentrated in vacuo and the resulting crude was purified by column chromatography over silica gel (solvent; hexane / ethyl acetate = 90/10 to 70/30) to give 6- (2-chlorophenyl) -7- ( 4-chlorophenyl) -3- [N- (4-tetrahydrothiopyran) carbamoyl] pyrazolo [1,5-a] pyrimidine (50 mg; yield: 24%) as a light yellow powder.

MS (APCI) m / z; 483/485 [M + H] +

Example 29

To a solution of the compound obtained in Example 28 in methylene chloride (1.0 mL) was added methane sulfonic acid (20 µL) and 3-chloroperbenzoic acid (57 mg) and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added an aqueous saturated sodium hydrogen carbonate solution and the mixture was stirred. The organic layer was extracted and the extract was concentrated in vacuo. The resulting crude product was purified by silica gel column chromatography (solvent; chloroform / ethyl acetate = 100/0 to 70/30) to give 6- (2-chlorophenyl) -7- (4-clo -rophenyl) -3- [N- [4- (1,1-dioxo) tetrahydrothiopyranyl] carbamoyl] pyrazolo [1,5-a] pyrimidine (37.3 mg; yield: 73%) as a pale yellow powder .

MS (APCI) m / z; 515/517 [M + H] +

Example 30

To a solution of the compound obtained in Reference Example 9 (2) (50 mL) in methanol (1 mL) was added 36% solution of formaldehyde (118μL), sodium triacetoxyborohydride (75 mg) and triethylamine (39 μί) and The mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with chloroform and to it was added an aqueous sodium hydrogen carbonate solution. The mixture was extracted with chloroform and the extract concentrated in vacuo. The resulting crude product was purified by column chromatography on silica gel (solvent; chloroform / ethyl acetate = 100/0 to 70/30), dissolved in tert-butanol and lyophilized to give 3-dimethylamino. 6- (2-chlorophenyl) -7- (4-chlorophenyl) pyrazolo [1,5-a] pyrimidine (13.5 mg; yield: 26%) as a red powder.

MS (APCI) m / z; 383/385 [M + H] + Example 31

(1) The corresponding material (200 mg) was treated in the same manner as described in Example 3 to give 6- (2-bromophenyl) -7- (4-chlorophenyl) -3 - [[N'-methyl-N ' - (2-pyridyl) hydrazino] carbonyl] pyrazolo [1,5-a] pyrimidine (249 mg) as a yellow powder.

MS (APCI) m / z; 533/535 [M + H] +

(2) To a solution of the compound obtained in the above step (1) (80 mg) in dimethylformamide (1 mL) was added zinc cyanide (20 mg) and tetrakis (triphenylphosphine) palladium (0) (17 mg) and the mixture was stirred under nitrogen at 1100 ° C for 19 hours. The reaction mixture was cooled to room temperature and to it was added water and ethyl acetate and the mixture was stirred. The organic layer was extracted and the extract was concentrated in vacuo. The resulting crude product was purified by column chromatography over silica gel (solvent; hexane / ethyl acetate = 50/50 to 25/75), dissolved in tert-butanol and lyophilized to give 7- (4-chlorophenyl) -6. - (2-cyanophenyl) -3- [N'-methyl-N '- (2-pyridyl) hydrazino] carbonyl pyrazolo [1,5-a] pyrimidine (42 mg; yield: 58%) as a solid colorless.

MS (APCI) m / z; 480/482 [M + H] +

Example 32

To a solution of the compound obtained in Reference Example 6 (1.0 g) in chloroform (20 mL) was added cyclopentylamine (260 mg), water-soluble carbodiimide HCl salt (620 mg) and 1-hydroxybenzotriazole (540 mg) and the mixture was stirred at room temperature overnight. To the reaction mixture was added a saturated aqueous solution of sodium hydrogen carbonate and chloroform and the mixture was stirred. The organic layer was extracted and the extract was concentrated in vacuo. The resulting crude product was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 82/18 to 67/33) to give 6- (2-chlorophenyl) -7- (4-chloro-phenyl). nyl) -3- (N-cyclopentylcarbamoyl) -2-methylthiopyrazolo [1,5-a] pyrimidine (940 mg; yield: 81%) as a yellow solid.

MS (APCI) m / z; 497/499 [M + H] +

Example 33A A solution of the compound obtained in Example 32 (940 mg) in methylene chloride (40 mL) was added 3-chloroperbenzoic acid (1.09 g) under cooling and the mixture was stirred at room temperature for 3 hours. To the reaction was added an aqueous solution of sodium thiosulfate and the mixture was stirred and extracted with chloroform. The extract was concentrated in vacuo and the resulting crude product was purified by column chromatography over NH silica gel (Chromatorex NH silica gel / Fuji Silicia Chem., Solvent; hexane / ethyl acetate = 50/50 to 0/100) to give 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- (N-cyclopentylcarbamoyl) -2-methylsulfonyl-pyrazolo [1,5-a] pyrimidine (1.0 g; yield: 100%) as a colorless solid.

MS (APCI) m / z; 529/531 [M + H] +

Example 34

To a solution of the compound obtained in Example 33 (100 mg) in tetrahydrofuran / methanol (3 ml / 3 ml) was added sodium methoxide (102 mg) and the mixture was stirred at 50 ° C overnight. After cooling to room temperature, to the reaction mixture was added water and ethyl acetate and the mixture was stirred. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resulting product was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 80/20 to 60/40) to give 6- (2-chloro-phenyl) - 7- (4-chlorophenyl) -3- (N-cyclopentylcarbamoyl) -2-methoxypyrazolo [1,5-a] pyrimidine (57.2 mg; yield: 63%) as a pale yellow powder.

MS (APCI) m / z; 481/483 [M + H] +

Example 35

To a solution of the compound obtained in Example 33 (300 mg) in dimethylformamide (7 mL) was added sodium cyanide (167 mg) and the mixture was stirred at 50 ° C overnight. After cooling to room temperature, to the reaction mixture was added ethyl acetate and sodium hydrogen carbonate solution and the mixture was stirred. After separating the organic layer, the aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over filtrated magnesium sulfate. The filtrate was concentrated in vacuo and the resulting crude product purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 90/10 to 70/30) to give 6- (2-chlorophenyl) - 7- (4-chlorophenyl) -5-cyano-2-methylsulfonyl-3- (N-cyclopentylbamoyl) pyrazolo [1,5-a] pyrimidine (compound (a), 138 mg; yield: 44%) and 6- (2-chlorophenyl) -7- (4-chlorophenyl) -2,5-dicyano-3- (N-cyclopentylcarbamoyl) pyrazolo [1,5-a] pyrimidine (compound (b), 18, 3 mg; yield: 6%) as a pale yellow solid, respectively.

Compound (a): MS (APCI) m / z; 554/556 [M + H] +

Compound (b): MS (APCI) m / z; 501/503 [M + H] +

Example 36

To a solution of compound (a) obtained in Example 35 (50 mg) in methanol / tetrahydrofuran (3 mL / 3 mL) was added sodium methoxide (49 mg) and the mixture was stirred at room temperature overnight. To the reaction mixture was added ethyl acetate and a saturated organic brine was separated. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resulting crude product was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 80/20 to 30/70) to give 6- (2- chloro-phenyl) -7- (4-chlorophenyl) -3- (N-cyclopentylcarbamoyl) -5-methoxy-2-methylsulfonyl-pyrazolo [1,5-a] pyrimidine (50.5 mg; yield: 100%) as a colorless solid.

MS (APCI) m / z; 559/561 [M + H] +

Example 37

To a solution of the compound obtained in Example 36 (24 mg) in methanol / tetrahydrofuran (2 mL / 1 mL) was added sodium methoxide (23 mg) and the mixture was stirred at 100 ° C for 2 hours in a microwave reactor. After cooling to room temperature, the reaction mixture was added chloroform and water and the organic layer was separated and concentrated in vacuo and the resulting crude was purified by column chromatography over NH silica gel (Chromatorex NH silica). -gel / Fuji Silicia Chem., solvent; hexane / ethyl acetate = 65/35 to 30/70) to give 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- (N-cyclopentylcarbamoyl) ) -2,5-dimethoxypyrazolo [1,5-a] pyrimidine (17.8 mg; yield: 81%) as a colorless solid. MS (APCI) m / z; 511/513 [Μ + Η] +

Example 38

To a solution of the compound obtained in Example 33 (300 mg) in dimethylformamide (10 mL) was added sodium cyanide (42.1 mg) and the mixture was stirred at 100 ° C for 1.5 hours in a microwave reactor. After cooling to room temperature, to the reaction mixture was added ethyl acetate and an aqueous sodium hydrogen carbonate solution and mixture was stirred. The organic layer was washed with water and concentrated in vacuo. The resulting crude product was purified by column chromatography over silica gel (solvent; hexane / ethyl acetate = 80/20 to 65/35) to give 6- (2-chlorophenyl) -7- (4-chlorophenyl) -2 -cyano-3- (N-cyclopentylcarbamoyl) p-razolo [1,5-a] pyrimidine (17.8 mg; yield: 81%) as a pale yellow solid.

MS (APCI) m / z; 476/478 [M + H] +

Example 39

To a solution of the compound obtained in Reference Example 10 (2) (138 mg) in ethanol (7 mL) was added divinyl sulfone (42 µL) and triethylamine (72 µL) and the mixture was refluxed under heating for 6 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo. To the residue was added water and methylene chloride and the mixture was stirred and the organic layer was extracted. The extract was washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and the resulting crude product was purified by column chromatography over silica gel (solvent; chloroform / methanol = 100/0 to 95/5) and then over NH silica gel (Chromatorex NH silica gel / Fuji Silicia Chem., Solvent; hexane / ethyl acetate = 50/50 to 20/80), dissolved in lyophilized tert-butanole to give 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- [ N- [4- (1,1-dioxo) thio-morpholino] carbamoyl] pyrazolo [1,5-a] pyrimidine (57 mg; yield: 31%) as a pale yellow powder.

MS (APCI) m / z; 516/518 [M + H] +

Example 40

To a solution of the compound obtained in Reference Example 11 (1.1 g) in tetrahydrofuran / water (2.8 mL / 4.2 mL) was added acetic acid (7 mL) and the mixture was stirred at 100 ° C for 1 h. 1 hour in a microwave reactor. After cooling to room temperature, the reaction mixture was a 2 N aqueous solution of sodium hydroxide and the mixture extracted with chloroform. The extract was dried over filtered magnesium sulfate. The filtrate was concentrated in vacuo and the resulting crude product purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 80/20 to 60/40) to give 2-amino-6- (2-chlorophenyl ) -7- (4-chlorophenyl) -3- (N-cyclopentylcarbamoyl) pyrazolo [1,5-a] pyrimidine (529 mg; yield: 75%) as a yellow solid.

MS (APCI) m / z; 466/468 [M + H] +

Example 42

A mixture of the compound obtained in Example 40 (60 mg), pyridine (600 µL) and acetic anhydride (200 µL) was stirred at 100 ° C for 3 days. After cooling to room temperature, to the reaction mixture was added 1 N aqueous HCl and ethyl acetate and the mixture was stirred. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resulting crude product was purified by column chromatography over NH silica gel (Chromatorex NH silica gel / Fuji Silicia Chem., Solvent; hexane / ethyl acetate = 90/10 to 50/50 ) to give 2-acetylamino-6- (2-chloro-phenyl) -7- (4-chlorophenyl) -3- (N-cyclopentylcarbamoyl) pyrazolo [1,5-a] pyrimidine (38.2mg; yield: 58% ) as a pale yellow solid.

MS (APCI) m / z; 508/510 [M + H] +

Example 43

To a solution of the compound obtained in Example 40 (60 mg) in water / acetonitrile (0.3 mL / 2.4 mL) was added 1,4-dichlorobutane (81.6 mg), potassium carbonate (88.8 mg) and sodium iodide (6.8 mg) and the mixture was stirred at 150 ° C for 3 hours in a microwave reactor. After cooling to room temperature, to the reaction mixture was added ethyl acetate and water and the mixture was stirred. The organic layer was extracted and dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resulting crude product was purified by column chromatography over silica gel (solvent; hexane / ethyl acetate = 90/10 to 70/30) to 6- (2-chlorophenyl) -7- (4 -chlorophenyl) -3- (N-cyclopentylcarbamoyl) -2- (1-pyrrolidinyl) piperolo [1,5-a] pyrimidine (25 mg; yield: 37%) as a yellow solid.

MS (APCI) m / z; 520/522 [M + H] +

Example 44

To a solution of the compound obtained in Reference Example 1 (4) (77 mg) in methylene chloride (1 mL) was added water-soluble carbodiimide HCl (58 mg), 1-hydroxybenzotriazole (46 mg) and triethylamine (84 µL). ) and the mixture was stirred at room temperature overnight. To the reaction mixture was added an aqueous solution of sodium hydrogen carbonate and methylene chloride and the mixture was stirred. The organic layer was separated and concentrated in vacuo to give 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- [N- (4-cyano-tetrahydrothiopyran-4-yl) carbamoyl] pyrazolo [1, 5-a] pyrimidine (50.8 mg; yield: 50%) as a pale yellow powder.

MS (APCI) m / z; 508/510 [M + H] +

Examples 45 to 202

Corresponding materials were treated in the same manner as described in any of Examples 1, 2 and 3 to obtain the compounds as shown in Tables 2 to 4 below.

Table 2 (No. 1)

<table> table see original document page 66 </column> </row> <table> <table> table see original document page 67 </column> </row> <table>

Table 2 (No. 2)

<table> table see original document page 67 </column> </row> <table> Table 2 (# 3)

<table> table see original document page 68 </column> </row> <table> Table 2 (# 4)

<table> table see original document page 69 </column> </row> <table> Table 2 (# 5)

<table> table see original document page 70 </column> </row> <table> Table 2 (N ° 6)

<table> table see original document page 71 </column> </row> <table> Table 2 (# 7)

<table> table see original document page 72 </column> </row> <table> Table 2 (# 8)

<table> table see original document page 73 </column> </row> <table> Table 2

<table> table see original document page 74 </column> </row> <table> Table 2 (# 10)

<table> table see original document page 75 </column> </row> <table> Table 2 (Ν ° 11)

<table> table see original document page 76 </column> </row> <table> Table 2 (N ° 12)

<table> table see original document page 77 </column> </row> <table> Table 2 (Ν ° 13)

<table> table see original document page 78 </column> </row> <table> Table 2 (N ° 14)

<table> table see original document page 79 </column> </row> <table> Table 2 (Ν ° 15)

<table> table see original document page 80 </column> </row> <table> Table 2 (Ν ° 16)

<table> table see original document page 81 </column> </row> <table> Table 3 (Ν ° 1)

<table> table see original document page 82 </column> </row> <table> Table 3 (N ° 2)

<table> table see original document page 83 </column> </row> <table> Table 4

<table> table see original document page 84 </column> </row> <table> Example 203

Corresponding materials were treated in the same manner as described in Example 3 to obtain 6- (2-chloropyridin-3-yl) -7- (4-chlorophenyl) -3- (N-cyclopentylcarbamoyl) pyrazolo [1.5 -a] pyrimidine (39 mg, yield: 67%) as a pale yellow powder.

MS (APCI) m / z: 452/454 [M + H] + Example 204 The compound obtained in Example 181 (36 mg) was treated in the same manner as described in Example 33 to obtain 6- (2-chlorophenyl) -7. - (4-chlorophenyl) -2-methylsulfonyl-3- [N- (1,1-dioxo-tetrahydrothiophen-3-yl) carbamoyl] pyrazolo [1,5-a] pyrimidine (33.1 mg, yield: 86 %) as an in-color solid.

MS (APCI) mlz: 579/581 [M + H] +

Example 205

The compound obtained in Example 204 was treated in the same manner as described in Example 34 to obtain 6- (2-chlorophenyl) -7- (4-chlorophenyl) -2-methoxy-3- [N- (1,1-dioxo -tetrahydrothiophen-3-yl) carbamoyl] pyrazolo [1,5-a] pyrimidine (72 mg, yield: 79%) as a powder.MS (APCI) m / z: 531/533 [M + H] + Example 206

The compound obtained in Example 144 (80 mg) was treated in the same manner as described in Example 29 to obtain 6- (2-chlorophenyl) -7- (4-trifluoro-methoxyphenyl) -3- [N- (1,1 -dioxo-tetrahydrothiopyran-4-yl) carbamoyl] pyrazolo [1,5-a] pyrimidine (61.1 mg, yield: 72%) as a pale yellow powder.

MS (APCI) mlz: 565/567 [M + H] +

Example 207

(1) The compound obtained in Example 204 (300 mg) was treated in the same manner as described in Example 35 to obtain 5-cyano-6- (2-chlorophenyl) -7- (4-chlorophenyl) -2-methylsulfonyl-2-one. 3- [N- (1,1-dioxo-tetrahydrothio-phen-3-yl) carbamoyl] pyrazolo [1,5-a] pyrimidine (60 mg, yield: 19%) as a pale yellow solid.

MS (APCI) mlz: 604/606 [M + H] +

(2) The compound obtained in the above step (1) (60 mg) was treated in the same manner as described in Example 36 to obtain 6- (2-chlorophenyl) -7- (4-chlorophenyl) -5-methoxy-2 -methylsulfonyl-3- [N- (1,1-dioxo-tetrahydrothiophen-3-yl) carbamoyl] pyrazolo [1,5-a] pyrimidine (29 mg, yield: 49%) as a pale yellow powder.

MS (APCI) mlz: 609/611 [M + H] + Examples 208 to 209

The compound obtained in Reference Example 18 or 19 was treated in the same manner as described in Example 39 to obtain the compounds as shown in the following Table 5.

Table 5

<table> table see original document page 86 </column> </row> <table>

Examples 210 to 212

The compound obtained in Example 152, 194 or 156 was treated in the same manner as described in Example 29 to obtain the compounds as shown in the following Table 6.

Table 6

<table> table see original document page 86 </column> </row> <table> Examples 213 to 214

Corresponding raw materials were treated in the same manner as described in Example 28 and then the product was treated in the same manner as described in Example 29 to obtain the compounds as shown in the following Table 7.

Table 7

Examples 215

The compound obtained in Example 40 and 2-chloroethyl ether were treated in the same manner as described in Example 43 to obtain 6- (2-chlorophenyl) -7- (4-chlorophenyl) -2-morpholin-3- (N-cyclopentylcarbamoyl) pyrazole [1,5-a] pyrimidine (23 mg, yield: 33%) as a powder.

MS (APCI) mlz: 536/538 [M + H] +

Examples 216 to 223

The corresponding raw materials were treated in the same manner as described in Example 11 and then the product was treated in the same manner as described in Example 40 to obtain the compounds as shown in the following Table 8. Table 8

<table> table see original document page 88 </column> </row> <table>

Examples 224 to 231

Corresponding raw materials were treated in the same manner as described in Example 42 to obtain the compounds as shown in the following Table 9. Table 9

<table> table see original document page 89 </column> </row> <table>

Examples 232 to 237

Corresponding raw materials were treated in the same manner as described in Example 43 to obtain the compounds as shown in the following Table 10. Table 10

<table> table see original document page 90 </column> </row> <table>

Example 238

To a solution of pyrrolidine (15.5 μL) and pyridine (20 μL) in chloroform (2 mL) was added dropwise a solution of the compound (60 mg) obtained in Reference Example 54 in chloroform (1 mL). under cooling and the mixture was stirred at room temperature for 2.5 hours. To the darning mixture was subsequently added pyrrolidine (15.5 μL) and the mixture was stirred for 2.5 hours. To the reaction mixture was added water and the mixture extracted with chloroform. The organic layer was concentrated in vacuo and the resulting crude product was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 82/18 to 67/33) to obtain 6- (2-chlorophenyl) -7. - (4-trifluoromethylphenyl) -2-methyl-3- (1-pyrrolidinyl) sulfonylpyrazolo [1,5-a] pyrimidine (43.8 mg; yield: 68%) as a colorless solid. MS (APCI) m / z ; 521/523 [M + H] + Example 239

To a solution of the compound obtained in Reference Example 53 (60 mg) in ethanol (0.5 mL) was added divinyl sulfone (20 μΙ) and the mixture stirred at 120 ° C for 1 hour and at 130 ° C for 4 hours. hours in a microwave reactor. After cooling to room temperature, water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was concentrated in vacuo and the resulting crude product purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 70/30 to 55/45) to obtain 6- (2-chlorophenyl) -7- ( 4-trifluoromethyl-phenyl) -3- (1,1-dioxothiomorphino) pyrazolo [1,5-a] pyrimidine (40 mg; yield: 51%) as a red solid.

MS (APCI) m / z; 507/509 [M + H] + Example 240

To a solution of the compound obtained in Reference Example 55 (128 mg) in chloroform (2 mL) was added a solution of bromine (21 µL) in chloroform (1.3 mL) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and to the residue was added dimethylformamide (2 mL) and N-methylaniline (181 μί) and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added water and a saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The organic layer was concentrated in vacuo and the resulting crude product was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 88/12 to 75/25) to obtain 6- (2-chlorophenyl) -7. - (4-chlorophenyl) -3- [2- (N-methyl-N-phenylamino) acetyl] pyrazolo [1,5-a] pyrimidine (115 mg; yield: 70%) as a yellow solid.

MS (APCI) m / z; 487/489 [M + H] + Example 241

To a solution of the compound obtained in Example 434 (125 mg) in dichloromethane (2 mL) was added m-chloro-perbenzoic acid (146 mg) and the mixture was stirred at room temperature overnight. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resulting crude product was purified by column chromatography over NH silica gel (C-Chromatorex NH silica gel, solvent: hexane / ethyl acetate = 50/50). The fractions were concentrated and the precipitates were washed with hexane to obtain 6- (2-chlorophenyl) -7- (1,1-dioxothiomorpholino) -2-methyl-3 - [[N'-methyl-N '- (2-pyridyl) hydrazino] carbonyl] pyrazolo [1,5-a] pyrimidine (70 mg; yield: 53%) as a solid.

MS (APCI) m / z; 526/528 [M + H] +

Example 242

(1) The corresponding starting materials were treated in the same manner as described in Reference Example 2 to obtain 6- (2-bromophenyl) -7- (4-chloro-2-fluorophenyl) -3-carboxy-2-methylpyrazolo [1, 5-a] pyrimidine (1.51 g; yield: 20%) as a pale yellow powder. MS (APCI) m / z; 460/462 [M + H] +

(2) To a solution of the compound obtained in the above step (1) (100mg) in methylene chloride (3 mL) was added 1-methyl-1- (2-pyridyl) hydrazine (37 mg), carbodiimide hydrochloride water soluble (58 mg) and 1-hydroxybenzotriazole hydrate (46 mg) and the mixture was stirred at room temperature overnight. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution and the mixture was stirred and extracted with chloroform. The extract was concentrated in vacuo and the resulting product was purified by column chromatography over NH silica gel (Chromatorex NH silica gel, solvent: hexane / ethyl acetate = 80/20 to 55/45) to obtain 6- ( 2-bromophenyl) -7- (4-chloro-2-fluorophenyl) -2-methyl-3 - [[N'-methyl-N '- (2-pyridyl) hydrazino] carbonyl] pyrazolo [1,5- a] pyrimidine (119.5 mg; yield: 96%) as a pale yellow solid.

MS (APCI) m / z; 565/567 [M + H] +

(3) To a solution of the compound obtained in the above step (2) (119 mg) in dimethylformamide (2 mL) was added zinc cyanide (15.5 mg), tris (dibenzylidene acetone) dipaladium (4.2 mg) and 1,1'-bis (diphenylphosphino) ferrocene (5.1 mg) and the mixture was stirred at 180 ° C for 20 minutes in a microwave oven reactor. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution and the mixture was stirred and extracted with chloroform. The extract was washed with water and concentrated in vacuo. The resulting product was purified by column chromatography over NH silica gel (Chromatorex NH silica gel, solvent: hexane / ethyl acetate = 70/30 to 55/45) to obtain 6- (2-cyanophenyl) -7- (4-chloro-2-fluorophenyl) -2-methyl-3 - [[N'-methyl-N '- (2-pyridyl) hydrazino] carbonyl] pyrazolo [1,5-a] pyrimidine (22.1 mg; yield: 21%) as a yellow solid.

MS (APCI) m / z; 512/514 [M + H] +

Example 243

(1) To a solution of the compound obtained in Reference Example 33 (2.08 g) in N, N-dimethylformamide (20 mL) was added 2 M solution of demethylamine-methanol (5 mL), water-soluble carbodiimide (1.92 g ) and 1-hydroxybenzortriazole (1.53 g) and triethylamine (1.01 g) and the mixture was stirred at room temperature overnight. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resulting crude product was purified by column chromatography over NH silica gel (Chromatorex NH silica gel, solvent: chloroform / methanol = 100/0 to 95/5) to obtain 6- (2- chlorophenyl) -7- (4-trifluoromethylphenyl) -3- (N-methylcarbamoyl) pyrazolo [1,5-a] pyrimidine (1.83 g; yield: 85%) as a yellow powder.

MS (APCI) m / z; 431/433 [M + H] +

(2) To a solution of the compound obtained in the above step (1) (832mg) in toluene (10ml) was added Lawesson's reagent (809mg) and the mixture was stirred at 110 ° C for 2 hours. After cooling, to the reaction mixture was added NH silica gel (2.0 g) and the mixture was filtered. The residue was washed with ethyl acetate and the organic layers were combined and concentrated in vacuo. The resulting crude product was purified by column chromatography over silica gel (solvent: hexane / ethyl acetate = 80/20 to 60/40) to obtain 6- (2-chlorophenyl) -7- (4-trifluoromethylphenyl) - 3- [N- (methyl) thiocarbamoyl] pyrazolo [1,5-a] pyrimidine (730 mg; yield: 82%) as a powder.

MS (APCI) m / z; 447/449 [M + H] +

(3) To a solution of 4-chlorobenzenesulfonyl chloride (5.28 g) in tetrahydrofuran (25 mL) was added a solution of sodium azide (1.79 g) in water (12.5 mL) and the mixture was stirred. at room temperature overnight. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give 4-chlorobenzenesulfonyl azide (4.27 g, yield: 78%) as a colorless liquid.

(4) A solution of the compound obtained in the above step (2) (223 mg) and the compound obtained in the above step (3) (326 mg) in pyridine (5 mL) was stirred at 110 ° C for 2 days. After cooling, to the reaction mixture was added water and the mixture was extracted with chloroform. The organic layer was vacuum concentrated and the resulting crude product was purified by column chromatography over silica gel (solvent: hexane / ethyl acetate = 30/70 to 50/50) to obtain compound a (24 mg; yield: 8%) and compound b (0.8mg, yield: 0.4%) as shown in the following Table 11.

Table 11

<table> table see original document page 94 </column> </row> <table> Example 244

The compound obtained in Example 332 was treated in the same manner as described in Example 31 (2) to obtain 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3 - [[N'-methyl-N'- (6-cyanopyridin-3-yl) hydrazino] carbonyl] pyrazolo [1,5-a] pyrimidine.

MS (APCI) m / z; 514/516 [M + H] +

Example 245

To a solution of the compound obtained in Example 292 (6- (2-chlorophenyl) -7- (4-chlorophenyl) -3 - [[N, methyl-N '- (6-fluoropyridin-2-yl) hydrazino] carbonyl ] pyrazolo [1,5-a] pyrimidine) in N-methylpiperidine (1mL) were added diisopropylethylamine (52 µl) and morpholine (26 µl) and the mixture was stirred at 90 ° C overnight and 120 ° C for 4 hours in a shielding container. After cooling to room temperature, to the reaction mixture was added morpholine (60 µl) and the mixture was stirred at 120 ° C overnight in a shielding vessel and 100 ° C for 15 minutes in a microwave reactor. After cooling to room temperature, the reaction mixture was concentrated in vacuo and the resulting crude product was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 70/30 to 40 / 60) and the eluted fraction was concentrated. The residue was purified by gel permeation chromatography (mobile phase: chloroform) and the eluted fraction was concentrated. The resulting residue was dissolved in tert-butanol and the solution was lyophilized to give 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3 - [[N'-methyl-N '- (6-morpholinopyridin-2-yl ) hydrazino] carbonyl] pyrazolo [1,5-a] pyrimidine (12.9 mg; yield: 23%) as a pale yellow powder.

MS (APCI) m / z; 574/576 [M + H] + Example 246

(1) The corresponding starting materials were treated in the same manner as described in Reference Example 2 to obtain 6- (2-bromophenyl) -7- (4-chloro-2-fluoro-phenyl) -3-carboxypyrazolo [1,5- a] pyrimidine (2.09 g; yield: 22%) as a pale yellow powder.

MS (APCI) m / z; 446/448 [M + H] + (2) The compound obtained in the above step (1) and the corresponding raw materials were treated in the same manner as described in Example 3 to obtain 6- (2-bromophenyl) -7- (4- chloro-2-fluorophenyl) -3 - [[N'-methyl-N '- (2-pyridyl) hydrazino] carbonyl] pyrazolo [1,5-a] pyrimidine (148 mg, yield: 89%) like a pale yellow solid.

MS (APCI) m / z; 551/553 [M + H] +

(3) The compound obtained in the above step (2) (119 mg) was treated in the same manner as described in Example 242 (3) to give 6- (2-cyanophenyl) -7- (4-chloro-2-fluorophenyl). ) -3 - [[N'-methyl-N '- (2-pyridyl) hydrazino] carbonyl] pyrazolo [1,5-a] pyrimidine (compound a: 51.6 mg, yield: 40%) as a yellow solid and 6- (2-cyanophenyl) -7- (4-cyano-2-fluorophenyl) -3 - [[N'-methyl-N '- (2-pyridyl) hydrazino] carbonyl] pyrazolo [1,5-a] pyrimidine (compound b: 34.1 mg, yield: 27%) as a yellow solid.

Compound a: MS (APCI) m / z; 498/500 [M + H] +

Compound b: MS (APCI) m / z; 489 [M + H] +

Example 247

(1) The corresponding raw material (3-carboxy-6- (2-chlorophenyl) -7- (4-chlorophenyl) pyrazolo [1,5-a] pyrimidine; 576 mg) was treated in the same manner as described in Example 3 to give 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- [N- [1- (tert-butoxycarbonyl) pyrrolidin-3-yl] carbamoyl] pyrazolo [1,5-a ] pyrimidine (656 mg, yield: 79%) as a yellow solid.

MS (APCI) m / z; 552/554 [M + H] +

(2) A solution of the compound obtained in the above step (1) (650 mg) in 4N-HCl-dioxane (5 mL) was stirred at room temperature overnight. The reaction mixture was neutralized (pH 7 to 8) with a saturated aqueous solution of sodium hydrogen carbonate on cooling. The mixture was extracted with methylene chloride and the organic layer was dried over magnesium sulfate and concentrated in vacuo. The resulting crude product was purified by column chromatography over NH-silica gel (ChromatorexNH-silica gel, solvent: chloroform / methanol = 100/0 to 95/5) and dried in vacuo to obtain 6- (2-chlorophenyl) -7. - (4-chlorophenyl) -3- [N- (pyrrolidin-3-yl) carbamoyl] pyrazolo [1,5-a] pyrimidine (515.8 mg; yield: 97%) as a pale yellow solid.

MS (APCI) m / z; 452/454 [M + H] +

(3) To a solution of the compound obtained in the above step (2) (46 mg) in dichloromethane (1 mL containing amylene) was added triethylamine (28 μΙ_) and to this was added dropwise acetyl chloride (9 μΙ_) under atmosphere and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with methylene chloride. The extract was concentrated in vacuo and the resulting crude was purified by column chromatography over silica gel (solvent: chloroform / methanol = 100/0 to 95/5) and the eluted fraction was concentrated in vacuo. The resulting residue was dissolved in tert-butanol and lyophilized to give 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- [N- (1-acetylpyrrolidin-3-yl) carbamoyl] pyrazolo [1, 5-a] pyrimidine (50.7 mg; yield: 100%) as a pale yellow powder.

MS (APCI) m / z; 494/496 [M + H] +

Examples 248 to 250

Corresponding raw materials were treated in the same manner as described in Example 247 to obtain the compounds as shown in the following Table 12.

Table 12

<table> table see original document page 97 </column> </row> <table>

Examples 251 to 278The corresponding raw materials were treated in the same way as

manner as described in Example 31 or 242 to obtain the compounds as shown in the following Table 13.

Table 13 (No. 1)

<table> table see original document page 98 </column> </row> <table> Table 13 (N ° 2)

<table> table see original document page 99 </column> </row> <table> Table 13 (N ° 3)

<table> table see original document page 100 </column> </row> <table> Table 13 (# 4)

<table> table see original document page 101 </column> </row> <table>

Examples 279 to 423

Corresponding raw materials were treated in the same manner as described in Example 3 to obtain the compounds as shown in the following Table 14. Table 14 (No. 1)

<table> table see original document page 102 </column> </row> <table>

Table 14 (# 2) <table> table see original document page 103 </column> </row> <table> Table 14 (# 3)

<table> table see original document page 104 </column> </row> <table> Table 14 (# 4)

<table> table see original document page 105 </column> </row> <table> Table 14 (# 5)

<table> table see original document page 106 </column> </row> <table> Table 14 (N ° 6)

<table> table see original document page 107 </column> </row> <table> Table 14 (# 7)

<table> table see original document page 108 </column> </row> <table> Table 14 (# 8)

<table> table see original document page 109 </column> </row> <table> Table 14 (# 9)

<table> table see original document page 110 </column> </row> <table> Table 14 (# 10)

<table> table see original document page 111 </column> </row> <table> Table 14 (N ° 11)

<table> table see original document page 112 </column> </row> <table> Table 14 (Ns 12)

<table> table see original document page 113 </column> </row> <table> Table 14 (# 13)

<table> table see original document page 114 </column> </row> <table> Table 14 (N- 14)

<table> table see original document page 115 </column> </row> <table> Table 14 (N ° 15)

<table> table see original document page 116 </column> </row> <table> Table 14 (Ne 16)

<table> table see original document page 117 </column> </row> <table> Table 14 (N5 17)

<table> table see original document page 118 </column> </row> <table> Table 14 (Ne 18)

<table> table see original document page 119 </column> </row> <table> Table 14 (Ns 19)

<table> table see original document page 120 </column> </row> <table> Table 14 (Ns 20)

<table> table see original document page 121 </column> </row> <table> Table 14 (Ne 21)

<table> table see original document page 122 </column> </row> <table> Table 14 (Ν ° 22)

<table> table see original document page 123 </column> </row> <table> Table 14 (Ne 23)

<table> table see original document page 124 </column> </row> <table>

Examples 424 to 427

Corresponding raw materials were treated in the same manner as described in Example 3 or 242 to obtain the compounds as shown in the following Table 15. Table 15

<table> table see original document page 125 </column> </row> <table>

Examples 428 to 430

Corresponding raw materials were treated in the same manner as described in Example 28 to obtain the compounds as shown in the following Table 16. Table 16

<table> table see original document page 126 </column> </row> <table>

Examples 431 to 439

Corresponding raw materials were treated in the same manner as described in Example 1 to obtain the compounds as shown in the following Table 17. Table 17

<table> table see original document page 127 </column> </row> <table> Example 440

(1) To a solution the compound obtained in Example 484 (2) (1.0 g) ethylethylamine (1.81 mL) in tetrahydrofuran (20 mL) was gradually added methanesulfonyl chloride (1.0 g) under cooling and the mixture It was stirred at room temperature for 40 minutes. The reaction mixture was diluted with ethyl comacetate and to it was added water under cooling. After stirring, the aqueous layer was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resulting crude product was purified by column chromatography over NH silica gel (Chromatorex NH silica gel, solvent: hexane / ethyl acetate = 80/20 to 60/40) to give 6- ( 2-chlorophenyl) -7- (4-trifluoromethylphenyl) -3-ethoxycarbonyl-2- [N, N-bis (methylsulfonyl) amino] pyrazolo [1,5-a] pyrimidine (1.01 g, yield : 75%) as a pale yellow solid.

MS (APCI) m / z; 617/619 [M + H] +

(2) To a solution of the compound obtained in the above step (1) (1.01 g) in tetrahydrofuran (20 mL) was added tetrabutyl ammonium fluoride trihydrate (1.03 g) and the mixture was stirred at room temperature. for 15 minutes. To the reaction mixture was added water and the mixture was stirred and extracted with chloroform. The extract was dried over magnesium sulfate and filtered and the filtrate was concentrated in vacuo. The resulting crude product was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 70/30 to 50/50) to give 6- (2-chlorophenyl) -7- (4-trifluoromethylphenyl) -3- ethoxycarbonyl-2- (methylsulfonyl-amino) pyrazolo [1,5-a] pyrimidine (0.71 g, yield: 81%) as a pale yellow powder.

MS (APCI) m / z; 539/541 [M + H] +

(3) A solution of the compound obtained in the above step (2) (0.69 g) sodium ethoxide (0.87 g) in ethanol (20 mL) was stirred at 80 ° C for 10 minutes. Methyl iodide (1.59 mL) is added dropwise and the mixture is stirred overnight. The reaction mixture was concentrated in vacuo and water was added to the residue. The mixture was extracted with ethyl acetate and the organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resulting crude product was purified by column chromatography over NH silica gel (Chromatorex NH silica gel, solvent: hexane / ethyl acetate = 75/25 to 60/40) to give 6- (2) -chlorophenyl) -7- (4-trifluoromethylphenyl) -3-ethoxycarbonyl-2- [N-methyl-N- (methylsulfonyl) amino] pyrazolo [1,5-a] pyrimidine (0.70 g, yield: 99 %) as a powder.

MS (APCI) m / z; 553/555 [M + H] +

Examples 441 to 452

Corresponding raw materials were treated in the same manner as described in Reference Example 1 (3) and Example 3 to obtain the compounds as shown in the following Table 18.

Table 18 (No. 1)

<table> table see original document page 129 </column> </row> <table> 129

Table 18 (No. 2)

<table> table see original document page 130 </column> </row> <table>

Examples 453 to 454

Corresponding raw materials were treated in the same manner as described in Example 3 to obtain the compounds as shown in the following Table 19. Table 19

<table> table see original document page 131 </column> </row> <table>

Examples 455 to 460

Corresponding raw materials were treated in the same manner as described in Example 238 to obtain the compounds as shown in the following Table 20.

Table 20

<table> table see original document page 131 </column> </row> <table> Example 461

To a solution of the compound obtained in Reference Example 53 (60 mg) in tetrahydrofuran (1 mL) -dimethylacetamide (0.2 mL) was added diiodopentane (34.5 μL) and sodium carbonate (24.5 mg). and the mixture was stirred at 70 ° C for 17 hours. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The extract was concentrated in vacuo and the resulting crude product was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 85/15 to 60/40) to give 6- (2-chloro-phenyl) 7- (4-trifluoromethylphenyl) -3- (piperidin-1-yl) pyrazolo [1,5-a] pyrimidine (17 mg, yield: 24%) as a red powder.

MS (APCI) m / z; 457/459 [M + H] + Examples 462 to 465

Corresponding raw materials were treated in the same manner as described in Example 240 to obtain the compounds as shown in the following Table 21.

Table 21

<table> table see original document page 132 </column> </row> <table>

Example 466

(1) The compound obtained in Reference Example 33 was treated in the same manner as described in Example 1 to give 6- (2-chlorophenyl) -7- (4-trifluoromethyl-phenyl) -3- [N- (1- hydroxy-4-methylthio-2-butyl) carbamoyl] pyrazo [1,5-a] pyrimidine (357 mg, yield: 56%) as a yellow powder.

MS (APCI) m / z; 535/537 [M + H] +

(2) To a solution of the compound obtained in the above step (1) (349mg) in methylene chloride (2 mL) was added thionyl chloride (170 μL) and the mixture was stirred at room temperature for 23 hours. To the reaction mixture was added chloroform (2 mL) and the mixture was stirred at 60 ° C for 5 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo and the resulting crude product was purified by column chromatography over silica gel (solvent: hexane / ethyl acetate = 85/15 to 60/40) to give 6- (2-chlorophenyl) -7- (4-trifluoromethylphenyl) -3 - [(tetrahydrothiophen-3-yl) carbamoyl] pyrazolo [1,5-a] pyrimidine (106 mg, yield: 32%) as a pale yellow powder.

MS (APCI) m / z; 503/505 [M + H] +

(3) To a solution of the compound obtained in the above step (2) (96 mg) in methylene chloride (3 mL) was added m-chloro-perbenzoic acid (75%, 44 mg) under cooling and the mixture was stirred at room temperature. same temperature for 15 minutes. To the reaction mixture was added sodium sulfite and an aqueous sodium hydrogen carbonate solution and the mixture was extracted with chloroform. The extract was concentrated in vacuo and the resulting crude product purified by silica gel column chromatography (solvent: chloroform / methanol = 100/0 to 92/8) to give 6- (2-chlorophenyl) -7- (4- trifluoromethylphenyl) -3 - [(1-oxo-tetrahydrothiophen-3-yl) carbamoyl] pyrazolo [1,5-a] pyrimidine (81 mg, yield: 82%) as a colorless powder.

MS (APCl) m / z; 519/520 [M + H] +

Example 467

The compound obtained in Reference Example 47 was treated in the same manner as described in Example 3 to give (R) -6- (2-chlorophenyl) -7- (4-chlorophenyl) -3 - [(1,1-dioxide -tetrahydrothiophen-3-yl) carbamoyl] -2- (2-methoxyethoxy) pyrazolo [1,5-a] pyrimidine (77 mg, yield: 67%) as a powder.

MS (APCI) m / z; 575/577 [M + H] + Example 468

The corresponding starting materials were treated in the same manner as described in Example 3 to give (R) -6- (2-chlorophenyl) -7- (4-chlorophenyl) -3 - [(1,1-dioxo-tetrahydrothiophene-3-one). yl) carbamoyl] -2- (2-hydroxyethoxy) pyrazolo [1,5-a] pyrimidine (91 mg, yield: 84%) as a powder.

MS (APCI) m / z; 561/563 [M + H] +

Example 469

(1) The compound obtained in Reference Example 59 was treated in the same manner as described in Example 3 to give (R) -6- (2-chlorophenyl).

Nyl) -7- (4-chlorophenyl) -3 - [(1,1-dioxo-tetrahydrothiophen-3-yl) carbamoyl] -2-methylthiomethylpyrazolo [1,5-a] pyrimidine (183.6 mg, yield: 91 %) as a pale yellow powder.

MS (APCI) m / z; 561/563 [M + H] +

(2) The compound obtained in the above step (1) (183 mg) was treated in

same way as described in Example 29 to give (R) -6- (2-chlorophenyl)

nyl) -7- (4-chlorophenyl) -3 - [(1,1-dioxo-tetrahydrothiophen-3-yl) carbamoyl] -2- (methylsulfonylmethyl) pyrazolo [1,5-a] pyrimidine (91.6 mg, yield: 47%) as a powder.

MS (APCI) m / z; 593/595 [M + H] + Example 470

The compound obtained in Reference Example 9 (50 mg) and 3-pyridylacetate hydrochloride (31.8 mg) were treated in the same manner as described in Example 3 to give 6- (2-chlorophenyl) -7- (4-chlorofe -nyl) -3 - [[2- (2-pyridyl) acetyl] amino] pyrazolo [1,5-a] pyrimidine (52.6 mg, yield: 79%) as a yellow powder.

MS (APCI) m / z; 474/476 [M + H] +

Example 471

(1) The compound obtained in Reference Example 5 (7.3 g) was nitrate in the same manner as described in Example 484 to give 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3-ethoxycarbonyl-2-aminopyrazole [1,5-a] pyrimidine (1.43 g).

MS (APCI) m / z; 427/429 [M + H] +

(2) The compound obtained in the above step (1) (2.64 g) was treated in the same manner as described in Example 440 (1) to (2) to give 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3-ethoxycarbonyl-2- (methylsulfonylamino) pyrazolo [1,5-a] pyrimidine (2.20 g).

MS (APCI) m / z; 505/507 [M + H] +

(3) The compound obtained in the above step (2) (70 mg) was treated in the same manner as described in Reference Example 1 (3) to give 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3-carboxy -2- (methylsulfonylamino) pyrazolo [1,5-a] pyrimidine as a crude product.

MS (APCI) m / z; 477/479 [M + H] +

(4) The compound obtained in the above step (3) was treated in the same manner as described in Example 3 to give 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3 - [[N'-methyl] N '- (2-pyridyl) hydrazino] carbonyl] -2- (methylsulfonylamino) pyrazolo [1,5-a] pyrimidine (27 mg, yield: 32%) as a powder.

MS (APCI) m / z; 596/598 [M + H] + Example 472

The corresponding starting materials were treated in the same manner as described in Example 471 to give 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- (N-isobutylcarbamoyl) -2- (methylsulfonylamino) pyrazolo [1]. , 5-a] pyrimidine (52 mg, yield: 79%) as a powder.

MS (APCI) m / z; 546/548 [M + H] + Example 473

To a solution of the compound obtained in Reference Example 9 (2) (50 mg) in tetrahydrofuran (1.5 mL) was added phenyl isocyanate (30.5 μι.) Ethylethylamine (49 μΙ_) and the mixture was stirred at 60 °. C overnight. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The extract was concentrated in vacuo and the resulting crude product was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 75/25 to 65/35) to obtain 6- (2-chlorophenyl) -7 - (4-chlorophenyl) -3- (N'-phenyleneuride) pyrazolo [1,5-a] pyrimidine (37.8 mg, yield: 57%) as a powder.

MS (APCI) m / z; 474/476 [M + H] + Examples 474

The corresponding starting materials were treated in the same manner as described in Example 473 to obtain 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- (N'-cyclopentylureido) pyrazolo [1,5-a] pyrimidine (48.3 mg, yield: 74%) as a powder.

MS (APCI) m / z; 466/468 [M + H] +

Examples 475 to 478

Corresponding raw materials were treated in the same manner as described in Example 3 to obtain the compounds as shown in the following Table 22.

Table 22

<table> table see original document page 136 </column> </row> <table>

Examples 479

The corresponding starting materials were treated in the same manner as described in Example 31 to obtain 6- (2-cyanophenyl) -7- (4-trifluoromethylphenyl) -3- [N- (1,1-dioxothiomorphino) carbamoyl] pyrazolo [ 1,5-a] pyrimidine as a powder.MS (APCI) m / z; 541 [M + H] +

Example 480

(1) The compound obtained in Example 471 (1) (440 mg) was treated in the same manner as described in Reference Example 1 (3) to give 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3-carboxy -2-aminopyrazolo [1,5-a] pyrimidine as a crude product.

MS (APCI) m / z; 399/401 [M + H] +

(2) The compound obtained in the above step (1) was treated in the same manner as described in Example 3 to give (R) -6- (2-chlorophenyl) -7-

(4-chlorophenyl) -3- [N- (1,1-dioxotetrahydrothiophen-3-yl) carbamoyl] -2-aminopyrazolo [1,5-a] pyrimidine (254 mg, yield: 48%) as a powder.

MS (APCI) m / z; 516/518 [M + H] +

(3) The compound obtained in the above step (2) (250 mg) was treated in the same manner as described in Example 43 to give (R) -6- (2-chlorophenyl) -7- (4-chloro-phenyl) -3- [N- (1,1-dioxotetrahydrothiophen-3-yl) carbamoyl] -2- (pyrrolidin-1-yl) pyrazolo [1,5-a] pyrimidine (106 mg, yield: 38%) as a powder .

MS (APCI) m / z; 570/572 [M + H] +

(4) The compound obtained in the above step (3) (95 mg) was treated in the same manner as described in Example 33 to give the compound as shown in the following Table 23.

Table 23

<formula> formula see original document page 137 </formula>

Example 481The compound obtained in Reference Example 46 (3.0 g) e3- (N, N-dimethylamino) -1- (4-chlorophenyl) -2- (2-chlorophenyl) -2-propen-1-one (6 , 18 g) were treated in the same manner as described in Reference Example 1 (2) to give 6- (2-chlorophenyl) -7- (4-chlorophenyl) -2-ethoxycarbonylpyrazolo [1,5-a] pyrimidine (3.57 g, yield: 45%) as a colorless powder.

MS (APCI) m / z; 412/414 [M + H] +

Example 482

(1) The compound obtained in Example 481 (2.5 g) was treated in the same manner as described in Reference Example 1 (3) to give

2-carboxy-6- (2-chlorophenyl) -7- (4-chlorophenyl) pyrazolo [1,5-a] pyrimidine (1.65 g) as a crude product.

MS (APCI) m / z; 384/386 [M + H] +

(2) The compound obtained in the above step (1) (80 mg) and 1-methyl-1- (2-pyridyl) hydrazine (26 mg) were treated in the same manner as described in Example 3 to give 6- (2 -chlorophenyl) -7- (4-chlorophenyl) -2 - [[N'-methyl-N '- (2-pyridyl) hydrazino] carbonyl] pyrazolo [1,5-a] pyrimidine (85 mg) as a colorless powder.

MS (APCI) m / z; 489/491 [M + H] +

Example 483

The compound obtained in Reference Example 18 (5-amino-4-ethoxycarbonyl-3-methylthio-1H-pyrazole, 10.1 g) and 3- (N, N-dimethylamino) -1- (4-tri- fluoromethyl-phenyl) -2- (2-chlorophenyl) -2-propen-1-one (17.7 g) were treated in the same manner as described in Reference Example 5 (1) to give 6- (2-chlorophenyl) -7 - (4-chlorophenyl) -3-ethoxycarbonyl-2-methylthiopyrazolo [1,5-a] pyrimidine (11.4 g, yield: 45%) as a colorless powder.

MS (APCI) m / z; 492/494 [M + H] +

Example 484

(1) The compound obtained in Example 483 (11 g) was treated in the same manner as described in Reference Example 5 (2) to give 2-azido-6- (2-chlorophenyl) -7- (4-trifluoromethylphenyl) -3- ethoxycarbonylpyrazolo [1,5-a] pyrimidine (10.6 g, yield: 91%) as a crude product (colorless powder). The product (10.6 g) was treated in the same manner as described in Reference Example 11 to give 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3-ethoxycarbonyl-n-triphenylphosphoranylidenamino] pyrazoloth-1-alpyrimidine (11 , 4 g) as a colorless powder.

(2) The compound obtained in the above step (1) (11.1 g) and acetic acid (70 mL) were treated in the same manner as described in Example 40 to give 6- (2-chlorophenyl) -7- (4-trifluoromethylphenyl ) -3-ethoxycarbonyl-2-aminopyrazolo [1,5-a] pyrimidine (5.2 g, yield: 73%) as a colorless solid.

MS (APCI) m / z; 461/463 [M + H] + Example 485

The compound obtained in Example 484 (2.1 g) and 1,4-dichlorobutane

(2.9 g) were treated in the same manner as described in Example 43 to give 6- (2-chlorophenyl) -7- (4-trifluoromethylphenyl) -3-ethoxycarbonyl-2- (pyrroli-din-1-yl) pyrazolo [ 1,5-a] pyrimidine (0.61 g, yield: 26%) as a yellow oil.

MS (APCI) m / z; 515/517 [M + H] +

Example 486

The compound obtained in Example 485 (0.61 g) was treated in the same manner as described in Reference Example 8 to give 6- (2-chlorophenyl) -7- (4-trifluoromethylphenyl) -3-carboxy-2- (pyrrolidin-1) -yl) pyrazolo [1,5-a] pyrimidine (0.45 g) as a crude product. The product (70 mg) and 1-aminopyrrolidine hydrochloride (17.6 mg) were treated in the same manner as described in Example 3 to give 6- (2-chlorophenyl) -7- (4-trifluoromethylphenyl) -3- [N- ( pyrrolidin-1-yl) carbamoyl] -2- (pyrrolidin-1-yl) pyrazolo [1,5-a] pyrimidine (14.8 mg; compound a) and 6- (2-chlorophenyl) -7 - (4-trifluoromethylphenyl) -2- (pyrrolidin-1-yl) pyrazolo [1,5-a] pyrimidine (32.6 mg; compound b) as a yellow powder, respectively.

Compound a: MS (APCI) m / z; 555/557 [M + H] +

Compound b: MS (APCI) m / z; 443/445 [M + H] + Example 487

(1) To a solution of the compound obtained in Reference Example 4B (300 mg) in dimethylformamide (5 mL) was added portionwise hydride sodium (60%, 137 mg) under a nitrogen gas atmosphere and the mixture was stirred. To the mixture was gradually added 4-chloro-N-methylaniline (125 µL) and the mixture was stirred at 80 ° C for 30 minutes. After cooling to room temperature, water and ethyl acetate were added to the reaction mixture and the aqueous layer was neutralized with 2 Ν HCl. The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was vacuum concentrated and the resulting crude was purified by column chromatography over silica gel (solvent: chloroform / methanol = 98/2 to 85/15) to obtain 6- (2-chlorophenyl) -7- [N -methyl-N- (4-chlorophenyl) amino] -3-carboxy-2-methyl-pyrazolo [1,5-a] pyrimidine (54.2 mg, yield: 15%) as a colorless powder.

MS (APCI) m / z; 427/429 [M + H] +

(2) The compound obtained in the above step (1) (27 mg) was treated in the same manner as described in Example 3 to give 6- (2-chlorophenyl) -7- [N-methyl-N- (4-chlorophenyl ) amino] -3- [N'-methyl-N '- (pyridin-2-yl) hydrazino] -2-methylpyrazolo [1,5-a] pyrimidine (18.5 mg, yield: 55%) as a powder colorless.

MS (APCI) m / z; 532/533 [M + H] +

Examples 488 to 489

Corresponding raw materials were treated in the same manner as described in Example 487 to obtain the compounds as shown in the following Table 24.

Table 24

<table> table see original document page 140 </column> </row> <table>

Examples 490 to 500 Corresponding raw materials were treated in the same manner as described in Example 487 to obtain the compounds as shown in the following Table 25.

Table 25 (No. 1)

<table> table see original document page 141 </column> </row> <table> Table 25 (N ° 2)

<table> table see original document page 142 </column> </row> <table> Reference Example 1

(1) To diethyl ether (250 mL) was added magnesium (6.04 g) as a catalytic amount of iodine and the mixture was stirred and thereto was gradually added dropwise 2-chlorobenzyl chloride (20.0 g). ). After stirring for 1 hour from the time when the temperature of the similar mixture began to rise, to this was added a solution of 4-chlorobenzonitrile (18.8 g) in tetrahydrofuran / diethyl ether (20 mL / 50 mL) and the mixture was stirred for 2 hours. 3 hours. To the reaction mixture was added 2 N HCl (150 mL) under cooling and the mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate and the organic layer was washed with 1 N HCl, water and saturated brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resulting product was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 40/1 to 20/1) to obtain 2- (chloro-benzyl) (4-chlorophenyl ) methanone (24.40 g; yield: 74%) as a powder.

MS (APCI) m / z; 265/267 [M + H] +

(2) A solution of the compound obtained in the above step (1) (6.4 g) eΝ, β-dimethylformamide dimethyl acetal (6.4 mL) in N, N-dimethylformamide (24 mL) was stirred at 150 ° C for 4 hours . After cooling the reaction mixture to room temperature, water was added thereto and the mixture was extracted with a mixture of ethyl acetate and hexane (x 3). The organic layer was washed with saturated brine, dried over filtered magnesium sulfate. The filtrate was concentrated in vacuo to obtain 3- (N, N-dimethylamino) -1- (4-chlorophenyl) -2- (2-chlorophenyl) -2-propen-1-one as an oil. To a solution of the compound in acetic acid (8 mL) was added 3-amino-4-ethoxycarbonyl-1H-pyrazole (3.75 g) and piperidine (0.48 mL) and the mixture cooled to 80 ° C for 16 hours. After cooling the reaction mixture to room temperature, water and ethyl acetate were added thereto and the organic layer was washed with saturated brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resulting crude product was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 17/3 to 67/33) to obtain 6- (2-chlorophenyl) - 7- (4-chlorophenyl) -3-ethoxycarbonylpyrazolo [1,5-a] pyrimidine (5.02 g, yield: 50%) as a powder.

MS (APCI) m / z; 412/414 [M + H] +

(3) To a solution of the compound obtained in the above step (2) (2.5 g) in ethanol (30 mL) was added 2 N sodium hydroxide (6 mL) and the mixture stirred at room temperature for 5 hours. To the reaction mixture was 2N HCl (6 mL) and the mixture was stirred and concentrated in vacuo. The residue was extracted with ethyl acetate and the organic layer was washed with saturated brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to obtain 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3-carboxypyrazolo [1,5-a] pyrimidine (2.1 g, yield: 90%) as a powder.

MS (APCI) m / z; 384/386 [M + H] +

Reference Example 2 (1) To dimethoxyethane (100 mL) was added 4-chlorobenzylbromide (4.1 g), 4-chlorobenzoylchloride (2.56 mL), bis (triphenylphosphine) palladium dichloride (702 mg) and zinc powder (2.6 g) and the mixture was stirred for 2 hours under nitrogen gas atmosphere. The reaction mixture was filtered and the filtrate was concentrated in vacuo and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resulting crude product was purified by column chromatography over silica gel (solvent: hexane / ethyl acetate = 49/1 to 9/1) to obtain (4-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) was treated in the same manner as described in Reference Example 1 (2) and (3) to give 3-carboxyl-6- (4-chlorophenyl) -7- (4-chlorophenyl) pyrazolo [1,5-a] pyrimidine (165 mg, yield: 20%) as a powder.

MS (APCI) m / z; 384/386 [M + H] +

Reference Example 3

Corresponding raw materials were treated in the same manner as described in Reference Example 1 to give 3-carbo-xyl-6-phenyl-7- (4-chlorophenyl) pyrazolo [1,5-a] pyrimidine (2.06 g Yield: 22%) as a powder.

MS (APCI) m / z; 350/352 [M + H] + Reference Example 4 (1) To a solution of methyl 2-chlorophenylacetate (10 g) in dimethyl

Tilformamide (150 mL) was added α, β-dimethylformamide dimethylacetal (14.4 mL) and the mixture was stirred at 85 ° C overnight. After cooling to room temperature, to the reaction mixture was added ethyl acetate and water and the mixture was stirred. The organic layer was extracted, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was diluted with acetic acid (18 mL). To this was added 3-amino-4-ethoxycarbonyl-1H-pyrazole (8.4 g) and piperidine (1.1 mL) and the mixture stirred at 80 ° C for 3.5 hours. After cooling to room temperature, to the reaction mixture was added ethyl acetate and water and the mixture was stirred and filtered. The resulting solid materials were dried to obtain 5- [2- (2-chlorophenyl) -2-methoxycarbonylvinylamino] -4-methoxycarbonyl-1H-pyrazole (11.8 g, yield: 62%) as a powder.

MS (APCI) m / z; 350/352 [M + H] +

(2) To a solution of the compound obtained in the above step (1) (10.7 g) in ethanol (250 mL) was added 3.24 g of sodium carbonate and the mixture was

refluxed under heating for 4 days. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated in vacuo. To the residue was added water and the mixture was stirred and filtered (said filtration step was repeated 5 times). The resulting solid materials were dried to obtain 6- (2-chlorophenyl) -3-ethoxycarbonyl-7-oxo-4,7-dihydropyrazolo [1,5-a] pyrimidine (8.5 g, yield: 87%) as a dust.

MS (APCI) m / z; 318/320 [M + H] +

(3) To a solution of the compound obtained in the above step (2) (300mg) in acetonitrile (2 mL) was added N, N-dimethylaniline (319 μί) and

phosphorus oxychloride (270 μί) and the mixture was refluxed under heating for 1 day. After cooling to room temperature, the reaction mixture was poured into ice water and extracted with methylene chloride. The extract was dried over magnesium sulfate and filtered and the filtrate was concentrated in vacuo. The resulting crude product was purified by column chromatography over silica gel (solvent; hexane / ethyl acetate = 80/20 to 60/40) to give 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) A solution of the compound obtained in the above step (3) (100 mg), [1,1'-bis (diphenylphosphonium) ferrocene] palladium (11) -methylene chloride (7.3 mg) dichloride complex phosphate (189 mg) and 4-fluorophenylboronic acid (846mg) in 1,4-dioxane (3 ml) was stirred at 80 ° C for 5 hours under nitrogen atmosphere. After cooling to room temperature, to the reaction mixture was added methylene chloride and a brine and the mixture stirred. The organic layer was extracted and the extract was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resulting crude product was purified by column chromatography over silica gel (solvent; hexane / ethyl acetate = 80/20 to 65/35) to give 6- (2- chloro-phenyl) -3-ethoxycarbonyl-7- (4-fluorophenyl) pyrazolo [1,5-a] pyrimidine (106 mg, yield: 90%) as a powder.

MS (APCI) m / z; 396/398 [M + H] +

4B Reference Example

A solution of methyl 2-chlorophenylacetate (25 g) in dimethylformamide (400 mL) was added α, β-dimethylformamide dimethyl acetal (36 mL) and the mixture was stirred at 90 ° C overnight. After cooling to room temperature, to the reaction mixture was added ethyl acetate and water and the mixture was stirred and extracted. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was diluted with acetic acid (60 mL). To this was added 3-amino-4-ethoxycarbonyl-2-methyl-1H-pyrazole (19.7 g) and the mixture was stirred at 120 ° C overnight. After cooling to room temperature, the precipitates were collected by filtration and washed to give 6- (2-chloro-phenyl) -3-ethoxycarbonyl-2-methyl-7-oxo-4,7-dihydropyrazolo [1, 5-a] pyrimidine (26.0 g, two-step yield: 62%) as a powder. MS (APCI) m / z; 332/334 [M + H] +

Reference Example 5

(1) A solution of 5-amino-4-ethoxycarbonyl-3-methylthio-1H-pyrazole (compound obtained in Reference Example 18, 6.8 g), 3- (N, N-dimethylamino) -1- (4-Chlorophenyl) -2- (2-chlorophenyl) -2-propene-1-one (10.9 g) and piperidine (578 mg) in acetic acid (13 mL) was stirred at 80 ° C overnight. the other.After cooling to room temperature, the reaction mixture was added with water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resulting crude product was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 85/15 to 70/30) to give 6- (2-chlorophenyl) - 7- (4-fluorophenyl) -3-ethoxycarbonyl-2-methylthiopyrazolo [1,5-a] pyrimidine (5.88 g, yield: 38%) as a yellow solid.

(2) To a solution of the compound obtained in the above step (1) (5.86 g) in methylene chloride (200 mL) was added 3-chloroperbenzoic acid (70%, 9.46 g) under cooling and the mixture was Stir at the same temperature for 10 minutes and at room temperature for 3 hours. To the reaction mixture was added an aqueous sodium thiosulfate solution. The mixture was stirred at room temperature and to it was added ethyl acetate and water. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resulting crystals were washed with frozen ethanol and dried to give 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3-ethoxycarbonyl-2-methylsulfonylpyrazolo [1,5-a] pyrimidine (5.52 g, yield: 88%) as a pale yellow solid.

(3) To a solution of the compound obtained in the above step (2) (1.0 g) in ethanol / tetrahydrofuran (26 mL / 30 mL) was added sodium ethoxide (1.66 g) and the mixture was refluxed under heating. . After cooling to room temperature, water and sodium acetate were added to the reaction mixture. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resulting product was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 80/20 to 40/60) to give 6- (2-chlorofenyl) - 7- (4-fluorophenyl) -2-ethoxy-3-ethoxycarbonylpyrazolo [1,5-a] pyrimidine (86 mg, yield: 9.2%) as a pale yellow solid.

MS (APCI) m / z; 456/458 [M + H] +

(4) The compound obtained in the above step (3) (455 mg) was treated in the same manner as described in Reference Example 1 (3) to give 3-carboxy-6- (2-chlorophenyl) -7- (4-fluorophenyl) -2-ethoxypyrazolo [1,5-a] pyrimidine (490mg) as a pale yellow solid.

MS (APCI) m / z; 428/430 [M + H] +

Reference Example 6

(1) A mixture of 1- (4-chlorophenyl) ethanone (13.1 g) and C-tert-butoxy-N, N, N ', N'-tetramethylmethylenediamine (16.3 g) was stirred at 60 °. C from one day to the next. After cooling to room temperature, the reaction mixture was concentrated in vacuo to give 1- (4-chlorophenyl) -3- (N, N-dimethylamino) -2-propen-1-one (18.4 g, yield: 100%) as a yellow solid.

MS (APCI) m / z; 210/212 [M + H] +

(2) To a solution of the compound obtained in the above step (1) (18.4 g) in methylene chloride (105 mL) was added dropwise bromine (13.6 g) over cooling over a period of 10 minutes and The mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added dropwise a solution of triethylamine (11.8 mL) in diethyl ether (130 mL) over a period of 5 minutes and the mixture was stirred for 2 hours. After warming to room temperature, the reaction mixture was filtered and to the residue was added methylene chloride (20 mL) and diisopropyl ether (50mL). After stirring for 1 hour, the resulting crystals were collected by filtration and vacuum dried to give 2-bromo-1- (4-chlorophenyl) -3- (N, N-dimethylamino) -2-propene-1-one (20.2 g, yield: 82%) as a pale yellow solid.

MS (APCI) m / z; 288/290 [M + H] +

(3) To a solution of the compound obtained in the above step (2) (20.2 g) and 3-amino-4-ethoxycarbonylpyrazole (10.9 g) in ethanol (65 mL) was added 25% hydrogen bromide solution. Acetic acid (13 mL) and the mixture was refluxed under heating for 1 hour. After cooling to room temperature, the reaction mixture was concentrated in vacuo and the residue was dissolved in chloroform (200 mL). The solution was washed with saturated aqueous sodium hydrogen carbonate solution and brine, and dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resulting crude product was purified by a silica gel column chromatography (solvent; ethyl acetate / chloroform = 0/100 to 10/90) and crystallized from diisopropyl ether to give 6-bromo-7. - (4-fluorophenyl) -3-ethoxycarbonylpyrazolo [1,5-a] pyrimidine (13.8 g, yield: 52%) as a colorless solid.

MS (APCI) m / z; 380/382 [M + H] +

(4) A solution of the compound obtained in the above step (3) (1.0 g), 2- (trifluoromethyl) phenylboronic acid (549 mg), [1,1'-bis (diphenylphosphium) ferrocene] palladium dichloride complex (11) Methylene chloride (77 mg) and potassium phosphate (1.55 g) in 1,4-dioxane (51 mL) was stirred at 80 ° C overnight and at 90 ° C for 1 h. 8 hours under nitrogen gas atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl comacetate and filtered. The filtrate was concentrated in vacuo and the residue was diluted with tetrahydrofuran (34 mL). To this was added an aqueous 1 N Ifthio hydroxide solution (16 mL) and the mixture was stirred at 55 ° C overnight. After cooling to room temperature, to the reaction mixture was added chloroform, water and 1 N aqueous HCl and the organic layer was separated. The organic layer was washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and the resulting product was recrystallized to give 3-carboxy-7- (4-chlorophenyl) 6- (2-trifluoromethylphenyl) pyrazolo [1,5-a] pyrimidine (370 mg, yield: 34% ) as a pale yellow solid.

MS (APCI) m / z; 418/420 [M + H] +

Reference Example 7

To a solution of the compound obtained in Reference Example 4 (3) (168 mg) in dimethylformamide (5 mL) was added pyrrolidine (50 µL) and potassium carbonate (138 mg) and the mixture was stirred at 160 ° C for 5 min. a microwave reactor. After cooling to room temperature, to the reaction mixture was added water and the mixture was stirred and extracted with methylene chloride. The extract was concentrated in vacuo and the resulting product was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 80/20 to 65/35) to give 6- (2-chlorophenyl) - 3-ethoxycarbonyl-7- (1-pyrrolidinyl) pyrazolo [1,5-a] pyrimidine (116 mg, yield: 63%) as a powder.

MS (APCI) m / z; 371/373 [M + H] +

Reference Example 7B

(1) The corresponding raw materials were treated in the same manner as described in Reference Example 4B and 4 (3) to 6- (2-chlorophenyl) -7-chloro-3-ethoxycarbonyl-2-methylpyrazolo [1,5-a ] pyrimidine.

(2) To a solution of the compound obtained in the above step (1) (300mg) in dimethylformamide (3 ml) was added thiomorpholine (103 µL) and potassium carbonate (237 mg) and the mixture was stirred at 80 ° C for 40 minutes. After cooling to room temperature, the reaction mixture was added water and the mixture was stirred and extracted with ethyl acetate. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resulting crude product was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 5/2) to give 6- (2-chlorophenyl) -7-thiomorpholino-3 -ethoxycarbonyl-2-methyl-pyrazolo [1,5-a] pyrimidine (324 mg, yield: 91%) as a powder.

MS (APCI) m / z; 417/419 [M + H] +

Reference Example 8

To a solution of the compound obtained in Reference Example 5 (1) (11.5 g) in ethanol / tetrahydrofuran (58 mL / 58 mL) was added a 2 N aqueous solution of sodium hydroxide (50.2 mL) and The mixture was stirred at 60 ° C for 8 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo. To the residue was added chloroform, brine and 2N aqueous HCl and the mixture was stirred (pH 2 to 3). The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the precipitated crystals were washed with diethyl ether to give 3-carboxy-6- (2-chlorophenyl) -7- (4-chlorophenyl) -2-methylthiopyrazolo [1,5-a] pyrazine. rimidine (11.1 g, yield: 100%) as a pale yellow solid.

MS (APCI) m / z; 430/432 [M + H] +

Reference Example 9

(1) To a solution of the compound obtained in Reference Example 1 (4) (2.0 g) in tert-butyl alcohol (15 mL) was added diphenyl phosphoryl azide (1.15 mL) and triethylamine (725 µL) and The mixture was stirred at 80 ° C overnight. After cooling to room temperature, to the browning mixture was added water and ethyl acetate and the mixture was stirred. The organic layer was washed with brine, dried over magnesium sulfate and filtered.

The filtrate was concentrated in vacuo and the resulting crude product was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 80/20 to 55/45) to give 3-tert-butoxycarbonylamino-6- (2- chloro-phenyl) -7- (4-chlorophenyl) pyrazolo [1,5-a] pyrimidine (1.0 g, yield: 42%) as a powder.

MS (APCI) m / z; 455/457 [M + H] +

(2) To a solution of the compound obtained in the above step (1) (1.0 g) in 1,4-dioxane (8 mL) was added 4 N HCl-1,4-dioxane (16 mL) and the mixture was added. stirred at room temperature for 1.5 hours. To the reaction mixture was added methanol (2 mL) and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was concentrated in vacuo and the residue crystallized from diisopropyl ether to give 3-amino-6- (2-chlorophenyl) -7- (4-chlorophenyl) pyrazolo [1,5-a] hydrochloride pyrimidine (809 mg, yield: 94%) as a pale orange powder.

MS (APCI) m / z; 355/357 [M + H] +

Reference Example 10

(1) To a solution of the compound obtained in Reference Example 1 (4) (300 mg) in methylene chloride (4.0 mg) was added N-tert -butoxycarbonylhydrazine (135 mL), water-soluble carbodiimide HCl (224 mL). mg), 1-hydroxybenzotriazole (179 mg) and triethylamine (326 mg) and the mixture was stirred at room temperature overnight. To the reaction mixture was added an aqueous solution of sodium hydrogen carbonate and methylene chloride and the mixture was stirred. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resulting crude product was purified by column chromatography over NH silica gel (Chromatorex NH silica gel / Fuji Silicia Chem., Solvent; hexane / ethyl acetate = 70/30 to 40/60 ) to give 3- (N'-tert -butoxycarbonylhydrazino) carbonyl-6- (2-chlorophenyl) -7- (4-chlorophenyl) pyrazolo [1,5-a] pyrimidine (379 mg, yield: 97 %) as a powder.

MS (APCI) m / z; 498/500 [M + H] +

(2) To a solution of the compound obtained in the above step (1) (345mg) in 1,4-dioxane (5 mL) was added 4 N HCl-1,4-dioxane (500 μΐ_) and the mixture was stirred at 40 ° C. ° C overnight. To the reaction mixture was added 2N HCl and the mixture was at 40 ° C for 8 hours. To the reaction mixture was added an aqueous solution of sodium hydrogen carbonate and methylene chloride and the mixture was stirred. The organic layer was extracted and the extract was dried and filtered. The filtrate was concentrated in vacuo and the resulting crude product was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 80/20 to 0/100) to give 3-hydrazino carbonyl. -6- (2-chlorophenyl) -7- (4-chlorophenyl) pyrazolo [1,5-a] pyrimidine (142 mg, yield: 52%) as a yellow gum. MS (APCI) m / z; 398/400 [M + H] +

Reference Example 11

(1) To a solution of the compound obtained in Example 33 (1.5 g) in dimethylformamide (20 mL) was added sodium azide (1.11 g) and the mixture stirred at 110 ° C overnight. After cooling to room temperature, the reaction mixture was a saturated brine and the mixture was stirred and extracted with ethyl acetate. The organic layer was washed with water and concentrated in vacuo and the resulting crude product was purified by column chromatography over silica gel (solvent; hexane / ethyl acetate = 80/20 to 30/70) to give 2-azide. -6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- (N-cyclopentylcarbampyl) pyrazolo [1,5-a] pyrimidine (1.15 g, a yellow viscosity). To a solution of the product (870 mg) in tetrahydrofuran (16mL) was added triphenylphosphine (896 mg) and the mixture was stirred at 40 ° C for 1 hour. After cooling to room temperature, the darning mixture was concentrated in vacuo and the resulting crude product was purified by column chromatography over silica gel (solvent; chloroform / methanol = 100/0 to 97/3) to give 6- ( 2-chlorophenyl) -7- (4-chlorophenyl) -2-triphenylphosphoranylidene-pyrazolo [1,5-a] pyrimidine (942 mg, yield: 58%) as a yellow solid

MS (APCI) m / z; 726/728 [M + H] +

Reference Example 12

(1) 7-Chloro-6- (2-chlorophenyl) -3-ethoxycarbonylpyrazolo [1,5-a] pyrimidine (1 g) was treated in the same manner as described in Reference Example 4 (5) to give 6 - (2-chlorophenyl) -3-ethoxycarbonyl-7- (4-formylphenyl) pyrazo [1,5-a] pyrimidine (910 mg) as a pale yellow powder.

MS (APCI) m / z; 428/430 [M + H] +

(2) To a solution of the compound obtained in the above step (1) (406 mg) in methylene chloride (1 mL) was added bis- (2-methoxy) trifluoride.

xylethyl) amino sulfur (trade name: Deoxo-Fluor, Scott Inc.) (184 μΙ_) and the mixture was stirred at room temperature for 4 hours. The organic layer was washed with brine and extracted with methylene chloride. The extract was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and the resulting crude product was purified by a silica gel column chromatography (solvent; hexane / ethyl acetate = 70/30 to 60/40) to give 6- (2-chlorophenyl) -7- ( 4-Difluoromethylphenyl) -3-ethoxycarbonylpyrazolo [1,5-a] pyrimidine (25 mg, yield: 37%) as a pale yellow solid.

MS (APCI) m / z; 428/430 [M + Hf (3) The compound obtained in the above step (2) (278 mg) was treated in the same manner as described in Reference Example 1 (3) to give 3-carboxy-6- (2-chlorophenyl) - 7- (4-difluoromethylphenyl) pyrazolo [1,5-a] pyrimidine (223mg, yield: 86%) as a pale yellow solid.

MS (APCI) m / z; 400/402 [M + H] +

Reference Example 13

(1) To a solution of tetrahydro-4H-thiopyran-4-one (2.32 g) in e-tanol (100 mL) was added sodium acetate (3.28 g) and hydroxylamine HCl (1.81 g ) at room temperature and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was concentrated in vacuo and to the residue was added ethyl acetate and an aqueous sodium hydrogen carbonate solution. After stirring, the mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to give 4-hydroxyimino-tetrahydro-4H-thiopyran (2.53 g, yield: 96%) as a colorless solid.

MS (APCI) m / z; 132 [M + H] +

(2) To a solution of the compound obtained in the above step (1) (500mg) in diethyl ether (10mL) was added lithium aluminum hydride (289mg) under nitrogen gas atmosphere and freezing and the mixture was stirred at the same temperature for 2 hours. 30 minutes and at room temperature for 1 hour. To the reaction mixture was added lithium aluminum hydride (72 mg) and the mixture was stirred at 40 ° C for 2 hours. To the reaction mixture was added water (1 mL) and 2 N aqueous sodium hydroxide solution (1 mL) at room temperature and the mixture was stirred and filtered. The filtrate was concentrated in vacuo to give 4-amino-tetrahydro-4H-thiopyran (150 mg, yield: 34%) as a yellow fluid.

MS (APCI) m / z; 118 [M + H] +

Reference Example 14A

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

MS (APCI) m / z; 222 [M + H] +

(2) To a solution of the compound obtained in the above step (1) (3.94 g) in acetic acid (65 mL) was added concentrated hydrochloric acid (7.7 mL) and the mixture was refluxed under heating one day to the other. After cooling to room temperature, the reaction mixture was concentrated in vacuo. To the residue was added an aqueous solution of sodium hydroxide (50 mL) and chloroform (100 mL) and the mixture was stirred. To the organic layer was added magnesium sulfate and silica gel and the mixture was stirred and filtered. The filtrate was concentrated in vacuo and the resulting crude product was washed with isopropyl ether and dried to give (R) -N- (tetrahydrothiophen-3-yl) benzamide (2.80 g, yield: 76%) as a colorless solid.

MS (APCl) m / z; 208 [M + H] +

(3) To a solution of the compound obtained in the above step (2) (3.59 g) in methylene chloride (70 mL) was gradually added 3-chloroperbenzoic acid (75%, 10 g) under cooling and the mixture was stirred at room temperature overnight. To the reaction mixture was added water (35 mL), sodium sulfite (3.5 g) and a saturated aqueous sodium hydrogen carbonate solution (100 mL) and the mixture was stirred for 30 minutes and extracted with chloroform. The extract was washed with an aqueous saturated sodium hydrogen carbonate solution and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and the resulting solid materials were washed with ethyl acetate to give (R) -N- (1,1-dioxo-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 obtained in the above step (3) (3.51 g) in ethanol (13 mL) was added 6 N HCl (52 mL) and the mixture was refluxed under heating for 1 day. After cooling to room temperature, the aqueous layer was washed with ethyl acetate and concentrated in vacuo. Precipitated solid materials were washed with ethanol / diethyl ether, collected by filtration and further washed with diethyl ether to give (R) -N- (1,1-dioxo-tetrahydrothiophen-3-yl) amine hydrochloride (2.52 g, yield: 100%) as a colorless solid.

MS (APCI) m / z; 136 [M + H] +

Reference Example 14B (S) -MetioninoI (4.83 g) was treated in the same manner as described in Reference Example 14A to give (S) -N- (1,1-dioxo-tetrahydro-phenyl-3-yl) amine hydrochloride (3.86 g,) as a colorless solid.

MS (APCI) m / z; 136 [M + H] +

Reference Example 15

(1) To a solution of 4,4-difluoropiperidine hydrochloride (2.0 g) in water was added 2 N sodium hydroxide (7.6 ml) and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added sodium nitrit (1.75 g) at room temperature and acetic acid (1.27 mL) was added under cooling, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added an aqueous sodium hydrogen carbonate solution and the mixture was extracted with chloroform. The extract was dried over magnesium sulfate and filtered, and the filtrate was concentrated in vacuo. The resulting crude product was purified by column chromatography over silica gel (solvent; hexane / ethyl acetate = 4/1) to give 4,4-difluoro-1-nitrosopiperidine (1.89 g, yield: 99%) as a solid pale yellow.

MS (APCI) m / z; 151 [M + H] +

(2) To a solution of the compound obtained in the above step (1) (1.89 g) in tetrahydrofuran was added in portions of lithium aluminum hydride (837 mg) under cooling and the mixture was refluxed under heating for 1 hour. To the reaction mixture was added water under cooling and the mixture was refluxed under heating for 30 minutes. After cooling to room temperature, the reaction mixture was filtered and the filtrate concentrated in vacuo. To the residue was added an aqueous solution of sodium hydrogen carbonate and chloroform and the mixture was stirred. The organic layer was dried over sodium sulfate and filtered and the filtrate was concentrated in vacuo to give 1-amino-4,4-difluoropiperidine (500 mg, yield: 29%) as a pale yellow oil.

MS (APCI) m / z; 137 [M + H] +

Reference Example 16

(1) To a solution of 3-fluoromethoxyphenylmethylamine (278 mg) in water (400 μΐ_) was added acetic acid (125 μΙ_) and a solution of disodium nitrite (201 mg) in water (600 μΙ_) under cooling and the mixture was stirred. . To this was added methanol (500 µl) and tetrahydrofuran (500 µl) and the mixture was stirred at room temperature overnight. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution and the mixture was stirred and extracted with ethyl acetate. The extract was concentrated in vacuo and the resulting crude product was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 100/0 to 87/13) to give N- (3-trifluoromethoxyphenyl) methyl nitrosoamine (282 mg, yield: 88%) as a pale yellow oil.

MS (APCI) m / z; 192 [M + H] +

(2) To a solution of lithium aluminum hydride (82.7 mg) in tetrahydrofuran (5 mL) was added a solution of the compound obtained in the above step (1) (282 mg) in tetrahydrofuran (2.5 mL) under cooling and The mixture was stirred at room temperature for 1 hour under a nitrogen gas atmosphere. To the reaction mixture was added water (90 μΙ_), a 15% aqueous solution of sodium hydroxide (90 μΙ_) and water (180 μΙ_) and the mixture stirred and filtered. The filtrate was concentrated in vacuo and the resulting crude product was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 85/15 to 65/35) to give N-methyl-N- ( 3-trifluorome-toxiphenyl) hydrazine (187 mg, yield: 71%) as an orange viscosity.

MS (APCI) m / z; 207 [M + H] +

Reference Example 17

To a solution of tetrahydro-4H-thiopyran-4-one (500 mg) in water ethanol (10 mL / 10 mL) was added potassium cyanide (1.4 g) and ammonium chloride (1.15 g) and the mixture It was stirred at room temperature for 4 days. To the reaction mixture was added diethyl ether and 1 N aqueous sodium hydroxide solution and the mixture was stirred. The organic layer was separated and the aqueous layer was extracted with diethyl ether and ethyl acetate. The combined organic layer was dried over calcium chloride and filtered. The filtrate was concentrated in vacuo and the resulting crude product was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 70/30 to 30/70) to give 4-amino-4-cyano-tetrahydro-4H- thiopyran (315 mg) as a colorless solid.

Reference Example 18

A solution of ethyl 2-cyano-3,3-bismethylthioacrylate (40 g), hydrazine chlorochloride (12.6 g) and sodium acetate (22.6 g) in ethanol was stirred at 90 ° C for 2 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo. To the residue was added water and ethyl acetate and the organic layer was separated, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was added with ethyl acetate and hexane. Precipitated solid materials were collected by filtration and dried to give 5-amino-4-ethoxycarbonyl-3-methylthio-1H-pyrazole (17.4 g, yield: 47%) as a colorless solid. Reference Examples 19 to 20

3-Carboxy-6- (2-chlorophenyl) -7- (4-trifluoromethoxyphenyl) pyrazolo [1,5-a] pyrimidine or 3-carboxy-6- (2-chlorophenyl) -7- (4-trifluoromethylphenyl) pyrazole [1,5-a] pyrimidine was treated in the same manner as described in Reference Example 10 to give the following compound.

(Ex. Ref. 19) 3-Hydrazinocarbonyl-6- (2-chlorophenyl) -7- (4-trifluoro-methoxy-phenyl) pyrazolo [1,5-a] pyrimidine; MS (APCI) m / z; 448/450 [M + H] +

(Ex. Ref. 20) 3-Hydrazinocarbonyl-6- (2-chlorophenyl) -7- (4-trifluoromethylphenyl) pyrazolo [1,5-a] pyrimidine; MS (APCI) m / z; 432/434 [M + H] + Reference Examples 21 to 40

Corresponding raw materials were treated in the same manner as described in any of Reference Examples 1, 4 and 6 to give the compound as shown in the following Table B1.Table Β1 (No. 1)

<table> table see original document page 159 </column> </row> <table> Table Β1 (N ° 2)

<table> table see original document page 160 </column> </row> <table> Table Β1 (N ° 3)

<table> table see original document page 161 </column> </row> <table>

Table B1 (# 4)

<table> table see original document page 161 </column> </row> <table>

Reference Examples 41 to 45

Corresponding raw materials were treated in the same manner as described in Reference Example 7 to give the compost as shown in the following Table B2.Table B2

<table> table see original document page 162 </column> </row> <table>

Reference Example 46

(1) To a solution of 5-nitropyrazole-3-carboxylic acid (19.9 g) in ethanol (200 mL) was added dropwise thionyl chloride (9.7 mL) over a period of 5 minutes and the mixture was refluxed. for 4 hours. After cooling to room temperature, the reaction mixture was diluted with water (25 mL) and ethanol (50 mL) and the mixture was neutralized with sodium hydrogen carbonate (54 g). The mixture was filtered and the residue was washed with ethanol. The filtrate and washings were combined and concentrated in vacuo. The residue was azeotropically distilled with ethanol and the residue was dissolved in ethyl acetate, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and to the residue was added isopropyl ether. Precipitates were collected by filtration and washed with ethyl acetate / isopropyl ether (1/2) to give ethyl 5-nitropyrazole-3-carboxylate (20 g, yield: 85%) as a colorless solid.

MS (APCI): 186 [M + H] +

(2) To a solution of the compound obtained in the above step (1) (22.5 g) in acetic acid (130 mL) and tetrahydrofuran (130 mL) was added 10% palladium carbon (4.1 g) and the mixture was added. stirred under hydrogen gas atmosphere for 4 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. To the residue was added hexane and the mixture was stirred and decanted to remove hexane. To the residue was added ether / diisopropyl ether (1/1) and precipitates were collected by filtration to give

Ethyl 5-aminopyrazole-3-carboxylate (17.2 g, yield: 91%) as a colorless solid.

MS (APCI): 156 [M + H] + Reference Example 47

(1) To a solution of 2 - [(cyano) (ethoxycarbonyl) vinyl] -1,3-dioxolane (2.0 g) in ethanol (20 mL) was added hydrazine hydrochloride (748 mg) and sodium acetate (1 , 34 g) and the mixture was stirred at 80 ° C (external temperature) for 1 hour. After cooling to room temperature, the

The reaction mixture was filtered through Cerite and the filtrate was concentrated in vacuo. The resulting crude product was purified by column chromatography over silica gel (solvent; chloroform / methanol = 100/0 to 85/15) to 3-amino-4-ethoxycarbonyl-5- (2-hydroxy) ethoxypyrazole (2.01 g, yield: 86%) as a light pink solid. MS (APCI) m / z; 216 M + H] +

(2) To the compound obtained in the above step (1) (2.65 g) and 3- (N, N-dimethylamino) -1- (4-chlorophenyl) -2- (2-chlorophenyl) -2-propen 1-one (cf. Reference Example 1 (2)) Ethanol (20 mL) and 21% sodium ethoxide in ethanol (5 mL) were added and the mixture was stirred at room temperature for 15 minutes.

To the reaction mixture was added ethyl acetate and water and the mixture was acidified with 2 N HCl and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over filtered magnesium sulfate. The filtrate was concentrated in vacuo and the resulting crude product purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 72/28 to 30/70) and triturated in diethyl ether to give

6- (2-chlorophenyl) -7- (4-chlorophenyl) -3-ethoxycarbonyl-2- (2-hydroxyethoxy) pyrazolo [1,5-a] pyrimidine (2.25 g, yield: 39%) as a solid colorless.MS (APCI) m / z; 472/474 M + H] +

(3) To a solution of the compound obtained in the above step (2) (100mg) in acetonitrile (10 mL) was added silver oxide (1) (320 mg) and methyliodide (350 μl) and the mixture was stirred at room temperature. environment for 3 days. The reaction mixture was filtered through Cerite and the filtrate was concentrated in vacuo. The resulting crude product was purified by a silica gel column chromatography (solvent; hexane / ethyl acetate = 80/20 to 50/50) to give 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3-ethoxycarbonyl-2- (2-methoxy-ethoxy) pyrazolo [1,5-a] pyrimidine (98.6 mg, yield: 96%) as an in-color powder.

MS (APCI) m / z; 486/488 M + H] +

(4) The compound obtained in the above step (3) (98 mg) was treated in the same manner as described in Reference Example 1 (3) to give 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3-carboxy -2- (2-hydroxyethoxy) pyrazolo [1,5-a] pyrimidine (92 mg, yield: 99%) as a colorless powder.

MS (APCI) m / z; 458/460 M + H] +

Reference Example 48

(1) To a solution 1,3-dibromo-2,2-dimethoxypropane (26.45 g) in dimethyl sulfoxide (200 mL) was added sodium sulfate (9.46 g) and the mixture stirred at 110 to 140 ° C ( outside temperature) for 30 minutes. The reaction mixture was diluted with cooling diethyl ether and to it was added a saturated aqueous sodium hydrogen carbonate solution and water. The mixture was extracted with diethyl ether (x 2). The organic layer was washed with saturated brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resulting crude product was purified by silica gel column chromatography (solvent; hexane / diethyl ether = 100/0 to 15/1) to give 3,3-dimethoxycyclobutane (10.55 g, yield : 78%) as a pale yellow liquid.

MS (APCI) m / z; 103 [M + H-MeOH] +

(2) To a solution of the compound obtained in the above step (1) (9.0 g) in acetone (70 mL) was added ion exchange resin (Amberlyt 15E, 3.5g) and the mixture was stirred at room temperature for 2 hours. 21 hours. The reaction mixture was filtered through Cerite and the residue was washed with acetone. The filtrate was filtered and the washings were combined and concentrated in vacuo. Precipitates were collected by filtration and washed with cooled hexane to give 3-oxothiaciclobutane (1.58 g, yield: 27%) as colorless crystals.

(3) To a solution of the compound obtained in the above step (2) (100mg) in ethanol (3ml) was added hydroxylamine hydrochloride (236mg) and sodium carbonate (360mg) and the mixture was refluxed under heating for 17 hours. After cooling to room temperature, an aqueous solution of sodium hydrogen carbonate and water were added to the reaction mixture. The mixture was extracted with chloroform. The organic layer was concentrated in vacuo and the resulting crude product was purified by column chromatography over silica gel (solvent; hexane / diethyl ether = 90/10 to 50/50) to give 3-hydroxyiminothiaciclobutane (93 mg, yield: 80%). ) as a colorless solid.

(4) To a solution of lithium aluminum hydride (58 mg) in tetrahydrofuran (2 mL) was added dropwise a solution of the compound obtained in the above step (3) (93 mg) in tetrahydrofuran (1.5 mL). ) under nitrogen gas cooling and atmosphere. The mixture was stirred at room temperature for 1 hour. Successively water (60 μL), 15% sodium hydroxide solution (60 μί) and water (120 μί) under cooling were added to the reaction mixture and the mixture was stirred at room temperature and filtered through Cerite. The filtrate was concentrated in vacuo to give 3-amino-thiaciclobutane as crude product.

(1) To a solution of sodium ethoxide (14.32 g) in ethanol (20 mL) was added ethyl cyanoacetate (4.7 mL) and the mixture was stirred at room temperature for 1 hour. . To the reaction mixture was added difluoroacetic acid (4.85 mL) and the mixture was stirred at room temperature for 4 hours and then stirred at 60 ° C (external temperature) for 17 hours. The reaction mixture was concentrated in vacuo and to the residue was added toluene (10 mL) and phosphorus chloride (3.2 g) and the mixture was stirred at 45 ° C for 1 hour. To the reaction mixture was added phosphorus chloride (1.9 g) and the mixture was stirred at 55 ° C for 2 hours. The reaction mixture was cooled with ice filtered through Cerite and the filtrate was concentrated in vacuo. To the residue was added ethanol (20 mL), hydrazine monohydrate (0.8 mL) and triethylamine (3.0 mL) and the mixture was stirred at 60 ° C for 2 hours. After cooling to room temperature, a saturated aqueous solution of sodium hydrogen carbonate and water were added to the reaction mixture. The mixture was extracted with chloroform (x 4) and the organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resulting crude product was purified by column chromatography over silica gel (solvent; chloroform / methanol = 100/0 to 94/6) and washed with chloroform to give 3-amino-4-ethoxycarbonyl. Difluoromethylpyrazole (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 1 (2) to (3) to 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 50

(1) To a solution of methyl cyanoacetate (14.6 g) in methylene chloride (260 mL) was added trifluoroacetic anhydride (37.2 g) and the mixture was stirred at room temperature. To the mixture was added droplet triethylamine (51.7 mL) at 0 ° C and the mixture was stirred at room temperature overnight. To the reaction mixture was added water and the mixture extracted with methylene chloride. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give methyl 2-cyano-2- (2-trifluoroacetyl) acetate (compound 2a) and methyl 2-cyano-4,4,4-trifluoro-3-trifluoromethoxycarbonyl-2-butenoate (compound 2b) as a mixture (55.3 g).

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

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

(2) To a solution of the mixture of compound 2a and 2b (27.6 g) in methylene chloride (200 mL) was added dropwise oxalyl chloride (31.6 mL) and a few drops of pyridine and the mixture was refluxed under - heating for 4 hours. The reaction mixture was poured into water gradually and the mixture was extracted with methylene chloride. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to methyl 2-cyano-3-chloro-4,4,4-trifluoro-2-butenoate as a crude product.

(3) To the compound obtained in the above step (2) was added water (20 mL) and to it was added dropwise hydrazine monohydrate (80%, 6.74 g) at 0 ° C. To the mixture was added triethylamine (2 mL) at room temperature and the mixture was stirred for 1 hour. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was added chloroform and precipitates were collected by filtration to 3-amino-4-ethoxycarbonyl-5-trifluoromethylpyrazole (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 1 (2) to (3) to 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 51

(1) To a solution of 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3-ethoxycarbonyl-2-methylpyrazolo [1,5-a] pyrimidine (1.50 g: correspondingly decomposed ethyl ester obtained in Reference Example 39) in carbon tetrachloride (20mL) was added N-bromosuccinimide (1.88 g) and 2,2'-azobisisobutyl nitrile (30 mg). The mixture was stirred at 85 ° C (external temperature) for 26 hours. After cooling to room temperature, the reaction mixture was filtered through Cerite and the filtrate was concentrated in vacuo. The resulting product was purified by column chromatography over silica gel (solvent; hexane / diethyl ether = 85/15 and 67/33) to give 2-bromomethyl-6- (2-chlorophenyl) -7- (4- chlorophenyl) -3-ethoxycarbonylpyrazolo [1,5-a] pyrimidine (827 mg, yield: 47%) as a pale yellow solid.

MS (APCI) m / z; 504/506 [M + H] +

(2) To a solution of the compound obtained in the above step (1) (825mg) in methanol / tetrahydrofuran (7 mL / 4 mL) was added 28% sodium methoxide-methanol solution (3 mL) and the mixture was stirred in ambient temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and water was added thereto. The mixture was extracted with ethyl acetate and the organic layer was washed with saturated brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resulting product was purified by column chromatography over silica gel (solvent; hexane / ethyl acetate = 75/25 to 60/40) to give 6- (2-chlorophenyl) -7- ( 4-Chlorophenyl) -3-methoxycarbonyl-2-methoxymethylpyrazolo [1,5-a] pyrimidine (404 mg, yield: 56%) as a pale yellow solid.

MS (APCI) m / z; 442/444 [M + H] +

(3) The compound obtained in the above step (2) (404 mg) was treated in the same manner as described in Reference Example 1 (3) to give 3-carboxy-6- (2-chlorophenyl) -7- (4-chlorophenyl) -2-methoxymethylpyrazolo [1,5-a] pyrimidine (367 mg, yield: 94%) as a colorless solid.

MS (APCI) m / z; 428/430 [M + H] +

Reference Example 52

(1) Dimethylformamide (75 mL) was added sodium hydride (60%, 6.77 g) under a nitrogen gas atmosphere and to it was added dropwise a solution of ethyl cyanoacetate (9.57 g) in dimethylformamide ( 15mL) over a period of 15 minutes and the mixture was stirred at room temperature for 10 minutes. To the mixture was added dropwise a solution of carbon disulfide (5.09 mL) in dimethylformamide (12 mL) under cooling at 0 ° C (internal temperature ≤ 10 ° C) over a period of 20 minutes. The mixture was stirred at room temperature overnight and to the reaction mixture was added dropwise a solution of debenzyl bromide (20.1 mL) in dimethylformamide (23 mL) under cooling at 0 ° C (internal temperature ≤ 25 ° C) and the mixture was stirred at 70 ° C for 7 hours and then stirred at room temperature overnight. The browning mixture was poured into ice water and the mixture was stirred. The precipitates were collected by filtration, recrystallized from hot ethanol and washed with cooled ethanol to give ethyl 2-cyano-3,3-bisbenzylthioacrylate (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 / ethanol (16 mL / 41 mL) was added a solution of hydrazine demonidate (2.04 g) in ethanol (18 mL). ) over a period of 5 minutes and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was crystallized from diisopropyl ether / hexane. Precipitated crystals were collected by filtration and washed to give 3-amino-4-ethoxycarbonyl-5-benzylthio pyrazole (9.45 g, yield 84%) as a colorless solid.

MS (APCI) m / z; [M + H] + (3) The compound obtained in the above step (2) (8.15 g) was treated in the same manner as described in Reference Example 5 (1) to give 2-benzylthio-6- (2-chlorophenyl ) -7- (4-chlorophenyl) -3-ethoxycarbonylpyrazolo [1,5-a] pyrimidine (8.24 g, yield: 51%) as a pale yellow solid.

MS (APCI) m / z; 534/536 [M + H] + Reference Example 53

(1) The compound obtained in Reference Example 33 (3.0 g) was nitrate in the same manner as described in Reference Example 9 (1) to give 6- (2-chlorophenyl) -7- (4-trifluoromethylphenyl) -3 - (tert-butoxycarbonylamino) pyrazolo [1,5-a] pyrimidine (1.06 g, yield: 30%) as an orange powder.

MS (APCI) m / z; 489/491 [M + H] +

(2) To a solution of the compound obtained in the above step (1) (1.06 g) in dioxane (5 mL) was added 4 N HCl-dioxane (10 mL) and the mixture stirred at room temperature for 7 hours. The reaction mixture was concentrated in vacuo and a saturated aqueous sodium hydrogen carbonate solution was added to the residue. The mixture was extracted with chloroform and the organic layer was concentrated in vacuo. The resulting crude product was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 70/30 to 40/60) to give 3-amino-6- (2-chlorophenyl) -7 - (4-trifluoromethylphenyl) pyrazolo [1,5-a] pyrimidine (850 mg, yield: 80%) as a pale yellow solid.

MS (APCI) m / z; 389/391 [M + H] +

Reference Example 54

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

(2) The compound obtained in the above step (1) (3.0 g) and 3-amino-5-methylpyrazole (977 mg) were treated in the same manner as described in Reference Example 1 (2) to give 6- ( 2-chlorophenyl) -7- (4-trifluoromethylphenyl) -2-methyl-pyrazolo [1,5-a] pyrimidine (2.63 g, yield: 67%) as a brown oil.

MS (APCI) m / z; 388/390 [M + H] +

(3) To a solution of the compound obtained in the above step (2) (2.27 g) in chloroform (50 mL) was added dropwise chlorosulfonic acid (1.35 mL) and the mixture was stirred at 70 ° C. ° C for 3.5 hours. The reaction mixture was concentrated in vacuo and to the residue was added thionyl chloride (20 mL) and the mixture was refluxed under heating for 2 hours. The reaction mixture was concentrated in vacuo and to the residue was added ice water and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and the resulting product was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 85/15 to 60/40) to give 6- (2-chlorophenyl) -7- ( 4-Tri-fluoromethylphenyl) -3-chlorosulfonyl-2-methylpyrazolo [1,5-a] pyrimidine (2.71 g, yield: 95%) as a pale yellow solid.

MS (APCI) m / z; 486/488 [M + H] +

Reference Example 55

(1) To a solution of ethyl potassium malonate (465 mg) in

acetonitrile (3.5 mL) was added magnesium chloride (309 mg) and triethylamine (580 μl) and the mixture was stirred at room temperature for 2 hours (solution A). To a solution of the compound obtained in Reference Example 1 (500 mg) in acetonitrile (3 mL) was added carbonyldiimidazole (232 mg) and tetrahydrofuran (2 mL) at room temperature and the mixture was stirred at the same temperature for 2 hours. To the reaction mixture was added solution A obtained above at room temperature and the mixture was stirred for 4 hours. To the reaction mixture was added 2 N HCl and the mixture was extracted with ethyl comacetate. The organic layer was washed with water and a saturated brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resulting crude was purified by column chromatography over silica gel (solvent; hexane / ethyl acetate = 90/10 to 75/25) paradar 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- (2-ethoxycarbonylacetyl) pyrazolo [1,5-a] pyrimidine (488 mg, yield: 83 %).

MS (APCI) m / z; 454/456 [M + H] +

(2) To a solution of the compound obtained in the above step (1) (475mg) in ethanol / tetrahydrofuran (2.5 mL / 2.5 mL) was added a 2 N aqueous solution of sodium hydroxide (1.05 mL). and the mixture was stirred at 60 ° C for 1 hour. To the reaction mixture was added 2N aqueous sodium hydroxide solution (1.05 mL) and ethanol (2.5 mL) and the mixture was stirred at the same temperature for 18 hours. After cooling to room temperature, a 2 N aqueous HCl (2.1 mL) was added to the reaction mixture and the mixture was diluted with ethyl acetate. To the solution was added water and the mixture was extracted with ethyl acetate. The organic layer was concentrated in vacuo and the resulting crude product was purified by column chromatography over silica gel (solvent; hexane / ethyl acetate = 80/20 to 70/30) to give 3-acetyl-6- (2-chlorophenyl) -7. - (4-chlorophenyl) pyrazolo [1,5-a] pyrimidine (233 mg, yield: 58%) as a pale yellow solid.

MS (APCI) m / z; 382/384 [M + H] + Reference Example 56

(1) The corresponding raw materials were treated in the same manner as described in Reference Example 2 (1) to give

(2-chlorobenzyl) (5-chlorothiophen-2-yl) methanone (5.06 g, yield: 61%).

(2) The compound obtained in the above step (1) (2.92 g) was treated in the same manner as described in Reference Example 1 (2) to give 3- (N, N-dimethylamino) -2- (2-chlorophenyl) -1- (5-chlorothiophen-2-yl) -2-propen-1-one as a crude product.

(3) To a solution of the compound obtained in the above step (2) in acetic acid (2 mL) was added 3-amino-4-ethoxycarbonyl-5-methylpyrazole (1.3g) and piperidine (153 μΙ_) and the mixture was stirred. at 80 ° C overnight. To the reaction mixture was added acetic acid (3 mL) and toluene (30 mL) and the mixture was stirred at the same temperature for 7 hours. After cooling to room temperature, to the reaction mixture was added a saturated aqueous solution of sodium hydrogen carbonate under cooling. The mixture was extracted with ethyl acetate and the organic layer was washed successively with water and a saturated brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the precipitates were collected by filtration and washed with diethyl ether. The filtrate was purified by column chromatography over silica gel (solvent; hexane / ethyl acetate = 80/20 to 60/40) and the eluted fraction was concentrated. The precipitates were washed with ethyl acetate / hexane (1/10) and combined with the precipitates mentioned above to give 6- (2-chlorophenyl) -7- (5-chlorothiophen-2-yl) -3-ethoxycarbonyl--

2-methylpyrazolo [1,5-a] pyrimidine (1.52 g, two-step yield: 45%) as a yellow solid.

MS (APCI) m / z; 432/434 [M + H] +

(4) The compound obtained in the above step (3) (1.51 g) was treated in the same manner as described in Reference Example 1 (3) to give

3-carboxy-6- (2-chlorophenyl) -7- (5-chlorothiophen-2-yl) -2-methylpyrazolo [1,5-a] pyrimidine (1.18 g, yield: 84%) as a yellow solid.

MS (APCI) m / z; 404/406 [M + H] +

Reference Example 57

(1) The corresponding raw materials were treated in the same manner as described in Reference Example 4 (1) to (4) to 6- (2-chlorophenyl) -7-chloro-3-ethoxycarbonylpyrazolo [1,5-a] pyrimidine .

(2) To a solution of the compound obtained in the above step (1) (672mg) in tetrahydrofuran (6ml) was added palladium acetate (2.2mg), 2-dicyclohexylphosphino-2'6'-dimethoxybiphenyl (4 0.1 mg), potassium phosphate trihydrate (1.27 g) and water (120 µl) under a nitrogen gas atmosphere and the mixture was stirred at room temperature for 2 hours and then stirred at 100 ° C for 24 hours. After cooling to room temperature, to the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1N aqueous sodium hydroxide solution, water and a saturated brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resulting product was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 80/20 to 50/50). The eluted fraction was concentrated and the precipitates were washed with diethyl ether / hexane to para 6- (2-chlorophenyl) -7- (4-dimethylamino-phenyl) -3-ethoxycarbonylpyrazolo [1,5-a] pyrimidine (288 mg, yield: 34%) as a yellow powder.

MS (APCI) m / z; 421/423 [M + Hf

Reference Example 58

The compound obtained in Example 440 (0.67 g) was treated in the same manner as described in Reference Example 1 (3) to give 3-carboxy-6- (2-chlorophenyl) -7- (4-trifluoromethylphenyl) -2- [ N-methyl-N- (methylsulfonyl) amino] pyrazolo [1,5-a] pyrimidine (0.64 g) as a crude product (powder).

MS (APCI) m / z; 525/527 [M + H] +

Reference Example 59

(1) The compound obtained in Reference Example 51 (1) (200 mg) in dimethyl sulfoxide (2 mL) was added sodium thiomethoxide (15 mg) and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The extract was concentrated in vacuo and the resulting crude was purified by column chromatography over silica gel (solvent; hexane / ethyl acetate = 87/13 to 60/40) to give 6- (2-chlorophenyl) -7- (4-Trifluoromethylphenyl) -3-ethoxycarbonyl-2-methylthiopyrazolo [1,5-a] pyrimidine (170 mg, yield: 91%) as a pale a-yellow solid.

MS (APCI) m / z; 472/474 [M + H] +

(2) The compound obtained in the above step (1) (170 mg) was treated in the same manner as described in Reference Example 1 (3) to give 3-carboxy-6- (2-chlorophenyl) -7- (4-trifluoromethylphenyl) -2-methylthiomethylpyrazolo [1,5-a] pyrimidine as a pale yellow powder.

MS (APCI) m / z; 444/446 [M + H] +

Reference Example 60

(1) To a solution of 1-benzyloxycarbonyl-3-pyrroline (5.0 g) in methylene chloride (125 mL) was added m-chloroperbenzoic acid (12.17 g) and the mixture was stirred at room temperature for 3 days. To the mixture was added a saturated aqueous sodium thiosulfate solution.

HCl (100 mL) and the mixture was stirred for 30 minutes. The reaction mixture was extracted with chloroform (x 2) and the organic layer was washed successively with a 2N aqueous sodium hydroxide solution (100 mL χ 2) and saturated brine, dried over magnesium sulfate and concentrated to vacuum. give benzyl 6-oxa-3-azabicyclo [3,1,0] hexane-3-carboxylate (5.58 g, yield: 100%) as an oil.

MS (APCI) m / z; 220 [M + H] +

(2) A mixture of the compound obtained in the above step (1) (26.5 g), (1R, 2R) - (-) - [1,2-cyclohexanediamino-N, N'-bis (3,5-hydroxy) chloride di-tert-butylsalicylidene) chromium (1.57 g) and trimethylsilylazide (17.7 mL) was stirred at room temperature for 2 days. To the reaction mixture was added chloroform and the mixture was washed successively with water and a saturated brine and dried over magnesium sulfate. The organic layer was concentrated in vacuo and the residue was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 10/1 to 2/1 - »chloroform / methanol = 20/1 to 9/1) to give (3S, 4S) -4-azido-1-benzyloxycarbonyl-3-trimethylsilyloxypyrrolidine (as at: 20.6 g, yield: 55%) and (3S, 4S) -4-azido-1-benzyloxycarbonyl -3-hydroxypyrrolidine (compound b: 8.16 g, yield: 28%) as an oil, respectively.

Compound a: MS (APCI) m / z; 335 [M + H] +

Compound b: MS (APCI) m / z; 263 [M + H] +

(3) To a solution of compound a (20.6 g) and compound b (8.16 g) in tetrahydrofuran (740 mL) was added triphenylphosphine (26.67 g) and the mixture was stirred at room temperature overnight. the other. The reaction mixture was concentrated in vacuo and to the residue was added methanol (380 mL) and 0.5 N aqueous sodium hydroxide solution (380 mL) and the mixture stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and to the residue was added 6N aqueous HCl (pH3). The mixture was washed with chloroform and the aqueous layer was basified (pH9) with 5% aqueous sodium hydroxide solution. The mixture was extracted with chloroform (x 3) and the organic layer was dried over magnesium sulfate and concentrated in vacuo to give (3S, 4S) -4-amino-1-benzyloxycarbonyl-3-hydroxypyrrolidine (19.6 g, yield : 90%) as an oil

MS (APCI) m / z; 237 [M + H] +

(4) To a solution of the compound obtained in the above step (3) (14.61 g) in chloroform (135 mL) was added dropwise a solution of di-tert-butyl dicarboxylate (16.18 g) in Chloroform (20 mL) under cooling and mixing was stirred at room temperature for 2 hours. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (100 mL) and the mixture was stirred. The mixture was extracted with chloroform and the organic layer was dried over magnesium sulfate. To this was added NH-silica gel (2 g) and the mixture was stirred and filtered. The filtrate was concentrated in vacuo and the resulting crude was triturated in hexane / ethyl acetate to give (3S, 4S) -1-benzyloxycarbonyl-3-hydroxy-4- (tert-butoxycarbonyl) pyrrolidine (18.59 g, yield: 94%) as crystals.

MS (APCI) m / z; 337 [M + H] +

(5) To a solution of the compound obtained in the above step (4) (18.56 g) in methanol (200 mL) was added 10% palladium-carbon (1.16 g) and

The mixture was stirred at room temperature under a hydrogen gas atmosphere for 3 hours. The reaction mixture was filtered through Cerite and the filtrate concentrated in vacuo. The residue was triturated in methanol / diisopropyl ether to give (3S, 4S) -3-hydroxy-4- (tert-butoxycarbonyl) pyrrolidine (10.8g, yield: 97%) as crystals.

MS (APCI) m / z; 203 [M + H] + Reference Example 61 to 83The corresponding raw materials were treated in the same manner as described in Reference Example 1, 4 or 6 to obtain the compounds as shown in the following Table B3.

Table B3 (No. 1)

<table> table see original document page 176 </column> </row> <table> Table B3 (N ° 2)

<table> table see original document page 177 </column> </row> <table> Table Β3 (N ° 3)

<table> table see original document page 178 </column> </row> <table> Reference Example 84 to 87

Corresponding raw materials were treated in the same manner as described in Reference Example 40 or 50 to obtain the compounds as shown in the following Table B4.Table B4

<table> table see original document page 179 </column> </row> <table>

Reference Example 88

The corresponding starting materials were treated in the same manner as described in Reference Example 51 to obtain 3-carboxy-6- (2-chlorophenyl) -7- (4-chlorophenyl) -2-ethoxymethylpyrazolo [1,5-a] pyrimidine (602 mg, yield: 95%) as a colorless solid.

MS (APCI) m / z; 442/444 [M + H] +

Reference Example 89

(1) To a solution of 4-methoxypiperidine (202 mg) in water (4 ml) was added acetic acid (200 µL) under cooling and the mixture was stirred at room temperature overnight. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution and mixture was stirred and extracted with chloroform. The extract was concentrated in vacuo and the resulting crude product was purified by column chromatography over silica gel (solvent; ethyl acetate) to give 4-methoxy-1-nitrosopi-peridine (260 mg, yield: 100%) as a yellow oil. pale.

MS (APCI) m / z; 145 [M + H] +

(2) To a solution of the compound obtained in the above step (1) (280 mg) in methanol (3 mL) was added zinc powder (654 mg). To this was added dropwise acetic acid (3 mL) under cooling and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. To the residue was added a saturated aqueous solution of sodium hydrogen carbonate and chloroform, and the mixture was stirred and extracted with chloroform. The extract was concentrated in vacuo to give 1-amino-4-methoxypiperidine (119 mg, yield: 57%) as a pale yellow oil.

MS (APCI) m / z; 131 [M + H] +

Reference Example 90

A mixture of 2,5-dibromopyridine (500 mg) and methylhydrazine (1 mL) was heated to 100 ° C. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over vacuum concentrated sodium sulfate. The resulting crude product was purified by column chromatography over silica gel (solvent; chloroform) and the eluted fraction concentrated. The residue was dissolved in tert-butanol and lyophilized to give 5-bromo-2- (N-methylhydrazino) pyridine (460 mg) as an oil.

MS (APCI) m / z; 202/204 [M + H] +

Reference Example 91 to 93

Corresponding raw materials were treated in the same manner as described in Reference Example 90 to obtain the compounds as shown in the following Table B5.Table B5

<formula> formula see original document page 181 </formula>

Reference Example 94

(1) To a solution of the compound obtained in Reference Example 4 (2) (1.0 g) in tetrahydrofuran (10 mL) was added 4-hydroxypiperidine (361

mg) and triethylamine (830 μΙ) and the mixture was stirred at 60 ° C for 2 hours. After cooling to room temperature, to the reaction mixture was added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and the resulting crude was triturated in isopropyl ether to give 6- (2-chlorophenyl) -7- (4-hydroxy-1-piperidinyl) -3-ethoxycarbonylpyrazolo [1,5-a ] pyrimidine (646 mg, yield: 54%) as a colorless solid.

MS (APCI) m / z; 401/403 [M + H] +

(2) To a solution of the compound obtained in the above step (1) (200mg) in dimethylformamide (3ml) was added sodium hydride (48mg) under

The mixture was stirred at room temperature for 15 minutes. To the reaction mixture was added ethyl iodide (120 μΙ) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and an aqueous dilute HCl was added thereto. The mixture was extracted with ethyl acetate and the extract was concentrated in vacuo. The resulting product was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 82/18 to 60/40) to give 6- (2-chlorophenyl) -7- (4-ethoxy-1 -piperidinyl) -3-ethoxycarbonylpyrazolo [1,5-a] pyrimidine (65 mg, yield: 30%) as a colorless viscosity.

MS (APCI) m / z; 429/431 [M + H] +

(3) The compound obtained in the above step (2) (65 mg) was treated in the same manner as described in Reference Example 1 (3) to give 3-carboxy-6- (2-chlorophenyl) -7- (4-ethoxy). 1-piperidinyl) pyrazolo [1,5-a] pyrimidine as a colorless powder.

MS (APCI) m / z; 401/403 [M + H] +

Reference Example 95

(1) The corresponding starting materials were treated in the same manner as described in Reference Example 4 (3) to obtain 6-chloro-7- (4-chlorobenzyl) -3-ethoxycarbonyl-2-methylpyrazolo [1,5-a] pyrimidine .

(2) To a solution of the compound obtained in the above step (1) (525 mg) in dimethoxyethane (5 mL) was added p-chlorobenzyl bromide (370 mg), bis (triphenylphosphine) palladium dichloride (53 mg) and zinc dust (235 mg) and the mixture was refluxed under heating and nitrogen gas atmosphere for 2 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. Water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resulting product was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 4/1) to give 7- (4-chlorobenzyl) -6- (2-chlorophenyl). nyl) -3-ethoxycarbonyl-2-methylpyrazolo [1,5-a] pyrimidine (113 mg, yield: 17%) as a pale yellow powder.

S (APCI) m / z; 440/442 [M + H] +

Reference Example 96

(1) To a solution of the compound obtained in Reference Example 51 (1) (200 mg) in dimethylformamide (2 mL) was added potassium acetate (116 mg) and the mixture was stirred at 60 ° C for 1 hour. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and water was added thereto. The organic layer was separated and concentrated in vacuo. The resulting crude product was purified by column chromatography over silica gel (solvent; hexane / ethyl acetate = 80/20 to 55/45) to give 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- ethoxycarbonyl-2-acetoxymethylpyrazolo1,5-a] pyrimidine (109.4 mg, yield: 57%) as a colorless powder.

S (APCI) m / z; 484/486 [M + H] +

(2) To a solution of the compound obtained in the above step (1) (109 mg) in ethanol / tetrahydrofuran (3 mL / 3 mL) was added 21% desodium dioxide / ethanol (0.2 mL) and the mixture was stirred. at 60 ° C for 30 minutes. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and water was added thereto. The mixture was extracted with

ethyl acetate and the organic layer was concentrated in vacuo. The resulting product was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 80/20 to 50/50) to give 6- (2-chlorophenyl) -7- (4-chlorophenyl) - 3-ethoxycarbonyl-2-hydroxymethylpyrazolo [1,5-a] pyrimidine (75 mg, yield: 75%) as a colorless solid.

MS (APCI) m / z; 442/444 [M + H] +

(3) To a solution of the compound obtained in the above step (2) (75 mg) in dimethylformamide (2 mL) was added imidazole (23 mg) and tert-butyldimethylsilyl chloride (31 mg) and the mixture was stirred at room temperature. hours To the reaction mixture was added imidazole (10 mg) and tert-butyldimethylsilyl chloride (15 mg) and the mixture was stirred for 6 hours. To the mixture was added water and the mixture was extracted with ethyl acetate. The extract was concentrated in vacuo and the resulting crude product was purified by column chromatography over silica gel (solvent; hexane / ethyl acetate = 85/15 to 60/40) to give 6- (2-chlorophenyl) -7- (4 -chlorophenyl) -3-ethoxycarbonyl-2- (tert-butyldimethylsilyloxymethyl) pyrazolo [1,5-a] pyrimidine (66.8 mg, yield: 71%) as a colorless solid.

MS (APCI) m / z; 556/558 [M + H] +

(4) The compound obtained in the above step (3) (66.8 mg) was treated in the same manner as described in Reference Example 1 (3) to give 3-carboxy-6- (2-chlorophenyl) -7- (4- chlorophenyl) -2-hydroxymethylpyrazolo [1,5-a] pyrimidine as a colorless powder.

MS (APCI) m / z; 414/416 [M + H] + Reference Example 97

(1) To a solution of benzyl 4-hydroxy-1-piperidinecarboxylate (1.0 g) in toluene / 2 N aqueous sodium hydroxide solution (10 mL / 10 mL) was added tetrabutyl ammonium bromide (550 g). mg) and methoxyethylabromide (1.2 mL) and the mixture was stirred at 60 ° C for 2.5 hours and then stirred at 80 ° C for 17 hours. To the reaction mixture was added sodium hydroxide (0.95 g) and methoxyethyl bromide (1.2 mL) and the mixture was stirred at 80 ° C for 24 hours. After cooling to room temperature, to the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resulting product was purified by column chromatography over silica gel (solvent; hexane / ethyl acetate = 75/25 to 40/60) to give 4- (2-methoxyethoxy) -1. benzyl piperidinecarboxylate (266 mg, yield: 21%) as a pale yellow liquid.

MS (APCI) m / z; 294 [M + H] +

(2) To a solution of the compound obtained in the above step (1) (266mg) in ethanol (5ml) was added 10% palladium-carbon (30mg) and the mixture was stirred at room temperature under a hydrogen gas atmosphere. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give 4- (2-methoxyethoxy) piperidine (138 mg, yield: 96%) as an in-color liquid.

MS (APCI) m / z; 160 [M + H] +

Reference Example 98 to 99

The corresponding starting materials were treated in the same manner as described in Example 484 and then the resulting product was treated in Reference Example 1 (3) to obtain the compounds as shown in the following Table B6.Table B6

<table> table see original document page 185 </column> </row> <table> Reference Example 100 to 102

Corresponding raw materials were treated in the same manner as described in Reference Example 7B to obtain the compounds as shown in the following Table B7.

Table B7

<table> table see original document page 185 </column> </row> <table>

Experiment 1

CB1 Human Receptor Binding Test

(1) Preparation of human receptor CB1 (membrane fraction): Materials)

Human CB1 expressing cell line: hCB1 / CHO no. C3 (Euroscreen)

Medium: F-12 (GIBCO No. 11765-062), 10% fetal calf serum, antibiotics (400 pg, Geneticin (GIBCO No. 11811 -031)

Buffer A: 50 mM tris-HCl (pH 7.5) containing ethylene diamine tetraacetic acid (2.5 mM), MgCfe (5 mM) and sucrose (200 mM) Procedure)

Receptor-expressing cells cultured in the above medium were washed with phosphate buffer (x 2) and to this was added Buffer A (2 ml) under cooling or 4 ° C (the following procedures were also performed at the same temperature). The cells were collected using a cell scraper, treated by a microtip-type ultrasound for 20 seconds (pulse on: 2 s, pulse off: 1 s) and centrifuged (500 χ g, 15min). The supernatant was separated and centrifuged (43000 χ g, 60 min). The resulting slurry was suspended in Buffer A and homogenized with a potter type homogenizer. To the homogenate an equal volume of 80% glycerol was added and stored at -80 ° C.

(2) CB1 receptor binding test procedure: Materials)

Buffer B: 50 mM tris-HCI (pH 7.5) containing ethylene diamine tetraacetic acid (2.5 mM), MgCl2 (5 mM) and bovine serum albumin (2 mg / mL, fatty acid free, SIGMA-A7030)

Buffer C: 50 mM tris-HCl (pH 7.5) containing ethylene diamine tetraacetic acid (2.5 mM), MgCfe (5 mM) and bovine serum albumin (2 mg / mL, SIGMA-A7906)

Coating solution: 0.3% ethyleneimine polymer

Radioligand: [3H] -CP55940 (30 nM / 7992 dpm ^ L) prepared by diluting 8.3 μΜ Buffered Radioligand solution (Method)

Each well of the test slide (96 wells, Costar Code No. 3371) was filled with Buffer B (140 µL), a test compound solution in dimethylsulfoxide (20 µL, final concentration: 0.1%), ra dioligant. (20 µL) and membrane preparation <20 µL, 0.5 µg / 20 µL) and the mixture was incubated at 30 ° C for 90 minutes to continue the ligation reaction. The reaction mixture was collected for each well of a slide pre-impregnated with the above coating solution (Packard UnifilterGF / B, Ns. 6005177). The slide was washed with Buffer C (200 μΙ_χ 10) and dried at 50 ° C for 1 hour and Microscinti 40 (40 μΙ_) was added to each well. Bound oradiomarker was quantified by scintillation counting (Top CountNXT, Packard). The IC 50 value of each test compound against radiolabel binding to CB1 receptors was calculated based on quantified radiolabel activity using Graphpad Prism 3.02.3) Results:

The IC50 value of each test compound is shown in the following Table C1. Meanwhile, the symbols (++ and +++) are defined as follows:

<formula> formula see original document page 0 </formula>

Table C1

<table> table see original document page 0 </column> </row> <table> INDUSTRIAL APPLICABILITY

The compounds [I] of the present invention are useful for treatment and / or prophylaxis of various CB1 receptor mediated diseases such as psychosis including schizophrenia. The compounds [I] of the present invention are also useful for withdrawal of chronic treatment, alcohol dependence or drug abuse. In addition, the compounds [I] of the present invention are useful as an agent for enhancing analgesic activity or an agent for stopping smoking.

Claims (27)

1. A pyrazolo [1,5-a] pyrimidine compound, characterized by the fat having the formula [I]: wherein: R1 and R2 are the same or different and an optionally substituted aryl group or an optionally substituted saturated or unsaturated heterocyclic group, Q is a single bond, a methylene group or a group of the formula: -N (RQ) -, RQ is an alkyl group, Ring A of 5 members is a substituted pyrazole ring fused to the adjacent pyrimidine ring having the following formula (A), (B) or (C) 1 <formula> formula see original document page 189 </formula> R3 and R4 are the same or different and ( a) a hydrogen atom, (b) a cyano group, (c) an alkyl group optionally substituted by one to three halogen atoms, (d) an alkyloxy group (the alkyl portion of this group being optionally substituted by one to three groups selected from a halogen atom, a hydroxyl group, an amino optionally substituted group by one or two alkyl groups, an alkyloxy group and an alkylsulfonyl group), (e) an alkylthio group, (f) an alkylsulfinyl group, (g) an alkylsulfonyl group or (h) a group of the formula: -N (R ' ) (R "), R 'and R" are the same or different and (a) a hydrogen atom, (b) an alkyl group optionally substituted by one to three groups selected from a halogen atom, an amino group optionally substituted by one or two alkyl groups and one alkyloxy group, (c) one acyl group, (d) one alkylsulfonyl group or (e) one amino sulfonyl group optionally substituted by one to two alkyl groups, or both R 'and R " combine each other at their termini to form together with an adjacent denitrogen atom an optionally substituted saturated or unsaturated nitrogen-containing heterocyclic group, E is one of the following groups (i) to (v): <formula> formula see original document page 190 </formula> R00 is an alkyl group, Q1 is a single bond, an alkyl group lene or a group of the formula: -N (R 7) -, R 7 is a hydrogen atom or an alkyl group, Q 2 is a single bond or an alkylene group, one of R 5 and R 6 is a hydrogen atom or an alkyl group and the other is (a) an alkyl group optionally substituted by one to three groups selected from a halogen atom, a cyano group, an alkyl group, an optionally substituted cycloalkyl group, an amino group optionally substituted by one or two alkyl groups, an alkylthio group an alkylsulfinyl group, an alkylsulfonyl group, an acyl group, an optionally substituted aryl group and optionally substituted saturated or unsaturated heterocyclic group, (b) an optionally substituted cycloalkyl group, (c) a group of the formula: -N (R 8) ( R9) 1 (d) an optionally substituted aryl group or (e) an optionally substituted saturated or unsaturated heterocyclic group, or both R5 and R6 combine to form together with a nitrogen atom adjacent to an optionally substituted saturated or unsaturated nitrogen heterocyclic group containing one of R 8 and R 9 is a hydrogen atom or an alkyl group and the other is (a) an alkyl group optionally substituted by one to three groups selected from a halogen atom, a group cyano and an aryl group, (b) a cycloalkyl group, (c) an optionally substituted aryl group or (d) an acyl group or (e) an optionally substituted saturated or unsaturated heterocyclic group, one of R 50 and R 60 is a hydrogen atom or an alkyl group and the other is a hydrogen atom, an alkyl group or an acyl group, or both combine together with the adjacent nitrogen atom to form a group cyclic of the following formula: <formula> formula see original document page 191 < wherein Ring A1 is a 5- to 7-membered aliphatic nitrogen-containing heterocyclic group optionally substituted by an oxo group, R51 is an alkyl group or an optionally arylsulfonyl group. substituted, R61 is an alkylamino group or an azido group, or a pharmaceutically acceptable salt thereof. A compound according to claim 1, characterized in that R 1 and R 2 are the same or different and: (i) a 6 to 10 membered monocyclic or bicyclic aryl group optionally substituted by one to three groups selected from a halogen atom, a cyano group, an alkyl group optionally substituted by one to three halogen atoms, an alkyloxy group optionally substituted by one to three halogen atoms, an amino group optionally substituted by one to two alkyl groups, an alkylthio group, an alkylsulfinyl group and a alkylsulfonyl group, or (ii) a 5- to 6-membered oxygen, saturated or unsaturated oxygen, sulfur or hetero-monocyclic group optionally substituted by one to three groups selected from a halogen atom, a cyano group, an oxo group, an alkyl group optionally substituted by one to three halogen atoms, an alkyloxy group optionally substituted by one to three halogen atoms nio, an amino group optionally substituted by one to two alkyl groups, an alkylthio group, an alkylsulfinyl group and an alkylsulfonyl group, the fact that the saturated or unsaturated heterocyclic group in R5, R6, R8 or R9 is: or a pharmaceutically salt acceptable of it. A compound according to claim 1, characterized in that (a) a saturated or unsaturated 4- to 7-membered hetero-monocyclic group, said hetero-monocyclic group containing one to four heteroatoms selected from oxygen atom, (b) a bicyclic or tricyclic 8 to 15 membered saturated or unsaturated nitrogen containing bicyclic or tricyclic heterocyclic group formed by fusing the above-mentioned heterocyclic group with one or two different cyclic groups selected from a C3 group -8 cycloalkyl, a 5- to 6-membered monocyclic aryl group and a saturated or unsaturated 4- to 7-membered hetero-monocyclic group, said hetero-monocyclic group containing a four heteroatoms selected from oxygen atom, sulfur atom nitrogen atom; or (c) a saturated or unsaturated 8 to 11 membered nitrogen-containing spiroheterocyclic group or a pharmaceutically acceptable salt thereof. A compound according to claim 1, characterized in that the saturated or unsaturated nitrogen-containing heterocyclic group combining R5 with R6 is (a) a saturated or unsaturated nitrogen-containing hetero-monocyclic group, said group optionally containing two or more nitrogen atoms and optionally containing one to two different heteroatoms of one or more similar nitro atoms selected from oxygen atom and sulfur atom (b) a bicyclic heterocyclic group or saturated or unsaturated 8- to 15-membered nitrogen- tricyclic tricyclic formed by fusing the heterocyclic group mentioned above with one or two different cyclic groups selected from a C3- and cycloalkyl group, a 5-5 monocyclic aryl group 6-membered and a 4-7 membered saturated or unsaturated hetero-monocyclic group, said hetero-monocyclic group containing a selected four heteroatoms between oxygen atom, sulfur atom, nitrogen atom; or (c) a saturated or unsaturated 8 to 11 membered nitrogen-containing spiroheterocyclic group, or a pharmaceutically acceptable salt thereof. A compound according to claim 3, characterized in that the saturated or unsaturated R51, R8, R8 or R9 heterocyclic group is a saturated or unsaturated heterocyclic group substituted by one to four groups selected from a halogen atom, a hydroxyl group, a group cyano, an oxo group, an alkyl group, an alkyl group substituted by one to three halogen atoms, an alkyloxyalkyl group, an aminoalkyl group, a cycloalkyl group, an arylalkyl group, an alkyloxy group, a one to three substituted alkyloxy group halogen atoms, an acyl group, an amino group optionally substituted by one to two alkyl groups, an acylamino group, an alkylsulfonyl group, an aminosulfonyl group optionally substituted by one to two alkyl groups, an aryl group optionally substituted by one to two halogen atoms and a saturated or unsaturated 5- to 6-membered heterocyclic nitrogen containing group, or a pharmaceutically acceptable of it. A compound according to claim 4, characterized in that the saturated or unsaturated heterocyclic group formed by combining R5 with R6 is the saturated or unsaturated nitrogen-containing heterocyclic group substituted by one to three groups selected from a halogen atom, a hydroxyl group, a cyano group, an oxo group, an alkyl group, an alkyl group substituted by one to three halogen atoms, an alkyloxyalkyl group, an aminoalkyl group, a cycloalkyl group, an arylalkyl group, an alkyloxy group, an alkyloxy group substituted by an a three halogen atoms, one acyl group, one amino group optionally substituted by one of two alkyl groups, one acylamino group, one alkylsulfonyl group, one aminosulfonyl group optionally substituted by one to two alkyl groups and one aryl group, or a pharmaceutically acceptable salt of the same. A compound according to claim 3, characterized in that the saturated or unsaturated heterocyclic group in R 5, R 6, R 8 or R 9 is (A) a heterocyclic group containing saturated or unsaturated oxygen or sulfur selected from a furyl group, a tetrahydrofuranoyl group, a pyranyl group, a tetrahydropyranyl group, a thiacyclobutyl group, a groupotienyl, a tetrahydrothienyl group, a thiopyranyl group, a tetrahydrothiopyranyl group, a benzofuranyl group, a dihydrobenzofuranyl group, aisanoyl group, an isoenzoyl group a groupocromenyl, an isocromenyl group, a benzothienyl group and a dihydrobenzothienyl group; or (B) a saturated or unsaturated nitrogen-containing heterocyclic group selected from an azetidyl group, a pyrrolidinyl group, a pyrrolinyl group, an imidazolidinyl group, an imidazolinyl group, a pyrazolinyl group, a pyrrolyl group, a 2H-pyrrolyl group, a imidazolyl group, a pyrazolyl group, a dihydropyrazolyl group, a group thiazolidinyl, a thiazolyl group, an isothiazolyl group, an isoxazolyl group, an oxazolidinyl group, a pyridyl group, a dihydropyridyl group, a te-trahydropyridyl group, a pyreridyl group, a , a piperazinyl group, a pyrimidinyl group, a tetrahydropyrimidinyl group, a pyridazinyl group, a morpholinyl group, an azocinyl group, an azacycloheptyl group, a benzimidazolyl group, a benzotriazolyl group, an indolyl group, an isoindolyl group indolyl, one indolinyl group, one isoindolinyl group, one H-indazolyl group, one pyrrolopyridyl group, one group rrolopyrimidinyl, a tetrazolyl group, a purinyl group, a pteridinyl group, a 4H-quinolizinyl group, a quinolyl group, a dihydroquinolyl group, a tetrahydroquinolyl group, an isoquinolyl group, a dihydroisoquinolyl group, a tetrahydroazinyl group, a phthalidazinyl group a naphthyridinyl group, a dihydronaphthyridinyl group, a tetrahydronaphthyridinyl group, a quinoxalinyl group, a quinazolinyl group, a dihydrobenzothiazinyl group, a dihydrobenzoxazinyl group, a cinolinyl group, a pteridinyl group, a xanthenyl group, a carbazolinyl group, a carbazolylenyl group, a carbidinyl group , an acridinyl group, a 5H-dihydro-dibenzazepinyl group and a spiroheterocyclic group of the formula: where RA and RB are the same or different and a hydrogen atom or a group alkyl, e.g. are an integer of 1 or 2, or a pharmaceutically acceptable salt thereof. A compound according to claim 3, characterized in that the saturated or unsaturated heterocyclic group at R51, R6, R8 or R9 is a tetrahydrofuranoyl group, a pyrrolyl group, a pyrrolidinyl group. a grouppiperidyl, an azacycloheptyl group, a tetrahydropyranyl group, a grouppiperazinyl, a morpholinyl group, a thiomorpholinyl group, a tiaci-clobutyl group, a tetrahydrothiopyran group, a thiazolyl group, a pyridyl group, a indolinyl, a group pyrrolopyridyl or a tetrahydronaphthyridinyl group, or a pharmaceutically acceptable salt thereof. A compound according to claim 4, characterized in that the saturated or unsaturated nitrogen-containing heterocyclic group combining R5 with R6 is a heterocyclic group containing saturated or unsaturated nitrogen selected from an azetidyl group, a pyrrolidinyl group, a pyrrolinyl group, an imidazolidinyl group, an imidazolinyl group, a pyrazolidinyl group, a pyrazolinyl group, a pyrrolyl group, aimidimidoyl group, a pyrazolyl group, a dihydropyrazolyl group, a thiazolidinyl group, an oxazolidinyl group, a dihydropyridyl group, a tetrahydropyridyl group, a piperidyl group, piperazinyl group, tetrahydropyrimidinyl group, morpholinyl group, azacycloheptyl group, benzimidazolyl group, benzotriazolyl group, indolyl group, isoindolyl group, isoindolinyl group, 1 H-indazole group a tetrazolyl group, a purinyl group, a dihydroquinoline group, a tetrahydroquinolyl group, a grupodihydroisoquinolyl, a tetrahydroisoquinolyl group, a dihydrophthalazinyl group, a dihydroquinazolinyl group, a dihydrobenzothiazinyl group, a dihydro-benzoxazinyl group, a carbazolyl group, a beta-carbolinyl group, a 5H-dihydro-dibenzazepinyl heterocyclic group: wherein Ra and Rb are the same or different and a hydrogen atom or an alkyl group is an integer of 1 or 2, or a pharmaceutically acceptable salt thereof. A compound according to claim 4, characterized in that the pharmaceutically saturated or unsaturated nitrogen-containing heterocyclic group combining R5 with R6 is a morpholino group, a thiomorpholine group, a piperidino group or a azacycloheptyl group, or a pharmaceutically acceptable moiety. acceptable of it. A compound according to claim 1, characterized in that the group of formula (ii) is one of the following groups (a) to (d): (a) -C (= O) -N (R 5) (R 6 ), (b) -C (= O) -Alk-N (R 5) (R 6), (c) -Alk-C (= O) -N (R 5) (R 6), (d) -N (R 7) -C (= O) -N (R 5) (R 6) wherein Alk is a straight or branched C 1-6 alkylene group or a pharmaceutically acceptable salt thereof. A compound according to claim 1, characterized in that R 1 and R 2 are the same or different and (a) a phenyl group optionally substituted by one to two groups selected from a dehalogen atom and a trihalogenoalkyl group, Q is Ring A is a substituted pyrazole ring of formula (A), E is a group of the following formula: -C (= O) O-R00 (i) R4 is an amino group optionally substituted by one to two groups selected from an alkyl group and an alkylsulfonyl group, or a pharmaceutically acceptable salt thereof. A compound according to claim 12, characterized in that R1 is a chlorophenyl group or a trifluoro-C1-4 alkenylphenyl group, R2 is a chlorophenyl group, R3 is a C1-4 alkyl group and R4 is (a) an amino group substituted by one to two groups selected from a C1-4 alkyl group and a C1-4 alkylsulfonyl group or (b) an aminosulfonyl group substituted by one to two C1-4 alkyl groups, or a pharmaceutically acceptable salt thereof. A compound according to claim 1, characterized in that R 1 and R 2 are the same or different and (a) a phenyl group optionally substituted by one to three groups selected from a halogen atom, a cyano group, a group alkyl optionally substituted by one to three halogen atoms, an alkyloxy group optionally substituted by one to three halogen atoms, an amino group optionally substituted by one to two alkyl groups and one alkylsulfonyl group or (b) a 5- to 7-membered heterocyclic group saturated or unsaturated optionally substituted by one to three groups selected from a halogen atom, an oxo group, an alkyl group optionally substituted by one to three halogen atoms, an alkyloxy group, an alkyloxyalkyl group and an alkyloxyalkyloxy group, Ring A is a substituted pyrazole ring of formula (A) or (B), E is one of the groups of the following formula (a) to (e): a) -C (= O) -N (R5) (R6), b) -C (= O) -Alk-N (R5) (R 6), c) -Alk-C (= O) -N (R 5) (R 6), d) -N (R 7) -C (= O) -N (R 5) (R 6), e) -C (= NR51) -R61, R3 is a hydrogen atom, a cyano group or an alkoxy group, R4 is (a) a hydrogen atom, (b) a cyano group, (c) an alkyl group optionally substituted by one to three groups selected from a halogen atom and a hydroxyl group, (d) an alkyloxy group optionally substituted by one to three groups selected from a halogen atom, a hydroxyl group, an amino group optionally substituted by one to two alkyl groups, an alkyloxy group and a alkylsulfonyl group, (e) an alkylthio group, (f) an alkylsulfinyl group, (g) an alkylsulfonyl group or (h) a group of the formula: -N (R ') (R "), R' and R" are the same or and (a) a hydrogen atom, (b) an alkyl group optionally substituted by one to three groups selected from a halogen atom, an amino group optionally substituted by one to two alkyl groups and an alkyloxy group, (c) a group 1a, (d) an alkylsulfonyl group or (e) an aminosulfonyl group optionally substituted by one to two alkyl groups, or (f) both combine together with the adjacent nitrogen atom to form a hetero-monocyclic nitrogen-containing group. 5-6 membered saturated or unsaturated optionally substituted by a hydroxyl group or an alkyloxy group, one of R5 and R6 is a hydrogen atom or an alkyl group and the other is (1) an alkyl group optionally substituted by one to three groups selected from one atom halogen, an alkyloxy group, a cycloalkyl group, an alkylthio group, an alkylsulfonyl group, an amino group optionally substituted by one or two alkyl groups, a morpholinecarbonyl group, a phenyl group optionally substituted by a cyano group and a hetero-monocyclic group containing saturated or unsaturated 5-6 membered nitrogen, said hetero-monocyclic group optionally being substituted by a group selected from a halogen moiety, an alkyl group and a trihalogenoalkyl group: (2) a cycloalkyl group optionally substituted by a cyano group or an alkyl group; (3) a group of the formula: -N (R 8) (R s); or (4) a phenyl group; or (5) a 4- to 10-membered saturated or unsaturated monocyclic or bicyclic heterocyclic group optionally substituted by one to four groups selected from a halogen atom, a cyano group, a hydroxyl group, an oxo group, an alkyl group optionally substituted by one to three atoms halogen, a cycloalkyl group, an alkylcarbonyl group, an alkyloxycarbonyl group, an alkylsulfonyl group, an aminosulfonyl group optionally substituted by one or two alkyl groups, a carbamoyl group optionally substituted by one to two alkyl groups, an alkyloxycarbonylamino group phenyl group optionally substituted by one to two halogen atoms and a saturated or unsaturated 5 to 6 membered hetero-monocyclic group; or (6) both R5 and R6 combine together with the adjacent nitrogen atom to form a 5- to 7-membered saturated or unsaturated heterocyclic group containing optionally substituted by one to two groups selected between a halogen atom and a group oxo, R 8 is hydrogen atom or an alkyl group, R 9 is (a) an alkyl group optionally substituted by one to three groups selected from a halogen atom, a cyano group and a phenyl group; (b) a phenyl group optionally substituted by a group selected from a halogen atom, a cyano group, an alkyl group, a trihalogenoalkyl group, a cycloalkyl group, a trihalogenoalkyloxy group, an alkyloxy group, an alkylthio group and an alkylsulfonyl group ; (c) an alkyloxycarbonyl group; or (d) a 5-6 membered saturated or unsaturated hetero-monocyclic group optionally substituted by a group selected from a halogen atom, a cyano group, an alkyl group, an alkyloxy group and a trihalogenoalkyl group, R7 is a hydrogen atom, R51 is an alkyl group or a phenylsulfonyl group optionally substituted by one to two halogen atoms and R61 is an alkylamino group or an azido group, or a pharmaceutically acceptable salt thereof. A compound according to claim 14, characterized in that R 1 is (a) a phenyl group optionally substituted by one or two groups selected from a halogen atom, a cyano group, a dihalogenoalkyl group, a trihalogenoalkyl group, an alkyloxy group, an alkyloxyalkyl group and a di (alkyl) amino group or (b) a saturated or unsaturated 5 to 7 membered heterocyclic group optionally substituted by one of two groups selected from an oxo group, an alkyl group, a grupotrihalogenoalkyl group, an alkyloxy group, an alkyloxyalkyl group , an alkyloxyalkyloxy group and a di (alkyl) amino group, R2 is (a) a phenyl group optionally substituted by one or two groups selected from a halogen atom and a cyano group or (b) a saturated or unsaturated 5- to 6-membered heterocyclic group optionally substituted by a halogen atom, R3 is a hydrogen atom, R4 is a hydrogen atom, an alkyl group, a dihalogene group alkyl, a hydroxyalkyl group, a trihalogenoalkyl group, an alkyloxyalkyl group, a hydroxyalkyloxy group, an alkyloxyalkyloxy group, an alkylsulfonylalkyl group or a group of the formula: -N (R ') (R "), one of R' and R" is an atom of hydrogen or an alkyl group and the other is an acyl group or an alkylsulfonyl group, E is one of the groups of the following formula (a), (b) and (e) :( a) -C (= 0) -N (R5 ) (R6), (b) -C (= O) -Alk-N (R5) (R6), (e) -C (= NR51) -R61, one of R5 and R6 is a hydrogen atom or a group alkyl, the other is (a) an alkyl group, (b) a cycloalkyl group, (c) a phenyl group, (d) a saturated or unsaturated 4- to 10-membered mono- or bicyclic heterocyclic group optionally substituted by one to four groups selected from a halogen atom, an oxo group, a cyano group, a hydroxy group, an alkyl group, a trihalogenoalkyl group, an alkyloxy group, an alkyloxyalkyl group, an alkylcarbonyl group, a di (alkyl) carbamoyl group, an alkylsulfonyl group, one di (alkyl) aminosulfonyl group, a phenyl group, a halogenophenyl group and a pyridyl group or (e) a group of the formula: -N (R8) (R9) 1 or (f) both combine together with the adjacent nitrogen atom to form a saturated or unsaturated 5 to 6 membered hetero monocyclic group optionally substituted by one to two groups selected from a halogen atom and an oxo group, R 8 is an alkyl group, R 9 is (a) an alkyl group, (b) a phenyl group optionally substituted by a halogen atom, (c) an alkyl group optionally substituted by a pyridyl group or (d) a saturated or unsaturated 4-6 membered hetero-monocyclic group optionally substituted by a group selected from a halogen atom, an alkyl group, a trihalogenoalkyl group and an alkyloxy group, R51 is an alkyl group or a halogenophenyl sulfonyl group, and R61 is an alkylamino group or an azido group or a pharmaceutically acceptable salt thereof. A compound according to claim 14, characterized in that R 1 is (a) a phenyl group optionally substituted by a group selected from a chlorine atom, a fluorine atom, a groupocyan, a difluoro-C 1-4 alkyl group and a C1-4 alkyl trifluoro group or (b) a pyridyl group optionally substituted by a C1-4 alkyl trifluoro group, R2 is a phenyl group optionally substituted by one to two groups selected from a chlorine atom, a fluorine atom, a bromine atom and a cyano group, R3 is a hydrogen atom, R4 is a hydrogen atom, a C1-4 alkyl group, a C1-4 alkyl group, trifluoro-C1-4 alkyl group, a C1-4 group C 1-4 alkyloxyalkyl or a C 1-4 alkylcarbonylamino group, E is one of the groups of the following formula (a) and (b) :( a) -C (= 0) -N (R 5) (R 6) , (b) -C (= 0) -Alk-N (R5) (R6), one of R5 and R6 is a hydrogen atom and the other is a Cmalkyl group, a pyridyl-C1-4 alkyl group, a C5-7 cycloalkyl, a group c lo-rophenyl, a saturated or unsaturated 4- to 6-membered hetero-monocyclic group optionally substituted by one to two groups selected from a halogen atom, an oxo group and a C1-4 alkyloxy-C1-4 alkyl group or a group of Formula: -N (R 8) (R 9) 1 or both combine together with the adjacent denitrogen atom to form a saturated or unsaturated 5-6 membered hetero-monocyclic group optionally substituted by one to two oxo groups, R8 is a C1-4 alkyl group and R 9 is a C 1-4 alkyl group, a group chlorophenyl, a pyridyl group or a C 1-4 alkyl pyridyl group, or a pharmaceutically acceptable salt thereof. A compound according to claim 1, wherein P1 and R2 are the same or different and a phenyl group optionally substituted by one to two groups selected from a dehalogen atom and a trihalogenoalkyl group, Q is a single bond. , Ring A is a substituted pyrazole ring of formula (A), R3 is a hydrogen atom, R4 is a hydrogen atom or an alkyl group, and is a group of formula (iii): <formula> formula see original document page 202 < one of R5 and R6 is a hydrogen atom or an alkyl group and the other is (a) an alkyl group, (b) a cycloalkyl group or (c) a sulfur or nitrogen hetero-monocyclic group containing from 5 to 6 saturated or unsaturated members, or (d) both combine together with the adjacent nitrogen atom to form a saturated or unsaturated 5- to 6-membered nitrogen-containing heterocyclic group optionally substituted by one to two oxo groups, or a pharmaceutically acceptable salt thereof . A compound according to claim 17, characterized in that R 1 is a trihaloalkylphenyl group, R 2 is a halo-genophenyl group, R 4 is an alkyl group, one of R 5 and R 6 is a hydrogen atom or an alkyl group the other is (a) an alkyl group, (b) a cycloalkyl group, (c) a 5-6 membered sulfur or nitrogen-containing hetero-monocyclic group, saturated or unsaturated optionally substituted by one to two oxo groups, or (d) both combine together with the adjacent nitrogen atom to form a saturated or unsaturated 5- to 6-membered hetero-monocyclic group optionally substituted by one or two oxo groups, or a pharmaceutically acceptable salt thereof. A compound according to claim 1, wherein P1 and R2 are the same or different and a phenyl group optionally substituted by one to two groups selected from a dehalogen atom and a trihalogenoalkyl group, Q is a single bond. , Ring A is a substituted pyrazole ring of formula (A), R3 is a hydrogen atom, R4 is a hydrogen atom or an alkyl group, and is a group of formula (iv): <formula> formula see original document page 203 < One of R 50 and R 60 is a hydrogen atom or an alkyl group and the other is an alkyl group or an acyl group, or both combine together with the adjacent denitrogen atom to form a saturated 5- to 6-membered nitrogen containing heterocyclic group. unsaturated optionally substituted by one or two oxo groups, or a pharmaceutically acceptable salt thereof. A compound according to claim 1, characterized by the fact that R 1 and R 2 are the same or different and a phenyl group optionally substituted by one to two groups selected from a dehalogen atom and a trihalogenoalkyl group, Q is a single bond. Ring A is a substituted pyrazole ring of the formula (C) 1 R 3 is a hydrogen atom, R 4 is a group of the formula -N (R ') (R "), R' and R" are the same or different and a hydrogen atom or an alkyl group, or both combine together with the adjacent denitrogen atom to form a saturated or unsaturated 5- to 6-membered nitrogen containing heterocyclic group, or a pharmaceutically acceptable salt thereof. 21. A compound characterized in that it is selected from the group consisting of: 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- (N-piperidinecarbamoyl) pyrazolo [1,5-a] pyrimidine; - (2-chlorophenyl) -7- (4-chlorophenyl) -3 - [(N'-methyl-N'-phenylhydrazino) carbonyl] pyrazolo [1,5-a] pyrimidine; 6- (2-chlorophenyl ) -7- (4-chlorophenyl) -3- (N-cyclohexylcarbamoyl) pyrazolo [1,5-a] pyrimidine; 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3 - [(N ' N'-dimethylhydrazino) carbonyl] -pyrazo [1,5-a] pyrimidine; -6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- (N-pyrrolidinecarbamoyl) pyrazolo [1,5 -a] pyrimidine; -6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- (N-cyclopentylcarbamoyl) pyrazolo [1,5-a] pyrimidine; -6- (2-chlorophenyl) 7- (4-chlorophenyl) -3- [N- (4-tetrahydropyranyl) carbamoyl] -pyrazo [1,5-a] pyrimidine; -6- (2-chlorophenyl) -7- (4-chlorophenyl) - 3- [N- (1,1-dioxo-tetrahydrothiophen-3-yl) carbamoyl] pyrazolo [1,5-a] pyrimidine; (R) -6- (2-chlorophenyl) -7- (4- difluoromethylphenyl) -3- [N- (1,1-dioxo-tetrahydro-thiophen --- 3-yl) carbamoyl] pyrazolo [1,5-a] pyrimidine; -6- (2-chlorophenyl) -7- (4-trifluoromethylphenyl) -2-methyl-3- [N- (1,1-dioxo-tetrahydro-thiophen-3-yl) carbamoyl] pyrazolo [1,5-a ] (S) -6- (2-chlorophenyl) -7- (4-trifluoromethylphenyl) -2-methyl-3- [N- (1,1-dioxo-tetrahydro-thiophen-3-yl) carbamoyl] pyrazole [1,5-a] pyrimidine; -6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- [N- [2- (2-pyridyl) ethyl] carbamoyl] pyrazolo [1,5- a] pyrimidine; -6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- (N-cyclopentylcarbamoyl) -2-methoxypyrazo [1,5-a] pyrimidine; (R) -6 - (2-chlorophenyl) -7- (4-chlorophenyl) -2-methyl-3- [N- (1,1-dioxo-tetrahydro-thiophen-3-yl) carbamoyl] pyrazolo [1,5-a] (S) -6- (2-chlorophenyl) -7- (4-chlorophenyl) -2-methyl-3- [N- (1,1-dioxo-tetrahydro-thiophen-3-yl) carbamoyl] pyrazolo [1,5-a] pyrimidine -6- (2-bromophenyl) -7- (4-chlorophenyl) -3- (N-cyclopentylcarbamoyl) pyrazolo [1,5-a] pyrimidine; (R, S) -6- (2-bromophenyl) -7- (4-chlorophenyl) -3- [N- (1,1-dioxo-tetrahydrothiophen-3-yl) carbamoyl] pyrazolo [1,5-a] pyrimidine; -6- (2-chlorophenyl) -7- (4-trifluoromethylphenyl) -3- [N- (1,1-dioxide o-tetrahydro-thiophen --- 3-yl) carbamoyl] pyrazolo [1,5-a] pyrimidine; (R) -6- (2-chlorophenyl) -7- (4-trifluoromethylphenyl) -3- [N- ( 1,1-dioxo-tetrahydro-thiophen --- 3-yl) carbamoyl] pyrazolo [1,5-a] pyrimidine; -6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- [N- [N- (3-chlorophenyl) -N-methylamino] -carbamoyl] pyrazolo [1,5-a] pyrimidine; 6- (2-cyanophenyl) -7- (4-chlorophenyl) -3- [N- [ N-methyl-N- (2-pyridyl) amino] carbamoyl] pyrazolo [1,5-a] pyrimidine 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- (N-isobutylcarbamoyl) ) pyrazolo [1,5-a] pyrimidine 6- (2-chlorophenyl) -7- (4-trifluoromethylphenyl) -3- [N- (1,1-dioxo-tetrahydro-thiophen-3-icarbamoyl] pyrazolo [ 1,5-a] pyrimidine 6- (2-chlorophenyl) -7- (4-trifluoromethylphenyl) -3- (N-cyclopentylcarbamoyl) -pyrazolo [1,5-a] pyrimidine; 6- (2-chlorophenyl) - 7- (44-trifluoromethylphenyl) -3- [N- [N-methyl-N- (2-iridyl) amino] carbamoyl] pyrazolo [1,5-a] pyrimidine; (R) -6- (2-chlorophenyl) - 7- (4-chlorophenyl) -3- [N- (1,1-dioxo-tetrahydrothiophen-3-yl) carbamoyl] pyrazolo [1,5-a] pyrimidine; 6- (2-chlorophenyl) -7- (4-cyanophenyl) -3- (N -cyclopentylcarbamoyl) pyrazolo [1,5-a] pyrimidine; (R, S) -6- (2-chlorophenyl) -7- (4-chlorophenyl) -2-methyl-3- [N- (1,1- dioxo-tetrahydro-phen-3-yl] carbamoyl] pyrazolo [1,5-a] pyrimidine; 6- (2-chlorophenyl) -7- (4-fluorophenyl) -3- (N-cyclopentylcarbamoyl) pyrazolo [1 , 5-a] pyrimidine; 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- [N- [N-methyl-N- (2-pyridyl) amino] carbamoyl] pyrazolo [1, (S) -6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- [N- (1,1-dioxo-tetrahydrothiophen-3-ylcarbamoyl] pyrazolo [1, 5- (2-chlorophenyl) -7- (4-chlorophenyl) -3- (N-ethylcarbamoyl) pyrazolo [1,5-a] pyrimidine; 6- (2-chlorophenyl) - 7- (4-chlorophenyl) -3- (N-cyclopropylcarbamoyl) -pyrazolo [1,5-a] pyrimidine; (S) -6- (2-chlorophenyl) -7- (4-chloro-2-fluorophenyl) - 3- [N- (1,1-dioxotetrahydro-thiophen-3-yl) carbamoyl] pyrazolo [1,5-a] pyrimidine; (S) -6- (2-chlorophenyl) -7- (4-difluoromethylphenyl) - 3- [N- (1,1-dioxothetrahydro-thiophen-3-yl) carbamoyl] pyrazolo [1,5-a] pyrimidine; (R) -6- (2-cyanophenyl) -7- (4-trifluoromethylphenyl) - 3- [N- (1,1-dioxothetrahydro fen-3-yl) carbamoyl] -2-methylpyrazolo [1,5-a] pyrimidine; (S) -6- (2-cyanophenyl) -7- (4-trifluoromethylphenyl) -3- [N- (1, 1-dioxothetrahydro-thiophen-3-yl) carbamoyl] -2-methylpyrazolo [1,5-a] pyrimidine 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3 - [[N'-methyl -N '- (2-methoxypyridin-5-yl) -hyano] carbonyl] pyrazolo [1,5-a] pyrimidine; 6- (2-cyanophenyl) -7- (4-chlorophenyl) -3- [N - (1-pyrrolidinyl) carbamoyl] -pyrazolo [1,5-a] pyrimidine; 6- (2-chlorophenyl) -7- (2-trifluoromethylpyridin-5-yl) -3- (N-cyclopentylcarbamoyl razolo [1, 5-a] pyrimidine; (R) -6- (2-cyanophenyl) -7- (4-chlorophenyl) -3- [N- (1,1-dioxothetrahydro-thiophen-3-yl) carbamoyl] -2 [1,5-a] pyrimidine; 6- (2-cyanophenyl) -7- (4-chlorophenyl) -3 - [[N'-methyl-N, (2-pyridyl) hydrazino] carbonyl ] -2-methylpyrazolo [1,5-a] pyrimidine; (R) -6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- [N- (1,1-dioxotetrahydro-thiophen-3-one) yl) Carbamoyl] -2-trifluoromethylpyrazolo [1,5-a] pyrimidine; 6- (2-chlorophenyl) -7- (4-trifluoromethylphenyl) -3 - [(N ', N'-dimethylhydrazino) -carbamide; nyl] -2-acetylaminopyrazole [1 5-a] pyrimidine 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3 - [[N'-phenyl] -2-acetylaminopyrazolo [1,5-a] pyrimidine; 6- (2- chlorophenyl) -7- (4-chlorophenyl) -3 - [[N'-methyl-N, - (2-pyridyl) hydrazino] carbonyl] -2- (trifluoromethyl) pyrazolo [1,5-a] pyrimidine 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- [N- (1-pyrrolidinyl) carbamoyl] -2-difluoromethylpyrazolo [1,5-a] pyrimidine; (R) -6- (2-chlorophenyl) -7- (4-trifluoromethylphenyl) -3- [N- (1,1-dioxotetrahydro-thiophen-3-yl) carbamoyl] -2-difluoromethylpyrazolo [1,5-a] pyrimidine; ) -6- (2-chlorophenyl) -7- (4-trifluoromethylphenyl) -3- [N- (1,1-dioxothetrahydro-thiophen-3-yl) carbamoyl] -2-difluoromethylpyrazolo [1,5-a] 6- (2-cyanophenyl) -7- (4-chlorophenyl) -3- (N-piperidinocarbamoyl) -2-difluoromethylpyrazolo [1,5-a] pyrimidine; 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- [N- (1,1-dioxoxycyclobutan-3-yl) carbamoyl] pyrazolo [1,5-a] pyrimidine 7- (4-chlorophenyl) -6- (2- cyano-4-fluorophenyl) -3- [N- (1-pyrrolidinyl) carbamoyl] -pyrazolo [1,5-a] pyrimidine; -7- (4-chlorophenyl) -6- (2-cyanophenyl) -3 - (N- piperidinocarbamoyl) -2-methyl-pyrazo [1,5-a] pyrimidine; (R) -7- (4-chloro-2-fluorophenyl) -6- (2-cyanophenyl) -3- [N- (1 -1-dioxothetrahydro-thiophen --- 3-yl) carbamoyl] -2-methylpyrazolo [1,5-a] pyrimidine; -6- (2-chlorophenyl) -7- (4-elorophenyl) -3 - [[N '-methyl-N' - (2-ethoxypyridin-5-yl) hydrazino] carbonyl] pyrazolo [1,5-a] pyrimidine; (R) -6- (2-chlorophenyl) -7- (4- chlorophenyl) -3- [N- (1,1-dioxotetrahydro-thiophen-3-yl) carbamoyl] -2-methoxymethylpyrazolo [1,5-a 3-pyrimidine; (S) -6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- [N- (1,1-dioxotetrahydro-thiophen-3-yl) carbamoyl] -2-methoxymethylpyrazolo [1,5-a] pyrimidine; -6- (2-chlorophenyl) - 7- (4-chlorophenyl) -3 - [[N'-methyl-N '- (2-iridyl) hydrazino] carbonyl] -2-methoxymethylpyrazolo [1,5-a] pyrimidine; -chlorophenyl) -7- (4-chlorophenyl) -3- [N- (1-pyrrolidinyl) carbamoyl] -2-methoxymethylpyrazolo [1,5-a] pyrimidine; -7- (4-chloro-2-fluorophenyl ) -6- (2-cyanophenyl) -3- [N- (1-pyrrolidinyl) carbamoyl] -2-methylpyrazolo [1,5-a] pyrimidine; -6- (2-chlorophenyl) -7- (4-chlorophenyl ) -3- [2- (1,1-dioxothiomorpholino) acetyl 1] -2-methylpyrazolo [1,5-a] pyrimidine; -6- (2-cyanophenyl) -7- (4-chlorophenyl) -3- [N- (4-fluoropiperidino) carbamoyl] -2-methyl -tylpyrazolo [1,5-a] pyrimidine; e-6- (2-chlorophenyl) -7- (4-trifluoromethylphenyl) -3- [N- (tetrahydrothiophen-3-yl) carbamoyl] pyrazolo [1,5-a] pyrimidine, or a pharmaceutically acceptable salt the same. 22. Pharmaceutical composition, characterized in that it comprises as an active ingredient a pyrazolo [1,5-a] pi-rimidine compound of the formula [I]: <formula> formula see original document page 208 </formula> in which: R 1 and R 2 are the same or different and an optionally substituted aryl group or an optionally substituted saturated or unsaturated heterocyclic group, Q is a single bond, a methylene group or a group of the formula: -N (RQ) -, Rq is a alkyl group, 5-membered Ring A is a substituted pyrazole ring fused to the adjacent ringpyrimidine having the following formula (A), (B) or (C), <formula> formula see original document page 208 </formula> R3 and R 4 are the same or different and (a) a hydrogen atom, (b) a cyano group, (c) an alkyl group optionally substituted by one to three halogen atoms, (d) an alkyloxy group (the preferred alkyl moiety) group being optionally substituted by one to three groups selected from a halogen atom a hydroxyl group, an amino group optionally substituted by one or two alkyl groups, an alkyloxy group and an alkylsulfonyl group), (e) an alkylthio group, (f) an alkylsulfinyl group, (g) an alkylsulfonyl group or (h) a group of the formula: -N (R ') (R "), R' and R" are the same or different and (a) a hydrogen atom, (b) an alkyl group optionally substituted by one to three groups selected from a halogen atom, an amino group optionally substituted by one or two alkyl groups and an alkyloxy group, (c) an acyl group, (d) an alkyl sulfonyl group or (e) an amino sulfonyl group optionally substituted by one to two alkyl groups , or both R 'and R "combine with each other at their termini to form together with an adjacent denitrogen atom an optionally substituted saturated or unsaturated nitrogen-containing heterocyclic group <formula> formula see original document page 209 </ formula > R00 is an alkyl group, Q1 is a single bond (eg, an alkylene group or a group of the formula: -N 7 R 7) -, R 7 is a hydrogen atom or an alkyl group, Q 2 is a single bond or an alkylene group, one of R 5 and R 6 is a hydrogen atom or an alkyl group and the other is (a) an alkyl group optionally substituted by one to three groups selected from a halogen atom, a cyano group, an alkoxy group, an optionally substituted cycloalkyl group, an amino optionally substituted by one or two alkyl groups, a alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group, an acyl group, an optionally substituted aryl group and optionally substituted saturated or unsaturated heterocyclic group, (b) an optionally substituted cycloalkyl group, (c) a group of the formula: -N (R 8) ) (R9) 1 (d) an optionally substituted aryl group or (e) an optionally substituted, saturated or unsaturated heterocyclic group, or both R5 and R6 combine to form together with a m Adjacent nitrogen atom is an optionally substituted saturated or unsaturated nitrogen heterocyclic group containing one of R 8 and R 9 is a hydrogen atom or an alkyl group and the other is (a) an alkyl group optionally substituted by one to three groups selected from a halogen atom , a cyano group and an aryl group, (b) a cycloalkyl group, (c) an optionally substituted aryl group or (d) an acyl group or (e) an optionally substituted saturated or unsaturated heterocyclic group, one of R 50 and R60 is a hydrogen atom or an alkyl group and the other is a hydrogen atom, an alkyl group or an acyl group, or both combine together with the adjacent nitrogen atom to form a group cyclic of the following formula: <formula> formula see original document where Ring A1 is a 5- to 7-membered aliphatic nitrogen-containing heterocyclic group optionally substituted by an oxo group, R51 is an alkyl group or a group optionally substituted arylsulfonyl, R61 is an alkylamino group or an azido group, or a pharmaceutically acceptable salt thereof. Pharmaceutical composition according to claim 22, characterized in that it is an agent for the prevention and / or treatment of some CB1 receptor mediated diseases. Pharmaceutical composition according to Claim 23, characterized in that the CB1 receptor-mediated disease is psychosis including schizophrenia, anxiety disorder, stress, depression, epilepsy, neurodegenerative disorder, spinocerebellar disorder, cognitive disorder, trauma. craniocerebral, panic attack, peripheral neuropathy, glaucoma, migraine, Parkinson's disease, Alzheimer's disease, Huntington's disease, Raynaud's syndrome, tremor, obsessive-compulsive disorder, amnesia, geriatric dementia, thymic disorder, Tourette's syndrome, dyskinesia tardive, bipolar disorder, cancer, drug-induced dyskinesia, dystonia, septic shock, hemorrhagic shock, hypotension, insomnia, immune disease including inflammation, multiple sclerosis, vomiting, diarrhea, asthma, appetite disorder including bulimarexia and anorexia, obesity, diabetesmelito non-insulin-dependent (NIDDM), memory disorder, cardiovascular disease, infertility disorder, infection, demyelination-related disease, neuroinflammation, viral encephalitis, cerebrovascular accident, liver cirrhosis or gastrointestinal disorder including intestinal transit disorder. Pharmaceutical composition according to claim 22, characterized in that it is an agent for withdrawal of chronic treatment, alcohol dependence or drug abuse. Pharmaceutical composition according to claim 22, characterized in that it is an agent for enhancing the analgesic activity of an analgesic or narcotic drug. Pharmaceutical composition according to Claim 22, characterized in that it is a smoking cessation agent (smoking cessation or nicotine dependence).