JP2008285482A - Medicinal composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medicinal composition containing a pyrazolo[1,5-a]pyrimidine compound having a CB1 receptor-antagonizing action as an active ingredient. <P>SOLUTION: This medicinal composition comprises a compound represented by general formula [I] (wherein, R<SP>1</SP>and R<SP>2</SP>are an aryl group or the like; Q is a single bonding group; the ring A is a substituted pyrazole ring condensed with the adjacent pyrimidine ring; R<SP>3</SP>is identically or differently H or the like) or its pharmacologically acceptable salt as an active ingredient. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a pharmaceutical composition comprising a novel pyrazolo [1,5-a] pyrimidine compound having an excellent central cannabinoid (CB1) receptor antagonistic action or a pharmaceutically acceptable salt thereof as an active ingredient.

  It is well known that cannabis can cause various neuropsychiatric reactions such as confusion in time and space, euphoria, memory impairment, decreased pain, and hallucinations. Many of these actions are due to compounds collectively referred to as cannabinoids, including delta 9-tetrahydrocannabinol (delta 9-THC). The effects of cannabinoids are thought to be due to interactions with specific high affinity receptors present in the body. So far, two cannabinoid receptors (CB1 receptor, CB2 receptor) have been identified and cloned, and CB1 receptors are distributed in the central nervous system (CNS) such as the brain (Non-patent Document 1). Receptors are distributed in immune tissues such as the spleen (Non-patent Document 2).

  Substances having an affinity for these cannabinoid receptors (agonists, antagonists, and inverse agonists) exhibit various pharmacological actions similar to cannabis, and in particular, substances having affinity for the central CB1 receptor are psychological. It is useful for the treatment of CNS diseases such as disorders and neurological disorders.

Examples of compounds having affinity for the CB1 receptor include pyrazole-3-carboxamide derivatives such as SR141716 (Non-patent Document 3), 4,5-dihydro-1H-pyrazole derivatives such as SLV-319 (Non-patent Document 4), Various compounds such as dihydropyrazolo [3,4-c] pyridin-7-one derivatives or 2H-pyrazolo [4,3-d] pyrimidin-7 (6H) -one derivatives (Patent Document 1) are known. Yes. In addition, among these compounds, at least SR141716 and SLV-319 have been clinically tested for their effectiveness as appetite suppressants (anti-obesity agents).
WO2004 / 094417 Nature, Vol. 346, pp561-564 (1990) Nature, Vol. 365, pp61-65 (1993) Similand, J .; et al, Life Science, Vol. 63, PL113-PL117 (1998) Lange, JH, et al, Journal of Medicinal Chemistry, Vol. 47 (3), p627-643 (2004)

  The object of the present invention is to provide a pharmaceutical composition comprising a novel pyrazolo [1,5-a] pyrimidine compound having an excellent CB1 receptor antagonistic action as an active ingredient.

  The present invention relates to general formula [I]:

[Where,
R ¹ and R ² are the same or different and each may have an aryl group which may have a substituent or a saturated or unsaturated heterocyclic group which may have a substituent,
Q is a single bond, a methylene group or a group represented by the formula: —N (R ^Q ) —,
^RQ is an alkyl group,
Ring A is fused with the adjacent pyrimidine ring (A), (B) or (C):

A substituted pyrazole ring represented by
R ³ and R ⁴ are the same or different and are (a) a hydrogen atom, (b) a cyano group, (c) an alkyl group optionally substituted with 1 to 3 halogen atoms, (d) an alkyloxy group ( The alkyl part of the group is substituted with 1 to 3 groups selected from a halogen atom, a hydroxyl group, an amino group optionally substituted with 1 to 2 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 represented by the formula: —N (R ′) (R ″),
R ′ and R ″ are the same or different and are selected from (1) a hydrogen atom, (2) a halogen atom, an amino group optionally substituted by 1 to 2 alkyl groups, and an alkyloxy group. (3) an acyl group, (4) an alkylsulfonyl group, or (5) an aminosulfonyl group optionally substituted with one or two alkyl groups, or Represents that both are bonded to each other at the end to form a saturated or unsaturated nitrogen-containing heterocyclic group with the adjacent nitrogen atom,
E represents the following formulas (i) to (v):

Any of the groups represented by
R ⁰⁰ is an alkyl group,
Q ¹ is a single bond, an alkylene group or a group represented by 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) a halogen atom, a cyano group, an alkyloxy group, an optionally substituted cycloalkyl group, 1 to 2 An amino group optionally substituted with an alkyl group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group, an acyl group, an aryl group which may have a substituent, and a saturated or unsaturated group which may have a substituent An alkyl group which may be substituted with 1 to 3 groups selected from saturated heterocyclic groups, (b) a cycloalkyl group which may have a substituent, (c) formula: —N (R ⁸ ) A group represented by (R ⁹ ), (d) an aryl group which may have a substituent, or (e) a saturated or unsaturated heterocyclic group which may have a substituent, or mutual both R ⁵ and ^{R 6} at the end Combine to form adjacent nitrogen atom may have a substituent with a saturated or unsaturated nitrogen-containing heterocyclic group,
One of R ⁸ and R ⁹ is a hydrogen atom or an alkyl group, and the other is (a) an alkyl group which may be substituted with 1 to 3 groups selected from a halogen atom, a cyano group and an aryl group, b) a cycloalkyl group, (c) an aryl group which may have a substituent, (d) an acyl group or (e) a saturated or unsaturated heterocyclic group which may have a substituent,
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 are bonded to each other together with an adjacent nitrogen atom in the following formula:

[Wherein, ring A ¹ represents a 5- to 7-membered aliphatic nitrogen-containing heteromonocyclic group which may be substituted with an oxo group. ]
Form the cyclic group shown,
R ⁵¹ represents an alkylsulfonyl group or an optionally substituted arylsulfonyl group,
R ⁶¹ represents an alkylamino group or an azide group. ]
The pharmaceutical composition which uses the pyrazolo [1,5-a] pyrimidine compound shown by these, or its pharmacologically acceptable salt as an active ingredient.

  The compound [I] is useful as a CB1 receptor ligand (particularly a CB1 receptor antagonist) because it exhibits high affinity for the CB1 receptor. Therefore, the pharmaceutical composition of the present invention is useful for the prevention and treatment of various diseases involving the above receptors (for example, psychosis including schizophrenia, appetite disorders (bulimia, anorexia), etc.). The pharmaceutical composition of the present invention is useful for chronic treatment and withdrawal from alcohol or drug abuse (eg, opioids). Furthermore, the pharmaceutical composition of the present invention is useful as an analgesic activity enhancer or a smoking cessation aid. In addition, the above compound [I] or a pharmacologically acceptable salt thereof has low toxicity, and the pharmaceutical composition of the present invention has a feature that it is highly safe as a medicine.

In the compound [I] which is an active ingredient of the present invention, when R ¹ and R ² are aryl groups, the aryl group is, for example, a 6 to 10 membered monocyclic or bicyclic ring such as a phenyl group or a naphthyl group And aryl groups, of which the phenyl group is preferred.

When R ¹ , R ² , R ³ or R ⁴ is a saturated or unsaturated heterocyclic group, examples of the heterocyclic group include 1 to 3 selected from a sulfur atom, an oxygen atom and a nitrogen atom. Saturated or unsaturated 5- to 7-membered heteromonocyclic groups containing heteroatoms are exemplified. More specifically, a 5- or 6-membered oxygen-containing heterocyclic group such as a furyl group, a tetrahydrofuranyl group, a pyranyl group, or a tetrahydropyranyl group, a thienyl group, a tetrahydrothienyl group, a thiopyranyl group, or a tetrahydrothiopyranyl group. Saturated or unsaturated 5- to 6-membered sulfur-containing heterocyclic group, or pyrrolidinyl group, imidazolyl group, pyrazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, pyridyl group, piperidyl group, pyrimidinyl group, pyrazinyl group, pyridazinyl Groups, morpholinyl groups, thiomorpholinyl groups, azacycloheptyl groups, and saturated or unsaturated 5- to 7-membered nitrogen-containing heterocyclic groups such as R ¹ or R ² include thienyl group, pyrrolidinyl group, piperidyl group A saturated or unsaturated group such as a group or pyridyl group Preferably membered sulfur- or nitrogen-containing heteromonocyclic group, the R ³ or R ^4, pyrrolidinyl group, piperidyl group, such as unsaturated 5- to 6-membered oxygen-containing morpholino group or a thiomorpholino group, sulfur- or nitrogen-containing Heteromonocyclic groups are preferred.

The aryl group in R ¹ , R ² , R ³ or R ⁴ is substituted with a halogen atom, a cyano group, an alkyl group which may be substituted with 1 to 3 halogen atoms, or 1 to 3 halogen atoms. An alkyloxy group which may be substituted, an amino group which may be substituted with 1 to 2 alkyl groups, an alkylthio group, an alkylsulfinyl group and an alkylsulfonyl group which may be substituted with 1 to 3 groups Good.

The saturated or unsaturated heterocyclic group in R ¹ , R ² , R ³ or R ⁴ is a halogen atom, a cyano group, an oxo group, an alkyl group optionally substituted with 1 to 3 halogen atoms, an alkyl group Oxyalkyl group, alkyloxy group optionally substituted with 1 to 3 halogen atoms, alkyloxyalkyloxy group, amino group optionally substituted with 1 to 2 alkyl groups, alkylthio group, alkylsulfinyl It may be substituted with 1 to 3 groups selected from a group and an alkylsulfonyl group.

When R ⁵ , R ⁶ , R ⁸ or R ⁹ is a cycloalkyl group, the cycloalkyl group may be substituted with 1 to 2 groups selected from a cyano group and an alkyl group.

Examples of the aryl group in R ⁵ , R ⁶ , R ⁸ or R ⁹ include 6 to 10-membered monocyclic or bicyclic aryl groups such as a phenyl group and a naphthyl group, and among these, a phenyl group is preferable. The aryl group may be substituted with 1 to 2 halogen atoms.

When R ⁵ , R ⁶ , R ⁸ or R ⁹ is a saturated or unsaturated heterocyclic group, the heterocyclic group includes (a) a saturated or unsaturated 4- to 7-membered heteromonocyclic group (including The heteromonocyclic group includes 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom); (b) the heteromonocyclic group, a 3 to 8 membered cycloalkyl group, and 5 to 6 From a member monocyclic aryl group and a saturated or unsaturated 4- to 7-membered heteromonocyclic group (the heteromonocyclic group contains 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom) 8- to 15-membered saturated or unsaturated nitrogen-containing bicyclic or tricyclic heterocyclic group formed by condensation with 1 to 2 selected cyclic groups; or (c) saturated or unsaturated 8 to 11 And a nitrogen-containing spiroheterocyclic group.

Examples of the saturated or unsaturated heterocyclic group for R ⁵ , R ⁶ , R ⁸ or R ⁹ include:
(A) Furyl group, tetrahydrofuranyl group, pyranyl group, tetrahydropyranyl group, thiacyclobutyl group, thienyl group, tetrahydrothienyl group, thiopyranyl group, tetrahydrothiopyranyl group, benzofuranyl group, dihydrobenzofuranyl group, isobenzo Saturated or unsaturated oxygen-containing or sulfur-containing heterocyclic group selected from furanyl group, chromanyl group, isochromanyl group, chromenyl group, isochromenyl group, benzothienyl group and dihydrobenzothienyl group, or (B) azetidyl group, pyrrolidinyl group Pyrrolinyl group, imidazolidinyl group, imidazolinyl group, pyrazolidinyl group, pyrazolinyl group, pyrrolyl group, 2H-pyrrolyl group, imidazolyl group, pyrazolyl group, dihydropyrazolyl group, thiazolidinyl group, thiazolyl group, isothiazolyl group, Soxazolyl group, oxazolidinyl group, pyridyl group, dihydropyridyl group, tetrahydropyridyl group, piperidyl group, pyrazinyl group, piperazinyl group, pyrimidinyl group, tetrahydropyrimidinyl group, pyridazinyl group, morpholinyl group, azosinyl group, azacycloheptyl group, indolizinyl group, Benzimidazolyl group, benzotriazolyl group, indolyl group, isoindolyl group, 3H-indolyl group, indolinyl group, isoindolinyl group, 1H-indazolyl group, pyrrolopyridyl group, pyrrolopyrimidinyl group, tetrazolyl group, purinyl group, pteridinyl group, 4H- Quinolidinyl group, quinolyl group, dihydroquinolyl group, tetrahydroquinolyl group, isoquinolyl group, dihydroisoquinolyl group, tetrahydroisoquinolyl group, phthalazinyl , Dihydrophthalazinyl group, naphthyridinyl group, dihydronaphthyridinyl group, tetrahydronaphthyridinyl group, quinoxalinyl group, quinazolinyl group, dihydrobenzothiazinyl group, dihydrobenzoxazinyl group, cinnolinyl group, pteridinyl group, xanthenyl group, carbazolyl Group, β-carbolinyl group, phenanthridinyl group, acridinyl group, 5H-dihydrodibenzazepinyl group and the general formula:

[Wherein, R ^A and R ^B are the same or different and represent a hydrogen atom or an alkyl group, and q and r each represent an integer of 1 or 2. ]
And a saturated or unsaturated nitrogen-containing heterocyclic group selected from spiroheterocyclic groups represented by the formula:

  Among the above, preferred saturated or unsaturated heterocyclic groups include, for example, tetrahydrofuranyl group, pyrrolyl group, pyrrolidinyl group, piperidyl group, azacycloheptyl group, tetrahydropyranyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, Examples include a thiacyclobutyl group, a tetrahydrothienyl group, a tetrahydrothiopyranyl group, a thiazolyl group, a pyridyl group, a pyrimidinyl group, an indolinyl group, a pyrrolopyridyl group, and a tetrahydronaphthyridinyl group.

Examples of the saturated or unsaturated nitrogen-containing heterocyclic group formed by combining R ⁵ and R ⁶ with each other include (a) a saturated or unsaturated 4- to 7-membered nitrogen-containing heterocyclic monocyclic group (the heterocyclic The monocyclic group may contain 2 or more nitrogen atoms, and may contain 1 to 2 heteroatoms selected from oxygen atoms and sulfur atoms in addition to the nitrogen atoms); (b) The heteromonocyclic group, a 3- to 8-membered cycloalkyl group, a 5- to 6-membered monocyclic aryl group, and a saturated or unsaturated 4- to 7-membered heteromonocyclic group (the heteromonocyclic group is an oxygen atom, An 8- to 15-membered saturated or unsaturated nitrogen-containing bicyclic ring formed by condensation of 1 to 2 cyclic groups selected from (including 1 to 4 heteroatoms selected from a sulfur atom and a nitrogen atom) A tricyclic heterocyclic group; or (c) a saturated or unsaturated 8- to 11-membered nitrogen-containing spiro compound Cyclic group, and the like.

  Specific examples of the saturated or unsaturated nitrogen-containing heterocyclic group include, for example, azetidyl group, pyrrolidinyl group, pyrrolinyl group, imidazolidinyl group, imidazolinyl group, pyrazolidinyl group, pyrazolinyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, Dihydropyrazolyl group, thiazolidinyl group, oxazolidinyl group, dihydropyridyl group, tetrahydropyridyl group, piperidyl group, piperazinyl group, tetrahydropyrimidinyl group, morpholinyl group, azacycloheptyl group, benzimidazolyl group, benzotriazolyl group, indolyl group, isoindolyl Group, indolinyl group, isoindolinyl group, 1H-indazolyl group, purinyl group, dihydroquinolyl group, tetrahydroquinolyl group, dihydroisoquinolyl group, tetrahydroisoquinolyl group, Hydro lid pyrazinyl group, dihydroquinazolinyl group, dihydro-benzothiazinyl group, dihydro benzoxazinyl group, carbazolyl group, beta-carbolinyl group, 5H-dihydrodibenz dithienoazepinyl groups and the general formula:

[Wherein, R ^A and R ^B are the same or different and represent a hydrogen atom or an alkyl group, and q and r each represent an integer of 1 or 2. ]
And a saturated or unsaturated nitrogen-containing heterocyclic group selected from spiroheterocyclic groups represented by the formula:

  Among the above, preferred saturated or unsaturated nitrogen-containing heterocyclic groups include, for example, saturated 5- to 7-membered nitrogen-containing heterocyclic monocyclic groups such as morpholino group, thiomorpholino group, piperidino group, piperazino group or azacycloheptyl group. Group.

Furthermore, the saturated or unsaturated heterocyclic group (and the nitrogen-containing heterocyclic group formed by combining R ⁵ and R ⁶ ) in R ⁵ , R ⁶ , R ⁸ or R ⁹ is a halogen atom, a hydroxyl group , Cyano group, oxo group, alkyl group, alkyl group substituted with 1 to 3 halogen atoms, alkyloxyalkyl group, aminoalkyl group, cycloalkyl group, arylalkyl group, alkyloxy group, 1 to 3 An alkyloxy group substituted with a halogen atom, an acyl group, an amino group optionally substituted with 1 to 2 alkyl groups, an acylamino group, an alkylsulfonyl group, or an alkyl group substituted with 1 to 2 alkyl groups 1-4 selected from a good aminosulfonyl group, an aryl group optionally substituted by 1 to 2 halogen atoms, and a saturated or unsaturated 5- to 6-membered nitrogen-containing heterocyclic group It may be substituted with the group.

Examples of the acyl group in R ⁴ , R ⁵ , R ⁶ , R ⁸ or R ⁹ include the following general formula:
R ^X -COOH [Ac-1]
[In the formula, R ^X represents (a) a hydrogen atom, (b) an alkyl group optionally substituted with 1 to 3 groups selected from a halogen atom, a cyano group, an alkylsulfonyl group and a pyridyl group, (c 1) or 2 groups selected from an alkyloxy group optionally substituted with an aryl group, (d) a cycloalkyl group, (e) a halogen atom, a cyano group, an alkyl group, a trihalogenoalkyl group and an alkyloxy group An aryl group optionally substituted with (f) an amino group optionally substituted with 1 to 2 alkyl groups, or (g) a halogen atom, a cyano group, an alkyl group and a trihalogenoalkyl group. Represents a saturated or unsaturated heterocyclic group optionally substituted by 1 to 2 groups. ]
And a group formed by removing one hydroxyl group from the carboxylic acid represented by (i.e., a group represented by the formula: R < ^X > CO-). Specific examples of such an acyl group include, for example, (a1) formyl group, (b1) acetyl group, C _1-6 alkyl-carbonyl group such as propionyl group, and trihalogeno C _1-6 alkyl such as trifluoroacetyl group. - carbonyl group, such as cyano _{C 1-6} alkyl cyanoacetyl group - carbonyl group, such as pyridyl _{-C 1-6} alkyl pyridyl acetyl - carbonyl group, (c1) methoxycarbonyl group, an ethoxycarbonyl group, tert- butoxycarbonyl such _{C 1-6} alkyloxy group - carbonyl group, such as an aryl _{-C 1-6} alkyloxy benzyloxycarbonyl group - carbonyl group, (d1) cyclopropylcarbonyl group, such as _{C 3-8} cycloalkyl cyclopentyl group -Carbonyl group, (e1) benzoy An aryl-carbonyl group such as a chlorobenzoyl group, a chlorobenzoyl group, a fluorobenzoyl group, a mono- or dihalogenoaryl-carbonyl group such as a difluorobenzoyl group, a cyanoaryl-carbonyl group such as a cyanobenzoyl group, or a trihalogeno group such as a trifluoromethylbenzoyl group. C _1-6 alkyl - aryl - carbonyl group, such as _{C 1-6} alkyloxy methoxybenzoyl group - aryl - carbonyl group, (f1) carbamoyl group, _{N-(C 1-6} alkyl) carbamoyl group, or (g1) Examples include a furoyl group, a thenoyl group, a bromothenoyl group, a cyanothenoyl group, a pyridylcarbonyl group, a chloropyridylcarbonyl group, a cyanopyridylcarbonyl group, a trifluoromethylpyridylcarbonyl group, and a pyrazinylcarbonyl group.

In the compound [I], when E is a group represented by the formula (ii), the group (ii) is, for example, the following formula:
(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), or ^{(d) -N (R 7)} -C (= O) -N (R 5) (R 6)
[Wherein, Alk represents a linear or branched C _1-6 alkylene group, and other symbols have the same meaning as described above. ]
And a group represented by

  Among the above-mentioned compound [I], preferable compounds include, for example, compounds of the following group A to group E.

Group A:
In the general formula [I], R ¹ and R ² are the same or different and may be substituted with one or two groups selected from a halogen atom and a trihalogenoalkyl group, Q is a single bond, Ring A is a substituted pyrazole ring represented by formula (A), E is the following formula (i):
-C (= O) O-R ⁰⁰ (i)
R ⁴ is a group represented by (1) an amino group optionally substituted with 1 to 2 groups selected from an alkyl group and an alkylsulfonyl group, or (2) substituted with 1 to 2 alkyl groups. Or a pharmacologically acceptable salt thereof, which may be an aminosulfonyl group.

Among the group A compounds, more preferable compounds include, for example, R ¹ and chlorophenyl group or trifluoro-C _1-4 alkylphenyl group, R ² is chlorophenyl group, R ⁰⁰ is C _1-4 alkyl group, R ⁴ compound is an amino group substituted with one to two groups selected from C _1-4 alkyl and C _1-4 alkylsulfonyl group.

Group B:
In the general formula [I], R ¹ and R ² are the same or different, and (1) a halogen atom, a cyano group, an alkyl group which may be substituted with 1 to 3 halogen atoms, and 1 to 3 halogens. An alkyloxy group optionally substituted by an atom, a phenyl group optionally substituted by 1 to 3 groups selected from an amino group optionally substituted by 1 to 2 alkyl groups and an alkylsulfonyl group Or (2) 1 to 3 groups selected from a halogen atom, an oxo group, an alkyl group optionally substituted with 1 to 3 halogen atoms, an alkyloxy group, an alkyloxyalkyl group and an alkyloxyalkyloxy group A saturated or unsaturated 5- to 7-membered heterocyclic group optionally substituted by
A substituted pyrazole ring in which ring A is represented by formula (A) or (B),
E represents the following formulas (a) to (e):
(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 >) and (e) -C (= NR < ⁵¹ >)-R < ⁶¹ >.
A group selected from
R ³ is a hydrogen atom, a cyano group or an alkyloxy group,
R ⁴ is an alkyl group optionally substituted by 1 to 3 groups selected from (a) a hydrogen atom, (b) a cyano group, (c) a halogen atom and a hydroxyl group, (d) an alkyloxy group (the group The alkyl moiety of may be substituted with 1 to 3 groups selected from a halogen atom, a hydroxyl group, an amino group optionally substituted with 1 to 2 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 represented by the formula: —N (R ′) (R ″),
R ′ and R ″ are the same or different and are selected from (1) a hydrogen atom, (2) a halogen atom, an amino group optionally substituted by 1 to 2 alkyl groups, and an alkyloxy group. (3) an acyl group, (4) an alkylsulfonyl group, or (5) an aminosulfonyl group optionally substituted with one or two alkyl groups, or (6) Both are bonded to each other at the end to form a saturated or unsaturated nitrogen-containing heterocyclic group together with the adjacent nitrogen atom (the heterocyclic group may be substituted with a hydroxyl group or an alkyloxy group);
R ⁵ and R ⁶ are
One is a hydrogen atom or an alkyl group, and the other is (1) a halogen atom, an alkyloxy group, a cycloalkyl group, an alkylthio group, an alkylsulfonyl group, an amino group optionally substituted by 1 to 2 alkyl groups, A morpholinocarbonyl group, a phenyl group optionally substituted with a cyano group, and a saturated or unsaturated 5- to 6-membered heteromonocyclic group (the heterocyclic group is a group selected from a halogen atom, an alkyl group, and a trihalogenoalkyl group) An alkyl group which may be substituted with 1 to 3 groups selected from
(2) a cycloalkyl group optionally substituted with a cyano group or an alkyl group,
(3) a group represented by the formula: -N (R ⁸ ) (R ⁹ ),
(4) phenyl group, or (5) halogen atom, cyano group, hydroxyl group, oxo group, alkyl group optionally substituted by 1 to 3 halogen atoms, cycloalkyl group, alkylcarbonyl group, alkyloxycarbonyl group , An alkylsulfonyl group, an aminosulfonyl group optionally substituted with 1 to 2 alkyl groups, a carbamoyl group optionally substituted with 1 to 2 alkyl groups, an alkyloxycarbonylamino group, 1 to 2 A saturated or unsaturated 4 to 10 member optionally substituted with 1 to 4 groups selected from a phenyl group optionally substituted with a halogen atom and a 5 to 6 membered saturated or unsaturated heteromonocyclic group A heteromonocyclic or bicyclic group, or (6) both R ⁵ and R ⁶ are bonded together and saturated or unsaturated nitrogen-containing 4 together with the adjacent nitrogen atom 4 To form a 7-membered heteromonocyclic group (the heterocyclic group may be substituted by 1 to 2 groups selected from a halogen atom and an oxo group);
R ⁸ is a hydrogen atom or an alkyl group, R ⁹ is an alkyl group which may be substituted with 1 to 3 groups selected from (a) a halogen atom, a cyano group and a phenyl group; (b) a halogen atom and a cyano group A phenyl group optionally substituted by a group selected from 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- or 6-membered saturated or unsaturated heteromonocyclic group which may be substituted with a group selected from a halogen atom, a cyano group, an alkyl group, an alkyloxy group and a trihalogenoalkyl group;
R ⁷ is a hydrogen atom,
R ⁵¹ is an alkyl group or a phenylsulfonyl group (the phenyl portion of the group may be substituted with 1 to 2 halogen atoms),
A compound or a pharmaceutically acceptable salt thereof, wherein R ⁶¹ is an alkylamino group or an azide group.

Among the group B compounds, more preferred compounds are, for example, ¹ to 2 wherein R ¹ is selected from (1) a halogen atom, a cyano group, a dihalogenoalkyl group, a trihalogenoalkyl group, an alkyloxy group, and a dialkylamino group. A phenyl group optionally substituted with 1 group or (2) an oxo group, an alkyl group, a trihalogenoalkyl group, an alkyloxy group, an alkyloxyalkyl group, an alkyloxyalkyloxy group, and a dialkylamino group, A 5- to 7-membered saturated or unsaturated heterocyclic group optionally substituted by two groups,
R ² is (1) a phenyl group which may be substituted with 1 to 2 groups selected from a halogen atom and a cyano group, or (2) a 5 to 6 membered saturated or unsaturated group which may be substituted with a halogen atom. A heterocyclic group,
R ³ is a hydrogen atom,
R ⁴ is a hydrogen atom, an alkyl group, a dihalogenoalkyl group, a hydroxyalkyl group, a trihalogenoalkyl group, an alkyloxyalkyl group, a hydroxyalkyloxy group, an alkyloxyalkyloxy group, an alkylsulfonylalkyl group, or a formula: —N (R ') A group represented by (R "),
One of R ′ and R ″ is a hydrogen atom or an alkyl group, and the other is an acyl group or an alkylsulfonyl group,
E is the following formula:
(A) -C (= O) -N (R 5) (R 6)
(B) -C (= O) -Alk-N (R 5) (R 6) or ^{(e) -C (= NR 51} ) -R 61
A group represented by
R ⁵ and R ⁶ are
One is a hydrogen atom or an alkyl group,
The other is (1) alkyl group, (2) cycloalkyl group, (3) phenyl group, (4) halogen atom, oxo group, cyano group, hydroxyl group, alkyl group, trihalogenoalkyl group, alkyloxy group, alkyloxyalkyl Saturated or unsaturated 4 to 4 which may be substituted with 1 to 4 groups selected from a group, alkylcarbonyl group, dialkylcarbamoyl group, alkylsulfonyl group, dialkylaminosulfonyl group, phenyl group, halogenophenyl group and pyridyl group A 10-membered monocyclic or bicyclic heterocyclic group or a group represented by the formula (5): —N (R ⁸ ) (R ⁹ ), or (6) 5 to 6 members bonded together. A saturated or unsaturated nitrogen-containing heteromonocyclic group (the heterocyclic group may be substituted with 1 to 2 groups selected from a halogen atom and an oxo group),
R ⁸ is an alkyl group,
R ⁹ is (1) an alkyl group, (2) a phenyl group that may be substituted with a halogen atom, (3) an alkyl group that may be substituted with a pyridyl group, or (4) a halogen atom, an alkyl group, or a trihalogeno. A 4-6 membered saturated or unsaturated heteromonocyclic group optionally substituted with a group selected from an alkyl group and an alkyloxy group,
R ⁵¹ is an alkyl group or a halogenophenylsulfonyl group,
Examples thereof include compounds in which R ⁶¹ is an alkylamino group or an azide group.

Among the group B compounds, more preferred compounds include, for example, (a) R ^{1 selected} from a chlorine atom, a fluorine atom, a cyano group, a difluoro-C _1-4 alkyl group, and a trifluoro-C _1-4 alkyl group. A phenyl group optionally substituted with a group or (b) a pyridyl group optionally substituted with a trifluoro-C _1-4 alkyl group,
R ² is a phenyl group which may be substituted with one or two groups selected from a chlorine atom, a fluorine atom, a bromine atom and a cyano group;
R ³ is a hydrogen atom,
R ⁴ is a hydrogen atom, a C _1-4 alkyl group, a difluoro-C _1-4 alkyl group, a trifluoro-C _1-4 alkyl group, a C _1-4 alkyloxy-C _1-4 alkyl group or a C _1-4 An alkyl-carbonylamino group,
E is the following formula:
(A) -C (= O) -N (R 5) (R 6) , or (b) -C (= O) -Alk-N (R 5) (R 6)
A group represented by
One of R ⁵ and R ⁶ is a hydrogen atom, and the other is a C _1-4 alkyl group, a pyridyl-C _1-4 alkyl group, a C _5-7 cycloalkyl group, a chlorophenyl group, a saturated or unsaturated 4 to 6 member A heteromonocyclic group (which may be substituted with one or two groups selected from a halogen atom, an oxo group and a _C1-4 alkyloxy- _C1-4 alkyl group) or a formula : A group represented by —N (R ⁸ ) (R ⁹ ), or both are bonded to each other to form a 5- to 6-membered nitrogen-containing heteromonocyclic group (the heteromonocyclic group having 1 to 2 oxo groups) Optionally substituted with a group),
R ⁸ is a C _1-4 alkyl group,
_Examples thereof include compounds in which R ⁹ is a C _1-4 alkyl group, a chlorophenyl group, a pyridyl group, or a C _1-4 alkyloxypyridyl group.

Group C:
In the general formula [I], R ¹ and R ² are the same or different and may be substituted with one or two groups selected from a halogen atom and a trihalogenoalkyl group, Q is a single bond, Ring A is a substituted pyrazole ring represented by formula (A), R ³ is a hydrogen atom, R ⁴ is a hydrogen atom or an alkyl group, and E is formula (iii):

One of the groups represented by R ⁵ and R ⁶ is a hydrogen atom or an alkyl group, and the other is substituted with (1) an alkyl group, (2) a cycloalkyl group, or (3) 1-2 oxo groups. Or a 5- or 6-membered saturated or unsaturated sulfur-containing or nitrogen-containing heterocyclic group, or (4) they may be bonded to each other and substituted with 1 to 2 oxo groups together with adjacent nitrogen atoms. A compound or a pharmaceutically acceptable salt thereof which forms a good 5- to 6-membered saturated or unsaturated nitrogen-containing heterocyclic group.

Among the group C compounds, more preferred compounds include, for example, R ¹ is a trihalogenoalkyl-phenyl group, R ² is a halogenophenyl group, R ⁴ is an alkyl group, and one of R ⁵ and R ⁶ is a hydrogen atom or an alkyl group. The other is (1) an alkyl group, (2) a cycloalkyl group, or (3) a 5- or 6-membered saturated or unsaturated sulfur-containing or nitrogen-containing complex optionally substituted with 1-2 oxo groups. A cyclic group, or (4) a 5- or 6-membered saturated or unsaturated nitrogen-containing heterocyclic group that may be bonded to each other and substituted with 1 to 2 oxo groups together with adjacent nitrogen atoms. Examples of the compound to be formed.

Group D:
In the general formula [I], R ¹ and R ² are the same or different and may be substituted with one or two groups selected from a halogen atom and a trihalogenoalkyl group, Q is a single bond, Ring A is a substituted pyrazole ring represented by formula (A), R ³ is a hydrogen atom, R ⁴ is a hydrogen atom or an alkyl group, and E is formula (iv):

R ⁵⁰ and R ⁶⁰ are either a hydrogen atom or an alkyl group, and the other is an alkyl group or an acyl group, or both are bonded to each other and are bound to one to two oxo groups together with an adjacent nitrogen atom. The compound or its pharmacologically acceptable salt which forms the 5-6 membered saturated or unsaturated nitrogen-containing heterocyclic group which may be substituted.

Group E:
In the general formula [I], R ¹ and R ² are the same or different and may be substituted with one or two groups selected from a halogen atom and a trihalogenoalkyl group, Q is a single bond, Ring A is a substituted pyrazole ring represented by the formula (C), R ³ is a hydrogen atom, R ⁴ is a group represented by the formula: —N (R ′) (R ″), and R ′ and R ″ are the same or different. , A hydrogen atom or an alkyl group, or (6) a compound in which both are bonded to each other at the end to form a 5- or 6-membered saturated or unsaturated nitrogen-containing heterocyclic group with an adjacent nitrogen atom, or a pharmacologically acceptable salt thereof Possible salt.

Among the compounds [I], particularly preferable compounds include, for example,
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] 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] 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-tetrahydrothien-3-yl) carbamoyl] pyrazolo [1,5-a] pyrimidine;
(R) -6- (2-Chlorophenyl) -7- (4-difluoromethylphenyl) -3- [N- (1,1-dioxo-tetrahydrothien-3-yl) carbamoyl] pyrazolo [1,5-a ] Pyrimidine;
(R) -6- (2-Chlorophenyl) -7- (4-trifluoromethylphenyl) -3- [N- (1,1-dioxo-tetrahydrothien-3-yl) carbamoyl] -2-methylpyrazolo [1 , 5-a] pyrimidine;
(S) -6- (2-Chlorophenyl) -7- (4-trifluoromethylphenyl) -3- [N- (1,1-dioxo-tetrahydrothien-3-yl) carbamoyl] -2-methylpyrazolo [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) -3- [N- (1,1-dioxo-tetrahydrothien-3-yl) carbamoyl] -2-methylpyrazolo [1,5- a] pyrimidine;
(S) -6- (2-Chlorophenyl) -7- (4-chlorophenyl) -3- [N- (1,1-dioxo-tetrahydrothien-3-yl) carbamoyl] -2-methylpyrazolo [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-tetrahydrothien-3-yl) carbamoyl] pyrazolo [1,5- a] pyrimidine;
(S) -6- (2-Chlorophenyl) -7- (4-trifluoromethylphenyl) -3- [N- (1,1-dioxo-tetrahydrothien-3-yl) carbamoyl] pyrazolo [1,5- a] pyrimidine;
(R) -6- (2-Chlorophenyl) -7- (4-trifluoromethylphenyl) -3- [N- (1,1-dioxo-tetrahydrothien-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-tetrahydrothien-3-yl) carbamoyl] pyrazolo [1,5-a] pyrimidine;
6- (2-chlorophenyl) -7- (4-trifluoromethylphenyl) -3- (N-cyclopentylcarbamoyl) pyrazolo [1,5-a] pyrimidine;
6- (2-chlorophenyl) -7- (4-trifluoromethylphenyl) -3- [N- [N-methyl-N- (2-pyridyl) amino] carbamoyl] pyrazolo [1,5-a] pyrimidine;
(R) -6- (2-Chlorophenyl) -7- (4-chlorophenyl) -3- [N- (1,1-dioxo-tetrahydrothien-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) -3- [N- (1,1-dioxo-tetrahydrothien-3-yl) carbamoyl] -2-methylpyrazolo [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;
(S) -6- (2-Chlorophenyl) -7- (4-chlorophenyl) -3- [N- (1,1-dioxo-tetrahydrothien-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-dioxotetrahydrothien-3-yl) carbamoyl] pyrazolo [1, 5-a] pyrimidine;
(S) -6- (2-Chlorophenyl) -7- (4-difluoromethylphenyl) -3- [N- (1,1-dioxotetrahydrothien-3-yl) carbamoyl] pyrazolo [1,5-a ] Pyrimidine;
(R) -6- (2-cyanophenyl) -7- (4-trifluoromethylphenyl) -3- [N- (1,1-dioxotetrahydrothien-3-yl) carbamoyl] -2-methylpyrazolo [ 1,5-a] pyrimidine;
(S) -6- (2-Cyanophenyl) -7- (4-trifluoromethylphenyl) -3- [N- (1,1-dioxotetrahydrothien-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) pyrazolo [1,5-a] pyrimidine;
(R) -6- (2-Cyanophenyl) -7- (4-chlorophenyl) -3- [N- (1,1-dioxotetrahydrothien-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-dioxotetrahydrothien-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-dioxotetrahydrothien-3-yl) carbamoyl] -2-difluoromethylpyra Zolo [1,5-a] pyrimidine;
(S) -6- (2-Chlorophenyl) -7- (4-trifluoromethylphenyl) -3- [N- (1,1-dioxotetrahydrothien-3-yl) carbamoyl] -2-difluoromethylpyra Zolo [1,5-a] pyrimidine;
6- (2-cyanophenyl) -7- (4-chlorophenyl) -3- (N-piperidinocarbamoyl) pyrazolo [1,5-a] pyrimidine;
6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- [N- (1,1-dioxothiacyclobutan-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-pyrrolidinyl) carbamoyl] -2-methylpyrazolo [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] pyrazolo [1,5-a] pyrimidine;
(R) -7- (4-Chloro-2-fluorophenyl) -6- (2-cyanophenyl) -3- [N- (1,1-dioxotetrahydrothien-3-yl) carbamoyl] -2- Methylpyrazolo [1,5-a] pyrimidine;
6- (2-Chlorophenyl) -7- (4-chlorophenyl) -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-dioxotetrahydrothien-3-yl) carbamoyl] -2-methoxymethylpyrazolo [1 , 5-a] pyrimidine;
(S) -6- (2-Chlorophenyl) -7- (4-chlorophenyl) -3- [N- (1,1-dioxotetrahydrothien-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-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] -2-methylpyrazolo [1,5-a] pyrimidine;
6- (2-cyanophenyl) -7- (4-chlorophenyl) -3- [N- (4-fluoro) piperidinocarbamoyl] -2-methylpyrazolo [1,5-a] pyrimidine;
And 6- (2-chlorophenyl) -7- (4-trifluoromethylphenyl) -3- [N- (tetrahydrothien-3-yl) carbamoyl] pyrazolo [1,5-a] pyrimidine;
Or a pharmacologically acceptable salt thereof.

  When the compound [I] has an asymmetric carbon atom in the molecule, it can exist as a plurality of stereoisomers (diastereoisomers, optical isomers) based on the asymmetric carbon atom. Any one of these stereoisomers or a mixture thereof is included.

  Since the compound [I] has a high affinity for the CB1 receptor, it is useful as a CB1 receptor ligand (especially a CB1 receptor antagonist). The pharmaceutical composition of the present invention comprising the compound is Various diseases involving the above receptors, such as psychosis including schizophrenia, anxiety disorder, stress, depression, epilepsy, neurodegeneration, cerebellum and old cerebellum (Spinocerebell) disorder, cognitive impairment, cranial trauma, panic attack, peripheral Neuropathy, glaucoma, migraine, Parkinson's disease, Alzheimer's disease, Huntington's disease, Raynaud's syndrome, tremor, obsessive compulsive disorder, amnesia, senile dementia, thymic disorder, Tourette syndrome, tardive dyskinesia, bipolar disorder, cancer, Drug-induced movement disorder, ataxia, endotoxemic shock, hemorrhagic shock, hypotension, insomnia, inflammation Immunological diseases including multiple sclerosis, vomiting, diarrhea, asthma, appetite disorders (bulimia, anorexia), obesity, non-insulin dependent diabetes mellitus (NIDDM), impaired glucose tolerance, hyperinsulinemia, Hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, lipid metabolism disorder, arteriosclerosis, hypertension, coronary disease, memory disorder, urological disease, cardiovascular disease, infertility, infection, demyelinating disease, neuritis It is useful for the prevention and treatment of gastrointestinal diseases including viral encephalitis, cerebrovascular disorder, cirrhosis, or intestinal transit disorders.

  The pharmaceutical compositions of the present invention are also useful for chronic treatment and withdrawal from substances (such as alcohol) or drug abuse (eg opioids, barbiturates, cannabis, cocaine, amphetamines, phencyclides, hallucinogens, benzodiazepines).

  Furthermore, the pharmaceutical composition of the present invention is also useful as an analgesic agent or an analgesic activity enhancer or an smoking cessation aid (withdrawal from smoking) of anesthetic and non-anesthetic drugs.

  The compound [I] or a pharmacologically acceptable salt thereof has low toxicity, and the pharmaceutical composition of the present invention has a feature that it is highly safe as a medicine.

  In the present invention, the above compound [I] can be used in a free form or a pharmaceutically acceptable salt form thereof. Examples of pharmaceutically acceptable salts include inorganic acid salts such as hydrochloride, sulfate, phosphate or hydrobromide, acetate, fumarate, oxalate, citrate, methanesulfone, and the like. And organic acid salts such as acid salts, benzenesulfonate, tosylate and maleate. In addition, when the compound has a carboxyl group in the molecule, the pharmacologically acceptable salt includes a salt with a base (for example, an alkali metal salt such as a sodium salt or a potassium salt, or an alkaline earth such as a calcium salt). Metal salts).

  The compound [I] or a pharmacologically acceptable salt thereof includes any of intramolecular salts and adducts thereof, solvates or hydrates thereof, and the like.

  The pharmaceutical composition of the present invention can be administered orally or parenterally, and can be used as conventional pharmaceutical preparations such as tablets, granules, capsules, powders, injections, inhalants and the like. .

  The dose of the above-mentioned compound [I] or a pharmacologically acceptable salt thereof varies depending on the administration method, the patient's age, body weight and condition, but in the case of an injection, it is about 0.0001-1. 0 mg / kg, especially about 0.001 to 0.1 mg / kg, orally, usually about 0.001 to 100 mg / kg, especially about 0.01 to 10 mg / kg per day. preferable.

  Although the said compound [I] can be manufactured with the following method, it is not limited to these.

  (1) Among the above compounds [I], ring A is a substituted pyrazole ring represented by formula (A), and E is formula (ii):

The compound which is group shown by can be manufactured according to the following method (Method AD), for example.

[Method A]
Compound [I] wherein Q ² is a single bond, that is, the following general formula [IA]:

[Wherein the symbols have the same meaning as described above. ]
The compound represented by the general formula [II-A]:

[Wherein, R ^a represents a hydrogen atom, an alkyl group or a benzyl group, and other symbols have the same meaning as described above. ]
And a compound of the general formula [III]:
HN (R ⁵ ) (R ⁶ ) [III]
[Wherein the symbols have the same meaning as described above. ]
It can manufacture by making it react with the amine compound or its salt shown by these.

When R ^a is a hydrogen atom, this reaction can be carried out in a solvent in the presence of a condensing agent, in the presence or absence of an activator, in the presence or absence of a base. Any solvent may be used as long as it does not affect the reaction. For example, methylene chloride, chloroform, dimethylformamide, dimethylacetamide, tetrahydrofuran, dioxane, toluene, benzene, 1,2-dichloroethane, 1-methylpyrrolidinone, 1,2 -Dimethoxyethane and the like. Examples of the condensing agent include dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC.HCl), diphenylphosphoryl azide (DPPA), carbonyldiimidazole (CDI), diethyl Cyanophosphonate (DEPC), diisopropylcarbodiimide (DIPCI), benzotriazol-1-yl-oxytrispyrrolidinophosphonium hexafluorophosphate (PyBOP), carbonylditriazole, N-cyclohexylcarbodiimide-N'-propyloxymethylpolystyrene (PS- Carbodiimide), N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), hexafluorophosphate 2- (7-azabenzo) Triazol-1-yl) -1,1,3,3-tetramethyluronium (HATU), 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyl hexafluorophosphate Uronium (HBTU), bromotrispyrrolidinophosphonium hexafluorophosphate (PyBroP), 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium (TBTU) tetrafluoroborate ), Chloro-1,1,3,3-tetramethyluronium hexachloroantimonate (ACTU), and the like. Examples of the activator include 1-hydroxybenzotriazole (HOBt), hydroxysuccinimide (HOSu), dimethylaminopyridine (DMAP), 1-hydroxy-7-azabenzotriazole (HOAt), hydroxyphthalimide (HOPht), pentafluoro Examples thereof include phenol (Pfp-OH), 1-hydroxybenzotriazole-6-sulfonamidomethylpolystyrene (PS-HOBt) and the like. Examples of the base include pyridine, triethylamine, diisopropylethylamine, 4-methylmorpholine, 1,8-diazabicyclo [5,4,0] -undecene (DBU) and the like.

  In the above reaction, the amount of compound [II-A] used can be 0.33 to 1.5 equivalents, preferably 0.5 to 1.2 equivalents, relative to compound [III]. The amount of the condensing agent to be used can be 1.0 to 3.0 equivalents, preferably 1.0 to 1.2 equivalents, relative to compound [II-A] or [III]. The amount of the base to be used can be 1.0 to 3.0 equivalents, preferably 1.0 to 1.2 equivalents, relative to compound [II-A] or [III]. The usage-amount of an activator can be 0.01-2.0 equivalent with respect to compound [II-A] or [III], Preferably it can be 0.1-1.0 equivalent. This reaction can be carried out at 0 to 150 ° C, preferably 20 to 80 ° C.

In the general formula [II-A], when R ^a is a hydrogen atom, the compound is converted to a reactive derivative such as a corresponding acid halide (for example, acid chloride) or a mixed acid anhydride, and then the reactivity is changed. Compound [IA] can also be produced by reacting the derivative with compound [III] in the presence or absence of a solvent in the presence of the above base.

In the general formula [II-A], when R ^a is an alkyl group or a benzyl group, this reaction may be carried out by subjecting the ester compound to hydrolysis, hydrochloric acid, formic acid, trifluoroacetic acid or the like, or The corresponding carboxylic acid compound by the reduction reaction, that is, the following general formula [II-Aa]:

[Wherein the symbols have the same meaning as described above. ]
The compound [II-Aa] and the compound [III] may be treated in the same manner as described above after conversion to the compound represented by

  In the reaction of compound [II-Aa] with compound [III], the 5-membered ring A is represented by the following formula (C):

The compound which is a substituted pyrazole ring represented by can be obtained as a by-product.

[Method B]
Compound [I] wherein Q ² is an alkylene group, that is, the following general formula [IB]:

[Wherein Q ²¹ represents an alkylene group, and other symbols have the same meaning as described above. ]
The compound represented by general formula [II-B]:

[Wherein, X represents a halogen atom, and other symbols have the same meaning as described above. ]
Can be produced by reacting the compound represented by the formula [III] or a salt thereof.

  The reaction of compound [II-B] and compound [III] can be carried out in a solvent in the presence or absence of a base. Any solvent may be used as long as it does not affect the reaction. For example, methylene chloride, chloroform, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, dioxane, toluene, benzene, 1,2-dichloroethane, 1-methylpyrrolidinone, 1,2-dimethoxyethane and the like. Examples of the base include sodium hydride, potassium carbonate, pyridine, triethylamine, diisopropylethylamine, 4-methylmorpholine, 1,8-diazabicyclo [5,4,0] -undecene (DBU) and the like. In the above reaction, the amount of compound [III] to be used can be 1.0 to 20 equivalents, preferably 1.0 to 3.0 equivalents, relative to compound [II-B]. The usage-amount of a base can be 0-20 equivalent with respect to compound [III] or compound [II-B], Preferably it can be 1.0-3.0 equivalent. This reaction can be carried out at -20 to 100 ° C, preferably 0 to 50 ° C.

[Method C]
Compound [I] wherein Q ¹ is —N (R ⁷ ) — and Q ² is a single bond, ie, the following general formula [IC]:

[Wherein the symbols have the same meaning as described above. ]
The compound represented by the general formula [II-C]:

[Wherein the symbols have the same meaning as described above. ]
And a compound [III] represented by the general formula [a]:
W ¹ —CO—W ² [a]
[Wherein, W ¹ and W ² are the same or different and represent a leaving group. ]
It can manufacture by making it react in presence of the compound shown by these.

Examples of W ¹ and W ² in the compound [a] include an imidazolyl group, a halogen atom, a phenoxy group, and the like. Specific examples of such compounds include 1,1′-carbonyldiimidazole, phosgene, triphosgene and the like. Any solvent may be used as long as it does not affect the reaction. Examples thereof include acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, dioxane, benzene, toluene, dimethylformamide and the like. The amount of compound [III] to be used can be 1.0 to 5.0 equivalents, preferably 1.0 to 1.2 equivalents, relative to compound [II-C]. The amount of compound [a] to be used can be 0.33 to 5.0 equivalents, preferably 1.0 to 2.0 equivalents, relative to compound [II-C] or compound [III]. This reaction can be carried out at -20 to 100 ° C, preferably 0 to 50 ° C.

  Further, the above compound [IC] is obtained by reacting the compound [II-C] with the compound [a] to give the general formula [IV].

[Wherein the symbols have the same meaning as above]
And then reacting the compound [IV] (or a reactive derivative thereof) with the compound [III] or reacting the compound [III] with the compound [a] Formula [V]:

[Wherein the symbols have the same meaning as above]
And then reacting the compound [V] (or a reactive derivative thereof) with the compound [II-C].

As a reactive derivative of compound [IV] or [V], for example, W ² is represented by the formula:

The reactive derivative can be obtained, for example, by reacting compound [IV] or [V] in which W ² is an imidazolyl group with methyl iodide. .

  The reaction of compound [II-C] or [III] with compound [a] can be carried out in a solvent. Any solvent may be used as long as it does not affect the reaction, and examples thereof include acetonitrile, dichloromethane, 1,2-dichloroethane, benzene, toluene, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, dimethylformamide and the like. The amount of compound [a] to be used can be 1.0 to 3.0 equivalents, preferably 1.0 to 2.0 equivalents, relative to compound [II-C] or [III]. This reaction can be carried out at 0 to 150 ° C, preferably 20 to 80 ° C.

  The corresponding reactive derivative of compound [IV] or [V] can be prepared, for example, by treating compound [IV] or [V] with an alkyl halide such as methyl iodide in a solvent. This reaction can be carried out at 0 to 150 ° C, preferably 20 to 80 ° C.

  The reaction between compound [IV] (or a reactive derivative thereof) and compound [III] and the reaction between compound [V] (or a reactive derivative thereof) and compound [II-C] are carried out in the presence of a base in a solvent. Can be implemented below. Any solvent may be used as long as it does not affect the reaction. For example, methylene chloride, chloroform, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, 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-diazabicyclo [5,4,0] -undecene (DBU) and the like. The usage-amount of each reactive derivative can be 0.33-3.0 equivalent with respect to compound [III] or [II-C], Preferably it can be 0.5-1.2 equivalent. This reaction can be carried out at -30 to 100 ° C, preferably 0 to 50 ° C.

[Method D]
The following general formula [ID]:

[Wherein the symbols have the same meaning as described above. ]
For example, the compound represented by the general formula [II-D]:

[Wherein the symbols have the same meaning as described above. ]
Can be produced by reacting the compound represented by the formula with divinylsulfone in a suitable solvent in the presence of a base. The solvent is not particularly limited as long as it does not affect this reaction, and examples thereof include ethanol, isopropyl alcohol, dioxane, toluene, N, N-dimethylformamide, dimethyl sulfoxide and the like. Examples of the base include triethylamine, diisopropylethylamine, N-methylmorpholine, dimethylaminopyridine and the like. The usage-amount of divinyl sulfone can be 1.0-3.0 equivalent with respect to compound [II-D], Preferably it can be 1.2-1.5 equivalent. This reaction can be carried out at 60 to 200 ° C, preferably 80 to 150 ° C.

  (2) Among the compounds [I], ring A is a substituted pyrazole ring represented by formula (B), and E is formula (ii):

The compound which is a group represented by, for example,
a) The following general formula [II-A ⁰¹ ]:

[Wherein the symbols have the same meaning as described above. ]
Or a compound represented by the following general formula [II-B ⁰¹ ]:

[Wherein the symbols have the same meaning as described above. ]
Or a compound represented by the following general formula [II-C ⁰¹ ]:

[Wherein the symbols have the same meaning as described above. ]
Or a compound represented by the following general formula [II-D ⁰¹ ]:

[Wherein the symbols have the same meaning as described above. ]
Can be manufactured by processing like the said D method.

(3) Among the compounds [I], ring A is a substituted pyrazole ring represented by formula (A) or (B), and E is formula (iii):
_{^{-SO 2 -N (R 5) (}} R 6) (iii)
The compound which is a group represented by, for example, the following general formula [II-E ⁰¹ ] or [II-E ⁰² ]:

[Wherein W ⁰⁰ represents a halogen atom, and other symbols have the same meaning as described above. ]
It can manufacture by making the sulfonyl halide compound shown by and amine compound [III] react. This reaction can be carried out in a solvent in the presence of a base. The solvent is not particularly limited as long as it does not affect this reaction, and examples thereof include chloroform, dichloromethane, tetrahydrofuran and the like. Examples of the base include pyridine, triethylamine, diisopropylethylamine and the like. The amount of amine compound [III] to be used is 0.5 to 5.0 equivalents, preferably 0.8 to 1.5 equivalents, relative to compound [II-E ⁰¹ ] or [II-E ⁰² ]. it can. The amount of the base to be used can be 1.0 to 5.0 equivalents, preferably 1.0 to 1.5 equivalents, relative to compound [II-E ⁰¹ ] or [II-E ⁰² ]. This reaction can be carried out at −10 to 100 ° C., preferably 0 to 40 ° C.

(4) Among the compounds [I], Q is a single bond, ring A is a substituted pyrazole ring represented by formula (A) or (B), E is a group represented by formula (iv), R ⁵⁰ and R ^A compound in which one is a hydrogen atom and the other is a hydrogen atom or an alkyl group can be produced, for example, according to Reaction Scheme C1 described later.

In addition, the compound in which R ⁵⁰ and R ⁶⁰ in formula (iv) are both alkyl groups is, for example, a compound in which R ⁷ is a hydrogen atom in the general formula [II-C] or [II-C ⁰¹ ] (compound [II -ca] or ^{[II-Ca 01])} and the formula [a-1]:
^Ry- CHO [a-1]
[Wherein, R ^y represents a hydrogen atom or an alkyl group. ]
In the presence of a reducing agent and in the presence or absence of a base (Method E). Examples of the reducing agent include sodium triacetoxyborohydride, sodium borohydride, sodium cyanoborohydride and the like. Examples of the base include triethylamine, diisopropylethylamine, N-methylmorpholine, dimethylaminopyridine and the like. The amount of compound [a-1] used in this reaction can be 1.0 to 3.0 equivalents, preferably 1.2 to 1.5 equivalents, relative to compound [II-Ca]. The usage-amount of a base can be 1.2-5.0 equivalent with respect to compound [II-Ca], Preferably it can be 1.5-2.0 equivalent. This reaction can be carried out at −50 to 100 ° C., preferably −10 to 40 ° C.

Furthermore, R ⁵⁰ and R ⁶⁰ in formula (iv) are bonded to each other to form the following formula:

[Wherein, ring A ¹ represents a 5- to 7-membered aliphatic nitrogen-containing heteromonocyclic group which may be substituted with an oxo group. ]
The compound that is the cyclic group shown is, for example,
a) A compound in which R ⁷ is a hydrogen atom in the general formula [II-C] or [II-C ⁰¹ ] (compound [II-Ca] or [II-Ca ⁰¹ ]) and the formula:
X ⁰¹ -Alk ¹ -X ⁰²
[Wherein, X ⁰¹ and X ⁰² represent a halogen atom, and Alk ¹ represents a C _4-6 alkylene group. ]
In a solvent (eg acetonitrile) in the presence of a base (potassium carbonate etc.) and in the presence or absence of an additive (sodium iodide etc.), or
b) It can be produced by reacting compound [II-Ca] or [II-Ca ⁰¹ ] with divinyl sulfone. The reaction of compound [II-Ca] or [II-Ca ⁰¹ ] with divinyl sulfone can be carried out in the same manner as in the above Method D.

(5) Among the above compounds, the compound in which ring A is a substituted pyrazole ring represented by formula (A) or (B) and E is a group represented by formula (v) is, for example, the compound [II- Aa] or [II-Da] and alkylamine (such as methylamine) in a solvent (such as methanol) in the presence of a condensing agent (such as water-soluble carbodiimide) and an activator (such as 1-hydroxybenzotriazole). The reaction product is then treated with Lawesson's reagent in a solvent (such as toluene) and the reaction product and the general formula:
_Ar-SO 2 -N ₃
[In the formula, Ar represents an aryl group which may have a substituent. ]
Can be produced by reacting in a solvent (such as pyridine). Examples of the substituent on Ar include a halogen atom.

The compound [I] can also be produced by further converting the substituents on R ¹ and R ² of the compound obtained as described above into other desired substituents. Such a substituent conversion method may be appropriately selected according to the type of the target substituent, and can be carried out, for example, as in the following methods a to h.

(Method a)
Compound [I] having a cyano group (or a group containing cyano) as a substituent is, for example, a corresponding compound [I] having a halogen atom or an alkylsulfonyl group (or a group containing a halogen atom or an alkylsulfonyl group) as a substituent. And a cyanide compound (such as zinc cyanide, copper cyanide, trimethylsilane cyanide or potassium cyanide) 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 the catalyst include palladium catalysts such as palladium acetate, tris (dibenzylideneacetone) dipalladium, trans-dichlorobis (tricyclohexylphosphine) palladium or tetrakis (triphenylphosphine) palladium or nickel catalysts such as dibromobis (triphenylphosphine) nickel. Etc. Examples of the additive include triphenylphosphine, 1,1′-bis (diphenylphosphino) ferrocene, racemic-2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, 2- (di-tert Phosphine compounds such as -butylphosphino) biphenyl, 2- (dicyclohexylphosphino) biphenyl, 2-dicyclohexylphosphino-2 '-(N, N'-dimethylamino) biphenyl, and tri-tert-butylphosphine. .

(Method b)
The compound [I] having an alkylamino group or a cycloalkylamino group (or a group containing an alkylamino group or a cycloalkylamino group) as a substituent has, for example, a halogen atom (or a group containing a halogen atom) as a substituent. It can be obtained by reacting the corresponding compound [I] with a mono- or dialkylamine or cycloalkylamine in a solvent in the presence of a catalyst, an additive and a base. Examples of the catalyst include a palladium catalyst or a copper catalyst used in the method (a). Examples of the additive include phosphine compounds used in the method (a), and examples of the base include potassium acetate, potassium carbonate, cesium carbonate, potassium tert-butoxide and the like.

(Method c)
Compound [I] having an alkyloxy group (or a group containing an alkyloxy group) as a substituent is, for example, (1) a corresponding compound [I] having a hydroxyl group (or a group containing a hydroxyl group) as a substituent and an alkyl halide. Or (2) the corresponding compound [I] having a hydroxyl group (or a group containing a hydroxyl group) as a substituent and an alkanol in a solvent in a base (potassium carbonate, cesium carbonate, sodium hydride) Etc.) or in the presence of an activator (diethylazodicarboxylate, etc.) and a trisubstituted phosphine, or (3) a reaction having an alkylsulfonyl group (or a group containing an alkylsulfonyl group) as a substituent. It can be obtained by reacting compound [I] with an alkali metal alkoxide in a suitable solvent.

(Method d)
Compound [I] having an alkylsulfinyl group or alkylsulfonyl group (or a group containing an alkylsulfinyl group or an alkylsulfonyl group) as a substituent is, for example, a corresponding compound having an alkylthio group (or a group containing an alkylthio group) as a substituent. [I] can be prepared by treating with an oxidizing agent such as 3-chloroperbenzoic acid in a suitable solvent.

(Method e)
The compound [I] having an acylamino group (a group containing an acylamino group) such as an alkylcarbonylamino group as a substituent includes, for example, the corresponding compound [I] having an amino group (or a group containing an amino group) as a substituent and General formula:
R ^X -COOH [Ac-1]
[Wherein, R ^X represents an alkyl group which may be substituted with an aryl group or an aryl group which may have a substituent. ]
Or a reactive derivative thereof (such as a corresponding acid anhydride or a corresponding acid halide). This reaction can be carried out in a solvent in the presence of a base (such as triethylamine) or a condensing agent (such as water-soluble carbodiimide) and in the presence or absence of an activating agent (such as 1-hydroxybenzotriazole).
The removal of the acyl group from the compound [I] can be carried out by a conventional method such as acid treatment or catalytic reduction depending on the kind of the acyl group.

(Method f)
The compound [I] having a carbamoyl group (or a group containing a carbamoyl group) as a substituent is obtained by converting the corresponding compound [I] having an alkyloxycarbonyl group (or a group containing an alkyloxycarbonyl group) as a substituent in an appropriate solvent. It can be manufactured by treating with ammonia.

(G method)
The compound [I] having an alkylcarbamoylamino group (or a group containing an alkylcarbamoylamino group) as a substituent is obtained by reacting the corresponding compound [I] having an amino group (or a group containing an amino group) as a substituent in an appropriate solvent. It can be produced by reacting with an alkyl isocyanate.

(Method h)
The following formula as a substituent:

[Wherein, ring A ¹ represents a 5- to 7-membered aliphatic nitrogen-containing heteromonocyclic group. ]
The compound [I] of the present invention having the group shown above is represented by the formula:
X ⁰¹ -Alk ¹ -X ⁰²
[Wherein the symbols have the same meaning as described above. ]
It can manufacture by making the compound shown by react. As the 5- to 7-membered aliphatic nitrogen-containing heteromonocyclic group represented by A ^1, e.g., 1-pyrrolidinyl group, a 1-piperidyl group.

  The compound [I] obtained as described above can be converted into a pharmaceutically acceptable salt according to a conventional method, if desired.

[Production of Intermediate Compound]
(I) Among the intermediate compounds in the present invention, a compound in which Q ¹ is a single bond or an alkylene group in the general formula [II-A] can be produced, for example, according to the following reaction schemes A1 to A4.

  (Reaction Scheme A1)

  (Reaction Scheme A2)

  (Reaction Scheme A3)

  (Reaction Scheme A4)

In the above reaction scheme, R ^aa is a hydrogen atom or an alkyl group, R ^c is an alkyl group, W ³ and W ⁴ are reactive residues, R ⁰¹ is an alkyl group, and R ¹¹ and R ²¹ are optionally substituted aryl. Group, an optionally substituted heteroaryl group or an optionally substituted aliphatic nitrogen-containing heterocyclic group, R ¹² and R ²² are an optionally substituted aryl group or an optionally substituted heteroaryl A group, R ¹³ and R ²³ are an optionally substituted aliphatic nitrogen-containing heterocyclic group, R ¹⁴ is an optionally substituted aryl group or an optionally substituted heteroaryl group, R ⁰² and R ⁰³ Are the same or different and each represents a hydrogen atom or an alkyl group, or both are bonded to each other to form an alkylene group, t-Bu is a tert-butyl group, W ⁰¹ and W ⁰² are halogen atoms It represents a child, and other symbols have the same meaning as described above.

Examples of the aryl group in R ¹¹ , R ¹² , R ²¹ or R ²² include 6 to 10-membered monocyclic or bicyclic aryl groups such as a phenyl group and a naphthyl group, and among these, a phenyl group is preferable. .

Examples of the heteroaryl group in R ¹¹ , R ¹² , R ^21, or R ²² include, for example, a 5- to 10-membered monocyclic or bicyclic compound containing 1 to 3 hetero atoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom. A cyclic heteroaryl group is mentioned, Among these, a furyl group, a thienyl group, or a pyridyl group is preferable.

Examples of the aliphatic nitrogen-containing heterocyclic group for R ¹¹ , R ¹² , R ²¹ or R ²² include a 5- to 7-membered aliphatic nitrogen-containing heterocyclic monocyclic group. The heterocyclic group may further contain 1 to 2 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom. Of such heterocyclic groups, a 1-pyrrolidinyl group, 1-piperidyl group, morpholino group or thiomorpholino group is preferable.

The aryl group, heteroaryl group and aliphatic nitrogen-containing heterocyclic group in R ¹¹ , R ¹² , R ²¹ or R ²² may be substituted with a halogen atom, a cyano group, or 1 to 3 halogen atoms. It may be substituted with 1 to 3 groups selected from an alkyl group, an alkyloxy group which may be substituted with 1 to 3 halogen atoms, and an alkylsulfonyl group.

Examples of the alkylene group formed by combining R ⁰² and R ⁰³ with each other include linear or branched C _2-6 such as ethylene group, trimethylene group, 1,1,2,2-tetramethylethylene group. Examples of the substituent on the alkylene group include an alkyl group such as a methyl group.

  Each reaction described in the above schemes A1 to A4 can be carried out, for example, as follows.

Reaction step A1-1:
The reaction of compound [VI] and compound [VII] can be carried out in a solvent under heating. Any solvent that does not affect the reaction may be used, and examples thereof include dimethylformamide, dimethylacetamide, dioxane, 1,2-dichloroethane, toluene, and xylene. The amount of compound [VII] to be used can be 1.0 to 10 equivalents, preferably 1.0 to 3.0 equivalents, relative to compound [VI]. This reaction can be carried out at 50 to 200 ° C, preferably 80 to 150 ° C.

Reaction step A1-2:
The reaction of compound [VIII] and compound [i] can be carried out in a solvent in the presence or absence of a base. Examples of the base include piperidine, morpholine, N-methylpiperazine, diethylamine and the like. Any solvent that does not affect the reaction may be used, and examples include acetic acid, methanol, ethanol, isopropanol, and ethylene glycol. The amount of compound [i] to be used can be 0.5 to 2.0 equivalents, preferably 0.8 to 1.2 equivalents, relative to compound [VIII]. The amount of the base used can be 0.01 to 2.0 equivalents, preferably 0.1 to 1.0 equivalents, relative to compound [VIII]. This reaction can be carried out at 50 to 150 ° C, preferably 70 to 100 ° C. This reaction can also be carried out in a solvent in the presence or absence of an acid. Examples of the acid include hydrogen bromide, hydrogen chloride, acetic acid and the like. Any solvent that does not affect the reaction may be used, and examples include acetic acid, methanol, ethanol, isopropanol, and ethylene glycol. The amount of compound [i] to be used can be 0.5 to 2.0 equivalents, preferably 0.8 to 1.2 equivalents, relative to compound [VIII]. The amount of the acid to be used can be 0.1 to 3.0 equivalents, preferably 0.3 to 1.0 equivalents, relative to compound [VIII]. This reaction can be carried out at 0 to 150 ° C., preferably 60 to 100 ° C.

Reaction step A2-1:
The reaction of compound [VI-a] and compound [VII] can be carried out in the same manner as in reaction step A1-1.

Reaction step A2-2:
The reaction of compound [VIII-a] and compound [i] can be carried out in the same manner as in reaction step A1-2. Moreover, compound [Xa] can be obtained by implementing this reaction in acetic acid, without implementing reaction process A2-3.

Reaction step A2-3:
The intramolecular ring closure reaction of compound [IX-a] can be carried out in a solvent in the presence of a base. Any solvent that does not affect the reaction may be used, and examples thereof include ethanol, acetonitrile, chloroform, tetrahydrofuran, dioxane, toluene, N, N-dimethylformamide and the like. Examples of the base include sodium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, dimethylaminopyridine and the like. The amount of the base used can be 1.0 to 10.0 equivalents, preferably 1.2 to 3.0 equivalents, relative to compound [IX-a]. This reaction can be carried out at 30 to 150 ° C, preferably 60 to 100 ° C.

Reaction step A2-4:
Conversion of compound [Xa] to compound [XII-a] can be carried out in a solvent in the presence of a halogenating agent and in the presence or absence of a base. Any solvent that does not affect the reaction may be used, and examples thereof include acetonitrile, chloroform, tetrahydrofuran, dioxane, toluene, N, N-dimethylformamide and the like. Examples of the halogenating agent include phosphorus oxychloride, thionyl chloride, phosphorus pentachloride, oxalyl chloride and the like. Examples of the base include N, N-dimethylaniline, diisopropylethylamine, N-methylmorpholine and the like. The amount of the halogenating agent to be used can be 1.1 to 5.0 equivalents, preferably 1.2 to 1.5 equivalents, relative to compound [X-a]. The amount of the base to be used can be 1.2 to 10.0 equivalents, preferably 1.5 to 2.0 equivalents, relative to compound [X-a]. This reaction can be carried out at 50 to 200 ° C, preferably 80 to 150 ° C.

Reaction step A2-5:
(1) The reaction of the compound [XII-a] and the boronic acid compound [XIII-a] can be carried out in a solvent in the presence of a catalyst and a base. Boronic acid compound as the ^{[XIII-a], R 02} and ^{R 03} is a hydrogen atom or an alkyl group (a methyl group, an ethyl group, an isopropyl group, etc.) compounds which are, or ^{R 02} and the alkylene group ^{R 03} may bond to each other ( A compound that forms an ethylene group, a propylene group, a 1,1,2,2-tetramethylethylene group, and the like. Among these, a compound in which R ⁰² and R ⁰³ are hydrogen atoms (or a compound represented by the formula: [R ¹² -BO] ₃ corresponding boroxine compound) is preferred. Any solvent may be used as long as it does not affect the reaction, and examples thereof include dioxane, toluene, dimethoxyethane, ethanol, N, N-dimethylformamide, tetrahydrofuran, water and the like. Examples of the catalyst include tetrakis (triphenylphosphine) palladium (0), palladium (II) acetate, bis (dibenzylideneacetone) palladium (0), bis (triphenylphosphine) palladium (II) dichloride, bis (tri- palladium catalysts such as o-tolylphosphine) palladium (II) dichloride, bis (tricyclohexylphosphine) palladium (II) dichloride, [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride, Examples thereof include nickel catalysts such as 3-bis (diphenylphosphino) propane nickel (II) dichloride and bis (triphenylphosphine) nickel (II) dichloride. Examples of the base include potassium phosphate, sodium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium fluoride, triethylamine, lithium chloride and the like. The amount of compound [XIII-a] to be used in this reaction can be 1.0 to 5.0 equivalents, preferably 1.1 to 2.0 equivalents, relative to compound [XII-a]. The amount of the catalyst to be used can be 0.001 to 0.5 equivalent, preferably 0.01 to 0.05 equivalent, relative to compound [XII-a]. The amount of the base to be used can be 1.0 to 10.0 equivalents, preferably 2.0 to 5.0 equivalents, relative to compound [XII-a]. This reaction can be carried out at 20 to 150 ° C, preferably 60 to 120 ° C.

  (2) The reaction of the compound [XII-a] and the nitrogen-containing heterocyclic compound [XIII-b] can be carried out in a solvent in the presence of a base. Any solvent may be used as long as it does not affect the reaction. Examples thereof include dimethylformamide, toluene, dioxane, and tetrahydrofuran. Examples of the base include potassium carbonate, sodium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium fluoride, triethylamine, diisopropylethylamine, dimethylaminopyridine and the like. The amount of compound [XIII-b] used in this reaction can be 0.8 to 5.0 equivalents, preferably 1.0 to 1.5 equivalents, relative to compound [XII-a]. The amount of the base to be used can be 1.0 to 10.0 equivalents, preferably 2.0 to 5.0 equivalents, relative to compound [XII-a]. This reaction can be carried out at 80 to 200 ° C, preferably 120 to 180 ° C.

Reaction step A2-6:
The reaction of compound [XII-a] and compound [XIII-c] can be carried out in a solvent in the presence of a base. Any solvent that does not affect the reaction may be used, and examples thereof include N, N-dimethylformamide, dimethyl sulfoxide, dimethoxyethane, and tetrahydrofuran. Examples of the base include sodium hydride, potassium hydride, sodium ethoxide, tert-butoxy potassium and the like. The amount of compound [XIII-c] to be used in this reaction can be 0.5 to 5.0 equivalents, preferably 1.0 to 3.0 equivalents, relative to compound [XII-a]. The amount of the base to be used can be 0.5 to 10.0 equivalents, preferably 1.2 to 6.0 equivalents, relative to compound [XII-a]. This reaction can be carried out at 40 to 200 ° C, preferably 60 to 120 ° C.

Reaction step A2-7:
The reaction of compound [XII-a] and compound [XIII-d] can be carried out in a solvent in the presence of a catalyst and zinc. Any solvent that does not affect the reaction may be used, and examples thereof include dimethoxyethane, tetrahydrofuran, N, N-dimethylformamide and the like. Examples of the catalyst include bis (triphenylphosphine) palladium (II) dichloride, tetrakis (triphenylphosphine) palladium (0), palladium (II) acetate, bis (dibenzylideneacetone) palladium (0), bis (tri- palladium catalysts such as o-tolylphosphine) palladium (II) dichloride, bis (tricyclohexylphosphine) palladium (II) dichloride, [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride, and the like. It is done. The amount of compound [XIII-d] used in this reaction can be 0.5 to 5.0 equivalents, preferably 1.0 to 3.0 equivalents, relative to compound [XII-a]. The amount of the catalyst to be used can be 0.001 to 1.0 equivalent, preferably 0.01 to 0.3 equivalent, relative to compound [XII-a]. The amount of zinc to be used can be 1.0 to 5.0 equivalents, preferably 1.5 to 3.0 equivalents, relative to compound [XII-a]. This reaction can be carried out at 40 to 200 ° C, preferably 60 to 120 ° C.

Reaction step A3-1:
The reaction of compound [VI-b] and compound [VII-b] can be carried out in a solvent or without a solvent. Any solvent may be used as long as it does not affect the reaction, and examples thereof include dimethylformamide, toluene, dioxane, tetrahydrofuran, and dimethoxyethane. The amount of compound [VII-b] used in this reaction can be 0.5 to 5.0 equivalents, preferably 0.9 to 1.5 equivalents, relative to compound [VI-b]. This reaction can be carried out at 0 to 150 ° C, preferably 50 to 80 ° C.

Reaction step A3-2:
The halogenation of compound [VIII-b] can be carried out in a solvent in the presence of a halogenating agent and in the presence or absence of a base. Any solvent may be used as long as it does not affect the reaction. Examples thereof include methylene chloride, carbon tetrachloride, chloroform, acetic acid, and tetrahydrofuran. 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 amount of the halogenating agent to be used can be 0.5 to 10.0 equivalents, preferably 1.0 to 3.0 equivalents, relative to compound [VIII-b]. This reaction can be carried out at -40 to 100 ° C, preferably -5 to 20 ° C.

Reaction step A3-3:
The reaction of compound [IX-b] and compound [i] can be carried out in the same manner as in reaction step A1-2.

Reaction step A3-4:
The reaction of compound [Xb] with boronic acid compound [XIII-b] or nitrogen-containing heterocyclic compound [XIII-c] is carried out in the same manner as in reaction step A2-5 (1) or (2), respectively. be able to.

Reaction step A4-1:
Conversion of compound [II-A11] to the corresponding reactive derivative (compound [IX]) can be carried out by a conventional method. Examples of the reactive derivative include a corresponding acid halide (compound [IX] in which W ³ is a halogen atom) or a mixed acid anhydride (compound [IX] in which W ³ is an alkyloxycarbonyloxy group or the like). . The corresponding acid halide is, for example, compound [II-A11] and a halogenating agent (thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride, etc.) in a solvent or without solvent in the presence of a catalytic amount of dimethylformamide or It can be obtained by reacting in the absence. Any solvent that does not affect the reaction may be used, and examples thereof include methylene chloride, chloroform, tetrahydrofuran, benzene, and toluene. This reaction can be carried out at -20 to 150 ° C, preferably 0 to 120 ° C. The corresponding mixed acid anhydride can be obtained, for example, by reacting compound [II-A11] with alkyl chlorocarbonate (such as ethyl chlorocarbonate) in a solvent in the presence of a base (such as triethylamine or diisopropylethylamine). it can. Any solvent that does not affect the reaction may be used, and examples thereof include methylene chloride, chloroform, tetrahydrofuran, benzene, and toluene. This reaction can be carried out at −60 to 100 ° C., preferably −40 to 80 ° C.

Reaction step A4-2:
Conversion of compound [IX] to compound [X] can be carried out in a solvent in the presence of a diazomethane compound (eg, diazomethane, trimethylsilyldiazomethane, etc.). Any solvent may be used as long as it does not affect the reaction. Examples thereof include diethyl ether, dioxane, benzene, toluene and the like. The amount of the diazomethane compound to be used can be 1.0 to 10 equivalents, preferably 1.0 to 3.0 equivalents, relative to compound [IX]. This reaction can be carried out at −50 to 80 ° C., preferably −10 to 50 ° C.

Reaction step A4-3:
Conversion of compound [X] to compound [II-A12] can be carried out in a solvent in the presence or absence of a silver salt under heating. Any solvent may be used as long as it does not affect the reaction. Examples thereof include water and alkanols (methanol, ethanol, etc.). Examples of the silver salt include silver oxide and silver benzoate. The usage-amount of silver salt can be 1.0-20 equivalent with respect to compound [X], Preferably it can be 1.0-5.0 equivalent. This reaction can be carried out at 50 to 200 ° C, preferably 80 to 150 ° C.

Reaction step A4-4:
The reaction for reducing compound [II-A11] to obtain compound [XI] can be carried out in a solvent in the presence of a reducing agent (such as lithium aluminum hydride). Any solvent may be used as long as it does not affect the reaction. Examples thereof include diethyl ether and tetrahydrofuran. The amount of the reducing agent to be used can be 0.25 to 20 equivalents, preferably 2.0 to 5.0 equivalents, relative to compound [II-A11]. This reaction can be carried out at −50 to 100 ° C., preferably −10 to 40 ° C.

Compound [XI] can also be produced by reducing compound [II-A1] wherein ^Ra is an alkyl group. This reaction can be carried out in a solvent in the presence of a reducing agent such as sodium borohydride. Any solvent may be used as long as it does not affect the reaction. Examples thereof include a mixed solvent of tetrahydrofuran and methanol. The amount of the reducing agent to be used can be 1.0 to 20 equivalents, preferably 2.0 to 5.0 equivalents, relative to compound [II-A1]. This reaction can be carried out at 30 to 100 ° C, preferably 50 to 80 ° C.

Reaction step A4-5:
Conversion of compound [XI] to the corresponding reactive derivative (compound [XII]) can be carried out according to a conventional method. For example, compound [XII] in which W ⁴ is a halogen atom or an alkylsulfonyloxy group is obtained by, for example, treating compound [XI] with thionyl halide (such as thionyl chloride) or alkylsulfonyl halide (such as methanesulfonyl chloride), respectively. Can be manufactured.

Reaction step A4-6:
The reaction of compound [XII] with compound [d] or a salt thereof can be carried out in a solvent in the presence of a base. Examples of the salt of compound [d] include metal salts such as potassium salt. Any solvent may be used as long as it does not affect the reaction. Examples thereof include 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 hexamethyldisilazane and the like. The amount of compound [d] or a salt thereof used can be 1.0 to 10.0 equivalents, preferably 1.5 to 3.0 equivalents, relative to compound [XII]. The amount of the base used can be 1.0 to 10.0 equivalents, preferably 1.5 to 3.0 equivalents, relative to compound [XII]. This reaction can be carried out at -20 to 200 ° C, preferably 20 to 100 ° C.

Compound [II-A] in which Q ¹ is an alkylene group having 3 or more carbon atoms is prepared by reacting, for example, the target compound of Reaction Step A4-3 (or Reaction Step A4-6) with a corresponding carboxylic acid. After converting into a compound, a series of operations consisting of the above steps A4-1, A4-2, and A4-3 (or steps A4-4, A4-5, and A4-6) are repeated on the carboxylic acid compound a desired number of times. It can be manufactured by applying.

In addition, compound [II-A] in which Q ¹ is a group represented by the formula: —N (R ⁷ ) — is, for example, compound [II-Ae] or [II-Af] (see reaction step C1-4 described later). Can be prepared by subjecting to a conventional deesterification reaction.

  (Ii) Compound [II-B] is prepared according to the following reaction scheme B1 using, for example, compound [II-Aa] or its corresponding amide compound (such as corresponding dialkylamide or corresponding N-alkyl-N-alkyloxyamide compound). can do.

  (Reaction Scheme B1)

[In the above reaction scheme, R ^c represents an alkyl group, Y represents a halogen atom, and other symbols have the same meaning as described above. ]
Each reaction described in the above scheme B1 can be carried out, for example, as follows.

Reaction step B1-1:
The reaction of compound [II-Aa] or its corresponding amide compound with alkyl metal compound [b1] or [b2] can be carried out in a solvent. Any solvent may be used as long as it does not affect the reaction. Examples thereof include diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, benzene, and toluene. The amount of compound [b1] or [b2] to be used is 1.0 to 3.0 equivalents, preferably 1.0 to 2.2 equivalents, relative to compound [II-Aa] or its corresponding amide compound. it can. This reaction can be carried out at −78 to 50 ° C., preferably −40 to 30 ° C.

Reaction step B1-2:
The halogenation of compound [XIV] can be carried out in a solvent. Examples of the halogenating agent include bromine, N-bromosuccinimide, bis (dimethylacetamide) dibromobromate, and the like. Any solvent may be used as long as it does not affect the reaction. Examples thereof include diethyl ether, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride and the like. The amount of the halogenating agent to be used can be 1.0 to 3.0 equivalents, preferably 1.0 to 2.0 equivalents, relative to compound [XIV]. This reaction can be carried out at −10 to 50 ° C., preferably 0 to 30 ° C.

(Iii) Compound [II-C] can be produced according to the following reaction scheme C1 using, for example, a compound (compound [IIa]) in which Q ¹ is a single bond in general formula [II-Aa].

  (Reaction Scheme C1)

[In the above reaction scheme, R ⁷¹ represents an alkyl group, tBu represents a tert-butyl group, and other symbols have the same meaning as described above. ]
Each reaction described in the above scheme C1 can be carried out, for example, as follows.

Reaction step C1-1:
The reaction of compound [IIa] with an azidating agent can be carried out in a solvent in the presence or absence of a base. Any solvent that does not affect the reaction may be used, and examples thereof include acetone, benzene, toluene, tetrahydrofuran, and diethyl ether. Examples of the azidating agent include diphenyl phosphate azide and sodium azide. Examples of the base include pyridine, triethylamine, diisopropylethylamine, 4-methylmorpholine, 1,8-diazabicyclo [5,4,0] -undecene (DBU) and the like. The amount of the azidating agent to be used is 1.1 to 5.0 equivalents, preferably 1.2 to 1.5 equivalents, relative to compound [IIa]. The amount of the base to be used can be 1.2 to 10.0 equivalents, preferably 1.5 to 3.0 equivalents, relative to compound [IIa]. This reaction can be carried out at -30 to 50 ° C, preferably -10 to 10 ° C.

Reaction step C1-2:
The compound [XVI-a] can be prepared by heating in a solvent by a Curtius rearrangement reaction. The solvent may be any solvent that does not affect the reaction, and examples thereof include benzene, toluene, dioxane, chloroform and the like. This reaction can be carried out at 40 to 200 ° C, preferably 60 to 120 ° C. Moreover, compound [XVI-b] can be obtained by implementing this reaction in t-butanol.

Reaction step C1-3:
Acid treatment of compound [XVI-a] or compound [XVI-b] can be carried out in a solvent or without solvent. Any solvent that does not affect the reaction may be used, and examples thereof include water, ethyl acetate, tetrahydrofuran, dioxane, methylene chloride, chloroform, toluene and the like. Examples of the acid include strong acids such as sulfuric acid, hydrochloric acid, nitric acid, trifluoroacetic acid, and hydrobromic acid. The amount of the acid to be used can be 1.0 to 50.0 equivalents, preferably 5.0 to 10.0 equivalents, relative to compound [XVI-a] or compound [XVI-b]. This reaction can be carried out at -20 to 200 ° C, preferably 20 to 120 ° C.

Reaction step C1-4:
Alkylation of the compound [II-Ca] is carried out by, for example, (1) base (sodium hydride, potassium carbonate, pyridine, triethylamine, diisopropylethylamine, 4-methylmorpholine, 1,8-diazabicyclo [5,4, 0] -undecene etc.) and general formula [XVIII]:
R ⁷² -X ⁴ [XVIII]
[Wherein R ⁷² represents an alkyl group, and X ⁴ represents a halogen atom. ]
Or (2) reducing agents (lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, etc.), acids (acetic acid, formic acid, etc.) and general Formula [XIX]:
R ⁷³ —CHO [XIX]
[Wherein R ⁷³ represents an alkyl group. ]
Or (3) an activator (such as diethyl azodicarboxylate), a trisubstituted phosphine (such as triphenylphosphine, tributylphosphine) and the general formula [XX]:
R ⁷⁴ —OH [XX]
[Wherein, R ⁷⁴ represents an alkyl group. ]
It can carry out in presence of alkanol shown by these. 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. This reaction can be carried out at -20 to 100 ° C, preferably 0 to 40 ° C.

  Prior to the alkylation reaction of the compound [II-Ca], if necessary, an appropriate protecting group (an alkyloxycarbonyl group such as a tert-butoxycarbonyl group, a benzyloxycarbonyl group or the like is added to the 3-position amino group of the compound. An arylalkyloxycarbonyl group such as the above may be introduced. The introduction and removal of the protecting group can be carried out according to a conventional method depending on the kind of the protecting group.

In addition, compound [II-Cb] is obtained by reacting the above reaction step C1-2 (Cultius rearrangement reaction) with general formula [e]:
R ^e —OH [e]
[Wherein R ^e represents a tert-butyl group or a benzyl group. ]
Is carried out in an alcohol represented by the general formula [II-Ae]:

[Wherein the symbols have the same meaning as described above. ]
Then, the compound [II-Ae] is reacted with the alkyl halide compound [XVIII] or the alkanol compound [XX] to give a general formula [II-Af]:

[Wherein the symbols have the same meaning as described above. ]
It is also possible to prepare the compound by removing the acyl group represented by the formula: R ^e OCO- from the compound [II-Af]. Examples of the method for removing the acyl group include (1) acid treatment with hydrochloric acid, trifluoroacetic acid or hydrobromic acid, (2) heat treatment (about 150 ° C.), or (3) catalytic reduction.

(Iv) Compound [II-D] is compound [II-Aa] and the following general formula [c]:
H ₂ N-NHZ [c]
[In the formula, Z represents an acyl group. ]
The hydrazine compound represented by the formula (1) or a salt thereof is reacted in the same manner as in the above method A, and then the acyl group (Z) is removed from the reaction product according to a conventional method.

For the intermediate compound [II-A ⁰¹ ], [II-B ⁰¹ ] or [II-C ⁰¹ ] in the present invention, the corresponding raw material compound having a desired substituent at the 2-position of the pyrazolopyrimidine skeleton is converted into the reaction scheme A1. , B1 or C1 can be manufactured by processing.

Furthermore, the compound [II-D ⁰¹ ] is represented, for example, by the following general formula [II-Da]:

[Wherein the symbols have the same meaning as described above. ]
And the hydrazine compound [c] is reacted in the same manner as in the above Method A, and then the acyl group (Z) is removed from the reaction product according to a conventional method.

  Of the raw material / intermediate compounds in the present invention, compound [i], compound [VI], compound [VI-a], compound [VI-b], compound [VII], compound [VII-b], compound [XIII -A], compound [XIII-b], compound [XIII-c] or compound [XIII-d] is itself a known compound, or can be produced from a known compound by a conventional method of synthetic chemistry. it can.

  In the present invention, the “halogen atom” means a fluorine atom, a chlorine atom, an iodine atom or a bromine atom, and the “alkyl” is a straight chain having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms or The branched alkyl, “cycloalkyl” represents cycloalkyl having 3 to 8 carbon atoms, preferably 5 to 7 carbon atoms. “Alkylene” represents linear or branched alkylene having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms.

  Specific examples (production examples) of the compound [I], which is an active ingredient of the present invention synthesized by the above-described methods, are shown below, but the present invention is not limited thereto.

Production Example 1
3-Carboxyl-6- (2-chlorophenyl) -7- (4-chlorophenyl) pyrazolo [1,5-a] pyrimidine (compound obtained in Reference Example 1) 200 mg of toluene in 1.5 mL suspension of thionyl chloride Add 114 μL and stir at room temperature for 2 hours. The reaction solution is concentrated under reduced pressure, and the resulting crude product is dissolved in 1.5 mL of methylene chloride. To this solution, 217 μL of triethylamine and 56 μL of 1-aminopiperidine are added and stirred at room temperature for 10 minutes. The reaction solution is concentrated under reduced pressure, and the resulting crude product is purified by silica gel column chromatography (solvent: chloroform / methanol = 100: 0 to 19: 5, and hexane / ethyl acetate = 67: 33 to 2: 3). Gives 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- (N-piperidinocarbamoyl) pyrazolo [1,5-a] pyrimidine (162 mg, 67% yield) as a powder.
MS (APCI) m / z; 466/468 [M + H] ^< +>.

Production Example 2
To a suspension of 200 mg of the compound obtained in Reference Example 1 in 2 mL of toluene, 136 μL of oxalyl chloride is added and stirred at 60 ° C. for 1 hour. The reaction solution is concentrated under reduced pressure, and the resulting crude product is dissolved in 2 mL of methylene chloride. To this solution are added 217 μL of triethylamine and 61 μL of 1-methyl-1-phenylhydrazine, and the mixture is stirred at room temperature for 2 hours. Water and methylene chloride are added to the reaction mixture, and the organic layer is washed with saturated brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 4: 1-7: 3) to give 6- (2-chlorophenyl) -7- ( 4-Chlorophenyl) -3-[(N′-methyl-N′-phenylhydrazino) carbonyl] pyrazolo [1,5-a] pyrimidine (204 mg, 80% yield) is obtained as a powder.
MS (APCI) m / z; 488/490 [M + H] ^< +>.

Production Example 3
To a solution of 57.6 mg of the compound obtained in Reference Example 1 and 24.5 mg of 1-aminopyrrolidine hydrochloride in 1.0 mL of chloroform (amylene added) was added 1-hydroxybenzotriazole monohydrate (0.5 M chloroform solution, amylene). 0.23 mL, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.5 M, N, N-dimethylformamide solution) and 63 μL of triethylamine are added, and the mixture is stirred at room temperature overnight. . Saturated aqueous sodium hydrogen carbonate solution (2 mL), water (2 mL) and chloroform (5 mL) are added to the reaction mixture, and the mixture is vigorously stirred for 15 minutes. After separating the organic layer, the aqueous layer is extracted with 3 mL of chloroform. The combined organic layer was washed successively with 3 mL of saturated aqueous sodium bicarbonate solution and 3 mL of saturated brine, and then concentrated under reduced pressure. The resulting crude product was subjected to liquid chromatography / mass spectrometry (LCMS) (column: XTerra MS C18, solvent: 10 mM). Purification using aqueous ammonium carbonate solution / methanol = 40/60 to 10/90). The eluate was concentrated, and the residue was dissolved in tert-butanol and then freeze-dried to give 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- (N-pyrrolidinocarbamoyl) pyrazolo [1, 5-a] pyrimidine (47.2 mg, 70% yield) is obtained as a powder.
MS (ESI) m / z; 452 [M + H] ^< +>.

Production Examples 4 to 27
The corresponding starting material compounds are treated in the same manner as in Production Examples 1, 2, or 3, to obtain the compounds shown in Table 1 below.

Production Example 28
3-Carboxy-6- (2-chlorophenyl) -7- (4-chlorophenyl) pyrazolo [1,5-a] pyrimidine (compound obtained in Reference Example 1 (4)) 165 mg of chloroform (amylene added) 1.0 mL 50 mg of the compound obtained in Reference Example 13 (2), 123 mg of water-soluble carbodiimide hydrochloride, 97 mg of 1-hydroxybenzotriazole hydrate and 178 μL of triethylamine are added to the solution, and the mixture is stirred overnight at room temperature. To the reaction solution is added 2 mL of aqueous sodium hydrogen carbonate solution, and the mixture is stirred and extracted with chloroform. The extract was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 90/10 to 70/30) to give 6- (2-chlorophenyl) -7- ( 4-Chlorophenyl) -3- [N- (4-tetrahydrothiopyranyl) carbamoyl] pyrazolo [1,5-a] pyrimidine (50 mg, 24% yield) is obtained as a yellow powder.
MS (APCI) m / z; 483/485 [M + H] ^< +>.

Production Example 29
To a 1.0 mL solution of the compound obtained in Production Example 28 in methylene chloride, 20 μL of methanesulfonic acid and 57 mg of 3-chloroperbenzoic acid are added and stirred at room temperature for 1 hour. An aqueous sodium hydrogen carbonate solution is added to the reaction solution and stirred, and then the organic layer is extracted. The extract was concentrated under reduced pressure, and 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-chlorophenyl) -3- [N- {4- (1,1-dioxo) tetrahydrothiopyranyl} carbamoyl] pyrazolo [1,5-a] pyrimidine (37.3 mg, 73% yield) as a pale yellow powder Get as.
MS (APCI) m / z; 515/517 [M + H] ^< +>.

Production Example 30
To a solution of 50 mg of the compound obtained in Reference Example 9 (2) in 1 mL of methanol is added 36% formaldehyde aqueous solution 118 μL, sodium triacetoxyborohydride 75 mg and triethylamine 39 μL, and the mixture is stirred at room temperature for 3 hours. The reaction mixture is diluted with chloroform, aqueous sodium hydrogen carbonate solution is added, and the mixture is extracted with chloroform. The extract is concentrated under reduced pressure, and the resulting crude product is purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 93/7 to 78/22), dissolved in tertbutyl alcohol, and freeze-dried. 3-Dimethylamino-6- (2-chlorophenyl) -7- (4-chlorophenyl) pyrazolo [1,5-a] pyrimidine (13.5 mg, 26% yield) is obtained as a red powder.
MS (APCI) m / z; 383/385 [M + H] ^< +>.

Production Example 31
(1) By treating 200 mg of the corresponding starting material compound in the same manner as in Production Example 3, 6- (2-bromophenyl) -7- (4-chlorophenyl) -3- [N′-methyl-N ′-(2- Pyridyl) hydrazino] carbonylpyrazolo [1,5-a] pyrimidine (249 mg) is obtained as a yellow powder.
MS (APCI) m / z; 533/535 [M + H] ^< +>.

(2) 20 mg of zinc cyanide and 17 mg of tetrakis (triphenylphosphine) palladium (0) are added to a solution of 80 mg of the compound obtained in (1) in 1 mL of dimethylformamide, and the mixture is stirred at 110 ° C. for 19 hours under a nitrogen atmosphere. After cooling the reaction solution to room temperature, water and ethyl acetate are added and stirred. The organic layer is extracted and the extract is concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 50/50 to 25/75), dissolved in tert-butyl alcohol, and lyophilized to give 7- (4-chlorophenyl). ) -6- (2-Cyanophenyl) -3- [N′-methyl-N ′-(2-pyridyl) hydrazino] carbonylpyrazolo [1,5-a] pyrimidine (42 mg, 58% yield) was colorless. Obtain as a solid.
MS (APCI) m / z; 480/482 [M + H] ^< +>.

Production Example 32
To a solution of 1.0 g of the compound obtained in Reference Example 6 in 20 mL of chloroform, 260 mg of cyclopentylamine, 620 mg of water-soluble carbodiimide hydrochloride and 540 mg of 1-hydroxybenzotriazole are added and stirred overnight at room temperature. An aqueous sodium hydrogen carbonate solution and chloroform are added to the reaction mixture and stirred, and then the organic layer is extracted, and the extract is concentrated under reduced pressure. The obtained crude product is purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 82/18 to 67/33) to give 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- (N-cyclopentylcarbamoyl) -2-methylthiopyrazolo [1,5-a] pyrimidine (940 mg, 81% yield) is obtained as a pale yellow solid.
MS (APCI) m / z; 497/499 [M + H] ^< +>.

Production Example 33
To a solution of 940 mg of the compound obtained in Production Example 32 in 40 mL of methylene chloride is added 1.09 g of 3-chloroperbenzoic acid under ice cooling, and the mixture is stirred at room temperature for 3 hours. To the reaction solution is added an aqueous sodium thiosulfate solution, and the mixture is stirred and extracted with chloroform. The extract was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (Chromatorex NH silica gel; manufactured by Fuji Silysia Chemical Ltd., solvent; hexane / ethyl acetate = 50/50 to 0/100). (2-Chlorophenyl) -7- (4-chlorophenyl) -3- (N-cyclopentylcarbamoyl) -2-methylsulfonylpyrazolo [1,5-a] pyrimidine (1.0 g, 100% yield) was obtained as a colorless solid. Get as.
MS (APCI) m / z; 529/531 [M + H] ^< +>.

Production Example 34
To a solution of 100 mg of the compound obtained in Production Example 33 in a solution of 3 mL of tetrahydrofuran / 3 mL of methanol is added 102 mg of sodium methoxide, and the mixture is stirred at 50 ° C. overnight. After cooling the reaction solution to room temperature, water and ethyl acetate are added and stirred. The organic layer is dried over magnesium sulfate and filtered, and the filtrate is concentrated under reduced pressure. The obtained crude product is purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 80/20 to 60/40) to give 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- (N-cyclopentylcarbamoyl) -2-methoxypyrazolo [1,5-a] pyrimidine (57.2 mg, 63% yield) is obtained as a pale yellow solid.
MS (APCI) m / z; 481/483 [M + H] ^< +>.

Production Example 35
To a solution of 300 mg of the compound obtained in Production Example 33 in 7 mL of dimethylformamide, 167 mg of sodium cyanide is added and stirred at 50 ° C. overnight. After cooling the reaction solution to room temperature, ethyl acetate and aqueous sodium hydrogen carbonate solution are added and stirred. After separating the organic layer, the aqueous layer is extracted with ethyl acetate. The combined organic layers are dried over magnesium sulfate and filtered, and the filtrate is concentrated under reduced pressure. The obtained crude product is 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-cyclopentylcarbamoyl) pyrazolo [1,5-a] pyrimidine (Compound (a): 138 mg, 44% yield), 6- (2-chlorophenyl) -7- ( 4-chlorophenyl) -2,5-dicyano-3- (N-cyclopentylcarbamoyl) pyrazolo [1,5-a] pyrimidine (compound (b): 18.3 mg, 6% yield) is obtained as a pale yellow solid. .

Compound (a): MS (APCI) m / z; 554/556 [M + H] ⁺
Compound (b): MS (APCI) m / z; 501/503 [M + H] ⁺ .

Production Example 36
To a solution of 50 mg of the compound (a) obtained in Production Example 35 in 3 mL of methanol and 3 mL of tetrahydrofuran, 49 mg of sodium methoxide is added and stirred overnight at room temperature. Ethyl acetate and saturated brine are added to the reaction solution, and the organic layer is separated. The organic layer is dried over magnesium sulfate and filtered, and the filtrate is concentrated under reduced pressure. The obtained crude product is purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 80 / 20-30: 70) to give 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3. -(N-cyclopentylcarbamoyl) -5-methoxy-2-methylsulfonylpyrazolo [1,5-a] pyrimidine (50.5 mg, 100% yield) is obtained as a colorless solid.
MS (APCI) m / z; 559/561 [M + H] ^< +>.

Production Example 37
Sodium methoxide (23 mg) is added to a solution of the compound obtained in Production Example 36 (24 mg) in methanol (2 mL) and tetrahydrofuran (1 mL), and the mixture is stirred at 100 ° C. for 2 hours in a microwave reactor. After cooling the reaction solution to room temperature, chloroform and water are added, and the organic layer is separated and concentrated under reduced pressure. The obtained crude product is purified by silica gel column chromatography (Chromatorex NH silica gel; manufactured by Fuji Silysia Chemical Ltd., solvent; hexane / ethyl acetate = 65 / 35-30: 70) to give 6- (2-chlorophenyl)- 7- (4-Chlorophenyl) -3- (N-cyclopentylcarbamoyl) -2,5-dimethoxypyrazolo [1,5-a] pyrimidine (17.8 mg, 81% yield) is obtained as a colorless solid.
MS (APCI) m / z; 511/513 [M + H] ^< +>.

Production Example 38
To a solution of 300 mg of the compound obtained in Production Example 33 in 10 mL of dimethylformamide, 42.1 mg of sodium cyanide is added, and the mixture is stirred at 100 ° C. for 1.5 hours in a microwave reactor. After cooling the reaction solution to room temperature, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution are added and stirred. The organic layer is washed with water and concentrated under reduced pressure. The resulting crude product is purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 80/20 to 65:35) to give 6- (2-chlorophenyl). -7- (4-Chlorophenyl) -2-cyano-3- (N-cyclopentylcarbamoyl) pyrazolo [1,5-a] pyrimidine (23.1 mg, 9% yield) is obtained as a pale yellow solid.
MS (APCI) m / z; 476/478 [M + H] ^< +>.

Production Example 39
To a solution of 138 mg of the compound obtained in Reference Example 10 (2) in 7 mL of ethanol are added 42 μL of divinylsulfone and 72 μL of triethylamine, and the mixture is heated to reflux for 6 hours. The reaction mixture is cooled to room temperature and concentrated under reduced pressure. Water and methylene chloride are added to the residue and stirred, and then the organic layer is extracted, washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting crude product was subjected to silica gel column chromatography (1st: solvent; chloroform / methanol = 100/0 to 95: 5, 2nd: Chromatorex NH silica gel; manufactured by Fuji Silysia Chemical, hexane / ethyl acetate = 50/50 to 20/80), dissolved in tertbutyl alcohol, and lyophilized to give 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- [N- {4- ( 1,1-dioxo) thiomorpholino} carbamoyl] pyrazolo [1,5-a] pyrimidine (57 mg, 31% yield) is obtained as a pale yellow powder.
MS (APCI) m / z; 516/518 [M + H] ^< +>.

Production Example 40
7 mL of acetic acid is added to a solution of 1.1 g of the compound obtained in Reference Example 11 in 2.8 mL of tetrahydrofuran / 4.2 mL of water, and the mixture is stirred at 100 ° C. for 1 hour in a microwave reactor. The reaction mixture is cooled to room temperature, 2N aqueous sodium hydroxide solution is added, and the mixture is extracted with chloroform. The extract is dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting crude product was 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, 75% yield) is obtained as a yellow solid.
MS (APCI) m / z; 466/468 [M + H] ^< +>.

Production Example 42
60 mg of the compound obtained in Production Example 40, 600 μL of pyridine, and 200 μL of acetic anhydride are stirred at 100 ° C. for 3 days. The reaction mixture is cooled to room temperature, 1N aqueous hydrochloric acid and ethyl acetate are added, and the mixture is stirred and extracted with ethyl acetate. The extract is dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (Chromatorex NH silica gel; manufactured by Fuji Silysia Chemical Ltd., solvent; hexane / ethyl acetate = 90/10 to 50:50). Acetylamino-6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- (N-cyclopentylcarbamoyl) pyrazolo [1,5-a] pyrimidine (38.2 mg, 58% yield) was obtained as a pale yellow solid Get as.
MS (APCI) m / z; 508/510 [M + H] ^< +>.

Production Example 43
To a solution of the compound obtained in Production Example 40 (60 mg) in water (0.3 mL) / acetonitrile (2.4 mL), 1,4-dichlorobutane (81.6 mg), potassium carbonate (88.8 mg) and sodium iodide (76.8 mg) were added. Stir at 150 ° C. for 3 hours. The reaction mixture is cooled to room temperature, concentrated under reduced pressure, and ethyl acetate and water are added to the residue and stirred. The organic layer is extracted, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 90/10 to 70:30) to give 6- (2-chlorophenyl) -7- ( 4-Chlorophenyl) -3- (N-cyclopentylcarbamoyl) -2- (1-pyrrolidinyl) pyrazolo [1,5-a] pyrimidine (25 mg, 37% yield) is obtained as a yellow solid.
MS (APCI) m / z; 520/522 [M + H] ^< +>.

Production Example 44
Add 34 mg of the compound obtained in Reference Example 17, 58 mg of water-soluble carbodiimide hydrochloride, 46 mg of 1-hydroxybenzotriazole and 84 μL of triethylamine to a solution of 77 mg of the compound obtained in Reference Example 1 (4) in 1 mL of methylene chloride, and stir at room temperature overnight. . An aqueous sodium hydrogen carbonate solution and methylene chloride were added to the reaction solution and stirred, and then the organic layer was separated and concentrated under reduced pressure to give 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- [N- ( 4-Cyano-tetrahydrothiopyran-4-yl) carbamoyl] pyrazolo [1,5-a] pyrimidine (50.8 mg, 50% yield) is obtained as a pale yellow powder.
MS (APCI) m / z; 508/510 [M + H] ^< +>.

Production Examples 45-202
The corresponding raw material compounds are treated in the same manner as in any one of Production Examples 1 to 3, to obtain the compounds described in Tables 2 to 4 below.

Production Example 203
The corresponding starting material compound was treated in the same manner as in Production Example 3 to give 6- (2-chloropyridin-3-yl) -7- (4-chlorophenyl) -3- (N-cyclopentylcarbamoyl) pyrazolo [1,5- a] Pyrimidine (39 mg, 67% yield) is obtained as a pale yellow powder.
MS (APCI) m / z; 452/454 [M + H] ^< +>.

Production Example 204
The compound (36 mg) obtained in Production Example 181 was treated in the same manner as in Production Example 33 to give 6- (2-chlorophenyl) -7- (4-chlorophenyl) -2-methylsulfonyl-3- [N- (1 , 1-Dioxo-tetrahydrothien-3-yl) carbamoyl] pyrazolo [1,5-a] pyrimidine (33.1 mg, 86% yield) is obtained as a colorless solid.
MS (APCI) m / z; 579/581 [M + H] ^< +>.

Production Example 205
The compound obtained in Production Example 204 was treated in the same manner as in Production Example 34 to give 6- (2-chlorophenyl) -7- (4-chlorophenyl) -2-methoxy-3- [N- (1,1-di- Oxotetrahydrothien-3-yl) carbamoyl] pyrazolo [1,5-a] pyrimidine (72 mg, 79% yield) is obtained as a powder.
MS (APCI) m / z; 531/533 [M + H] ^< +>.

Production Example 206
The compound (80 mg) obtained in Production Example 144 was treated in the same manner as in Production Example 29 to give 6- (2-chlorophenyl) -7- (4-trifluoromethoxyphenyl) -3- [N- (1,1 -Dioxo-tetrahydrothiopyran-4-yl) carbamoyl] pyrazolo [1,5-a] pyrimidine (61.1 mg, 72% yield) is obtained as a pale yellow powder.
MS (APCI) m / z; 565/567 [M + H] ^< +>.

Production Example 207
(1) The compound (300 mg) obtained in Production Example 204 is treated in the same manner as in Production Example 35 to give 5-cyano-6- (2-chlorophenyl) -7- (4-chlorophenyl) -2-methylsulfonyl- 3- [N- (1,1-dioxo-tetrahydrothien-3-yl) carbamoyl] pyrazolo [1,5-a] pyrimidine (60 mg, 19% yield) is obtained as a pale yellow solid.
MS (APCI) m / z; 604/606 [M + H] ^< +>.

(2) By treating the compound (60 mg) obtained in (1) in the same manner as in Production Example 36, 6- (2-chlorophenyl) -7- (4-chlorophenyl) -5-methoxy-2-methylsulfonyl -3- [N- (1,1-dioxo-tetrahydrothien-3-yl) carbamoyl] pyrazolo [1,5-a] pyrimidine (29 mg, 49% yield) is obtained as a pale yellow powder.
MS (APCI) m / z; 609/611 [M + H] ^< +>.

Production Examples 208-209
The compound shown in Table 5 below is obtained by treating the compound obtained in Reference Example 18 or Reference Example 19 in the same manner as in Production Example 39.

Production Examples 210 to 212
By treating the compound obtained in Production Example 152, Production Example 194 or Production Example 156 in the same manner as in Production Example 29, the compounds shown in Table 6 below are obtained.

Production Examples 213 to 214
The corresponding starting material compound is treated in the same manner as in Production Example 28, and then the product is treated in the same manner as in Production Example 29 to obtain the compounds shown in Table 7 below.

Production Example 215
The compound obtained in Production Example 40 and 2-chloroethyl ether were treated in the same manner as in Production Example 43 to give 6- (2-chlorophenyl) -7- (4-chlorophenyl) -2-morpholino-3- (N -Cyclopentylcarbamoyl) pyrazolo [1,5-a] pyrimidine (23 mg, 33% yield) is obtained as a powder.
MS (APCI) m / z; 536/538 [M + H] ^< +>.

Production Examples 216 to 223
The corresponding starting material compound is treated in the same manner as in Production Example 11, and then the product is treated in the same manner as in Production Example 40 to obtain the compounds described in Table 8 below.

Production Examples 224 to 231
The corresponding starting material compounds are treated in the same manner as in Production Example 42 to obtain the compounds shown in Table 9 below.

Production Examples 232 to 237
The corresponding starting material compounds are treated in the same manner as in Production Example 43 to give the compounds shown in Table 10 below.

Production Example 238
To a solution of 15.5 μL of pyrrolidine and 20 μL of pyridine in 2 mL of chloroform is added dropwise a solution of 60 mg of the compound obtained in Reference Example 54 in 1 mL of chloroform under ice cooling. After stirring the mixture at room temperature for 2.5 hours, 15.5 μL of pyrrolidine is added and stirred for an additional 2.5 hours. Add water to the reaction mixture and extract with chloroform. The organic layer was concentrated under reduced pressure, and 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-Trifluoromethylphenyl) -2-methyl-3- (1-pyrrolidinyl) sulfonylpyrazolo [1,5-a] pyrimidine (43.8 mg, 68% yield) is obtained as a colorless solid.
MS (APCI) m / z; 521/523 [M + H] +.

Production Example 239
To a solution of 60 mg of the compound obtained in Reference Example 53 in 0.5 mL of ethanol, 20 μL of divinylsulfone is added, and the mixture is stirred in a microwave reactor at 120 ° C. for 1 hour, and further stirred at 130 ° C. for 4 hours. The reaction mixture is cooled to room temperature, water is added, and the mixture is extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 70/30 to 55:45) to give 6- (2-chlorophenyl) -7- ( 4-Trifluoromethylphenyl) -3- (1,1-dioxothiomorpholino) pyrazolo [1,5-a] pyrimidine (40 mg, 51% yield) is obtained as a red solid.
MS (APCI) m / z; 507/509 [M + H] +.

Production Example 240
To a solution of 128 mg of the compound obtained in Reference Example 55 in 2 ml of chloroform, 21 μL of bromine in 1.3 ml of chloroform is added, and the mixture is stirred at room temperature for 2 hours. The reaction mixture is concentrated under reduced pressure, 2 mL of dimethylformamide and 181 μL of N-methylaniline are added to the residue, and the mixture is stirred at room temperature for 2 hours. Water and saturated aqueous sodium hydrogen carbonate solution are added to the reaction mixture, and the mixture is extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 88/12 to 75:25) to give 6- (2-chlorophenyl) -7- ( 4-Chlorophenyl) -3- [2- (N-methyl-N-phenylamino) acetyl] pyrazolo [1,5-a] pyrimidine (115 mg, 70% yield) is obtained as a yellow solid.
MS (APCI) m / z; 487/489 [M + H] ^< +>.

Production Example 241
To a solution of the compound obtained in Preparation Example 434 (125 mg) in 2 mL of dichloromethane, 146 mg of 75% metachloroperbenzoic acid is added, and the mixture is stirred at room temperature overnight. Saturated aqueous sodium hydrogen carbonate solution is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate is concentrated under reduced pressure, and the resulting crude product is purified by NH silica gel column chromatography (Chromatorex NH silica gel, solvent; hexane / ethyl acetate = 50/50). The eluate was concentrated, and the precipitate was washed with hexane to give 6- (2-chlorophenyl) -7- (1,1-dioxothiomorpholino) -2-methyl-3-[[N′-methyl- N ′-(2-pyridyl) hydrazino] carbonyl] pyrazolo [1,5-a] pyrimidine (70 mg, 53%) is obtained as a solid.
MS (APCI) m / z; 526/528 [M + H] +.

Production Example 242
(1) By treating the corresponding starting material compound in the same manner as in Reference Example 2, 6- (2-bromophenyl) -3-carboxy-7- (4-chloro-2-fluorophenyl) -2-methylpyrazolo [1, 5-a] pyrimidine (1.51 g, 20% yield) is obtained as a pale yellow powder.
MS (APCI) m / z; 460/462 [M + H] +.

(2) 37 mg of 1-methyl-1- (2-pyridyl) hydrazine, 58 mg of water-soluble carbodiimide hydrochloride and 46 mg of 1-hydroxybenzotriazole hydrate were added to 3 mL of methylene chloride in 100 mg of the compound obtained in (1) above. The mixture is stirred overnight at room temperature. Aqueous sodium hydrogen carbonate solution is added to the reaction mixture, and the mixture is stirred and extracted with chloroform. The extract was concentrated under reduced pressure, and the resulting crude product was purified by NH silica gel column chromatography (Chromatorex NH silica gel, solvent; hexane / ethyl acetate = 80/20 to 55/45) to give 6- (2-bromo Phenyl) -7- (4-chloro-2-fluorophenyl) -2-methyl-3-[[N′-methyl-N ′-(2-pyridyl) hydrazino] carbonyl] pyrazolo [1,5-a] pyrimidine (119.5 mg, 96% yield) is obtained as a pale yellow solid.
MS (APCI) m / z; 565/567 [M + H] ^< +>.

(3) 15.5 mg of zinc cyanide, 4.2 mg of tris (dibenzylideneacetone) dipalladium (Pd ₂ (dba) ₃ ), 4.2 mg, 1,1′- in a solution of 119 mg of the compound obtained in (2) above in 2 mL of dimethylformamide 5.1 mg of bis (diphenylphosphino) ferrocene (DPPF) is added and the mixture is stirred for 20 minutes at 180 ° C. in a microwave reactor. Saturated aqueous sodium hydrogen carbonate solution is added to the reaction mixture, and the mixture is stirred and extracted with chloroform. The extract is washed with water and concentrated under reduced pressure. The resulting crude product was purified by NH silica gel column chromatography (Chromatorex NH silica gel, solvent; hexane / ethyl acetate = 70/30 to 55/45) to give 7- (4-chloro-2-fluorophenyl)- 6- (2-Cyanophenyl) -2-methyl-3-[[N′-methyl-N ′-(2-pyridyl) hydrazino] carbonyl] pyrazolo [1,5-a] pyrimidine (22.1 mg, yield) 21%) is obtained as a yellow solid.
MS (APCI) m / z; 512/514 [M + H] ^< +>.

Production Example 243
(1) 2.08 g of the compound obtained in Reference Example 33 in 20 mL of N, N-dimethylformamide in 5 mL of 2M methylamine-methanol solution, 1.92 g of water-soluble carbodiimide, 1.53 g of 1-hydroxybenzotriazole, 1. 01 g is added and the mixture is stirred overnight at room temperature. Add water to the reaction mixture and extract with ethyl acetate. The organic layer is dried over magnesium sulfate and filtered, and the filtrate is concentrated under reduced pressure. The obtained crude product is purified by NH silica gel column chromatography (Chromatorex NH silica gel, solvent; chloroform / methanol = 100/0 to 95: 5) to give 6- (2-chlorophenyl) -7- (4-tri Fluoromethylphenyl) -3- (N-methylcarbamoyl) pyrazolo [1,5-a] pyrimidine (1.83 g, 85% yield) is obtained as a yellow powder.
MS (APCI) m / z; 431/433 [M + H] +.

(2) 809 mg of Lawson's reagent is added to a 10 mL toluene solution of 832 mg of the compound obtained in (1) above, and the mixture is stirred at 110 ° C. for 2 hours. After cooling the reaction solution, 2.0 g of NH silica gel is added and filtered, and the residue is washed with ethyl acetate. The organic layers were combined and concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 80/20 to 60:40) to give 6- (2-chlorophenyl)- 7- (4-Trifluoromethylphenyl) -3- [N- (methyl) thiocarbamoyl] pyrazolo [1,5-a] pyrimidine (730 mg, 82% yield) is obtained as a yellow powder.
MS (APCI) m / z; 447/449 [M + H] +.

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

  (4) A solution of 223 mg of the compound obtained in the above (2) and a solution of 326 mg of the compound obtained in the above (3) in 5 mL of pyridine is stirred at 110 ° C. for 2 days. The reaction mixture is cooled, water is added, and the mixture is extracted with chloroform. The organic layer was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 30/70 to 50:50), whereby compound a ( 24 mg, 8% yield) and compound b (0.8 mg, 0.4% yield) are obtained.

Production Example 244
The compound obtained in Production Example 332 is treated in the same manner as in Production Example 31 (2) to give 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3-[[(N′-methyl-N ′. -(6-Cyanopyridin-3-yl) hydrazino] carbonyl] pyrazolo [1,5-a] pyrimidine is obtained.
MS (APCI) m / z; 514/516 [M + H] +.

Production Example 245
6- (2-Chlorophenyl) -7- (4-chlorophenyl) -3-[[N′-methyl-N ′-(6-fluoropyridin-2-yl) hydrazino] carbonyl] pyrazolo [1,5-a] To a 1 mL solution of pyrimidine (the compound obtained in Production Example 292) in 1 mL of N-methylpiperidine, 52 μL of diisopropylethylamine and 26 μL of morpholine are added, and the mixture is stirred overnight at 90 ° C. and further stirred at 120 ° C. for 4 hours. After cooling the reaction solution to room temperature, 60 μL of morpholine is added, and the mixture is stirred overnight at 120 ° C. in a sealed vessel, and then stirred at 100 ° C. for 15 minutes in a microwave reactor. The reaction mixture is cooled to room temperature and concentrated under reduced pressure. The resulting crude product is purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 70/30 to 40/60), and then the eluate is concentrated. The resulting residue is purified by gel permeation chromatography (mobile bed; chloroform), and the eluate is concentrated. The residue obtained is dissolved in tert-butanol and lyophilized to give 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3-[[N′-methyl-N ′-(6-morpholinopyridine). 2-yl) hydrazino] carbonyl] pyrazolo [1,5-a] pyrimidine (12.9 mg, 23% yield) is obtained as a pale yellow powder.
MS (APCI) m / z; 574/576 [M + H] ^< +>.

Production Example 246
(1) The corresponding starting compound is treated in the same manner as in Reference Example 2 to give 6- (2-bromophenyl) -3-carboxy-7- (4-chloro-2-fluorophenyl) pyrazolo [1,5-a Pyrimidine (2.09 g, 22% yield) is obtained as a pale yellow powder.
MS (APCI) m / z; 446/448 [M + H] +.

(2) By treating the compound obtained in (1) above in the same manner as in Production Example 242 (2), 6- (2-bromophenyl) -7- (4-chloro-2-fluorophenyl) -3- [[N′-Methyl-N ′-(2-pyridyl) hydrazino] carbonyl] pyrazolo [1,5-a] pyrimidine (148 mg, 89% yield) is obtained as a pale yellow solid.
MS (APCI) m / z; 551/553 [M + H] ^< +>.

(3) By treating 145 mg of the compound obtained in the above (2) in the same manner as in Production Example 242 (3), 7- (4-chloro-2-fluorophenyl) -6- (2-cyanophenyl) -3 -[[N'-methyl-N '-(2-pyridyl) hydrazino] carbonyl] pyrazolo [1,5-a] pyrimidine (compound a: 51.6 mg, 40% yield) as a yellow solid, 7- ( 4-cyano-2-fluorophenyl) -6- (2-cyanophenyl) -3-[[N′-methyl-N ′-(2-pyridyl) hydrazino] carbonyl] pyrazolo [1,5-a] pyrimidine ( Compound b: 34.1 mg, 27% yield) Obtained as a yellow solid.
Compound a; MS (APCI) m / z; 498/500 [M + H] ⁺ .
Compound b; MS (APCI) m / z; 489 [M + H] ⁺ .

Production Example 247
(1) The corresponding starting compound (576 mg) was treated in the same manner as in Production 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, 79% yield) is obtained as a pale yellow solid.
MS (APCI) m / z; 552/554 [M + H] +.

(2) A solution of 650 mg of the compound obtained in (1) above in 5 mL of 4N hydrochloric acid-dioxane solution is stirred overnight at room temperature. The reaction solution is neutralized by adding a saturated aqueous sodium hydrogen carbonate solution under ice-cooling (pH 7.0 to 8.0). The mixture is extracted with methylene chloride, and the organic layer is dried over magnesium sulfate and concentrated under reduced pressure. The resulting crude product is purified by NH silica gel column chromatography (Chromatorex NH silica gel, solvent; chloroform / methanol = 100/0 to 95/5) and then dried under reduced pressure to give 6- (2-chlorophenyl) -7- (4-Chlorophenyl) -3- [N- (pyrrolidin-3-yl) carbamoyl] pyrazolo [1,5-a] pyrimidine (515.8 mg, 97% yield) is obtained as a pale yellow solid.
MS (APCI) m / z; 452/454 [M + H] ^< +>.

(3) Add 28 μL of triethylamine to a solution of 46 mg of the compound obtained in (2) above in 1 mL of dichloromethane (added with amylene). Under a nitrogen atmosphere, 9 μL of acetyl chloride is added dropwise to the mixture and stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate solution is added to the reaction mixture, the mixture is extracted with methylene chloride, and the extract is concentrated under reduced pressure. The resulting crude product is purified by silica gel column chromatography (solvent; chloroform / methanol = 100/0 to 95/5), and then the eluate is concentrated. The resulting residue was dissolved in tert-butanol and freeze-dried to give 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- [N- (1-acetylpyrrolidin-3-yl) carbamoyl] Pyrazolo [1,5-a] pyrimidine (50.7 mg, 100% yield) is obtained as a pale yellow powder.
MS (APCI) m / z; 494/496 [M + H] ^< +>.

Production Examples 248-250
The corresponding starting material compounds are treated in the same manner as in Production Example 247 to obtain the compounds described in Table 12 below.

Production Examples 251 to 278
By treating the corresponding starting material compound in the same manner as in Production Example 31 or Production Example 242, the compounds shown in Table 13 below are obtained.

Production Examples 279 to 423
The corresponding starting material compounds are treated in the same manner as in Production Example 3 to obtain the compounds shown in Table 14 below.

Production Examples 424 to 427
By treating the corresponding starting material compound in the same manner as in Production Example 3 or Production Example 242, the compounds shown in Table 15 below are obtained.

Production Examples 428 to 430
The corresponding starting material compounds are treated in the same manner as in Production Example 28 to give the compounds shown in Table 16 below.

Production Examples 431 to 439
The corresponding starting material compounds are treated in the same manner as in Production Example 1 to obtain the compounds shown in Table 17 below.

Production Example 440
(1) To the compound (1.0 g) obtained in Production Example 484 (2) and triethylamine (1.81 mL) in tetrahydrofuran (20 mL) was slowly added 1.0 g of methanesulfonyl chloride under ice cooling, followed by stirring at room temperature for 40 minutes. . The reaction mixture is diluted with ethyl acetate, water is added under ice-cooling and the mixture is stirred, and the aqueous layer is extracted with ethyl acetate. The extract is dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (Chromatorex NH silica gel, solvent; hexane / ethyl acetate = 80 / 20-60 / 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%) Is obtained as a pale yellow solid.
MS (APCI) m / z; 617/619 [M + H] ^< +>.

(2) Add 1.03 g of tetrabutylammonium fluoride trihydrate to a 20 mL tetrahydrofuran solution of 1.01 g of the compound obtained in (1) above and stir at room temperature for 15 minutes. After adding water and stirring, the mixture is extracted with chloroform. The extract is dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and 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- (methylsulfonylamino) pyrazolo [1,5-a] pyrimidine (0.71 g, 81% yield) is obtained as a pale yellow powder.
MS (APCI) m / z; 539/541 [M + H] ^< +>.

(3) A solution of the compound obtained in (2) (0.69 g) and sodium ethoxide (0.87 g) in ethanol (20 mL) is stirred at 80 ° C. for 10 minutes. The reaction mixture is concentrated under reduced pressure, water is added to the residue, and the mixture is extracted with ethyl acetate. The organic layer is dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (Chromatorex NH silica gel, solvent; hexane / ethyl acetate = 75 / 25-60 / 40) to give 3-ethoxycarbonyl-6- (2-Chlorophenyl) -7- (4-trifluoromethylphenyl) -2- [N-methyl-N- (methylsulfonyl) amino] pyrazolo [1,5-a] pyrimidine (0.70 g, 99% yield) ) As a powder.
MS (APCI) m / z; 553/555 [M + H] ^< +>.

Production Examples 441 to 452
The corresponding starting material compounds are treated in the same manner as in Reference Example 1 (3) and Production Example 3 to give the compounds described in Table 18 below.

Production Examples 453 to 454
The corresponding starting material compounds are treated in the same manner as in Production Example 3 to obtain the compounds described in Table 19 below.

Production Examples 455 to 460
The corresponding starting material compound is treated in the same manner as in Production Example 238 to give the compound shown in Table 20 below.

Production Example 461
34.5 μL of diiodopentane and 24.5 mg of sodium carbonate are added to a solution of 60 mg of the compound obtained in Reference Example 53 in 1 mL of tetrahydrofuran and 0.2 mL of dimethylacetamide, and the mixture is stirred at 70 ° C. for 17 hours. Water is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The extract is concentrated under reduced pressure. The obtained crude product is purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 85 / 15-60 / 40) to give 6- (2-chlorophenyl) -3- (piperidin-1-yl) -7- (4-Trifluoromethylphenyl) pyrazolo [1,5-a] pyrimidine (17 mg, 24% yield) is obtained as a red powder.
MS (APCI) m / z; 457/459 [M + H] ^< +>.

Production Examples 462 to 465
The corresponding starting material compounds are treated in the same manner as in Production Example 240 to give the compounds shown in Table 21 below.

Production Example 466
(1) By treating 500 mg of the compound obtained in Reference Example 33 in the same manner as in Production Example 1, 6- (2-chlorophenyl) -7- (4-trifluoromethylphenyl) -3- [N- (1-hydroxy -4-Methylthio-2-butyl) carbamoyl] pyrazolo [1,5-a] pyrimidine (357 mg, 56% yield) is obtained as a yellow powder.
MS (APCI) m / z; 535/537 [M + H] +.

(2) To a solution of 349 mg of the compound obtained in (1) above in 2 mL of methylene chloride, 170 μL of thionyl chloride is added and stirred at room temperature for 23 hours. Add 2 mL of chloroform to the reaction mixture and stir at 60 ° C. for 5 hours. The reaction solution is cooled to room temperature and then concentrated under reduced pressure. The resulting crude product is purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 85 / 15-60 / 40) to give 6- (2-chlorophenyl). ) -7- (4-Trifluoromethylphenyl) -3-[(tetrahydrothien-3-yl) carbamoyl] pyrazolo [1,5-a] pyrimidine (106 mg, 32% yield) is obtained as a pale yellow powder.
MS (APCI) m / z; 503/505 [M + H] +.

(3) To a solution of 96 mg of the compound obtained in (2) above in 3 mL of methylene chloride, 44 mg of 3-chloroperbenzoic acid (75%) is added under ice cooling, and the mixture is stirred at the same temperature for 15 minutes. To the reaction solution are added an aqueous sodium sulfite solution and a saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The extract was concentrated under reduced pressure, and the resulting crude product was 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-tetrahydrothien-3-yl) carbamoyl] pyrazolo [1,5-a] pyrimidine (81 mg, 82% yield) is obtained as a colorless powder.
MS (APCI) m / z; 519/521 [M + H] ^< +>.

Production Example 467
The compound obtained in Reference Example 47 was treated in the same manner as in Preparation Example 3 to give (R) -6- (2-chlorophenyl) -7- (4-chlorophenyl) -3-[(1,1-dioxo-tetrahydro Thien-3-yl) carbamoyl] -2- (2-methoxyethoxy) pyrazolo [1,5-a] pyrimidine (77 mg, 67% yield) is obtained as a powder.
MS (APCI) m / z; 575/577 [M + H] ^< +>.

Production Example 468
The corresponding starting material compound was treated in the same manner as in Production Example 3 to give (R) -6- (2-chlorophenyl) -7- (4-chlorophenyl) -3-[(1,1-dioxo-tetrahydrothien-3- Yl) carbamoyl] -2- (2-hydroxyethoxy) pyrazolo [1,5-a] pyrimidine (91 mg, 84% yield) as a powder.
MS (APCI) m / z; 561/563 [M + H] ^< +>.

Production Example 469
(1) By treating the compound obtained in Reference Example 59 in the same manner as in Production Example 3, (R) -6- (2-chlorophenyl) -7- (4-chlorophenyl) -3-[(1,1- Dioxo-tetrahydrothien-3-yl) carbamoyl] -2- (methylthiomethyl) pyrazolo [1,5-a] pyrimidine (183.6 mg, 91% yield) is obtained as a pale yellow powder.
MS (APCI) m / z; 561/563 [M + H] +.

(2) By treating 183 mg of the compound obtained in (1) above in the same manner as in Production Example 29, (R) -6- (2-chlorophenyl) -7- (4-chlorophenyl) -3-[(1, 1-Dioxo-tetrahydrothien-3-yl) carbamoyl] -2- (methylsulfonylmethyl) pyrazolo [1,5-a] pyrimidine (91.6 mg, 47% yield) is obtained as a powder.
MS (APCI) m / z; 593/595 [M + H] ^< +>.

Production Example 470
By treating 50 mg of the compound obtained in Reference Example 9 and 31.8 mg of 3-pyridylacetic acid hydrochloride in the same manner as in Production Example 3, 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3-[[ 2- (2-Pyridyl) acetyl] amino] pyrazolo [1,5-a] pyrimidine (52.6 mg, 79% yield) is obtained as a yellow powder.
MS (APCI) m / z; 474/476 [M + H] +.

Production Example 471
(1) The compound (7.3 g) obtained in Reference Example 5 is treated in the same manner as in Production Example 484 to give 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3-ethoxycarbonyl-2- Aminopyrazolo [1,5-a] pyrimidine (1.43 g) is obtained.
MS (APCI) m / z; 427/429 [M + H] ^< +>.

(2) The compound (2.64 g) obtained in (1) above is treated in the same manner as in Production Examples 440 (1) and (2) to give 6- (2-chlorophenyl) -7- (4-chlorophenyl)- 3-Ethoxycarbonyl-2- (methylsulfonylamino) pyrazolo [1,5-a] pyrimidine (2.20 g) is obtained.
MS (APCI) m / z; 505/507 [M + H] ^< +>.

(3) By treating the compound (70 mg) obtained in (2) in the same manner as in Reference Example 1 (3), 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3-carboxy-2 -(Methylsulfonylamino) pyrazolo [1,5-a] pyrimidine is obtained as a crude product.
MS (APCI) m / z; 477/479 [M + H] ^< +>.

(4) By treating the compound obtained in (3) in the same manner as in Production Example 3, 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3-[[N′-methyl-N ′ -(2-Pyridyl) hydrazino] carbonyl] -2- (methylsulfonylamino) pyrazolo [1,5-a] pyrimidine (27 mg, 32% yield) is obtained as a powder.
MS (APCI) m / z; 596/598 [M + H] ^< +>.

Production Example 472
The corresponding starting material compound is treated in the same manner as in Production Example 471 to give 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- (N-isobutylcarbamoyl) -2- (methylsulfonylamino) pyrazolo [1 , 5-a] pyrimidine (52 mg, 79% yield) is obtained as a powder.
MS (APCI) m / z; 546/548 [M + H] ^< +>.

Production Example 473
To a solution of 50 mg of the compound obtained in Reference Example 9 (2) in 1.5 mL of tetrahydrofuran are added 30.5 μL of phenyl isocyanate and 49 μL of triethylamine, and the mixture is stirred at 60 ° C. overnight. Add water to the reaction mixture and extract with ethyl acetate. The extract was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 75/25 to 65/35) to give 6- (2-chlorophenyl) -7- (4-Chlorophenyl) -3- (N′-phenylureido) pyrazolo [1,5-a] pyrimidine (37.8 mg, 57% yield) is obtained as a powder.
MS (APCI) m / z; 474/476 [M + H] ^< +>.

Production Example 474
The corresponding starting material compound was treated in the same manner as in Production Example 473 to give 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- (N′-cyclopentylureido) pyrazolo [1,5-a] pyrimidine ( 48.3 mg, 74% yield) is obtained as a powder.
MS (APCI) m / z; 466/468 [M + H] ^< +>.

Production Examples 475 to 478
The corresponding starting material compounds are treated in the same manner as in Production Example 3 to obtain the compounds shown in Table 22 below.

Production Example 479
The corresponding starting material compound is treated in the same manner as in Production Example 31 to give 6- (2-cyanophenyl) -7- (4-trifluoromethylphenyl) -3- [N- (1,1-dioxo-thiomorpholino). Carbamoyl] pyrazolo [1,5-a] pyrimidine is obtained as a powder.
MS (APCI) m / z; 541 [M + H] ^< +>.

Production Example 480
(1) The compound (440 mg) obtained in Production Example 471 (1) is treated in the same manner as in Reference Example 1 (3) to give 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3-carboxy- 2-Aminopyrazolo [1,5-a] pyrimidine is obtained as a crude product.
MS (APCI) m / z; 399/401 [M + H] ^< +>.

(2) By treating the compound obtained in (1) in the same manner as in Production Example 3, (R) -6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- [N- (1, 1-Dioxotetrahydrothien-3-yl) carbamoyl] -2-aminopyrazolo [1,5-a] pyrimidine (254 mg, 48% yield) is obtained as a powder.
MS (APCI) m / z; 516/518 [M + H] ^< +>.

(3) By treating the compound (250 mg) obtained in (2) in the same manner as in Production Example 43, (R) -6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- [N -(1,1-Dioxotetrahydrothien-3-yl) carbamoyl] -2- (pyrrolidin-1-yl) pyrazolo [1,5-a] pyrimidine (106 mg, 38%) is obtained as a powder.
MS (APCI) m / z; 570/572 [M + H] ^< +>.

  (4) By treating the compound (95 mg) obtained in (3) in the same manner as in Production Example 33, the compounds described in Table 23 below are obtained.

Production Example 481
3- (N, N-dimethylamino) -1- (4-chlorophenyl) -2- (2-chlorophenyl) -2-propen-1-one (6.18 g) and the compound obtained in Reference Example 46 By treating 0 g in the same manner as in Reference Example 1 (2), 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] +.

Production Example 482
(1) By treating 2.5 g of the compound obtained in Production Example 481 in the same manner as in Reference Example 1 (3), 2-carboxy-6- (2-chlorophenyl) -7- (4-chlorophenyl) pyrazolo [1 , 5-a] pyrimidine (1.65 g) is obtained as a crude product.
MS (APCI) m / z; 384/386 [M + H] +.

(2) By treating 80 mg of the compound obtained in the above (1) and 26 mg of 1-methyl-1- (2-pyridyl) hydrazine in the same manner as in Production Example 3, 6- (2-chlorophenyl) -7- (4 -Chlorophenyl) -2-[[N'-methyl-N '-(2-pyridyl) hydrazino] carbonyl] pyrazolo [1,5-a] pyrimidine (85 mg) is obtained as a colorless powder.
MS (APCI) m / z; 489/491 [M + H] +.

Production Example 483
10.1 g of 5-amino-4-ethoxycarbonyl-3-methylthio-1H-pyrazole (compound obtained in Reference Example 18) and 3- (N, N-dimethylamino) -1- (4-trifluoromethylphenyl) By treating 17.7 g of 2- (2-chlorophenyl) -2-propen-1-one in the same manner as in Reference Example 5 (1), 6- (2-chlorophenyl) -7- (4-chlorophenyl)- 3-Ethoxycarbonyl-2-methylthiopyrazolo [1,5-a] pyrimidine (11.4 g, 45% yield) is obtained as a colorless powder.
MS (APCI) m / z; 492/494 [M + H] +.

Production Example 484
(1) The compound (11 g) obtained in Production Example 483 is treated in the same manner as in Reference Example 5 (2) to give 2-azido-6- (2-chlorophenyl) -3-ethoxycarbonyl-7- (4- Trifluoromethylphenyl) pyrazolo [1,5-a] pyrimidine (10.6 g, 91% yield) is obtained as a colorless powder. The compound (10.6 g) was treated in the same manner as in Reference Example 11 to give 6- (2-chlorophenyl) -3-ethoxycarbonyl-7- (4-trifluoromethylphenyl) -2- (triphenylphosphorani Ridenamino) pyrazolo [1,5-a] pyrimidine (11.1 g) is obtained as a colorless powder.

(2) 2-amino-6- (2-chlorophenyl) -3-ethoxycarbonyl-7- is obtained by treating the compound (11.1 g) obtained in (1) above and 70 mL of acetic acid in the same manner as in Production Example 40. (4-Trifluoromethylphenyl) pyrazolo [1,5-a] pyrimidine (5.2 g, 73% yield) is obtained as a colorless solid.
MS (APCI) m / z; 461/463 [M + H] +.

Production Example 485
The compound (2.1 g) obtained in Production Example 484 and 1,4-dichlorobutane (2.9 g) are treated in the same manner as in Production Example 43 to give 6- (2-chlorophenyl) -3-ethoxycarbonyl-7. -(4-Trifluoromethylphenyl) -2- (pyrrolidin-1-yl) pyrazolo [1,5-a] pyrimidine (0.61 g, 26% yield) is obtained as a yellow oil.
MS (APCI) m / z; 515/517 [M + H] +.

Production Example 486
The compound (0.61 g) obtained in Production Example 485 is treated in the same manner as in Reference Example 8 to give 3-carboxy-6- (2-chlorophenyl) -7- (4-trifluoromethylphenyl) -2- ( Pyrrolidin-1-yl) pyrazolo [1,5-a] pyrimidine (0.45 g) is obtained as a crude product. The compound (70 mg) and 1-aminopyrrolidine hydrochloride (17.6 mg) were treated in the same manner as in Production Example 3 to give 6- (2-chlorophenyl) -3- [N- (pyrrolidin-1-yl) carbamoyl. ] -7- (4-trifluoromethylphenyl) -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) is obtained as a yellow powder.
Compound a: MS (APCI) m / z; 555/557 [M + H] +.
Compound b: MS (APCI) m / z; 443/445 [M + H] +.

Production Example 487
(1) Sodium hydride (60%, 137 mg) is added little by little to a 5 mL dimethylformamide solution of the compound (300 mg) obtained in Reference Example 4B and stirred. After gradually adding 125 μL of 4-chloro-N-methylaniline to the mixture, the mixture is stirred at 80 ° C. for 30 minutes. The reaction mixture is cooled to room temperature, water and ethyl acetate are added, and the aqueous layer is neutralized with 2N hydrochloric acid. The organic layer is washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (solvent; chloroform / methanol = 98/2 to 85:15) to give 6- (2-chlorophenyl) -7- [N -Methyl-N- (4-chlorophenyl) amino] -3-carboxy-2-methylpyrazolo [1,5-a] pyrimidine (54.2 mg, 15% yield) is obtained as a colorless powder.
MS (APCI) m / z; 427/429 [M + H] +.

(2) The compound (27 mg) obtained above was treated in the same manner as in Production 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, 55% yield) is obtained as a colorless powder.
MS (APCI) m / z; 532/534 [M + H] +.

Production Examples 488-489
The corresponding starting material compounds are treated in the same manner as in Production Example 487 to give the compounds shown in Table 24 below.

Production Examples 490-500
The corresponding starting material compounds are treated in the same manner as in Production Example 487 to give the compounds shown in Table 25 below.

Reference example 1
(1) To 250 mL of diethyl ether, 6.04 g of metal magnesium and a catalytic amount of iodine are added and stirred, and 20.0 g of 2-chlorobenzyl chloride is gradually added dropwise. After stirring the mixture for 1 hour, 18.8 g of 4-chlorobenzonitrile in 20 mL of tetrahydrofuran / 50 mL of diethyl ether is added to the reaction, and the mixture is stirred for 3 hours. Under ice cooling, 150 mL of 2N hydrochloric acid is added to the reaction mixture, and the mixture is stirred at room temperature for 2 hours. The reaction solution is extracted with ethyl acetate, and the organic layer is washed with 1N hydrochloric acid, water and saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 40/1 to 20/1) to give (2-chlorobenzyl) (4-chlorophenyl). Methanone (24.40 g, 74% yield) is obtained as a powder.
MS (APCI) m / z; 265/267 [M + H] ^< +>.

(2) A solution of 6.4 g of the compound obtained in (1) and 6.4 mL of N, N-dimethylformamide dimethylacetal in 24 mL of N, N-dimethylformamide is stirred at 150 ° C. for 4 hours. The reaction mixture is cooled to room temperature, water is added, and the mixture is extracted 3 times with a mixture of ethyl acetate and hexane. The organic layer is washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate is concentrated under reduced pressure to give 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) is added 3-amino-4-ethoxycarbonyl-1H-pyrazole (3.75 g) and piperidine (0.48 mL), and the mixture is heated at 80 ° C. for 16 hours. After cooling the reaction solution to room temperature, water and ethyl acetate are added. The organic layer is washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 17 / 3-67 / 33) to give 3-ethoxycarbonyl-6- (2-chlorophenyl). ) -7- (4-Chlorophenyl) pyrazolo [1,5-a] pyrimidine (5.02 g, 50% yield) is obtained as a powder.
MS (APCI) m / z; 412/414 [M + H] ^< +>.

(3) Add 6 mL of 2N aqueous sodium hydroxide solution to 30 mL of ethanol solution of 2.5 g of the compound obtained in (2) above, and stir at room temperature for 5 hours. 6 mL of 2N hydrochloric acid is added to the reaction mixture, and the mixture is stirred and concentrated under reduced pressure. The residue is extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give 3-carboxy-6- (2-chlorophenyl) -7- (4-chlorophenyl) pyrazolo [1,5-a] pyrimidine (2.1 g, yield 90%) as a powder. obtain.
MS (APCI) m / z; 384/386 [M + H] ^< +>.

Reference example 2
(1) To 100 mL of dimethoxyethane, 4.1 g of 4-chlorobenzyl bromide, 2.56 mL of 4-chlorobenzoyl chloride, 702 mg of bis (triphenylphosphine) palladium dichloride and 2.6 g of zinc dust are added, and the mixture is stirred for 2 hours under a nitrogen atmosphere. To do. The reaction mixture is filtered, the filtrate is concentrated under reduced pressure, and the residue is extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 49/1 to 9/1) to give (4-chlorobenzyl) (4-chlorophenyl). Methanone (4.85 g, 91% yield) is obtained as a powder.
MS (GC-EI) m / z; 264 [M] ^<+> .

(2) By treating the compound obtained in (1) in the same manner as in Reference Examples 1 (2) and (3), 3-carboxy-6- (4-chlorophenyl) -7- (4-chlorophenyl) pyrazolo [1,5-a] pyrimidine (165 mg, 20% yield) is obtained as a powder.
MS (APCI) m / z; 384/386 [M + H] ^< +>.

Reference example 3
The corresponding starting material compound was treated in the same manner as in Reference Example 1 to give 3-carboxy-6-phenyl-7- (4-chlorophenyl) pyrazolo [1,5-a] pyrimidine (2.06 g, yield 22%). obtain.
MS (APCI) m / z: 350/352 [M + H] ^< +>.

Reference example 4
(1) Add 14.4 mL of N, N-dimethylformamide dimethyl acetal to 150 mL of dimethylformamide in 10 g of 2-chlorophenylacetic acid methyl ester, and stir at 85 ° C. overnight. After cooling the reaction solution to room temperature, ethyl acetate and water are added and stirred. The organic layer is extracted, dried over sodium sulfate and filtered. The filtrate is concentrated under reduced pressure, and the residue is diluted with 18 mL of acetic acid. Then, 8.4 g of 3-amino-4-ethoxycarbonyl-1H-pyrazole and 1.1 mL of piperidine are added, and the mixture is stirred at 80 ° C. for 3.5 hours. After cooling the reaction solution to room temperature, ethyl acetate and water are added and stirred, followed by filtration. The obtained solid is 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 10.7 g of the compound obtained in (1) above in 250 mL of ethanol is added 3.24 g of sodium carbonate and heated to reflux for 4 days. The reaction solution is cooled to room temperature and then filtered, and the filtrate is concentrated under reduced pressure. Water is added to the residue, stirred, and filtered (the filtration operation is repeated 5 times). The resulting solid was dried to give 6- (2-chlorophenyl) -3-ethoxycarbonyl-7-oxo-4,7-dihydropyrazolo [1,5-a] pyrimidine (8.5 g, 87% yield). ) As a powder.
MS (APCI) m / z; 318/320 [M + H] ^< +>.

(3) Add 319 μL of N, N-dimethylaniline and 270 μL of phosphorus oxychloride to a solution of 300 mg of the compound obtained in (2) in 2 mL of acetonitrile, and heat and return for 1 day. The reaction mixture is cooled to room temperature, poured into ice water, and extracted with methylene chloride. The extract is dried over magnesium sulfate and filtered, and the filtrate is concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 80/20 to 60/40) to give 7-chloro-6- (2-chlorophenyl) -3-ethoxycarbonylpyrazolo. [1,5-a] pyrimidine (108 mg, 34% yield) is obtained as a powder.
MS (APCI) m / z; 336/338 [M + H] ^< +>.

(4) 100 mg of the compound obtained in the above (3), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride-methylene chloride complex 7.3 mg, potassium phosphate 189 mg and 4-fluorophenylboron A solution of 46 mg of acid in 3 mL of 1,4-dioxane is stirred at 80 ° C. for 5 hours under a nitrogen atmosphere. Cool the reaction to room temperature, add methylene chloride and brine and stir. The organic layer is extracted, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 80/20 to 65/35) to give 6- (2-chlorophenyl) -3-ethoxy. Carbonyl-7- (4-fluorophenyl) pyrazolo [1,5-a] pyrimidine (106 mg, 90% yield) is obtained as a powder.
MS (APCI) m / z; 396/398 [M + H] ^< +>.

Reference Example 4B
36 mL of N, N-dimethylformamide dimethylacetal is added to a solution of 25 g of 2-chlorophenylacetic acid methyl ester in 400 mL of dimethylformamide, and stirred at 90 ° C. overnight. After cooling the reaction solution to room temperature, ethyl acetate and water are added and stirred. The organic layer is dried over magnesium sulfate and then filtered. The filtrate is concentrated under reduced pressure, and the residue is diluted with 60 mL of acetic acid, and 19.7 g of 3-amino-4-ethoxycarbonyl-2-methyl-1H-pyrazole is added thereto, followed by stirring at 120 ° C. overnight. After cooling the reaction solution to room temperature, the precipitate is collected by filtration, washed with ethyl acetate / diisopropyl ether (= 1/1) and dried to give 6- (2-chlorophenyl) -3-ethoxycarbonyl-2-methyl. -7-oxo-4,7-dihydropyrazolo [1,5-a] pyrimidine (26.0 g, 2 step yield 62%) is obtained as a powder.
MS (APCI) m / z; 332/334 [M + H] ^< +>.

Reference Example 5
(1) 6.8 g of 5-amino-4-ethoxycarbonyl-3-methylthio-1H-pyrazole (compound obtained in Reference Example 18), 3- (N, N-dimethylamino) -1- (4-chlorophenyl) A solution of 10.9 g of 2- (2-chlorophenyl) -2-propen-1-one and 578 mg of piperidine in 13 mL of acetic acid is stirred at 80 ° C. overnight. After cooling the reaction solution to room temperature, water and ethyl acetate are added. The organic layer is washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, 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-Chlorophenyl) -3-ethoxycarbonyl-2-methylthiopyrazolo [1,5-a] pyrimidine (5.88 g, 38% yield) is obtained as a pale yellow solid.

  (2) 9.46 g of 3-chloroperbenzoic acid (70%) was added to a solution of 5.86 g of the compound obtained in (1) in 200 mL of methylene chloride under ice cooling, and the same temperature was maintained for 10 minutes and at room temperature for 3 hours. Stir. To the reaction mixture is added an aqueous sodium thiosulfate solution under ice-cooling, and the mixture is stirred at room temperature, followed by addition of ethyl acetate and water. The organic layer is dried over magnesium sulfate and filtered, and the filtrate is concentrated under reduced pressure. The obtained crystals are washed with ice-cold ethanol and dried to give 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3-ethoxycarbonyl-2-methylsulfonyl-3-ethoxycarbonyl-2-methyl. Sulfonylpyrazolo [1,5-a] pyrimidine (5.52 g, 88% yield) is obtained as a pale yellow solid.

(3) 1.66 g of sodium ethoxide is added to a solution of 1.0 g of the compound obtained in the above (2) in 26 mL of ethanol / 30 mL of tetrahydrofuran, and heated under reflux for 1 day. After cooling the reaction solution to room temperature, water and sodium acetate are added. The organic layer is washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 80/20 to 40/60) to give 6- (2-chlorophenyl) -7- ( 4-Chlorophenyl) -2-ethoxy-3-ethoxycarbonylpyrazolo [1,5-a] pyrimidine (86 mg, 9.2% yield) is obtained as a pale yellow solid.
MS (APCI) m / z; 456/458 [M + H] ^< +>.

(4) By treating the compound (445 mg) obtained in (3) in the same manner as in Reference Example 1 (3), 3-carboxy-6- (2-chlorophenyl) -7- (4-chlorophenyl) -2 -Ethoxypyrazolo [1,5-a] pyrimidine (490 mg) is obtained as a pale yellow solid.
MS (APCI) m / z; 428/430 [M + H] ^< +>.

Reference Example 6
(1) A mixture of 13.1 g of 1- (4-chlorophenyl) ethanone and 16.3 g of C-tert-butoxy-N, N, N ′, N′-tetramethylmethylenediamine is stirred at 60 ° C. overnight. The reaction solution was cooled to room temperature and then concentrated under reduced pressure to give 1- (4-chlorophenyl) -3- (N, N-dimethylamino) -2-propen-1-one (18.4 g, yield 100%). Is obtained as a yellow solid.
MS (APCI) m / z; 210/212 [M + H] ^< +>.

(2) To a solution of 18.4 g of the compound obtained in (1) above in 105 mL of methylene chloride, 13.6 g of bromine is added dropwise over 10 minutes under ice cooling, and the mixture is stirred at the same temperature for 30 minutes. A solution of triethylamine 11.8 mL in diethyl ether 130 mL is added dropwise over 5 minutes, and the mixture is stirred for 2 hours. The reaction is warmed to room temperature and filtered. The filtrate is concentrated under reduced pressure, 20 mL of methylene chloride and 50 mL of diisopropyl ether are added to the residue, and the mixture is stirred for 1 hour under ice cooling. The precipitated crystals were collected by filtration and dried under reduced pressure to give 2-bromo-1- (4-chlorophenyl) -3- (N, N-dimethylamino) -2-propen-1-one (20.2 g, yield). 82%) is obtained as a pale yellow solid.
MS (APCI) m / z; 288/290 [M + H] ^< +>.

(3) 13 mL of a 25% hydrogen bromide-acetic acid solution is added to a solution of 20.2 g of the compound obtained in (2) above and 10.9 g of 3-amino-4-ethoxycarbonylpyrazole in 65 mL of ethanol, and the mixture is heated to reflux for 1 hour. The reaction solution is cooled to room temperature and then concentrated under reduced pressure, and the residue is dissolved in 200 mL of chloroform. The solution was washed with saturated aqueous sodium hydrogen carbonate solution and brine, and dried over sodium sulfate. Filter. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (solvent; ethyl acetate / chloroform = 0/100 to 10/90) and then crystallized from diisopropyl ether to give 6-bromo. -7- (4-Chlorophenyl) -3-ethoxycarbonylpyrazolo [1,5-a] pyrimidine (13.8 g, 52% yield) is obtained as a colorless solid.
MS (APCI) m / z; 380/382 [M + H] ^< +>.

(4) 1.0 g of the compound obtained in the above (3), 549 mg of 2- (trifluoromethyl) phenylboronic acid, [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride-methylene chloride complex A 51 mL solution of 77 mg and 1.55 g of potassium phosphate in 1,4-dioxane is stirred at 80 ° C. overnight and at 90 ° C. for 8 hours under a nitrogen atmosphere. The reaction mixture is cooled to room temperature, diluted with ethyl acetate, and filtered. The filtrate is concentrated under reduced pressure, the residue is diluted with 34 mL of tetrahydrofuran, 16 mL of 1N aqueous lithium hydroxide solution is added, and the mixture is stirred at 55 ° C. overnight. After cooling the reaction solution to room temperature, chloroform, water and 1N aqueous hydrochloric acid solution are added, and then the organic layer is separated. The organic layer is washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and recrystallized from methylene chloride / diisopropyl ether and hexane to give 3-carboxy-7- (4-chlorophenyl) -6- (2-trifluoromethylphenyl) pyrazolo [1,5-a Pyrimidine (370 mg, 34% yield) is obtained as a pale yellow solid.
MS (APCI) m / z; 418/420 [M + H] ^< +>.

Reference Example 7
Pyrrolidine 50 μL and potassium carbonate 138 mg are added to a solution of the compound 168 mg obtained in Reference Example 4 (3) in 5 mL of dimethylformamide, and the mixture is stirred at 160 ° C. for 5 minutes in a microwave reactor. The reaction mixture is cooled to room temperature, added with water, stirred, and extracted with methylene chloride. The extract is concentrated under reduced pressure, and the resulting crude product is purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 80/20 to 65/35) to give 6- (2-chlorophenyl) -3-ethoxy. Carbonyl-7- (1-pyrrolidinyl) pyrazolo [1,5-a] pyrimidine (116 mg, 63% yield) is obtained as a powder.
MS (APCI) m / z; 371/373 [M + H] ^< +>.

Reference Example 7B
(1) The corresponding starting material compound is treated in the same manner as in Reference Example 4B and Reference Example 4 (3) to give 6- (2-chlorophenyl) -7-chloro-3-ethoxycarbonyl-2-methylpyrazolo [1,5- a] Pyrimidine is obtained.

(2) Add 103 μL of thiomorpholine and 237 mg of potassium carbonate to a solution of 300 mg of the compound obtained in (1) above in 3 mL of dimethylformamide, and stir at 80 ° C. for 40 minutes. The reaction mixture is cooled to room temperature, water is added, and the mixture is stirred and extracted with ethyl acetate. The extract is washed with water and saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, 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-2- Methyl-3-ethoxycarbonylpyrazolo [1,5-a] pyrimidine (324 mg, 91% yield) is obtained as a powder.
MS (APCI) m / z; 417/419 [M + H] ^< +>.

Reference Example 8
To a solution of 11.5 g of the compound obtained in Reference Example 5 (1) in 58 mL of ethanol / 58 mL of tetrahydrofuran is added 50.2 mL of 2N aqueous sodium hydroxide solution, and the mixture is stirred at 60 ° C. for 8 hours. The reaction solution is cooled to room temperature and then concentrated under reduced pressure. To the residue, chloroform, brine and 2N hydrochloric acid are added and stirred (pH = 2 to 3). The organic layer is dried over magnesium sulfate and filtered, and the filtrate is concentrated under reduced pressure. The precipitated crystals were washed with diethyl ether to give 3-carboxy-6- (2-chlorophenyl) -7- (4-chlorophenyl) -2-methylthiopyrazolo [1,5-a] pyrimidine (11.1 g, yield). 100%) is obtained as a pale yellow solid.
MS (APCI) m / z; 430/432 [M + H] ^< +>.

Reference Example 9
(1) To a solution of 2.0 g of the compound obtained in Reference Example 1 (4) in 15 mL of tert-butyl alcohol, add 1.15 mL of diphenyl phosphate azide and 725 μL of triethylamine, and stir at 80 ° C. overnight. After cooling the reaction solution to room temperature, water and ethyl acetate are added and stirred. The organic layer is washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, 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-Chlorophenyl) -7- (4-chlorophenyl) pyrazolo [1,5-a] pyrimidine (1.0 g, 42% yield) is obtained as an orange powder.
MS (APCI) m / z; 455/457 [M + H] ^< +>.

(2) 16N of 4N hydrochloric acid-1,4-dioxane is added to 8 mL of 1,4-dioxane in 1.0 g of the compound obtained in (1) above, and the mixture is stirred at room temperature for 1.5 hours. Add 2 mL of methanol to the reaction mixture and stir at room temperature for 3.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was crystallized from diisopropyl ether to give 3-amino-6- (2-chlorophenyl) -7- (4-chlorophenyl) pyrazolo [1,5-a] pyrimidine hydrochloride (809 mg). 94% yield) as a pale orange powder.
MS (APCI) m / z; 355/357 [M + H] ^< +>.

Reference Example 10
(1) N-tert-butoxycarbonylhydrazine 135 mL, water-soluble carbodiimide hydrochloride 224 mg, 1-hydroxybenzotriazole 179 mg and triethylamine 326 mg were added to a solution of the compound obtained in Reference Example 1 (4) in 4.0 mL of methylene chloride. Stir overnight at room temperature. An aqueous sodium hydrogen carbonate solution and methylene chloride are added to the reaction mixture and stirred. The organic layer is washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (Chromatorex NH silica gel; manufactured by Fuji Silysia Chemical Ltd., solvent; hexane / ethyl acetate = 70/30 to 40:60). (N′-tert-butoxycarbonylhydrazino) carbonyl-6- (2-chlorophenyl) -7- (4-chlorophenyl) pyrazolo [1,5-a] pyrimidine (379 mg, 97% yield) is obtained as a yellow solid. .
MS (APCI) m / z; 498/500 [M + H] ^< +>.

(2) Add 500 μL of 4N hydrochloric acid-dioxane solution to 5 mL of 1,4-dioxane in 345 mg of the compound obtained in (1) above, and stir at 40 ° C. overnight. A 2N aqueous hydrochloric acid solution is added to the reaction mixture, and the mixture is stirred at 40 ° C. for 8 hours. An aqueous sodium hydrogen carbonate solution and methylene chloride are added to the reaction solution and stirred, and then the organic layer is extracted. The extract is dried over sodium sulfate and filtered, and the filtrate is concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 80 / 20-0: 100) to give 3-hydrazinocarbonyl-6- (2-chlorophenyl) -7- (4 -Chlorophenyl) pyrazolo [1,5-a] pyrimidine (142 mg, 52% yield) is obtained as a yellow viscous body.
MS (APCI) m / z; 398/400 [M + H] ^< +>.

Reference Example 11
1.11 g of sodium azide is added to a solution of 1.5 g of the compound obtained in Production Example 33 in 20 mL of dimethylformamide, and stirred at 110 ° C. overnight. The reaction mixture is cooled to room temperature, saturated brine is added, and the mixture is stirred and extracted with ethyl acetate. The organic layer is washed with water and concentrated under reduced pressure, and the resulting crude product is purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 80/20 to 30:70) to give 2-azido-6- (2 1.15 g of -chlorophenyl) -7- (4-chlorophenyl) -3- (N-cyclopentylcarbamoyl) pyrazolo [1,5-a] pyrimidine are obtained as a yellow solid. To a solution of 870 mg of the compound in 16 mL of tetrahydrofuran is added 869 mg of triphenylphosphine, and the mixture is stirred at 40 ° C. for 1 hour. The reaction solution is cooled to room temperature and then concentrated under reduced pressure. The resulting crude product is purified by silica gel column chromatography (solvent; chloroform / methanol = 100/0 to 97: 3) to give 6- (2-chlorophenyl)- 7- (4-Chlorophenyl) -2-triphenylphosphoranylideneaminopyrazolo [1,5-a] pyrimidine (942 mg, 58% yield; 2 reactions) is obtained as a yellow solid.
MS (APCI) m / z; 726/728 [M + H] ^< +>.

Reference Example 12
(1) By treating 7-chloro-6- (2-chlorophenyl) -3-ethoxycarbonylpyrazolo [1,5-a] pyrimidine (1 g) in the same manner as in Reference Example 4 (5), 6- ( 2-Chlorophenyl) -3-ethoxycarbonyl-7- (4-formylphenyl) pyrazolo [1,5-a] pyrimidine (910 mg) is obtained as a pale yellow powder.
MS (APCI) m / z; 428/430 [M + H] ^< +>.
(2) 184 μL of bis- (2-methoxyethyl) aminosulfur trifluoride (trade name: Deoxo-Fluor, manufactured by Scott) was added to 1 mL of methylene chloride in 406 mg of the compound obtained in (1) above, and the mixture was stirred at room temperature for 4 hours. Stir. The organic layer is washed with brine and extracted with methylene chloride. The extract is dried over sodium sulfate and filtered, and the filtrate is concentrated under reduced pressure. The resulting crude product is purified by 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, 37% yield) is obtained as a pale yellow solid.
MS (APCI) m / z; 428/430 [M + H] ^< +>.

(3) The compound (278 mg) obtained in the above (2) is treated in the same manner as in Reference Example 1 (3) to give 3-carboxy-6- (2-chlorophenyl) -7- (4-difluoromethylphenyl) Pyrazolo [1,5-a] pyrimidine (223 mg, 86% yield) is obtained 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 ethanol (100 mL) is added sodium acetate (3.28 g) and hydroxylamine hydrochloride (1.81 g) at room temperature, and the mixture is stirred at the same temperature for 2 hours. The reaction mixture is concentrated under reduced pressure, ethyl acetate and aqueous sodium hydrogen carbonate solution are added to the residue, and the mixture is stirred and extracted with ethyl acetate. The organic layer is washed with brine, dried over sodium sulfate and filtered. The filtrate is concentrated under reduced pressure 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 500 mg of the compound obtained in (1) above in 10 mL of diethyl ether is added 289 mg of lithium aluminum hydride under ice cooling under a nitrogen atmosphere, and the mixture is stirred at the same temperature for 30 minutes and at room temperature for 1 hour. To the reaction solution, 72 mg of lithium aluminum hydride is added and stirred at 40 ° C. for 2 hours. 1 mL of water and 1 mL of 2N aqueous sodium hydroxide solution are added to the reaction mixture at room temperature, and the mixture is stirred and then filtered. The filtrate is concentrated under reduced pressure to give 4-amino-tetrahydro-4H-thiopyran (150 mg, 34% yield) as a yellow liquid.
MS (APCI) m / z; 118 [M + H] ^< +>.

Reference Example 14A
(1) A mixture of 4.95 g of (R) -methioninol, 8.3 mL of benzonitrile and 250 mg of zinc bromide is stirred at 120 ° C. for 90 hours under a nitrogen atmosphere. The reaction solution is cooled to room temperature and then filtered. The filtrate is washed with water and brine, dried over magnesium sulfate and filtered again. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 5 / 1-3 / 1) to give (R) -4- (2-methylthioethyl). ) -2-Phenyl-4,5-dihydrooxazole (3.94 g, 48.6% yield) is obtained as a colorless oil.
MS (APCI) m / z; 222 [M + H] ^< +>.

(2) Add 7.7 mL of concentrated hydrochloric acid to a solution of 3.94 g of the compound obtained in (1) above in 65 mL of acetic acid, and heat to reflux overnight. The reaction mixture is cooled to room temperature and concentrated under reduced pressure. Add 50 mL of aqueous sodium hydroxide and 100 mL of chloroform to the residue and stir. Magnesium sulfate and silica gel are added to the organic layer, and the mixture is stirred and then filtered. The filtrate was concentrated under reduced pressure, and the resulting crude product was washed with isopropyl ether and dried to give (R) -N- (tetrahydrothien-3-yl) benzamide (2.80 g, yield 76%) colorless. Obtain as a solid.
MS (APCI) m / z; 208 [M + H] ^< +>.

(3) 10 g of 3-chloroperbenzoic acid (75%) is gradually added to 70 mL of methylene chloride containing 3.59 g of the compound obtained in the above (2) under ice cooling, and the mixture is stirred at room temperature overnight. Water (35 mL), sodium sulfite (3.5 g) and saturated aqueous sodium hydrogen carbonate solution (100 mL) are added to the reaction mixture, and the mixture is stirred for 30 minutes and extracted with chloroform. The extract is washed with an aqueous sodium hydrogen carbonate solution, and the organic layer is dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting solid was washed with ethyl acetate to give (R) -N- (1,1-dioxotetrahydrothien-3-yl) benzamide (3.5 g, yield 85%). Obtained as a colorless solid.
MS (APCI) m / z; 240 [M + H] ^< +>.

(4) To a solution of 3.51 g of the compound obtained in (3) above in 13 mL of ethanol is added 52 mL of 6N aqueous hydrochloric acid, and the mixture is heated to reflux for 1 day. The reaction mixture is cooled to room temperature, and the aqueous layer is washed with ethyl acetate and concentrated under reduced pressure. The precipitated solid was washed with ethanol / diethyl ether, collected by filtration, and further washed with diethyl ether to give (R) -N- (1,1-dioxo-tetrahydrothien-3-yl) amine hydrochloride (2. 52 g, 100% yield) is obtained as a colorless solid.
MS (APCI) m / z; 136 [M + H] ^< +>.

Reference Example 14B
(S) -methioninol (4.83 g) was treated in the same manner as in Reference Example 14 to give (S) -N- (1,1-dioxo-tetrahydrothien-3-yl) amine hydrochloride (3.86 g). Is obtained as a colorless solid.
MS (APCI) m / z; 136 [M + H] ^< +>.

Reference Example 15
(1) 7.6 mL of 2N aqueous sodium hydroxide solution is added to an aqueous solution of 2.0 g of 4,4-difluoropiperidine hydrochloride and stirred at room temperature for 1 hour. To the reaction solution are added 1.75 g of sodium nitrite at room temperature and 1.27 mL of acetic acid under ice cooling, and the mixture is stirred at room temperature for 2 hours. Aqueous sodium hydrogen carbonate solution is added to the reaction mixture, and the mixture is stirred and extracted with chloroform. The extract is dried over magnesium sulfate and filtered, and the filtrate is concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 4/1) to give 4,4-difluoro-1-nitrosopiperidine (1.89 g, yield 99%) Obtained as a yellow solid.
MS (APCI) m / z; 151 [M + H] ^< +>.

(2) 837 mg of lithium aluminum hydride is added little by little to a tetrahydrofuran solution of 1.89 g of the compound obtained in (1) above under ice-cooling, and the mixture is heated to reflux for 1 hour. Water is added to the reaction mixture under ice cooling, and the mixture is heated to reflux for 30 minutes. The reaction solution is cooled to room temperature and then filtered, and the filtrate is concentrated under reduced pressure. To the residue, an aqueous sodium hydrogen carbonate solution and chloroform are added and stirred. The organic layer is dried over sodium sulfate and filtered, and the filtrate is concentrated under reduced pressure 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) 125 μL of acetic acid and 201 mg of sodium nitrite in 600 μL of water are added to a solution of 278 mg of 3-trifluoromethoxyphenylmethylamine in 400 μL of water under ice-cooling, and then 500 μL of methanol and 500 μL of tetrahydrofuran are added at room temperature overnight. Stir. Saturated aqueous sodium hydrogen carbonate solution is added to the reaction mixture and the mixture is stirred and extracted with ethyl acetate. The extract was concentrated under reduced pressure, 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. Nitrosamine (282 mg, 88% yield) is obtained 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) is added under ice cooling, 282 mg of the compound obtained in (1) above (2.5 mL in tetrahydrofuran) is added and stirred at room temperature for 1 hour in a nitrogen atmosphere. To the reaction solution, 90 μL of water, 90 μL of 15% aqueous sodium hydroxide solution and 180 μL of water are added and stirred, followed by filtration. The filtrate was concentrated under reduced pressure, 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-trifluoro). Methoxyphenyl) hydrazine (187 mg, 71% yield) is obtained as an orange gum.
MS (APCI) m / z; 207 [M + H] ^< +>.

Reference Example 17
Tetrahydro-4H-thiopyran-4-one To a solution of 500 mg of water 10 mL / ethanol 10 mL, 1.4 g of potassium cyanide and 1.15 g of ammonium chloride are added and stirred at room temperature for 4 days. Diethyl ether and 1N aqueous sodium hydroxide solution are added to the reaction mixture and stirred, and then the organic layer is separated. The aqueous layer is extracted with diethyl ether and ethyl acetate, and the organic layers are combined, dried over calcium chloride and filtered. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 70 / 30-30: 70) to give 4-amino-4-cyano-tetrahydro-4H. -315 mg of thiopyran is obtained as a crude product (colorless solid).

Reference Example 18
An ethanol solution of 40 g of 2-cyano-3,3-bismethylthioacrylic acid ethyl ester, 12.6 g of hydrazine hydrochloride and 22.6 g of sodium acetate is stirred at 90 ° C. for 2 hours. The reaction mixture is cooled to room temperature, concentrated under reduced pressure, and water and ethyl acetate are added to the residue. The organic layer is separated, dried over magnesium sulfate, filtered, and the filtrate is concentrated under reduced pressure. Ethyl acetate and hexane were added to the residue, and the precipitated solid was collected by filtration and dried to give 5-amino-4-ethoxycarbonyl-3-methylthio-1H-pyrazole (17.4 g, yield 47%) as a colorless solid. Get as.

Reference Examples 19-20
3-carboxy-6- (2-chlorophenyl) -7- (4-trifluoromethoxyphenyl) pyrazolo [1,5-a] pyrimidine or 3-carboxy-6- (2-chlorophenyl) -7- (4-tri The following compounds are obtained by treating fluoromethylphenyl) pyrazolo [1,5-a] pyrimidine in the same manner as in Reference Example 10.
Reference Example 19 3-hydrazinocarbonyl-6- (2-chlorophenyl) -7- (4-trifluoromethoxyphenyl) pyrazolo [1,5-a] pyrimidine MS (APCI) m / z; 448/450 [ M + H] ⁺ .
Reference Example 20 3-hydrazinocarbonyl-6- (2-chlorophenyl) -7- (4-trifluoromethylphenyl) pyrazolo [1,5-a] pyrimidine MS (APCI) m / z; 432/434 [ M + H] ⁺ .

Reference Examples 21-40
The corresponding starting material compound is treated in the same manner as in any of Reference Examples 1, 4 and 6, to obtain the compounds described in Table B1 below.

Reference Examples 41-45
The corresponding starting material compound is treated in the same manner as in Reference Example 7 to give the compounds described in Table B2 below.

Reference Example 46
(1) To a solution of 5-nitropyrazole-3-carboxylic acid (19.9 g) in 200 mL of ethanol is added dropwise 9.7 mL of thionyl chloride over 5 minutes, and then refluxed for 4 hours. The reaction mixture is cooled to room temperature, diluted with 25 mL of water and 50 mL of ethanol, and neutralized with sodium bicarbonate (about 54 g). The mixture is filtered and the residue is washed with ethanol. The filtrate and washings are combined and concentrated under reduced pressure, and then ethanol is added to azeotrope. The residue is dissolved in ethyl acetate, dried over magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure, and isopropyl ether is added to the residue. The precipitate is collected by filtration and washed with ethyl acetate / diisopropyl ether (1: 2) to give ethyl 5-nitropyrazole-3-carboxylate (20 g, yield 85%) as a colorless solid.
MS (APCI) m / z; 186 [M + H] +.

(2) 4.1 g of 10% palladium carbon is added to a solution of the compound obtained in (1) (22.5 g) in 130 mL of acetic acid and 130 mL of tetrahydrofuran, and the mixture is stirred for 4 hours in a hydrogen atmosphere. The reaction solution is filtered, and the filtrate is concentrated under reduced pressure. Hexane is added to the residue and stirred, and then hexane is removed by decantation. Ether / diisopropyl ether (1: 1) is added to the residue, and the precipitate is collected by filtration to give ethyl 5-aminopyrazole-3-carboxylate (17.2 g, yield 91%) as a colorless solid.
MS (APCI) m / z; 156 [M + H] +.

Reference Example 47
(1) Add 748 mg of hydrazine hydrochloride and 1.34 g of sodium acetate to 20 mL of ethanol in 2.0 g of 2-[(cyano) (ethoxycarbonyl) vinyl] -1,3-dioxolane, and stir at 80 ° C. for 1 hour. . The reaction mixture is cooled to room temperature, filtered through celite, and the filtrate is concentrated under reduced pressure. The resulting crude product is purified by silica gel column chromatography (solvent: chloroform / methanol = 100/0 to 85/15) to give 3-amino-4-ethoxycarbonyl-5- (2-hydroxy) ethoxypyrazole ( 2.01 g, 86% yield) is obtained as a pale pink solid.
MS (APCI) m / z; 216 [M + H] +.

(2) 2.65 g of the compound obtained in (1) above and 3- (N, N-dimethylamino) -1- (4-chlorophenyl) -2- (2-chlorophenyl) -2-propen-1-one ( To Reference Example 1 (2)), 20 mL of ethanol and 5 mL of an ethanol solution of 21% sodium ethoxide are added and stirred at room temperature for 15 minutes. Ethyl acetate and water are added to the reaction mixture, and the mixture is acidified with 2N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 72 / 28-30 / 70) and triturated with diethyl ether to give 6- ( 2-Chlorophenyl) -7- (4-chlorophenyl) -3-ethoxycarbonyl-2- (2-hydroxyethoxy) pyrazolo [1,5-a] pyrimidine (2.25 g, 39% yield) is obtained as a colorless solid. .
MS (APCI) m / z; 472/474 [M + H] +.

(3) To a solution of 100 mg of the compound obtained in (2) above in 10 mL of acetonitrile, 320 mg of silver (I) oxide and 350 μL of methyl iodide are added and stirred at room temperature for 3 days. The reaction solution is filtered through Celite, and the filtrate is concentrated under reduced pressure. The obtained crude product is 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- (2-methoxyethoxy) pyrazolo [1,5-a] pyrimidine (98.6 mg, 96% yield) is obtained as a colorless solid.
MS (APCI) m / z; 486/488 [M + H] +.

(4) By treating 98 mg of the compound obtained in the above (3) in the same manner as in Reference Example 1 (3), 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3-carboxy-2- ( 2-Hydroxyethoxy) pyrazolo [1,5-a] pyrimidine (92 mg, 99% yield) is obtained as a colorless powder.
MS (APCI) m / z; 458/460 [M + H] +.

Reference Example 48
(1) 9.46 g of sodium sulfide is added to a 200 mL solution of 1,3-dibromo-2,2-dimethoxypropane in 26.45 g of dimethyl sulfoxide, and the mixture is stirred at an external temperature of 110 ° C. to 140 ° C. for 30 minutes. The reaction mixture is diluted with diethyl ether under ice-cooling, saturated aqueous sodium hydrogen carbonate solution and water are added, and the mixture is extracted twice with diethyl ether. The organic layer is washed with saturated brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, 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-dimethoxythiacyclobutane (10.55 g). Yield 78%) as a pale yellow liquid.
MS (APCI) m / z; 103 [M + H-MeOH] +.

  (2) 3.5 g of an ion exchange resin (Amberlyt 15E) is added to a solution of 9.0 g of the compound obtained in (1) above in 70 mL of acetone, and the mixture is stirred at room temperature for 21 hours. The reaction mixture is filtered through celite, and the residue is washed with acetone. Combine the filtrate and washings and concentrate under reduced pressure. The precipitate is collected and washed with cold hexane to give 3-oxothiacyclobutane (1.58 g, yield 27%) as colorless crystals.

  (3) 236 mg of hydroxylamine hydrochloride and 360 mg of sodium carbonate are added to a solution of 100 mg of the compound obtained in (2) above in 3 mL of ethanol, and the mixture is heated to reflux for 17 hours. The reaction mixture is cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution and water are added, and the mixture is extracted with chloroform. The organic layer was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 90 / 10-50: 50) to give 3-hydroxyiminothiacyclobutane (93 mg, yield). 80%) is obtained as a colorless solid.

  (4) Under a nitrogen atmosphere, to a solution of 58 mg of lithium aluminum hydride in 2 mL of tetrahydrofuran is added dropwise a solution of 93 mg of the compound obtained in (3) above in 1.5 mL of tetrahydrofuran under ice cooling, and the mixture is stirred at room temperature for 1 hour. . Under ice cooling, 60 μL of water, 60 μL of 15% aqueous sodium hydroxide solution and 120 μL of water are sequentially added to the reaction solution. The mixture is stirred at room temperature and then filtered through celite. The filtrate is concentrated under reduced pressure to give 3-aminothiacyclobutane as a crude product.

Reference Example 49
(1) In a nitrogen atmosphere, 4.7 mL of ethyl cyanoacetate is added dropwise to a solution of 14.32 g of sodium ethoxide in 20 mL of ethanol, and the mixture is stirred at room temperature for 1 hour. 4.85 mL of difluoroacetic acid is added to the reaction mixture, and the mixture is stirred at room temperature for 4 hours, and further stirred at an external temperature of 60 ° C. for 17 hours. The reaction mixture is concentrated under reduced pressure, 10 mL of toluene and 3.2 g of phosphorus chloride are added to the resulting residue, and the mixture is stirred at 45 ° C. for 1 hour. 1.9 g of phosphorus chloride is further added to the reaction solution, and the mixture is stirred at 55 ° C. for 2 hours. The reaction mixture is ice-cooled, filtered through Celite, and the filtrate is concentrated under reduced pressure. Ethanol 20mL, hydrazine monohydrate 0.8mL, and triethylamine 3.0mL are added to the obtained residue, and it stirs at 60 degreeC for 2 hours. The reaction mixture is cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution and water are added, and the mixture is extracted with chloroform (4 times). The organic layer is dried over sodium sulfate and filtered, and the filtrate is concentrated under reduced pressure. The resulting crude product is purified by silica gel column chromatography (solvent; chloroform / methanol = 100/0 to 94/6) and washed with chloroform to give 3-amino-4-ethoxycarbonyl-5-difluoromethylpyrazole. (1.26 g, 41% yield) is obtained as a colorless solid.
MS (APCI) m / z; 206 [M + H] +.

(2) By treating the compound (400 mg) obtained in the above (1) in the same manner as in Reference Examples 1 (2) to (3), 3-carboxy-6- (2-chlorophenyl) -7- (4- Chlorophenyl) -2-difluoromethylpyrazolo [1,5-a] pyrimidine (405 mg, 48% yield) is obtained as a powder.
MS (APCI) m / z; 434/436 [M + H] +.

Reference Example 50
(1) Add 37.2 g of trifluoroacetic anhydride to a methylene chloride 260 m solution of 14.6 g of methyl cyanoacetate and stir at room temperature. To this mixture, 51.7 mL of triethylamine is slowly added dropwise at 0 ° C., and the mixture is stirred at room temperature overnight. Add water to the reaction mixture and extract with methylene chloride. The organic layer is dried over magnesium sulfate and filtered, and the filtrate is concentrated under reduced pressure to give methyl 2-cyano-2- (2-trifluoroacetyl) acetate (Compound 2a) and 2-cyano-4,4,4. A mixture (55.3 g) of methyl trifluoro-3-trifluoromethoxycarbonyl-2-butenoate (compound 2b) is obtained.
Compound 2a: MS (APCI) m / z; 196 [M + H] ⁺
Compound 2b: MS (APCI) m / z; 292 [M + H] ^< +>.

  (2) 31.6 mL of oxalyl chloride is gradually added dropwise to a solution of 27.6 g of the compounds 2a and 2b (mixture) obtained in (1) above in 200 mL of methylene chloride (added together with several drops of pyridine). After the mixture is heated to reflux for 4 hours, the reaction mixture is poured slowly into water and extracted with methylene chloride. The organic layer is dried over magnesium sulfate and filtered, and the filtrate is concentrated under reduced pressure to obtain methyl 2-cyano-3-chloro-4,4,4-trifluoro-2-butenoate as a crude product.

(3) Add 20 mL of water to the compound obtained in (2) above, and gradually drop 6.74 g of hydrazine monohydrate (80%) at 0 ° C. Add 2 mL of triethylamine to the mixture at room temperature and stir for 1 hour. Add water to the reaction mixture and extract with ethyl acetate. The organic layer is dried over magnesium sulfate and filtered, and the filtrate is concentrated under reduced pressure. Chloroform is added to the residue, and the precipitate is collected by filtration to give 3-amino-4-ethoxycarbonyl-5-trifluoromethylpyrazole (3.96 g) as an orange solid.
MS (APCI) m / z; 210 [M + H] +.

(4) By treating the compound (2.37 g) obtained in (3) in the same manner as in Reference Examples 1 (2) to (3), 3-carboxy-6- (2-chlorophenyl) -7- ( 4-Chlorophenyl) -2-trifluoromethylpyrazolo [1,5-a] pyrimidine (1.81 g) is obtained as a crude product (powder).
MS (APCI) m / z; 452/454 [M + H] +.

Reference Example 51
(1) 6- (2-Chlorophenyl) -7- (4-chlorophenyl) -3-ethoxycarbonyl-2-methylpyrazolo [1,5-a] pyrimidine (corresponding ethyl ester of the compound of Reference Example 39) 1.50 g 1.88 g of N-bromosuccinimide and 30 mg of 2,2′-azobisisobutyronitrile are added to a 20 mL solution of carbon tetrachloride, and the mixture is stirred at an external temperature of 85 ° C. for 26 hours. The reaction mixture is cooled to room temperature, filtered through celite, and the filtrate is concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (solvent; hexane / diethyl ether = 85/15 to 67/33) to give 2-bromomethyl-6- (2-chlorophenyl) -7- (4-chlorophenyl). ) -3-Ethoxycarbonylpyrazolo [1,5-a] pyrimidine (827 mg, 47% yield) is obtained as a pale yellow solid.
MS (APCI) m / z; 504/506 [M + H] +.

(2) To a solution of the compound 825 mg obtained in (1) above in 7 mL of methanol / 4 mL of tetrahydrofuran is added 3 mL of 28% sodium methoxide-methanol solution, and the mixture is stirred at room temperature for 1 hour. The reaction mixture is diluted with ethyl acetate, water is added, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The obtained crude product is purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 75 / 25-60 / 40) to give 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3. -Methoxycarbonyl-2-methoxymethylpyrazolo [1,5-a] pyrimidine (404 mg, 56% yield) is obtained as a pale yellow solid.
MS (APCI) m / z; 442/444 [M + H] +.

(3) By treating 404 mg of the compound obtained in (2) above in the same manner as in Reference Example 1 (3), 3-carboxy-6- (2-chlorophenyl) -7- (4-chlorophenyl) -2-methoxy Methylpyrazolo [1,5-a] pyrimidine (367 mg, 94% yield) is obtained as a colorless solid.
MS (APCI) m / z; 428/430 [M + H] +.

Reference Example 52
(1) Under a nitrogen atmosphere, 6.77 g of sodium hydride (60%) is added to 75 mL of dimethylformamide. The mixture is stirred at room temperature for 10 minutes, and then cooled to 0 ° C. (internal temperature of 10 ° C. or less), a solution of 5.09 mL of carbon disulfide in 12 mL of dimethylformamide is added dropwise over 20 minutes. The mixture is stirred at room temperature overnight, and then cooled to 0 ° C. (internal temperature of 25 ° C. or lower), and a solution of benzylformamide in 20.1 mL of dimethylformamide in 23 mL is added dropwise. The mixture is stirred at 70 ° C. for 7 hours and further stirred at room temperature overnight. The reaction mixture is poured into ice water and stirred. The precipitate was collected by filtration, recrystallized from hot ethanol, and then washed with cold ethanol to give 2-cyano-3,3-bisbenzylthioacrylic acid ethyl ester (25.63 g, yield 82%) colorless. Obtain as a solid.
MS (APCI) m / z; 370 [M + H] +.

(2) To a solution of 15.0 g of the compound obtained in (1) above in tetrahydrofuran 16 mL-ethanol 41 mL is added hydrazine monohydrate 2.04 g in ethanol 18 mL over 5 minutes, and the mixture is stirred at room temperature overnight. The reaction mixture is concentrated under reduced pressure, and the residue is crystallized with diilopropyl ether / hexane. The precipitated crystals are collected by filtration and washed to give 3-amino-4-ethoxycarbonyl-5-benzylthiopyrazole (9.45 g, yield 84%) as a colorless solid.
MS (APCI) m / z; 278 [M + H] +.

(3) By treating 8.15 g of the compound obtained in (2) above in the same manner as in Reference Example 5 (1), 2-benzylthio-6- (2-chlorophenyl) -7- (4-chlorophenyl) -3 -Ethoxycarbonylpyrazolo [1,5-a] pyrimidine (8.24 g, 51% yield) is obtained as a pale yellow solid.
MS (APCI) m / z; 534/536 [M + H] ^< +>.

Reference Example 53
(1) By treating 3.0 g of the compound obtained in Reference Example 33 in the same manner as in Reference Example 9 (1), 6- (2-chlorophenyl) -7- (4-trifluoromethylphenyl) -3- ( tert-Butoxycarbonylamino) pyrazolo [1,5-a] pyrimidine (1.06 g, 30% yield) is obtained as an orange solid.
MS (APCI) m / z; 489/491 [M + H] +.

(2) Add 10 mL of 4N hydrochloric acid-dioxane solution to 5 mL of dioxane in 1.06 g of the compound obtained in (1) above, and stir at room temperature for 7 hours. The reaction mixture is concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution is added to the residue, and the mixture is extracted with chloroform. The organic layer is concentrated under reduced pressure, and the resulting crude product is 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, 80% yield) is obtained as a pale yellow solid.
MS (APCI) m / z; 389/391 [M + H] +.

Reference Example 54
(1) (2-Chlorobenzyl) (4-trifluoromethylphenyl) methanone is obtained by treating the corresponding starting material compound in the same manner as in Reference Example 1 (1).

(2) By treating 3.0 g of the compound obtained in (1) and 977 mg of 3-amino-5-methylpyrazole in the same manner as in Reference Example 1 (2), 6- (2-chlorophenyl) -7- ( 4-Trifluoromethylphenyl) -2-methylpyrazolo [1,5-a] pyrimidine (2.63 g, 67% yield) is obtained as a brown oil.
MS (APCI) m / z; 388/390 [M + H] +.

(3) 1.35 mL of chlorosulfonic acid is gradually added dropwise to a solution of the compound 2.27 g obtained in (2) above in 50 mL of chloroform, and the mixture is stirred at 70 ° C. for 3.5 hours. The reaction mixture is concentrated under reduced pressure, 20 mL of thionyl chloride is added to the residue, and the mixture is heated to reflux for 2 hours. The reaction mixture is concentrated under reduced pressure, ice water is added to the residue, and the mixture is extracted with chloroform. The organic layer is dried over sodium sulfate and filtered, and the filtrate is concentrated under reduced pressure. The obtained crude product is purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 85 / 15-60 / 40) to give 6- (2-chlorophenyl) -3-chlorosulfonyl-7- (4- Trifluoromethylphenyl) -2-methylpyrazolo [1,5-a] pyrimidine (2.71 g, 95% yield) is obtained as a pale yellow solid.
MS (APCI) m / z; 486/488 [M + H] +.

Reference Example 55
(1) Add 309 mg of magnesium chloride and 580 μL of triethylamine to a solution of 465 mg of ethyl potassium malonate in 3.5 mL of acetonitrile, and stir at room temperature for 2 hours (solution A). To a solution of 500 mg of the compound obtained in Reference Example 1 in 3 mL of acetonitrile are added 232 mg of carbonyldiimidazole and 2 mL of tetrahydrofuran at room temperature, and the mixture is stirred at the same temperature for 2 hours. The solution A is added to the reaction solution at room temperature, and the mixture is stirred for 4 hours. To the reaction mixture is added 2N aqueous hydrochloric acid, and the mixture is extracted with ethyl acetate. The organic layer is washed with water and saturated brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 90 / 10-75 / 25) to give 6- (2-chlorophenyl) -7- ( 4-Chlorophenyl) -3- (2-ethoxycarbonylacetyl) pyrazolo [1,5-a] pyrimidine (488 mg, 83% yield) is obtained.
MS (APCI) m / z; 454/456 [M + H] ^< +>.

(2) To a solution of 475 mg of the compound obtained in (1) above in ethanol 2.5 mL / tetrahydrofuran 2.5 mL is added 2N aqueous sodium hydroxide solution 1.05 mL, and the mixture is stirred at 60 ° C. for 1 hour. To the reaction mixture are added 2N aqueous sodium hydroxide solution (1.05 mL) and ethanol (2.5 mL), and the mixture is stirred at the same temperature for 18 hours. After cooling the reaction solution to room temperature, 2.1 mL of 2N hydrochloric acid water is added and diluted with ethyl acetate. Water is added to the solution and extracted with ethyl acetate. The organic layer is concentrated under reduced pressure, and the resulting crude product is purified by silica gel column chromatography (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, 58% yield) is obtained as a pale yellow solid.
MS (APCI) m / z; 382/384 [M + H] ^< +>.

Reference Example 56
(1) (2-Chlorobenzyl) (5-chlorothien-2-yl) methanone (5.06 g, 61% yield) is obtained by treating the corresponding starting material compound in the same manner as in Reference Example 2 (1).

  (2) 3- (N, N-dimethylamino) -2- (2-chlorophenyl)-is obtained by treating the compound (2.92 g) obtained in (1) in the same manner as in Reference Example 1 (2). 1- (5-Chlorothien-2-yl) -2-propen-1-one is obtained as a crude product.

(3) Add 1.3 g of 3-amino-4-ethoxycarbonyl-5-methylpyrazole and 153 μL of piperidine to a 2 mL solution of the compound obtained in (2) above, and stir at 80 ° C. overnight. To the reaction solution are added 3 mL of acetic acid and 30 mL of toluene, and the mixture is stirred at the same temperature for 7 hours. The reaction mixture is cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution is added under ice cooling, and the mixture is extracted with ethyl acetate. The organic layer is washed successively with water and saturated brine, dried over magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure, and the precipitate is collected by filtration and washed with diethyl ether. The filtrate is purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 80 / 20-60 / 40), and the eluate is concentrated. The precipitate was washed with ethyl acetate / hexane = 1/10, and combined with the previously obtained precipitate, 6- (2-chlorophenyl) -7- (5-chlorothien-2-yl) -3-ethoxycarbonyl 2-Methylpyrazolo [1,5-a] pyrimidine (1.52 g, 2-step yield 45%) is obtained as a yellow solid.
MS (APCI) m / z; 432/434 [M + H] +.

(4) By treating the compound (1.51 g) obtained in the above (3) in the same manner as in Reference Example 1 (3), 3-carboxy-6- (2-chlorophenyl) -7- (5-chlorothien- 2-yl) -2-methylpyrazolo [1,5-a] pyrimidine (1.18 g, 84% yield) is obtained as a yellow solid.
MS (APCI) m / z; 404/406 [M + H] +.

Reference Example 57
(1) 6- (2-Chlorophenyl) -7-chloro-3-ethoxycarbonylpyrazolo [1,5-a] is obtained by treating the corresponding starting compound in the same manner as in Reference Examples 4 (1) to (4). Get the pyrimidine.

(2) Palladium acetate 2.2 mg, 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl 4.1 mg, potassium phosphate in a 6 mL tetrahydrofuran solution of the compound (672 mg) obtained in (1) above 1.27 g of trihydrate and 20 μL of water are added and the mixture is stirred at room temperature for 2 hours and then at 100 ° C. for 24 hours. Cool the reaction to room temperature, add water and extract with ethyl acetate. The organic layer is washed successively with 1N aqueous sodium hydroxide solution, water and saturated brine, dried over magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure, and the resulting crude product is purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 80/20 to 50/50). The eluate is concentrated and the precipitate is washed with diethyl ether / hexane to give 6- (2-chlorophenyl) -7- (4-dimethylaminophenyl) -3-ethoxycarbonylpyrazolo [1,5-a]. Pyrimidine (288 mg, 34% yield) is obtained as a yellow powder.
MS (APCI) m / z; 421/423 [M + H] ^< +>.

Reference Example 58
By treating 0.67 g of the compound obtained in Production Example 440 in the same manner as in Reference Example 1 (3), 3-carboxy-6- (2-chlorophenyl) -7- (4-trifluoromethylphenyl) -2- [N-methyl-N- (methylsulfonyl) amino] pyrazolo [1,5-a] pyrimidine (0.64 g) is obtained as a crude product (powder).
MS (APCI) m / z; 525/527 [M + H] ^< +>.

Reference Example 59
(1) 15 mg of sodium thiomethoxide is added to a solution of 200 mg of the compound obtained in Reference Example 51 (1) in 2 mL of dimethyl sulfoxide, and the mixture is stirred at room temperature for 1 hour. Water is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The extract is concentrated under reduced pressure. The obtained crude product is purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 87 / 13-60 / 40) to give 6- (2-chlorophenyl) -7- (4-trifluoromethylphenyl). -3-Ethoxycarbonyl-2-methylthiomethylpyrazolo [1,5-a] pyrimidine (170 mg, 91% yield) is obtained as a pale yellow solid.
MS (APCI) m / z; 472/474 [M + H] +.

(2) By treating 170 mg of the compound obtained in (1) above in the same manner as in Reference Example 1 (3), 3-carboxy-6- (2-chlorophenyl) -7- (4-trifluoromethylphenyl) -2 -Methylthiomethylpyrazolo [1,5-a] pyrimidine is obtained as a pale yellow powder.
MS (APCI) m / z; 444/446 [M + H] +.

Reference Example 60
(1) To a solution of 5.0 mL of 1-benzyloxycarbonyl-3-pyrroline in 125 mL of methylene chloride is added 12.17 g of metachloroperbenzoic acid and stirred at room temperature for 3 days. Add 100 mL of saturated aqueous sodium thiosulfate solution to the reaction mixture and stir for 30 minutes. The reaction mixture is extracted twice with chloroform, and the organic layer is washed successively with 2N aqueous sodium hydroxide solution (100 mL, twice) and saturated brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give benzyl 6-oxa-3-azabicyclo [3,1,0] hexane-3-carboxylate (5.58 g, yield 100%) as an oil. obtain.
MS (APCI) m / z; 220 [M + H] ^< +>.

(2) In a nitrogen atmosphere, 26.5 g of the compound obtained in (1) above, (1R, 2R)-(−)-[1,2-cyclohexanediamino-N, N′-bis (3,5-dichloride) chloride -T-Butylsalicylidene)] A mixture of 1.57 g of chromium and 17.7 mL of trimethylsilyl azide is stirred at room temperature for 2 days. Chloroform is added to the reaction solution, washed successively with water and saturated brine, and dried over magnesium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 10/1 to 2/1 → chloroform / methanol = 20/1 to 9/1) to obtain (3S, 4S). -4-azido-1-benzyloxycarbonyl-3-trimethylsilyloxypyrrolidine (compound a, 20.6 g, 55% yield) and (3S, 4S) -4-azido-1-benzyloxycarbonyl-3-hydroxypyrrolidine (Compound b, 8.16 g, 28% yield) are obtained as oils.
Compound a: MS (APCI) m / z; 335 [M + H] ⁺ .
Compound b: MS (APCI) m / z; 263 [M + H] ⁺ .

(3) Add 26.67 g of triphenylphosphine to a solution of 20.6 g and 8.16 g of tetrahydrofuran (740 mL) obtained in (2) above, respectively, and stir at room temperature overnight. The reaction mixture is concentrated under reduced pressure, 380 mL of methanol and 380 mL of 0.5N aqueous sodium hydroxide solution are added to the resulting residue, and the mixture is stirred overnight at room temperature. The reaction mixture is concentrated under reduced pressure, 6N aqueous hydrochloric acid is added to the residue (pH 3), and the mixture is washed with chloroform. The aqueous layer is adjusted to pH 9 with 5N aqueous sodium hydroxide solution and extracted three times with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give (3S, 4S) -4-amino-1-benzyloxycarbonyl-3-hydroxypyrrolidine (19.6 g, yield 90%) as an oil. obtain.
MS (APCI) m / z; 237 [M + H] ^< +>.

(4) To a solution of 14.61 g of chloroform obtained in (3) above in 135 mL of chloroform, a solution of 16.18 g of di-tert-butyl dicarbonate in 20 mL of chloroform is added dropwise and stirred at room temperature for 2 hours. To the reaction solution is added a saturated aqueous sodium hydrogen carbonate solution (100 mL), and the mixture is stirred and extracted with chloroform. The organic layer is dried over anhydrous magnesium sulfate, 2 g of NH silica gel (manufactured by Fuji Silysia Chemical) is added, and the mixture is stirred and then filtered. The filtrate was concentrated under reduced pressure, and the resulting crude product was triturated with hexane-ethyl acetate to give (3S, 4S) -1-benzyloxycarbonyl-3-hydroxy-4- (tert-butoxycarbonyl) pyrrolidine ( 18.59 g, 94% yield) are obtained as crystals.
MS (APCI) m / z; 337 [M + H] ^< +>.

(5) To a solution of 18.56 g of the compound obtained in (4) above in 200 mL of methanol is added 1.16 g of 10% palladium carbon, and the mixture is stirred at room temperature for 3 hours in a hydrogen atmosphere. The reaction mixture is filtered through celite, and the filtrate is concentrated under reduced pressure. The residue is triturated with methanol-diisopropyl ether to give (3S, 4S) -3-hydroxy-4- (tert-butoxycarbonyl) pyrrolidine (10.8 g, yield 97%) as crystals.
MS (APCI) m / z; 203 [M + H] ^< +>.

Reference Examples 61-83
By treating the corresponding raw material compound in the same manner as in Reference Example 1, 4 or 6, the compounds described in Table B3 below are obtained.

Reference examples 84-87
The corresponding starting material compound is treated in the same manner as in Reference Example 49 or 50 to obtain the compounds described in Table B4 below.

Reference Example 88
The corresponding starting material compound was treated in the same manner as in Reference Example 51 to give 3-carboxy-6- (2-chlorophenyl) -7- (4-chlorophenyl) -2-ethoxymethylpyrazolo [1,5-a] pyrimidine ( 602 mg, 95% yield) is obtained as a colorless solid.
MS (APCI) m / z; 442/444 [M + H] ^< +>.

Reference Example 89
(1) To a solution of 202 mg of 4-methoxypiperidine in 4 mL of water is added 200 μL of acetic acid under ice cooling, and the mixture is stirred at room temperature overnight. Saturated aqueous sodium hydrogen carbonate solution is added to the reaction mixture, and the mixture is stirred and extracted with chloroform. The extract was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (solvent; ethyl acetate) to give 4-methoxy-1-nitrosopiperidine (260 mg, yield 100%) as a pale yellow oil. Get as.
MS (APCI) m / z; 145 [M + H] ^< +>.

(2) 654 mg of zinc powder is added to a solution of the compound 280 mg obtained in (1) above in 3 mL of methanol, and 3 mL of acetic acid is added dropwise under ice cooling, followed by stirring at room temperature for 2 hours. The reaction solution is filtered, and the filtrate is concentrated under reduced pressure. To the residue are added a saturated aqueous sodium hydrogen carbonate solution and chloroform, and the mixture is stirred and extracted with chloroform. The extract is concentrated under reduced pressure to give 1-amino-4-methoxypiperidine (119 mg, 57% yield) as a pale yellow oil.
MS (APCI) m / z; 131 [M + H] ^< +>.

Reference Example 90
A mixture of 500 mg of 2,5-dibromopyridine and 1 mL of methyl hydrazine is heated at 100 ° C. The reaction mixture is cooled to room temperature, diluted with ethyl acetate, and washed with saturated brine. The organic layer is dried over sodium sulfate and concentrated under reduced pressure. The resulting crude product is purified by silica gel column chromatography (solvent: chloroform), and then the eluate is concentrated. The residue is dissolved in tert-butanol and freeze-dried to give 5-bromo-2- (N-methyl). Hydrazino) pyridine (450 mg) is obtained as an oil.
MS (APCI) m / z; 202/204 [M + H] ^< +>.

Reference Examples 91-93
The corresponding starting material compounds are treated in the same manner as in Reference Example 90 to give the compounds described in Table B5 below.

Reference Example 94
(1) To a solution of 1.0 g of the compound obtained in Reference Example 4 (2) in 10 mL of tetrahydrofuran is added 361 mg of 4-hydroxypiperidine and 830 μL of triethylamine, and the mixture is stirred at 60 ° C. for 2 hours. The reaction mixture is cooled to room temperature, water is added, the mixture is extracted with ethyl acetate, and the extract is washed with saturated brine. The organic layer is dried over sodium sulfate and filtered, and the filtrate is concentrated under reduced pressure. The resulting crude product was triturated with diisopropyl ether to give 6- (2-chlorophenyl) -3-ethoxycarbonyl-7- (4-hydroxy-1-piperidinyl) pyrazolo [1,5-a] pyrimidine (646 mg, 54% yield) is obtained as a colorless solid.
MS (APCI) m / z; 401/403 [M + H] +.

(2) To a solution of 200 mg of the compound obtained in (1) above in 3 mL of dimethylformamide is added 48 mg of sodium hydride under ice cooling, and the mixture is stirred at room temperature for 15 minutes. 120 μL of ethyl iodide is added to the solution and stirred at room temperature for 1 hour. The reaction mixture is diluted with ethyl acetate, diluted aqueous hydrochloric acid is added, and the mixture is extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 82 / 18-60 / 40) to give 6- (2-chlorophenyl) -3-ethoxy. Carbonyl-7- (4-ethoxy-1-piperidinyl) pyrazolo [1,5-a] pyrimidine (65 mg, 30% yield) is obtained as a colorless viscous body.
MS (APCI) m / z; 429/431 [M + H] +.

(3) By treating 65 mg of the compound obtained in (2) above in the same manner as in Reference Example 1 (3), 6- (2-chlorophenyl) -3-carboxy-7- (4-ethoxy-1-piperidinyl) Pyrazolo [1,5-a] pyrimidine is obtained as a colorless powder.
MS (APCI) m / z; 401/403 [M + H] +.

Reference Example 95
(1) 6-Chloro-7- (4-chlorobenzyl) -3-ethoxycarbonyl-2-methylpyrazolo [1,5-a] pyrimidine is obtained by treating the corresponding starting compound in the same manner as in Reference Example 4 (3). Get.

(2) 370 mg of p-chlorobenzyl bromide, 53 mg of bis (triphenylphosphine) palladium dichloride and 235 mg of zinc powder are added to a solution of 525 mg of the compound obtained in (1) above in 5 mL of dimethoxyethane, and heated under reflux for 2 hours in a nitrogen atmosphere. . The reaction mixture is filtered and the filtrate is concentrated under reduced pressure. Add water to the residue and extract with ethyl acetate. The organic layer is washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 4/1) to give 7- (4-chlorobenzyl) -6- (2-chlorophenyl). ) -3-Ethoxycarbonyl-2-methylpyrazolo [1,5-a] pyrimidine (113 mg, 17% yield) is obtained as a pale yellow powder.
MS (APCI) m / z; 440/442 [M + H] +.

Reference Example 96
(1) To a solution of 200 mg of the compound obtained in Reference Example 51 (1) in 2 mL of dimethylformamide is added 116 mg of potassium acetate, and the mixture is stirred at 60 ° C. for 1 hour. The reaction mixture is cooled to room temperature, diluted with ethyl acetate, water is added, the organic layer is separated, and concentrated under reduced pressure. The obtained crude product is purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 80/20 to 55/45) to give 2-acetoxymethyl-3-ethoxycarbonyl-6- (2-chlorophenyl)- 7- (4-Chlorophenyl) pyrazolo [1,5-a] pyrimidine (109.4 mg, 57% yield) is obtained as a colorless powder.
MS (APCI) m / z; 484/486 [M + H] +.

(2) To a solution of 109 mg of the compound obtained in (1) above in 3 mL of ethanol-3 mL of tetrahydrofuran, add 0.2 mL of a 21% sodium ethoxide-ethanol solution, and stir at 60 ° C. for 30 minutes. The reaction mixture is cooled to room temperature, diluted with ethyl acetate, water is added, and the mixture is extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting crude 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, 75% yield) is obtained as a colorless solid.
MS (APCI) m / z; 442/444 [M + H] +.

(3) To a solution of 75 mg of the compound obtained in (2) above in 2 mL of dimethylformamide, add 23 mg of imidazole and 31 mg of chloro tert-butyldimethylsilane, and stir at room temperature for 22 hours. Further, 10 mg of imidazole and 15 mg of chloro tert-butyldimethylsilane are added to the reaction solution and stirred for 6 hours. Water is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The extract is concentrated under reduced pressure. The obtained crude product is purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 85 / 15-60 / 40) to give 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- Ethoxycarbonyl-2- (tert-butyldimethylsilyloxymethyl) pyrazolo [1,5-a] pyrimidine (66.8 mg, 71% yield) is obtained as a colorless solid.
MS (APCI) m / z; 556/558 [M + H] +.

(4) By treating 66.8 mg of the compound obtained in (3) above in the same manner as in Reference Example 1 (3), 6- (2-chlorophenyl) -7- (4-chlorophenyl) -3-carboxy-2 -Hydroxymethylpyrazolo [1,5-a] pyrimidine is obtained as a colorless powder.
MS (APCI) m / z; 414/416 [M + H] +.

Reference Example 97 (1157220 intermediate)
(1) To a mixed solution of 1.0 g of 4-hydroxy-1-piperidinecarboxylic acid benzyl ester of 10 g of toluene and 2 N aqueous sodium hydroxide solution of 10 mL, 550 mg of tetrabutylammonium bromide and 1.2 mL of methoxyethyl bromide were added, Stir at 2.5C for 2.5 hours and then at 80C for 17 hours. To the reaction solution are further added 0.95 g of sodium hydroxide and 1.2 mL of methoxyethyl bromide, and the mixture is stirred at 80 ° C. for 24 hours. The reaction mixture is cooled to room temperature, water is added, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 75 / 25-40 / 60) to give 4- (2-methoxyethoxy) -1- Piperidinecarboxylic acid benzyl ester (266 mg, 21% yield) is obtained as a pale yellow liquid.
MS (APCI) m / z; 294 [M + H] +.

(2) Add 10% palladium-carbon (30 mg) to a solution of the compound (266 mg) obtained in (1) above in ethanol (5 mL) and stir at room temperature in a hydrogen atmosphere. The reaction solution is filtered, and the filtrate is concentrated under reduced pressure to give 4- (2-methoxyethoxy) piperidine (138 mg, yield 96%) as a colorless liquid.
MS (APCI) m / z; 160 [M + H] +.

Reference Examples 98-99
The corresponding starting material compound is treated in the same manner as in Production Example 484, and the resulting product is treated in the same manner as in Reference Example 1 (3) to obtain the compounds described in Table B6 below.

Reference examples 100 to 102
The corresponding starting material compound is treated in the same manner as in Reference Example 7B to give the compounds described in Table B7 below.

Experimental example 1
[Human CB1 receptor binding test]
(1) Preparation of CB1 receptor cell membrane fraction (Material)
Human CB1 receptor-expressing cell line: hCB1 / CHO-C3 (# ES-110-C, manufactured by Euroscreen)
Medium: F-12 (GIBCO # 11765-062), 10% fetal bovine serum, antibiotics,
Buffer A: 50 mM Tris-HCl (pH 7.5) [containing ethylenediaminetetraacetic acid (EDTA, 2.5 mM) and MgCl ₂ (5 mM) sucrose (200 mM)]
(Method)
The receptor-expressing cells cultured in the above medium are washed twice with a phosphate buffer (9.57 mM, pH 7.5), and then cooled on ice or at 4 ° C. (the following operations are also performed at the same temperature). 2 mL) was added, and the cells were recovered with a cell scraper. The cells were treated with a microchip ultrasonic device for 20 seconds (pulse on: 2 seconds, pulse off: 1 second), and then centrifuged at 500 × g for 15 minutes. The supernatant was collected and further centrifuged at 43000 × g for 60 minutes. Buffer A was added to the precipitate, homogenized with a potter homogenizer, an equal amount of 80% glycerol solution was added, and the mixture was stored at -80 ° C.

(2) Measurement of human CB1 receptor binding activity (Material)
Buffer B: 50 mM Tris-HCl (pH 7.5) [containing MgCl ₂ (5 mM), EDTA (2.5 mM) and bovine serum albumin (2 mg / mL, fatty acid free)]
Buffer C: 50 mM Tris-HCl (pH 7.5) [containing MgCl ₂ (5 mM), EDTA (2.5 mM) and bovine serum albumin (2 mg / mL)]
Coating solution: 0.3% ethyleneimine polymer Labeled ligand: [ ³ H] -CP55940 [30 nM (7992 dpm / μL); prepared by diluting an 8.3 μM solution with buffer B. ]
(Method)
In a 96-well plate (Costar Code # 3371), 140 μL of the above reaction buffer, sample (20 μL, dimethyl sulfoxide solution, final concentration 0.1%), labeled ligand (20 μL) and cell membrane fraction prepared in (1) above ( 20 μL, 0.5-8.0 μg / 20 μL) was added and incubated at 30 ° C. for 90 minutes, and then the reaction mixture was seeded on a plate (Unifilter GF / B, # 600005177, Packard) treated with the above coating solution. . The plate was washed with buffer C (200 μL × 10), dried at 50 ° C. for 1 hour, then added with Microscinti 40 (40 μL) to each well, and radiated using a scintillation counter (Top Count NXT; Packard). Activity was measured. The IC ₅₀ value of each specimen for the binding of the labeled ligand to the human CB1 receptor was calculated using Microsoft Excel 2000 (manufactured by Microsoft) based on the radioactivity measurement results.

(3) Results The IC ₅₀ values for each specimen are shown in Table C1 below. In addition, the symbol (++ and +++) in a table | surface represents the following meaning.

++: 10 nM <IC ₅₀ <100 nM
+++: 10 nM> IC ₅₀

Experimental example 2
[Selectivity of analyte compound for human CB1 receptor]
(1) Method a) Human CB1 receptor binding activity:
The title binding activity was measured in the same manner as in Experimental Example 1.

b) Human CB2 receptor binding activity:
Using human CB2 receptor-expressing CHO cells (hCB2 / CHO) instead of human CB1 receptor-expressing cells, the binding activity (IC ₅₀ value) of each sample compound to the human CB2 receptor was determined in the same manner as in Experimental Example 1. The selectivity for human CB1 receptor was evaluated by human CB2 receptor binding activity (IC ₅₀ value) / human CB1 receptor binding activity (IC ₅₀ value).

(2) Results The IC ₅₀ values and selectivity for human CB1 receptor of each specimen are shown in Table C2 below. The symbols (++ and +++) in the table have the same meaning as in Experimental Example 1.

  The pharmaceutical composition of the present invention is useful for the prevention and treatment of various diseases involving CB1 receptor (for example, psychosis including schizophrenia). The pharmaceutical composition of the present invention is also useful for chronic treatment and withdrawal from alcohol or drug abuse. Furthermore, the pharmaceutical composition of the present invention is useful as an analgesic activity enhancer or a smoking cessation aid.

Claims (27)

Formula [I]:

[Where,
R ¹ and R ² are the same or different and each may have an aryl group which may have a substituent or a saturated or unsaturated heterocyclic group which may have a substituent,
Q is a single bond, a methylene group or a group represented by the formula: —N (R ^Q ) —, R ^Q is an alkyl group,
Ring A is fused with the adjacent pyrimidine ring (A), (B) or (C):

A substituted pyrazole ring represented by
R ³ and R ⁴ are the same or different and are (a) a hydrogen atom, (b) a cyano group, (c) an alkyl group optionally substituted with 1 to 3 halogen atoms, (d) an alkyloxy group ( The alkyl part of the group is substituted with 1 to 3 groups selected from a halogen atom, a hydroxyl group, an amino group optionally substituted with 1 to 2 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 represented by the formula: —N (R ′) (R ″),
R ′ and R ″ are the same or different and are selected from (1) a hydrogen atom, (2) a halogen atom, an amino group optionally substituted by 1 to 2 alkyl groups, and an alkyloxy group. (3) an acyl group, (4) an alkylsulfonyl group, or (5) an aminosulfonyl group optionally substituted with one or two alkyl groups, or Represents that both are bonded to each other at the end to form a saturated or unsaturated nitrogen-containing heterocyclic group with the adjacent nitrogen atom,
E represents the following formulas (i) to (v):

Any of the groups represented by
R ⁰⁰ is an alkyl group,
Q ¹ is a single bond, an alkylene group or a group represented by 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) a halogen atom, a cyano group, an alkyloxy group, an optionally substituted cycloalkyl group, 1 to 2 An amino group optionally substituted with an alkyl group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group, an acyl group, an aryl group which may have a substituent, and a saturated or unsaturated group which may have a substituent An alkyl group which may be substituted with 1 to 3 groups selected from saturated heterocyclic groups, (b) a cycloalkyl group which may have a substituent, (c) formula: —N (R ⁸ ) A group represented by (R ⁹ ), (d) an aryl group which may have a substituent, or (e) a saturated or unsaturated heterocyclic group which may have a substituent, or mutual both R ⁵ and ^{R 6} at the end Combine to form adjacent nitrogen atom may have a substituent with a saturated or unsaturated nitrogen-containing heterocyclic group,
One of R ⁸ and R ⁹ is a hydrogen atom or an alkyl group, and the other is (a) an alkyl group which may be substituted with 1 to 3 groups selected from a halogen atom, a cyano group and an aryl group, b) a cycloalkyl group, (c) an aryl group which may have a substituent, (d) an acyl group or (e) a saturated or unsaturated heterocyclic group which may have a substituent,
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 are bonded to each other together with an adjacent nitrogen atom in the following formula:

[Wherein, ring A ¹ represents a 5- to 7-membered aliphatic nitrogen-containing heteromonocyclic group which may be substituted with an oxo group. ]
Form the cyclic group shown,
R ⁵¹ represents an alkylsulfonyl group or an optionally substituted arylsulfonyl group,
R ⁶¹ represents an alkylamino group or an azide group. ]
A pharmaceutical composition comprising as an active ingredient a pyrazolo [1,5-a] pyrimidine compound or a pharmaceutically acceptable salt thereof. R ¹ and R ² may be the same or different and (i) a halogen atom, a cyano group, an alkyl group which may be substituted with 1 to 3 halogen atoms, or a substituent with 1 to 3 halogen atoms A good alkyloxy group, an amino group optionally substituted with 1 to 2 alkyl groups, an alkylthio group, an alkylsulfinyl group and an alkylsulfonyl group optionally substituted with 1 to 3 groups 10-membered monocyclic or bicyclic aryl group, or (ii) halogen atom, cyano group, oxo group, alkyl group optionally substituted with 1 to 3 halogen atoms, substituted with 1 to 3 halogen atoms An alkyloxy group which may be substituted, an amino group which may be substituted with one or two alkyl groups, an alkylthio group, an alkylsulfinyl group and an alkylsulfonyl group 1-3 Good oxygenated substituted with a group, the pharmaceutical composition of claim 1 wherein the sulfur-containing or nitrogen-containing 5- or 6-membered saturated or unsaturated heteromonocyclic group barrel. The saturated or unsaturated heterocyclic group in R ⁵ , R ⁶ , R ⁸ or R ⁹ is (a) a saturated or unsaturated 4- to 7-membered heterocyclic monocyclic group (the heterocyclic monocyclic group is an oxygen atom, sulfur 1 to 4 heteroatoms selected from an atom and a nitrogen atom); (b) the heteromonocyclic group, a 3- to 8-membered cycloalkyl group, a 5- to 6-membered monocyclic aryl group, and a saturated or unsaturated group. 1-2 cyclic groups selected from saturated 4- to 7-membered heteromonocyclic groups (the heteromonocyclic group includes 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atoms) Or an 8- to 15-membered saturated or unsaturated nitrogen-containing bicyclic or tricyclic heterocyclic group; or (c) a saturated or unsaturated 8- to 11-membered nitrogen-containing spiro heterocyclic group. Item 1. A pharmaceutical composition according to Item 1. The saturated or unsaturated nitrogen-containing heterocyclic group formed by combining R ⁵ and R ⁶ is (a) a saturated or unsaturated 4- to 7-membered nitrogen-containing heterocyclic monocyclic group (the heterocyclic monocyclic group). May contain two or more nitrogen atoms, and may contain one or two heteroatoms selected from oxygen and sulfur atoms in addition to the nitrogen atoms); (b) the heteromonocycle A formula group, a 3- to 8-membered cycloalkyl group, a 5- to 6-membered monocyclic aryl group, and a saturated or unsaturated 4- to 7-membered heteromonocyclic group (the heteromonocyclic group is an oxygen atom, a sulfur atom, and a nitrogen atom) 8- to 15-membered saturated or unsaturated nitrogen-containing bicyclic or tricyclic heterocycle formed by condensation of 1 to 2 cyclic groups selected from (including 1 to 4 heteroatoms selected from atoms) Or (c) a saturated or unsaturated 8- to 11-membered nitrogen-containing spiroheterocyclic group. The pharmaceutical compositions of the mounting. An alkyl group in which the saturated or unsaturated heterocyclic group in R ⁵ , R ⁶ , R ⁸ or R ⁹ is substituted with a halogen atom, a hydroxyl group, a cyano group, an oxo group, an alkyl group, or 1 to 3 halogen atoms; Alkyloxyalkyl group, aminoalkyl group, cycloalkyl group, arylalkyl group, alkyloxy group, alkyloxy group substituted with 1 to 3 halogen atoms, acyl group, substituted with 1 to 2 alkyl groups An amino group, an acylamino group, an alkylsulfonyl group, an aminosulfonyl group optionally substituted with 1 to 2 alkyl groups, an aryl group optionally substituted with 1 to 2 halogen atoms, and a saturated or 4. A saturated or unsaturated heterocyclic group substituted with 1 to 4 groups selected from unsaturated 5 to 6-membered nitrogen-containing heterocyclic groups. Pharmaceutical compositions. A saturated or unsaturated nitrogen-containing heterocyclic group formed by R ⁵ and R ⁶ is a halogen atom, a hydroxyl group, a cyano group, an oxo group, an alkyl group, an alkyl group substituted with 1 to 3 halogen atoms, Alkyloxyalkyl group, aminoalkyl group, cycloalkyl group, arylalkyl group, alkyloxy group, alkyloxy group substituted with 1 to 3 halogen atoms, acyl group, substituted with 1 to 2 alkyl groups Saturated or unsaturated substituted with 1 to 3 groups selected from amino group, acylamino group, alkylsulfonyl group, aminosulfonyl group optionally substituted with 1 to 2 alkyl groups and aryl group The pharmaceutical composition according to claim 4, which is a nitrogen-containing heterocyclic group. The saturated or unsaturated heterocyclic group in R ⁵ , R ⁶ , R ⁸ or R ⁹ is (A) furyl group, tetrahydrofuranyl group, pyranyl group, tetrahydropyranyl group, thiacyclobutyl group, thienyl group, tetrahydrothienyl. Group, thiopyranyl group, tetrahydrothiopyranyl group, benzofuranyl group, dihydrobenzofuranyl group, isobenzofuranyl group, chromanyl group, isochromanyl group, chromenyl group, isochromenyl group, benzothienyl group and dihydrobenzothienyl group Or unsaturated oxygen-containing or sulfur-containing heterocyclic group, or (B) azetidyl group, pyrrolidinyl group, pyrrolinyl group, imidazolidinyl group, imidazolinyl group, pyrazolidinyl group, pyrazolinyl group, pyrrolyl group, 2H-pyrrolyl group, imidazolyl group, pyrazolyl Group, Jihi Lopyrazolyl, thiazolidinyl, thiazolyl, isothiazolyl, isoxazolyl, oxazolidinyl, pyridyl, dihydropyridyl, tetrahydropyridyl, piperidyl, pyrazinyl, piperazinyl, pyrimidinyl, tetrahydropyrimidinyl, pyridazinyl, morpholinyl Azosinyl group, azacycloheptyl group, indolizinyl group, benzimidazolyl group, benzotriazolyl group, indolyl group, isoindolyl group, 3H-indolyl group, indolinyl group, isoindolinyl group, 1H-indazolyl group, pyrrolopyridyl group, pyrrolopyrimidinyl group , Tetrazolyl group, purinyl group, pteridinyl group, 4H-quinolidinyl group, quinolyl group, dihydroquinolyl group, tetrahydroquinolyl group, isoquinolyl , Dihydroisoquinolyl group, tetrahydroisoquinolyl group, phthalazinyl group, dihydrophthalazinyl group, naphthyridinyl group, dihydronaphthyridinyl group, tetrahydronaphthylidinyl group, quinoxalinyl group, quinazolinyl group, dihydrobenzothiazinyl group, dihydrobenzo Oxazinyl group, cinnolinyl group, pteridinyl group, xanthenyl group, carbazolyl group, β-carbolinyl group, phenanthridinyl group, acridinyl group, 5H-dihydrodibenzazepinyl group and general formula:

[Wherein, R ^A and R ^B are the same or different and represent a hydrogen atom or an alkyl group, and q and r each represent an integer of 1 or 2. ]
The pharmaceutical composition according to claim 3, which is a saturated or unsaturated nitrogen-containing heterocyclic group selected from spiroheterocyclic groups represented by: The saturated or unsaturated heterocyclic group in R ⁵ , R ⁶ , R ⁸ or R ⁹ is a tetrahydrofuranyl group, a pyrrolyl group, a pyrrolidinyl group, a piperidyl group, an azacycloheptyl group, a tetrahydropyranyl group, a piperazinyl group, or a morpholinyl group. 4. A pharmaceutical composition according to claim 3, which is a thiomorpholinyl group, a thiacyclobutyl group, a tetrahydrothienyl group, a tetrahydrothiopyranyl group, a thiazolyl group, a pyridyl group, a pyrimidinyl group, an indolinyl group, a pyrrolopyridyl group or a tetrahydronaphthyridinyl group. A saturated or unsaturated nitrogen-containing heterocyclic group formed by bonding R ⁵ and R ⁶ to each other is an azetidyl group, pyrrolidinyl group, pyrrolinyl group, imidazolidinyl group, imidazolinyl group, pyrazolidinyl group, pyrazolinyl group, pyrrolyl group, Imidazolyl, pyrazolyl, dihydropyrazolyl, thiazolidinyl, oxazolidinyl, dihydropyridyl, tetrahydropyridyl, piperidyl, piperazinyl, tetrahydropyrimidinyl, morpholinyl, azacycloheptyl, benzimidazolyl, benzotriazolyl Group, indolyl group, isoindolyl group, indolinyl group, isoindolinyl group, 1H-indazolyl group, tetrazolyl group, purinyl group, dihydroquinolyl group, tetrahydroquinolyl group, dihydroisoquinolyl group, Trahydroisoquinolyl group, dihydrophthalazinyl group, dihydroquinazolinyl group, dihydrobenzothiazinyl group, dihydrobenzoxazinyl group, carbazolyl group, β-carbolinyl group, 5H-dihydrodibenzazepinyl group and general formula:

[Wherein, R ^A and R ^B are the same or different and represent a hydrogen atom or an alkyl group, and q and r each represent an integer of 1 or 2. ]
The pharmaceutical composition according to claim 4, which is a saturated or unsaturated nitrogen-containing heterocyclic group selected from spiroheterocyclic groups represented by: The saturated or unsaturated nitrogen-containing heterocyclic group formed by combining R ⁵ and R ⁶ with each other is a morpholino group, a thiomorpholino group, a piperidino group, a piperazino group or an azacycloheptyl group. Pharmaceutical composition. The groups represented by formula (ii) are represented by the following formulas (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 represents a linear or branched alkylene group having 1 to 6 carbon atoms, and other symbols have the same meaning as described above. ]
The pharmaceutical composition according to claim 1, which is any group represented by the formula: R ¹ and R ² are the same or different and may be substituted with one or two groups selected from a halogen atom and a trihalogenoalkyl group, Q is a single bond, and ring A is a group represented by formula (A) A substituted pyrazole ring represented by the formula (i):
-C (= O) O-R ⁰⁰ (i)
R ⁴ is a group represented by (1) an amino group optionally substituted with 1 to 2 groups selected from an alkyl group and an alkylsulfonyl group, or (2) substituted with 1 to 2 alkyl groups. The pharmaceutical composition according to claim 1, which may be an aminosulfonyl group. R ¹ and chlorophenyl group or trifluoro-C _1-4 alkylphenyl group, R ² is chlorophenyl group, R ⁰⁰ is C _1-4 alkyl group, R ⁴ is (1) C _1-4 alkyl group and C _1- The pharmaceutical composition according to claim 12, which is an amino group substituted with 1 to 2 groups selected from ₄ alkylsulfonyl groups or (2) an aminosulfonyl group substituted with 1 to 2 _C1-4 alkyl groups. object. R ¹ and R ² may be the same or different and (1) a halogen atom, a cyano group, an alkyl group which may be substituted with 1 to 3 halogen atoms, or a substituent with 1 to 3 halogen atoms A good alkyloxy group, a phenyl group optionally substituted with 1 to 3 groups selected from an amino group optionally substituted with 1 to 2 alkyl groups and an alkylsulfonyl group, or (2) a halogen atom, An oxo group, an alkyl group which may be substituted with 1 to 3 halogen atoms, an alkyloxy group, an alkyloxyalkyl group and an alkyloxyalkyloxy group which may be substituted with 1 to 3 groups Saturated or unsaturated 5- to 7-membered heterocyclic group,
A substituted pyrazole ring in which ring A is represented by formula (A) or (B),
E represents the following formulas (a) to (e):
(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 >) and (e) -C (= NR < ⁵¹ >)-R < ⁶¹ >.
A group selected from
R ³ is a hydrogen atom, a cyano group or an alkyloxy group,
R ⁴ is an alkyl group optionally substituted by 1 to 3 groups selected from (a) a hydrogen atom, (b) a cyano group, (c) a halogen atom and a hydroxyl group, (d) an alkyloxy group (the group The alkyl moiety of may be substituted with 1 to 3 groups selected from a halogen atom, a hydroxyl group, an amino group optionally substituted with 1 to 2 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 represented by the formula: —N (R ′) (R ″),
R ′ and R ″ are the same or different and are selected from (1) a hydrogen atom, (2) a halogen atom, an amino group optionally substituted by 1 to 2 alkyl groups, and an alkyloxy group. (3) an acyl group, (4) an alkylsulfonyl group, or (5) an aminosulfonyl group optionally substituted with one or two alkyl groups, or (6) Both are bonded to each other at the end to form a saturated or unsaturated nitrogen-containing heterocyclic group together with the adjacent nitrogen atom (the heterocyclic group may be substituted with a hydroxyl group or an alkyloxy group);
One of R ⁵ and R ⁶ is a hydrogen atom or an alkyl group, and the other is (1) substituted with a halogen atom, an alkyloxy group, a cycloalkyl group, an alkylthio group, an alkylsulfonyl group, or 1 to 2 alkyl groups. An optionally substituted amino group, a morpholinocarbonyl group, a phenyl group optionally substituted with a cyano group, and a saturated or unsaturated 5- to 6-membered heteromonocyclic group (the heterocyclic group is a halogen atom, an alkyl group, An alkyl group which may be substituted with 1 to 3 groups selected from a group selected from halogenoalkyl groups, and (2) a cyano group or a cyclo which may be substituted with an alkyl group. alkyl group, (3): ^-N (R 8) a group represented by ^{(R 9),} (4) phenyl, or (5) a halogen atom, a cyano group, a hydroxyl group, an oxo group, 1-3 An alkyl group which may be substituted with a halogen atom, a cycloalkyl group, an alkylcarbonyl group, an alkyloxycarbonyl group, an alkylsulfonyl group, an aminosulfonyl group which may be substituted with 1 to 2 alkyl groups, 1 to 2 A carbamoyl group optionally substituted with one alkyl group, an alkyloxycarbonylamino group, a phenyl group optionally substituted with 1 to 2 halogen atoms, and a 5- or 6-membered saturated or unsaturated heteromonocyclic group A saturated or unsaturated 4- to 10-membered heteromonocyclic or bicyclic group which may be substituted with 1 to 4 groups selected from: or (6) R ⁵ and R ⁶ are bonded to each other And a saturated or unsaturated nitrogen-containing 4- to 7-membered heteromonocyclic group together with the adjacent nitrogen atom (the heterocyclic group is one or two selected from a halogen atom and an oxo group) Optionally substituted with a group)
R ⁸ is a hydrogen atom or an alkyl group, R ⁹ is an alkyl group which may be substituted with 1 to 3 groups selected from (a) a halogen atom, a cyano group and a phenyl group; (b) a halogen atom and a cyano group A phenyl group optionally substituted with a group selected from 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 halogen atom, a cyano group, an alkyl group, an alkyloxy group and trihalogenoalkyl 5-6 membered optionally substituted with a group selected from the group saturated or unsaturated heteromonocyclic group, R ⁷ is A hydrogen atom, R ⁵¹ is an alkyl group or a phenylsulfonyl group (the phenyl portion of the group is substituted with 1 to 2 halogen atoms) The pharmaceutical composition according to claim 1, wherein R ⁶¹ is an alkylamino group or an azide group. R ¹ is (1) a phenyl group which may be substituted with one or two groups selected from a halogen atom, a cyano group, a dihalogenoalkyl group, a trihalogenoalkyl group, an alkyloxy group and a dialkylamino group, or (2 ) 5-7 member optionally substituted with 1-2 groups selected from oxo, alkyl, trihalogenoalkyl, alkyloxy, alkyloxyalkyl, alkyloxyalkyloxy and dialkylamino groups Saturated or unsaturated heterocyclic groups,
R ² is (1) a phenyl group which may be substituted with 1 to 2 groups selected from a halogen atom and a cyano group, or (2) a 5 to 6 membered saturated or unsaturated group which may be substituted with a halogen atom. A heterocyclic group,
R ³ is a hydrogen atom,
R ⁴ is a hydrogen atom, an alkyl group, a dihalogenoalkyl group, a hydroxyalkyl group, a trihalogenoalkyl group, an alkyloxyalkyl group, a hydroxyalkyloxy group, an alkyloxyalkyloxy group, an alkylsulfonylalkyl group, or a formula: —N (R ') (R "), one of R' and R" is a hydrogen atom or an alkyl group, the other is an acyl group or an alkylsulfonyl group,
E is the following formula:
(A) -C (= O) -N (R 5) (R 6),
(B) -C (= O) -Alk-N (R 5) (R 6) or ^{(e) -C (= NR 51} ) -R 61
A group represented by
One of R ⁵ and R ⁶ is a hydrogen atom or an alkyl group, and the other is (1) an alkyl group, (2) a cycloalkyl group, (3) a phenyl group, (4) a halogen atom, an oxo group, a cyano group, 1 to 3 selected from hydroxyl group, alkyl group, trihalogenoalkyl group, alkyloxy group, alkyloxyalkyl group, alkylcarbonyl group, dialkylcarbamoyl group, alkylsulfonyl group, dialkylaminosulfonyl group, phenyl group, halogenophenyl group and pyridyl group A saturated or unsaturated 4- to 10-membered monocyclic or bicyclic heterocyclic group which may be substituted with 4 groups, or a group represented by formula (5): -N (R ⁸ ) (R ⁹ ) Or (6) they are bonded to each other to form a 5- or 6-membered saturated or unsaturated nitrogen-containing heteromonocyclic group (the heterocyclic group is a halogen atom or oxo May be one or two optionally substituted by a group selected from), R ⁸ is an alkyl group, R ⁹ is (1) alkyl, (2) phenyl group optionally substituted with a halogen atom, (3 4) 6-membered saturated or unsaturated complex optionally substituted with an alkyl group optionally substituted with a pyridyl group or (4) a group selected from a halogen atom, an alkyl group, a trihalogenoalkyl group and an alkyloxy group The pharmaceutical composition according to claim 14, wherein R ⁵¹ is a monocyclic group, R ⁵¹ is an alkyl group or a halogenophenylsulfonyl group, and R ⁶¹ is an alkylamino group or an azide group. R ¹ is (a) a phenyl group optionally substituted with a group selected from a chlorine atom, a fluorine atom, a cyano group, a difluoro-C _1-4 alkyl group and a trifluoro-C _1-4 alkyl group, or (b) A pyridyl group optionally substituted with a trifluoro-C _1-4 alkyl group, R ² is phenyl optionally substituted with 1 to 2 groups selected from a chlorine atom, a fluorine atom, a bromine atom and a cyano group Group, R ³ is hydrogen atom, R ⁴ is hydrogen atom, C _1-4 alkyl group, difluoro-C _1-4 alkyl group, trifluoro-C _1-4 alkyl group, C _1-4 alkyloxy-C _{1- 4} alkyl group or _{C 1-4} alkyl - carbonyl amino group, E is the formula: (a) -C (= O ) -N (R 5) (R 6) , or (b) -C (= O) -Alk- A group represented by N (R ⁵ ) (R ⁶ ), R ^{One of 5} and R ⁶ is a hydrogen atom, and the other is a C _1-4 alkyl group, a pyridyl-C _1-4 alkyl group, a C _5-7 cycloalkyl group, a chlorophenyl group, a saturated or unsaturated 4- to 6-membered complex A monocyclic group (the heterocyclic group may be substituted with one or two groups selected from a halogen atom, an oxo group and a C _1-4 alkyloxy-C _1-4 alkyl group) or a formula: Or a group represented by -N (R ⁸ ) (R ⁹ ), or both bonded to each other and a 5- to 6-membered nitrogen-containing heteromonocyclic group (even if substituted with 1 to 2 oxo groups) The pharmaceutical composition according to claim 14, wherein R ⁸ is a C _1-4 alkyl group, and R ⁹ is a C _1-4 alkyl group, a chlorophenyl group, a pyridyl group, or a C _1-4 alkyloxypyridyl group. R ¹ and R ² are the same or different and may be substituted with one or two groups selected from a halogen atom and a trihalogenoalkyl group, Q is a single bond, and ring A is a group represented by formula (A) Embedded image wherein R ³ is a hydrogen atom, R ⁴ is a hydrogen atom or an alkyl group, and E is a formula (iii):

One of the groups represented by R ⁵ and R ⁶ is a hydrogen atom or an alkyl group, and the other is substituted with (1) an alkyl group, (2) a cycloalkyl group, or (3) 1-2 oxo groups. Or a 5- or 6-membered saturated or unsaturated sulfur-containing or nitrogen-containing heterocyclic group, or (4) they may be bonded to each other and substituted with 1 to 2 oxo groups together with adjacent nitrogen atoms. The pharmaceutical composition according to claim 1, which forms a good 5- to 6-membered saturated or unsaturated nitrogen-containing heterocyclic group. R ¹ is a trihalogenoalkyl-phenyl group, R ² is a halogenophenyl group, R ⁴ is an alkyl group, R ⁵ and R ⁶ are either a hydrogen atom or an alkyl group, the other is (1) an alkyl group, (2 ) A cycloalkyl group or (3) a 5- or 6-membered saturated or unsaturated sulfur-containing or nitrogen-containing heterocyclic group optionally substituted by 1 to 2 oxo groups, or (4) 18. Combined to form a 5- or 6-membered saturated or unsaturated nitrogen-containing heterocyclic group with an adjacent nitrogen atom (the heterocyclic group may be substituted with 1 to 2 oxo groups). Pharmaceutical composition. R ¹ and R ² are the same or different and may be substituted with one or two groups selected from a halogen atom and a trihalogenoalkyl group, Q is a single bond, and ring A is a group represented by formula (A) Embedded image wherein R ³ is a hydrogen atom, R ⁴ is a hydrogen atom or an alkyl group, and E is a formula (iv):

R ⁵⁰ and R ⁶⁰ are either a hydrogen atom or an alkyl group and the other is an alkyl group or an acyl group, or both are bonded to each other and are bound to one to two oxo groups together with an adjacent nitrogen atom. The pharmaceutical composition according to claim 1, which forms a 5-6 membered saturated or unsaturated nitrogen-containing heterocyclic group which may be substituted. R ¹ and R ² are the same or different and may be substituted with one or two groups selected from a halogen atom and a trihalogenoalkyl group, Q is a single bond, and ring A is a group represented by formula (C) R ³ is a hydrogen atom, R ⁴ is a group represented by the formula: —N (R ′) (R ″), R ′ and R ″ are the same or different, and a hydrogen atom or an alkyl group The pharmaceutical composition according to claim 1, wherein the two are bonded to each other at the end to form a 5- or 6-membered saturated or unsaturated nitrogen-containing heterocyclic group together with the adjacent nitrogen atom. 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] 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] 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-tetrahydrothien3-yl) carbamoyl] pyrazolo [1,5-a] pyrimidine;
(R) -6- (2-Chlorophenyl) -7- (4-difluoromethylphenyl) -3- [N- (1,1-dioxo-tetrahydrothien-3-yl) carbamoyl] pyrazolo [1,5-a ] Pyrimidine;
(R) -6- (2-Chlorophenyl) -7- (4-trifluoromethylphenyl) -3- [N- (1,1-dioxo-tetrahydrothien-3-yl) carbamoyl] -2-methylpyrazolo [1 , 5-a] pyrimidine;
(S) -6- (2-Chlorophenyl) -7- (4-trifluoromethylphenyl) -3- [N- (1,1-dioxo-tetrahydrothien-3-yl) carbamoyl] -2-methylpyrazolo [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) -3- [N- (1,1-dioxo-tetrahydrothien-3-yl) carbamoyl] -2-methylpyrazolo [1,5- a] pyrimidine;
(S) -6- (2-Chlorophenyl) -7- (4-chlorophenyl) -3- [N- (1,1-dioxo-tetrahydrothien-3-yl) carbamoyl] -2-methylpyrazolo [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-tetrahydrothien-3-yl) carbamoyl] pyrazolo [1,5- a] pyrimidine;
(S) -6- (2-Chlorophenyl) -7- (4-trifluoromethylphenyl) -3- [N- (1,1-dioxo-tetrahydrothien-3-yl) carbamoyl] pyrazolo [1,5- a] pyrimidine;
(R) -6- (2-Chlorophenyl) -7- (4-trifluoromethylphenyl) -3- [N- (1,1-dioxo-tetrahydrothien-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-tetrahydrothien-3-yl) carbamoyl] pyrazolo [1,5-a] pyrimidine ;
6- (2-chlorophenyl) -7- (4-trifluoromethylphenyl) -3- (N-cyclopentylcarbamoyl) pyrazolo [1,5-a] pyrimidine;
6- (2-chlorophenyl) -7- (4-trifluoromethylphenyl) -3- [N- [N-methyl-N- (2-pyridyl) amino] carbamoyl] pyrazolo [1,5-a] pyrimidine;
(R) -6- (2-Chlorophenyl) -7- (4-chlorophenyl) -3- [N- (1,1-dioxo-tetrahydrothien-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) -3- [N- (1,1-dioxo-tetrahydrothien-3-yl) carbamoyl] -2-methylpyrazolo [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;
(S) -6- (2-Chlorophenyl) -7- (4-chlorophenyl) -3- [N- (1,1-dioxo-tetrahydrothien-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-dioxotetrahydrothien-3-yl) carbamoyl] pyrazolo [1, 5-a] pyrimidine;
(S) -6- (2-Chlorophenyl) -7- (4-difluoromethylphenyl) -3- [N- (1,1-dioxotetrahydrothien-3-yl) carbamoyl] pyrazolo [1,5-a ] Pyrimidine;
(R) -6- (2-cyanophenyl) -7- (4-trifluoromethylphenyl) -3- [N- (1,1-dioxotetrahydrothien-3-yl) carbamoyl] -2-methylpyrazolo [ 1,5-a] pyrimidine;
(S) -6- (2-Cyanophenyl) -7- (4-trifluoromethylphenyl) -3- [N- (1,1-dioxotetrahydrothien-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) pyrazolo [1,5-a] pyrimidine;
(R) -6- (2-Cyanophenyl) -7- (4-chlorophenyl) -3- [N- (1,1-dioxotetrahydrothien-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-dioxotetrahydrothien-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-dioxotetrahydrothien-3-yl) carbamoyl] -2-difluoromethylpyra Zolo [1,5-a] pyrimidine;
(S) -6- (2-Chlorophenyl) -7- (4-trifluoromethylphenyl) -3- [N- (1,1-dioxotetrahydrothien-3-yl) carbamoyl] -2-difluoromethylpyra Zolo [1,5-a] pyrimidine;
6- (2-cyanophenyl) -7- (4-chlorophenyl) -3- (N-piperidinocarbamoyl) pyrazolo [1,5-a] pyrimidine;
6- (2-chlorophenyl) -7- (4-chlorophenyl) -3- [N- (1,1-dioxothiacyclobutan-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-pyrrolidinyl) carbamoyl] -2-methylpyrazolo [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] pyrazolo [1,5-a] pyrimidine;
(R) -7- (4-Chloro-2-fluorophenyl) -6- (2-cyanophenyl) -3- [N- (1,1-dioxotetrahydrothien-3-yl) carbamoyl] -2- Methylpyrazolo [1,5-a] pyrimidine;
6- (2-Chlorophenyl) -7- (4-chlorophenyl) -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-dioxotetrahydrothien-3-yl) carbamoyl] -2-methoxymethylpyrazolo [1 , 5-a] pyrimidine;
(S) -6- (2-Chlorophenyl) -7- (4-chlorophenyl) -3- [N- (1,1-dioxotetrahydrothien-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-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] -2-methylpyrazolo [1,5-a] pyrimidine;
6- (2-cyanophenyl) -7- (4-chlorophenyl) -3- [N- (4-fluoro) piperidinocarbamoyl] -2-methylpyrazolo [1,5-a] pyrimidine;
And 6- (2-chlorophenyl) -7- (4-trifluoromethylphenyl) -3- [N- (tetrahydrothien-3-yl) carbamoyl] pyrazolo [1,5-a] pyrimidine;
A pharmaceutical composition comprising, as an active ingredient, a compound selected from: or a pharmacologically acceptable salt thereof. The pharmaceutical composition according to any one of claims 1 to 21, which is a CB1 receptor antagonist. Psychiatric disorders including schizophrenia, anxiety disorders, stress, depression, epilepsy, neurodegeneration, cerebellar and old cerebellum (Spinocerebellar) disorders, cognitive impairment, cranial trauma, panic attacks, peripheral neuropathy, glaucoma, migraine, Parkinson's disease, Alzheimer Disease, Huntington's disease, Raynaud's syndrome, tremor, obsessive compulsive disorder, amnesia, senile dementia, thymic disorder, Tourette syndrome, tardive dyskinesia, bipolar disorder, cancer, drug-induced movement disorder, ataxia, endotoxin Septic shock, hemorrhagic shock, hypotension, insomnia, immunological diseases including inflammation, multiple sclerosis, vomiting, diarrhea, asthma, appetite disorder (bulimia, anorexia), obesity, non Insulin dependent diabetes mellitus (NIDDM), impaired glucose tolerance, hyperinsulinemia, hyperlipidemia, hypercholesterolemia, high triglycerides Disease, lipid metabolism abnormality, arteriosclerosis, hypertension, coronary disease, memory disorder, urological disease, cardiovascular disease, infertility, infection, demyelinating disease, neuritis, viral encephalitis, cerebrovascular disorder, cirrhosis, or intestine The pharmaceutical composition according to any one of claims 1 to 21, which is a prophylactic / therapeutic agent for gastrointestinal tract diseases including passage disorder (intestinal transdisorders). The pharmaceutical composition according to any one of claims 1 to 21, which is an agent for promoting withdrawal from chronic treatment and substance, substance dependence or drug abuse. The pharmaceutical composition according to any one of claims 1 to 21, which is an analgesic agent or an enhancer of analgesic activity of an anesthetic and non-anesthetic drug. The pharmaceutical composition according to any one of claims 1 to 21, which is a smoking cessation aid (an agent for promoting withdrawal from smoking). Formula [Ia]:

[Where,
R ¹ and R ² are the same or different,
(I) a halogen atom, a cyano group, an alkyl group which may be substituted with 1 to 3 halogen atoms, an alkyloxy group which may be substituted with 1 to 3 halogen atoms, or 1 to 2 alkyls A 6-10 membered monocyclic or bicyclic aryl group optionally substituted with 1 to 3 groups selected from an amino group, an alkylthio group, an alkylsulfinyl group and an alkylsulfonyl group, which may be substituted with a group, Or (ii) a halogen atom, a cyano group, an oxo group, an alkyl group which may be substituted with 1 to 3 halogen atoms, an alkyloxy group which may be substituted with 1 to 3 halogen atoms, Substituted with 1 to 3 groups selected from amino group, alkylthio group, alkylsulfinyl group and alkylsulfonyl group which may be substituted with 2 alkyl groups Oxygen-containing, sulfur-containing or nitrogen-containing 5-6 membered saturated or unsaturated heteromonocyclic group,
Ring A is fused to the adjacent pyrimidine ring below (A) or (B):

A substituted pyrazole ring represented by
R ³ and R ⁴ are the same or different and are (a) a hydrogen atom, (b) a cyano group, (c) an alkyl group optionally substituted with 1 to 3 halogen atoms, (d) an alkyloxy group ( The alkyl part of the group is substituted with 1 to 3 groups selected from a halogen atom, a hydroxyl group, an amino group optionally substituted with 1 to 2 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 represented by the formula: —N (R ′) (R ″),
R ′ and R ″ are the same or different and are selected from (1) a hydrogen atom, (2) a halogen atom, an amino group optionally substituted by 1 to 2 alkyl groups, and an alkyloxy group. (3) an acyl group, (4) an alkylsulfonyl group, or (5) an aminosulfonyl group optionally substituted with one or two alkyl groups, or Both are bonded to each other at the end to form a 5- or 6-membered saturated or unsaturated nitrogen-containing heterocyclic group together with the adjacent nitrogen atom (the nitrogen-containing heterocyclic group may be substituted with a hydroxyl group or an alkyloxy group). Represents
E represents the following formulas (ii) to (v):

Any of the groups represented by
Q ¹ is a single bond, an alkylene group or a group represented by 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) a halogen atom, a cyano group, an alkyloxy group, or a cycloalkyl group (the cycloalkyl group is selected from a cyano group and an alkyl group) An amino group optionally substituted with 1 to 2 alkyl groups, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group, an acyl group, a 6 to 10-membered single group. A cyclic or bicyclic aryl group (the aryl group may be substituted with 1 to 2 halogen atoms), a 4-7 membered saturated or unsaturated heteromonocyclic group (the heteromonocyclic group is 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom), the above-mentioned heteromonocyclic group and a C _3-8 cycloalkyl group, a 5-6 membered monocyclic aryl group and a saturated group Or 4 ~ unsaturated 1 to 2 other cyclic groups selected from membered monocyclic heterocyclic groups (the heterocyclic monocyclic group includes 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom) 1-3 selected from saturated or unsaturated 8- to 15-membered nitrogen-containing bicyclic or tricyclic heterocyclic group and saturated or unsaturated 8- to 11-membered nitrogen-containing spiro heterocyclic group formed by condensation of the group An alkyl group which may be substituted with a group of (b), a cycloalkyl group which may be substituted with 1 to 2 groups selected from (b) a cyano group and an alkyl group, (c) a formula: —N (R ⁸ ) (groups represented by R ^9), optionally substituted with (d) 6 to 10 membered monocyclic or bicyclic aryl group (the aryl group 1 to 2 halogen atoms) or (e) Saturated or unsaturated heterocyclic group selected from the group consisting of (i) to (iii) below: (i) 4 to A membered saturated or unsaturated heteromonocyclic group (the heteromonocyclic group contains 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom), (ii) the above heteromonocyclic group A group and a C _3-8 cycloalkyl group, a 5- to 6-membered monocyclic aryl group, and a saturated or unsaturated 4- to 7-membered monocyclic heterocyclic group (the heterocyclic monocyclic group includes an oxygen atom, a sulfur atom, and Saturated or unsaturated 8- to 15-membered nitrogen-containing bicyclic or tricyclic heterocycle formed by condensation of 1 to 2 cyclic groups selected from (including 1 to 4 hetero atoms selected from nitrogen atoms) (Iii) a cyclic group, and (iii) a saturated or unsaturated 8- to 11-membered nitrogen-containing spiroheterocyclic group, or both of R ⁵ and R ⁶ are bonded to each other at the terminal, together with adjacent nitrogen atoms, (a) 2 or more And may contain oxygen atoms and sulfur atoms in addition to the nitrogen atoms. 1-2 hetero atoms which may contain saturated or unsaturated 4-7-membered nitrogen-containing heteromonocyclic group, (b) said heteromonocyclic group and a C _3-8 cycloalkyl group selected 5-6 membered monocyclic aryl group and saturated or unsaturated 4-7 membered monocyclic heterocyclic group (the heterocyclic monocyclic group is 1-4 selected from oxygen atom, sulfur atom and nitrogen atom) A saturated or unsaturated 8- to 15-membered nitrogen-containing bicyclic or tricyclic heterocyclic group formed by condensation of 1 to 2 other cyclic groups selected from ) Forming a saturated or unsaturated nitrogen-containing heterocyclic group selected from the group consisting of saturated or unsaturated 8- to 11-membered nitrogen-containing spiro heterocyclic groups;
One of R ⁸ and R ⁹ is a hydrogen atom or an alkyl group, and the other is (a) an alkyl group which may be substituted with 1 to 3 groups selected from a halogen atom, a cyano group and an aryl group, b) a cycloalkyl group, (c) a 6-10 membered monocyclic or bicyclic aryl group (the aryl group may be substituted with 1 to 2 halogen atoms), (d) an acyl group, or (E) a saturated or unsaturated heterocyclic group selected from the group consisting of (i) to (iii) below: (i) a 4 to 7-membered saturated or unsaturated heterocyclic monocyclic group (the heterocyclic monocyclic group is (Including 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom), (ii) the above-mentioned heteromonocyclic group and a C _3-8 cycloalkyl group, 5 to 6-membered monocyclic aryl A saturated or unsaturated 4- to 7-membered monocyclic heterocyclic group (the heterocyclic monocyclic group is A saturated or unsaturated 8- to 15-membered nitrogen-containing bicycle formed by condensation of 1 to 2 cyclic groups selected from 1 to 4 hetero atoms selected from elemental atoms, sulfur atoms and nitrogen atoms) A saturated or unsaturated heterocyclic group selected from the group consisting of a formula or tricyclic heterocyclic group, and (iii) a saturated or unsaturated 8- to 11-membered nitrogen-containing spiro 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 are bonded to each other together with an adjacent nitrogen atom in the following formula:

[Wherein, ring A ¹ represents a 5- to 7-membered aliphatic nitrogen-containing heteromonocyclic group which may be substituted with an oxo group. ]
Form the cyclic group shown,
R ⁵¹ represents an alkyl group or a 6 to 10-membered monocyclic or bicyclic aryl-sulfonyl group (the aryl group portion of the group may be substituted with 1 to 2 halogen atoms),
R ⁶¹ represents an alkylamino group or an azide group,
a) The saturated or unsaturated heterocyclic group in R ⁵ , R ⁶ , R ⁸ or R ⁹ is a halogen atom, a hydroxyl group, a cyano group, an oxo group, an alkyl group, or an alkyl substituted with 1 to 3 halogen atoms. Group, alkyloxyalkyl group, aminoalkyl group, cycloalkyl group, 6-10 membered monocyclic or bicyclic aryl-alkyl group, alkyloxy group, alkyloxy group substituted with 1 to 3 halogen atoms, acyl Group, amino group optionally substituted with 1 to 2 alkyl groups, acylamino group, alkylsulfonyl group, aminosulfonyl group optionally substituted with 1 to 2 alkyl groups, 1 to 2 halogen atoms 1-4 selected from 6 to 10-membered monocyclic or bicyclic aryl group optionally substituted with atoms and saturated or unsaturated 5 to 6-membered nitrogen-containing heterocyclic group May be substituted with a group, and b) R ⁵ and saturated or unsaturated heterocyclic group is a halogen atom R ⁶ are attached to each other to form a hydroxyl group, a cyano group, an oxo group, an alkyl group, 1 Alkyl group, alkyloxyalkyl group, aminoalkyl group, cycloalkyl group, 6-10 membered monocyclic or bicyclic aryl-alkyl group, alkyloxy group, 1-3 halogen substituted with 3 halogen atoms An alkyloxy group substituted with an atom, an acyl group, an amino group optionally substituted with 1 to 2 alkyl groups, an acylamino group, an alkylsulfonyl group, and optionally substituted with 1 to 2 alkyl groups Substituted with 1 to 3 groups selected from an aminosulfonyl group and a 6 to 10 membered monocyclic or bicyclic aryl group optionally substituted with 1 to 2 halogen atoms Even though it is indicating that it may. ]
A pharmaceutical composition comprising as an active ingredient a pyrazolo [1,5-a] pyrimidine compound or a pharmaceutically acceptable salt thereof.