Heterocyclic compound

Abstract

Provided is a compound having calcium-sensitive receptor antagonistic activity, and which may be expected to be useful as an agent for the prevention or treatment of cardiac failure, pulmonary hypertension and the like, or a salt of said compound. The compound represented by formula (I) or a salt of said compound has calcium-sensitive receptor antagonistic activity, and may be expected to be useful in the prevention or treatment of cardiac failure, pulmonary hypertension or the like. [In the formula, each of the symbols is as described in the description.]

Description

heterocyclic compounds

[0001] The present invention relates to heterocyclic compounds which have calcium-sensing receptor antagonistic activity and are useful as agents for the prevention or treatment of heart failure, pulmonary hypertension, and the like.

[0002] [Background of the invention] Heart failure is a disease characterized by a pathological condition in which cardiac output is reduced due to dysfunction of myocardial cells, and a pathological condition resulting from the burden on the body caused by the mechanism for maintaining cardiac output. The functions of myocardial cells are contraction and relaxation, and contraction and relaxation require Ca 2+ Contraction of cardiac muscle cells begins with the action potential propagating to the transverse tubule, depolarizing the membrane of the transverse tubule, and then the voltage-dependent L-type Ca 2+ Channel to Ca 2+ The stage where ions flow into the cell, and the flowing Ca 2+ Ions are Ca in the sarcoplasmic reticulum 2+ It binds to a release channel (ryanodine receptor, or RYR) and transports Ca from the sarcoplasmic reticulum to the cytoplasm. 2+ The stage where ions are released, Ca released into the cell 2+ This occurs when Ca ions bind to troponin C and induce contraction of cardiac muscle cells. 2+ Ca2+ is released into the sarcoplasmic reticulum via the SERCA release pump. 2+ Ions are taken up and cytoplasmic Ca 2+ ions decrease, and troponin C is converted to Ca 2+ This occurs when ions dissociate. Therefore, if an abnormality occurs at any stage above, Ca 2+ If the ions are not released into the cytoplasm, the myocardial cells will malfunction, leading to heart failure.

[0003] As therapeutic drugs for heart failure, beta-blockers, antialdosterone drugs, diuretics, digitalis, cardiotonic drugs, etc. are used in clinical settings to improve short-term symptoms and stabilize hemodynamics. However, these drugs are insufficient to improve readmission rates and long-term life prognosis, and recently there has been a demand for the provision of new therapeutic drugs for heart failure that improve readmission rates and long-term life prognosis.

[0004] Pulmonary hypertension is a disease with an extremely poor prognosis. It occurs when abnormal proliferation, remodeling, and constriction of myocardial and pulmonary vascular tissues cause elevated pulmonary arterial pressure. As the disease progresses, right heart failure and death occur. The main therapeutic agents used to treat pulmonary hypertension include endothelin receptor antagonists, phosphodiesterase 5 inhibitors, prostacyclin analogs, and soluble guanylate cyclase (sGC) stimulators. While these drugs have shown some improvement in symptoms, the prognosis remains poor. In recent years, it has become clear that multiple molecules are involved in the pathogenesis of this disease. Furthermore, current therapeutic agents have limited efficacy when used alone, necessitating the development of new therapeutic agents.

[0005] Calcium-sensing receptors (CaSRs) are G protein-coupled receptors (GPCRs) that sense changes in extracellular calcium concentration and are known to be associated with various diseases.

[0006] Patent Document 1 describes compounds represented by the following formula or salts thereof as heterocyclic compounds, and describes that they have a modulating action (agonist activity or antagonist activity) of calcium-sensing receptor (CaSR) and thereby a modulating action of parathyroid hormone (PTH) secretion.

[0007]

[0008] Furthermore, Patent Document 2 describes a compound represented by the following formula or a salt thereof, and describes that the compound has a modulating action (agonist activity or antagonist activity) of calcium-sensing receptor (CaSR) and thereby a modulating action of parathyroid hormone (PTH) secretion.

[0009]

[0010] Regarding heart failure, Non-Patent Documents 1 and 2 state that parathyroid hormone treatment improves cardiac function, but Non-Patent Document 3 states that parathyroid hormone treatment worsens cardiac function. Therefore, the relationship between parathyroid hormone treatment and improvement of cardiac function has not yet been fully elucidated.

[0011] Furthermore, Non-Patent Document 4 describes that the CaSR inhibitor Calhex231 improves cardiac hypertrophy in aortic banding (TAC) models, but the effects after cardiac dysfunction have not been elucidated. Non-Patent Document 5 shows that administration of Calhex231 after cardiac stress does not improve cardiac dysfunction. Furthermore, Non-Patent Document 6 describes that CaSR antagonists nullify cardioprotective effects in ischemic preconditioning models. Therefore, the relationship between CaSR inhibition and improvement of cardiac dysfunction and survival rate has not been fully elucidated.

[0012] On the other hand, with regard to pulmonary hypertension, it has recently been reported that CaSR is overexpressed in pulmonary artery smooth muscle cells (PASMCs) isolated from patients with pulmonary hypertension, and that its enhanced function leads to abnormal proliferation of pulmonary vascular tissue. Furthermore, it has been reported that NPS-2143, a compound that acts as a CaSR antagonist, suppresses cardiac hypertrophy, increased right ventricular systolic pressure, myocardial tissue fibrosis, and pulmonary vascular remodeling in rats with monocrotaline (MCT)-induced pulmonary hypertension and mice with hypoxia-induced pulmonary hypertension (HPH) (Non-Patent Documents 7 to 11). However, there remains a high medical need for therapeutic agents for pulmonary hypertension, and there is a need for the development of pharmaceuticals for the prevention or treatment of pulmonary hypertension that have excellent properties in terms of efficacy, specificity, and low toxicity.

[0013] WO2004 / 017908 JP2005-239611

[0014] Cardiovascular research, 77:722-731, 2008Cardiovascular research, 93:330-339, 2012Experimental and molecularmedicine 42, 61-68, 2010Cell Physiol. Biochem., 36:1597-1612, 2015Cell Physiol. Biochem., 33:557-568, 2014Am. J. Physiol. Heart Circ. Physiol., 299: H1309-H1317, 2010Circ. Res., 111(4): 469-481, 2012Circ. Res., 112(4): 640-650, 2013YAKUGAKU ZASSHI, 133(12):1351-1359, 2013J. Smooth Muscle Res., 50: 8-17, 2014Hypertens Res. 37(2): 116-124, 2014

[0015] An object of the present invention is to provide a compound or a salt thereof which has calcium-sensing receptor antagonistic activity and is expected to be useful as an agent for preventing or treating heart failure, pulmonary hypertension, and the like.

[0016] The present inventors have found that a compound represented by the following formula (I) or a salt thereof has calcium-sensing receptor antagonistic activity and is expected to be useful as an agent for preventing or treating heart failure, pulmonary hypertension, etc. The present invention has been completed as a result of intensive research by the present inventors based on the above findings.

[0017] That is, the present invention is as follows: [1] A compound represented by formula (I): wherein ring A represents an aromatic ring which may be further substituted; １ represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkylthio group, or an optionally substituted alkoxy group; R ２ and R ３ each independently represents an optionally substituted alkyl group, or R ２ and R ３may form, together with the adjacent carbon atom, a ring which may be further substituted; R ４ represents an optionally substituted aromatic ring group or an optionally substituted alkyl group; R ５ and R ６ each independently represents a hydrogen atom or a halogen atom.] or a salt thereof (hereinafter also referred to as "compound (I)"). [2] The compound or salt thereof according to the above [1], wherein ring A is a benzene ring. [3] R １ The compound or salt thereof according to the above-mentioned [1], wherein R is a hydrogen atom. ２ and R ３ But both are C １－６ The compound according to the above-mentioned [1], or a salt thereof, wherein R is an alkyl group. ４ (a) a halogen atom, (b) a C group optionally substituted by 1 to 3 halogen atoms １－６ (c) an alkyl group optionally substituted with 1 to 3 halogen atoms; １－６ C, each of which may be substituted with 1 or 2 substituents selected from the group consisting of alkoxy groups; ６－１４ an aryl group, a 5- or 6-membered monocyclic aromatic heterocyclic group, or C １－６ The compound according to the above-mentioned [1], or a salt thereof, wherein R is an alkyl group. ５ and R ６ are each independently a hydrogen atom or a fluorine atom. [7] The compound or salt thereof according to the above-mentioned [1], wherein ring A is a benzene ring; １ is a hydrogen atom; R ２ and R ３ But both are C 1-6 alkyl; R ４ (a) a halogen atom, (b) a C group optionally substituted by 1 to 3 halogen atoms １－６ (c) an alkyl group optionally substituted with 1 to 3 halogen atoms; １－６ C, each of which may be substituted with 1 or 2 substituents selected from the group consisting of alkoxy groups; ６－１４ an aryl group, a 5- or 6-membered monocyclic aromatic heterocyclic group, or C １－６ alkyl group; R５ and R ６ are each independently a hydrogen atom or a fluorine atom. [8] The compound or salt thereof according to the above-mentioned [1], wherein ring A is a benzene ring; １ is a hydrogen atom; R ２ and R ３ But both are C 1-6 alkyl; R ４ (a) a halogen atom, and (b) a C group optionally substituted with 1 to 3 halogen atoms. １－６ an alkyl group; a phenyl group substituted with one or two substituents selected from the group consisting of ５ and R ６and R are hydrogen atoms, or a salt thereof. [9] ((1S,5R)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hex-3-yl)((5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)methanone or a salt thereof.

[10] (1-(3,5-dichlorophenyl)-3-azabicyclo[3.1.0]hex-3-yl)((5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)methanone or a salt thereof.

[11] (1-(4-chloro-3-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hex-3-yl)((5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)methanone or a salt thereof.

[12] A medicament comprising the compound according to the above-mentioned [1] or a salt thereof.

[13] The medicament according to the above-mentioned

[12] , which is a calcium-sensing receptor antagonist.

[14] The medicament according to the above-mentioned

[12] , which is a prophylactic or therapeutic agent for heart failure.

[15] The medicament according to the above-mentioned

[12] , which is a prophylactic or therapeutic agent for pulmonary hypertension.

[16] The compound according to the above-mentioned [1], or a salt thereof, for use in the prophylaxis or treatment of heart failure.

[17] The compound according to the above-mentioned [1], or a salt thereof, for use in the prophylaxis or treatment of pulmonary hypertension.

[18] A method for antagonizing a calcium-sensing receptor in a mammal, comprising administering an effective amount of the compound described in [1] above or a salt thereof to the mammal.

[19] A method for preventing or treating heart failure in a mammal, comprising administering an effective amount of the compound described in [1] above or a salt thereof to the mammal.

[20] A method for preventing or treating pulmonary hypertension in a mammal, comprising administering an effective amount of the compound described in [1] above or a salt thereof to the mammal.

[21] Use of the compound described in [1] above or a salt thereof for the manufacture of an agent for the prevention or treatment of heart failure.

[22] Use of the compound described in [1] above or a salt thereof for the manufacture of an agent for the prevention or treatment of pulmonary hypertension.

[0018] INDUSTRIAL APPLICABILITY The present invention provides compounds or salts thereof which have calcium-sensing receptor antagonistic activity and are expected to be useful as agents for the prevention or treatment of heart failure, pulmonary hypertension, and the like.

[0019] Figure 1 is a graph showing the results of Test Example 5 "Effect of the compound of Example 1 on the survival rate of heart failure model animals", i.e., the survival rates of the vehicle-administered group and the compound of Example 1-administered group (log-rank test, p<0.025). Figure 2 is a graph showing the results of Test Example 5 "Effect of the compound of Example 1 on the survival rate of heart failure model animals", i.e., the survival rates of the candesartan cilexetil monotherapy group and the combined administration of candesartan cilexetil and the compound of Example 1 at 10 mg / kg body weight / day (log-rank test, p<0.001).

[0020] (Detailed Description of the Invention) The present invention will now be described in detail.

[0021] The definition of each substituent used in the present specification will be described in detail below. Unless otherwise specified, each substituent has the following definition. In the present specification, examples of "halogen atom" include fluorine, chlorine, bromine, and iodine. In the present specification, "C １－６ Examples of the "alkyl group" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl. １－６ The alkyl group may be, for example, a C alkyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. １－６Specific examples include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, propyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, and 6,6,6-trifluorohexyl. ２－６ Examples of the "alkenyl group" include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, and 5-hexenyl. ２－６ Examples of the "alkynyl group" include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, and 4-methyl-2-pentynyl. ３－１０ Examples of the "cycloalkyl group" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, and adamantyl. ３－１０ The "cycloalkyl group" includes, for example, a C alkyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. ３－１０ Specific examples include cyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.３－１０ Examples of the "cycloalkenyl group" include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. ６－１４ Examples of the "aryl group" include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, and 9-anthryl. ７－１６ Examples of the "aralkyl group" include benzyl, phenethyl, naphthylmethyl, and phenylpropyl.

[0022] In this specification, "C １－６ Examples of the "alkoxy group" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, and hexyloxy. １－６ The "alkoxy group" includes, for example, a C alkoxy group optionally having 1 to 7, preferably 1 to 5, halogen atoms. １－６ Specific examples include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, and hexyloxy. ３－１０ Examples of the "cycloalkyloxy group" include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy. １－６ Examples of the "alkylthio group" include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio, and hexylthio. １－６ The "alkylthio group" includes, for example, a C alkylthio group optionally having 1 to 7, preferably 1 to 5, halogen atoms. １－６Specific examples include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, and hexylthio. １－６ Examples of the "alkyl-carbonyl group" include acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl, hexanoyl, and heptanoyl. １－６ The alkyl-carbonyl group includes, for example, a C alkyl-carbonyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. １－６ Specific examples include acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl, and hexanoyl. １－６ Examples of the "alkoxy-carbonyl group" include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, and hexyloxycarbonyl. ６－１４ Examples of the "aryl-carbonyl group" include benzoyl, 1-naphthoyl, and 2-naphthoyl. ７－１６ As used herein, examples of the "aralkyl-carbonyl group" include phenylacetyl and phenylpropionyl. As used herein, examples of the "5- to 14-membered aromatic heterocyclylcarbonyl group" include nicotinoyl, isonicotinoyl, thenoyl and furoyl. As used herein, examples of the "3- to 14-membered non-aromatic heterocyclylcarbonyl group" include morpholinylcarbonyl, piperidinylcarbonyl and pyrrolidinylcarbonyl.

[0023] As used herein, "mono- or di-C １－６Examples of the "alkyl-carbamoyl group" include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, and N-ethyl-N-methylcarbamoyl. ７－１６ Examples of the "aralkyl-carbamoyl group" include benzylcarbamoyl and phenethylcarbamoyl. １－６ Examples of the "alkylsulfonyl group" include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl, and tert-butylsulfonyl. １－６ The alkylsulfonyl group includes, for example, a C alkylsulfonyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. １－６ Specific examples include methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl, pentylsulfonyl, and hexylsulfonyl. ６－１４ The "arylsulfonyl group" includes, for example, phenylsulfonyl, 1-naphthylsulfonyl, and 2-naphthylsulfonyl.

[0024] In the present specification, examples of the "substituent" include a halogen atom, a cyano group, a nitro group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfamoyl group, an optionally substituted hydroxy group, an optionally substituted sulfanyl (SH) group, and an optionally substituted silyl group. In the present specification, examples of the "hydrocarbon group" (including the "hydrocarbon group" in the "optionally substituted hydrocarbon group") include C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１０Cycloalkyl group, C ３－１０ Cycloalkenyl group, C ６－１４ Aryl group, C ７－１６ Examples include aralkyl groups.

[0025] In the present specification, examples of the "optionally substituted hydrocarbon group" include hydrocarbon groups which may have a substituent selected from the following Substituent Group A. [Substituent Group A] (1) a halogen atom, (2) a nitro group, (3) a cyano group, (4) an oxo group, (5) a hydroxy group, (6) an optionally halogenated C １－６ an alkoxy group, (7) C ６－１４ Aryloxy groups (e.g., phenoxy, naphthoxy), (8) C ７－１６ (9) an aralkyloxy group (e.g., benzyloxy), (10) a 5- to 14-membered aromatic heterocyclic oxy group (e.g., pyridyloxy), (11) a 3- to 14-membered non-aromatic heterocyclic oxy group (e.g., morpholinyloxy, piperidinyloxy), (12) a C １－６ Alkyl-carbonyloxy group (e.g., acetoxy, propanoyloxy), (12) C ６－１４ Aryl-carbonyloxy groups (e.g., benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy), (13) C １－６ Alkoxy-carbonyloxy groups (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy), (14) mono- or di-C １－６ Alkyl-carbamoyloxy groups (e.g., methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy), (15) C ６－１４ (16) a 5- to 14-membered aromatic heterocyclylcarbonyloxy group (e.g., nicotinoyloxy), (17) a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group (e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy), (18) an optionally halogenated C １－６ Alkyl sulfonyloxy groups (e.g., methyl sulfonyloxy, trifluoromethyl sulfonyloxy), (19) C１－６ C optionally substituted with an alkyl group ６－１４ (20) an arylsulfonyloxy group (e.g., phenylsulfonyloxy, toluenesulfonyloxy), optionally halogenated C １－６ (21) an alkylthio group, (22) a 3- to 14-membered non-aromatic heterocyclic group, (23) a formyl group, (24) a carboxy group, (25) an optionally halogenated C １－６ alkyl-carbonyl group, (26) C ６－１４ (27) an aryl-carbonyl group, (28) a 3- to 14-membered non-aromatic heterocyclyl group, (29) C １－６ an alkoxy-carbonyl group, (30) C ６－１４ Aryloxy-carbonyl groups (e.g., phenyloxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl), (31) C ７－１６ an aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl), (32) a carbamoyl group, (33) a thiocarbamoyl group, (34) a mono- or di-C １－６ alkyl-carbamoyl group, (35) C ６－１４ (36) an aryl-carbamoyl group (e.g., phenylcarbamoyl), (37) a 3- to 14-membered non-aromatic heterocyclic carbamoyl group (e.g., morpholinylcarbamoyl, piperidinylcarbamoyl), (38) an optionally halogenated C １－６ an alkylsulfonyl group, (39) C ６－１４ (40) an arylsulfonyl group, (41) an optionally halogenated C １－６ an alkylsulfinyl group, (42) C ６－１４(43) an arylsulfinyl group (e.g., phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl), (44) an amino group, (45) a mono- or di-C １－６ alkylamino groups (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, N-ethyl-N-methylamino), (46) mono- or di-C ６－１４ (47) an arylamino group (e.g., phenylamino), (48) a 5- to 14-membered aromatic heterocyclic amino group (e.g., pyridylamino), ７－１６ (49) an aralkylamino group (e.g., benzylamino), (50) C １－６ Alkyl-carbonylamino group (e.g., acetylamino, propanoylamino, butanoylamino), (51) (C １－６ alkyl) (C １－６ alkyl-carbonyl)amino group (e.g., N-acetyl-N-methylamino), (52) C ６－１４ Aryl-carbonylamino group (e.g., phenylcarbonylamino, naphthylcarbonylamino), (53) C １－６ Alkoxycarbonylamino groups (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino), (54) C ７－１６ an aralkyloxy-carbonylamino group (e.g., benzyloxycarbonylamino), (55) C １－６ Alkyl sulfonylamino group (e.g., methyl sulfonyl amino, ethyl sulfonyl amino), (56) C １－６ C optionally substituted with an alkyl group ６－１４ (57) an arylsulfonylamino group (e.g., phenylsulfonylamino, toluenesulfonylamino), optionally halogenated C １－６ an alkyl group, (58) C ２－６ an alkenyl group, (59) C ２－６ an alkynyl group, (60) C ３－１０a cycloalkyl group, (61) C ３－１０ a cycloalkenyl group, and (62) C ６－１４ Aryl groups.

[0026] The number of the substituents in the "optionally substituted hydrocarbon group" is, for example, 1 to 5, preferably 1 to 3. When the number of substituents is 2 or more, the substituents may be the same or different. In this specification, examples of the "heterocyclic group" (including the "heterocyclic group" in the "optionally substituted heterocyclic group") include (i) an aromatic heterocyclic group, (ii) a non-aromatic heterocyclic group, and (iii) a 7- to 10-membered bridged heterocyclic group, each of which contains, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom.

[0027] In the present specification, examples of the "aromatic heterocyclic group" (including "5- to 14-membered aromatic heterocyclic group") include 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic groups containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom. Preferable examples of the "aromatic heterocyclic group" include 5- or 6-membered monocyclic aromatic heterocyclic groups such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl, etc.; Benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thia and 8- to 14-membered fused polycyclic (preferably bi- or tricyclic) aromatic heterocyclic groups such as pyrazolopyrimidinyl, pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl, isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl.

[0028] In the present specification, examples of the "non-aromatic heterocyclic group" (including "3- to 14-membered non-aromatic heterocyclic group") include 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocyclic groups containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom. Preferable examples of the "non-aromatic heterocyclic group" include aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydrofuranyl, tetrahydroisothiazolyl ... 3- to 8-membered monocyclic non-aromatic heterocyclic groups such as dihydroisoxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, diazocanyl, and the like; Dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolizinyl, indolinyl, isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl, tetrahydroquinoxalinyl, tetrahydrophenanthridinyl, hexyl and 9- to 14-membered fused polycyclic (preferably bi- or tricyclic) non-aromatic heterocyclic groups such as tetrahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl, tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl, tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacridinyl, tetrahydrophenazinyl, tetrahydrothioxanthenyl, and octahydroisoquinolyl.

[0029]

[0033] In the present specification, suitable examples of the "7- to 10-membered heterobridged ring group" include quinuclidinyl and 7-azabicyclo[2.2.1]heptanyl. In the present specification, the "nitrogen-containing heterocyclic group" includes, among "heterocyclic groups", those containing at least one nitrogen atom as a ring-constituting atom. In the present specification, the "optionally substituted heterocyclic group" includes, for example, a heterocyclic group which may have a substituent selected from the aforementioned substituent group A. The number of substituents in the "optionally substituted heterocyclic group" is, for example, 1 to 3. When the number of substituents is 2 or more, the respective substituents may be the same or different.

[0030] As used herein, the term "acyl group" refers to, for example, a halogen atom, an optionally halogenated C １－６ C, each of which may have 1 to 3 substituents selected from an alkoxy group, a hydroxy group, a nitro group, a cyano group, an amino group and a carbamoyl group; １－６ Alkyl group, C ２－６ Alkenyl group, C ３－１０ Cycloalkyl group, C ３－１０ Cycloalkenyl group, C ６－１４ Aryl group, C ７－１６ Examples of the "acyl group" include a formyl group, a carboxy group, a carbamoyl group, a thiocarbamoyl group, a sulfino group, a sulfo group, a sulfamoyl group, and a phosphono group, each of which optionally has one or two substituents selected from an aralkyl group, a 5- to 14-membered aromatic heterocyclic group, and a 3- to 14-membered non-aromatic heterocyclic group. In addition, examples of the "acyl group" also include a hydrocarbon-sulfonyl group, a heterocyclic-sulfonyl group, a hydrocarbon-sulfinyl group, and a heterocyclic-sulfinyl group. Here, the term "hydrocarbon-sulfonyl group" refers to a sulfonyl group having a hydrocarbon group bonded thereto, the term "heterocyclic-sulfonyl group" refers to a sulfonyl group having a heterocyclic group bonded thereto, the term "hydrocarbon-sulfinyl group" refers to a sulfinyl group having a hydrocarbon group bonded thereto, and the term "heterocyclic-sulfinyl group" refers to a sulfinyl group having a heterocyclic group bonded thereto. Preferred examples of the "acyl group" include a formyl group, a carboxy group, a C １－６ Alkyl-carbonyl group, C ２－６ Alkenyl-carbonyl group (e.g., crotonoyl), C３－１０ Cycloalkyl-carbonyl group (e.g., cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), C ３－１０ Cycloalkenyl-carbonyl group (e.g., 2-cyclohexenecarbonyl), C ６－１４ Aryl-carbonyl group, C ７－１６ aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclylcarbonyl group, 3- to 14-membered non-aromatic heterocyclylcarbonyl group, C １－６ Alkoxy-carbonyl group, C ６－１４ Aryloxy-carbonyl group (e.g., phenyloxycarbonyl, naphthyloxycarbonyl), C ７－１６ Aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl), carbamoyl group, mono- or di-C １－６ Alkyl-carbamoyl group, mono- or di-C ２－６ Alkenyl-carbamoyl group (e.g., diallylcarbamoyl), mono- or di-C ３－１０ Cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl), mono- or di-C ６－１４ Aryl-carbamoyl group (e.g., phenylcarbamoyl), mono- or di-C ７－１６ Aralkyl-carbamoyl group, 5- to 14-membered aromatic heterocyclic carbamoyl group (e.g., pyridylcarbamoyl), thiocarbamoyl group, mono- or di-C １－６ Alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), mono- or di-C ２－６ Alkenyl-thiocarbamoyl group (e.g., diallylthiocarbamoyl), mono- or di-C ３－１０ Cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C ６－１４ Aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl), mono- or di-C ７－１６aralkyl-thiocarbamoyl group (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), 5- to 14-membered aromatic heterocyclic thiocarbamoyl group (e.g., pyridylthiocarbamoyl), sulfino group, C １－６ Alkyl sulfinyl group (e.g., methyl sulfinyl, ethyl sulfinyl), sulfo group, C １－６ Alkylsulfonyl group, C ６－１４ Arylsulfonyl group, phosphono group, mono- or di-C １－６ Examples include alkylphosphono groups (e.g., dimethylphosphono, diethylphosphono, diisopropylphosphono, dibutylphosphono).

[0031] In the present specification, examples of the "optionally substituted amino group" include C １－６ Alkyl group, C ２－６ Alkenyl group, C ３－１０ Cycloalkyl group, C ６－１４ Aryl group, C ７－１６ Aralkyl group, C １－６ Alkyl-carbonyl group, C ６－１４ Aryl-carbonyl group, C ７－１６ aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclylcarbonyl group, 3- to 14-membered non-aromatic heterocyclylcarbonyl group, C １－６ Alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C １－６ Alkyl-carbamoyl group, mono- or di-C ７－１６ Aralkyl-carbamoyl group, C １－６ Alkylsulfonyl group and C ６－１４ and arylsulfonyl groups. Preferred examples of the optionally substituted amino group include an amino group, a mono- or di-(optionally halogenated C １－６ alkyl)amino group (e.g., methylamino, trifluoromethylamino, dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino), mono- or di-C ２－６ Alkenylamino group (e.g., diallylamino), mono- or di-C３－１０ Cycloalkylamino group (e.g., cyclopropylamino, cyclohexylamino), mono- or di-C ６－１４ Arylamino group (e.g., phenylamino), mono- or di-C ７－１６ Aralkylamino group (e.g., benzylamino, dibenzylamino), mono- or di-(optionally halogenated C １－６ alkyl)-carbonylamino group (e.g., acetylamino, propionylamino), mono- or di-C ６－１４ Aryl-carbonylamino group (e.g., benzoylamino), mono- or di-C ７－１６ Aralkyl-carbonylamino group (e.g., benzylcarbonylamino), mono- or di-5- to 14-membered aromatic heterocyclylcarbonylamino group (e.g., nicotinoylamino, isonicotinoylamino), mono- or di-3- to 14-membered non-aromatic heterocyclylcarbonylamino group (e.g., piperidinylcarbonylamino), mono- or di-C １－６ Alkoxy-carbonylamino group (e.g., tert-butoxycarbonylamino), 5- to 14-membered aromatic heterocyclic amino group (e.g., pyridylamino), carbamoylamino group, (mono- or di-C １－６ alkyl-carbamoyl)amino group (e.g., methylcarbamoylamino), (mono- or di-C ７－１６ aralkyl-carbamoyl)amino group (e.g., benzylcarbamoylamino), C １－６ Alkyl sulfonylamino group (e.g., methyl sulfonyl amino, ethyl sulfonyl amino), C ６－１４ Arylsulfonylamino group (e.g., phenylsulfonylamino), (C １－６ alkyl) (C １－６ alkyl-carbonyl)amino group (e.g., N-acetyl-N-methylamino), (C １－６ alkyl) (C ６－１４ and N-aryl-carbonyl)amino groups (eg, N-benzoyl-N-methylamino).

[0032] In the present specification, examples of the "optionally substituted carbamoyl group" include "a carbamoyl group which optionally has 1 to 3 substituents selected from substituent group A, each of which may have 1 to 3 substituents selected from substituent group A, C １－６Alkyl group, C ２－６ Alkenyl group, C ３－１０ Cycloalkyl group, C ６－１４ Aryl group, C ７－１６ Aralkyl group, C １－６ Alkyl-carbonyl group, C ６－１４ Aryl-carbonyl group, C ７－１６ aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclylcarbonyl group, 3- to 14-membered non-aromatic heterocyclylcarbonyl group, C １－６ Alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C １－６ Alkyl-carbamoyl group and mono- or di-C ７－１６ Examples of the optionally substituted carbamoyl group include a carbamoyl group which may have one or two substituents selected from an aralkyl-carbamoyl group. Preferred examples of the optionally substituted carbamoyl group include a carbamoyl group, a mono- or di-C １－６ Alkyl-carbamoyl group, mono- or di-C ２－６ Alkenyl-carbamoyl group (e.g., diallylcarbamoyl), mono- or di-C ３－１０ Cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl, cyclohexylcarbamoyl), mono- or di-C ６－１４ Aryl-carbamoyl group (e.g., phenylcarbamoyl), mono- or di-C ７－１６ Aralkyl-carbamoyl group, mono- or di-C １－６ Alkyl-carbonyl-carbamoyl group (e.g., acetylcarbamoyl, propionylcarbamoyl), mono- or di-C ６－１４ Examples thereof include aryl-carbonyl-carbamoyl groups (eg, benzoylcarbamoyl) and 5- to 14-membered aromatic heterocyclic carbamoyl groups (eg, pyridylcarbamoyl).

[0033] In the present specification, examples of the "optionally substituted thiocarbamoyl group" include "thiocarbamoyl groups each optionally having 1 to 3 substituents selected from substituent group A, C １－６ Alkyl group, C ２－６ Alkenyl group, C ３－１０ Cycloalkyl group, C ６－１４ Aryl group, C７－１６ Aralkyl group, C １－６ Alkyl-carbonyl group, C ６－１４ Aryl-carbonyl group, C ７－１６ aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclylcarbonyl group, 3- to 14-membered non-aromatic heterocyclylcarbonyl group, C １－６ Alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C １－６ Alkyl-carbamoyl group and mono- or di-C ７－１６ and aralkyl-carbamoyl groups. Preferred examples of the optionally substituted thiocarbamoyl group include a thiocarbamoyl group, a mono- or di-C １－６ Alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), mono- or di-C ２－６ Alkenyl-thiocarbamoyl group (e.g., diallylthiocarbamoyl), mono- or di-C ３－１０ Cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C ６－１４ Aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl), mono- or di-C ７－１６ Aralkyl-thiocarbamoyl group (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), mono- or di-C １－６ Alkyl-carbonyl-thiocarbamoyl group (e.g., acetylthiocarbamoyl, propionylthiocarbamoyl), mono- or di-C ６－１４ Examples thereof include aryl-carbonyl-thiocarbamoyl groups (eg, benzoylthiocarbamoyl) and 5- to 14-membered aromatic heterocyclic thiocarbamoyl groups (eg, pyridylthiocarbamoyl).

[0034] In the present specification, examples of the "optionally substituted sulfamoyl group" include "a sulfamoyl group which optionally has 1 to 3 substituents selected from substituent group A, each of which may have 1 to 3 substituents selected from substituent group C １－６Alkyl group, C ２－６ Alkenyl group, C ３－１０ Cycloalkyl group, C ６－１４ Aryl group, C ７－１６ Aralkyl group, C １－６ Alkyl-carbonyl group, C ６－１４ Aryl-carbonyl group, C ７－１６ aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclylcarbonyl group, 3- to 14-membered non-aromatic heterocyclylcarbonyl group, C １－６ Alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C １－６ Alkyl-carbamoyl group and mono- or di-C ７－１６ and a sulfamoyl group which may have one or two substituents selected from an aralkyl-carbamoyl group. Preferred examples of the optionally substituted sulfamoyl group include a sulfamoyl group, a mono- or di-C １－６ Alkyl-sulfamoyl group (e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl, N-ethyl-N-methylsulfamoyl), mono- or di-C ２－６ Alkenyl-sulfamoyl group (e.g., diallylsulfamoyl), mono- or di-C ３－１０ Cycloalkyl-sulfamoyl group (e.g., cyclopropylsulfamoyl, cyclohexylsulfamoyl), mono- or di-C ６－１４ Aryl-sulfamoyl group (e.g., phenylsulfamoyl), mono- or di-C ７－１６ Aralkyl-sulfamoyl group (e.g., benzylsulfamoyl, phenethylsulfamoyl), mono- or di-C １－６ Alkyl-carbonyl-sulfamoyl group (e.g., acetylsulfamoyl, propionylsulfamoyl), mono- or di-C ６－１４ Examples thereof include aryl-carbonyl-sulfamoyl groups (eg, benzoylsulfamoyl) and 5- to 14-membered aromatic heterocyclylsulfamoyl groups (eg, pyridylsulfamoyl).

[0035] In the present specification, examples of the "optionally substituted hydroxy group" include "a hydroxy group which may have 1 to 3 substituents selected from substituent group A, each of which may have 1 to 3 substituents selected from substituent group C １－６ Alkyl group, C ２－６ Alkenyl group, C ３－１０ Cycloalkyl group, C ６－１４ Aryl group, C ７－１６ Aralkyl group, C １－６ Alkyl-carbonyl group, C ６－１４ Aryl-carbonyl group, C ７－１６ aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclylcarbonyl group, 3- to 14-membered non-aromatic heterocyclylcarbonyl group, C １－６ Alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C １－６ Alkyl-carbamoyl group, mono- or di-C ７－１６ Aralkyl-carbamoyl group, C １－６ Alkylsulfonyl group and C ６－１４ A hydroxy group which may have a substituent selected from an arylsulfonyl group and an arylsulfonyl group is preferable. １－６ Alkoxy group, C ２－６ Alkenyloxy groups (e.g., allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy), C ３－１０ cycloalkyloxy group (e.g., cyclohexyloxy), C ６－１４ Aryloxy group (e.g., phenoxy, naphthyloxy), C ７－１６ Aralkyloxy group (e.g., benzyloxy, phenethyloxy), C １－６ Alkyl-carbonyloxy group (e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), C ６－１４ Aryl-carbonyloxy group (e.g., benzoyloxy), C ７－１６ Aralkyl-carbonyloxy group (e.g., benzylcarbonyloxy), 5- to 14-membered aromatic heterocyclylcarbonyloxy group (e.g., nicotinoyloxy), 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group (e.g., piperidinylcarbonyloxy), C １－６Alkoxy-carbonyloxy group (e.g., tert-butoxycarbonyloxy), 5- to 14-membered aromatic heterocyclic oxy group (e.g., pyridyloxy), carbamoyloxy group, C １－６ Alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy), C ７－１６ Aralkyl-carbamoyloxy group (e.g., benzylcarbamoyloxy), C １－６ Alkyl sulfonyloxy group (e.g., methyl sulfonyloxy, ethyl sulfonyloxy), C ６－１４ Examples include arylsulfonyloxy groups (e.g., phenylsulfonyloxy).

[0036] In the present specification, examples of the "optionally substituted sulfanyl group" include "a sulfanyl group which optionally has 1 to 3 substituents selected from substituent group A, each of which may have 1 to 3 substituents selected from substituent group A, C １－６ Alkyl group, C ２－６ Alkenyl group, C ３－１０ Cycloalkyl group, C ６－１４ Aryl group, C ７－１６ Aralkyl group, C １－６ Alkyl-carbonyl group, C ６－１４ Examples of the sulfanyl group that may have a substituent selected from an aryl-carbonyl group and a 5- to 14-membered aromatic heterocyclic group include a sulfanyl group and a halogenated sulfanyl group. Preferred examples of the sulfanyl group that may have a substituent include a sulfanyl (—SH) group, a C １－６ Alkylthio group, C ２－６ alkenylthio groups (e.g., allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), C ３－１０ cycloalkylthio group (e.g., cyclohexylthio), C ６－１４ Arylthio group (e.g., phenylthio, naphthylthio), C ７－１６ Aralkylthio groups (e.g., benzylthio, phenethylthio), C １－６ Alkyl-carbonylthio groups (e.g., acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), C ６－１４Examples thereof include aryl-carbonylthio groups (eg, benzoylthio), 5- to 14-membered aromatic heterocyclic thio groups (eg, pyridylthio), and halogenated thio groups (eg, pentafluorothio).

[0037] In the present specification, examples of the "optionally substituted silyl group" include "a silyl group which optionally has 1 to 3 substituents selected from substituent group A, C １－６ Alkyl group, C ２－６ Alkenyl group, C ３－１０ Cycloalkyl group, C ６－１４ Aryl groups and C ７－１６ and aralkyl groups. Preferred examples of the optionally substituted silyl groups include tri-C １－６ Examples include alkylsilyl groups (e.g., trimethylsilyl, tert-butyl(dimethyl)silyl). ３ H ７ )-,-CH(CH(CH ３ ) ２ )-,-(CH(CH ３ )) ２ -, -CH ２ -CH(CH ３ ) -, -CH(CH ３ )-CH ２ -, -CH ２ -CH ２ -C(CH ３ ) ２ -, -C(CH ３ ) ２ -CH ２ -CH ２ -, -CH ２ -CH ２ -CH ２ -C(CH ３ ) ２ -, -C(CH ３ ) ２ -CH ２ -CH ２ -CH ２ In the present specification, "C ２－６ Examples of the "alkenylene group" include -CH=CH-, -CH ２ -CH=CH-, -CH=CH-CH ２ -, -C(CH３ ) ２ -CH=CH-, -CH=CH-C(CH ３ ) ２ -, -CH ２ -CH=CH-CH ２ -, -CH ２ -CH ２ -CH=CH-, -CH=CH-CH ２ -CH ２ -, -CH=CH-CH=CH-, -CH=CH-CH ２ -CH ２ -CH ２ -, -CH ２ -CH ２ -CH ２ In the present specification, "C ２－６ Examples of the "alkynylene group" include -C≡C- and -CH ２ -C≡C-, -C≡C-CH ２ -, -C(CH ３ ) ２ -C≡C-, -C≡C-C(CH ３ ) ２ -, -CH ２ -C≡C-CH ２ -, -CH ２ -CH ２ -C≡C-, -C≡C-CH ２ -CH ２ -, -C≡C-C≡C-, -C≡C-CH ２ -CH ２ -CH ２ -, -CH ２ -CH ２ -CH ２ -C≡C- is an example.

[0038] In the present specification, examples of the "hydrocarbon ring" include C ６－１４ Aromatic hydrocarbon ring, C ３－１０ Cycloalkane, C ３－１０ In the present specification, "C ６－１４ Examples of the "aromatic hydrocarbon ring" include benzene and naphthalene. ３－１０Examples of "cycloalkane" include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane. ３－１０ Examples of "cycloalkene" include cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, and cyclooctene. In the present specification, examples of "heterocycle" include aromatic heterocycles and non-aromatic heterocycles each containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from nitrogen atoms, sulfur atoms, and oxygen atoms.

[0039] In the present specification, examples of the "aromatic heterocycle" include 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycles containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom. Preferable examples of the "aromatic heterocycle" include 5- or 6-membered monocyclic aromatic heterocycles such as thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, triazole, tetrazole, and triazine; Benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzotriazole, imidazopyridine, thienopyridine, furopyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazolopyridine, imidazopyrazine, imidazopyrimidine, thienopyrimidine, furopyrimidine, pyrrolopyrimidine, pyrazolopyrimidine, oxazolopyrimidine, thiazolopyrimidin and 8- to 14-membered fused polycyclic (preferably bi- or tricyclic) aromatic heterocycles such as benzophenone, pyrazolopyrimidine, pyrazolotriazine, naphtho[2,3-b]thiophene, phenoxathiin, indole, isoindole, 1H-indazole, purine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, β-carboline, phenanthridine, acridine, phenazine, phenothiazine, and phenoxazine.

[0040]

[0023] In the present specification, examples of the "non-aromatic heterocycle" include 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocycles containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. Preferable examples of the "non-aromatic heterocycle" include 3- to 8-membered monocyclic non-aromatic heterocycles such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline, pyrazolidine, thiazoline, thiazolidine, tetrahydroisothiazole, tetrahydrooxazole, tetrahydroisoxazole, piperidine, piperazine, tetrahydropyridine, dihydropyridine, dihydrothiopyran, tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, tetrahydropyran, tetrahydrothiopyran, morpholine, thiomorpholine, azepanine, diazepane, azepine, azocane, diazocane, and oxepane; Examples thereof include 9- to 14-membered fused polycyclic (preferably bi- or tricyclic) non-aromatic heterocycles such as dihydrobenzofuran, dihydrobenzimidazole, dihydrobenzoxazole, dihydrobenzothiazole, dihydrobenzisothiazole, dihydronaphtho[2,3-b]thiophene, tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinolizine, indoline, isoindoline, tetrahydrothieno[2,3-c]pyridine, tetrahydrobenzazepine, tetrahydroquinoxaline, tetrahydrophenanthridine, hexahydrophenothiazine, hexahydrophenoxazine, tetrahydrophthalazine, tetrahydronaphthyridine, tetrahydroquinazoline, tetrahydrocinnoline, tetrahydrocarbazole, tetrahydro-β-carboline, tetrahydroacridine, tetrahydrophenazine, tetrahydrothioxanthene, and octahydroisoquinoline. In the present specification, the "nitrogen-containing heterocycle" includes, among "heterocycles", those containing at least one nitrogen atom as a ring-constituting atom.

[0041] In the present specification, examples of the "aromatic ring" include "C ６－１４In the present specification, examples of the "aromatic ring group" include "C ６－１４ In the present specification, examples of the "ring" include "hydrocarbon ring (e.g., C ６－１４ Aromatic hydrocarbon ring, C ３－１０ Cycloalkane, C ３－１０ "cycloalkene" and "heterocycle (e.g., aromatic heterocycle, non-aromatic heterocycle)".

[0042] The definition of each symbol in compound (I) is described in detail below. Ring A represents an aromatic ring which may be further substituted. In one embodiment, the "aromatic ring" in the "optionally further substituted aromatic ring" of ring A is C ６－１４ It is an aromatic hydrocarbon ring (preferably a benzene ring), and the "aromatic ring" in the "optionally further substituted aromatic ring" of ring A may have 1 to 5 substituents at substitutable positions. The substituents are, for example, substituents selected from the above [Substituent group A]. When a plurality of each substituent is present, the respective substituents may be the same or different.

[0043] Ring A is preferably an optionally further substituted benzene ring, more preferably a benzene ring.

[0044] R １ represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkylthio group, or an optionally substituted alkoxy group. １ The "alkyl group" in the "optionally substituted alkyl group" is "C １－６ alkyl group." １ The "alkylthio group" in the "optionally substituted alkylthio group" includes "C １－６ alkylthio group." R １ The "alkoxy group" in the "optionally substituted alkoxy group" includes "C １－６ Alkoxy group" can be exemplified. R １The "alkyl group" of the "optionally substituted alkyl group", the "alkylthio group" of the "optionally substituted alkylthio group", and the "alkoxy group" of the "optionally substituted alkoxy group" each may have 1 to 3 substituents at substitutable positions. Examples of such substituents include those selected from the above [Substituent Group A]. When there are two or more substituents, the respective substituents may be the same or different.

[0045] R １ is preferably a hydrogen atom or an optionally substituted C １－６ an alkyl group (e.g., methyl), more preferably a hydrogen atom or C １－６ It is preferably an alkyl group (eg, methyl), and more preferably a hydrogen atom.

[0046] R ２ and R ３ each independently represents an optionally substituted alkyl group, or R ２ and R ３ R forms a ring together with the adjacent carbon atom which may be further substituted. ２ and R ３ The "alkyl group" in the "optionally substituted alkyl group" is "C １－６ The "alkyl group" in the "optionally substituted alkyl group" may have 1 to 3 substituents at substitutable positions. Examples of such substituents include those selected from the above [Substituent group A]. When there are two or more substituents, the respective substituents may be the same or different. R ２ and R ３ The "ring" in the "optionally further substituted ring" formed together with the adjacent carbon atom is "C ３－１０ The "ring" in the "optionally further substituted ring" may have 1 to 3 substituents at substitutable positions. Examples of such substituents include those selected from the above-mentioned [Substituent group A]. When there are two or more substituents, the respective substituents may be the same or different.

[0047] R ２ is preferably a hydrogen atom or an optionally substituted C １－６ an alkyl group (e.g., methyl), more preferably a hydrogen atom or C １－６ Alkyl groups (e.g., methyl), more preferably C １－６ R is an alkyl group (e.g., methyl). ３ is preferably a hydrogen atom or an optionally substituted C １－６ an alkyl group (e.g., methyl), more preferably a hydrogen atom or C １－６ Alkyl groups (e.g., methyl), more preferably C １－６ It is an alkyl group (e.g., methyl).

[0048] R ４ represents an optionally substituted aromatic ring group or an optionally substituted alkyl group. ４ The "aromatic ring group" in the "optionally substituted aromatic ring group" includes "C ６－１４ Examples of the "aromatic ring group" in the "optionally substituted aromatic ring group" include "aryl group" and "aromatic heterocyclic group". The "aromatic ring group" in the "optionally substituted aromatic ring group" may have 1 to 3 substituents at substitutable positions. Examples of such substituents include those selected from the above [Substituent group A]. When there are two or more substituents, the respective substituents may be the same or different. R ４ The "alkyl group" in the "optionally substituted alkyl group" is "C １－６ The "alkyl group" in the "optionally substituted alkyl group" may have 1 to 3 substituents at substitutable positions. Examples of such substituents include those selected from the above [Substituent group A]. When there are two or more substituents, the respective substituents may be the same or different.

[0049] R ４ are preferably each optionally substituted, C ６－１４ an aryl group (e.g., a phenyl group), a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., a pyridyl group, a thienyl group), or C １－６ It is an alkyl group (for example, an isopropyl group).

[0050] R４ is more preferably (a) a halogen atom (e.g., a fluorine atom, a chlorine atom), or (b) a C optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom, a chlorine atom). １－６ (c) an alkyl group (e.g., methyl, isopropyl), and (d) a C group optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atom, chlorine atom). １－６ each of which may be substituted with 1 or 2 substituents selected from the group consisting of an alkoxy group (e.g., methoxy), ６－１４ an aryl group (e.g., a phenyl group), a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., a pyridyl group, a thienyl group), or C １－６ It is an alkyl group (for example, an isopropyl group).

[0051] R ４ is more preferably (a) a halogen atom (e.g., a fluorine atom, a chlorine atom), and (b) a C optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom, a chlorine atom). １－６ an alkyl group (e.g., methyl, isopropyl), optionally substituted with 1 or 2 substituents selected from the group consisting of ６－１４ It is an aryl group (e.g., a phenyl group).

[0052] R ４ is even more preferably (a) a halogen atom (e.g., a chlorine atom), and (b) a C optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom). １－６ and a phenyl group substituted with one or two substituents selected from the group consisting of alkyl groups (e.g., methyl).

[0053] R ５ and R ６ R each independently represents a hydrogen atom or a halogen atom (e.g., a fluorine atom). ５ is preferably a hydrogen atom or a fluorine atom, more preferably a hydrogen atom. ６ is preferably a hydrogen atom or a fluorine atom, more preferably a hydrogen atom.

[0054] Preferred embodiments of compound (I) include the following compounds: [Compound A] Ring A is an optionally further substituted benzene ring; １ is a hydrogen atom or an optionally substituted C １－６ an alkyl group (e.g., methyl); R ２ a hydrogen atom or optionally substituted C １－６ an alkyl group (e.g., methyl); R ３ is a hydrogen atom or an optionally substituted C １－６ an alkyl group (e.g., methyl); R ４ is optionally substituted, C ６－１４ an aryl group (e.g., a phenyl group), an aromatic heterocyclic group (e.g., a pyridyl group, a thienyl group), or C １－６ an alkyl group (e.g., an isopropyl group); R ５ and R ６ are each independently a hydrogen atom or a halogen atom (e.g., fluorine).

[0055] [Compound A′] Ring A is a benzene ring; R １ is a hydrogen atom; R ２ But C １－６ an alkyl group (e.g., methyl); R ３ But C １－６ an alkyl group (e.g., methyl); R ４ (a) a halogen atom (e.g., a fluorine atom, a chlorine atom), (b) a C optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom, a chlorine atom), １－６ (c) an alkyl group (e.g., methyl, isopropyl), and (d) a C group optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atom, chlorine atom). １－６ each of which may be substituted with 1 or 2 substituents selected from the group consisting of an alkoxy group (e.g., methoxy), ６－１４ an aryl group (e.g., a phenyl group), a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., a pyridyl group, a thienyl group), or C １－６ an alkyl group (e.g., an isopropyl group); R ５ and R ６and each represent a hydrogen atom or a fluorine atom.

[0056] [Compound B] Ring A is a benzene ring; R １ is a hydrogen atom or C １－６ an alkyl group (e.g., methyl); R ２ is a hydrogen atom or C １－６ an alkyl group (e.g., methyl); R ３ is a hydrogen atom or C １－６ an alkyl group (e.g., methyl); R ４ (a) a halogen atom (e.g., a fluorine atom, a chlorine atom), (b) a C optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom, a chlorine atom), １－６ (c) an alkyl group (e.g., methyl, isopropyl), and (d) a C group optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atom, chlorine atom). １－６ each of which may be substituted with 1 or 2 substituents selected from the group consisting of an alkoxy group (e.g., methoxy), ６－１４ an aryl group (e.g., a phenyl group), a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., a pyridyl group, a thienyl group), or C １－６ an alkyl group (e.g., an isopropyl group); R ５ and R ６ and each represent a hydrogen atom.

[0057] [Compound C] Ring A is a benzene ring; R １ is a hydrogen atom or C １－６ an alkyl group (e.g., methyl); R ２ is a hydrogen atom or C １－６ an alkyl group (e.g., methyl); R ３ is a hydrogen atom or C １－６ an alkyl group (e.g., methyl); R ４ (a) a halogen atom (e.g., a fluorine atom, a chlorine atom), and (b) a C optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom, a chlorine atom), １－６ an alkyl group (e.g., isopropyl), optionally substituted with 1 or 2 substituents selected from the group consisting of ６－１４an aryl group (e.g., a phenyl group); R ５ and R ６ and each represent a hydrogen atom.

[0058] [Compound D] Ring A is a benzene ring; R １ is a hydrogen atom or C １－６ an alkyl group (e.g., methyl); R ２ is a hydrogen atom or C １－６ an alkyl group (e.g., methyl); R ３ is a hydrogen atom or C １－６ an alkyl group (e.g., methyl); R ４ is a phenyl group substituted with 1 or 2 halogen atoms (e.g., chlorine atoms); R ５ and R ６ and each represent a hydrogen atom.

[0059] [Compound E] Ring A is a benzene ring; R １ is a hydrogen atom; R ２ But C １－６ an alkyl group (e.g., methyl); R ３ But C １－６ an alkyl group (e.g., methyl); R ４ (a) a halogen atom (e.g., a chlorine atom) or (b) a C optionally substituted with 1 to 3 halogen atoms (e.g., a fluorine atom), １－６ R is one or two substituents selected from the group consisting of alkyl groups (e.g., methyl); ５ and R ６ and each represent a hydrogen atom.

[0060] Specific examples of compound (I) include the compounds of Examples 1 to 52 described below. Specific preferred examples of compound (I) include ((1S,5R)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hex-3-yl)((5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)methanone (Example 1) or a salt thereof; (1-(3,5-dichlorophenyl)-3-azabicyclo[3.1.0]hex-3-yl)((5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)methanone (Example 4) or a salt thereof; (1-(4-chloro-3-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hex-3-yl)((5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)methanone (Example 13) or a salt thereof; and the like.

[0061] When compound (I) is a salt, examples of such salts include salts with inorganic bases, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids.

[0062] Suitable examples of salts with inorganic bases include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts, magnesium salts and barium salts; and aluminum salts.

[0063] Suitable examples of salts with organic bases include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, and N,N'-dibenzylethylenediamine.

[0064] Suitable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.

[0065] Suitable examples of salts with organic acids include salts with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.

[0066] Suitable examples of salts with basic amino acids include salts with arginine, lysine, ornithine, etc.

[0067] Suitable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid, and the like.

[0068] Among these salts, pharmaceutically acceptable salts are preferred.

[0069] The method for producing compound (I) is explained below.

[0070] The raw materials and reagents used in each step of the following production methods, as well as the resulting compounds, may each form a salt. Examples of such salts include the same salts as those of Compound (I) described above.

[0071] When the compound obtained in each step is a free compound, it can be converted into the desired salt by a method known per se. Conversely, when the compound obtained in each step is a salt, it can be converted into the free form or another desired type of salt by a method known per se.

[0072] The compound obtained in each step can be used in the next reaction either as a reaction solution or as a crude product, or the compound obtained in each step can be isolated and / or purified from the reaction mixture by a separation means such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractional distillation, chromatography, etc., according to a conventional method.

[0073] When the raw materials and reagent compounds for each step are commercially available, the commercially available products can be used as they are.

[0074] In the reaction of each step, the reaction time may vary depending on the reagents and solvents used, but unless otherwise specified, it is usually 1 minute to 48 hours, preferably 10 minutes to 16 hours.

[0075] In the reactions of each step, the reaction temperature may vary depending on the reagents and solvents used, but is usually −78° C. to 300° C., preferably −78° C. to 150° C., unless otherwise specified.

[0076] In the reaction of each step, the pressure may vary depending on the reagents and solvents used, but unless otherwise specified, it is usually 1 atm to 20 atm, preferably 1 atm to 3 atm.

[0077] In the reactions of each step, a microwave synthesizer such as Initiator manufactured by Biotage may be used. The reaction temperature may vary depending on the reagents and solvent used, but unless otherwise specified, it is usually room temperature to 300°C, preferably 50°C to 250°C. The reaction time may vary depending on the reagents and solvent used, but unless otherwise specified, it is usually 1 minute to 48 hours, preferably 1 minute to 8 hours.

[0078] In the reactions of each step, unless otherwise specified, the reagent is used in an amount of 0.5 to 20 equivalents, preferably 0.8 to 5 equivalents, relative to the substrate. When a reagent is used as a catalyst, the reagent is used in an amount of 0.001 to 1 equivalent, preferably 0.01 to 0.2 equivalents, relative to the substrate. When a reagent also serves as a reaction solvent, the reagent is used in the amount of the solvent.

[0079] Unless otherwise specified, the reactions in each step are carried out without solvent or by dissolving or suspending the compounds in a suitable solvent. Specific examples of solvents include those described in the Examples, as well as the following: alcohols: methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol, etc.; ethers: diethyl ether, diphenyl ether, tetrahydrofuran, 1,2-dimethoxyethane, etc.; aromatic hydrocarbons: chlorobenzene, toluene, xylene, etc.; saturated hydrocarbons: cyclohexane, hexane, etc.; amides: N,N-dimethylformamide, N-methylpyrrolidone, etc.; halogenated hydrocarbons: dichloromethane, carbon tetrachloride, etc.; nitriles: acetonitrile, etc.; sulfoxides: dimethyl sulfoxide, etc.; aromatic organic bases: pyridine, etc.; acid anhydrides: acetic anhydride, etc.; organic acids: formic acid, acetic acid, trifluoroacetic acid, etc.; inorganic acids: hydrochloric acid, sulfuric acid, etc.; esters: ethyl acetate, etc.; ketones: acetone, methyl ethyl ketone, etc.; and water. The above solvents may be used by mixing two or more kinds in an appropriate ratio.

[0080] When a base is used in the reaction of each step, for example, the following bases or bases described in the Examples can be used: inorganic bases: sodium hydroxide, magnesium hydroxide, etc.; basic salts: sodium carbonate, calcium carbonate, sodium hydrogencarbonate, etc.; organic bases: triethylamine, diethylamine, pyridine, 4-dimethylaminopyridine, N,N-dimethylaniline, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-7-undecene, imidazole, piperidine, etc.; metal alkoxides: sodium ethoxide, potassium tert-butoxide, etc.; alkali metal hydrides: sodium hydride, etc.; metal amides: sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, etc.; organic lithiums: n-butyllithium, etc.

[0081] When an acid or an acidic catalyst is used in the reaction of each step, for example, the following acids or acidic catalysts or acids or acidic catalysts described in the Examples can be used: inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc.; organic acids: acetic acid, trifluoroacetic acid, citric acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc.; Lewis acids: boron trifluoride diethyl ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous iron chloride, etc.

[0082] Unless otherwise specified, the reactions in each step are carried out according to a method known per se, for example, those described in "Experimental Chemistry Lectures, 5th Edition, Vol. 13-19 (edited by the Chemical Society of Japan); "New Experimental Chemistry Lectures, Vol. 14-15 (edited by the Chemical Society of Japan); "Fine Organic Chemistry Revised 2nd Edition" (L. F. Tietze, Th. Eicher, Nankodo); "Revised Organic Named Reactions: Their Mechanisms and Key Points" (by Hideo Togo, Kodansha); "ORGANIC SYNTHESES Collective Volumes I-VII" (John Wiley & Sons Inc.); "Modern Organic Synthesis in the Laboratory: A Collection of Standard Experimental" (published by John Wiley & Sons Inc.); The synthesis is carried out in accordance with the methods described in "Comprehensive Heterocyclic Chemistry III, Vol. 1 to Vol. 14" (Elsevier Japan Co., Ltd.); "Strategies for Organic Synthesis Learned from Named Reactions" (translated and supervised by Kiyoshi Tomioka, published by Kagaku Dojin); "Comprehensive Organic Transformations" (VCH Publishers Inc.) 1989, or the methods described in the Examples.

[0083] In each step, the protection or deprotection reaction of a functional group is carried out according to a method known per se, for example, the method described in "Protective Groups in Organic Synthesis, 4th Ed." (Theodora W. Greene, Peter G. M. Wuts), published by Wiley-Interscience in 2007; "Protecting Groups 3rd Ed." (P. J. Kocienski), published by Thieme in 2004, or the method described in the Examples. Examples of the protecting group for the hydroxyl group of an alcohol or the like or a phenolic hydroxyl group include ether-type protecting groups such as methoxymethyl ether, benzyl ether, t-butyldimethylsilyl ether, and tetrahydropyranyl ether; carboxylic acid ester-type protecting groups such as acetate ester; sulfonic acid ester-type protecting groups such as methanesulfonate ester; and carbonate-type protecting groups such as t-butyl carbonate.

[0084] Examples of the protecting group for the carbonyl group of an aldehyde include acetal-type protecting groups such as dimethyl acetal; and cyclic acetal-type protecting groups such as cyclic 1,3-dioxane.

[0085] Examples of the protecting group for the carbonyl group of a ketone include ketal-type protecting groups such as dimethyl ketal; cyclic ketal-type protecting groups such as cyclic 1,3-dioxane; oxime-type protecting groups such as O-methyloxime; and hydrazone-type protecting groups such as N,N-dimethylhydrazone.

[0086] Examples of the protecting group for a carboxyl group include ester-type protecting groups such as methyl ester, and amide-type protecting groups such as N,N-dimethylamide. Examples of the protecting group for a thiol group include ether-type protecting groups such as benzylthioether, and ester-type protecting groups such as thioacetate, thiocarbonate, and thiocarbamate.

[0087] Examples of the protecting group for an amino group or an aromatic heterocycle such as imidazole, pyrrole, or indole include carbamate-type protecting groups such as benzylcarbamate; amide-type protecting groups such as acetamide; alkylamine-type protecting groups such as N-triphenylmethylamine; and sulfonamide-type protecting groups such as methanesulfonamide.

[0088] The protecting group can be removed by a method known per se, for example, a method using an acid, a base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, or a trialkylsilyl halide (e.g., trimethylsilyl iodide, trimethylsilyl bromide), or a reduction method.

[0089] When a reduction reaction is carried out in each step, examples of the reducing agent to be used include metal hydrides such as lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), sodium borohydride, and tetramethylammonium triacetoxyborohydride; boranes such as borane tetrahydrofuran complex; Raney nickel; Raney cobalt; hydrogen; formic acid; etc. When a carbon-carbon double bond or triple bond is reduced, a method using a catalyst such as palladium-carbon or Lindlar's catalyst may be used.

[0090] When an oxidation reaction is carried out in each step, examples of the oxidizing agent to be used include peracids such as m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, and t-butyl hydroperoxide; perchlorates such as tetrabutylammonium perchlorate; chlorates such as sodium chlorate; chlorites such as sodium chlorite; periodates such as sodium periodate; high-valent iodine reagents such as iodosylbenzene; manganese-containing reagents such as manganese dioxide and potassium permanganate; lead compounds such as lead tetraacetate; chromium-containing reagents such as pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), and Jones reagent; halogen compounds such as N-bromosuccinimide (NBS); oxygen; ozone; sulfur trioxide-pyridine complex; osmium tetroxide; zelene dioxide; and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).

[0091] When a radical cyclization reaction is carried out in each step, examples of the radical initiator used include azo compounds such as azobisisobutyronitrile (AIBN), water-soluble radical initiators such as 4-4'-azobis-4-cyanopentanoic acid (ACPA), triethylboron in the presence of air or oxygen, benzoyl peroxide, etc. Examples of the radical reaction reagent used include tributylstannane, tristrimethylsilylsilane, 1,1,2,2-tetraphenyldisilane, diphenylsilane, samarium iodide, etc.

[0092] When a Wittig reaction is carried out in each step, examples of the Wittig reagent used include alkylidenephosphoranes, etc. The alkylidenephosphoranes can be prepared by a method known per se, for example, by reacting a phosphonium salt with a strong base.

[0093] When Horner-Emmons reaction is carried out in each step, examples of the reagent to be used include phosphonoacetates such as methyl dimethylphosphonoacetate and ethyl diethylphosphonoacetate; and bases such as alkali metal hydrides and organolithium compounds.

[0094] When the Friedel-Crafts reaction is carried out in each step, the reagents used include a Lewis acid and an acid chloride or an alkylating agent (e.g., alkyl halides, alcohols, olefins, etc.). Alternatively, an organic acid or an inorganic acid can be used instead of the Lewis acid, and an acid anhydride such as acetic anhydride can be used instead of the acid chloride.

[0095] In each step, when an aromatic nucleophilic substitution reaction is carried out, a nucleophile (e.g., amines, imidazole, etc.) and a base (e.g., basic salts, organic bases, etc.) are used as reagents.

[0096] In each step, when a nucleophilic addition reaction by a carbanion, a nucleophilic 1,4-addition reaction (Michael addition reaction) by a carbanion, or a nucleophilic substitution reaction by a carbanion is carried out, examples of the base used to generate the carbanion include organolithiums, metal alkoxides, inorganic bases, and organic bases.

[0097] When a Grignard reaction is carried out in each step, examples of the Grignard reagent include arylmagnesium halides such as phenylmagnesium bromide, and alkylmagnesium halides such as methylmagnesium bromide. The Grignard reagent can be prepared by a method known per se, for example, by reacting an alkyl halide or aryl halide with metallic magnesium using ether or tetrahydrofuran as a solvent.

[0098] In each step, when a Knoevenagel condensation reaction is carried out, an active methylene compound sandwiched between two electron-withdrawing groups (e.g., malonic acid, diethyl malonate, malononitrile etc.) and a base (e.g., organic bases, metal alkoxides, inorganic bases) are used as reagents.

[0099] When the Vilsmeier-Haack reaction is carried out in each step, phosphoryl chloride and an amide derivative (eg, N,N-dimethylformamide, etc.) are used as reagents.

[0100] In each step, when an azidation reaction of alcohols, alkyl halides, or sulfonate esters is carried out, examples of the azidation agent used include diphenylphosphoryl azide (DPPA), trimethylsilyl azide, sodium azide, etc. For example, when an alcohol is azidated, there are methods using diphenylphosphoryl azide and 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) and methods using trimethylsilyl azide and a Lewis acid.

[0101] When a reductive amination reaction is carried out in each step, examples of the reducing agent used include sodium triacetoxyborohydride, sodium cyanoborohydride, hydrogen, formic acid, etc. When the substrate is an amine compound, examples of the carbonyl compound used include paraformaldehyde, as well as aldehydes such as acetaldehyde, and ketones such as cyclohexanone. When the substrate is a carbonyl compound, examples of the amines used include ammonia, primary amines such as methylamine, and secondary amines such as dimethylamine.

[0102] When Mitsunobu reaction is carried out in each step, an azodicarboxylic acid ester (eg, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), etc.) and triphenylphosphine are used as reagents.

[0103] In each step, when an esterification reaction, an amidation reaction, or a urea reaction is carried out, examples of the reagent to be used include acyl halides such as acid chlorides and acid bromides; and activated carboxylic acids such as acid anhydrides, activated esters, and sulfates. Examples of activators for carboxylic acids include carbodiimide-based condensing agents such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD); triazine-based condensing agents such as 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride-n-hydrate (DMT-MM); carbonate-based condensing agents such as 1,1-carbonyldiimidazole (CDI); diphenylphosphoric acid azide (DPPA); benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent); 2-chloro-1-methyl-pyridinium iodide (Mukaiyama reagent); thionyl chloride; lower alkyl haloformates such as ethyl chloroformate; O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU); sulfuric acid; or combinations thereof. When a carbodiimide-based condensing agent is used, an additive such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), or dimethylaminopyridine (DMAP) may be further added to the reaction.

[0104] When a coupling reaction is carried out in each step, examples of the metal catalyst to be used include palladium compounds such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), dichlorobis(triethylphosphine)palladium(II), tris(dibenzylideneacetone)dipalladium(0), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride, and palladium(II) acetate; nickel compounds such as tetrakis(triphenylphosphine)nickel(0); rhodium compounds such as tris(triphenylphosphine)rhodium(III) chloride; cobalt compounds; copper compounds such as copper oxide and copper(I) iodide; platinum compounds; and the like. A base may also be added to the reaction, and examples of such a base include inorganic bases and basic salts.

[0105] When a thiocarbonylation reaction is carried out in each step, diphosphorus pentasulfide is typically used as the thiocarbonylating agent. However, in addition to diphosphorus pentasulfide, a reagent having a 1,3,2,4-dithiadiphosphetane-2,4-disulfide structure, such as 2,4-bis(4-methoxyphenyl-1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lowesson's reagent) may also be used.

[0106] When the Wohl-Ziegler reaction is carried out in each step, examples of the halogenating agent used include N-iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, sulfuryl chloride, etc. Furthermore, the reaction can be accelerated by adding a radical initiator such as heat, light, benzoyl peroxide, or azobisisobutyronitrile to the reaction.

[0107] When a halogenation reaction of a hydroxy group is carried out in each step, examples of the halogenating agent used include hydrohalic acid and acid halides of inorganic acids, specifically, for chlorination, hydrochloric acid, thionyl chloride, phosphorus oxychloride, etc., and for bromination, 48% hydrobromic acid, etc., may be used. Alternatively, a method may be used in which an alkyl halide is obtained from an alcohol by the reaction of triphenylphosphine with carbon tetrachloride or carbon tetrabromide, etc. Alternatively, a method may be used in which an alkyl halide is synthesized via a two-step reaction, in which an alcohol is converted into a sulfonic acid ester and then reacted with lithium bromide, lithium chloride, or sodium iodide.

[0108] When Arbuzov reaction is carried out in each step, examples of the reagent to be used include alkyl halides such as ethyl bromoacetate and the like; and phosphites such as triethyl phosphite, tri(isopropyl) phosphite and the like.

[0109] When a sulfone esterification reaction is carried out in each step, examples of the sulfonating agent to be used include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonic anhydride, and the like.

[0110] In each step, when a hydrolysis reaction is carried out, an acid or a base is used as a reagent. When an acid hydrolysis reaction of a t-butyl ester is carried out, formic acid, triethylsilane, or the like may be added to reductively trap the by-product t-butyl cation.

[0111] When a dehydration reaction is carried out in each step, examples of the dehydrating agent to be used include sulfuric acid, diphosphorus pentoxide, phosphorus oxychloride, N,N'-dicyclohexylcarbodiimide, alumina, polyphosphoric acid, and the like.

[0112] [Reaction Scheme 1] Compound (1) can be produced by an amidation reaction using compounds (2) and (3).

[0113] In the formula, the symbols have the same meanings as defined above.

[0114] Compounds (2) and (3) can be prepared using commercially available reagents or by known methods.

[0115] [Reaction Scheme 2] Compound (3-1) can be produced from compounds (4) and (5) by the following method.

[0116] In the formula, R 7 indicates a protecting group for an amino group, and the other symbols have the same meanings as above.

[0117] The compound (3-1) can be produced by activating the compound (7) with thionyl chloride or the like, followed by a cyclization reaction with a base.

[0118] Compound (3-1) can also be produced by deprotecting (8-1), which is produced by protecting the crude product of (3-1). Compounds (4) and (5) can be produced using commercially available reagents or by methods known per se.

[0119] [Reaction Scheme 3] Compound (3-2) can be produced from compound (9), compound (10), or compound (12) and compound (13) by the following method.

[0120] In the formula, X is chlorine, bromine, iodine or triflate, M is an optionally substituted metal, and the other symbols are as defined above.

[0121] Compound (14) can be produced by activating compound (11) with methanesulfonyl chloride or the like, followed by dehydration reaction with a base.

[0122] Compound (14) can also be produced by a coupling reaction of compound (12) and compound (13).

[0123] Compound (8-2) can be produced by subjecting compound (14) to a difluoromethylcyclopropanation reaction. Examples of the difluoromethylcyclopropanation agent include a combination of (trifluoromethyl)trimethylsilane and sodium iodide.

[0124] Compounds (9), (10), (12) and (13) can be prepared using commercially available reagents or by known methods.

[0125] When compound (I) contains optical isomers, stereoisomers, positional isomers, or rotational isomers, these are also included in compound (I), and each can be obtained as a single product by a synthesis method or separation method known per se (e.g., concentration, solvent extraction, column chromatography, recrystallization, etc.). For example, when compound (I) contains optical isomers, optical isomers resolved from the compound are also encompassed in compound (I).

[0126] Optical isomers can be produced by methods known per se, specifically by using optically active synthetic intermediates or by optically resolving the final racemic compound in accordance with a conventional method.

[0127] As the optical resolution method, a method known per se, for example, fractional recrystallization, chiral column method, diastereomer method, etc., can be used.

[0128] 1) Fractional recrystallization method: A salt is formed between a racemate and an optically active compound (for example, (+)-mandelic acid, (-)-mandelic acid, (+)-tartaric acid, (-)-tartaric acid, (+)-1-phenethylamine, (-)-1-phenethylamine, cinchonine, (-)-cinchonidine, brucine, etc.), which is then separated by fractional recrystallization, and, if desired, a neutralization step is carried out to obtain the free optical isomer.

[0129] 2) Chiral Column Method: This method involves separating a racemate or a salt thereof through a column for separating optical isomers (chiral column). For example, in the case of liquid chromatography, a mixture of optical isomers is added to a chiral column such as ENANTIO-OVM (manufactured by Tosoh Corporation) or the CHIRAL series (manufactured by Daicel Chemical Industries, Ltd.), and the optical isomers are separated by developing the mixture with water, various buffer solutions (e.g., phosphate buffer, etc.), organic solvents (e.g., ethanol, methanol, 2-propanol, acetonitrile, trifluoroacetic acid, diethylamine, etc.), either alone or in combination. Alternatively, in the case of gas chromatography, separation is performed using a chiral column such as CP-Chirasil-DeX CB (manufactured by GL Sciences, Inc.).

[0130] 3) Diastereomeric Method: A racemic mixture is chemically reacted with an optically active reagent to produce a mixture of diastereomers, which is then separated into a single substance by conventional separation techniques (e.g., fractional recrystallization, chromatography, etc.), followed by chemical treatment such as hydrolysis to separate the optically active reagent moiety, thereby obtaining optical isomers. For example, when compound (I) contains a hydroxyl or primary or secondary amino group in the molecule, the compound can be condensed with an optically active organic acid (e.g., MTPA [α-methoxy-α-(trifluoromethyl)phenylacetic acid], (-)-menthoxyacetic acid, etc.) to obtain the respective ester or amide diastereomers. On the other hand, when compound (I) contains a carboxyl group, the compound can be condensed with an optically active amine or alcohol reagent to obtain the respective amide or ester diastereomers. The separated diastereomers can be converted to the optical isomers of the original compound by acid hydrolysis or basic hydrolysis.

[0131] Compound (I) may be in the form of a crystal. The crystal of compound (I) can be produced by crystallizing compound (I) using a crystallization method known per se.

[0132] Examples of the crystallization method include crystallization from a solution, crystallization from vapor, and crystallization from a melt.

[0133] A typical "crystallization method from solution" involves changing a factor related to the solubility of the compound (e.g., solvent composition, pH, temperature, ionic strength, redox state, etc.) or the amount of solvent to transition from a non-saturated state to a supersaturated state. Specific examples include concentration, slow cooling, reaction methods (diffusion, electrolysis), hydrothermal growth, and fluxing. Examples of solvents that can be used include aromatic hydrocarbons (e.g., benzene, toluene, xylene, etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform, etc.), saturated hydrocarbons (e.g., hexane, heptane, cyclohexane, etc.), ethers (e.g., diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, etc.), nitriles (e.g., acetonitrile, etc.), ketones (e.g., acetone, etc.), sulfoxides (e.g., dimethyl sulfoxide, etc.), acid amides (e.g., N,N-dimethylformamide, etc.), esters (e.g., ethyl acetate, etc.), alcohols (e.g., methanol, ethanol, 2-propanol, etc.), and water. These solvents may be used alone or in combination in an appropriate ratio (for example, 1:1 to 1:100 (volume ratio)). Seed crystals may also be used if necessary.

[0134] Examples of the "crystallization method from vapor" include vaporization methods (sealed tube method, gas flow method), vapor phase reaction methods, chemical transport methods, and the like.

[0135] Examples of the "crystallization method from a melt" include normal freezing methods (pulling method, temperature gradient method, Bridgman method), zone melting methods (zone leveling method, float zone method), and special growth methods (VLS method, liquid phase epitaxy method).

[0136] A preferred example of the crystallization method includes a method in which compound (I) is dissolved in a suitable solvent (e.g., alcohols such as methanol and ethanol) at a temperature of 20 to 120°C, and the resulting solution is cooled to a temperature equal to or lower than the temperature at which the compound (I) was dissolved (e.g., 0 to 50°C, preferably 0 to 20°C).

[0137] The crystals of the present invention thus obtained can be isolated, for example, by filtration.

[0138] The crystals thus obtained are generally analyzed by powder X-ray diffraction. Furthermore, methods for determining the crystal orientation include mechanical and optical methods.

[0139] The crystals of Compound (I) obtained by the above production method are expected to be highly pure, high quality, and low hygroscopic, and to be stable even when stored for a long period under normal conditions. Furthermore, they are also excellent in biological properties (e.g., pharmacokinetics (absorbability, distribution, metabolism, excretion), efficacy, etc.), and may be useful as a pharmaceutical.

[0140] A prodrug of compound (I) refers to a compound that is converted to compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in a living body, i.e., a compound that is converted to compound (I) by enzymatic oxidation, reduction, hydrolysis, or the like, or a compound that is converted to compound (I) by hydrolysis, or the like, with gastric acid, or the like. Examples of prodrugs of compound (I) include compounds in which the amino group of compound (I) is acylated, alkylated, or phosphorylated [e.g., compounds in which the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, or tert-butylated, etc.]; compounds in which the hydroxyl group of compound (I) is acylated, alkylated, phosphorylated, or borated [e.g., compounds in which the hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, etc.]; compounds in which the carboxyl group of compound (I) is esterified or amidated (e.g., compounds in which the carboxyl group of compound (I) is ethyl-esterified, phenyl-esterified, carboxymethyl-esterified, dimethylaminomethyl-esterified, pivaloyloxymethyl-esterified, ethoxycarbonyloxyethyl-esterified, phthalidyl-esterified, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl-esterified, cyclohexyloxycarbonylethyl-esterified, methylamidized, etc.). These compounds can be produced from compound (I) by methods known per se.

[0141] Furthermore, the prodrug of compound (I) may be one that is converted into compound (I) under physiological conditions, as described in "Drug Development," Vol. 7, Molecular Design, pp. 163 to 198, Hirokawa Publishing, 1990.

[0142] In the present specification, compound (I) and a prodrug of compound (I) may be collectively referred to as "the compound of the present invention."

[0143] Compound (I) may be a non-solvate or a solvate. The solvent of the solvate may be a solvent such as ethanol or water. A solvate in which the solvent incorporated is water is a hydrate. Hydrates include stoichiometric hydrates as well as those containing various amounts of water.

[0144] Compound (I) may contain an isotope (e.g., ３ H. １３ C. １４ C. １８ F. ３５ S. １２５ I), and the isotope-labeled or substituted compound can be used, for example, as a tracer (PET tracer) used in positron emission tomography (PET), and can be useful in fields such as medical diagnosis.

[0145] moreover, １ H ２ Compound (I) also encompasses deuterium-converted derivatives converted to H(D). Compound (I) also encompasses tautomers.

[0146] Compound (I) may be a pharmaceutically acceptable cocrystal or cocrystal salt. Here, a cocrystal or cocrystal salt refers to a crystalline substance composed of two or more distinct solids at room temperature, each having different physical properties (e.g., structure, melting point, heat of fusion, hygroscopicity, solubility, stability, etc.). A cocrystal or cocrystal salt can be produced by a cocrystallization method known per se.

[0147] Compound (I) has a potent antagonistic effect on calcium-sensing receptors.

[0148] Compound (I) has low toxicity and can be safely administered to mammals (for example, humans, rats, mice, dogs, rabbits, cats, cows, horses, pigs, etc.).

[0149] Therefore, a pharmaceutical comprising the compound of the present invention is a calcium-sensing receptor antagonist, and is expected to be useful in the prevention or treatment of diseases associated with calcium-sensing receptors, such as heart failure; pulmonary hypertension; hyperthyroidism; hypocalcemia; bone and joint diseases (e.g., postmenopausal osteoporosis, senile osteoporosis, secondary osteoporosis, osteomalacia, renal osteodystrophy, fractures, osteoarthritis, rheumatoid arthritis, osteosarcoma, and myeloma); and central nervous system diseases.

[0150] The preventive or therapeutic use of the compounds of the present invention for heart failure will now be described in more detail.

[0151] The clinical state of heart failure is classified by the New York Heart Association (NYHA) into four stages according to severity, as shown in Table 1.

[0152]

[0153] In addition, the AHA / ACC stage classification (American Heart Association / American College of Cardiology) classifies the severity into four stages as shown in Table 2.

[0154]

[0155] The correspondence between the NYHA classification and the AHA / ACC stage classification is generally as shown in Table 3 below.

[0156]

[0157] The compounds of the present invention can also be used as prophylactic or therapeutic agents for heart failure, reduced cardiac output, ischemic or non-ischemic heart failure, decompensated heart failure, acute heart failure, and acute decompensated heart failure, as determined by the above-mentioned reports. The compounds of the present invention can also be used to improve reduced ejection fraction or increase ejection fraction in subjects with heart failure. The compounds of the present invention can also suppress the deterioration or progression of cardiac function in subjects with heart failure. The compounds of the present invention can also reduce cardiac load, suppress cardiac hypertrophy, suppress interstitial fibrosis, and suppress increased apoptosis in subjects with heart failure.

[0158] The preventive or therapeutic use of the compounds of the present invention for pulmonary hypertension will now be described in more detail.

[0159] The criteria for diagnosing pulmonary hypertension are described, for example, in the Pulmonary Hypertension Treatment Guidelines (revised 2012 edition) by the Japanese Circulation Society.

[0160] Pulmonary hypertension in humans is usually diagnosed based on mean pulmonary artery pressure (mean PAP) measured by right heart catheterization at rest, and pulmonary hypertension can be diagnosed when the mean pulmonary artery pressure is 25 mmHg or higher. Recent advances in echocardiography have made it possible to estimate pulmonary artery pressure noninvasively, and pulmonary hypertension can sometimes be diagnosed based on the estimated pulmonary artery pressure.

[0161] Pulmonary hypertension is clinically classified into five groups, from Group 1 to Group 5, according to the Dana Point classification. Group 1 is pulmonary arterial hypertension (PAH), Group 2 is pulmonary hypertension associated with left ventricular heart disease, Group 3 is pulmonary hypertension associated with lung disease and / or hypoxemia, Group 4 is chronic thromboembolic pulmonary hypertension, and Group 5 is pulmonary hypertension due to unspecified multiple factors. Subtypes of Group 1 are known as Group 1' (pulmonary venous embolic disease and / or pulmonary capillary hemangiomatosis) and Group 1'' (persistent pulmonary hypertension of the newborn).

[0162] Group 1 pulmonary arterial hypertension is the most typical type of pulmonary hypertension, and is broadly divided into idiopathic PAH, hereditary PAH, drug / toxin-induced PAH, and PAH associated with various diseases.

[0163] The compound of the present invention can be used as a preventive or therapeutic agent for pulmonary hypertension as determined by the above-mentioned reports, and can also reduce pulmonary arterial pressure in a subject, thereby improving various symptoms associated with pulmonary hypertension (such as increased right ventricular pressure).

[0164] The compound of the present invention can be used for the prevention or treatment of heart diseases such as cardiomyopathy and arrhythmia.

[0165] The compound of the present invention can be used as a preventive or therapeutic agent for myocardial hypertrophy, myocardial remodeling, myocardial cell damage, arrhythmia, cardiac pump dysfunction and sudden death in the following cardiomyopathies.

[0166] There are several classification methods for cardiomyopathies, including those proposed by (i) WHO / ISFC (1995), (ii) American Heart Association (AHA, 2006), and (iii) European Society of Cardiology (ESC, 2008). Details of the types of cardiomyopathies are given below.

[0167] (i) WHO / ISFC 1995 proposal (Table 4) The WHO / ISFC (1995) proposal defines cardiomyopathy as "myocardial disease accompanied by cardiac dysfunction." Based on clinical pathology, cardiomyopathy is classified into 1) dilated cardiomyopathy, 2) hypertrophic cardiomyopathy, 3) restrictive cardiomyopathy, 4) arrhythmogenic right ventricular cardiomyopathy, and 5) unclassifiable cardiomyopathy. On the other hand, myocardial diseases with a clear cause or association with systemic disease are classified as specific cardiomyopathy. Specific cardiomyopathy includes cardiomyopathy associated with ischemic (angina pectoris, myocardial infarction, etc.), valvular (valvular heart disease, etc.), hypertensive, inflammatory (infectious, myocarditis, etc.), metabolic (endocrine diseases such as thyroid dysfunction and adrenal insufficiency, amyloidosis, nutritional disorders, glycogen storage disease, and inherited metabolic disorders such as Fabry disease), hypersensitivity / toxicity (alcoholic cardiomyopathy, drug-induced, radiation-induced, etc.), postpartum (poor health during pregnancy and childbirth), muscular dystrophy (tonic muscular atrophy, etc.), neuromuscular diseases (Noonan syndrome, Friedreich's ataxia, etc.), and systemic diseases (collagen disease, sarcoidosis, rheumatoid arthritis, scleroderma, etc.).

[0168]

[0169] (ii) Proposal by the American College of Cardiology (AHA, 2006) (Table 5) The AHA (2006) proposal defines cardiomyopathy as "a diverse group of disorders involving organic or electrophysiological dysfunction of the myocardium, often resulting in inappropriate ventricular hypertrophy or dilation, with a wide range of causes, frequently resulting from genetic abnormalities" (Definition and Classification of Cardiomyopathy (AHA Proposal) (Table 5)). Depending on the location of the lesion, cardiomyopathy is classified as primary when the lesion is primarily located in the heart, and as secondary when the myocardial lesion is related to a systemic disease. Primary cardiomyopathy is further classified into three types: hereditary, acquired, and mixed. Genetic cardiomyopathy includes hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, left ventricular noncompaction, glycogen storage diseases (PPKA2, Danon disease), conduction abnormalities, mitochondrial cardiomyopathy, and ion channelopathies (long QT syndrome, Vulgata syndrome, short QT syndrome, catecholaminergic polymorphic ventricular tachycardia, and Asian SUNDS (sudden nocturnal death syndrome)). Acquired cardiomyopathy includes inflammatory (myocarditis), stress-induced (takotsubo cardiomyopathy), postpartum, tachycardia-induced, and infant cardiomyopathy of insulin-dependent mothers. Mixed cardiomyopathy includes dilated cardiomyopathy and restrictive cardiomyopathy (without left ventricular hypertrophy or dilation).

[0170]

[0171] (iii) Proposal by the European Society of Cardiology (ESC, 2008) (Table 6) The ESC (2008) proposal defines cardiomyopathy as "myocardial diseases associated with structural or functional abnormalities of the myocardium that are not due to coronary artery disease, hypertension, valvular disease, or congenital heart disease" (Table 6). Similar to the WHO / ISFC classification, cardiomyopathy is broadly classified into five types: 1) dilated cardiomyopathy, 2) hypertrophic cardiomyopathy, 3) restrictive cardiomyopathy, 4) arrhythmogenic right ventricular cardiomyopathy, and 5) unclassifiable cardiomyopathy. Similar to the AHA classification, the concept of hereditary / non-hereditary is introduced, and these diseases are classified into two groups: familial / hereditary and non-familial / non-hereditary.

[0172]

[0173] The compound of the present invention can be used as an agent for preventing or treating the following arrhythmias and sudden death associated with arrhythmia.

[0174] Arrhythmias are broadly classified into bradyarrhythmia and tachyarrhythmia based on their symptoms. The mechanism of arrhythmia is believed to be mainly (i) abnormal impulse generation and (ii) abnormal impulse conduction (excitation conduction abnormality) due to myocardial damage. When myocardium is damaged due to various causes (genetic predisposition, environmental stress, etc.), areas of the myocardium where electrical signals are easily transmitted or where abnormal excitation occurs are created, resulting in arrhythmia.

[0175] Arrhythmias can also be classified according to their mechanism of occurrence (cause): (i) Types and main causes of arrhythmias caused by abnormal stimulus generation: Sinus bradycardia (main causes include myocardial infarction, sick sinus syndrome, hypothyroidism, severe jaundice, drugs such as digoxin, beta-blockers, and calcium channel blockers, increased intracranial pressure, and idiopathic causes); Atrial premature contractions (main causes include hypertensive heart disease, angina pectoris, myocardial infarction, valvular heart disease, cardiomyopathy, myocarditis, heart failure, congenital heart disease, lung disease, hyperthyroidism, drugs such as bronchodilators and catecholamines, and idiopathic causes); Paroxysmal supraventricular tachycardia (main causes include hyperthyroidism, hypertensive heart disease, drugs such as atropine, and idiopathic causes).・Atrial fibrillation (major causes include mitral valve stenosis, hyperthyroidism, ischemic heart disease, increased atrial pressure, hypoxemia, sick sinus syndrome, cardiomyopathy, pulmonary disease, and idiopathic (isolated) cases) ・Atrial flutter (major causes include mitral or tricuspid valve disease, cor pulmonale, coronary artery disease, cardiomyopathy, myocarditis, hyperthyroidism, electrolyte abnormalities, drugs such as catecholamines, and idiopathic cases) ・Atrioventricular junctional rhythm (major causes include acute myocardial infarction, other ischemic heart disease, hypertension, myocarditis, and idiopathic cases) ・Ventricular premature contractions (major causes include acute myocardial infarction, cardiomyopathy, and idiopathic cases) ・Ventricular fibrillation (major causes include acute myocardial infarction, cardiomyopathy, Wolff-Parkinson-White syndrome, long QT syndrome, Vulgata syndrome, catecholamine-induced polymorphic ventricular tachycardia, and idiopathic cases) - Ventricular tachycardia (major causes include acute myocardial infarction, cardiomyopathy, valvular heart disease, and idiopathic causes) (ii) Types and major causes of arrhythmias caused by conduction abnormalities - Bradycardiac atrial fibrillation (major causes include digitalis intoxication and idiopathic causes) - Sick sinus syndrome (major causes include aging, coronary artery disease, and drugs such as quinidine and digoxin, and idiopathic causes)・Sinoatrial block (major causes include myocardial infarction, coronary artery occlusion, drugs such as digoxin, antiarrhythmic drugs, beta-blockers, and calcium channel blockers, and idiopathic causes) ・Atrioventricular block (major causes include acute myocardial infarction, valvular heart disease, drugs such as cardiomyopathy, digoxin, and beta-blockers, and aging, congenital causes, and idiopathic causes) ・Bundle branch block (major causes include hypertensive heart disease, myocardial infarction, cardiomyopathy, damage to the legs due to cardiac surgery, congenital causes, and idiopathic causes) ・Premature ventricular contractions (major causes include digitalis toxicity, myocardial infarction, cardiomyopathy, electrolyte abnormalities, and idiopathic causes)

[0176] Among these arrhythmia disorders, some are characterized as being caused by genetic abnormalities, particularly in myocardial ion channels. These disorders are a group of intractable diseases that cause fatal arrhythmias and sudden death in relatively young people. Effective prevention and treatment can not only improve patients' quality of life but also have socioeconomic benefits. Examples of hereditary arrhythmia disorders include congenital long QT syndrome, short QT syndrome, Vulgata syndrome, catecholamine-induced polymorphic ventricular tachycardia, progressive cardiac conduction disorder (familial heart block), congenital sick sinus syndrome, familial atrial fibrillation, arrhythmogenic right ventricular cardiomyopathy, acquired long QT syndrome, and early repolarization syndrome.

[0177] In a particular embodiment of the present invention, the medicament of the present invention is used to treat the following pulmonary hypertension: pulmonary arterial hypertension; pulmonary hypertension due to pulmonary venous embolic disease; pulmonary hypertension due to pulmonary capillary hemangiomatosis; persistent pulmonary hypertension of the newborn; pulmonary hypertension associated with left ventricular systolic dysfunction, left ventricular diastolic dysfunction, valvular disease, or congenital / acquired left ventricular inflow / outflow tract obstruction; chronic obstructive pulmonary disease, interstitial lung disease, other lung diseases with mixed high-velocity and obstructive disorders, sleep-disordered breathing, alveolar hypoventilation, chronic exposure to high altitude, or pulmonary hypertension due to developmental disorders. The pharmaceutical composition of the present invention can be used for the prevention or treatment of pulmonary hypertension selected from the group consisting of: hypertension, chronic thromboembolic pulmonary hypertension, and pulmonary hypertension associated with a blood disease (chronic hemolytic anemia, myeloproliferative disease, or splenectomy), a systemic disease (sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, or vasculitis), a metabolic disease (glycogen storage disease, Gaucher disease, or thyroid disease), or other pulmonary vascular compression (tumor embolism, fibrosing mediastinitis, or chronic renal failure). The pharmaceutical composition of the present invention is preferably used for the prevention or treatment of pulmonary arterial hypertension.

[0178] In a further specific embodiment of the present invention, the medicament of the present invention is a medicament for improving one or more conditions selected from the group consisting of right ventricular pressure, right ventricular systolic pressure, survival rate, and cardiac hypertrophy in a subject with pulmonary hypertension.

[0179] The medicament of the present invention comprises a compound represented by formula (I) or a salt thereof. The medicament of the present invention may further comprise a pharmaceutically acceptable carrier and, if necessary, formulation additives.

[0180] As the pharmaceutically acceptable carrier, various organic or inorganic carrier substances commonly used as formulation materials are used, and are incorporated as excipients, lubricants, binders, or disintegrants in solid formulations, or as solvents, solubilizers, suspending agents, isotonicity agents, buffers, or soothing agents in liquid formulations. Furthermore, formulation additives such as preservatives, antioxidants, stabilizers, coloring agents, or sweeteners can also be used as necessary.

[0181] In one embodiment, the pharmaceutical agent of the present invention can be a pharmaceutical agent for parenteral administration or oral administration.

[0182] Medicaments for oral administration may be in the form of a solid preparation such as a powder, granules, tablet or capsule, or a liquid preparation such as a syrup or emulsion.

[0183] The pharmaceutical composition of the present invention can be prepared by conventional methods, such as blending, kneading, granulation, tableting, coating, sterilization, and emulsification, depending on the formulation. Regarding the preparation of pharmaceutical compositions, the various sections of the General Provisions for Preparations in the Japanese Pharmacopoeia can be referenced. The pharmaceutical composition of the present invention may also be formed into a sustained-release formulation containing an active ingredient and a biodegradable polymer compound.

[0184] The dosage will vary depending on the subject, administration route, disease, symptoms, etc., but for example, when orally administered to a human (body weight about 50 kg) for the purpose of treating heart failure or pulmonary hypertension, the dosage can be selected from the range of about 0.1 mg to about 500 mg of Compound (I), preferably from about 1 mg to about 100 mg, and when parenterally administered, from about 0.01 mg to about 100 mg, preferably from about 0.1 mg to about 10 mg. This amount can be administered once or in divided doses (e.g., 1 to 3 times a day).

[0185] The medicament of the present invention can be used in combination with other drugs (concomitant drugs).

[0186] In a specific embodiment of the present invention, the medicament of the present invention is used in combination with other drugs for the treatment or prevention of heart failure. The other drugs may be, for example, one or more of the following drugs: (1) Drugs for treating heart failure (i) β-receptor antagonists: carvedilol, metoprolol, atenolol; (ii) diuretics: hydrochlorothiazide, spironolactone, furosemide, indapamide, bendrofluazide, cyclopenthiazide, bumetanide, ethacrynic acid; (iii) cardiac inotropes: digoxin, dobutamine; (iv) antialdosterone agents: spironolactone, eplerenone; (v) heart rate reducers: ivabradine; (vi) intravenous inotropes: h-ANP; (vii) others: relaxin; (2) others (viii) Ca sensitizers: MCC-135; (ix) Ca channel antagonists: nifedipine, diltiazem, verapamil, lomerizine hydrochloride, amlodipine besylate; (x) antiplatelet agents, anticoagulants: heparin, aspirin, warfarin, dabigatran, rivaroxaban, pixaban, edoxaban; (xi) HMG-CoA reductase inhibitors: atorvastatin, simvastatin; (xii) uric acid lowering agents: probenecid, allopurinol, febuxostat; (xiii) alpha-blockers: doxazosin; (xiv) oral adsorbents: kremezin; (xv) hyperkalemia treatment agents: calticol; (xvi) hyperphosphatemia treatment agents: sevelamer, lanthanum carbonate; (xvii) metabolic acidosis improvement agents: sodium bicarbonate; (xviii) others: active vitamins;

[0187] In another aspect of the present invention, the medicament of the present invention is a medicament for preventing or treating pulmonary hypertension in a subject in need thereof, which comprises compound (I) and can be used in combination with other drugs (concomitant drugs).

[0188] In a specific embodiment of the present invention, the medicament of the present invention is used in combination with other drugs for the treatment or prevention of pulmonary hypertension. The other drugs may be, for example, one or more of the following drugs: (i) Endothelin receptor antagonists: endothelin receptor antagonists such as macitentan, bosentan, and ambrisentan; (ii) Prostaglandin preparations: prostaglandin preparations (or prostacyclin preparations) such as epoprostenol, beraprost, treprostinil, iloprost, and selexipag; (iii) Phosphodiesterase-5 inhibitors: phosphodiesterase-5 inhibitors such as sildenafil and tadalafil; (iv) Soluble adenylate cyclase stimulators: soluble adenylate cyclase stimulators such as riociguat; (v) Calcium channel antagonists: calcium channel antagonists such as nifedipine, diltiazem, and amlodipine; (vi) Rho kinase inhibitors: Rho kinase inhibitors such as fasudil; (vii) Others: tyrosine kinase inhibitors such as imatinib and sorafenib, anticoagulants such as warfarin and aspirin, furosemide, Diuretics such as spironolactone, cardiac stimulants such as dopamine and digoxin.

[0189] The pharmaceutical preparations of the present invention used in combination with other drugs, or the pharmaceutical preparations of the present invention containing other drugs, include both pharmaceutical preparations containing compound (I) and the concomitant drug in a single formulation, and pharmaceutical preparations containing compound (I) and the concomitant drug in separate formulations. Hereinafter, these will be collectively referred to as the concomitant drug of the present invention.

[0190] The combination drug of the present invention can be formulated by mixing compound (I) and a concomitant drug separately or simultaneously, either as is or with a pharmaceutically acceptable carrier, in the same manner as in the case of the above-mentioned medicament containing compound (I).

[0191] The daily dose of the combination drug of the present invention varies depending on the severity of symptoms; the age, sex, weight, and sensitivity of the subject; the timing and interval of administration, the properties, formulation, and type of the medicine; and the type of active ingredient, and is not particularly limited.

[0192] When administering the combination drug of the present invention, compound (I) and the concomitant drug may be administered simultaneously, or the concomitant drug may be administered first followed by compound (I) or a salt thereof, or compound (I) or a salt thereof may be administered first followed by the concomitant drug. When administering with a time lag, the time lag varies depending on the active ingredient, dosage form, and administration method to be administered. For example, when the concomitant drug is administered first, compound (I) or a salt thereof may be administered within 1 minute to 3 days, preferably within 10 minutes to 1 day, and more preferably within 15 minutes to 1 hour, after the administration of the concomitant drug. When compound (I) is administered first, the concomitant drug may be administered within 1 minute to 1 day, preferably within 10 minutes to 6 hours, and more preferably within 15 minutes to 1 hour, after the administration of the ingredient.

[0193] In the combination preparation of the present invention containing compound (I) and a concomitant drug together, the contents of compound (I) and the concomitant drug vary depending on the form of the preparation, but are usually about 0.01 to 90% by weight, preferably about 0.1 to 50% by weight, and more preferably about 0.5 to 20% by weight, of the total preparation.

[0194] The content of the carrier in the combination drug of the present invention is usually about 0 to 99.8% by weight, preferably about 10 to 99.8% by weight, more preferably about 10 to 90% by weight, based on the total weight of the preparation.

[0195] In addition, in a combination preparation containing compound (I) or a salt thereof and a concomitant drug separately, the combination preparation containing the concomitant drug can be produced and used in the same manner as compound (I) or a salt thereof.

[0196] The inventions relating to the compounds and medicines of the present invention can be converted into inventions of other embodiments, such as inventions relating to methods for preventing or treating diseases, and inventions relating to the use of compounds, etc. for producing medicines.

[0197] In certain aspects of the present invention, there is provided a method of preventing or treating heart failure in a subject in need thereof, comprising administering to said subject Compound (I).

[0198] In a particular aspect of the present invention, there is provided the use of Compound (I) for the manufacture of a medicament for use in preventing or treating heart failure in a subject in need thereof.

[0199] In certain aspects of the present invention, there is provided a method of preventing or treating pulmonary hypertension in a subject in need thereof, comprising administering to said subject Compound (I).

[0200] In a particular aspect of the present invention, there is provided the use of Compound (I) for the manufacture of a medicament for preventing or treating pulmonary hypertension in a subject in need thereof.

[0201] The technical matters relating to these methods of the present invention, such as the diseases and symptoms to be treated, can be the same as the technical matters described above for the medicament of the present invention. When compound (I) is administered in the method of the present invention, a medicament containing compound (I) or a salt thereof may be administered.

[0202] The present invention will be further explained in detail by the following examples, test examples and formulation examples, but these do not limit the present invention and may be modified within the scope of the present invention.

[0203] In the following examples, "room temperature" generally refers to about 10° C. to about 35° C. Ratios shown for mixed solvents are by volume unless otherwise specified. % refers to % by weight unless otherwise specified.

[0204] Unless otherwise specified, elution in the column chromatography in the examples was carried out under observation by TLC (Thin Layer Chromatography). In the TLC observation, a 60 F TLC plate manufactured by Merck was used. ２５４The developing solvent was the same as the solvent used as the elution solvent in column chromatography. A UV detector was used for detection. In silica gel column chromatography, NH indicates aminopropylsilane-bonded silica gel, and Diol indicates 3-(2,3-dihydroxypropoxy)propylsilane-bonded silica gel. In preparative HPLC (high performance liquid chromatography), C18 indicates octadecyl-bonded silica gel. The ratios shown for elution solvents are by volume unless otherwise specified.

[0205] １ H NMR analysis was performed using ACD / SpecManager (trade name) software, etc. Very gentle proton peaks such as those of hydroxyl groups and amino groups may not be recorded.

[0206] MS was measured by LC / MS. ESI or APCI was used as the ionization method. Data shows actual measurements (found values). Molecular ion peaks are usually observed, but fragment ions may also be observed. In the case of salts, free molecular ion peaks or fragment ion peaks are usually observed.

[0207] Optical rotation ([α] Ｄ The unit of sample concentration (c) in (a) is g / 100 mL.

[0208] Elemental analysis values ​​(Anal.) are shown as calculated values ​​(Calcd) and found values ​​(Found).

[0209] The peaks measured by powder X-ray diffraction in the examples refer to peaks measured at room temperature using an Ultima IV (Rigaku Corporation, Japan) with Cu Kα radiation as the radiation source. The measurement conditions are as follows: Electric pressure / electric current: 40 kV / 50 mA Scan speed: 6 degrees / min Scan range of 2 Theta: 2-35 degrees The crystallinity measured by powder X-ray diffraction in the examples was calculated by the Hermans method.

[0210] ​In the following examples, the following abbreviations are used: mp: melting point, MS: mass spectrum, M: molar concentration, N: normality, CDCl ３ : deuterated chloroform DMSO-d ６ : deuterated dimethyl sulfoxide １ H NMR: Proton nuclear magnetic resonance LC / MS: Liquid chromatograph mass spectrometer LC / MS / MS: Liquid chromatograph / tandem mass spectrometer ESI: Electrospray ionization APCI: Atmospheric pressure chemical ionization HATU: (Dimethylamino)-N,N-dimethyl(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methaniminium hexafluorophosphate DIPEA: N-Ethyl-N-isopropylpropan-2-amine COMU: (((Z)-(1-cyano-2-ethoxy-2-oxoethylidene)amino)oxy)-N,N-dimethylmorpholin-4-ylmethaniminium Hexafluorophosphate DMA: N,N-dimethylacetamide DMF: N,N-dimethylformamide THF: Tetrahydrofuran

[0211] Example 1 ((1S,5R)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hex-3-yl)((5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)methanone

[0212] A mixture of (5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid (1.272 g), COMU (2.108 g), DIPEA (1.719 mL), and DMF (25 mL) was stirred at room temperature for 15 minutes. (1S,5R)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane hydrochloride (1.24 g) was then added, and the resulting mixture was stirred at 70 °C for 3 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, hexane / ethyl acetate). The resulting fraction was concentrated under reduced pressure, and the residue was purified again by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (2.00 g). 1 H NMR (300 MHz, DMSO-d6) δ0.77 (1H, t, J = 4.7 Hz), 1.09-1.17 (1H, m), 1.49 (3H, s), 1.52 (3H, s), 1.99-2.26 (3H, m), 3.37-4.00 (3H, m), 4.22 (1H, d, J = 10.4 Hz), 4.69 (1H, dd, J = 11.4, 3.1 Hz), 6.87 (1H, s), 7.26-7.49 (6H, m), 7.52-7.89 (3H, m).

[0213] Example 2 ((1R,5S)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hex-3-yl)((5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)methanone

[0214] A mixture of (5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid (86 mg), HATU (86 mg), DIPEA (0.079 mL), and DMA (1 mL) was stirred at room temperature for 15 minutes. (1R,5S)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane hydrochloride (50.0 mg) was then added, and the resulting mixture was stirred at 70 °C for 4 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (53.6 mg). 1 H NMR (300 MHz, DMSO-d6) δ0.77 (1H, t, J = 4.7 Hz), 1.10-1.17 (1H, m), 1.48 (3H, s), 1.52 (3H, s), 1.99-2.23 (3H, m), 3.38-4.15 (3H, m), 4.27 (1H, d, J = 10.7 Hz), 4.69 (1H, dd, J = 11.2, 2.8 Hz), 6.87 (1H, s), 7.26-7.49 (6H, m), 7.51-7.84 (3H, m).

[0215] Example 3 (1-(3,5-dichlorophenyl)-3-azabicyclo[3.1.0]hex-3-yl)((5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)methanone

[0216] A) tert-Butyl 1-(3,5-dichlorophenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate To a solution of (3,5-dichlorophenyl)acetonitrile (5.00 g) and 2-(chloromethyl)oxirane (3.31 g) in THF (40 mL) was added sodium bis(trimethylsilyl)amide (1.0 M THF solution, 47.3 mL) dropwise at -10 to 5 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 to 5 °C for 3 hours and then at 10 to 15 °C for 16 hours. Borane-dimethyl sulfide complex (10.0 M dimethyl sulfide solution, 8.33 mL) was then added dropwise at 0 °C. The resulting mixture was heated to 40 °C over 1 hour and stirred at 40 °C for 2 hours under a nitrogen atmosphere. 2 M hydrochloric acid (50 mL) was then added at room temperature. The resulting mixture was stirred at 40°C for 1 hour under a nitrogen atmosphere, after which 28% aqueous ammonia (10.5 g) was added. The aqueous layer was separated and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was mixed with isopropyl acetate (150 mL) and added to a solution of thionyl chloride (4.83 g) in isopropyl acetate (150 mL) at 0°C. The resulting mixture was stirred at 0°C for 10 minutes, after which 5 M aqueous sodium hydroxide (31 mL) was added. The resulting mixture was stirred at 20°C for 30 minutes under a nitrogen atmosphere, after which di-tert-butyl dicarbonate (11.7 g) was added, and the resulting mixture was stirred at 20°C for 30 minutes. The reaction mixture was diluted with saturated brine (150 mL) and extracted with ethyl acetate (200 mL x 2). The extract was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give the title compound (2.10 g). 1H NMR (400 MHz, CDCl3) δ0.80-1.00 (1H, m), 1.04-1.15 (1H, m), 1.46 (9H, s), 1.77-1.89 (1H, m), 3.45-3.58 (2H, m), 3.58-3.77 (1H, m), 3.77-4.00 (1H, m), 7.00-7.06 (2H, m), 7.21 (1H, s).

[0217] B) 1-(3,5-Dichlorophenyl)-3-azabicyclo[3.1.0]hexane Hydrochloride A mixture of tert-butyl 1-(3,5-dichlorophenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (2.10 g) and 4 M hydrogen chloride / ethyl acetate (30 mL) was stirred at 20°C for 1 hour. The reaction mixture was concentrated under reduced pressure. Ethyl acetate (40 mL) was added to the residue, followed by concentration under reduced pressure. Ethyl acetate (40 mL) was added to the resulting residue again, and the mixture was concentrated under reduced pressure to give the title compound (1.57 g). 1 H NMR (400 MHz, DMSO-d6) δ 1.19 (1H, t, J = 7.6 Hz), 1.37 (1H, t, J= 5.6 Hz), 2.21-2.30 (1H, m), 3.29-3.41 (1H, m), 3.47 (2H, d, J = 11.2 Hz), 3.71 (1H, d, J = 11.2 Hz), 7.39 (2H, d, J = 2.0 Hz), 7.49 (1H, t, J = 2.0 Hz), 9.39 (1H, brs), 9.70 (1H, brs).

[0218] C) (1-(3,5-Dichlorophenyl)-3-azabicyclo[3.1.0]hex-3-yl)((5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)methanone. A mixture of (5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid (51.3 mg), HATU (86 mg), DIPEA (0.079 mL), and DMA (1 mL) was stirred at room temperature for 5 minutes. Then, 1-(3,5-dichlorophenyl)-3-azabicyclo[3.1.0]hexane hydrochloride (50.0 mg) was added, and the resulting mixture was stirred at 70°C for 2 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (70.9 mg).

[0219] Example 4 (1-(3,5-Dichlorophenyl)-3-azabicyclo[3.1.0]hex-3-yl)((5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)methanone (optical isomer) (1-(3,5-Dichlorophenyl)-3-azabicyclo[3.1.0]hex-3-yl)((5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)methanone (70.9 mg) was separated by HPLC (CHIRALPAK IC (trade name), 50 mmID×500 mmL), mobile phase: hexane / ethanol=600 / 400 (v / v)), and the fraction with a shorter retention time was obtained as the title compound (24.2 mg). Optical purity: >99.9% de. The shorter retention time under the following optical analysis conditions. Column: CHIRALPAK IC (trade name) 4.6 mmID x 250 mmL Mobile phase: hexane / ethanol = 600 / 400 (v / v) 1H NMR (300 MHz, DMSO-d6) δ0.77 (1H, t, J = 4.8 Hz), 1.13-1.21 (1H, m), 1.49 (3H, s), 1.52 (3H, s), 1.97-2.25 (3H, m), 3.35-4.11 (3H, m), 4.23 (1H, d, J = 10.4 Hz), 4.69 (1H, dd, J = 11.3, 3.0 Hz), 6.88 (1H, s), 7.29-7.53 (8H, m), 7.80 (1H, brs).

[0220] Example 5 (1-(3,5-Dichlorophenyl)-3-azabicyclo[3.1.0]hex-3-yl)((5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)methanone (optical isomer) (1-(3,5-Dichlorophenyl)-3-azabicyclo[3.1.0]hex-3-yl)((5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)methanone (70.9 mg) was separated by HPLC (CHIRALPAK IC (trade name), 50 mmID×500 mmL), mobile phase: hexane / ethanol=600 / 400 (v / v)), and the fraction with a longer retention time was obtained as the title compound (19.2 mg). Optical purity: >99.9% de The longer retention time under the following optical analysis conditions Column: CHIRALPAK IC (trade name) 4.6 mmID x 250 mmL Mobile phase: hexane / ethanol = 600 / 400 (v / v) 1 H NMR (300 MHz, DMSO-d6) δ0.77 (1H, t, J = 4.8 Hz), 1.12-1.21 (1H, m), 1.48 (3H, s), 1.52 (3H, s), 1.99-2.31 (3H, m), 3.40-3.98 (3H, m), 4.27 (1H, d, J = 10.6 Hz), 4.69 (1H, dd, J = 11.3, 2.8 Hz), 6.88 (1H, s), 7.21-7.48 (8H, m), 7.72 (1H, brs).

[0221] Example 6 ((5R)-7,7-Dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)(1-(4-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hex-3-yl)methanone A mixture of (5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid (49.0 mg), HATU (82 mg), DIPEA (0.076 mL), and DMA (1 mL) was stirred at room temperature for 5 minutes. Then, 1-(4-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane hydrochloride (50.0 mg) was added, and the resulting mixture was stirred at 70°C for 3 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (63.5 mg).

[0222] Example 7 ((5R)-7,7-Dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)(1-(4-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hex-3-yl)methanone (optical isomer) ((5R)-7,7-Dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)(1-(4-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hex-3-yl)methanone (63.5 mg) was separated by SFC (CHIRALPAK IC (trade name), 20 mmID×250 mmL), mobile phase: carbon dioxide / ethanol=740 / 260 (v / v)), and the fraction with a shorter retention time was obtained as the title compound (24.0 mg). Optical purity: >99.9% de. The shorter retention time under the following optical analysis conditions. Column: CHIRALPAK IC (trade name) 4.6 mmID x 150 mmL Mobile phase: carbon dioxide / ethanol = 700 / 300 (v / v) 1H NMR (300 MHz, DMSO-d6) δ0.83 (1H, t, J = 4.8 Hz), 1.12-1.21 (1H, m), 1.49 (3H, s), 1.52 (3H, s), 1.98-2.30 (3H, m), 3.37-4.06 (3H, m), 4.26 (1H, d, J = 10.5 Hz), 4.70 (1H, dd, J = 11.4, 3.0 Hz), 6.88 (1H, s), 7.31-7.57 (7H, m), 7.66 (2H, d, J = 8.3 Hz), 7.72 (1H, brs).

[0223] Example 8 ((5R)-7,7-Dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)(1-(4-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hex-3-yl)methanone (optical isomer) ((5R)-7,7-Dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)(1-(4-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hex-3-yl)methanone (63.5 mg) was separated by SFC (CHIRALPAK IC (trade name), 20 mmID×250 mmL), mobile phase: carbon dioxide / ethanol=740 / 260 (v / v)), and the fraction with a longer retention time was obtained as the title compound (23.7 mg). Optical purity: 98.9% de The longer retention time under the following optical analysis conditions Column: CHIRALPAK IC (trade name) 4.6 mmID x 150 mmL Mobile phase: carbon dioxide / ethanol = 700 / 300 (v / v) 1H NMR (300 MHz, DMSO-d6) δ0.84 (1H, t, J = 4.8 Hz), 1.08-1.21 (1H, m), 1.49 (3H, s), 1.52 (3H, s), 1.98-2.26 (3H, m), 3.35-4.19 (3H, m), 4.31 (1H, d, J = 10.7 Hz), 4.70 (1H, dd, J = 11.4, 3.0 Hz), 6.89 (1H, s), 7.27-7.56 (7H, m), 7.63-7.79 (3H, m).

[0224] Example 9 (1-(3-chloro-5-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hex-3-yl)((5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)methanone (optical isomer)

[0225] A) 1-(3-chloro-5-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane Hydrochloride To a solution of (3-chloro-5-(trifluoromethyl)phenyl)acetonitrile (2.81 g) and 2-(chloromethyl)oxirane (1.55 g) in THF (40 mL) was added dropwise sodium bis(trimethylsilyl)amide (1.9 M THF solution, 10 mL) at -10 to 0 °C. The resulting mixture was stirred at 0 °C for 3 hours and then at room temperature overnight under a nitrogen atmosphere, after which borane-dimethyl sulfide complex (10.0 M dimethyl sulfide solution, 4.0 mL) was added dropwise at 0 °C. The resulting mixture was warmed to 40 °C over 1 hour and stirred at 40 °C for 2 hours under a nitrogen atmosphere. 2 M hydrochloric acid was then added at room temperature. The resulting mixture was stirred at 40 °C for 1 hour under a nitrogen atmosphere, after which 28% aqueous ammonia (6.0 mL) was added, and the aqueous layer was removed. Ethyl acetate (300 mL) and 5% aqueous sodium carbonate were added, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure. The residue was mixed with isopropyl acetate (80 mL) and added to a solution of thionyl chloride (1.5 mL) in isopropyl acetate (40 mL) at 0°C. The resulting mixture was stirred at 0°C for 10 minutes, after which 5 M aqueous sodium hydroxide (13 mL) was added. The resulting mixture was stirred at room temperature for 30 minutes, after which the reaction mixture was added to 5% aqueous sodium chloride at room temperature and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a solution of the residue in THF (30 mL), di-tert-butyl dicarbonate (4 mL) and DIPEA (4 mL) were added, and the resulting mixture was stirred overnight at room temperature. The reaction mixture was added to water and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, hexane / ethyl acetate). The resulting fraction was concentrated under reduced pressure, and the residue (1.29 g) was mixed with 4 M hydrogen chloride / ethyl acetate (5 mL) and ethyl acetate (2 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was washed with diisopropyl ether to give the title compound (0.890 g). 1H NMR (300 MHz, DMSO-d6) δ 1.11-1.31 (1H, m), 1.34-1.57 (1H, m), 2.17-2.39 (1H, m), 3.20-3.61 (3H, m), 3.75 (1H, d, J = 11.0 Hz), 7.46-7.87 (3H, m), 9.25-10.02 (2H, m).

[0226] B) (1-(3-chloro-5-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hex-3-yl)((5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)methanone (enantiomer). A mixture of (5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid (69.3 mg), HATU (117 mg), DIPEA (0.107 mL), and DMA (1 mL) was stirred at room temperature for 5 minutes. Then, 1-(3-chloro-5-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane hydrochloride (80.0 mg) was added, and the resulting mixture was stirred at 70 °C overnight. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate). The resulting fraction was concentrated under reduced pressure. The resulting residue (93.7 mg) was separated by HPLC (CHIRALCEL AD (trade name), 50 mmID x 500 mmL), mobile phase: hexane / ethanol = 450 / 550 (v / v)). The fraction with the shortest retention time was obtained as the title compound (36.5 mg). Optical purity: >99.9% de. The fraction with the shortest retention time under the following optical analysis conditions: Column: CHIRALPAK AD-H (trade name), 4.6 mmID x 250 mmL, mobile phase: hexane / ethanol = 250 / 750 (v / v) 1H NMR (300 MHz, DMSO-d6) δ0.81 (1H, t, J = 4.8 Hz), 1.18-1.27 (1H, m), 1.49 (3H, s), 1.52 (3H, s), 1.98-2.35 (3H, m), 3.36-4.11 (3H, m), 4.28 (1H, d, J = 10.5 Hz), 4.69 (1H, dd, J = 11.4, 3.1 Hz), 6.88 (1H, s), 7.28-7.49 (5H, m), 7.56-8.00 (4H, m).

[0227] Example 10 (1-(3-chloro-5-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hex-3-yl)((5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)methanone (optical isomer) A mixture of (5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid (69.3 mg), HATU (117 mg), DIPEA (0.107 mL), and DMA (1 mL) was stirred at room temperature for 5 minutes. Then, 1-(3-chloro-5-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane hydrochloride (80.0 mg) was added, and the resulting mixture was stirred at 70°C overnight. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate). The resulting fraction was concentrated under reduced pressure. The resulting residue (93.7 mg) was separated by HPLC (CHIRALCEL AD (trade name), 50 mmID x 500 mmL), mobile phase: hexane / ethanol = 450 / 550 (v / v)). The fraction with the longest retention time was obtained as the title compound (25.6 mg). Optical purity: 99.9% de. The fraction with the longest retention time was obtained under the following optical analysis conditions: Column: CHIRALPAK AD-H (trade name), 4.6 mmID x 250 mmL, mobile phase: hexane / ethanol = 250 / 750 (v / v). 1H NMR (300 MHz, DMSO-d6) δ0.81 (1H, t, J = 4.7 Hz), 1.10-1.29 (1H, m), 1.49 (3H, s), 1.52 (3H, s), 1.94-2.32 (3H, m), 3.40-4.09 (3H, m), 4.33 (1H, d, J = 10.7 Hz), 4.69 (1H, dd, J = 11.2, 3.1 Hz), 6.88 (1H, s), 7.31-7.49 (5H, m), 7.54-7.88 (4H, m).

[0228] Example 11 (1-(3-chloro-4-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hex-3-yl)((5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)methanone (optical isomer)

[0229] A) tert-Butyl 1-(3-chloro-4-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate To a solution of (3-chloro-4-(trifluoromethyl)phenyl)acetonitrile (3.0 g) and 2-(chloromethyl)oxirane (1.517 g) in THF (30 mL) was added dropwise sodium bis(trimethylsilyl)amide (1.9 M THF solution, 12.58 mL) at -10 to 0 °C. The resulting mixture was stirred at 0 °C for 3 hours and then at room temperature overnight under a nitrogen atmosphere. Borane-dimethyl sulfide complex (10.0 M dimethyl sulfide solution, 4.24 mL) was then added dropwise at 0 °C. The resulting mixture was heated to 40 °C over 1 hour and stirred at 40 °C for 2 hours under a nitrogen atmosphere. 2 M hydrochloric acid (21.18 mL) was then added at room temperature. The resulting mixture was stirred at 40°C for 1 hour under a nitrogen atmosphere, after which 28% aqueous ammonia (5.91 mL) was added and the aqueous layer was removed. Ethyl acetate (300 mL) and 5% aqueous sodium carbonate were added, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure. The residue was mixed with isopropyl acetate (80 mL) and added to a solution of thionyl chloride (1.495 mL) in isopropyl acetate (30 mL) at 0°C. The resulting mixture was stirred at 0°C for 10 minutes, after which 4 M aqueous sodium hydroxide (19.13 mL) was added. The resulting mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere. The reaction mixture was then added to 5% aqueous sodium chloride at room temperature and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Di-tert-butyl dicarbonate (6.34 mL) was added to a solution of the residue and DIPEA (11.90 mL) in DMF (30 mL), and the resulting mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (0.83 g). 1H NMR (300 MHz, CDCl3) δ0.92-1.07 (1H, m), 1.09-1.19 (1H, m), 1.38-1.52 (9H, m), 1.82-1.97 (1H, m), 3.42-4.05 (4H, m), 7.07-7.18 (1H, m), 7.21-7.34 (1H, m), 7.54-7.68 (1H, m).

[0230] B) 1-(3-chloro-4-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane hydrochloride To a mixture of tert-butyl 1-(3-chloro-4-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.83 g) and ethyl acetate (10 mL), 4 M hydrogen chloride in CPME (2 mL) was added at room temperature. The resulting mixture was stirred at 50°C under a nitrogen atmosphere overnight. The precipitate was collected by filtration to give the title compound (510 mg). 1 H NMR (300 MHz, DMSO-d6) δ1.13-1.32 (1H, m), 1.47-1.66 (1H, m), 2.20-2.41 (1H, m), 3.27-3.58 (3H, m), 3.68-3.83 (1H, m), 7.37-7.50 (1H, m), 7.59-7.73 (1H, m), 7.76-7.83 (1H, m), 9.19-10.47 (2H, m).

[0231] C) (1-(3-chloro-4-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hex-3-yl)((5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)methanone (enantiomer). A mixture of (5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid (69.3 mg), HATU (117 mg), DIPEA (0.107 mL), and DMA (1 mL) was stirred at room temperature for 5 minutes. Then, 1-(3-chloro-4-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane hydrochloride (80.0 mg) was added, and the resulting mixture was stirred at 70 °C overnight. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate). The resulting fraction was concentrated under reduced pressure. The resulting residue (104 mg) was separated by HPLC (CHIRALPAK AD (trade name), 50 mmID x 500 mmL), mobile phase: hexane / 2-propanol = 600 / 400 (v / v)). The fraction with the shortest retention time was obtained as the title compound (33.6 mg). Optical purity: >99.9% de. The fraction with the shortest retention time under the following optical analysis conditions: Column: CHIRALPAK AD-H (trade name), 4.6 mmID x 250 mmL, mobile phase: hexane / 2-propanol = 600 / 400 (v / v) 1 H NMR (300 MHz, DMSO-d6) δ0.86 (1H, t, J = 4.8 Hz), 1.17-1.29 (1H, m), 1.49 (3H, s), 1.52 (3H, s), 1.98-2.33 (3H, m), 3.35-4.08 (3H, m), 4.26 (1H, d, J = 10.5 Hz), 4.70 (1H, dd, J = 11.4, 2.8 Hz), 6.88 (1H, s), 7.30-7.50 (6H, m), 7.54-7.97 (3H, m).

[0232] Example 12 (1-(3-chloro-4-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hex-3-yl)((5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)methanone (optical isomer) A mixture of (5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid (69.3 mg), HATU (117 mg), DIPEA (0.107 mL), and DMA (1 mL) was stirred at room temperature for 5 minutes. Then, 1-(3-chloro-4-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane hydrochloride (80.0 mg) was added, and the resulting mixture was stirred at 70°C overnight. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate). The resulting fraction was concentrated under reduced pressure. The resulting residue (104 mg) was separated by HPLC (CHIRALPAK AD (trade name), 50 mmID x 500 mmL), mobile phase: hexane / 2-propanol = 600 / 400 (v / v)). The fraction with the longest retention time was obtained as the title compound (37.2 mg). Optical purity: 99.5% de. The fraction with the longest retention time was obtained under the following optical analysis conditions: Column: CHIRALPAK AD-H (trade name), 4.6 mmID x 250 mmL, mobile phase: hexane / 2-propanol = 600 / 400 (v / v) 1 H NMR (300 MHz, DMSO-d6) δ0.86 (1H, t, J = 4.9 Hz), 1.18-1.31 (1H, m), 1.49 (3H, s), 1.52 (3H, s), 1.99-2.38 (3H, m), 3.41-4.12 (3H, m), 4.31 (1H, d, J = 10.7 Hz), 4.70 (1H, dd, J = 11.3, 3.0 Hz), 6.88 (1H, s), 7.29-7.50 (6H, m), 7.52-7.88 (3H, m).

[0233] Example 13 (1-(4-chloro-3-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hex-3-yl)((5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)methanone (optical isomer)

[0234] A mixture of (5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid (72.8 mg), HATU (122 mg), DIPEA (0.112 mL), and DMA (1 mL) was stirred at room temperature for 5 minutes. Then, 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane hydrochloride (80.0 mg) was added, and the resulting mixture was stirred at 70 °C overnight. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate). The resulting fractions were concentrated under reduced pressure. The resulting residue (93.4 mg) was separated by HPLC (CHIRALPAK IC (trade name), 50 mmID x 500 mmL), mobile phase: hexane / 2-propanol = 550 / 450 (v / v)). The fraction with the shortest retention time was obtained as the title compound (27.3 mg). Optical purity: >99.9% de. The fraction with the shortest retention time was obtained under the following optical analysis conditions: Column: CHIRALPAK IC (trade name), 4.6 mmID x 250 mmL, mobile phase: hexane / 2-propanol = 550 / 450 (v / v). 1 H NMR (300 MHz, DMSO-d6) δ0.79 (1H, t, J = 4.7 Hz), 1.20 (1H, dd, J = 11.7, 6.2 Hz), 1.48 (3H, s), 1.52 (3H, s), 1.99-2.29 (3H, m), 3.34-4.08 (3H, m), 4.26 (1H, d, J = 10.2 Hz), 4.69 (1H, dd, J = 11.4, 3.1 Hz), 6.88 (1H, s), 7.27-7.50 (5H, m), 7.56-7.87 (4H, m).

[0235] Example 14 (1-(4-chloro-3-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hex-3-yl)((5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)methanone (optical isomer) A mixture of (5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid (72.8 mg), HATU (122 mg), DIPEA (0.112 mL), and DMA (1 mL) was stirred at room temperature for 5 minutes. Then, 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane hydrochloride (80.0 mg) was added, and the resulting mixture was stirred at 70°C overnight. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate). The resulting fraction was concentrated under reduced pressure. The resulting residue (93.4 mg) was separated by HPLC (CHIRALPAK IC (trade name), 50 mmID x 500 mmL), mobile phase: hexane / 2-propanol = 550 / 450 (v / v)). The fraction with the longest retention time was obtained as the title compound (33.8 mg). Optical purity: 99.4% de. The fraction with the longest retention time was obtained under the following optical analysis conditions: Column: CHIRALPAK IC (trade name), 4.6 mmID x 250 mmL, mobile phase: hexane / 2-propanol = 550 / 450 (v / v) 1 H NMR (300 MHz, DMSO-d6) δ0.80 (1H, t, J = 4.8 Hz), 1.16-1.25 (1H, m), 1.48 (3H, s), 1.52 (3H, s), 1.93-2.28 (3H, m), 3.33-4.10 (3H, m), 4.31 (1H, d, J = 10.7 Hz), 4.69 (1H, dd, J = 11.4, 3.0 Hz), 6.87 (1H, s), 7.25-7.49 (5H, m), 7.55-7.84 (4H, m).

[0236] Example 16 (1-(3-chlorophenyl)-3-azabicyclo[3.1.0]hex-3-yl)((5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)methanone (optical isomer) (1-(3-chlorophenyl)-3-azabicyclo[3.1.0]hex-3-yl)((5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)methanone (75 mg) was separated by HPLC (CHIRALPAK IC (trade name), 50 mmID×500 mmL), mobile phase: hexane / ethanol=600 / 400 (v / v)), and the fraction with a shorter retention time was obtained as the title compound (23.8 mg). Optical purity: >99.9% de. The shorter retention time under the following optical analysis conditions. Column: CHIRALPAK IC (trade name) 4.6 mmID x 250 mmL Mobile phase: hexane / ethanol = 600 / 400 (v / v) 1 H NMR (300 MHz, DMSO-d6) δ 0.75 (1H, t, J = 4.6 Hz), 1.06-1.20 (1H, m), 1.49 (3H, s), 1.52 (3H, s), 1.97-2.23 (3H, m), 3.37-4.10 (3H, m), 4.22 (1H, d, J = 10.6 Hz), 4.69 (1H, dd, J = 11.2, 2.9 Hz), 6.88 (1H, s), 7.18-7.55 (9H, m), 7.72 (1H, brs).

[0237] Example 17 (1-(3-chlorophenyl)-3-azabicyclo[3.1.0]hex-3-yl)((5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)methanone (optical isomer) (1-(3-chlorophenyl)-3-azabicyclo[3.1.0]hex-3-yl)((5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)methanone (75 mg) was separated by HPLC (CHIRALPAK IC (trade name), 50 mmID×500 mmL), mobile phase: hexane / ethanol=600 / 400 (v / v)), and the fraction with a longer retention time was obtained as the title compound (25.5 mg). Optical purity: 99.9% de The longer retention time under the following optical analysis conditions Column: CHIRALPAK IC (trade name) 4.6 mmID x 250 mmL Mobile phase: hexane / ethanol = 600 / 400 (v / v) 1 H NMR (300 MHz, DMSO-d6) δ0.75 (1H, t, J = 4.7 Hz), 1.12 (1H, dd, J = 7.8, 4.9 Hz), 1.48 (3H, s), 1.52 (3H, s), 1.91-2.25 (3H, m), 3.42-4.19 (3H, m), 4.27 (1H, d, J = 10.7 Hz), 4.69 (1H, dd, J = 11.3, 2.9 Hz), 6.88 (1H, s), 7.19-7.51 (9H, m), 7.71 (1H, brs).

[0238] Example 19 ((5R)-7,7-Dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)(1-(3-methoxyphenyl)-3-azabicyclo[3.1.0]hex-3-yl)methanone (optical isomer) ((5R)-7,7-Dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)(1-(3-methoxyphenyl)-3-azabicyclo[3.1.0]hex-3-yl)methanone (81.5 mg) was separated by SFC (CHIRALPAK AS-H (trade name), 20 mmID×250 mmL), mobile phase: carbon dioxide / ethanol=820 / 180 (v / v)), and the fraction with a shorter retention time was obtained as the title compound (24.7 mg). Optical purity: >99.9% de. The shortest retention time under the following optical analysis conditions. Column: CHIRALPAK AS-H (trade name) 4.6 mmID x 150 mmL Mobile phase: carbon dioxide / ethanol = 800 / 200 (v / v) 1 H NMR (300 MHz, DMSO-d6) δ0.71 (1H, t, J = 4.6 Hz), 1.08 (1H, dd, J = 7.7, 4.8 Hz), 1.49 (3H, s), 1.52 (3H, s), 1.97-2.23 (3H, m), 3.37-4.11 (6H, m), 4.20 (1H, d, J = 10.4 Hz), 4.69 (1H, dd, J = 11.3, 3.0 Hz), 6.71-6.93 (4H, m), 7.23 (1H, t, J = 8.0 Hz), 7.30-7.51 (5H, m), 7.69 (1H, brs).

[0239] Example 20 ((5R)-7,7-Dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)(1-(3-methoxyphenyl)-3-azabicyclo[3.1.0]hex-3-yl)methanone (optical isomer) ((5R)-7,7-Dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)(1-(3-methoxyphenyl)-3-azabicyclo[3.1.0]hex-3-yl)methanone (81.5 mg) was separated by SFC (CHIRALPAK AS-H (trade name), 20 mmID×250 mmL), mobile phase: carbon dioxide / ethanol=820 / 180 (v / v)), and the fraction with a longer retention time was obtained as the title compound (26.1 mg). Optical purity: >99.9% de The longer retention time under the following optical analysis conditions Column: CHIRALPAK AS-H (trade name) 4.6 mmID x 150 mmL Mobile phase: carbon dioxide / ethanol = 800 / 200 (v / v) 1 H NMR (300 MHz, DMSO-d6) δ 0.71 (1H, t, J = 4.6 Hz), 1.08 (1H, dd, J = 7.9, 4.6 Hz), 1.48 (3H, s), 1.52 (3H, s), 1.96-2.26 (3H, m), 3.39-4.15 (6H, m), 4.25 (1H, d, J = 10.7 Hz), 4.69 (1H, dd, J = 11.3, 2.9 Hz), 6.70-6.92 (4H, m), 7.23 (1H, t, J = 8.0 Hz), 7.29-7.50 (5H, m), 7.67 (1H, brs).

[0240] Example 22 ((5R)-7,7-Dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)(1-(3-methylphenyl)-3-azabicyclo[3.1.0]hex-3-yl)methanone (optical isomer) ((5R)-7,7-Dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)(1-(3-methylphenyl)-3-azabicyclo[3.1.0]hex-3-yl)methanone (163 mg) was separated by HPLC (CHIRALPAK IC (trade name), 50 mmID×500 mmL), mobile phase: hexane / 2-propanol=500 / 500 (v / v)), and the fraction with a shorter retention time was obtained as the title compound (43.9 mg). Optical purity: >99.9% de. The shorter retention time under the following optical analysis conditions. Column: CHIRALPAK IC (trade name) 4.6 mmID x 250 mmL Mobile phase: hexane / 2-propanol = 500 / 500 (v / v) 1 H NMR (300 MHz, DMSO-d6) δ0.70 (1H, t, J = 4.5 Hz), 1.06 (1H, dd, J = 7.7, 4.8 Hz), 1.49 (3H, s), 1.52 (3H, s), 1.95-2.23 (3H, m), 2.30 (3H, s), 3.36-4.11 (3H, m), 4.19 (1H, d, J = 10.4 Hz), 4.69 (1H, dd, J = 11.6, 3.0 Hz), 6.88 (1H, s), 6.99-7.15 (3H, m), 7.16-7.25 (1H, m), 7.29-7.52 (5H, m), 7.69 (1H, brs).

[0241] Example 23 ((5R)-7,7-Dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)(1-(3-methylphenyl)-3-azabicyclo[3.1.0]hex-3-yl)methanone (optical isomer) ((5R)-7,7-Dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)(1-(3-methylphenyl)-3-azabicyclo[3.1.0]hex-3-yl)methanone (163 mg) was separated by HPLC (CHIRALPAK IC (trade name), 50 mmID×500 mmL), mobile phase: hexane / 2-propanol=500 / 500 (v / v)), and the fraction with a longer retention time was obtained as the title compound (49.3 mg). Optical purity: 99.8% de The longer retention time under the following optical analysis conditions Column: CHIRALPAK IC (trade name) 4.6 mmID x 250 mmL Mobile phase: hexane / 2-propanol = 500 / 500 (v / v) 1 H NMR (300 MHz, DMSO-d6) δ0.70 (1H, t, J = 4.5 Hz), 1.06 (1H, dd, J = 7.8, 5.0 Hz), 1.48 (3H, s), 1.52 (3H, s), 1.95-2.24 (3H, m), 2.29 (3H, s), 3.35-4.17 (3H, m), 4.24 (1H, d, J = 10.7 Hz), 4.69 (1H, dd, J = 11.3, 3.1 Hz), 6.89 (1H, s), 6.99-7.15 (3H, m), 7.16-7.25 (1H, m), 7.33-7.53 (5H, m), 7.67 (1H, brs).

[0242] Example 25 ((5R)-7,7-Dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)(1-(3-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hex-3-yl)methanone (optical isomer) ((5R)-7,7-Dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)(1-(3-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hex-3-yl)methanone (145 mg) was separated by HPLC (CHIRALPAK IA (trade name), 50 mmID×500 mmL), mobile phase: hexane / ethanol=500 / 500 (v / v)), and the fraction with a shorter retention time was obtained as the title compound (51.8 mg). Optical purity: 99.4% de The shorter retention time under the following optical analysis conditions Column: CHIRALPAK IA (trade name) 4.6 mmID x 250 mmL Mobile phase: hexane / ethanol = 500 / 500 (v / v) 1 H NMR (300 MHz, DMSO-d6) δ0.79 (1H, t, J = 4.7 Hz), 1.13-1.20 (1H, m), 1.49 (3H, s), 1.52 (3H, s), 1.98-2.25 (3H, m), 3.36-4.19 (3H, m), 4.27 (1H, d, J = 10.5 Hz), 4.70 (1H, dd, J = 11.4, 3.0 Hz), 6.88 (1H, s), 7.28-7.49 (5H, m), 7.52-7.66 (4H, m), 7.74 (1H, brs).

[0243] Example 26 ((5R)-7,7-Dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)(1-(3-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hex-3-yl)methanone (optical isomer) ((5R)-7,7-Dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)(1-(3-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hex-3-yl)methanone (145 mg) was separated by HPLC (CHIRALPAK IA (trade name), 50 mmID×500 mmL), mobile phase: hexane / ethanol=500 / 500 (v / v)), and the fraction with a longer retention time was obtained as the title compound (57.4 mg). Optical purity: 99.9% de The longer retention time under the following optical analysis conditions Column: CHIRALPAK IA (trade name) 4.6 mmID x 250 mmL Mobile phase: hexane / ethanol = 500 / 500 (v / v) 1 H NMR (300 MHz, DMSO-d6) δ0.79 (1H, t, J = 4.7 Hz), 1.17 (1H, dd, J = 7.8, 4.9 Hz), 1.49 (3H, s), 1.52 (3H, s), 1.95-2.31 (3H, m), 3.40-4.11 (3H, m), 4.32 (1H, d, J = 10.7 Hz), 4.70 (1H, dd, J = 11.3, 2.8 Hz), 6.88 (1H, s), 7.30-7.50 (5H, m), 7.52-7.64 (4H, m), 7.68 (1H, brs).

[0244] Example 28 ((5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)(1-(2-fluoro-4-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hex-3-yl)methanone (optical isomer) ((5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)(1-(2-fluoro-4-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hex-3-yl)methanone (93.8 mg) was subjected to SFC (CHIRALPAK IC (trade name), 20 mmID×250 The fraction with the shortest retention time was obtained as the title compound (22.0 mg). Optical purity: 99.6% de. The fraction with the shortest retention time was obtained under the following optical analysis conditions: Column: CHIRALPAK IC (trade name) 4.6 mmID x 150 mmL, Mobile phase: Carbon dioxide / ethanol = 770 / 230 (v / v) 1 H NMR (400 MHz, DMSO-d6) δ0.74-0.91 (1H, m), 1.12-1.31 (2H, m), 1.48 (3H, s), 1.51 (3H, s), 1.95-2.21 (3H, m), 3.41-3.92 (1H, m), 4.01 (1H, d, J = 10.8 Hz), 4.17 (1H, d, J = 10.4 Hz), 4.69 (1H, d, J = 9.5 Hz), 6.85 (1H, s), 7.29-7.50 (5H, m), 7.53-7.74 (4H, m).

[0245] Example 29 ((5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)(1-(2-fluoro-4-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hex-3-yl)methanone (optical isomer) ((5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)(1-(2-fluoro-4-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hex-3-yl)methanone (93.8 mg) was subjected to SFC (CHIRALPAK IC (trade name), 20 mmID×250 The eluate with the longest retention time was obtained as the title compound (26.9 mg). Optical purity: >99.2% de. The eluate with the longest retention time was obtained under the following optical analysis conditions: Column: CHIRALPAK IC (trade name) 4.6 mmID x 150 mmL, Mobile phase: Carbon dioxide / ethanol = 770 / 230 (v / v) 1 H NMR (400 MHz, DMSO-d6) δ0.72-0.83 (1H, m), 1.11-1.27 (2H, m), 1.48 (3H, s), 1.51 (3H, s), 1.97-2.22 (3H, m), 3.47-3.99 (2H, m), 4.22 (1H, d, J = 10.0 Hz), 4.69 (1H, d, J = 11.2 Hz), 6.86 (1H, s), 7.31-7.50 (5H, m), 7.52-7.75 (4H, m).

[0246] Example 48 (6,6-Difluoro-1-(4-methylphenyl)-3-azabicyclo[3.1.0]hex-3-yl)((5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)methanone

[0247] A) tert-Butyl 3-(4-methylphenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate. To a solution of tert-butyl 3-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro-1H-pyrrole-1-carboxylate (0.5 g) in dioxane (20 mL) and water (1 mL) was added (4-methylphenyl)boronic acid (257 mg), sodium carbonate (0.544 g), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (0.064 g). The resulting mixture was stirred at 80°C for 16 hours under an argon atmosphere. The reaction mixture was cooled to room temperature, and water (15 mL) was added, followed by stirring for 15 minutes. The mixture was filtered through Celite (trade name) and extracted with ethyl acetate (60 mL x 3). The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (140 mg). 1 H NMR (CDCl3, 400 MHz) δ1.41-1.63 (9H, m), 2.21-2.41 (3H, m), 3.66-3.81 (2H, m), 4.23-4.33 (1H, m), 4.40-4.51 (1H, m), 6.01-6.12 (1H, m), 7.15 (1H, d, J = 7.4 Hz), 7.32 (1H, d, J= 7.4Hz), 7.38 (2H, d, J = 7.8 Hz).

[0248] B) tert-Butyl 6,6-difluoro-1-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate. To a solution of tert-butyl 3-(4-methylphenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (4.4 g) in THF (10 mL) was added (trifluoromethyl)trimethylsilane (12.58 mL) and sodium iodide (7.64 g), and the resulting mixture was stirred at 110 °C for 36 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), filtered through Celite (trade name), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (4.5 g). 1 H NMR (400 MHz, DMSO-d6) δ1.45 (9H, s), 2.34 (3H, s), 2.39-2.41(1H, m), 3.60-3.68 (1H, m), 3.78-3.81 (1H, m), 3.90-3.99 (1H, m), 4.11-4.26(1H, m), 7.15-7.25 (4H, m).

[0249] C) 6,6-Difluoro-1-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane hydrochloride To a solution of tert-butyl 6,6-difluoro-1-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (4.5 g) in dioxane (2 mL), 4 M hydrogen chloride in dioxane (30 mL) was added at room temperature, and the resulting mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was washed with hexane to give the title compound (3.0 g). 1 H NMR (400 MHz, DMSO-d6) δ 2.31 (3H, s), 3.22-3.27 (1H, m), 3.56-3.60 (1H, m), 3.65-3.68 (1H, m), 3.83-3.86 (1H, m), 4.03-4.06 (1H, m), 7.12-7.31 (4H, m), 9.28 (1H, brs), 10.33 (1H, brs).

[0250] D) (6,6-Difluoro-1-(4-methylphenyl)-3-azabicyclo[3.1.0]hex-3-yl)((5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)methanone To a solution of (5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.022 g), HATU (0.037 g), DMAP (0.977 mg), and DIPEA (0.042 mL) in DMA (0.8 mL) was added 6,6-difluoro-1-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane hydrochloride (0.029 g), and the resulting mixture was stirred at 80° C. for 5 hours. Water (0.2 mL) was added to the reaction mixture, and the mixture was purified by HPLC (C18, acetonitrile / 10 mM aqueous ammonium bicarbonate solution) to obtain the title compound (0.034 mg).

[0251] Example 51 (6,6-difluoro-1-(3-methoxyphenyl)-3-azabicyclo[3.1.0]hex-3-yl)((5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)methanone

[0252] A) tert-Butyl 3-(3-methoxyphenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate. To a solution of 1-bromo-3-methoxybenzene (5.56 g) in THF (50 mL), n-butyllithium (1.74 M in hexane, 17 mL) was added dropwise over 15 minutes at −78°C, and the resulting mixture was stirred at −78°C for 45 minutes. The reaction mixture was added to a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (5.0 g) in THF (20 mL) at −78°C, and the resulting mixture was stirred at −78°C for 1 hour, then warmed to room temperature and stirred at room temperature for 1 hour. The reaction mixture was cooled again to −78°C, and methanesulfonyl chloride (8.35 mL) and triethylamine (24.44 mL) were slowly added. The resulting mixture was stirred at −78°C for 1 hour and then at room temperature for 2 hours. A saturated aqueous solution of ammonium chloride (100 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (100 mL × 2). The extract was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (3.5 g). 1 H NMR (400 MHz, DMSO-d6) δ 1.45 (9H, s), 3.78 (3H, s), 4.18-4.21 (2H, m), 4.39 (2H, brs), 6.37-6.40 (1H, m), 6.87-6.89 (1H, m), 7.00-7.04 (2H, m), 7.26-7.30 (1H, m).

[0253] B) tert-Butyl 6,6-difluoro-1-(3-methoxyphenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate. To a solution of tert-butyl 3-(3-methoxyphenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (3.0 g) in THF (12 mL) was added (trifluoromethyl)trimethylsilane (5.42 mL) and sodium iodide (1.87 g), and the resulting mixture was stirred at 110 °C for 36 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), filtered through Celite (trade name), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (1.5 g). 1 H NMR (400 MHz, DMSO-d6) δ 1.40 (9H, s), 2.95-2.98 (1H, m), 3.49-3.56 (1H, m), 3.76-3.83 (5H, m), 4.15-4.24 (1H, m), 6.89-6.93 (3H, m), 7.27-7.31 (1H, m).

[0254] C) 6,6-Difluoro-1-(3-methoxyphenyl)-3-azabicyclo[3.1.0]hexane hydrochloride To a solution of tert-butyl 6,6-difluoro-1-(3-methoxyphenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.4 g) in dioxane (2 mL), 4 M hydrogen chloride in dioxane (25 mL) was added at room temperature, and the resulting mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was washed with pentane to obtain the title compound (1.1 g). 1 H NMR (400 MHz, DMSO-d6) δ 3.32-3.37 (1H, m), 3.46-3.47 (1H, m), 3.49-3.66 (1H, m), 3.77 (3H, s), 3.81-4.08 (2H, m), 6.94-7.01 (3H, m), 7.31-7.34 (1H, m), 9.88 (2H, brs)

[0255] D) (6,6-Difluoro-1-(3-methoxyphenyl)-3-azabicyclo[3.1.0]hex-3-yl)((5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)methanone To a solution of (5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.022 g), HATU (0.037 g), DMAP (0.977 mg), and DIPEA (0.042 mL) in DMA (0.8 mL) was added 6,6-difluoro-1-(3-methoxyphenyl)-3-azabicyclo[3.1.0]hexane hydrochloride (0.031 g), and the resulting mixture was stirred at 80° C. for 5 hours. Water (0.2 mL) was added to the reaction mixture, and the mixture was purified by HPLC (C18, acetonitrile / 10 mM aqueous ammonium bicarbonate solution) to obtain the title compound (0.024 mg).

[0256] The example compounds are shown in the following table. MS in the table indicates the actually measured value. The compounds of Examples 15, 18, 21, 24, 27, 30 to 47, 49, 50 and 52 in the following table were prepared according to the methods shown in the above examples or methods similar thereto.

[0257]

[0258] [Test Example 1] CYP induction Cryopreserved hepatocytes were cultured in a culture medium (In VitroGRO TM CP Medium (Celsis In Vitro Technologies, USA) and plated on BioCoat at a concentration of 40,000 viable cells / well. TM Matrigel (R)TMAfter 24 hours of incubation, the culture medium was removed and replaced with incubation medium (In VitroGRO TM The medium was replaced with HI Medium with Torpedo Antibiotic Mix (Celsis In Vitro Technologies, USA). The cells were cultured for another 3 days. On the 4th day, the medium was removed, and the cells were treated with induction medium containing the test compound in the presence or absence of 10 μmol / L rifampicin for 3 days. The induction medium was replaced every day. The wells containing the test compound in the presence of 10 μmol / L rifampicin were used to evaluate the inhibitory effect of the test compound on the CYP3A activity induction by rifampicin. CYP3A activity was evaluated by measuring the amount of luciferin produced after the addition of 2 μmol / L luciferin-IPA as a P450-Glo activity inhibitor. TM CYP3A4 activity was measured and evaluated using CYP3A4 assay systems (Promega, USA). All cultures were performed at 37°C in a humidified atmosphere with 5% CO2. The induction ability of rifampicin was defined as 100%, and the induction ability of the test compound (% of positive control) was calculated using the following formula: [(luciferin fluorescence intensity in the absence of rifampicin and the presence of the test compound) - (luciferin fluorescence intensity in the absence of rifampicin and the test compound) / (luciferin fluorescence intensity in the presence of rifampicin and the absence of the test compound) - (luciferin fluorescence intensity in the presence of rifampicin and the absence of the test compound)] x 100.

[0259] The results are shown in Table 8.

[0260]

[0261] Test Example 2: CYP3A4 TDI Human liver microsomes purchased from Xenotech, LLC (Lenexa, KS) were used. Test compounds were dissolved in acetonitrile, acetonitrile / methanol (1:1, v / v), or DMSO / acetonitrile (1:4, v / v). A test compound solution was added to human liver microsome solution prepared with phosphate buffer (pH 7.4) to prepare a human liver microsome reaction solution containing 30 μM test compound. An NADPH-producing system was added to the human liver microsome reaction solution, followed by preincubation at 37°C for 0 or 60 minutes. After preincubation, testosterone, a probe substrate, was added, and the enzyme activity of CYP3A4 was analyzed by LC / MS / MS using 6β-hydroxytestosterone, a metabolite of testosterone.

[0262] The enzyme activity (% of control) at each preincubation time point was calculated using the following formula: % of control = [(activity in test compound-added group) / (activity in test compound-free group)] × 100. The remaining activity (% remaining) after 60 minutes of preincubation was calculated using the following formula: Remaining activity (%) = [activity after 60 minutes (% of control 60min )] / [Activity at 0 min (% of control 0min )] × 100.

[0263] The results are shown in Table 9.

[0264]

[0265] Test Example 3: Human CaSR Antagonist Activity. CaSR antagonist activity was measured using the Bright-Glo Luciferase assay system (Promega). CHO cells overexpressing human CaSR and NFAT-luciferase reporter genes were suspended in MEM alpha (Wako Pure Chemical Industries, Ltd.) containing 10% dialyzed serum (HyClone) and seeded at 10,000 cells / 20 μL / well in a 384-well white plate (Corning). The cells were cultured for one day in a 37°C, 5% CO2 incubator. 5 μL / well of the test compound diluted in assay buffer (MEM alpha containing 10 mM HEPES (Life Technologies), 10% dialyzed serum) was added and incubated at 37°C for 10 minutes. 5 μL / well of 7.8 mM CaCl2 (final concentration: 1.3 mM) diluted in assay buffer was added and incubated at 37°C for 2 hours in a 5% CO2 incubator. Bright-Glo reagent (Promega) was added at 10 μL / well, and the mixture was stirred for 5 minutes. Luminescence intensity was measured using a Multi-label reader (Envision) (PerkinElmer). The activity (%) of the test compound was calculated by defining the luminescence intensity when DMSO was added instead of the test compound as 0% inhibition and the luminescence intensity when 10 μM of (5R)-N-(1-ethyl-1-(4-ethylphenyl)propyl)-2,7,7-trimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide was added at a final concentration of 10 μM as 100% inhibition.

[0266] The results are shown in Table 10. As shown below, compound (I) was shown to have excellent CaSR antagonist activity.

[0267]

[0268] Test Example 4 Heart Weight-Reducing Effect of the Compound of Example 1 in an Animal Model of Heart Failure In this test example, CSQ-Tg mice were used as an animal model of heart failure, and the heart weight-reducing effect of the compound of Example 1 was evaluated.

[0269] The compound of Example 1 was suspended in a 0.5% aqueous methylcellulose solution (hereinafter sometimes referred to as "vehicle" in the Test Examples) (10 mL / kg) and orally administered once daily (QD) for 21 days to 5-week-old female CSQ-Tg mice with heart failure at a dose of 10 mg / kg body weight / day (n=7) or 30 mg / kg body weight / day (n=10). A 0.5% aqueous methylcellulose solution was administered as a negative control (vehicle-treated group) (n=7). Heart weight was then measured. The heart was divided into four compartments: left ventricle, right ventricle, left atrium, and right atrium, and the sum of these was used as the heart weight. Heart weights are shown in Table 11, and the weights of each compartment are shown in Table 12.

[0270]

[0271]

[0272] Test Example 5: Effect of the Compound of Example 1 on Survival Rate of Heart Failure Model Animals In this test example, the effect of the compound of Example 1 on survival rate was examined using a heart failure model animal. Cardiac-specific transgenic mice (CSQ-Tg mice), a heart failure model, were obtained from the University of Pennsylvania and bred in-house, as reported in Larry R. Jones et al., J. Clin. Invest. 101: 1385-1393, 1998. Female mice were used in the test, and administration began at 5 weeks of age. The animals were maintained at a room temperature of 20 to 26°C, humidity of 40 to 70%, and light exposure of 12 hours / day (7:00-19:00), and were fed solid food (CE-2, CLEA Japan) and tap water. CSQ-Tg mice, as previously reported, were used in the treatment of cardiac failure with calsequestrin (CSQ)-induced cardiac failure. ２＋ This suppression of intracellular release of ATP resulted in decreased myocardial contractility and cardiac output, leading to cardiac hypertrophy and heart failure.

[0273] The compound of Example 1 was orally administered to 5-week-old female CSQ-Tg mice at a dose of 10 mg / kg body weight / day once daily (QD) for 47 days (n=24). A control group was administered a vehicle (0.5% aqueous methylcellulose solution) (n=24). The results are shown in Figure 1.

[0274] The compound of Example 1 was orally administered once daily (QD) at a dose of 10 mg / kg body weight / day to 5-week-old female CSQ-Tg mice (n=18) in combination with candesartan cilexetil (1 mg / kg body weight / day) for 68 days. A control group (n=18) was administered candesartan cilexetil (1 mg / kg body weight / day). The results are shown in Figure 2.

[0275] [Formulation Example 1] Production of capsules 1) Compound of Example 1 30 mg 2) Finely powdered cellulose 10 mg 3) Lactose 19 mg 4) Magnesium stearate 1 mg Total 60 mg 1), 2), 3) and 4) are mixed and filled into a gelatin capsule.

[0276] [Formulation Example 2] Tablet preparation 1) Compound of Example 1 30 g 2) Lactose 50 g 3) Corn starch 15 g 4) Carboxymethylcellulose calcium 44 g 5) Magnesium stearate 1 g Total 1000 tablets 140 g The total amount of 1), 2), 3) and 30 g of 4) are kneaded with water, vacuum dried, and then sized. This sized powder is mixed with 14 g of 4) and 1 g of 5) and tableted using a tablet press. In this way, 1000 tablets containing 30 mg of the compound of Example 1 per tablet are obtained.

[0277] The compounds of the present invention have calcium-sensing receptor antagonistic activity and are expected to be useful as agents for the prevention or treatment of diseases such as heart failure and pulmonary hypertension.

Claims

1. Formula (I): [In the formula, ring A represents an aromatic ring which may be further substituted; R １ represents a hydrogen atom, an alkyl group which may be substituted, an alkylthio group which may be substituted, or an alkoxy group which may be substituted; R ２ and R ３ each independently represent an alkyl group which may be substituted, or R ２ and R ３ may form a ring which may be further substituted together with adjacent carbon atoms; R ４ represents an aromatic ring group which may be substituted or an alkyl group which may be substituted; R ５ and R ６ each independently represent a hydrogen atom or a halogen atom. ] A compound represented thereby or a salt thereof.

2. The compound or a salt thereof according to claim 1, wherein ring A is a benzene ring.

3. The compound or a salt thereof according to claim 1, wherein R １ is a hydrogen atom.

4. The compound or a salt thereof according to claim 1, wherein R ２ and R ３ are both C １－６ alkyl groups.

5. R ４ is a C １－６ aryl group, a 5- or 6-membered monocyclic aromatic heterocyclic group, or a C １－６ alkyl group, each of which may be substituted with one or two substituents selected from the group consisting of (a) a halogen atom, (b) a C ６－１４ alkyl group which may be substituted with 1 to 3 halogen atoms, and (c) a C １－６ alkoxy group which may be substituted with 1 to 3 halogen atoms. The compound or a salt thereof according to claim 1.

6. The compound or a salt thereof according to claim 1, wherein R ５ and R ６ are each independently a hydrogen atom or a fluorine atom.

7. Ring A is a benzene ring; R １ is a hydrogen atom; R２ and R ３ are both C 1-6 alkyl; R ４ is (a) a halogen atom, (b) a C １－６ alkyl group which may be substituted with 1 to 3 halogen atoms, and (c) a C １－６ alkoxy group which may be substituted with 1 or 2 substituents selected from the group consisting of, and each may be substituted with, a C ６－１４ aryl group, a 5- or 6-membered monocyclic aromatic heterocyclic group, or a C １－６ alkyl group; R ５ and R ６ are each independently a hydrogen atom or a fluorine atom, the compound according to claim 1, or a salt thereof.

8. Ring A is a benzene ring; R １ is a hydrogen atom; R ２ and R ３ are both C 1-6 alkyl; R ４ is (a) a halogen atom, and (b) a phenyl group substituted with 1 or 2 substituents selected from the group consisting of a C １－６ alkyl group which may be substituted with 1 to 3 halogen atoms; R ５ and R ６ are both hydrogen atoms, the compound according to claim 1, or a salt thereof.

9. ((1S,5R)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hex-3-yl)((5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)methanone or a salt thereof.

10. (1-(3,5-dichlorophenyl)-3-azabicyclo[3.1.0]hex-3-yl)((5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)methanone or a salt thereof.

11. (1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hex-3-yl)((5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)methanone or a salt thereof.

12. A medicament comprising the compound according to claim 1 or a salt thereof.

13. The medicament according to claim 12, which is a calcium-sensing receptor antagonist.

14. The medicament according to claim 12, which is a prophylactic or therapeutic agent for heart failure.

15. The medicament according to claim 12, which is a prophylactic or therapeutic agent for pulmonary hypertension.

16. The compound according to claim 1 or a salt thereof for use in the prophylaxis or treatment of heart failure.

17. The compound according to claim 1 or a salt thereof for use in the prophylaxis or treatment of pulmonary hypertension.

18. A method for antagonizing calcium-sensing receptors in a mammal, which comprises administering to the mammal an effective amount of the compound according to claim 1 or a salt thereof.

19. A method for preventing or treating heart failure in a mammal, which comprises administering to the mammal an effective amount of the compound according to claim 1 or a salt thereof.

20. A method for preventing or treating pulmonary hypertension in a mammal, which comprises administering to the mammal an effective amount of the compound according to claim 1 or a salt thereof.

21. Use of the compound according to claim 1 or a salt thereof for the manufacture of a prophylactic or therapeutic agent for heart failure.

22. Use of the compound according to claim 1 or a salt thereof for the manufacture of a prophylactic or therapeutic agent for pulmonary hypertension.

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