WO2010147234A1 - Diarylamide-spirodiamine derivative - Google Patents

Abstract

To provide a melanin concentrating hormone receptor antagonist useful as medicines for central system disorders, cardiovascular disorders and metabolic disorders. Provided is a compound of a formula (I): wherein R^1a and R^1b each are a hydrogen atom, etc.; R² is a hydrogen atom, a C_1-6 alkyl, etc.; Ar₁ is a 6-membered aromatic carbocyclic group or a 6-membered aromatic nitrogen-containing heterocyclic group; Ar₂ is a group to be formed by removing two hydrogen atoms from a 6-membered aromatic carbon ring, a 6-membered aromatic nitrogen-containing hetero ring, etc.; Ar₃ is a mono- or bi-cyclic aromatic carbocyclic group or aromatic heterocyclic group; m1, m2, m3 and m4 are independently 0, 1, 2, 3 or 4, provided that the total of m1 and m2 is from 2 to 6, and the total of m3 and m4 is from 2 to 6. The compound is useful as medicines for central system disorders, cardiovascular disorders and metabolic disorders.

Description

DESCRIPTION

DIARYLAMIDE-SPIRODIAMINE DERIVATIVE

FIELD OF THE INVENTION

The present invention relates to a novel diarylamide-spirodiamine derivative. The compound acts as a melanin concentrating hormone receptor antagonist, and is useful as a preventive or remedy for various circular system diseases, nervous system diseases, metabolic diseases, genital diseases, respiratory diseases, digestive diseases, etc.

BACKGROUND OF THE INVENTION

Melanin concentrating hormone (hereafter referred to as "MCH") is a cyclic peptide hormone/neuro-peptide, which was for the first time isolated by Kawauchi, et al., in 1983 from sermon hypophysis [see Nature, Vol. 305, 321 (1983)]. The hormone is known to functionally antagonize for melanin cell stimulating hormone in fishes, to cause concentration of melanin granules in melanophore and participate in body color change [see International Review of Cytology, Vol. 126, 1 (1991); Trends in Endocrinology and Metabolism, Vol. 5, 120 (1994)]. Also in mammals, MCH-containing neuron cells are localized in the hypothalamus lateral field and uncertain zone, but their nerve fibers project over a very wide scope in the brain [see The Journal of Comparative Neurology, Vol. 319, 218 (1992)], and MCH is considered to preside over various central functions in living bodies.

Hypothalamus lateral field is known of old as a feeding center, and furthermore, recently, molecular biological and pharmacological knowledges suggesting participation of MCH in controlling energetic homeostasis are much accumulated. That is, it is reported that expression of mRNA, which is an MCH precursor, is accelerated in the brains of ob/ob mice, db/db mice, KKAy mice, Zucker fatty rats which are model animals of hereditary obesity, and in the brains of fasting mice [see Nature, Vol. 380, 243 (1996); Diabetes, Vol. 47, 294 (1998); Biochemical and Biophysical Research Communications, Vol. 268, 88 (2000); Molecular Brain Research, Vol. 92, 43 (2001)]. Acute ventricular administration of MCH to rats was observed to induce accelerated feeding activity [Nature, Vol. 380, 243 (1996)] and chronic administration thereof invites obesity accompanied by polyphagy [see Proceedings of the National Academy of Sciences of the United States of America, Vol. 99, 3240 (2002)]. Moreover, MCH precursor gene-deficient mice show reduced feed ingestion or rise in oxygen consumption per body weight compared to wild type mice, and their low body weight due to decrease in body fat was observed [see Nature, Vol. 396, 670 (1998)].

On the contrary, transgenic mice which express excessive MCH precursor develop obesity accompanied by polyphagy and insulin resistance [see The Journal of Clinical Investigation, Vol. 107, 379 (2001)]. Consequently, it is suggested that MCH is an important factor for developing obesity and participates in diseases induced by metabolic disorders or respiratory diseases for which obesity is one risk factor. Besides, MCH is known to participate also in anxiety-causing action, epilepsy, memory, learning, diuretic action, sodium/potassium excretory action, oxytocin secreting action, reproduction and reproductive function [see Peptides, Vol. 17, 171 (1996); Peptides, Vol. 18, 1095 (1997); Peptides, Vol. 15, 757 (1994); Journal of Neuroendocrinology, Vol. 8, 57 (1996); Critical Reviews in Neurobiology, Vol. 8, 221 (1994)].

MCH causes versatile pharmacological actions through MCH receptors which are present mainly in the central nervous system. As receptors of MCH, at least two types of type 1 receptors (MCH- 1 R or SLC- 1 ) and type 2 receptors (MCH-2R or SLT) are known [see Nature, Vol. 400, 261 (1999); Nature, Vol. 400, 265 (1999); Biochemical and Biophysical Research Communications, Vol. 261, 622 (1999); Nature Cell Biology, Vol. 1, 267 (1999); FEBS Letters, Vol. 457, 522 (1999); Biochemical and Biophysical Research Communications, Vol. 283, 1013 (2001); The Journal of Biological Chemistry, Vol. 276, 20125 (2001); Proceedings of the National Academy of Sciences of the United States of America, Vol. 98, 7564 (2001 );

Proceedings of the National Academy of Sciences of the United States of America, Vol. 98, 7576 (2001); The Journal of Biological Chemistry, Vol. 276, 34664 (2001); Molecular Pharmacology, Vol. 60, 632 (2001)].

Of those, the pharmacological action observed on rodents is induced mainly via MCH-IR [see Genomics, Vol. 79, 785 (2002)]. Because MCH-IR gene-deficient mice chronically administered with MCH do not develop polyphagy or obesity, it is known that controlling of energy metabolism by MCH is induced via MCH-IR. Furthermore, the deficiency of MCH-IR is known to promote the activity amount of mice [see Proceedings of the National Academy of Sciences of the United States of America, Vol. 99, 3240 (2002)], and its participation in central system diseases accompanied by behavioral disorders, for example, attention-deficit hyperactivity disorder, schizophrenia, depression and the like also is strongly suggested [see Molecular Medicine Today, Vol. 6, 43 (2000); Trends in Neuroscience, Vol. 24, 527 (2001)].

It is also reported that an autoantibody to MCH-IR is present in serum of vitiligo vulgaris patients [see The Journal of Clinical Investigation, Vol. 109, 923 (2002)]. Furthermore, expression of MCH-IR in certain species of cancer cells was reported, and in vivo MCH and MCH-IR expression sites also suggest MCH's participation in cancer, sleep, vigil, drug dependence and digestive disorders [see Biochemical and Biophysical Research Communications, Vol. 289, 44 (2001); Neuroendocrinology, Vol. 61, 348 (1995); Endocrinology, Vol. 137, 561 (1996); The Journal of Comparative Neurology, Vol. 435, 26 (2001)].

Functions of MCH are expressed upon its binding to MCH receptors. Therefore, when its binding to MCH receptor is inhibited, then expression of MCH action can be inhibited. In consequence, substances which are antagonists for binding of MCH with its receptor are expected to be useful as preventive or remedy for those various diseases in which MCH participates, for example, metabolic disorders such as obesity, diabetes, hormone disorder, hyperlipidemia, gout, fatty liver, etc.; cardiovascular disorders such as stenocardia, acute/congestive heart failure, myocardial infarction, coronary atherosclerosis, hypertension, renal diseases, electrolyte abnormality, etc.; central and peripheral nervous system disorders such as bulimia, emotional disturbance, depression, anxiety, epilepsy, delirium, dementia, schizophrenia, attention-deficit hyperactivity disorder, memory impairment, sleep disorders, cognitive failure, dyskinesia, paresthesias, smell disorders, morphine tolerance, drug dependence, alcoholism, etc.; reproductive disorders such as infertility, preterm labor, sexual dysfunction, etc.; and other digestive disorders, respiratory disorders, cancer or pigmentation.

As compounds having an MCH receptor-antagonistic effect, for example, the compounds described in Patent Reference 1 or Patent Reference 2 are listed. The compounds described in these references have a diarylketimine skeleton but do not have a spirodiamine moiety that is one characteristic feature of the present invention, and therefore, these differ from the present invention.

Patent Reference 1 : WO2009/041567

Patent Reference 2: WO2008/047544

DISCLOSURE OF THE INVENTION PROBLEMS THAT THEINVENTION IS TO SOLVE

The present inventors have assiduously studied compounds having an MCH receptor-antagonistic effect and, as a result, have found that a compound in which an aryl group bonds to one nitrogen atom of a spirodiamine and an amide structure-having diaryl bonds to the other nitrogen atom thereof via methylene is a novel compound unknown in literature, and that the compound has an MCH receptor-antagonistic effect and is useful for prevention or remedy for MCH receptor-related various diseases, and have completed the present invention.

Specifically, the invention provides the following:

(I) A compound of a formula (I) or a pharmaceutically-acceptable salt thereof:

wherein,

R^{1 a} and R^{1 b} each independently represent a hydrogen atom, or a Ci_-6 alkyl; R² represents a hydrogen atom, a hydroxy, a Ci_-6 alkyl, a C_3-6 cycloalkyl or a C_1-6 alkoxy, wherein the alkyl, the cycloalkyl or the alkoxy may be substituted with a halogen, a hydroxy or a Ci_-6 alkoxy;

R³ represents a hydrogen atom, a Ci_-6 alkyl or a C_3-6 cycloalkyl, wherein the alkyl or the cycloalkyl may be substituted with a halogen, a hydroxy or a C_1-6 alkoxy;

Z represents a Ci_-6 alkyl, a C_3-6 cycloalkyl, a C_1-6 alkoxy, an aryl, a heteroaryl or N(R^{4 a} )(R^{4 b} ), wherein the alkyl, the cycloalkyl, the alkoxy, the aryl or the heteroaryl may be substituted with a halogen, a hydroxy, a Ci_-6 alkyl, a halo-Ci_-6 alkyl, a Ci_-6 alkoxy or a halo-Ci.₆ alkoxy; or R² and Z, taken together with the atom to which they bond, form a 4- to 6- membered nitrogen-containing hetero ring, wherein the nitrogen-containing hetero ring may have a double bond in the ring, or may further contain a hetero atom selected from a group consisting of nitrogen, oxygen and sulfur, or the nitrogen-containing hetero ring may form a condensed ring with an aryl ring or a heteroaryl ring, and wherein the nitrogen-containing hetero ring may be substituted with a halogen, a hydroxy, a Ci_-6 alkyl, a halo-Ci_-6 alkyl, a Ci_-6 alkoxy, a halo-Ci_-6 alkoxy or an oxo;

R^{4 a} and R^{4 b} each independently represent a hydrogen atom or a C_1-6 alkyl, or R^{4 a} and R^{4 b} , taken together with the nitrogen atom to which they bond, form a 5- or 6- membered nitrogen-containing hetero ring, wherein the nitrogen-containing hetero ring may further contain a hetero atom selected from a group consisting of nitrogen, oxygen and sulfur, or may be substituted with a halogen, a hydroxy, a C_1-6 alkyl, a halo-Ci_-6 alkyl, a Ci_-6 alkoxy, a halo-Ci_-6 alkoxy or an oxo;

W represents C, S or SO;

Ari represents a 6-membered aryl, or a 6-membered nitrogen-containing heteroaryl, wherein the aryl or the nitrogen-containing heteroaryl may be substituted with a substituent selected from the group oc;

Ar₂ represents a 6-membered aryl, or a 5- or 6-membered heteroaryl, wherein the aryl or the heteroaryl may be substituted with a substituent selected from the group α;

Ar₃ represents a mono- or bi-cyclic aryl or heteroaryl, or a pyridone, wherein the aryl or the heteroaryl may form a condensed ring with a non-aromatic cyclic hydrocarbon or a non-aromatic hetero ring, and wherein the aryl, the heteroaryl or the pyridone may be optionally mono- to tetra-substituted with a substituent selected from a halogen, a C_1-6 alkyl, a halo-Ci_-6 alkyl, a hydroxy-Ci_-6 alkyl, a Ci_-6 alkoxy, a halo-C_1-6 alkoxy, a C_3-6 cycloalkyl, a hydroxy-C_3-6 cycloalkyl, a cyano, a carbamoyl, a mono-Ci_-6 alkylcarbamoyl, a di-Ci-₆ alkylcarbamoyl, a C_1-6 alkylsulfonyl and a sulfonylamide; ml, m2, m3 and m4 each independently indicate 0, 1, 2, 3 or 4, provided that the total of ml and m2 is from 2 to 6, and the total of m3 and m4 is from 2 to 6, and any -CH₂- forming the spiro ring may be replaced by -O- and/or -C(O)-]. Substituents of group α: a halogen, a cyano, a hydroxy, an amino, a mono-Ci_-6 alkylamino, a di-C_1-6 alkylamino, a Cj_-6 alkyl, a halo-Ci_-6 alkyl, a C_1-6 alkoxy, a halo-Cj_-6 alkoxy, a C_1-6 alkoxy-Cj_-6 alkyl, a Ci_-6 alkoxycarbonyl, a Ci_-6 alkoxycarbonylamino, a Ci_-6 alkoxycarbonyl(Ci_-6 alkyl)amino, a C_1-6 alkylcarbonyl, a Ci_-6 alkylcarbonyloxy, a C_1-6 alkylcarbonylamino, a Ci_-6 alkylcarbonyl(Ci_-6 alkyl)amino, a carbamoyl, a mono-Cj_-6 alkylcarbamoyl, a di-Ci.₆ alkylcarbamoyl, a carbamoylamino, a mono-Ci_-6 alkylcarbamoylamino, a di-Ci_-6 alkylcarbamoylamino, a mono-Ci- ₆ alkylcarbamoyl(Ci_-6 alkyl)amino, a di-Ci_-6 alkylcarbamoyl(Ci_-6 alkyl)amino, a carbamoyloxy, a mono-C_1-6 alkylcarbamoyloxy, a di-Ci_-6 alkylcarbamoyloxy, a Ci_-6 alkylsulfonyl, a Cj_-6 alkylsulonylamino, a Ci_-6 alkylsulfonyl(Ci_-6 alkyl)amino, a sulfamoyl, a mono-Cj.₆ alkylsulfamoyl, a di-Ci_-6 alkylsulfamoyl, a sulfamoylamino, a mono-Ci_-6 alkylsulfamoylamino, a di-d-₆ alkylsulfamoylamino, a mono-Ci_-6 alkylsulfamoyl(C_1-6 alkyl)amino, and a di-Ci_-6 alkylsulfamoyl(C_1-6 alkyl)amino.

Further, the invention provides the following: (2) A melanin concentrating hormone receptor antagonist comprising the compound of (1) or the pharmaceutically-acceptable salt thereof as the active ingredient;

(3) A pharmaceutical composition containing a pharmaceutically-acceptable additive and the compound of (1) or the pharmaceutically-acceptable salt thereof;

(4) A preventive or remedy comprising the compound of (1) or the pharmaceutically-acceptable salt thereof as the active ingredient, for metabolic disorders such as obesity, diabetes, hormone disorder, hyperlipidemia, gout, fatty liver, hepatitis, and cirrhosis; cardiovascular disorders such as stenocardia, acute/congestive heart failure, myocardial infarction, coronary atherosclerosis, hypertension, renal diseases, and electrolyte abnormality; central and peripheral nervous system disorders such as bulimia, emotional disturbance, depression, anxiety, epilepsy, delirium, dementia, schizophrenia, attention-deficit hyperactivity disorder, memory impairment, sleep disorders, cognitive failure, dyskinesia, paresthesias, smell disorders, morphine tolerance, drug dependence, and alcoholism; reproductive disorders such as infertility, preterm labor, and sexual dysfunction; digestive disorders; respiratory disorders; cancer or pigmentation; especially for bulimia, obesity, diabetes, fatty liver, depression or anxiety;

(5) A pharmaceutical composition based on an MCHlR receptor antagonistic effect, comprising the compound of (1) or the pharmaceutically-acceptable salt of thereof as the active ingredient;

(6) A method for preventing or remedying for melanine concentrating hormone receptor-related disorders, comprising administering an effective amount of the compound of (1) or the pharmaceutically-acceptable salt thereof to a patient;

(7) The method of (6), wherein the melanin concentrating hormone receptor- related disorders are metabolic disorders such as obesity, diabetes, hormone disorder, hyperlipidemia, gout, fatty liver, hepatitis, and cirrhosis; cardiovascular disorders such as stenocardia, acute/congestive heart failure, myocardial infarction, coronary atherosclerosis, hypertension, renal diseases, and electrolyte abnormality; central and peripheral nervous system disorders such as bulimia, emotional disturbance, depression, anxiety, epilepsy, delirium, dementia, schizophrenia, attention-deficit hyperactivity disorder, memory impairment, sleep disorders, cognitive failure, dyskinesia, paresthesias, smell disorders, morphine tolerance, drug dependence, and alcoholism; reproductive disorders such as infertility, preterm labor, and sexual dysfunction; digestive disorders; respiratory disorders; cancer or pigmentation; especially bulimia, obesity, diabetes, fatty liver, depression or anxiety. The invention is described in more detail hereinunder.

In this description, the term "lower" means that the number of the carbon atoms constituting the group or the compound with the term is at most 6, preferably at most 4.

"C_1-6 alkyl" includes a linear alkyl having from 1 to 6 carbon atoms or a branched alkyl having from 3 to 6 carbon atoms, concretely, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, 2- propyl, 2-methylbutyl, 1 ,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2- methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1 ,2-dimethylbutyl, 2,2-dimethylbutyl, 1- ethylbutyl, 1 , 1 ,2-trimethylpropyl, 1 ,2,2-trimethylpropyl, l-ethyl-2-methylpropyl, 1 -ethyl- 1- methylpropyl, etc. "Halogen atom" includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

"C_3-6 cycloalkyl " means a cycloalkyl having from 3 to 6 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

"HaIo-Ci_-6 alkyl " includes a Ci_-6 alkyl in which a part or all of the hydrogen atoms are substituted with halogen, for example, including fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1 ,2-difluoroethyl, etc.

"Hydroxy-Ci_-6 alkyl " includes a Cj_-6 alkyl in which a part or all of the hydrogen atoms are substituted with hydroxy, preferably with one or two hydroxyls, for example, including hydroxymethyl, dihydroxymethyl, 2-hydroxyethyl, 2-hydroxymethylpropyl, etc. "Hydroxy-C_3-6 cycloalkyl " includes the above-mentioned cycloalkyl in which a part or all of the hydrogen atoms are substituted with hydroxy, preferably with one or two hydroxyls, for example, including hydroxycyclopropyl, hydroxycyclobutyl, etc.

"Ci_-6 alkyl optionally substituted with a halogen or a hydroxy" includes the above-mentioned Ci_-6 alkyl, the above-mentioned halo-Ci_-6 alkyl, and the above-mentioned hydroxy-C_1-6 alkyl.

"Ci_-6 alkyloxy" includes a group of a Ci_-6 alkyl bonding to an oxygen atom, concretely including, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butoxy, n- pentyloxy, etc. "HaIo-C_1-6 alkyloxy" includes a group of a halo-Ci_-6 alkyl bonding to an oxygen atom, concretely including, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1,2-difluoroethoxy, etc.

"MOnO-C_{1 -6} alkylamino" is a group of an amino (-NH₂) in which one hydrogen atom is substituted with a C_1-6 alkyl, and concretely includes, for example, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, etc.

"Di-Ci_-6 alkylamino" is a group of an amino in which two hydrogen atoms are substituted with a Ci_-6 alkyl, and concretely includes, for example, dimethylamino, diethylamino, ethylmethylamino, di(n-propyl)amino, methyl(n-propyl)amino, diisopropylamino, etc. "Ci_-6 alkyloxy-Ci_-6 alkyl" is a Ci_-6 alkyl substituted with a Ci_-6 alkyloxy, and concretely includes, for example, methoxymethyl, ethoxymethyl, n-propyloxymethyl, isopropyloxymethyl, 1-methoxyethyl, 2-methoxyethyl, etc.

"Ci-₆ alkyloxycarbonyl" is a C_1-6 alkyloxy bonding to a carbonyl (-CO-) and includes an alkyloxycarbonyl having from 1 to 6 carbon atoms, concretely, for example, methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n- butoxycarbonyl, etc.

"Ci_-6 alkyloxycarbonylamino" is a group of an amino in which one hydrogen atom is substituted with a Ci_-6 alkyloxycarbonyl, and includes an alkyloxycarbonylamino having from 1 to 6 carbon atoms, concretely, for example, methoxycarbonylamino, ethoxycarbonylamino, n-propyloxycarbonylamino, isopropyloxycarbonylamino, n- butoxycarbonylamino, n-pentyloxycarbonylamino, etc.

"Ci_-6 alkyloxycarbonyl (C i_-6 alkyl)amino" is a group of a mono-Ci_-6 alkylamino in which the hydrogen atom on the nitrogen atom is substituted with a Ci_-6 alkyloxycarbonyl, and concretely includes, for example, methoxycarbonyl(methyl)amino, ethoxycarbonyl(methyl)amino, n-propyloxycarbonyl(methyl)amino, etc.

"Ci_-6 alkylcarbonyl" is a group of a Ci_-6 alkyl bonding to a carbonyl, and includes an alkylcarbonyl having from 1 to 6 carbon atoms, concretely, for example, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, etc.

"Ci_-6 alkylcarbonyloxy" is a Ci_-6 alkylcarbonyl bonding to an oxygen atom, and concretely includes, for example, acetoxy, propionyl oxy, valeryloxy, isovaleryloxy, pivaloyloxy, etc.

"Ci_-6 alkylcarbonylamino " is a group of an amino in which one hydrogen atom is substituted with a Ci_-6 alkylcarbonyl, and concretely includes, for example, acetylamino, propionylamino, isobutyrylamino, valerylamino, isovalerylamino, pivaloylamino, etc. "Ci_-6 alkylcarbonyl(Ci_-6 alkyl)amino " is a mono-Ci_-6 alkylamino in which the hydrogen atom on the nitrogen atom is substituted with a Ci_-6 alkylcarbonyl, and includes, for example, methylcarbonyl(methyl)amino, ethylcarbonyl(methyl)amino, n- proρylcarbonyl(methyl)amino, etc. "Mono-Ci_-6 alkylcarbamoyl" is a carbamoyl (-CONH₂) in which one hydrogen atom is substituted with a C_1-6 alkyl, and concretely includes, for example, methylcarbamoyl, ethylcarbamoyl, n-propylcarbamoyl, isopropylcarbamoyl, n-butylcarbamoyl, etc.

"Di-C_1-6 alkylcarbamoyl " is a carbamoyl in which two hydrogen atoms are substituted with a C_1-6 alkyl, and concretely includes, for example, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, di(n-propyl)carbamoyl, methyl(n-propyl)carbamoyl, diisopropylcarbamoyl, etc.

"Mono-C_1-6 alkylcarbamoylamino" is an amino in which one hydrogen atom is substituted with a mono-Ci_-6 alkylcarbamoyl, and concretely includes, for example, methylcarbamoylamino, ethylcarbamoylamino, n-propylcarbamoylamino, isopropylcarbamoylamino, n-butylcarbamoylamino, etc.

"Di-Cj_-6 alkylcarbamoylamino" is an amino in which one hydrogen atom is substituted with a di-C_1-6 alkylcarbamoyl, and concretely includes, for example, dimethylcarbamoylamino, diethylcarbamoylamino, di(n-propyl)carbamoylamino, diisopropylcarbamoylamino, etc.

"Mono-Ci_-6 alkylcarbamoyl(Ci_-6 alkyl)amino " is a mono-Ci.₆ alkylamino in which a hydrogen atom on the nitrogen atom is substituted with a mono-C_1-6 alkylcarbamoyl, and concretely includes, for example, monomethylcarbamoyl(methyl)amino, monoethylcarbamoyl(methyl)amino, [mono(n-propyl)carbamoyl](methyl)amino, etc. "Di-Cj_-6 alkylcarbamoyl(C_1-6 alkyl)amino" is a mono-Ci_-6 alkylamino in which the hydrogen atom on the nitrogen atom is substituted with a di-Ci-₆ alkylcarbamoyl, and concretely includes, for example, dimethylcarbamoyl(methyl)amino, diethylcarbamoyl(methyl)amino, [di(n-propyl)carbamoyl] (methyl)amino, etc.

"Mono-Ci_-6 alkylcarbamoyloxy" is a mono-Ci.₆ alkylcarbamoyl bonding to an oxygen atom, and concretely includes, for example, methylcarbamoyloxy, ethylcarbamoyloxy, n-propylcarbamoyloxy, isopropylcarbamoyloxy, n-butylcarbamoyloxy, etc.

"Di-Ci_-6 alkylcarbamoyloxy" is a di-Ci_-6 alkylcarbamoyl bonding to an oxygen atom, and concretely includes, for example, dimethylcarbamoyloxy, diethylcarbamoyloxy, ethylmethylcarbamoyloxy, di(n-propyl)carbamoyloxy, methyl(n-propyl)carbamoyloxy, diisopropylcarbamoyloxy, etc.

"Ci_-6 alkylsulfonyl " is a Ci_-6 alkyl bonding to a sulfonyl (-SO₂-), and concretely includes, for example, methanesulfonyl, ethanesulfonyl, n-propanesulfonyl, isopropanesulfonyl, n-butanesulfonyl, etc.

"Ci_-6 alkylsulfonylamino " is an amino in which one hydrogen atom is substituted with a Ci_-6 alkylsulfonyl, and concretely includes, for example, methanesulfonylamino, ethanesulfonylamino, n-propanesulfonylamino, isopropanesulfonylamino, n- butanesulfonylamino, etc. "Cj_-6 alkylsulfonyl(Ci_-6 alkyl)amino" is a group of a mono-Ci_-6 alkylamino in which the hydrogen atom on the nitrogen atom is substituted with a Cj_-6 alkylsulfonyl, and concretely includes, for example, methanesulfonyl(methyl)amino, ethanesulfonyl(methyl)amino, n-propanesulfonyl(methyl)amino, isopropanesulfonyl(methyl)amino, etc. "Mono-C_1-6 alkylsulfamoyl" is a group of a sulfamoyl (-SO₂NH₂) in which one hydrogen atom is substituted with a Cj_-6 alkyl, and concretely includes, for example, monomethylsulfamoyl, monoethylsulfamoyl, mono(n-propyl)sulfamoyl, monoisopropylsulfamoyl, mono(n-butyl)sulfamoyl, etc.

"Di-C_1-6 alkylsulfamoyl " is a group of a sulfamoyl in which two hydrogen atoms are substituted with a Ci_-6 alkyl, and concretely includes, for example, dimethylsulfamoyl, diethylsulfamoyl, di(n-propyl)sulfamoyl, diisopropylsulfamoyl, di(n-butyl)sulfamoyl, etc.

"Mono-C_1-6 alkylsulfamoylamino" is a group of an amino in which one hydrogen atom is substituted with a mono-Ci.₆ alkylsulfamoyl, and concretely includes, for example, (monomethylsulfamoyl)amino, (monoethylsulfamoyl)amino, [mono(n-propyl)sulfamoyl]amino, (monoisopropylsulfamoyl)amino, [mono(n-butyl)sulfamoyl]amino, etc.

"Di-Cj_-6 alkylsulfamoylamino" is a group of an amino in which one hydrogen atom is substituted with a di-Ci_-6 alkylsulfamoyl, and concretely includes, for example, (dimethylsulfamoyl)amino, (diethylsulfamoyl)amino, (ethylmethylsulfamoyl)amino, [di(n- propyl)sulfamoyl]amino, [methyl(n-propyl)sulfamoyl]amino, (diisopropylsulfamoyl)amino, etc. "Mono-C_1-6 alkylsulfamoyl (C i_-6 alkyl)amino" is a group of a mono-Ci_-6 alkylamino in which the hydrogen atom on the nitrogen atom is substituted with a mono-Ci_-6 alkylsulfamoyl, and concretely includes, for example, monomethylsulfarnoyl(methyl)arnino, monoethylsulfamoyl(methyl)amino, [mono(n-propyl)sulfamoyl](methyl)amino, etc.

"Di-Ci_-6 alkylsulfamoyl(Ci_-6 alkyl)amino " is a group of a mono-Ci_-6 alkylamino in which the hydrogen atom on the nitrogen atom is substituted with a di-Ci_-6 alkylsulfamoyl, and concretely includes, for example, dimethylsulfamoyl(methyl)amino, diethylsulfamoyl(methyl)amino, [di(n-propyl)sulfamoyl](methyl)amino, etc.

"Aryl" includes, for example, phenyl, naphthyl, etc.

"Heteroaryl" means a 5-membered or 6-membered monocyclic heteroaryl having the same or different, one or more, preferably one or two hetero atoms selected from a group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, or a condensed cyclic heteroaryl formed through condensation of the monocyclic heteroaryl and the above-mentioned aryl, or through condensation of the same or different monocyclic heteroaryls; and this includes, for example, pyrrolyl, furyl, thienyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzopyrazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, indazolyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, puteridinyl, pyrido[3,2-b]pyridyl, etc.

"Pharmaceutically-acceptable salts" of a compound of formula [I] mean ordinary salts that are acceptable as medicines. Their examples are acid-addition salts to the amine moiety of the compound of formula (I) or acid-addition salts to the nitrogen-containing hetero ring thereof, or base-addition salts to the acidic substituent, if any, of the compound of formula

(I)-

The acid-addition salts include inorganic acid salts such as hydrochlorides, sulfates, nitrates, phosphates, perchlorates; organic acid salts such as maleates, fumarates, tartrates, citrates, ascorbates, trifluoroacetates; and sulfonates such as methanesulfonates, isothiocyanates, benzenesulfonates, p-toluenesulfonates.

The base-addition salts include alkali metal salts such as sodium salts, potassium salts; alkaline earth metal salts such as calcium salts, magnesium salts; ammonium salts; and organic amine salts such as trimethylamine salts, triethylamine salts, dicyclohexylamine salts, ethanolamine salts, diethanolamine salts, triethanolamine salts, procaine salts, N₉N¹- dibenzylethylenediamine salts.

For the purpose of more concretely disclosing the compounds of the invention hereinunder, various symbols used in formula [I] are described in detail with reference to their examples. R^la and R^lb independently represent a hydrogen atom, or a C_1-6 alkyl optionally substituted with a halogen or a hydroxy; or R^la and R^lb, taken together, form a cyclopropyl.

Concretely, R^la and R^Ib are independently a hydrogen atom, methyl, ethyl, n- propyl, hydroxymethyl, chloromethyl, fluoromethyl, etc., preferably a hydrogen atom or methyl.

R² represents a hydrogen atom, a hydroxy, a C_1-6 alkyl, a C_3-6 cycloalkyl, or a Ci_-6 alkoxy, wherein the alkyl, the cycloalkyl or the alkoxy may be substituted with a halogen, a hydroxy or a Ci_-6 alkoxy.

R² is concretely a hydrogen atom; a hydroxy; a Ci_-6 alkyl such as methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2,2-difluoroethyl, 2-methoxyethyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl, methoxymethyl, methoxyethyl, etc.; a C_3-6 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy cyclopropyl, methoxycyclobutyl, etc.; or a Ci_-6 alkoxy such as methoxy, ethoxy, propyloxy, fluoromethoxy, trifiuoromethoxy, 2-methoxyethoxy, methoxymethoxy, etc.

Preferably, R² is, for example, a hydrogen atom, methyl, ethyl, n-propyl, isopropyl, 2-fluoroethyl, or 2,2-difluoroethyl, more preferably a hydrogen atom, methyl, or ethyl. R³ represents a hydrogen atom, a Ci_-6 alkyl or a C_3-6 cycloalkyl, wherein the alkyl or the cycloalkyl may be substituted with a halogen, a hydroxy or a Ci_-6 alkoxy.

R³ is concretely a hydrogen atom; a hydroxy; a Ci_-6 alkyl such as methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2,2-difluoroethyl, 2-methoxyethyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl, methoxymethyl, methoxyethyl, etc.; a C_3-6 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxycyclopropyl, methoxycyclobutyl, etc.; or a Cj_-6 alkoxy such as methoxy, ethoxy, propyloxy, fluoromethoxy, trifluoromethoxy, 2-methoxyethoxy, methoxymethoxy, etc. Preferably, R³ is, for example, a hydrogen atom, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifiuoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, cyclopropyl, etc., more preferably a hydrogen atom, methyl, ethyl, fluoromethyl, difluoromethyl, trifiuoromethyl or cyclopropyl.

Z represents a Cj_-6 alkyl, a C_3-6 cycloalkyl, a C_1-6 alkoxy, an aryl, a heteroaryl or N(R ^a )(R^{4 b} ), wherein the alkyl, the cycloalkyl, the alkoxy, the aryl or the heteroaryl may be mono- to tri-substituted with a halogen, a hydroxy, a Ci_-6 alkyl, a halo-Ci_-6 alkyl, a Ci_-6 alkoxy or a halo-Ci_-6 alkoxy;

R² and Z, taken together with the atom to which they bond, form a 4- to 6- membered nitrogen-containing hetero ring, wherein the nitrogen-containing hetero ring may have a double bond in the ring, or may further contain a hetero atom selected from a group consisting of nitrogen, oxygen and sulfur, and wherein the nitrogen-containing hetero ring may form a condensed ring with an aryl ring or a heteroaryl ring, and the nitrogen-containing hetero ring may be substituted with a halogen, a hydroxy, a Cj_-6 alkyl, a halo-Ci_-6 alkyl, a Ci_-6 alkoxy, a halo-Ci-₆ alkoxy or an oxo; R^{4 a} and R^{4 b} each independently represent a hydrogen atom or a Ci_-6 alkyl, or

R^{4 a} and R^{4 b} , taken together with the nitrogen atom to which they bond, form a 5- or 6- membered nitrogen-containing hetero ring, wherein the nitrogen-containing hetero ring may further contain a hetero atom selected from a group consisting of nitrogen, oxygen and sulfur, or may be substituted with a halogen, a hydroxy, a Cj_-6 alkyl, a halo-Ci_-6 alkyl, a Ci_-6 alkoxy, a halo-Ci-₆ alkoxy or an oxo.

Concretely, R^{4 a} and R^{4 b} are independently a hydrogen atom, methyl, ethyl, n- propyl, isopropyl, etc.; or R^{4 a} and R^{4 b} , taken together with the nitrogen atom to which they bond, form a nitrogen-containing hetero ring, such as pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, 3-hydroxypyrrolidine, 3-methoxypyrrolidine, N-methylpiperazine, pyrrolidin-2-one, etc.

Concretely, Z includes a Ci_-6 alkyl such as methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, tert-butyl, 2,2-dimethylpropyl, difluoromethyl, trifiuoromethyl, hydroxymethyl, 1 -hydroxy- 1 -methylethyl, 1 -hydroxy-2,2-dimethylpropyl, 2-hydroxy-2-methylpropyl, methoxymethyl, etc.; a C_3-6 cycloalkyl such as cyclopropyl, cyclobutyl, 1 -hydroxycyclopropyl, 1 -methylcyclopropyl, 2-methyl-2 -hydroxycyclopropyl, l-hydroxy-2,2-dimethylcyclopropyl, etc.; a Ci_-6 alkoxy such as methoxy, ethoxy, n-propyloxy, isopropyloxy, tert-butoxy, etc.; an aryl such as phenyl, 2-trifiuoromethylphenyl, 2-trifluoromethoxyphenyl, naphthyl, etc.; a heteroaryl such as pyridyl, oxazolyl, pyrrolyl, furanyl, isoxazolyl, fluoropyridyl, trifluoromethylpyridyl, difluoromethoxypyridyl, trifluoromethoxypyridyl, etc.; N(R^{4 a})(R^{4 b}) such as amino, methylamino, dimethylamino, ethylamino, diethylamino, ethylmethylamino, etc.; and preferred are methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, 1 -hydroxy- 1-methylethyl, 1- hydroxycyclopropyl, methoxy, phenyl, isoxazolyl, etc.

The nitrogen-containing hetero ring to be formed by R² and Z that are taken together with the atom to which they bond, includes the following:

In the formulae, R^{5 a} represents a hydrogen atom, a halogen, a hydroxy, a C_1-6 alkyl, a halo-Ci-₆ alkyl, a C_1-6 alkoxy, or a 1IaIo-C_1-6 alkoxy; R^{5 b} represents a hydrogen atom, a C_1-6 alkyl, or a halo-Ci-₆ alkyl; n is from 0 to 2.

Above all, preferred are the

In the formulae, R^{5 a} represents a hydrogen atom, a halogen, a hydroxy, a Cj_-6 alkyl, a halo-Ci-₆ alkyl, a Ci_-6 alkoxy, or a halo-Ci_-6 alkoxy; R^{5 b} represents a hydrogen atom, a Ci_-6 alkyl, or a halo-Ci_-6 alkyl. ml, m2, m3 and m4 each independently indicate 0, 1, 2, 3 or 4, provided that the total of ml and m2 is from 2 to 6, and the total of m3 and m4 is from 2 to 6, and any -CH₂- forming the spiro ring may be replaced by -O- and/or -C(O)-. That is, when ml, m2, m3 or m4 is from 1 to 4, any -CH₂- may be replaced by -O- and/or -C(O)-. The total of ml and m2 is preferably from 2 to 4, and the total of m3 and m4 is preferably from 2 to 3.

W represents C, S or SO.

In one embodiment, W is C. In another embodiment, W is S. In still another embodiment, W is SO. In the invention, the group of a formula (A):

includes, for example, the following:

Above all, the following are recommended:

Ar₁ represents a 6-membered aryl optionally substituted with a substituent selected from the group α, or represents a 6-membered nitrogen-containing heteroaryl optionally substituted with a substituent selected from the group α. Ar₁ may be substituted with the same or different, from 1 to 4, preferably 1 or 2 substituents selected from the group α. The 6-membered aryl for Ar₁ includes a benzene ring; and the 6-membered nitrogen-containing heteroaryl includes a pyridine ring, a pyrazine ring, a pyrimidine ring, a pyridazine ring, etc.

The substituent selected from the group α for Ar₁ is preferably a halogen, especially a fluorine atom, a cyano group or a chlorine atom. Concretely, the 6-membered aryl for Ar₁ includes phenyl, 4-fluorophenyl, 3,4- difluorophenyl, 3,4,5-trifluorophenyl, etc.; and the 6-membered nitrogen-containing heteroaryl includes pyridyl, 5-fluoropyridin-2-yl, 5-chloropyridin-2-yl, etc. Preferred is the 6-membered aryl group substituted with from 1 to 3 fluorine atoms, cyano groups or chlorine atoms, or the 6- membered nitrogen-containing heteroaryl substituted with from 1 to 3 fluorine atoms, cyano groups or chlorine atoms; more preferred is a phenyl substituted with from 1 to 3 fluorine atoms, cyano groups or chlorine atoms, or a pyridyl substituted with from 1 to 3 fluorine atoms, cyano groups or chlorine atoms; and even more preferred is 4-fluorophenyl, 3,4-difluorophenyl or 3,4,5 -trifluoropheny 1.

Ar₂ represents a 6-membered aryl or a 5- or 6-membered heteroaryl, wherein the aryl or the heteroaryl may be substituted with a substituent selected form the group α, for example, with the same or different, from 1 to 4, preferably one or two substituents selected from the group α. The 6-membered aryl for Ar₂ includes a benzene ring; and the 5- or 6-membered heteroaryl includes a pyridine ring, an pyrazine ring, a pyrimidine ring, a pyridazine ring, a thiophene ring, a thiazole ring, an oxazole ring, a thiadiazole ring, an oxadiazole ring, etc. These may be optionally substituted with a substituent selected from the group α.

Preferably, the substituent selected from the group α for Ar₂ includes a halogen such as fluorine, chlorine, etc.; a Ci_-6 alkyl such as methyl, ethyl, etc.; a C_1-6 alkyloxy such as methoxy, ethoxy, etc.; a C]_-6 alkylsulfonyl such as methanesulfonyl, ethanesulfonyl, etc.; a cyano group, etc.

More concretely, Ar₂ preferably includes 1 ,4-phenylenediyl, 3- methoxyphenylene- 1 ,4-diyl, 3-methanesulfonylphenylene- 1 ,4-diyl, 2-fluorophenylene- 1 ,4-diyl, 3-fluorophenylene-l,4-diyl, 2-methylphenylene-l,4-diyl, pyridine-2,5-diyl, pyrimidine-2,5-diyl, pyrazine-2,5-diyl, pyridazine-3,6-diyl, thiophene-2,5-diyl, pyridonediyl, etc.

More preferably, Ar₂ is phenylenediyl, pyridinediyl or pyrimidinediyl, even more preferably 1 ,4-phenylenediyl, pyridin-2,5-diyl or pyrimidine-2,5-diyl.

Ar₃ represents a mono- or bi-cyclic aryl or heteroaryl, or a pyridone, wherein the aryl, the heteroaryl or the pyridine may form a condensed ring with a non-aromatic cyclic hydrocarbon or a non-aromatic hetero ring, and wherein the aryl, the heteroaryl or the pyridone may be optionally substituted with the same or different, from 1 to 4 substituents selected from a halogen, a Ci_-6 alkyl, a halo-Ci_-6 alkyl, a hydroxy-Ci-₆ alkyl, a Ci_-6 alkyloxy, a halo-Ci_-6 alkyloxy, a C_3-6 cycloalkyl, a hydroxy-C_3-6 cycloalkyl, a cyano, a carbamoyl, a mono-Ci_-6 alkylcarbamoyl, a di-d-₆ alkylcarbamoyl, a Ci_-6 alkylsulfonyl and a sulfonylamide.

The substituent for Ar₃ includes a halogen such as fluorine, chlorine, etc.; a Ci_-6 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, etc.; a halo-Ci_-6 alkyl such as fiuoromethyl, difiuoromethyl, trifluoromethyl, trichloromethyl, etc.; a hydroxy-Ci_-6 alkyl such as hydroxymethyl, hydroxyethyl, etc.; a Ci_-6 alkyloxy such as methoxy, ethoxy, n-propyloxy, isopropyloxy, etc.; a halo-Ci_-6 alkyloxy such as chloromethoxy, fluoromethoxy, trifluoromethoxy, etc.; a C_3-6 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, etc.; a hydroxy-C_3-6 cycloalkyl such as hydroxycyclopropyl, hydroxycyclobutyl, etc.; a cyano; a carbamoyl; a mono-C_1-6 alkylcarbamoyl such as methylcarbamoyl, ethylcarbamoyl, etc.; a di-Cj. 6 alkylcarbamoyl such as dimethylcarbamoyl, diethylcarbamoyl, etc.; a Ci_-6 alkylsulfonyl such as methanesulfonyl, ethanesulfonyl, etc.; and a sulfonylamide. Ar₃ may be substituted with the same or different, from 1 to 4, preferably 1 or 2 these substituents.

The mono- or bi-cyclic aryl includes a benzene ring, a naphthalene ring, etc.

The monocyclic heteroaryl includes a pyridine ring, a pyrazine ring, a pyridazine ring, a pyrimidine ring, a thiadiazole ring, an isothiazole ring, etc.

The bicyclic heteroaryl which may form a condensed ring with a non-aromatic cyclic hydrocarbon or a non-aromatic hetero ring includes an imidazopyridine ring, a naphthyridine ring, a quinoxaline ring, a quinazoline ring, etc., and the following:

Ar₃ preferably includes the following:

Above all, more preferred are the following:

Of the compounds of formula (I), preferred are those selected from the following group:

N-[(lR) or (lS)-l-(5-{[6-(5-cyano-3-pyridinyl)-2,6-diazaspiro[3.3]hept-2-yl]methyl}-2- pyridinyl)- 1 -(3,4-difluorophenyl)ethyl]-2,2-difluoroacetamide,

N-[(1R) or (lS)-l-(5-{(lR) or (lS)-l-[6-(5-cyano-3-pyridinyl)-2,6-diazaspiro[3.3]hept-2- yl]ethyl}-2-pyridinyl)-l-(3,4-difluorophenyl)ethyl]-2,2-difluoroacetamide,

N- [( 1 R) or ( 1 S)- 1 -(5- { [6-(5-cyano-3 -pyridinyl)-2,6-diazaspiro [3.3 ]hept-2-yl]methyl } -2- pyridinyl)- 1 -(3 ,4-difluorophenyl)ethyl] -2-methylpropanamide, N-[(1R) or (lS)-l-(5-{[6-(5-cyano-3-pyridinyl)-2,6-diazaspiro[3.3]hept-2-yl]methyl}-2- pyridinyl)- 1 -(3 ,4-difluorophenyl)ethyl]cyclopropanecarboxamide trifluoroacetate, N-[(lR) or (lS)-l-(5-{[6-(5-cyano-3-pyridinyl)-2,6-diazaspiro[3.3]hept-2-yl]methyl}-2- pyridinyl)- 1 -(3 ,4-difluorophenyl)ethyl]-2-hydroxy-2-methylpropanemide trifluoroacetate, N-[(R) or (S)-(5-{[6-(5-cyano-3-pyridinyl)-2,6-diazaspiro[3.3]hept-2-yl]methyl}-2- pyridinyl)(cyclopropyl)(3,4-difluorophenyl)methyl]-2,2-difluoroacetamide trifluoroacetate, N-[( 1 R) or ( 1 S)- 1 -(5- { [6-(5-cyano-3-pyridinyl)-2,6-diazaspiro[3.3]hept-2-yl]methyl} -2- pyridinyl)- 1 -(3 ,4-difluorophenyl)-2,2-difluoroethyl]acetamide trifluoroacetate, N- [( 1 R) or ( 1 S)- 1 -(3 ,4-difluorophenyl- 1 -5 - { [6-(5-methyl-3 -pyridinyl)-2,6-diazaspiro [3.3]hept-2- yl]methyl } -2-pyridinyl)ethyl-2,2-difluoroacetamide trifluoroacetate, N-[(lR) or (lS)-l-(3,4-difluorophenyl-l-5-{[6-(5-fluoro-3-pyridinyl)-2,6-diazaspiro[3.3]hept-2- yl]methyl}-2-pyridinyl)ethyl-2,2-difluoroacetamide trifluoroacetate, N-[(lR) or (lS)-l-(5-{[6-(5-chloro-3-pyridinyl)-2,6-diazaspiro[3.3]hept-2-yl]methyl}-2- pyridinyl)- 1 -(3 ,4-difluorophenyl)ethyl-2,2-difluoroacetamide trifluoroacetate, N-[(lR) or (lS)-l-(3,4-difluorophenyl)-l-[5-({6-[5-(trifluoromethyl)-3-pyridinyl]-2,6- diazaspiro[3.3]hept-2-yl}methyl)-2-pyridinyl]ethyl}-2,2-difluoroacetamide trifluoroacetate, N-[(lR) or (lS)-l-(3,4-difluorophenyl)-l-(5-{[6-(6-methyl-2-pyridinyl)-2,6-diazaspiro[3.3]hept- 2-yl]methyl}-2-pyridinyl)ethyl]-2,2-difluoroacetamide trifluoroacetate,

N-[(lR) or (lS)-l-(3,4-difluorophenyl)-l-(5-{[6-(6-methyl-3-pyridinyl)-2,6-diazaspiro[3.3]hept- 2-yl]methyl}-2-pyridinyl)ethyl]-2,2-difluoroacetamide trifluoroacetate, N-[(1R) or (lS)-l-(3,4-difluorophenyl)-l-(5-{[6-(6-fluoro-3-pyridinyl)-2,6-diazaspiro[3.3]hept- 2-yl]methyl}-2-pyridinyl)ethyl]-2,2-difluoroacetamide trifluoroacetate, N-[(lR) or (lS)-l-(5-{[6-(5-cyano-3-pyridinyl)-2,6-diazaspiro[3.3]hept-2-yl]methyl}-2- pyridinyl)- 1 -(3 ,4,5-trifluorophenyl)ethyl]-2,2-difluoroacetamide trifluoroacetate, and N-[(lR) or (lS)-l-(5-{[6-(5-cyano-3-pyridinyl)-2,6-diazasρiro[3.3]hept-2-yl]methyl}-2- pyridinyl)- 1 -(3,4-difluorophenyl)-2,2,2-trifluoroethyl]acetamide trifluoroacetate.

Especially more preferred are those selected from the following group: N-[(lR) or (lS)-l-(5-{[6-(5-cyano-3-pyridinyl)-2,6-diazaspiro[3.3]hept-2-yl]methyl}-2- pyridinyl)- 1 -(3 ,4-difluorophenyl)ethyl] -2,2-difluoroacetamide, N-[(1R) or (lS)-l-(5-{(lR) or (lS)-l-[6-(5-cyano-3-pyridinyl)-2,6-diazaspiro[3.3]hept-2- yl]ethyl}-2-pyridinyl)-l-(3,4-difluorophenyl)ethyl]-2,2-difluoroacetamide,

N-[(R) or (S)-(5-{[6-(5-cyano-3-pyridinyl)-2,6-diazaspiro[3.3]hept-2-yl]methyl}-2- pyridinyl)(cyclopropyl)(3,4-difluorophenyl)methyl]-2,2-difluoroacetamide trifluoroacetate, N-[(lR) or (lS)-l-(5-{[6-(5-cyano-3-pyridinyl)-2,6-diazasρiro[3.3]hept-2-yl]methyl}-2- pyridinyl)- 1 -(3,4-difluorophenyl)-2,2-difluoroethyl]acetamide trifluoroacetate, N-KlR) or (IS)-I -(3,4-difluorophenyl-l -5-{ [6-(5-methyl-3-ρyridinyl)-2,6-diazaspiro[3.3]hept-2- yl]methyl}-2-pyridinyl)ethyl -2,2-difluoroacetamide trifluoroacetate,

N-[(lR) or (lS)-l-(3,4-difluorophenyl-l-5-{[6-(5-fluoro-3-pyridinyl)-2,6-diazaspiro[3.3]hept-2- yl]methyl } -2-pyridinyl)ethyl-2,2-difluoroacetamide trifluoroacetate, N-[(lR) or (lS)-l-(5-{[6-(5-chloro-3-pyridinyl)-2,6-diazaspiro[3.3]hept-2-yl]methyl}-2- pyridinyl)- 1 -(3 ,4-difluorophenyl)ethyl-2,2-difluoroacetamide trifluoroacetate,

N-[(1R) or (lSVl-CS^-difluorophenyO-l-CS-ltό-Cό-fluoro-S-pyridinyO^^-diazaspiropJlhept- 2-yl]methyl}-2-pyridinyl)ethyl]-2,2-difluoroacetamide trifluoroacetate, N-KlR) or (lS)-l-(5-{[6-(5-cyano-3-pyridinyl)-2,6-diazaspiro[3.3]hept-2-yl]methyl}-2- pyridinyl)-l -(3,4,5-trifluorophenyl)ethyl]-2,2-difluoroacetamide trifluoroacetate, and N-[(1R) or (lS)-l-(5-{[6-(5-cyano-3-pyridinyl)-2,6-diazaspiro[3.3]hept-2-yl]methyl}-2- pyridinyl)-l-(3,4-difluorophenyl)-2,2,2-trifluoroethyl]acetamide trifluoroacetate.

Methods for preparing Compounds of Formula (I)

The compounds of formula [I] may be prepared, for example, according to the following production methods, to which, however, the invention should not be limited. Production Method 1 :

In the formulae, X₁ represents a hydroxyl group, a halogen, etc.; and the other symbols are the same as above. Step 1: A compound of formula (II) is reacted with a compound of formula (III) in a reaction solvent to give a compound of formula (I). For the step, referred to are conventional known amidation methods employed for peptide synthesis, for example, the methods described in "Basis and Experiment of Peptide Synthesis" (Nobuo Izumiya, et al., Maruzen, 1983).

The compound of formula (III) includes carboxylic acids, and reaction equivalents of those carboxylic acids, sulfinic acids and sulfonic acids.

The reaction equivalents of carboxylic acids, sulfinic acids or sulfonic acids of formula (III) include acid halides, acid anhydrides, mixed acid anhydrides, active esters, active amides, etc. These reaction equivalents may be commercial products, or may be readily prepared with reference to conventional known methods, for example, the above-mentioned "Basis and Experiment of Peptide Synthesis" (Nobuo Izumiya, et al., Maruzen, 1983).

The amount of the compound of formula (III) to be used may be from 1.0 mol to an excessive molar amount per mol of the compound of formula (II), preferably from 1.0 to 1.5 mols.

In particular, when the compound of formula (III) is a carboxylic acid, the condensation is preferably attained in the presence of a condensing agent. For example, a method is exemplified, in which is used a condensing agent such as N,N'- dicyclohexylcarbodiimide, 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (hereinafter referred to as "EDCI-HCl") or the like in the presence or absence of, preferably in the presence of an N-hydroxy compound such as 1 -hydroxybenzotriazole (hereinafter referred to as "HOBt"), l-hydroxy-7-azabenzotriazole (hereinafter referred to as "HOAt") or the like.

The amount of the condensing agent to be used may be generally from 1.0 mol to an excessive molar amount per mol of the compound of formula (II), preferably from 1.0 to 1.5 mols.

The amount of the N-hydroxy compound, when used, may be from 1.0 mol to an excessive molar amount per mol of the compound of formula (II), preferably from 1.0 to 1.5 mols. The condensation may go on in the absence of a base, but for smooth reaction, the reaction is preferably in the presence of a base. For example, usable is an organic base such as triethylamine, N,N-diisopropylamine, pyridine, lithium-bis(trimethylsilyl)arnide, etc,; an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, etc.

The amount of the base to be used may be generally from 1.0 mol to an excessive molar amount per mol of the compound of formula (II), preferably from 1.0 to 4.0 mols. When the base is liquid, the base may serve also as a solvent.

In the reaction with the above-mentioned reaction equivalent, a basic catalyst such as dimethylaminopyridine or the like may be used as a catalyst for promoting the reaction. The amount of the catalyst to be used may be from 0.1 to 5.0 mols per mol of the compound of formula (II), preferably from 0.1 to 0.5 mols.

The reaction solvent includes halogenohydrocarbons such as methylene chloride, chloroform, etc.; ethers such as diethyl ether, tetrahydrofuran (hereinafter referred to as "THF"), 1,4-dioxane, etc.; acetonitrile, N,N-dimethylformamide (hereinafter referred to as "DMF"), dimethylsulfoxide (hereinafter referred to as "DMSO"), pyridine, etc.; mixed solvents thereof, etc.

The reaction temperature may be generally from -50 to 100°C, preferably from 0 to 5O⁰C. The reaction time may be generally from 5 minutes to 7 days, preferably from 30 minutes to 24 hours. Production Method 2:

The production method 2 is method for preparing the compound of formula (I), starting from a compound of formula (IV). S

In the formulae, X₂ represents a leaving group such as methanesulfonyloxy, p- toluenesulfonyloxy, halogen, etc.; and the other symbols are the same as above. Step 2:

The compound of formula (IV) is reacted with a compound of formula (V) in a solvent, preferably in the presence of a base to give the compound of formula (I).

The amount of the compound of formula (V) to be used may be from 1.0 to 1.5 mols per mol of the compound of formula (IV), preferably from 1.0 to 1.3 mols. The base includes inorganic bases such as sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate, lithium carbonate, etc.; organic bases such as triethylamine, diisopropylethylamine, pyridine, etc. The amount of the base to be used may be from 1.0 to 5.0 mols per mol of the compound of formula (IV), preferably from 1.1 to 1.5 mols.

The reaction solvent includes halogenohydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, etc.; ethers such as diethyl ether, THF, 1,4-dioxane, etc.; DMF, DMSO, etc.

The reaction temperature may be from 0 to 100⁰C, preferably from 10 to 40⁰C, and the reaction may complete, generally from 1 to 24 hours.

The compounds of formula (IV) and formula (V) may be prepared according to the method described in PCT/JP2009/56096, PCT/JP2009/60687, or according to the methods to be described hereinunder. Production Method 3: The production method 3 is method for preparing the compound of formula (V).

Scheme 3

(V) In the formulae, Pi represents an amino-protective group; and the other symbols are the same as above.

Step 3: A compound of formula (VI) is reacted with a compound of formula (VII) according to PCT/JP2009/60687, to give a compound of formula (V-a). The compound of formula (VI) may be any conventional known compound, or may be prepared by introducing a protective group P₁ to the corresponding known spirodiamine.

Step 4: The protective group (Pi) of the compound of formula (V-a) is removed to give the compound of formula (V). The deprotection may be attained according to methods described in literature [see Protective Groups in Organic Synthesis, T. W. Greene, John Wiley & Sons,

1981], or according to methods similar thereto. For example, when P₁ is a tert-butyloxycarbonyl (Boc) group, the compound may be deprotected by treatment with trifluoroacetic acid, hydrochloric acid or the like, at room temperature to 100°C, preferably at room temperature to 6O⁰C, for 10 minutes to 6 hours, preferably for 0.5 to 2 hours. Production Method 4:

The production method 4 is method for stereoselective preparation of a compound of formula (I), starting from a compound 1. Scheme 4

1 2

8

In the formulae, the symbols are the same as above. Step 5:

A compound 1 (described in WO2008/038692) is condensed with an optically- active tert-butyl-sulfmamide in the presence of titanium tetraethoxide in a reaction solvent to give a compound 2. For the reaction, referred to is the method described in PCT/JP2009/56096. Step 6: The compound 2 is reacted with a compound 3 in an organic solvent to give a compound 4. For the reaction, referred to is the method described in PCT/JP2009/56096. The compound 3 includes Grignard reagents such as methylmagnesium bromide, cyclopropylmagnesium bromide, etc.; trifluoromethyl anion equivalents which are prepared from trifluoromethyltrimethylsilane and, tetrabutylammonium triphenyldifluorosilicate, etc. Step 7: The hydroxy-protective group Pl of the compound 4 is removed to give a compound 4. For the deprotection, referred to is the above-mentioned Protective Groups in Organic Synthesis. Step 8:

A leaving group is introduced into the hydroxyl group of the compound 5 to give a compound 6. The leaving group includes a halogen, a methanesulfonyloxy group, a p- toluenesulfonyloxy group, etc. Step 9:

The compound 6 is reacted with the compound of formula (V) according to the step 2 to give a compound 7. Step 10:

The tert-butylsulfinyl group of the compound 7 is removed by treating the compound with TFA or an aqueous hydrochloric acid solution at O⁰C to room temperature, thereby to give a compound 8. Step 11: The compound 8 is reacted with the compound of formula (III) according to the step 1 to give the compound of formula (I). Production Method 5:

The production method 5 is method for stereospecific preparation of the compound of formula (I) in an alternative production route.

Scheme 5

13

In the formulae, the symbols are the same as above. Step 12:

The tert-butylsulfinyl group of the compound 4 is removed according to the step 10 to give a compound 9. Step 13:

A protective group (P) is introduced into the hydroxyl group of the compound 9 to give a compound 10. For the protective group, usable are those described in Protective Groups in Organic Synthesis, for example, a silyl-protective group such as a tert- butyldimethylsilyl group, etc. Step 14:

The compound 10 is reacted with the compound of formula (III) according to the step 1 to give a compound 11. Step 15: The hydroxy-protective group P of the compound 11 is removed to give a compound 12. Step 16:

A leaving group is introduced into the hydroxyl group of the compound 12 to give a compound 13. The reaction condition is similar to that in the step 8. Step 17:

The compound 13 is reacted with the compound of formula (V) according to the step 2 to give the compound of formula (I). In the above-mentioned production methods where the reactant substances have an amino group, a hydro xyl group, a carboxyl group, an oxo group, a carbonyl group of the like not participating in the reaction, the amino group, the hydroxyl group, the carboxyl group, the oxo group and the carbonyl group may be suitably protected with an amino-protective group, a hydroxy-protective group, a carboxyl-protective group, or an oxo or carbonyl-protective group, then the reaction in the production method is attained, and after the reaction, the protective group may be removed.

The introduction and the removal of the protective group, through differing depending on the type of the protective group and the stability of the product compound, may be attained, for example, through solvolysis with acid or base, for example, according to the methods described in the above-mentioned Protective Groups in Organic Synthesis, or according to methods similar thereto, concretely, for example, according to a method of treating with from 0.01 mol to a large excessive amount of an acid, preferably trifluoroacetic acid, formic acid, hydrochloric acid or the like, or with from an equimolar amount to a large excessive amount of a base, preferably potassium hydroxide, calcium hydroxide or the like; or through chemical reduction with a metal hydride complex or the like, or through catalytic reduction with a palladium-carbon catalyst, a Raney-nickel catalyst or the like.

Not specifically limited, the amino and imino-protective group may be any one having its function, and includes, for example, an aralkyl such as benzyl, p-methoxybenzyl, 3,4- dimethoxybenzyl, benzhydryl, trityl, etc.; a lower alkanoyl such as formyl, acetyl, pivaloyl, etc.; benzoyl; an arylalkanoyl such as phenylacetyl, etc.; a lower alkyloxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.; an alkyloxycarbonyl such as benzyloxycarbonyl, etc.; a lower alkylsilyl such as trimethylsilyl, tert-butyldimethylsilyl, etc.; tetrahydropyranyl; trimethylsilylethoxymethyl; a lower alkylsulfonyl such as methylsulfonyl, ethylsulfonyl, etc; an arylsulfonyl such as benzenesulfonyl, toluenesulfonyl, etc. Especially preferred are acetyl, benzoyl, tert-butoxycarbonyl, trimethylsilylethoxymethyl, methylsulfonyl, etc.

Not specifically limited, the hydroxyl-protective group may be any one having its function, and includes, for example, a lower alkyl such as methyl, ethyl, tert-butyl, etc.; a lower alkylsilyl such as trimethylsilyl, tert-butyldimethylsilyl, etc.; a lower alkyloxymethyl such as methoxymethyl, 2-methoxyethoxymethyl, etc.; tetrahydropyranyl; trimethylsilylethoxymethyl; an aralkyl such as benzyl, p-methoxybenzyl, 2,3 -dimethoxybenzyl, trityl, etc.; an acyl such as formyl, acetyl, etc. Especially preferred are methyl, methoxymethyl, tetrahydropyranyl, trityl, trimethylsilylethoxymethyl, tert-butyldimethylsilyl, acetyl, etc. Not specifically limited, the carboxyl-protective group may be any one having its function, and includes, for example, a lower alkyl such as methyl, ethyl, tert-butyl, etc.; a halo- lower alkyl such as 2,2,2-trichloroethyl, etc.; a lower alkenyl such as 2-propenyl, etc.; an aralkyl such as benzyl, p-methoxybenzyl, benzhydryl, trityl, etc. Especially preferred are methyl, ethyl, tert-butyl, 2-propenyl, benzyl, p-methoxybenzyl, benzhydryl, etc.

Not specifically limited, the carbonyl-protective group may be any one having its function, and includes, for example, acetals and ketals such as ethylene ketal, trimethyl ketal, S,S'-dimethyl ketal, etc.

The compounds of formula (I) obtained in the manner as above may be readily isolated and purified in any ordinary separation method of, for example, solvent extraction, recrystallization, column chromatography, preparative thin-layer chromatography or the like.

The compounds may be formed into pharmaceutically-acceptable salts thereof in an ordinary manner, or on the contrary, the salts may be converted into free compounds in an ordinary manner.

The effect of the compounds of the invention as an MCH receptor antagonist is shown, for example, by the following pharmacological test example. Pharmacological Test Example: MCH binding inhibition test A human MCH-IR encoding cDNA sequence [FEBS Letters, Vol. 398, 253

(1996); Biochimica et Biophisica Acta, Vol. 1401, 216 (1998)] was cloned to a plasmid vector pEF/myc/cyto (by Invitrogen Corporation). The obtained expression vector was transfected to host cells CHO-Kl (American Type Culture Collection) using Lipofectamine Plus Reagent (by Life Technology Inc.) to provide MCH-IR expression cells. Membrane samples prepared from the MCH-IR expression cells were incubated with each test compound and 50 pM of [¹²⁵I]MCH (by NEN Co.), in an assay buffer (50 mM Tris buffer comprising 10 mM magnesium chloride, 2 mM ethylenediamine tetraacetate, 0.01 % bacitracin and 0.2 % bovine serum albumin; pH 7.4) at 25°C for an hour, followed by filtration through a glass filter GF/C (by Wattman Co.). After washing the glass filter with 50 mM Tris buffer (pH 7.4) comprising 10 mM magnesium chloride, 2 mM ethylenediamine tetraacetate and 0.04 % Tween-20, the radioactive activity on the glass filter was measured. The non-specific binding was measured in the presence of 1 μM human MCH, and the 50 % inhibition concentration (IC₅₀ value) of each test compound to the specific [¹²⁵I]MCH binding was determined. The results are shown in Table 1. Table 1

As in the above, the compounds of the invention strongly inhibit the binding of MCH to MCH-IR, and therefore exhibit an excellent effect as an MCH-IR antagonist.

Accordingly, the compounds of the invention are useful as a preventive or a remedy for various MCH-related diseases, for example, metabolic disorders such as obesity, diabetes, hormone disorder, hyperlipidemia, gout, fatty liver, etc.; cardiovascular disorders such as stenocardia, acute/congestive heart failure, myocardial infarction, coronary atherosclerosis, hypertension, renal diseases, electrolyte abnormality, etc.; central or peripheral nervous system disorders such as bulimia, emotional disturbance, depression, anxiety, epilepsy, delirium, dementia, schizophrenia, attention-deficit hyperactivity disorder, memory impairment, sleep disorders, cognitive failure, dyskinesia, paresthesias, smell disorders, morphine tolerance, drug dependence, alcoholism, etc.; reproductive disorders such as infertility, preterm labor, sexual dysfunction, etc.; and other digestive disorders; respiratory disorders; cancer or pigmentation; especially as a preventive or a remedy for bulimia, obesity, diabetes, fatty liver, depression, anxiety. Pharmaceutical Composition Comprising Compound of Formula OT

The compound of the invention can be orally or parenterally administered, and can be formulated into preparations suitable to the administration thereof, which may be used as pharmaceutical compositions for prevention or treatment for the above-mentioned diseases.

In its clinical use, the compound of the invention may be formulated into various preparations along with a pharmaceutically-acceptable carrier added thereto generally in accordance with the administration route thereof, and the thus-formulated pharmaceutical composition may be administered. Various ordinary additives used in the field of pharmaceutical preparations can be used. For example, they include gelatin, lactose, white sugar, titanium oxide, starch, crystalline cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, corn starch, microcrystalline wax, white petrolatum, magnesium aluminate metasilicate, anhydrous calcium phosphate, citric acid, trisodium citrate, hydroxypropyl cellulose, sorbitol, sorbitan fatty acid esters, polysorbate, sucrose fatty acid esters, polyoxyethylene, hardened castor oil, polyvinylpyrrolidone, magnesium stearate, light silicic anhydride, talc, vegetable oils, benzyl alcohol, gum arabic, propylene glycol, polyalkylene glycol, cyclodextrin, hydroxypropylcyclodextrin, etc.

Preparations to be formed with those additives include, for example, solid preparations such as tablets, capsules, granules, powders, suppositories, etc.; and liquid preparations such as syrups, elixirs, injections, etc. These may be formulated according to ordinary methods known in the field of pharmaceutical preparations. The liquid preparations may also be in such a form that may be dissolved or suspended in water or in any other suitable medium in their use. Especially for injections, if desired, the preparations may be dissolved or suspended in physiological saline water or glucose liquid, and a buffer or a preservative may be optionally added thereto.

The pharmaceutical compositions may contain the compound of the invention in an amount of from 1 to 99.9 % by weight, preferably from 1 to 60 % by weight of the composition. The compositions may further contain any other therapeutically-effective compound.

Specifically, the invention provides a pharmaceutical composition containing a medicinally-acceptable additive, and a therapeutically-effective amount of a compound of the invention or its pharmaceutically-acceptable salt.

The wording, therapeutically-effective amount as referred to herein means the amount of a medicine to induce biological or medical phenomena in animals and humans, that is found by researchers, veterinaries, medical doctors or any other clinicians. In case where the compounds of the invention are used for prevention or treatment for the above-mentioned diseases, then the dose and the dosing frequency may be varied, depending on the sex, the age, the body weight and the disease condition of the patient, on the type and the range of the intended remedial effect, etc. In general, in oral administration, the dose may be from 0.001 to 50 mg/kg of body weight/day, and it may be administered at a time or in a few times. The dose is preferably from about 0.01 to about 25 mg/kg/day, more preferably from about 0.05 to about 10 mg/kg/day.

As combination therapy, the compounds of the invention can be used in combination with drugs effective for hypertension, obesity-associated hypertension, hypertension-associated diseases, hypertrophy, left ventricular hypertrophy, metabolic disorders, obesity, obesity-associated diseases and the like (hereafter referred to as "co-drugs"). Such drugs can be administered simultaneously, separately or in succession, for prevention or treatment of the above-mentioned diseases. When a compound of the invention is used simultaneously with one, two or more of co-drugs, they may be formulated into a medical preparation suited for single administration form. Whereas, in combination therapy, a composition containing the compound of the invention and co-drugs may be administered to the object of medication in different packages, either simultaneously, separately or successively. They may be administered at time intervals.

The dose of the co-drug may be determined in accordance with the clinically adopted dose thereof, which can be suitably selected according to the individual object of medication, the administration route, the specific disease, the combination of drugs, and the like. The form of the co-drug for administration is not specifically defined, and it may be combined with the compound of the invention when they are administered.

The administration mode includes, for example, the following: (I) A compound of the invention is combined with a co-drug to give a single preparation for single administration; (2) a compound of the invention and a co-drug are separately formulated into different two preparations, and the two preparations are simultaneously administered in one administration route; (3) a compound of the invention and a co-drug are separately formulated into different two preparations, and they are administered at different times in one and the same administration route; (4) a compound of the invention and a co-drug are separately formulated into different two preparations, and they are administered at the same time in two different administration routes; (5) a compound of the invention and a co-drug are separately formulated into different two preparations, and they are administered at different times in different administration routes (for example, a compound of the invention and a co-drug are administered in that order, or in an order contrary to this). The blend ratio of the compound of the invention and the co-drug may be suitably determined depending on the administration object, the administration route, the disease for the administration, etc. The co-drugs usable in the invention include, for example, drugs for diabetes, drugs for hyperlipidemia, drugs for hypertension, anti-obesity drugs. Two or more such co- drugs may be combined in an adequate ratio and used.

The remedy for diabetes include, for example, 1) PPAR-γ agonists such as glitazones (e.g., ciglitazone, darglitazone, englitazone, isaglitazone (MCC-555) et al), pioglitazone, rosiglitazone, troglitazone, BRL49653, CLX-0921, 5 -BTZD, GW-0207, LG- 100641, LY-300512et al; 2) biguanides such as metformin, buformin, phenformin et al; 3) protein tyrosine phosphatase IB inhibitors; 4) sulfonylureas such as acetohexamide, chloropropamide, diabinese, glibenclamide, glipizide, glyburide, glimepiride, gliclazide, glipentide, gliquidone, glisolamide, trazamide, tolubutamide et al; 5) meglitinides such as repaglinide, nateglinide et al; 6) α-glucoside hydroxylase inhibitors such as acarbose, adiposine, camiglibose, emiglitate, miglitol, voglibose, pradimicin-Q, salbostatin, CKD-711, MDL-25, 673, MDL-73, 945, M0R14 et al; 7) α-amylase inhibitors such as tendamistat, trestatin, A13688 et al; 8) insulin secretion promoters such as linogliride, A-4166 et al; 9) fatty acid oxidation inhibitors such as clomoxir, etomoxir et al; 10) A2 antagonists such as midaglizole, isaglidole, deriglidole, idazoxan, earoxan, fluparoxan et al; 11) insulin or insulin mimetics such as biota, LP-100, novalapid, insulindetermir, insulin lispro, insulin glargine, insulin zinc, Lys-Pro-insulin, GLP-I (73-7), GLPl amide (7-36) et al; 12) non-thiazolidinediones such as JT-501, farglitazar et al; 13) PPARα/γ dual-agonists such as MK-0767, CLX-0940, GW- 1536, GW- 1929, GW-2433, KRP- 297, L-796449, LR-90 and SB219994 et al.

The remedy for hyperlipidemia include, for example, 1) bile acid absorption promoters such as cholesterylamine, colesevelem, colestipol, crosslinked dextran dialkylaminoalkyl derivatives, Colestid™, LoCholest™, Questran™ et al; 2) HMG-CoA reductase inhibitors such as atorvastatin, itavastatin, fluvastatin, lovastatin, pravastatin, rivastatin, rosuvastatin, simvastatin, ZD-4522 et al; 3) HMG-CoA synthase inhibitors; 4) cholesterol absorption inhibitors such as snatol ester, β-sitosterol, sterol glucoside, ezetimibe et al; 5) acyl- coenzyme A-cholesterol acyl transferase inhibitors such as avasimibe, eflucimibe, KY-505, SMP-709 et al; 6) CETP inhibitors such as JTT705, torcetrapib, CP532632, BAY-63-2149, SC- 591, SC-795 et al; 7) squalane synthesis inhibitors; 8) antioxidants such as probucol; 9) PPAR-α agonists such as beclofibrate, benzafibrate, ciprofibrate, clofibrate, etofibrate, fenofibrate, gemcabene, gemfibrozil, GW-7647, BM-170744, LY-518674, fibric acid derivatives (e.g., Atromid™, Lopid™, Tricor™) et al; 10) FXR receptor antagonists such as GW-4064, SR- 103912 et al; 11) LXR receptor agonists such as GW3965, T9013137, XTCO-179628 et al; 12) lipoprotein synthesis inhibitors such as niacin; 13) renin-angiotensin system inhibitors; 14) microsome-triglyceride transport inhibitors; 15) bile acid resorption inhibitors such as BARA1453, SC435, PHA384640, S-435, AZD7706 et al; 16) PPAR-δ agonists such as GW501516, GW590735 et al; 17) triglyceride synthesis inhibitors; 18) MTTP inhibitors such as LAB687, CP346086 et al; 19) low-density lipoprotein receptor inducers; 20) squalane epoxidase inhibitors; 21) platelet agglutination inhibitors; 22) 5 -lipoxygenase activated protein inhibitors such as MK-591.

The remedy for hypertension include, for example, 1) thiazide diuretics such as chlorothialidon, chlorothiazide, dichlorofenamide, hydrofluorothiazide, indapamide, hydrochlorothiazide et al; loop diuretics such as bumetanide, ethacrynic acid, flosemide, tolusemide et al; sodium diuretics such as amyloride, triamterene et al; aldosterone antagonist diuretics such as spironolactone, epilenone et al; 2) β-adrenaline blockers such as acebutolol, atenolol, betaxolol, bevantolol, bisoprolol, bopindolol, carteolol, carvedilol, celiprolol, esmolol, indenolol, metaprolol, nadolol, nebivolol, penbutolol, pindolol, probanolol, sotalol, tertatolol, tilisolol, timolol et al; 3) calcium channel blockers such as amlodipine, aranidipine, azelnidipine, barnidipine, benidipine, bepridil, cinaldipine, clevidipine, diltiazem, efonidipine, felodipine, gallopamil, isradipine, lacidipine, lemildipine, lercanidipine, nicardipine, nifedipine, nilvadipine, nimodepine, nisoldipine, nitrendipine, manidipine, pranidipine, verapamil et al; 4) angiotensin converting enzyme inhibitors such as benazepril, captopril, cilazapril, delapril, enalapril, fosinopril, imidapril, rosinopril, moexipril, quinapril, quinaprilat, ramipril, perindopril, perindoropril, quanipril, spirapril, tenocapril, trandolapril, zofenopril et al; 5) neutral endopeptidase inhibitors such as omapatrilat, cadoxatril, ecadotril, fosidotril, sampatrilat, AVE7688, ER4030 et al; 6) endotheline antagonists such as tezosentan, A308165, YM62899 et al; 7) vasodilators such as hydralazine, clonidine, minoxidil, nicotinyl alcohol et al; 8) angiotensin II antagonists such as candesartan, eporsartan, iribesartan, losartan, pratosartan, tasosartan, telmisartan, valsartan, EXP-3137, FI6828K, RNH6270 et al; 9) α/β adrenaline blockers such as nipradilol, arotinolol, amoslalol et al; 10) αl blockers such as terazosin, urapidil, prazosin, bunazosin, trimazosin, doxazosin, naphthopidil, indolamin, WHIP 164, XENOlO et al; 11) α2 agonists such as lofexidine, tiamenidine, moxonidine, rilmenidine, guanobenz et al; and 12) aldosterone inhibitors.

The anti-obesity drugs include, for example, 1) 5HT (serotonin) transporter inhibitors such as paroxetine, fluoxetine, fenfluramine, fluvoxamine, sertraline, imipramine et al; 2) norepinephrine transporter inhibitors such as GW320659, desipramine, talsupram, nomifensin et al; 3) cannabinoid-1 receptor 1 (CB-I) antagonists/inverse-agonists such as limonabant (Sanofi Synthelabo), SR- 147778 (Sanofi Synthelabo), BAY-65-2520 (Bayer), SLV-319 (Solvey), as well as compounds disclosed in USP 5,532,237, USP 4,973,587, USP 5,013,837, USP 5,081,122, USP 5,112,820, USP 5,292,736, USP 5,624,941, USP 6,028,084, WO96/33159, WO98/33765, WO98/43636, WO98/43635, WO01/09120, WO01/96330, WO98/31227, WO98/41519, WO98/37061, WO00/10967, WOOO/10968, WO97/29079, WO99/02499, WO01/58869, WO02/076949, WO01/64632, WO01/64633, WO01/64634, WO03/006007, WO03/007887 and EP-658546 et al; 4) ghrelin antagonists such as compounds disclosed in WO01/87355, WO02/08250 et al; 5) histamine(H3) antagonists/inverse-agonists such as thioperamide, 3-(lH-imidazol-4-yl)propyl N-(pentenyl)carbonate, clobenpropit, iodofenpropit, imoproxyfen, GT2395, A331440, compounds disclosed in WO02/15905, O-[3-(lH-imidazol-4- yl)propanol] carbamate, piperazine-containing H3-receptor antagonists (Lazewska, D. et al., Pharmazie, 56: 927-32 (2001), benzophenone derivatives (Sasse, A. et al., Arch. Pharm. (Weinheim) 334: 45-52 (2001)), substituted N-phenylcarbamates (Reidemeister, S. et al., Pharmazie, 55: 83-6 (2000)), proxyfen derivatives (Sasse, A. et al., J. Med. Chem., 43: 3335-43 (2000)) et al; 6) MCH-IR antagonists such as T-226296 (Takeda), SNP-7941 (Synaptic), other compounds disclosed in WO01/82925, WO01/87834, WO02/051809, WO02/06245, WO02/076929, WO02/076947, WO02/04433, WO02/51809, WO02/083134, WO02/094799, WO03/004027 and JP-A-2001-226269 et al; 7) MCH-2R agonists/antagonists; 8) NPYl antagonists such as isopropyl 3-chloro-5-(l-(6-[2-(5-ethyl-4-methyl-thiazol-2-yl)-ethyl]-4- morpholinyl-4-yl-piridin-2-ylamino)-ethyl)phenyl]carbamate, BIBP3226, BIBO3304, LY- 357897, CP-671906, GI-264879, and other compounds disclosed in USP 6,001,836, WO96/14307, WO01/23387, WO99/51600, WO01/85690, WO01/85098, WO01/85173 and WO01/89528 et al; 9) NPY5 antagonists such as 152804, GW-569180A, GW-594884A, GW- 587081X, GW-548118X, FR235,208, FR226928, FR240662, FR252384, 1229U91, GI-264879A, CGP71683A, LY-377897, LY366377, PD-160170, SR-120562A, SR-120819A, JCF-104, H409/22, and other compounds disclosed in USP 6,140,354, USP 6,191,160, USP 6,258,837, USP 6,313,298, USP 6,337,332, USP 6,329,395, USP 340,683, USP 6,326,375, USP 6,329,395, USP 6,337,332, USP 6,335,345, EP-01010691, EP-01044970, WO97/19682, WO97/20820, WO97/20821, WO97/20822, WO97/20823, WO98/27063, WO00/107409, WO00/185714, WOOO/185730, WO00/64880, WO00/68197, WO00/69849, WO01/09120, WO01/14376, WO01/85714, WO1/85730, WO01/07409, WO01/02379, WO01/02379, WO01/23388, WO01/23389, WO01/44201, WO01/62737, WO01/62738, WO01/09120, WO02/20488, WO02/22592, WO02/48152, WO02/49648, WO02/094789, and compounds disclosed in Norman et al., J. Med. Chem., 43:4288-4312(2000) et al; 10) leptins such as human recombinant leptin (PEG-OB, Hoffman La Roche), recombinant methionylleptin (Amgen) et al; 11) leptin derivatives such as compounds disclosed in USP 5,552,524, USP 5,552,523, USP 5,552,522, USP 5,521,283, WO96/23513, WO96/23514, WO96/23515, WO96/23516, WO96/23517, 96/23518, WO96/23519 and WO96/23520 et al; 12) opioid antagonists such as nalmefen (Revex ), 3-methoxynaltorexone, naloxone, naltorexone, compounds disclosed in WO00/21509 et al; 13) orexin antagonists such as SB-334867A, and other compounds disclosed in WO01/96302, WO01/68609, WO02/51232, WO02/51838 and WO03/023561 et al; 14) bombesin receptor subtype-3 agonists; 15) cholecystokinin A (CCK-A) agonists such as AR- R15849, GI-181771, JMV-180, A-71378, A-71623, SR-146131, and other compounds disclosed in USP 5,739,106 et al; 16) CNTF (ciliary neurotrophic factors) such as GI-181771 (Glaxo-

Smith Kline), SR146131 (Sanofi Synthelabo), butabindide, PD170,292, PD149164 (Pfizer) et al; 17) CNTF derivatives such as axokine (Regeneron), and other compounds disclosed in WO94/09134, WO98/22128, WO99/43813 et al; 18) growth hormone secretion receptor agonists such as NN703, hexarelin, MK-0677, SM-130686, CP-424,391, L-692,429, L-163,255, and compounds disclosed in USP 6,358,951, US Patent Application Nos. 2002/049196, 2002/022637, WO01/56592, WO02/32888 et al; 19) serotonin receptor-2C agonists such as BVT933, DPCA37215, IK264, PNU22394, WAY161503, R-1065, YM348, and other compounds disclosed in USP 3,914,250, WO02/36596, WO02/48124, WO02/10169, WO01/66548,

WO02/44152, WO02/51844, WO02/40456 and WO02/40457 et al; 20) melanocortin-3 receptor agonists; 21) melanocortin-4 receptor agonists such as CHIR86036 (Chiron), ME-10142, ME- 10145 (Melacure), and other compounds disclosed in WO99/64002, WO00/74679, WO01/991752, WO01/74844, WO01/70708, WO01/70337, WO01/91752, WO02/059095, WO02/059107, WO02/059108, WO02/059117, WO02/12166, WO02/11715, WO02/12178, WO02/15909, WO02/068387, WO02/068388, WO02/067869, WO03/007949 and WO03/009847 et al; 22) monoamine resorption inhibitors such as sibutramine (Meridia™/Reductil™) and its salts, and other derivatives disclosed in USP 4,746,680, USP 4,806,570, USP 5,436,272, US Patent Application No. 2002/0006964, WO01/27068 and WO01/62341 et al; 23) serotonin re-uptake inhibitors such as dexfenfluramine, fluoxetine, and other compounds disclosed in USP 6,365,633, WO01/27060 and WOOl/162341 et al; 24) glucagon-like peptide- 1 agonists; 25) topiramate (Topimax™); 26) phytopharm compound 57 (e.g., CP644,673); 27) acetyl CoA carboxylase-2 (ACC2) inhibitors; 28) β-adrenalin receptor-3 agonists such as AD9677/TAK677 (Dai-Nippon Pharmaceutical/Takeda Chemical), CL-316,243, SB418790, BRL-37344, L-796568, BMS-196085, BRL-35135A, CGP12177A, BTA-243, W427353, Trecadrine, Zeneca D7114, SR59119A, and other compounds disclosed in USP 5,705,515, USP 5,451,677, WO01/74782 and WO02/32897 et al; 29) diacylglycerol acyltransferase-1 inhibitors; 30) diacylglycerol acyltransferase-2 inhibitors, 31) fatty acid synthesis inhibitors such as carulenin, C75; 32) phosphodiesterase inhibitors such as theophylline, pentoxiphylline zaprinast, sildenafil, amrinone, milrinone, cilostamide, rolipram and cilomilast et al; 33) thyroid hormone-β agonists such as KB-2611 (KaroBio BMS), and other compounds disclosed in WO02/15845, JP-A-2000-256190 et al; 34) UCP (uncoupling protein)-l, 2, or 3 activators such as phytanic acid, 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2- naphthalenyl)-l-propenyl]benzoic acid (TTNPB), retinoic acid, and other compounds disclosed in WO99/00123 et al; 35) acylestrogens such as oleoylestrone, and other compounds disclosed in del Mar-Grasa, M. et al., Obesity Research, 9:202-9 (2001) et al; 36) glucocorticoid antagonists; 37) 11-β-hydroxysteroid dehydrogenase- 1 inhibitors such as BVT3498, BVT2733, and other compounds disclosed in WO01/90091, WO01/90090, WO01/90092 et al; 38) stearoyl-CoA desaturase-1 inhibitors; 39) dipeptidyl peptidase-IV inhibitors such as isoleucine thiazolidide, valine pyrrolidide, NVP-DPP728, AF237, P93/01, TSL225, TMC-2A/2B/2C, FE999011, P9310/K364, VIPOl 77, SDZ274-444, and other compounds disclosed in WO03/004498, WO03/004496, EP1258476, WO02/083128, WO02/062764, WO03/000250, WO03/002530, WO03/002531, WO03/002553, WO03/002593, WO03/000180 and WO03/000181 et al; 40) lipase inhibitors such as tetrahydroliptatin (Orlistat/Xenical™), Triton WRl 339, RHC80267, lipstatin, teasaponin, diethylumbelliferyl phosphate, FL-386, WAY-121898, Bay-N-3176, valilactone, esteracin, ebelactone A, ebelactone B, RHC80267, and other compounds disclosed in WO01/77094, USP 4,598,089, USP 4,452,813, USP 5,512,565, USP 5,391,571, USP 5,602,151, USP 4,405,644, USP 4,189,438 and USP 4,242,453 et al; 41) fatty acid transporter inhibitors; 42) dicarboxylate transporter inhibitors; 43) glucose transporter inhibitors; 44) phosphate transporter inhibitors.

The above-mentioned combined drugs are obtained by combining a compound of the invention with one, two or more of the above-mentioned co-drugs. Furthermore, the combined drugs are useful for prevention or treatment for metabolic disorders, when combined with one, two or more drugs selected from the group consisting of diabetes-treating agents and hyperlipidemia-treating agents. Combinations containing, in particular, hypertension-treating agent and anti-obesity agent are useful for prevention or treatment for metabolic disorders with synergistic effect, when diabetes-treating agent and/or hyperlipidemia-treating agent are added thereto.

On the other hand, the compound of the invention may be combined with an antipsychotic. An antipsychotic, especially an atypical antipsychotic is known to have a side effect of body weight increase; and the compound of the invention, when combined with such an antipsychotic, is useful for retarding the side effect. The antipsychotic includes, for example, olanzapine, risperidone, quetiapine, ziprasidone, aripiprazole, paliperidone, clozapine, etc.

Using an antipsychotic, as combined with a compound of the invention, may improve the level of metabolic parameters such as the level of blood pressure, glucose and lipid level that may be elevated by the antipsychotic. The above-mentioned methods may apply to the conditions of dose, administration subject, administration route, administration form, etc.

BEST MODE FOR CARRYING OUT THE INVENTION

The invention is described more concretely with reference to the following Examples, to which, however, the invention should not be limited. As silica gel for column, used was Wakogel™ C-200 (Wako Pure Chemical Industries); as a filled silica gel column, used was FLASH+™ cartridge, KP-SiI or FPNH, FLASH12+M, FLASH25+S, FLASH25+M, FLASH40+M (Biotage Japan), etc.; for partitioning thin-layer chromatography, used was Kieselgel 60F254 (Merck); for basic partitioning thin-layer chromatography, used was PLC05NH (FUJI Silysia); for reversed-phase high-performance liquid chromatography, used was ODS (YMC). For ' H-NMR, used was JNM-AL400 (JEOL) or MERCURYvx400 (VARIAN), ^{u N 1 τ γ} INOVA400 (VARIAN) or AVANCE-300 (Bruker); and for mass spectrometry, used was ZQ2000 (Waters).

Examples Reference Example 1 - Production of compound (V -a) (hereinafter referred to as "protected arylamine (V-a)"):

(V-a)

Reference Example 1-1 : Production of 1 ,1 -dimethyl ethyl 6-(5-cyano-3-pyridinyl)-2,6-diazaspiro[3.3]heptane-2- carboxylate:

A toluene solution (150 mL) of 1,1-dimethylethyl 2,6-diazaspiro[3.3]heptane-2- carboxylate oxalate (7.9 g), 5-bromo-3-pyridinecarbonitrile (5.0 g), 2,2'-bis(diphenylphosphino)- l,l'-binaphthyl (BFNAP) (1.7 g), cerium carbonate (45.0 g) and Pd₂ (dba)₃ (0.25 g) was purged with nitrogen, and then stirred overnight with heating under reflux. The reaction liquid was poured into water with ice, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate =

5/1) to give the entitled compound (8.8 g) as a yellow solid. ESI-MS Found: m/z 301[M+H]⁺

Protected arylamine derivatives (V-a) mentioned below were prepared in the same manner as in the above-mentioned Reference Example 1-1 but using various amines (VI) and aryl halides of formula (VII).

Table 1 - Production of Protected Arylamines (V-a)

Reference ESI-MS example

(Vl) (VII) (V-a)

1 -3 BocN 'O XC' NH 294 [M+H]⁺

1 —6 BocN O, XC' NH BOCN(X>-<Q> 290 [M+H]⁺

Reference Example 2- Production of compound of formula (V) (hereinafter referred to as "arylamine (V)"):

(V)

Reference Example 2-1 : Production of 5-(2,6-diazaspiro[3.3]hept-2-yl)-3-pyridinecarbonitrile trifluoroacetate:

At O⁰C, trifluoroacetic acid (20.0 mL) was added to a methylene chloride solution

(30.0 mL) of the compound (8.8 g) obtained in Reference Example 1-1, and stirred at room temperature for 6 hours. The reaction liquid was concentrated under reduced pressure and dried to give a crude product (20.0 g) of the entitled compound as a yellow solid.

ESI-MS Found: m/z 201[M+H]⁺

In the same manner as in Reference Example 2-1 but using various protected arylamines (V-a) obtained in Reference Examples 1-2 to 1-8, the corresponding arylamines (V) were produced. Reference Example 3 - 1 :

Production of 3,4-difluoro-N-methoxy-N-methylbenzamide:

At O⁰C, N,O-dimethylhydroxylamine hydrochloride (12.3 g), 1- hydroxybenzotriazole hydrate (HOBt-H₂ O) (14.5 g), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDCI-HCl) (18.2 g) and triethylamine (44.5 mL) were added to a chloroform solution (115 mL) of 3,4-difluorobenzoic acid (10.0 g), and stirred overnight at room temperature. Water was added to the reaction liquid, and extracted with chloroform. The organic layer was washed with saturated brine, and then dried with anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (hexane/ethyl acetate = 80/20 to 70/30) to give the entitled compound (12.8 g) as a colorless oily substance.

ESI-MS Found: m/z 202[M+H]⁺

Reference Example 3-2:

Production of 3,4,5-trifluoro-N-methoxy-N-methylbenzamide:

The entitled compound (9.0 g) was obtained as a colorless oily substance in the same manner as in Reference Example 3-1 but using 3,4,5-trifluorobenzoic acid (10.0 g).

ESI-MS Found: m/z 220[M+H]⁺

Reference Example 3-3:

Production of (3 ,4-difluorophenyl)[5-( {[(1,1 -dimethylethyl)(dimethyl)silyl] oxy } methyl)-2- pyridinyl]methanone: At -78°C, 1.6 M n-butyllithium/hexane solution (3.8 mL) was added to a toluene solution (32.0 mL) of 2-bromo-5-({[(l,l-dimethylethyl)(dimethyl)silyl]oxy}methyl)pyridine (2.0 g), and stirred for 2 hours. To this was added a toluene solution (5.0 mL) of the amide (1.0 g) obtained in Reference Example 3-1, at -78⁰C, then stirred for 2 hour, and then at O⁰C, stirred for

18 hours. Water was added to the reaction liquid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried with anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (hexane/ethyl acetate = 98/2 to 95/5) to give the entitled compound (1.2 g) as a brown oily substance. ESI-MS Found: m/z 364[M+H]⁺

Reference Example 3-4:

Production of [5-({ [(1 , 1 -dimethylethyl)(dimethyl)silyl]oxy }methyl)-2-pyridinyl](3,4,5- trifluorophenyl)methanone: The entitled compound (4.0 g) was obtained as a colorless oily substance in the same manner as in Reference Example 3-3 but using the compound (3.7 g) obtained in Reference

Example 3-2.

ESI-MS Found: m/z 382[M+H]⁺

Reference Example 3-5: Production of (3 ,4-difluorophenyl)[5- {[(1,1 -dimethylethyl)(dimethyl)silyl]oxy} ethyl)-2- pyridinyl]methanone:

The entitled compound (4.3 g) was obtained as a colorless oily substance in the same manner as in Reference Example 3-3 but using 2-bromo-5-(l-{[(l,l- dimethylethyl)(dimethyl)silyl]oxy}ethyl)pyridine (2.0 g) and the compound (4.0 g) obtained in Reference Example 3 - 1.

ESI-MS Found: m/z 378[M+H]⁺

Reference Example 3-6:

Production of N- { (3 ,4-difluorophenyl) [5 -({[(1,1 -dimethylethyl)(dimethyl)silyl]oxy } methyl)-2- pyridinyl]methylidene}-(R)-2-methyl-2-propanesulfinamide: The compound (1.4 g) obtained in Reference Example 3-3 and (R)-(+)-2-methyl-

2-propanesulfinamide (467 mg) were added to a THF solution (80.0 mL) of titanium tetraethoxide (1.6 mL), and then heated overnight under reflux in the presence of nitrogen. At

O⁰C, saturated brine was added to the reaction liquid, and the residue was removed through filtration through Celite. The filtrate was extracted with ethyl acetate, the organic layer was washed with saturated brine, and dried with anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (chloroform/methanol = 100/0 to 90/10) to give the entitled compound (1.4 g) as a yellow oily substance.

ESI-MS Found: m/z 467[M+H]⁺ Reference Example 3-7:

Production of N-[[5-({[(l,l-dimethylethyl)(dimethyl)silyl]oxy}methyl)-2-pyridinyl](3,4,5- trifluorophenyl)methylidene]-(R)-2-methyl-2-propanesulfinamide:

The entitled compound (0.52 g) was obtained as a yellow oily substance in the same manner as in Reference Example 3-6 but using the compound (0.62 g) obtained in Reference Example 3-4.

ESI-MS Found: m/z 485[M+H]⁺

Reference Example 3-8: Production of N- { (3 ,4-difluorophenyl)[5-( 1 - { [( 1 , 1 -dimethylethyl)(dimethyl)silyl]oxy} ethy l)-2- pyridinyl]methylidene}-(R)-2-methyl-2-propanesulfinamide:

The entitled compound (1.8 g) was obtained as a yellow oily substance in the same manner as in Reference Example 3-6 but using the compound (2.6 g) obtained in Reference Example 3-5.

ESI-MS Found: m/z 481[M+H]⁺

Reference Example 3-9:

Production of N-{(1R) or (lS)-l-(3,4-difluorophenyl)-l-[5-({[(l,l- dimethylethyl)(dimethyl)silyl]oxy}methyl)-2-pyridinyl]ethyl}-(R)-2-methyl-2- propanesulfinamide:

At -78⁰C, 3.0 M methylmagnesium bromide/THF solution (3.0 mL) was added to a THF solution (15.0 mL) of the compound (1.4 g) obtained in Reference Example 3-6, and stirred for 1 hour. Aqueous sodium hydrogencarbonate solution was added to the reaction liquid, extracted with ethyl acetate, and dried with anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (hexane/ethyl acetate = 100/0 to 50/50) to give the entitled compound (1.3 g) as a colorless oily substance.

ESI-MS Found: m/z 483[M+H]⁺

Reference Example 3-10: Production of N-[(1R) or (lS)-l-[5-({[(l,l-dimethylethyl)(dimethyl)silyl]oxy}methyl)-2- pyridinyl]-l-(3,4,5-trifluorophenyl)ethyl]-(R)-2-methyl-2-propanesulfmamide:

The entitled compound (0.52 g) was obtained as a colorless oily substance in the same manner as in Reference Example 3-9 but using the compound (0.52 g) obtained in

Reference Example 3-7. ESI-MS Found: m/z 501 [M+H]⁺

Reference Example 3-11:

Production of N-{(1R) or (lS)-l-(3,4-difluorophenyl)-l-[5-(l-{[(l,l- dimethylethyl)(dimethyl)silyl]oxy}ethyl)-2-pyridinyl]ethyl}-(R)-2-methyl-2- propanesulfinamide: The entitled compound (2.7 g) was obtained as a colorless oily substance in the same manner as in Reference Example 3-9 but using the compound (3.0 g) obtained in Reference

Example 3-8.

ESI-MS Found: m/z 497[M+H]⁺

Reference Example 3-12: Production of N-{(R) or (S)-cyclopropyl(3,4-difluorophenyl)[5-({[(l,l- dimethylethyl)(dimethyl)silyl]oxy}methyl)-2-pyridinyl]methyl}-(R)-2-methyl-2- propanesulfinamide : The entitled compound (1.1 g) was obtained as a colorless oily substance in the same manner as in Reference Example 3-9 but using the compound (1.0 g) obtained in Reference Example 3-6 and cyclopropylmagnesium bromide. ESI-MS Found: m/z 509[M+H]⁺ Reference Example 3-13:

Production of N-{(1R) or (lS)-l-(3,4-difluorophenyl)-l-[5-({[(l,l- dimethylethyl)(dimethyl)silyl]oxy}methyl)-2-pyridinyl]-2-difluoro-2-(phenylsulfonyl)ethyl}- (R)-2-methyl-2-propanesulfinamide :

1.0 M lithium-bis(trimethylsilyl)amide/THF solution (0.60 mL) was added to a THF solution (10.0 mL) of the compound (0.20 g) obtained in Reference Example 3-6 and difluoromethylphenyl sulfone (77.0 mg), in a nitrogen atmosphere at -78⁰C, then stirred for 1 hour, and gradually heated up to -3O⁰C. Saturated brine was added to the reaction liquid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried with anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (hexane/ethyl acetate = 83/17) to give the entitled compound (0.20 g) as a colorless oily substance. ESI-MS Found: m/z 659[M+H]⁺ Reference Example 3-14: Production of N-{(1R) or (lS)-l-(3,4-difluorophenyl)-l-[5-({[(l,l- dimethylethyl)(dimethyl)silyl]oxy}methyl)-2-pyridinyl]-2,2-difluoroethyl}-(R)-2-methyl-2- propanesulfinamide :

At room temperature, 8.0 M acetic acid/sodium acetate (1/1) buffer (3.0 mL) was added to a DMF solution (7.0 mL) of the compound (0.20 g) obtained in Reference Example 3- 13. Magnesium (0.72 g) was added little by little to the reaction liquid, and stirred overnight at room temperature. The reaction liquid was dropwise added to water with ice, and extracted with diethyl ether. The organic layer was washed with aqueous saturated sodium hydro gencarbonate solution, water and saturated brine, and dried with anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (hexane/ethyl acetate = 67/23) to give the entitled compound (0.10 g) as a colorless oily substance.

ESI-MS Found: m/z 519[M+H]⁺

Reference Example 3-15:

Production of N-{(1R) or (lS)-l-(3,4-difluorophenyl)-l-[5-({[(l,l- dimethylethyl)(dimethyl)silyl]oxy}methyl)-2-pyridinyl]-2,2,2-trifluoroethyl}-2-methyl-2- propanesulfϊnamide, and N-{(1S) or (lR)-l-(3,4-difluorophenyl)-l-[5-({[(l,l- dimethylethyl)(dimethyl)silyl]oxy}methyl)-2-pyridinyl]-2,2,2-trifluoroethyl}-2-methyl-2- propanesulfinamide : In a nitrogen atmosphere at -78⁰C, a THF solution (20.0 mL) of tetrabutylammonium triphenyldifluorosilicate (1.1 g) was added to a THF solution (20.0 mL) of the compound (1.0 g) obtained in Reference Example 3-6 and trifluoromethyltrimethylsilane (0.90 g), and gradually heated up to -30°C. Saturated brine was added to the reaction liquid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried with anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (YMC-ODS, 70 % methanol- 30 % acetonitrile (0.1 % trifluoroacetic acid)/water = 70/30 to 36/64) to give a diastereomers (first eluate, 0.25 g) and (second eluate, 0.45 g) of the entitled compound both as a colorless oily substance.

ESI-MS Found: m/z 537[M+H]⁺

Reference Example 3-16:

Production of N-{(1R) or (lS)-l-(3,4-difluorophenyl)-l-[5-(hydroxymethyl)-2-pyridinyl]ethyl}-

2-methyl-2-propanesulfinamide: 1.0 M tetrabutylammonium fluoride/THF solution (0.93 mL) was added to a THF solution (10.0 mL) of the compound (0.45 g) obtained in Reference Example 3-9, and stirred at room temperature for 1 hour. Aqueous sodium hydrogencarbonate solution was added to the reaction liquid, extracted with ethyl acetate, and dried with anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (hexane/ethyl acetate = 100/0 to 50/50) to give the entitled compound (0.32 g) as a yellow oily substance. ESI-MS Found: m/z 369[M+H]⁺ Example 3-17: Production of N-{(1R) or (lS)-l-(3,4-difluoroρhenyl)-l-[5-(l-hydroxyethyl)-2-pyridinyl]ethyl}- (R)-2-methyl-2-propanesulfmamide:

The entitled compound (0.40 g) was obtained as a yellow oily substance in the same manner as in Reference Example 3-16 but using the compound (0.53 g) obtained in Reference Example 3-11. ESI-MS Found: m/z 383[M+H]⁺ Reference Example 3-18:

Production of N-{(R) or (S)-cyclopropyl(3,4-difluorophenyl)[5-(hydroxymethyl)-2- pyridinyl]methyl}-2-methyl-2-propanesulfinarnide:

The entitled compound (0.70 g) was obtained as a colorless oily substance in the same manner as in Reference Example 3-16 but using the compound (1.1 g) obtained in Reference Example 3-12.

ESI-MS Found: m/z 395[M+H]⁺ Reference Example 3-19: Production of N-{(1R) or (lS)-l-(3,4-difiuorophenyl)-2,2-difluoro-l-[5-(hydroxymethyl)-2- pyridinyl]ethyl}-2-methyl-2-propanesulfinamide:

The entitled compound (0.38 g) was obtained as a colorless oily substance in the same manner as in Reference Example 3-16 but using the compound (0.45 g) obtained in Reference Example 3-14.

ESI-MS Found: m/z 405[M+H]⁺

Reference Example 3-20:

Production of N-[(1R) or (lS)-l-(5-{[6-(5-cyano-3-pyridinyl)-2,6-diazaspiro[3.3]hept-2- yl]methyl } -2-pyridinyl)- 1 -(3 ,4-difluorophenyl)ethyl] -2-methyl-2-propanesulfmamide : At 0⁰C, methanesulfonyl chloride (5.6 g) was added to a THF solution ( 100 mL) of the compound (9.0 g) obtained in Reference Example 3-16 and diisopropylethylamine (13.0 g), and stirred at room temperature for 1 hour. The reaction liquid was poured into water with ice, and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogencarbonate solution, water and saturated brine, and dried with anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to give a crude product (10.0 g) of a mesylate as a colorless oily substance.

A DMF solution (100 mL) of the crude product (10.0 g) obtained in the above, the compound (11.0 g) obtained in Reference Example 2-1 and diisopropylethylamine (26.0 g) was stirred overnight at room temperature. The reaction liquid was poured into water with ice, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried with anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified through silica gel chromatography (hexane/acetone = 50/50) to give the entitled compound (7.1 g) as a colorless oily substance. ESI-MS Found: m/z 551 [M+H]⁺ Reference Example 3-21:

Production of N-[(1R) or (lS)-l-(5-{ l-[6-(5-cyano-3-pyridinyl)-2,6-diazaspiro[3.3]hept-2- yl] ethyl } -2-pyridinyl)- 1 -(3 ,4-difluorophenyl)ethyl] -2-methyl-2-propanesulfinamide :

The entitled compound (0.15 g) was obtained as a colorless oily substance in the same manner as in Reference Example 3-20 but using the compound (0.40 g) obtained in Reference Example 3-17 and the compound (0.41 g) obtained in Reference Example 2-1. ESI-MS Found: m/z 565[M+H]⁺ Reference Example 3-22:

Production of N-[(R) or (S)-l-(5-{[6-(5-cyano-3-pyridinyl)-2,6-diazaspiro[3.3]hept-2- yl]methyl}-2-pyridinyl)(cyclopropyl)(3,4-difluorophenyl)methyl]-2-methyl-2- propanesulfinamide:

The entitled compound (0.26 g) was obtained as a colorless oily substance in the same manner as in Reference Example 3-20 but using the compound (0.35 g) obtained in Reference Example 3-18 and the compound (0.70 g) obtained in Reference Example 2-1. ESI-MS Found: m/z 577[M+H]⁺

Reference Example 3-23:

Production of N-[(1R) or (lS)-l-(5-{[6-(5-cyano-3-pyridinyl)-2,6-diazasρiro[3.3]hept-2- yl]methyl}-2-pyridinyl)-l-(3,4-difluorophenyl)-2,2-difluoroethyl]-2-methyl-2- propanesulfinamide:

The entitled compound (0.15 g) was obtained as a colorless oily substance in the same manner as in Reference Example 3-20 but using the compound (0.38 g) obtained in

Reference Example 3-19 and the compound (0.40 g) obtained in Reference Example 2-1.

ESI-MS Found: m/z 587[M+H]⁺ Reference Example 3 -24 :

Production of 5-[6-({6-[(lR) or (lS)-l-amino-l-(3,4-difluorophenyl)ethyl]-3-pyridinyl}methyl)-

2,6-diazaspiro[3.3]hept-2-yl]-3-pyridinecarbonitrile:

At 0⁰C, concentrated hydrochloric acid (1.0 mL) was added to a methanol solution (120 mL) of the compound (7.1 g) obtained in Reference Example 3-20, and stirred at room temperature for 1 hour. The reaction liquid was poured into water with ice, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried with anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure and dried to give a crude product (6.2 g) of the entitled compound as a colorless oily substance.

ESI-MS Found: m/z 447[M+H]⁺ Reference Example 3-25:

Production of 5-[6-(l-{6-[(lR) or (lS)-l-amino-l-(3,4-difluorophenyl)ethyl]-3-pyridinyl}ethyl)-

2,6-diazaspiro[3.3]hept-2-yl]-3-pyridinecarbonitrile:

A crude product (0.12 g) of the entitled compound was obtained as a colorless oily substance in the same manner as in Reference Example 3-24 but using the compound (0.15 g) obtained in Reference Example 3-21.

ESI-MS Found: m/z 461 [M+H]⁺

Reference Example 3-26:

Production of 5-[6-({6-[(R) or (S)-l-amino(cyclopropyl)(3,4-difluorophenyl)methyl]-3- pyridinyl}methyl)-2,6-diazaspiro[3.3]hept-2-yl]-3-pyridinecarbonitrile: A crude product (70.0 mg) of the entitled compound was obtained as a colorless oily substance in the same manner as in Reference Example 3-24 but using the compound (0.13 g) obtained in Reference Example 3-22.

ESI-MS Found: m/z 473[M+H]⁺

Reference Example 3-27: Production of 5-[6-({6-[(lR) or (lS)-l-amino-l-(3,4-difluorophenyl)-2,2-difluoroethyl]-3- pyridinyl}methyl)-2,6-diazaspiro[3.3]hept-2-yl]-3-pyridinecarbonitrile: A crude product (0.12 g) of the entitled compound was obtained as a colorless oily substance in the same manner as in Reference Example 3-24 but using the compound (0.15 g) obtained in Reference Example 3-23.

ESI-MS Found: m/z 483[M+H]⁺ Reference Example 4-1 :

Production of (6-[(1R) or ( IS)-I -amino- 1 -(3 ,4-difluorophenyl)ethyl] -3 -pyridinyl} methanol: At O⁰C, concentrated hydrochloric acid (30.0 mL) was added to a methanol solution (50.0 mL) of the compound (3.0 g) obtained in Reference Example 3-9, and stirred overnight at room temperature. The reaction liquid was poured into water with ice, then aqueous 6 N sodium hydroxide solution was added thereto to make it have pH = 10, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried with anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure and dried to give a crude product (1.7 g) of the entitled compound as a colorless oily substance.

ESI-MS Found: m/z 265[M+H]⁺ Reference Example 4-2 :

Production of (6-[(1R) or (lS)-l-amino-l-(3,4,5-trifluorophenyl)ethyl]-3-pyridinyl}methanol: A crude product (0.25 g) of the entitled compound was obtained as a colorless oily substance in the same manner as in Reference Example 4-1 but using the compound (0.52 g) obtained in Reference Example 3-10. ESI-MS Found: m/z 283 [M+H]⁺

Reference Example 4-3 :

Production of (6-[(1R) or (lS)-l-amino-l-(3,4-difluorophenyl)-2,2,2-trifluoroethyl]-3- pyridiny 1 } methanol :

A crude product (0.15 g) of the entitled compound was obtained as a colorless oily substance in the same manner as in Reference Example 4-1 but using the compound (first eluate, 0.25 g) obtained in Reference Example 3-15.

ESI-MS Found: m/z 319[M+H]⁺

Reference Example 4-4:

Production of (IR) or (lS)-l-(3,4-difluorophenyl)-l-[5-({[(l,l- dimethylethyl)(dimethy l)silyl] oxy } methyl)-2-pyridinyl] ethanamine :

T-butyldimethylsilyl chloride (2.7 g) was added to a DMF solution (20.0 mL) of the compound (1.7 g) obtained in Reference Example 4-1, imidazole (2.7 g) and 4- dimethylaminopyridine (0.30 g), and stirred overnight at room temperature. The reaction liquid was poured into water with ice, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried with anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure and dried to give a mixture (2.2 g) containing the entitled compound as a colorless oily substance.

ESI-MS Found: m/z 379[M+H]⁺ Reference Example 4-5:

Production of (IR) or (lS)-l-(3,4,5-trifluorophenyl)-l-[5-({[(l,l- dimethylethyl)(dimethyl)silyl]oxy}methyl)-2-pyridinyl]ethanamine:

A crude product (0.40 g) of the entitled compound was obtained as a colorless oily substance in the same manner as in Reference Example 4-4 but using the compound (0.25 g) obtained in Reference Example 4-2.

ESI-MS Found: m/z 397[M+H]⁺

Reference Example 4-6:

Production of (IR) or (lS)-l-(3,4-difluorophenyl)-l-[5-({[(l,l- dimethylethyl)(dimethyl)silyl]oxy}methyl)-2-pyridinyl]-2,2,2-trifluoroethanamine:

The entitled compound (0.15 g) was obtained as a colorless oily substance in the same manner as in Reference Example 4-4 but using the compound (0.15 g) obtained in

Reference Example 4-3.

ESI-MS Found: m/z 433[M+H]⁺ Reference Example 4-7:

Production of N-{(1R) or (lS)-l-(3,4-difluorophenyl)-l-[5-({[(l,l- dimethylethyl)(dimethyl)silyl]oxy}methyl)-2-pyridinyl]ethyl}-2,2-difluoroacetamide: At 0°C, triethylamine (5.0 g) and 1 -hydroxy-7-azabenzotriazole hydrate

(HOAc-H₂O) (0.87 g) were added to a DMF solution (30.0 niL) of the compound (2.2 g) obtained in Reference Example 4-4 and difluoroacetic acid (1.2 g), and stirred at room temperature for 10 minutes. At O⁰C, l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.2 g) was added to the reaction liquid, and stirred overnight at room temperature.

The reaction liquid was poured into water with ice, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried with anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (hexane/ethyl acetate = 10/1) to give the entitled compound (2.1 g) as a colorless oily substance.

ESI-MS Found: m/z 457[M+H]⁺

Reference Example 4-8: Production of N-{(1R) or (lS)-l-(3,4,5-trifluorophenyl)-l-[5-({[(l,l- dimethylethyl)(dimethyl)silyl]oxy}methyl)-2-pyridinyl]ethyl}-2,2-difluoroacetamide:

The entitled compound (0.20 g) was obtained as a colorless oily substance in the same manner as in Reference Example 4-7 but using the compound (0.40 g) obtained in

Reference Example 4-5. ESI-MS Found: m/z 475[M+H]⁺

Reference Example 4-9:

Production of N-{(1R) or (lS)-l-(3,4-difluorophenyl)-l-[5-({[(l,l- dimethylethyl)(dimethyl)silyl]oxy}methyl)-2-pyridinyl]-2,2,2-trifluoroethyl}acetamide: At -78⁰C, a THF solution (1.0 mL) of 1.0 M lithium-bis(trimethylsilyl)amide was added to a THF solution (10.0 mL) of the compound (0.15 g) obtained in Reference Example 4-6, and stirred for 30 minutes. Acetic anhydride (0.10 g) was added to the reaction liquid, and heated up to room temperature. The reaction liquid was poured into water with ice, and extracted with ethyl acetate. The organic layer was washed with water, and dried with anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (hexane/ethyl acetate = 5/1) to give the entitled compound (0.16 g) as a colorless oily substance.

ESI-MS Found: m/z 475[M+H]⁺ Reference Example 4-10:

Production of N-{(1R) or (lS)-l-(3,4-difluorophenyl)-l-[5-(hydroxymethyl)-2-pyridinyl]ethyl}-

2,2-difiuoroacetamide:

The entitled compound (1.1 g) was obtained as a colorless oily substance in the same manner as in Reference Example 3-16 but using the compound (2.1 g) obtained in Reference Example 4-7.

ESI-MS Found: m/z 343[M+H]⁺

Reference Example 4-11 :

Production of N-{(1R) or (lS)-l-(3,4,5-trifluorophenyl)-l-[5-(hydroxymethyl)-2- pyridinyl] ethyl } -2,2-difiuoroacetamide: The entitled compound (0.13 g) was obtained as a colorless oily substance in the same manner as in Reference Example 3-16 but using the compound (0.20 g) obtained in

Reference Example 4-8.

ESI-MS Found: m/z 361[M+H]⁺

Reference Example 4-12: Production of N-{(1R) or (lS)-l-(3,4-difluorophenyl)-2,2,2-trifluoro-l-[5-(hydroxymethyl)-2- pyridiny 1] ethyl } acetamide :

The entitled compound (90.0 mg) was obtained as a colorless oily substance in the same manner as in Reference Example 3-16 but using the compound (0.15 g) obtained in

Reference Example 4-9. ESI-MS Found: m/z 361 [M+H]⁺

Example 1-1 :

Production of N-[(1R) or (lS)-l-(5-{[6-(5-cyano-3-pyridinyl)-2,6-diazaspiro[3.3]heρt-2- yl]methyl}-2-pyridinyl)-l-(3,4-difluorophenyl)ethyl]-2,2-difluoroacetamide:

The entitled compound (7.1 g, >99 %ee) was obtained as a white solid in the same manner as in Reference Example 4-7 but using the compound (6.2 g) obtained in Reference

Example 3-24. ¹ HNMR (400M Hz, CDCl₃ , δ ppm): 2.24 (3H, s), 4.29 (4H, br s), 4.53 (4H, br s), 4.56 (2H, s),

6.19 (IH, t, J = 54 Hz), 7.30 (3H, m), 7.32 (IH, m), 7.46 (IH, dd, J = 8.4, 2.4 Hz), 7.97 (IH, dd,

J = 8.4, 2.4 Hz), 8.09 (IH, d, J = 2.8 Hz), 8.30 (IH, d, J = 1.2 Hz), 8.79 (IH, d, J = 1.2 Hz).

ESI-MS Found: m/z 525[M+H]⁺ Example 1-2:

Production of N-[(1R) or (lS)-l-(5-{(lR) or (lS)-l-[6-(5-cyano-3-pyridinyl)-2,6- diazaspiro[3.3]hept-2-yl]ethyl}-2-pyridinyl)-l-(3,4-difluorophenyl)ethyl]-2,2-difluoroacetamide: A racemate (30.0 mg) of the entitled compound was obtained as a colorless oily substance in the same manner as in Reference Example 4-7 but using the compound (122 mg) obtained in Reference Example 3-25. The racemate was optically resolved under the condition mentioned below to give the individual enantiomers.

Supercritical Fluid Chromatography (SFC), CHIRALPAK AD-H (methanol, 0.1 % diethylamine,

40 % carbon dioxide), 2nd eluate:

¹ HNMR (400M Hz, CDCl₃ , δ ppm): 1.14 (3H, d, J = 6.4 Hz), 2.04 (3H, s), 3.19-3.30 (5H, m), 3.96 (4H, br s), 5.77 (IH, t, J = 54 Hz), 6.78 (IH, s), 7.02-7.08 (3H, m), 7.55 (IH, d, J = 8.0 Hz),

7.89 (IH, s), 8.14 (IH, s), 8.38 (IH, s), 9.73 (IH, s).

ESI-MS Found: m/z 539[M+H]⁺

Example 1-3:

Production of N-[(1R) or (lS)-l-(5-{[6-(5-cyano-3-pyridinyl)-2,6-diazaspiro[3.3]hept-2- yljmethyl } -2-pyridinyl)- 1 -(3 ,4-difluorophenyl)ethyl] -2-methylpropanamide :

The entitled compound (10.0 mg) was obtained as a colorless oily substance in the same manner as in Reference Example 4-9 but using the compound (20.0 mg) obtained in

Reference Example 3-24 and isobutyric anhydride.

¹ HNMR (400M Hz, CDCl₃ , δ ppm): 1.10 (3H, d, J = 7.2 Hz), 1.16 (3H, d, J = 7.2 Hz), 1.20 (3H, s), 2.44 (IH, m), 3.38 (4H, br s), 3.53 (2H, s), 3.97 (4H, br s), 6.82 (2H, m), 6.95-7.07 (3H, m),

7.46 (IH, d, J = 7.6 Hz), 7.90 (IH, s), 8.14 (IH, s), 8.35 (IH, s), 8.70 (IH, s).

ESI-MS Found: m/z 517[M+H]⁺

Example 1-4:

Production of N-[(1R) or (lS)-l-(5-{[6-(5-cyano-3-pyridinyl)-2,6-diazaspiro[3.3]hept-2- yl]methyl}-2-pyridinyl)-l-(3,4-difluorophenyl)ethyl]-cyclopropanecarboxamide trifluoroacetate: The entitled compound (5.0 mg) was obtained as a colorless solid in the same manner as in Reference Example 4-9 but using the compound (20.0 mg) obtained in Reference

Example 3-24 and cyclopropanecarboxylic acid.

¹ HNMR (400M Hz, MeOD, δ ppm): 0.75 (4H, m), 1.80 (IH, m), 2.07 (3H, s), 4.17 (4H, br s), 4.41 (4H, br s), 4.43 (2H, s), 7.16-7.28 (4H, m), 7.37 (IH, d, J = 7.6 Hz), 7.83 (IH, d, J = 8.8 Hz),

7.98 (IH, s), 8.19 (IH, s), 8.64 (IH, s).

ESI-MS Found: m/z 515[M+H]⁺

Example 1-5: Production of N-[(1R) or (lS)-l-(5-{[6-(5-cyano-3-pyridinyl)-2,6-diazaspiro[3.3]hept-2- yljmethyl } -2-pyridinyl)- 1 -(3 ,4-difluorophenyl)ethyl] -2-hydroxy-2-methylpropanemide trifluoroacetate:

The entitled compound (2.9 mg) was obtained as a colorless solid in the same manner as in Reference Example 4-9 but using the compound (20.0 mg) obtained in Reference Example 3-24 and 2-hydroxy-2-methylpropionic acid.

¹ HNMR (400M Hz, MeOD, δ ppm): 1.44 (3H, s), 1.47 (3H, s), 2.01 (3H, s), 4.10 (4H, br s), 4.33 (4H, br s), 4.36 (2H, s), 7.05-7.23 (5H, m), 7.75 (IH, dd, J = 8.4, 2.0 Hz), 7.90 (IH, s), 8.11 (IH, s), 8.60 (IH, d, J = 1.6 Hz). ESI-MS Found: m/z 533 [M+H]⁺ Example 1-6:

Production of N-[(R) or (S)-(5-{[6-(5-cyano-3-pyridinyl)-2,6-diazaspiro[3.3]hept-2-yl]methyl}- 2-pyridinyl)(cyclopropyl)(3,4-difluorophenyl)methyl]-2,2-difluoroacetamide trifluoroacetate: The entitled compound (50.0 mg) was obtained as a colorless oily substance in the same manner as in Reference Example 4-7 but using the compound (70.0 mg) obtained in Reference Example 3-26.

¹ HNMR (300M Hz, CDCl₃ , δ ppm): -0.02 (IH, m), 0.19 (IH, m), 0.50 (IH, m), 0.77 (IH, m), 2.24 (IH, m), 3.45 (4H, s), 3.59 (2H, s), 4.08 (4H, br s), 5.86 (IH, t, J = 54 Hz), 6.66 (IH, d, J = 8.1 Hz), 6.84 (IH, s), 7.14 (IH, m), 7.26-7.38 (2H, m), 7.51 (IH, m), 7.96 (IH, d, J = 2.7 Hz), 8.22 (IH, d, J = 1.2 Hz), 8.45 (IH, s), 9.66 (IH, s). ESI-MS Found: m/z 551 [M+H]⁺ Example 1-7:

Production of N-[(1R) or (lS)-l-(5-{[6-(5-cyano-3-pyridinyl)-2,6-diazaspiro[3.3]hept-2- yl]methyl}-2-pyridinyl)-l-(3,4-difluorophenyl)-2,2-difluoroethyl]acetamide trifluoroacetate: The entitled compound (5.0 mg, >99.2 %ee) was obtained as a white solid in the same manner as in Reference Example 4-9 but using the compound (50.0 mg) obtained in Reference Example 3-27.

IHNMR (400M Hz, MeOD, δ ppm): 1.96 (3 H, s), 4.09 (4H, br s), 4.36 (4H, br s), 4.40 (2H, s), 7.01-7.19 (5H, m), 7.32 (IH, d, J = 8.0 Hz), 7.82 (IH, dd, J = 8.0, 2.4 Hz), 7.92 (IH, s), 8.11 (IH, s), 8.66 (IH, s).

ESI-MS Found: m/z 525[M+H]⁺

Example 2-1 :

Production of N-[(1R) or (lS)-l-(3,4-difluorophenyl-l-(5-{[6-(5-methyl-3-pyridinyl)-2,6- diazaspiro[3.3]hept-2-yl]methyl}-2-pyridinyl)ethyl-2,2-difluoroacetamide trifluoroacetate: The entitled compound (55.0 mg) was obtained as a white solid in the same manner as in Reference Example 3-20 but using the arylamine (145 mg) obtained by removing the Boc group from the compound obtained in Reference Example 1 -2, under the same condition as in Reference Example 2-1, and the compound (600 mg) obtained in Reference Example 4-10. ¹ HNMR (400M Hz, MeOD, δ ppm): 2.17 (3H, s), 2.45 (3H, s), 4.27 (4H, br s), 4.46 (4H, br s),

4.48 (2H, s), 6.13 (IH, t, J = 54 Hz), 7.23-7.40 (5H, m), 7.79 (IH, m), 7.91 (IH, d, J = 8.0 Hz),

7.95 (IH, s), 8.73 (IH, s).

ESI-MS Found: m/z 514[M+H]⁺ The entitled compounds of Examples 2-2 to 2-17 were produced in the same manner as in Example 2-1 but using various protected arylamines (V-a) obtained in Reference

Examples 1-3 to 1-8 and the compound obtained in Reference Example 4-10.

Example 2-2:

Production of N-[(1R) or (lS)-l-(3,4-difluorophenyl-l-(5-{[6-(5-fluoro-3-ρyridinyl)-2,6- diazaspiro[3.3]hept-2-yl]methyl} -2-pyridinyl)ethyl-2,2-difluoroacetamide trifluoroacetate:

¹ HNMR (400M Hz, MeOD, δ ppm): 2.17 (3H, s), 4.21 (4H, br s), 4.46 (4H, br s), 4.49 (2H, s),

6.13 (IH, t, J = 54 Hz), 6.92 (IH, d, J = 10.8 Hz), 7.22-7.40 (4H, m), 7.71 (IH, s), 7.90 (IH, s),

7.91 (IH, s), 8.73 (IH, s).

ESI-MS Found: m/z 518[M+H]⁺ Example 2-3 :

Production of N-[(1R) or (lS)-l-(5-{[6-(5-chloro-3-ρyridinyl)-2,6-diazaspiro[3.3]hept-2- yl]methyl } -2-pyridinyl)- 1 -(3 ,4-difluorophenyl)ethyl-2,2-difluoroacetamide trifluoroacetate :

¹ HNMR (400M Hz, MeOD, δ ppm): 2.16 (3H, s), 4.21 (4H, br s), 4.36 (4H, br s), 4.48 (2H, s),

6.12 (IH, t, J = 54 Hz), 7.13 (IH, s), 7.25 (2H, m), 7.33 (IH, m), 7.37 (IH, d, J = 8.4 Hz), 7.77 (IH, s), 7.91 (IH, dd, J = 8.4, 2.4 Hz), 7.97 (IH, s), 8.72 (IH, d, J = 1.6 Hz).

ESI-MS Found: m/z 534[M+H]⁺

Example 2-4:

Production of N-[QR) or (lS)-l-(3,4-difluorophenyl)-l-[5-({6-[5-(trifluoromethyl)-3-pyridinyl]-

2,6-diazaspiro[3.3]hept-2-yl}methyl)-2-pyridinyl]ethyl}-2,2-difluoroacetamide trifluoroacetate: ^l HNMR (400M Hz, MeOD, δ ppm): 2.15 (3H, s), 4.25 (4H₅ br s), 4.45 (4H, br s), 4.49 (2H, s),

6.12 (IH, t, J = 54 Hz), 7.19-7.38 (5H, m), 7.91 (IH, dd, J = 8.4, 2.4 Hz), 8.04 (IH, s), 8.24 (IH, s), 8.72 (IH, d, J = 2.0 Hz).

ESI-MS Found: m/z 568[M+H]⁺

Example 2-5: Production of N-[QR) or QS)-l-(3,4-difluorophenyl)-l-(5-{[6-(6-methyl-2-pyridinyl)-2,6- diazaspiro [3.3 ]hept-2-yl] methyl } -2-pyridinyl)ethyl] -2 ,2-difluoroacetamide trifluoroacetate :

¹ HNMR (400M Hz, MeOD, δ ppm): 2.15 (3H, s), 2.51 (3 H, s), 4.47-4.51 (1OH, m), 6.12 (IH, t,

J = 54 Hz), 6.65 (IH, d, J = 9.2 Hz), 6.76 (IH, d, J = 7.2 Hz), 7.21-7.38 (4H, m), 7.83-7.92 (2H, m), 8.71 (IH, d, J = 2.0 Hz). ESI-MS Found: m/z 514[M+H]⁺

Example 2-6:

Production of N-[QR) or QS)-l-(3,4-difluorophenyl)-l-(5-{[6-(6-methyl-3-pyridinyl)-2,6- diazaspiro[3.3]hept-2-yl]methyl}-2-pyridinyl)ethyl]-2,2-difluoroacetamide trifluoroacetate: ¹ HNMR (400M Hz, MeOD, δ ppm): 2.15 (3H, s), 2.61 (3H, s), 4.28 (4H, br s), 4.44 (4H, br s), 4.48 (2H, s), 6.12 (IH, t, J = 54 Hz), 7.21-7.38 (4H, m), 7.52 (IH, dd, J = 8.8, 2.8 Hz), 7.63 (IH, d, J = 8.8 Hz), 7.80 (IH, d, J = 2.4 Hz), 7.92 (IH, dd, J = 8.4, 2.0 Hz), 8.69 (IH, s). ESI-MS Found: m/z 514[M+H]⁺ Example 2-7:

Production of N-[(1R) or (lS)-l-(3,4-difluorophenyl)-l-(5-{[6-(6-fluoro-3-pyridinyl)-2,6- diazaspiro[3.3]hept-2-yl]methyl}-2-pyridinyl)ethyl]-2,2-difluoroacetamide trifluoroacetate: 1 HNMR (400M Hz, MeOD, δ ppm): 2.16 (3H, s), 4.25 (4H, br s), 4.43 (4H, br s), 4.48 (2H, s), 6.12 (IH, t, J = 54 Hz), 6.92 (IH, dd, J = 8.8, 2.4 Hz), 7.10 (IH, m), 7.21-7.38 (5H, m), 7.90 (IH, dd, J = 8.4, 2.4 Hz), 8.72 (IH, d, J = 2.0 Hz). ESI-MS Found: m/z 518[M+H]⁺ Example 2-8:

Production of N-[(1R) or (lS)-l-(5-{[6-(5-cyano-3-pyridinyl)-2,6-diazasρiro[3.3]hept-2- yl]methyl}-2-pyridinyl)-l-(3 ,4, 5-trifluorophenyl)ethyl]-2,2-difluoroacetamide trifluoroacetate: The entitled compound (5.0 mg) was obtained as a colorless solid in the same manner as in Reference Example 3-20 but using the compound (60.0 mg) obtained in Reference Example 4-11 and the compound (70.0 mg) obtained in Reference Example 2-1. 1 HNMR (400M Hz, MeOD, δ ppm): 2.12 (3H, s), 4.17 (4H, br s), 4.42 (4H, br s), 4.46 (2H, s), 6.11 (IH, t, J = 54 Hz), 7.18 (3H, m), 7.38 (IH, d, J = 8.4 Hz), 7.89 (IH, dd, J = 8.4, 2.4 Hz), 7.98 (IH, d, J = 2.0 Hz), 8.18 (IH, s), 8.90 (IH, d, J = 1.6 Hz). ESI-MS Found: m/z 543[M+H]⁺ Example 2-9:

Production of N-[(1R) or (lS)-l-(5-{[6-(5-cyano-3-pyridinyl)-2,6-diazasρiro[3.3]hept-2- yl]methyl}-2-pyridinyl)-l-(3,4-difluorophenyl)-2,2,2-trifluoroethyl]acetamide trifluoroacetate: The entitled compound (5.0 mg) was obtained as a colorless solid in the same manner as in Reference Example 3-20 but using the compound (20.0 mg) obtained in Reference Example 4-12 and the compound (200 mg) obtained in Reference Example 2-1. 1 HNMR (400M Hz, CDCl₃ , δ ppm): 2.09 (3H, s), 3.40 (4H, br s), 3.60 (2H, s), 4.07 (4H, br s), 6.79 (IH, m), 6.88 (IH, m), 7.08-7.26 (3H, m), 7.54 (IH, dd, J = 8.0, 2.0 Hz), 7.92 (IH, d, J = 2.8 Hz), 8.17 (IH, d, J = 1.2 Hz), 8.47 (IH, s), 8.69 (IH, s). ESI-MS Found: m/z 543[M+H]⁺

INDUSTRIAL APPLICABILITY

The compounds of the invention have an MCH-IR antagonistic effect and are useful as a preventive or remedy for metabolic disorders such as obesity, diabetes, hormone disorder, hyperlipidemia, gout, fatty liver, hepatitis, and cirrhosis; cardiovascular disorders such as stenocardia, acute/congestive heart failure, myocardial infarction, coronary atherosclerosis, hypertension, renal diseases and electrolyte abnormality; central and peripheral nervous system disorders such as bulimia, emotional disturbance, depression, anxiety, epilepsy, delirium, dementia, schizophrenia, attention-deficit hyperactivity disorder, memory impairment, sleep disorders, cognitive failure, dyskinesia, paresthesias, smell disorders, morphine tolerance, drug dependence and alcoholism; reproductive disorders such as infertility, preterm labor and sexual dysfunction; other digestive disorders, respiratory disorders, cancer or pigmentation.

Claims

1. A compound of a formula (I) or a pharmaceutically-acceptable salt thereof:

wherein,

R^{1 a} and R^{1 b} each independently represent a hydrogen atom, or a C_1-6 alkyl;

R² represents a hydrogen atom, a hydroxy, a Ci_-6 alkyl, a C_3-6 cycloalkyl or a C_1-6 alkoxy, wherein the alkyl, the cycloalkyl or the alkoxy may be substituted with a halogen, a hydroxy or a C i _-6 alkoxy;

R³ represents a hydrogen atom, a Ci_-6 alkyl or a C_3-6 cycloalkyl, wherein the alkyl or the cycloalkyl may be substituted with a halogen, a hydroxy or a Ci_-6 alkoxy;

Z represents a Ci_-6 alkyl, a C_3-6 cycloalkyl, a Ci_-6 alkoxy, an aryl, a heteroaryl or N(R^{4 a} )(R^{4 b} ), wherein the alkyl, the cycloalkyl, the alkoxy, the aryl or the heteroaryl may be substituted with a halogen, a hydroxy, a Ci_-6 alkyl, a halo-Ci_-6 alkyl, a Ci_-6 alkoxy or a halo-Ci_-6 alkoxy; or R² and Z, taken together with the atom to which they bond, a 4- to 6-membered nitrogen-containing hetero ring, wherein the nitrogen-containing hetero ring may have a double bond in the ring, or may further contain a hetero atom selected from a group consisting of nitrogen, oxygen and sulfur, wherein the nitrogen-containing hetero ring may form a condensed ring with an aryl ring or a heteroaryl ring, and wherein the nitrogen-containing hetero ring may be substituted with a halogen, a hydroxy, a Ci_-6 alkyl, a halo-Ci_-6 alkyl, a Ci_-6 alkoxy, a halo-Ci_-6 alkoxy or an oxo;

R^{4 a} and R^{4 b} each independently represent a hydrogen atom or a Ci_-6 alkyl, or R^{4 a} and R^{4 b} , taken together with the nitrogen atom to which they bond, form a 5- or 6- membered nitrogen-containing hetero ring, wherein the nitrogen-containing hetero ring may further contain a hetero atom selected from a group consisting of nitrogen, oxygen and sulfur, and may be substituted with a halogen, a hydroxy, a Cj_-6 alkyl, a halo-Ci_-6 alkyl, a Ci_-6 alkoxy, a halo-Ci_-6 alkoxy or an oxo; W represents C, S or SO;

Ari represents a 6-membered aryl, or a 6-membered nitrogen-containing heteroaryl, wherein the aryl or the nitrogen-containing heteroaryl may be substituted with a substituent selected from the group α; Ar₂ represents a 6-membered aryl, or a 5- or 6-membered heteroaryl, wherein the aryl or the heteroaryl may be substituted with a substituent selected from the group α;

Ar₃ represents a mono- or bi-cyclic aryl or heteroaryl, or a pyridone, wherein the aryl or the heteroaryl may form a condensed ring with a non-aromatic cyclic hydrocarbon or a non-aromatic hetero ring, and wherein the aryl, the heteroaryl or the pyridone may be optionally mono- to tetra-substituted with a substituent selected from a halogen, a C_1-6 alkyl, a halo-C_1-6 alkyl, a hydroxy-C_1-6 alkyl, a Ci_-6 alkyloxy, a halo-C_1-6 alkyloxy, a C_3-6 cycloalkyl, a hydroxy-C_3- β cycloalkyl, a cyano, a carbamoyl, a mono-C_1-6 alkylcarbamoyl, a di-Ci_-6 alkylcarbamoyl, a C_1-6 alkylsulfonyl and a sulfonylamide; ml, m2, m3 and m4 each independently indicate 0, 1, 2, 3 or 4, provided that the total of ml and m2 is from 2 to 6, and the total of m3 and m4 is from 2 to 6, and any -CH₂- forming the spiro ring may be replaced by -O- and/or -C(O)-; Substituents of group α: a halogen, a cyano, a hydroxy, an amino, a mono-C_1-6 alkylamino, a di-Cj_-6 alkylamino, a C_1-6 alkyl, a halo-C_1-6 alkyl, a C_1-6 alkoxy, a halo-Ci_-6 alkoxy, a C_1-6 alkoxy-Ci_-6 alkyl, a C_1-6 alkoxycarbonyl, a Ci_-6 alkoxycarbonylamino, a Ci_-6 alkoxycarbonyl(C_1-6 alkyl)amino, a Ci_-6 alkylcarbonyl, a C_1-6 alkylcarbonyloxy, a C_1-6 alkylcarbonylamino, a Ci_-6 alkylcarbonyl(Ci_-6 alkyl)amino, a carbamoyl, a mono-Ci_-6 alkylcarbamoyl, a di-C_1-6 alkylcarbamoyl, a carbamoylamino, a mono-C]_-6 alkylcarbamoylamino, a di-Ci_-6 alkylcarbamoylamino, a HiOnO-C_{1- 6} alkylcarbamoyl(C]_-6 alkyl)amino, a di-Ci_-6 alkylcarbamoyl(Ci_-6 alkyl)amino, a carbamoyloxy, a mono-Ci-₆ alkylcarbamoyloxy, a di-Ci_-6 alkylcarbamoyloxy, a C_1-6 alkylsulfonyl, a Ci_-6 alkylsulonylamino, a Ci_-6 alkylsulfonyl(Ci_-6 alkyl)amino, a sulfamoyl, a mono-C_1-6 alkylsulfamoyl, a di-Ci_-6 alkylsulfamoyl, a sulfamoylamino, a mono-Ci_-6 alkylsulfamoylamino, a di-Ci-₆ alkylsulfamoylamino, a mono-Cj_-6 alkylsulfamoyl(Ci_-6 alkyl)amino, and a di-Ci_-6 alkylsulfamoyl(Ci_-6 alkyl)amino.

2. The compound or the pharmaceutically-acceptable salt thereof as claimed in claim 1, wherein R^{1 a} and R^{1 b} are dependency a hydrogen atom or a methyl.

3. The compound or the pharmaceutically-acceptable salt thereof as claimed in claim 1 or 2, wherein R² is a hydrogen atom, a methyl, an ethyl, an n-propyl, an isopropyl, a 2-fluoroethyl or a 2,2-difluoroethyl.

4. The compound or the pharmaceutically-acceptable salt thereof as claimed in any of claims 1 to 3, wherein R³ is a hydrogen atom, a methyl, an ethyl, a fluoromethyl, a difluoromethyl, a trifluoromethyl or a cyclopropyl.

5. The compound or the pharmaceutically-acceptable salt thereof as claimed in any of claims 1 to 4, wherein Z is a methyl, an ethyl, an isopropyl, a difluoromethyl, a trifluoromethyl, a 1 -hydroxy- 1 -methyl ethyl, a 1 -hydroxycyclopropyl, a methoxy, a phenyl or an isoxazolyl.

6. The compound or the pharmaceutically-acceptable salt thereof as claimed in claim 1 , wherein R² and Z, taken together with the atom to which they bond, form a ring mentioned below:

wherein R^{5 a} represents a hydrogen atom, a halogen, a hydroxy, a Ci_-6 alkyl, a halo-Ci-₆ alkyl, a Cj.₆ alkoxy or a halo-Ci_-6 alkoxy; and R^{5 b} represents a hydrogen atom, a Ci_-6 alkyl or a halo-Ci_-6 alkyl.

7. The compound or the pharmaceutically-acceptable salt thereof as claimed in claim 6, wherein R^{5 a} is a hydrogen atom, a fluorine atom, a hydroxy or a methoxy; and R^{5 b} is a hydrogen atom or a methyl.

8. The compound or the pharmaceutically-acceptable salt thereof as claimed in claim 1, wherein W is C or SO.

9. The compound or the pharmaceutically-acceptable salt thereof as claimed in any of claims 1 to 8, wherein the group of a formula (A):

in formula (I) is selected from the following group:

10. The compound or the pharmaceutically-acceptable salt thereof as claimed in any of claims 1 to 9, wherein Ar₂ is a phenylenediyl, a pyridine-diyl or a pyrimidine-diyl.

11. The compound or the pharmaceutically-acceptable salt thereof as claimed in claim 10, wherein Ar₂ is a 1 ,4-phenylenediyl, a pyridine-2,5-diyl or a pyrimidine-2,5-diyl.

12. The compound or the pharmaceutically-acceptable salt thereof as claimed in any of claims 1 to 11 , wherein Ari is a 6-membered aryl substituted with from 1 to 3 substituents of fluorine atoms, cyano groups and chlorine atoms, or a 6-membered nitrogen- containing heteroaryl substituted with from 1 to 3 substituents of fluorine atoms, cyano groups and chlorine atoms.

13. The compound or the pharmaceutically-acceptable salt thereof as claimed in claim 12, wherein Ari is a phenyl substituted with from 1 to 3 substituents of fluorine atoms, cyano groups and chlorine atoms, or a pyridyl substituted with from 1 to 3 substituents of fluorine atoms, cyano groups and chlorine atoms.

14. The compound or the pharmaceutically-acceptable salt thereof as claimed in any of claims 1 to 13, wherein Ar₃ is selected from the following group:

15. The compound or the pharmaceutically-acceptable salt thereof as claimed in claim 1 , wherein the compound of formula (I) is selected from the group consisting of: N-[(1R) or (lS)-l-(5-{[6-(5-cyano-3-pyridinyl)-2,6-diazaspiro[3.3]hept-2-yl]methyl}-2- pyridinyl)- 1 -(3 ,4-difluorophenyl)ethyl] -2,2-difluoroacetamide,

N-[(1R) or (lS)-l-(5-{(lR) or (lS)-l-[6-(5-cyano-3-pyridinyl)-2,6-diazaspiro[3.3]hept-2- yl] ethyl } -2-pyridinyl)- 1 -(3 ,4-difluorophenyl)ethyl]-2,2-difluoroacetamide, N-[(lR) or (lS)-l-(5-{[6-(5-cyano-3-pyridinyl)-2,6-diazaspiro[3.3]hept-2-yl]methyl}-2- pyridinyl)-l-(3,4-difluorophenyl)ethyl]-2-methylpropanamide,

N-[(lR) or (lS)-l-(5-{[6-(5-cyano-3-pyridinyl)-2,6-diazaspiro[3.3]hept-2-yl]methyl}-2- pyridinyl)- 1 -(3,4-difluorophenyl)ethyl]cyclopropanecarboxamide trifluoroacetate, N-[(lR) or (lS)-l-(5-{[6-(5-cyano-3-pyridinyl)-2,6-diazaspiro[3.3]hept-2-yl]methyl}-2- pyridinyl)- 1 -(3 ,4-difluorophenyl)ethyl] -2-hydroxy-2-methylpropanemide trifluoroacetate, N-[(R) or (S)-(5-{[6-(5-cyano-3-pyridinyl)-2,6-diazaspiro[3.3]hept-2-yl]methyl}-2- pyridinyl)(cyclopropyl)(3,4-difluorophenyl)methyl]-2,2-difluoroacetamide trifluoroacetate, N-[(lR) or (lS)-l-(5-{[6-(5-cyano-3-pyridinyl)-2,6-diazaspiro[3.3]hept-2-yl]methyl}-2- pyridinyl)- 1 -(3 ,4-difluorophenyl)-2,2-difluoroethyl] acetamide trifluoroacetate, N-[(lR) or (lS)-l-(3,4-difiuorophenyl-l-5-{[6-(5-methyl-3-pyridinyl)-2,6-diazaspiro[3.3]hept-2- yl]methyl} -2-pyridinyl)ethyl-2,2-difluoroacetamide trifluoroacetate, N-[(lR) or (lS>l-(3Adifluorophenyl-l-5-{[6<5-fluoroO-pyridinyl)-2,6^iazaspiro[3.3]hept-2- yl]methyl}-2-pyridinyl)ethyl-2,2-difluoroacetamide trifluoroacetate, N-[(lR) or (lS)-l-(5-{[6-(5-chloro-3-pyridinyl)-2,6-diazaspiro[3.3]hept-2-yl]methyl}-2- pyridinyl)- 1 -(3 ,4-difluorophenyl)ethyl-2,2-difluoroacetamide trifluoroacetate, N-[(1R) or (lS)-l-(3,4-difluorophenyl)-l-[5-({6-[5-(trifluoromethyl)-3-pyridinyl]-2,6- diazaspiro[3.3]hept-2-yl}methyl)-2-pyridinyl]ethyl}-2,2-difluoroacetamide trifluoroacetate,

N-[(lR) or (lS)-l-(3,4-difluorophenyl)-l-(5-{[6-(6-methyl-2-pyridinyl)-2,6-diazaspiro[3.3]hept-

2-yl]methyl } -2 -pyridinyl)ethyl] -2,2-difluoroacetamide trifluoroacetate,

N-[(l R) or ( 1 S)- 1 -(3 ,4-difluorophenyl)- 1 -(5- { [6-(6-methyl-3 -pyridinyl)-2,6-diazaspiro[3.3]hept- 2-yl]methyl}-2-pyridinyl)ethyl]-2,2-difluoroacetamide trifluoroacetate,

N-[(l R) or ( 1 S)- 1 -(3,4-difluorophenyl)-l -(5- { [6-(6-fluoro-3-pyridinyl)-2,6-diazaspiro[3.3]hept- 2-yl]methyl } -2-pyridinyl)ethyl]-2,2-difluoroacetamide trifluoroacetate, N-[(lR) or (lS)-l-(5-{[6-(5-cyano-3-pyridinyl)-2,6-diazaspiro[3.3]hept-2-yl]methyl}-2- pyridinyl)-l -(3,4,5-trifluorophenyl)ethyl]-2,2-difluoroacetamide trifluoroacetate, and N-[(1R) or (lS)-l-(5-{[6-(5-cyano-3-pyridinyl)-2,6-diazaspiro[3.3]hept-2-yl]methyl}-2- pyridinyl)-l-(3,4-difluorophenyl)-2,2,2-trifluoroethyl]acetamide trifluoroacetate.

16. A melanin concentrating hormone receptor antagonist comprising the compound of any of claims 1 to 15 or the pharmaceutically-acceptable salt thereof as the active ingredient.

17. A pharmaceutical composition containing a pharmaceutically-acceptable additive and the compound of any of claims 1 to 15 or the pharmaceutically-acceptable salt thereof.

18. A preventive or remedy for bulimia, obesity, diabetes, fatty liver, depression or anxiety comprising the compound of any of claims 1 to 15 or the pharmaceutically-acceptable salt thereof as the active ingredient.