TW201302730A - Pyrazole compounds - Google Patents

Abstract

To provide a compound useful for the prevention of and/or as a therapeutic agent for schizophrenia, anxiety, Huntington's disease, drug dependence, and/or Alzheimer's disease. The inventors studied compounds having PDE10A inhibitory actions, and confirmed that a pyrazole compound has PDE10A inhibitory actions, thus resulting in the present invention. This pyrazole compound has PDE10A inhibitory actions, and can be used for the prevention of and/or as a therapeutic agent for schizophrenia, anxiety, Huntington's disease, drug dependence, and/or Alzheimer's disease.

Description

Pyrazole compound

The present invention relates to a pharmaceutical composition, for example, a pyrazole compound which is useful as an active ingredient of a pharmaceutical composition for prevention and/or treatment of a disease associated with phosphodiesterase 10A (PDE10A).

Phosphodiesterase (PDE) is an enzyme that breaks down cyclic AMP (cAMP) and cyclic GMP (cGMP), which are the second messengers in cells. PDE is based on the nature of enzyme chemistry (using cAMP as a specific matrix, cGMP as a specific matrix, or both as a matrix), amino acid sequence identity of the catalytic site, and structural motif (calmodulin binding region) , GAF area, PAS area, etc., which are classified into 11 types of families. The above-mentioned PDE family will be associated with specific tissue expression or intracellular local interaction with specific proteins, and is therefore thought to be associated with intracellular messages in specific organs and tissues (Folia Pharmacologica Japonica., 2005, Vol. 126, p. 121).

It has been reported that in the PDE family, in particular, PDE10A is preserved genetically in any type of mammal, which is manifested in the brain, especially on the linear and lateral nucleus of the spine. Highly expressed, both cAMP and cGMP are used as a matrix (Neuropharmacology, 2010, Vol. 59, p. 367). PDE10A is specifically tested for the use of Phencyclidine, a disorder in which schizophrenia-like disorders are induced in humans. In this case, the sensitivity to the induced drug can be reduced (Neuropharmacology, 2006, Vol. 51, p. 374). Moreover, social actions are higher than wild populations (Journal of Neurochemistry., 2008, Vol. 105, p. 546), and no extrapyramidal disorders are induced (Neuropharmacology, 2008, Vol. 54, p. 417). ). For the study of the inhibitory drug selected using PDE10A, the inhibitory drug can promote various intracellular communication in the line body to increase the cAMP and cGMP in the nerve cells. This result has been reported to have improved the auditory sensory gating disorder observed in Phencyclidine-induced activity and specificity in schizophrenia patients (Journal of Pharmacology and Experimental Therapeutics, 2008, pp. 325 volumes, p.681). In addition, the effectiveness of the PDE10A selective inhibitory drug is also shown in any animal model corresponding to the positive symptoms, negative symptoms, and cognitive dysfunction of the main symptoms of schizophrenia. On the other hand, it has been reported that the risk of induction of extrapyramidal disorders by existing antipsychotic drugs is relatively low (Journal of Pharmacology and Experimental Therapeutics, 2009, Vol. 331, p. 574). From the above, it is known that the obstruction drug selected by PDE10A is low in the risk of induction of extrapyramidal disorders, and it is expected to be an effective antipsychotic for any main symptom of schizophrenia.

It is known that PDE10A is a genetically deficient small mouse showing a social improvement, or for an animal model of Huntington's disease, PDE10A inhibitors can inhibit the drug-induced neurodegeneration (Neurobiology of disease, 2009, Vol. 34, p .450). Also known for use in schizophrenia Positive symptoms of animal models of stimulants (Phenamine) and anesthetic (Phencyclidine)-induced changes in action, PDE10A inhibitors show improvement (Journal of Pharmacology and Experimental Therapeutics, 2008, 325 volumes, p.681), N-methyl-D-aspartate (NMDA) antagonist induction showed improvement in cognitive impairment (European Journal of Neuroscience, 2005, Vol. 21, p. 1070) . It is known from the above that PDE10A can be used not only as a drug treatment target for schizophrenia, but also as a drug treatment for anxiety disorders, Huntington's disease, drug dependence or cognitive impairment of Alzheimer's disease and its peripheral symptoms. Subject.

Compounds A (Patent Document 1), Compound B (Patent Document 2), Compound C (Patent Document 3), and Compound D (Previous Techniques 4 and 5) of the following formula have been reported as compounds exhibiting an inhibitory action on PDE10. .

[The symbol in the formula refers to the bulletin]

Further, as a compound exhibiting a PDE10A inhibitory action, a compound E (Patent Document 6), a compound F (Patent Document 7), and a compound G (Patent Document 8) of the following formula have been reported.

[The symbol in the formula refers to the bulletin]

However, the disclosure or description of the compound of the formula (I) or a salt thereof in the present invention is not one of the above documents.

[Advanced technical literature] [Patent Literature]

[Patent Document 1] International Publication No. WO2006/072828

[Patent Document 2] International Publication No. WO2007/077490

[Patent Document 3] International Publication No. WO2007/129183

[Patent Document 4] International Publication No. WO2009/158393

[Patent Document 5] International Publication No. WO2009/158473

[Patent Document 6] International Publication No. WO2004/002484

[Patent Document 7] International Publication No. WO2006/034491

[Patent Document 8] International Publication No. WO2008/084299

The present invention provides a pharmaceutical composition which is useful as an active ingredient of a pharmaceutical composition for treating schizophrenia, for example.

The inventors of the present invention conducted a detailed review of the compound having a PDE10A inhibitory effect, and found that the pyrazole compound of the present invention has a PDE10A inhibitory action to complete the present invention.

That is, the present invention relates to a compound of the formula (I) or a salt thereof, and a pharmaceutical composition comprising the compound of the formula (I) or a salt thereof and an excipient.

(wherein, ring A is an aromatic heterocyclic ring which may be substituted, and B is a cycloalkyl group which may be substituted by a C _1-6 alkyl group, a halogen, -OC _1-6 alkyl group, and may be substituted a non-aromatic heterocyclic group in which the same or different one or more groups are substituted with a phenyl, pyridyl or thiophenediyl group, or -C≡C-, n is an integer of 0 or 1. , L ¹ is, -C _1-6 alkylene -, - C _1-6 alkylene or -T- -TC _1-6 alkylene -, but when n is 0, L ¹ is - A three extension a radical -T- or -tetramethyl-T-, X is CR ⁰ or N, and R ¹ may be selected from the group consisting of halogen, -OH, -OC _1-6 alkyl, -CN, -C(O)OH, And C _1-6 alkyl or H substituted by the same or different one or more groups of -C(O)OC _1-6 alkyl groups, and ring E is a cycloalkyl group which may be substituted, a substituted aryl group, an aromatic heterocyclic ring which may be substituted or a non-aromatic heterocyclic ring which may be substituted, T is O, S, -NH-, or -N(C _1-6 alkyl)-, R ⁰ Is H or C _1-6 alkyl)

Further, unless otherwise stated, the symbols in the chemical formulae in the present specification are used in the other chemical formulas to indicate the same symbols or the same meanings.

Further, the present invention relates to a pharmaceutical composition for preventing and/or treating schizophrenia, anxiety, Huntington's disease, drug dependence and/or Alzheimer's disease containing a compound of the formula (I) or a salt thereof . Further, the pharmaceutical composition is a prophylactic and/or therapeutic agent comprising schizophrenia, anxiety, Huntington's disease, drug dependence, and/or Alzheimer's disease containing the compound of the formula (I) or a salt thereof .

Further, the present invention relates to a compound of the formula (I) for the manufacture of a pharmaceutical composition for the prevention and/or treatment of schizophrenia, anxiety, Huntington's disease, drug dependence, and/or Alzheimer's disease or Use of a salt thereof, use of a compound of the formula (I) or a salt thereof for the prevention and/or treatment of schizophrenia, anxiety, Huntington's disease, drug dependence, and/or Alzheimer's disease, a compound of the formula (I) or a salt thereof for the prevention and/or treatment of schizophrenia, anxiety, Huntington's disease, drug dependence, and/or Alzheimer's disease, and a compound of the formula (I) or The effective amount of salt is administered to the subject of schizophrenia, anxiety, Huntington's disease, drug dependence, and / or prevention and / or treatment of Alzheimer's disease. Further, the "subject" is a human body or other animal that must be prevented or treated, and this aspect is a human body that is necessary for prevention or treatment.

The compound of the formula (I) or a salt thereof has a PDE10A inhibitory action and can be used as a prophylactic and/or therapeutic agent for schizophrenia, anxiety, Huntington's disease, drug dependence, and/or Alzheimer's disease.

Form of implementing the invention

The invention is described in detail below.

In the present specification, the "alkyl group" is a linear alkyl group and a branched alkyl group. Therefore, the "C _1-6 alkyl group" is a linear or branched alkyl group having 1 to 6 carbon atoms, and is, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a tert-butyl group, or a pentyl group. The group, the hexyl group and the like may be a methyl group, an ethyl group, a propyl group or an isopropyl group as another aspect, and may further be a methyl group, an ethyl group or an isopropyl group as another aspect.

The "alkylene group" is a divalent group formed by removing any one of the hydrogen atoms of the above "alkyl group". Therefore, the "C _1-6 alkylene group" is a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, trimethyl, tetramethyl, and Methyl, hexamethyl, methyl methyl, dimethyl methyl, ethyl methyl, methyl ethyl, dimethyl ethyl, ethyl ethyl, etc., as other aspects Methyl, ethylene.

The "cycloalkyl group" is a saturated hydrocarbon group ring group having a ring number of 3 to 8, and the cycloalkyl group may have a crosslinkage and may be condensed with a benzene ring, and a part of the bond may be unsaturated. For example, it is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, etc., and has C _3-6 cycloalkyl group as another aspect.

The "aryl group" is a monocyclic to tricyclic aromatic hydrocarbon ring group having 6 to 14 carbon atoms. Specific examples are phenyl, naphthyl and the like.

The "aromatic heterocyclic ring" is a ring-constituting atom containing one or more hetero atoms selected from O, N and S, and is a monocyclic aromatic heterocyclic group having a ring member number of 5 to 6, and the monocyclic aromatic group The heterocyclic ring may be condensed with a ring selected from the group consisting of cyclohexane, benzene, or thiophene, imidazole, pyrazole, pyridine, triazole, and pyrazine. Further, the nitrogen constituting the atom of the ring can be oxidized. Specifically, for example, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, triazolyl, triazinyl, tetrazolyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, Isoxazolyl, thiadiazolyl, isodoxyl, thienyl, furyl, decyl, isodecyl, benzimidazolyl, oxazolyl, quinolyl, isoquinolyl, quinazoline Polinyl, quinoxalinyl, pyridazinyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, benzoxazolyl, benzisoxazolyl, benzofuranyl, benzo Thienyl, benzotriazolyl, thienopyridyl, thienopyrimidinyl, thienopyrazine, 5,6,7,8-tetrahydroquinolyl, imidazo[1,2-a]pyridinyl, Imidazo[1,2-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, pyrazol[1,5-a]pyrimidinyl, imidazo[4,5-b]pyridinyl, 1 , 8-naphthyridinyl, imidazo[2,1-b][1,3]thiazolyl, [1,2,4]triazolo[1,5-a]pyridinyl, pyrido[2,3 -b] pyrazinyl, N-oxide pyridyl and the like.

The "non-aromatic heterocyclic ring" contains 1 selected from O, N, and S. To four hetero atoms as a ring-constituting atom, which is a monocyclic non-aromatic heterocyclic group having a ring number of 4 to 8. The monocyclic non-aromatic heterocyclic ring can be condensed with a benzene ring. Further, the sulfur atom constituting the ring may be oxidized, and a part of the ring may be unsaturated. Specific examples thereof include azetidinyl group, pyrrolidinyl group, piperidinyl group, piperazinyl group, azepanyl group, diazepanyl group, morpholinyl group, cyclobutytidine, and thiamorpholine. 1,1,1-dioxythiamorpholinyl, tetrahydropyridyl, tetrahydropyrimidinyl, oxycyclobutane, tetrahydrofuranyl, tetrahydropyranyl, dioxiranyl, dioxoalkyl , tetrahydrothiapyran, porphyrin, 1,2-dihydropyridyl, 1,2-dihydropyrimidinyl, 1,2-dihydropyrazinyl, 1,2-dihydropyridazinyl, etc. .

The "halogen" is F, Cl, Br, and I.

The aspect of "stretching phenyl" is 1,4-phenylene, and the aspect of "pyridinediyl" is pyridine-2,5-diyl, and the aspect of "thiophenediyl" is thiophene-2. , 5-diyl.

In the present specification, the term "may be substituted" means unsubstituted or has 1 to 5 substituents. Also, when there are a plurality of substituents, these substituents may be the same or different.

The substituent which may be permitted in the "aromatic heterocyclic ring which may be substituted" in the ring A of the formula (I) may, for example, be selected from the group consisting of halogen, -OH, -OC _1-6 alkyl group, and -N (C _1-6 alkyl) ₂ identical or different groups of one or more of the groups substituted C _1-6 alkyl, (2) halo, (3) -O- (by the same Or a C ₁ alkyl group substituted by one or more halogens, (4)-NH ₂ , (5)-NH(C _1-6 alkyl), (6)-N (C _{1- 6} alkyl) ₂ , (7)-CN, (8) cycloalkyl, (9)-C(O)OC _1-6 alkyl, (10)-C(O)H.

As a substituent of a pendant phenyl group, a pyridyldiyl group or a thiophenediyl group which may be substituted in the formula (I), a "cycloalkyl group which may be substituted" or a non-aromatic group which may be substituted may be permitted. Examples of the substituent which may be permitted in the ring include a C _1-6 alkyl group, a halogen, and -OH.

As a permissible substituent of the "cycloalkyl group which may be substituted" in the ring E of the formula (I), a C _1-6 alkyl group, -OH, -C(O)NH ₂ , -C may be mentioned. (O) NH(C _1-6 alkyl), -C(O)N(C _1-6 alkyl) ₂ , -CN, =NOC _1-6 alkyl, and pendant oxygen.

Examples of the permissible substituent in the "aryl group which may be substituted" in the ring E of the formula (I) include a C _1-6 alkyl group, a halogen, and -OH.

As a pharmaceutically acceptable substituent for the "aromatic heterocyclic ring which may be substituted" in the ring E of the formula (I), it may be selected from the group consisting of i) halogen, -OH, -OC _1-6 alkyl group, C ₁ substituted by the same or different one or more groups of -O-tert-butyldimethylhydrazine (hereinafter -O-TBS) and -N(C _1-6 alkyl) _{2 -6} alkyl, ii) halogen, iii) -OC _1-6 alkyl, iv)-OH, and v) cycloalkyl.

As a permissible substituent of the "non-aromatic heterocyclic ring which may be substituted" for the ring E of the formula (I), (1) may be selected from a halogen, -OH, -OC _1-6 alkyl group. And C- _1-6 alkyl, (2) halogen, (3)-OH, (4) substituted with the same or different one or more groups of -N(C _1-6 alkyl) ₂ ) -S (O) ₂ -C _1-6 alkyl, (5) -C (O) - (- OC 1-6 alkyl substituted C _1-6 alkyl group), (6) -C (O -N(C _1-6 alkyl) ₂ , (7)-C(O)OC _1-6 alkyl, (8) side oxygen.

The aspect of the compound of the formula (I) or a salt thereof is shown below.

(1) Ring A is the same or different one selected from the group consisting of i) selected from the group consisting of halogen, -OH, -OC _1-6 alkyl, and -N(C _1-6 alkyl) ₂ the above groups substituted with C _1-6 alkyl, ii) halogen, iii) -O- (by the same or different one or more substituted with halogen or C _1-6 alkyl), iv) -N ( a compound of the formula (I) wherein C _1-6 alkyl) ₂ , v)-CN, and vi) an aromatic heterocyclic ring substituted with the same or different one or more groups of cycloalkyl groups; salt.

As a further aspect, Ring A may be the same or different 1 selected from i) selected from the group consisting of halogen, -OH, -OC _1-6 alkyl, and -N(C _1-6 alkyl) ₂ one of the above groups substituted with C _1-6 alkyl, ii) halogen, iii) -O- (by the same or different one or more substituted with halogen or C _1-6 alkyl), iv) -N (C _1-6 alkyl) ₂ , v)-CN, and vi) a benzimidazolyl group, a pyridyl group, a quinolyl group substituted with the same or different one or more groups of a cycloalkyl group. Formula (I) of imidazo[1,2-a]pyridinyl, imidazo[4,5-b]pyridinyl, 1,8-naphthyridinyl, or imidazo[1,2-b]pyridazinyl a compound or a salt thereof.

Further, as another aspect, the ring A is a compound of the formula (I) or a salt thereof of the benzimidazolyl group substituted by a C _1-6 alkyl group.

Further, as another aspect, the ring A is a compound of the formula (I) or a salt thereof of the benzimidazol-4-yl group substituted by a C _1-6 alkyl group.

Further, as another aspect, the ring A is a compound of the formula (I) or a salt thereof of the benzimidazol-4-yl group substituted by a methyl group or an ethyl group.

Further, as another aspect, ring A is the same or a group which may be grouped by a group selected from a C _1-6 alkyl group, a —OC _1-6 alkyl group, a —N(C _1-6 alkyl) ₂ group, and a cycloalkyl group. A compound of the formula (I) or a salt thereof, which has a pyridyl group substituted with one or more substituents.

Further, as another aspect, the ring A is a pyridin-2-yl group which may be substituted by the same or different one or more groups selected from the group consisting of a C _1-6 alkyl group and a -OC _1-6 alkyl group. a compound of (I) or a salt thereof.

Further, as another aspect, the ring A is a pyridin-2-yl group-substituted compound of the formula (I) or a salt thereof.

Further as another aspect, Ring A is the same dissimilarly groupable from the group consisting of: i) may be selected from the group consisting of halogen, -OH, -OC _1-6 alkyl, and -N(C _1-6 alkyl) ₂ one or more of the groups substituted with C _1-6 alkyl, ii) halogen, iii) -O- (by the same or different one or more substituted with halogen or C _1-6 alkyl), iv) - a compound of formula (I) wherein N(C _1-6 alkyl) ₂ , v)-CN, and vi) a quinolyl group substituted by the same or different one or more groups of cycloalkyl groups or Its salt.

Further, as another aspect, the ring A is a C ₁ which may be substituted by the same or different one or more groups selected from the group consisting of halogen and -N(C _1-6 alkyl) ₂ selected from i). A compound of the formula (I) or a salt thereof, wherein the _-6 alkyl group, the ii) halogen group, and the iii)-OC _1-6 alkyl group are substituted by the same or different one or more substituents.

Further, as another aspect, Ring A is the same or different one group which may be grouped by a group selected from methyl, ethyl, difluoromethyl, dimethylaminomethyl, F, and -O-methyl. A compound of the formula (I) or a salt thereof of the quinolyl group substituted by the above group.

Further, as another aspect, Ring A is the same or different one group selected from the group consisting of methyl, ethyl, difluoromethyl, dimethylaminomethyl, F, and -O-methyl. A compound of the formula (I) or a salt thereof, which is substituted with the above quinolin-2-yl group.

Further, as another aspect, the ring A is a quinoline-2-yl group which may be substituted by the same or different one or more groups selected from the group consisting of methyl, ethyl, F, and -O-methyl groups. a compound of the formula (I) or a salt thereof.

Further, as another aspect, Ring A is the same or different one group which may be grouped by a group selected from methyl, ethyl, difluoromethyl, dimethylaminomethyl, F, and -O-methyl. A compound of the formula (I) or a salt thereof of the quinoline-8-yl group substituted by the above group.

Further, as another aspect, the ring A is selected from the group consisting of methyl and B. A compound of the formula (I) or a salt thereof, wherein the group, the F, and the -O-methyl group are substituted by the same or different one or more substituents of the quinoline-8-yl group.

(2) B is the same or a group which may be grouped by a C _1-6 alkyl group, a halogen, a -OC _1-6 alkyl group, a cycloalkyl group which may be substituted, and a non-aromatic heterocyclic ring which may be substituted A compound of the formula (I) or a salt thereof, which is substituted with a phenyl or pyridyl group, each of which is substituted by one or more substituents.

As another aspect, B is a compound of the formula (I) wherein -C≡C- or a salt thereof.

Further, as another aspect, B is a group which may be grouped by a C _1-6 alkyl group, a halogen, a -OC _1-6 alkyl group, a cycloalkyl group which may be substituted, and a non-aromatic heterocyclic ring which may be substituted. A compound of the formula (I) or a salt thereof, which is substituted with a phenyl group substituted by the same or different one or more groups.

Further, as another aspect, B is a _phenyl group substituted by the same or different one or more groups selected from the group consisting of a C _1-6 alkyl group, a halogen group, and a —OC _1-6 alkyl group. a compound of (I) or a salt thereof.

Further, as another aspect, B is a compound of the formula (I) which may be substituted with a phenyl group which is substituted by the same or different one or more groups selected from the group consisting of methyl, F, and -O-methyl or Its salt.

Further, as another aspect, B is a formula (I) of 1,4-phenylene group which may be substituted by the same or different one or more groups selected from the group consisting of methyl, F, and -O-methyl groups. a compound or a salt thereof.

Further, as another aspect, B is a compound of the formula (I) or a salt thereof which is a 1,4-phenylene group.

Further, as another aspect, B is a formula of a pyridyl group which may be substituted by the same or different one or more groups selected from the group consisting of a C _1-6 alkyl group, a halogen group, and a —OC _1-6 alkyl group. a compound of (I) or a salt thereof.

Further, as another aspect, B is pyridine-2,5 which may be substituted by the same or different one or more groups selected from the group consisting of C _1-6 alkyl, halogen, and -OC _1-6 alkyl. a dibasic compound of the formula (I) or a salt thereof.

Further, as another aspect, B is a pyridine-2,5-diyl compound of the formula (I) or a salt thereof.

(3) A compound of the formula (I) wherein n is 1 or a salt thereof.

(4) A compound of the formula (I) wherein L ¹ is -C _1-6 alkyl-T- or -TC _1-6 alkylene or a salt thereof.

As another aspect, the compound of the formula (I) wherein L ¹ is -C _1-6 alkylene- or a salt thereof.

Further, as another aspect, the compound of the formula (I) wherein L ¹ is -C _1-6 alkyl-O- or -OC _1-6 alkylene or a salt thereof.

Further, as another aspect, the compound of the formula (I) wherein L ¹ is -C _1-6 alkyl-NH- or -NH-C _1-6 alkylene or a salt thereof.

Further, as another aspect, the compound of the formula (I) wherein L ¹ is -CH ₂ -O- or -O-CH ₂ - or a salt thereof.

Further, as another aspect, the compound of the formula (I) wherein L ¹ is -CH ₂ -O- or a salt thereof. Further, as another aspect, the compound of the formula (I) wherein L ¹ is -O-CH ₂ - or a salt thereof.

Still further, as another aspect, L ¹ is a compound of the formula (I) or a salt thereof which is an ethyl group.

(5) A compound of the formula (I) wherein X is CH or N or a salt thereof.

As another aspect, the compound of the formula (I) wherein X is CH or a salt thereof.

Further, as another aspect, X is a compound of the formula (I) or a salt thereof.

(6) R ¹ is the same or may be grouped from halogen, -OH, -OC _1-6 alkyl, -CN, -C(O)OH, and -C(O)OC _1-6 alkyl A compound of the formula (I) or a salt thereof of a C _1-6 alkyl group substituted with one or more different groups.

As a further aspect, R ¹ is the same or different from a group selected from the group consisting of F, -OH, -O-methyl, -CN, -C(O)OH, and -C(O)O-ethyl. A compound of the formula (I) or a salt thereof of the C _1-6 alkyl group substituted with one or more substituents.

Further, as another aspect, R ¹ is a C _1-6 alkyl group-substituted compound of the formula (I) or a salt thereof.

Further, as another aspect, the compound of the formula (I) wherein R ¹ is a trifluoromethyl group or a salt thereof.

Further, as another aspect, R ¹ is a C _1-6 alkyl group-substituted compound of the formula (I) or a salt thereof.

Further, as another aspect, the compound of the formula (I) wherein R ¹ is a methyl group or a salt thereof.

(7) A compound of the formula (I) wherein the ring E is an aromatic heterocyclic ring or a non-aromatic heterocyclic ring which may be substituted, or a salt thereof. As another aspect, the ring E is a compound of the formula (I) or a salt thereof which can be substituted with an aromatic heterocyclic ring.

Further, as another aspect, the ring E is a compound of the formula (I) or a salt thereof which may be substituted with a non-aromatic heterocyclic ring.

Further, as another aspect, the ring E may be grouped from the group consisting of halogen, -OH, -OC _1-6 alkyl, -O-TBS, and -N(C _1-6 alkyl) ₂ selected from i) Groups of C _1-6 alkyl, ii) halogen, iii) -OC _1-6 alkyl, iv)-OH, and v) cycloalkyl substituted by the same or different one or more groups A compound of the formula (I) or a salt thereof, which is an aromatic heterocyclic ring substituted with one or more substituents which are the same or different.

Further, as another aspect, the ring E is one or more of the same or different ones selected from the group consisting of halogen, -OH, -OC _1-6 alkyl, and -N(C _1-6 alkyl) ₂ . A compound of the formula (I) or a salt thereof, which is substituted with an aromatic heterocyclic ring substituted by a C _1-6 alkyl group.

Further, as another aspect, the ring E is an aromatic group substituted by a C _1-6 alkyl group substituted by the same or different one or more groups selected from the group consisting of -OC _1-6 alkyl group and -OH group. A heterocyclic compound of formula (I) or a salt thereof.

Further, as another aspect, the ring E is a pyridyl group substituted by a C _1-6 alkyl group substituted by the same or different one or more groups selected from the group consisting of -OC _1-6 alkyl group and -OH group. A compound of the formula (I) or a salt thereof.

Further, as another aspect, the ring E is N-substituted by a C _1-6 alkyl group substituted by the same or different one or more groups selected from the group consisting of -OC _1-6 alkyl and -OH. Oxide pyridyl compound of formula (I) or a salt thereof.

Further, as another aspect, the ring E may be a pyridazine group substituted with a C _1-6 alkyl group substituted with the same or different one or more groups selected from the group consisting of -OC _1-6 alkyl group and -OH group. A compound of the formula (I) or a salt thereof.

Further, as another aspect, the ring E is a pyrazole substituted with a C _1-6 alkyl group substituted by the same or different one or more groups selected from the group consisting of -OC _1-6 alkyl and -OH. a compound of the formula (I) or a salt thereof.

Further as another aspect, the ring E is the same or different from the group selected from the group consisting of halogen, -OH, -OC _1-6 alkyl, and -N(C _1-6 alkyl) ₂ a C _1-6 alkyl group substituted by one or more groups, ii) halogen, iii) -OH, iv)-S(O) ₂ -C _1-6 alkyl, v)-C(O)-( -OC _1-6 alkyl substituted with C _1-6 alkyl), vi) -C (O) -N (C 1-6 _{alkyl) 2, vii) -C (O} ) OC 1-6 alkyl And a compound of the formula (I) or a salt thereof in which the non-aromatic heterocyclic ring is substituted with one or more of the same or different groups of side oxygen groups.

Further as another aspect, ring E is the same or different selected from the group consisting of halogen, -OH, -OC _1-6 alkyl, and -N(C _1-6 alkyl) ₂ a C _1-6 alkyl group substituted with one or more groups, and one or more groups having the same or different groups of side oxygen groups, a substituted non-aromatic heterocyclic compound of the formula (I) or salt.

Further as another aspect, ring E is the same or different selected from the group consisting of halogen, -OH, -OC _1-6 alkyl, and -N(C _1-6 alkyl) ₂ a C _1-6 alkyl group substituted with one or more groups, and one or more groups having the same or different groups of side oxygen groups, and a substituted formula of the formula (I) of the 1,2-dihydropyridyl group a compound or a salt thereof.

Further, as another aspect, the ring E is a formula (I) of a 1,2-dihydropyridyl group which may be substituted by the same or different one or more groups selected from the group consisting of a C _1-6 alkyl group and a side oxygen group. a compound or a salt thereof.

Further as another aspect, ring E is the same or different selected from the group consisting of halogen, -OH, -OC _1-6 alkyl, and -N(C _1-6 alkyl) ₂ A compound of the formula (I) or a salt thereof, wherein the C _1-6 alkyl group substituted with one or more groups and the same or different one or more groups in which the side oxygen groups are the same, the substituted piperidinyl group.

Further, as another aspect, the ring E is a compound of the formula (I) which may be substituted with one or more of the same or different ones selected from the group consisting of a C _1-6 alkyl group and a side oxygen group. Or its salt.

(8) A compound of the formula (I) or a salt thereof, which is a combination of two or more of the groups described in the above (1) to (7).

In the present invention, the compound or a salt thereof, which is a combination of two or more of the groups described in the above (1) to (7), is contained, and the following aspects of the specific examples are also included.

(9) B is the same or a group which may be grouped by a C _1-6 alkyl group, a halogen group, a -OC _1-6 alkyl group, a cycloalkyl group which may be substituted, and a non-aromatic heterocyclic ring which may be substituted a compound of formula (I) wherein phenyl is substituted with one or more substituents, n is 1, and L ¹ is -C _1-6 alkyl-T- or -TC _1-6 alkylene or salt.

(10) B is the same or a group which may be grouped by a C _1-6 alkyl group, a halogen, a -OC _1-6 alkyl group, a cycloalkyl group which may be substituted, and a non-aromatic heterocyclic ring which may be substituted A compound of the formula (I) or a salt thereof, wherein one or more substituents are substituted with a phenyl group, n is 1, and L ¹ is a -C _1-6 alkyl group.

(11) A compound of the formula (I) wherein B is -C≡C-, n is 1, and L ¹ is -C _1-6 alkyl-T- or a salt thereof.

(12) The compound of (9) or a salt thereof, wherein L ¹ is -C _1-6 alkyl-O- or -OC _1-6 alkylene.

(13) The compound of (10) wherein L ¹ is an ethyl group or a salt thereof.

(14) The compound of (10) wherein L ¹ is -C _1-6 alkyl-O- or a salt thereof.

(15) Ring A is the same or different one selected from the group consisting of halogen, -OH, -OC _1-6 alkyl, and -N(C _1-6 alkyl) ₂ the above groups substituted with C _1-6 alkyl, ii) halogen, iii) -O- (by the same or different one or more substituted with halogen or C _1-6 alkyl), iv) -N ( (12), (13), an aromatic heterocyclic ring substituted with one or more groups in which the C _1-6 alkyl group ₂ , v)-CN, and vi) are the same or different groups of cycloalkyl groups, Or the compound of (14) or a salt thereof.

(16) R ¹ is the same or may be grouped by halogen, -OH, -OC _1-6 alkyl, -CN, -C(O)OH, and -C(O)OC _1-6 alkyl The compound of the above (15) which is a C _1-6 alkyl group substituted with one or more different groups or a salt thereof.

(17) A compound according to (16), wherein X is CH or N, or a salt thereof.

(18) Ring E is the same or may be grouped from i) selected from the group consisting of halogen, -OH, -OC _1-6 alkyl, -O-TBS, and -N(C _1-6 alkyl) ₂ The same or phase of a group of C _1-6 alkyl, ii) halogen, iii) -OC _1-6 alkyl, iv)-OH, and v) cycloalkyl substituted with one or more different bases The compound of (17) or a salt thereof, which is an aromatic heterocyclic ring substituted with one or more different groups.

(19) Ring E is an identical or different one selected from the group consisting of halogen, -OH, -OC _1-6 alkyl, and -N(C _1-6 alkyl) ₂ selected from i) Substituted C _1-6 alkyl, ii) halogen, iii) -OH, iv) -S(O) ₂ -C _1-6 alkyl, v)-C(O)-(-OC _{1 1-6} alkyl substituted with C _1-6 alkyl), vi) -C (O) -N (C 1-6 _{alkyl) 2, vii) -C (O} ) OC 1-6 alkyl, and viii A compound of the above (17) or a salt thereof, which is a non-aromatic heterocyclic ring substituted with one or more of the same or different groups of side oxygen.

Other aspects of the compound of the formula (I) or a salt thereof are shown below.

(20)

(20-1)

Ring A is one or more selected from the group consisting of (i) the same or different groups selected from the group consisting of halogen, -OH, -OC _1-6 alkyl, and -N(C _1-6 alkyl) ₂ Substituted C _1-6 alkyl group, (ii) halogen, (iii)-O- (C _1-6 alkyl group substituted by the same or different one or more halogens), (iv)-N (C _1-6 alkyl) ₂ , (v)-CN, (vi) cycloalkyl, (vii)-C(O)H, substituted by one or more groups of the same or different groups An aromatic heterocyclic compound of the formula (I) or a salt thereof.

(20-2)

(20-2-1)

Ring A is one or more groups which may be the same or different from the group selected from the group consisting of halogen, -OH, -OC _1-6 alkyl, and -N(C _1-6 alkyl) ₂ substituted C _1-6 alkyl, ii) halogen, iii) -O- (by the same or different one or more substituted with halogen or C _1-6 alkyl), iv) -CN, v) ring a quinolyl group substituted by an alkyl group and one or more of the same or different groups of vi)-C(O)H, i) may be selected from the group consisting of -OH and -OC _1-6 alkyl The C _1-6 alkyl group, ii)-O-(C _1-6 alkyl), and iii) substituted by the same or different one or more groups may be selected from -N (C _1-6 alkane) yl) _two or more identical or different groups of the groups substituted pyridyl, or selected from i) may be selected from halogen, and groups of the same or different alkyl group -OC _1-6 Formula of benzimidazolyl substituted with one or more groups in which one or more of the groups are substituted with a C _1-6 alkyl group, ii) a cycloalkyl group, and iii) a group of the same or different groups of halogens a compound of (I) or a salt thereof.

(20-2-2)

Ring A is a quinolyl group which may be substituted by the same or different one or more groups selected from the group consisting of halogen, C _1-6 alkyl and -OC _1-6 alkyl, and may be the same or different a pyridyl group substituted with a C _1-6 alkyl group, or a benzimidazolyl compound of the same or different one or more C _1-6 alkyl groups, or a salt thereof.

(20-3)

(20-3-1)

Ring A is one or more groups which may be the same or different from the group selected from the group consisting of halogen, -OH, -OC _1-6 alkyl, and -N(C _1-6 alkyl) ₂ substituted C _1-6 alkyl, ii) halogen, iii) -O- (by the same or different one or more substituted with halogen or C _1-6 alkyl), iv) -CN, v) ring An alkyl group, and a quinolyl group substituted with the same or different one or more groups of vi)-C(O)H, or may be selected from the group consisting of halogen, and -OC _1-6 One or more of the same or different groups of C _1-6 alkyl groups, ii) cycloalkyl groups substituted with one or more groups in which the alkyl groups are the same or different, and iii) halogen groups A compound of the formula (I) or a salt thereof, substituted with a benzimidazolyl group.

(20-3-2)

Ring A is a C _1-6 alkyl group, ii) cycloalkyl group which may be substituted by one or more groups selected from i) which may be selected from the group consisting of halogen and -OC _1-6 alkyl group. And iii) a compound of the formula (I) or a salt thereof, wherein the halogen is a group of the same or different one or more substituted benzimidazolyl groups.

(20-3-3)

Ring A is substituted by the same or different one or more C _1-6 alkyl groups which may be substituted by the same or different one or more groups selected from the group consisting of halogen and -OC _1-6 alkyl group. A benzimidazolyl compound of the formula (I) or a salt thereof.

(20-3-4)

Ring A is a 1-methylbenzimidazol-4-yl compound of formula (I) or a salt thereof.

(20-4)

(20-4-1)

Ring A is one or more groups which may be the same or different from the group selected from the group consisting of halogen, -OH, -OC _1-6 alkyl, and -N(C _1-6 alkyl) ₂ substituted C _1-6 alkyl, ii) halogen, iii) -O- (by the same or different one or more substituted with halogen or C _1-6 alkyl), iv) -CN, v) ring A compound of the formula (I) or a salt thereof, wherein the alkyl group and the violinyl group substituted with one or more of the same or different groups of vi)-C(O)H are grouped.

(20-4-2)

a compound of the formula (I) wherein ring A may be a quinolinyl group substituted by the same or different one or more groups selected from the group consisting of halogen, C _1-6 alkyl and -OC _1-6 alkyl or salt.

(20-4-3)

Ring A is one or more groups which may be the same or different from the group selected from the group consisting of halogen, -OH, -OC _1-6 alkyl, and -N(C _1-6 alkyl) ₂ substituted C _1-6 alkyl, ii) halogen, iii) -O- (by the same or different one or more substituted with halogen or C _1-6 alkyl), iv) -CN, v) ring An alkyl group, and a quinoline-2-yl group substituted with one or more of the same or different groups of vi)-C(O)H, or may be selected from _C1-6 alkyl and -OC ₁ A compound of the formula (I) or a salt thereof, wherein the _-6 alkyl group is substituted by the same or different one or more substituents of the quinoline-8-yl group.

(20-4-4)

Ring A is one or more groups which may be the same or different from the group selected from the group consisting of halogen, -OH, -OC _1-6 alkyl, and -N(C _1-6 alkyl) ₂ substituted C _1-6 alkyl, ii) halogen, iii) -O- (by the same or different one or more substituted with halogen or C _1-6 alkyl), iv) -CN, v) ring A compound of the formula (I) or a salt thereof, wherein the alkyl group and the quinoline-2-yl group substituted with one or more of the same or different groups of vi)-C(O)H are present.

(20-4-5)

Ring A is a compound of formula (I) wherein quinoline-8-yl which may be substituted by the same or different one or more groups selected from the group consisting of C _1-6 alkyl and -OC _1-6 alkyl Or its salt.

(20-4-6)

Ring A is quinolin-2-yl, 3-methylquinolin-2-yl, 3-hydroxymethylquinolin-2-yl, 3-methoxyquinolin-2-yl, 6-fluoroquinoline a compound of formula (I) wherein 2-yl, 6-methoxyquinolin-2-yl, 6-methoxy-3-methylquinolin-2-yl, or quinoline-8-yl or salt.

(20-4-7)

Ring A is quinolin-2-yl, 3-methylquinolin-2-yl, 3-hydroxymethylquinolin-2-yl, 3-methoxyquinolin-2-yl, 6-fluoroquinoline a compound of the formula (I) wherein 2-yl, 6-methoxyquinolin-2-yl or 6-methoxy-3-methylquinolin-2-yl or a salt thereof.

(20-4-8)

Ring A is quinolin-2-yl, 3-hydroxymethylquinolin-2-yl, 3-methoxyquinolin-2-yl, 6-fluoroquinolin-2-yl, 6-methoxyquin A compound of the formula (I) or a salt thereof, which is oxa-2-yl, 6-methoxy-3-methylquinolin-2-yl, or quinoline-8-yl.

(20-4-9)

Ring A is quinolin-2-yl, 3-hydroxymethylquinolin-2-yl, 3-methoxyquinolin-2-yl, 6-fluoroquinolin-2-yl, 6-methoxyquin A compound of the formula (I) or a salt thereof, which is a quinolin-2-yl group or a 6-methoxy-3-methyl quinolin-2-yl group.

(20-4-10)

Ring A is a quinolin-2-yl compound of formula (I) or a salt thereof.

(20-4-11)

Ring A is a 3-methylquinolin-2-yl compound of the formula (I) or a salt thereof.

(20-4-12)

Ring A is a compound of formula (I) wherein 3-hydroxymethylquinolin-2-yl or a salt thereof.

(20-4-13)

The compound of the formula (I) wherein ring A is 3-methoxyquinolin-2-yl or a salt thereof.

(20-4-14)

The compound of the formula (I) wherein ring A is 6-fluoroquinolin-2-yl or a salt thereof.

(20-4-15)

The compound of the formula (I) wherein ring A is 6-methoxyquinolin-2-yl or a salt thereof.

(20-4-16)

The compound of the formula (I) wherein ring A is 6-methoxy-3-methylquinolin-2-yl or a salt thereof.

(20-4-17)

Ring A is a quinoline-8-yl compound of formula (I) or a salt thereof.

(twenty one)

(21-1)

B is a group which may be substituted by the same or different one or more groups selected from the group consisting of a C _1-6 alkyl group, a halogen group, a —OC _1-6 alkyl group, a cycloalkyl group, and a non-aromatic heterocyclic ring. A compound of the formula (I) or a salt thereof, which is a phenyl group, a pyridyldiyl group, or a thiophenediyl group, or -C≡C-.

(21-2)

B is a group which may be substituted by the same or different one or more groups selected from the group consisting of a C _1-6 alkyl group, a halogen group, a —OC _1-6 alkyl group, a cycloalkyl group, and a non-aromatic heterocyclic ring. A compound of formula (I), or a salt thereof, of phenyl, pyridyldiyl or thiophenediyl.

(twenty two)

A compound of the formula (I) wherein R ¹ is a C _1-6 alkyl group or a salt thereof.

(twenty three)

(23-1)

Ring E is selected from C _1-6 alkyl, -OH, -C(O)NH ₂ , -C(O)NH(C _1-6 alkyl), -C(O)N(C _1-6 Alkyl) ₂ , -CN, =NOC _1-6 alkyl, and a cycloalkyl group, an aryl group, i) substituted with the same or different one or more groups of side oxygen groups may be selected from halogens, C _1-6 alkane substituted with one or more groups of the same or different groups of -OH, -OC _1-6 alkyl, -O-TBS, and -N(C _1-6 alkyl) ₂ a aryl group, ii) halogen, iii) -OC _1-6 alkyl, iv)-OH, and v) an aromatic heterocyclic ring substituted with the same or different one or more groups of cycloalkyl groups, or It may be substituted by one or more groups selected from i) which may be the same or different groups selected from the group consisting of halogen, -OH, -OC _1-6 alkyl, and -N(C _1-6 alkyl) ₂ C _1-6 alkyl, ii)-OH, iii)-S(O) ₂ -C _1-6 alkyl, iv)-C(O)- (C ₁ substituted by -OC _1-6 alkyl) _-6 alkyl), v)-C(O)-N(C _1-6 alkyl) ₂ , vi)-C(O)OC _1-6 alkyl, and vii) the same group of side oxygen groups or A compound of the formula (I) or a salt thereof which is a non-aromatic heterocyclic ring substituted with one or more different groups.

(23-2)

The compound of the formula (I) wherein ring E is 1-methyl-6-oxo-oxy-1,6-dihydropyridin-3-yl or a salt thereof.

(23-3)

The compound of the formula (I) wherein ring E is 2-methylpyridin-4-yl or a salt thereof.

(24) A compound of the formula (I) or a salt thereof in combination of two or more of the groups described in the above (1) to (7) and (20) to (23).

In the present invention, the compound or a salt thereof in combination of two or more of the groups (1) to (7) and (20) to (23) described in the above (24) is contained, but the specific example may be included. The following aspects are presented.

(25) A compound of the formula (I) wherein the ring A is (1) or (20) or a salt thereof.

(26) B is the compound of (2), or (21) (25) or a salt thereof.

(27) The compound of (25) to (26) or a salt thereof.

(28) L ¹ is (4) of (25) to (27) or a salt thereof described.

(29) The compound according to any one of (25) to (28), wherein X is (5) or a salt thereof.

(30) R ¹ is (6), or (22) of (25) to (29) or a salt thereof described.

(31) The compound of the formula (25), or the compound of (25) to (30), or a salt thereof.

Examples of the specific compound contained in the compound of the formula (I) or a salt thereof include the following compounds.

8-[4-({[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)oxy}methyl)phenyl]quinoline, 1-Methyl-5-(1-methyl-3-{[4-(3-methylquinolin-2-yl)phenoxy]methyl}-1H-pyrazol-4-yl)pyridine- 2(1H)-ketone, 1-methyl-5-(1-methyl-3-{[4-(1-methyl-1H-benzimidazol-4-yl)phenoxy]methyl}- 1H-pyrazol-4-yl)pyridine-2(1H)-one, 1-methyl-5-(1-methyl-3-{[4-(1-methyl-1H-benzimidazole-4) -yl)benzyloxy]-1H-pyrazol-4-yl)pyridine-2(1H)-one, 2-(3-{[1-methyl-4-(pyridin-4-yl) -1H-pyrazol-3-yl]oxy}prop-1-yn-1-yl)quinoline, 1-methyl-5-(1-methyl-3-{[4-(3-methyl) Quinoline-2-yl)benzyloxy]-1H-pyrazol-4-yl)piperidin-2-one, 4-(3-{[4-(6-fluoro-3-methylquin) Phenyl-2-yl)benzyloxy]-1-methyl-1H-pyrazol-4-yl)-1-methylpyridine-2(1H)-one, 5-(3-{[4 -(6-methoxy-3-methylquinolin-2-yl)benzyl}oxy}-1-methyl-1H-pyrazol-4-yl)-1-methylpyridine-2 ( 1H)-keto, 1-methyl-4-(4-{[1-methyl-4-(2-methylpyridin-4-yl)-1H-pyrazol-3-yl]methoxy}benzene -1H-benzimidazole, 5-(3-{[4-(3-ethylquinolin-2-yl)benzyl)oxy}-1-methyl-1H-pyrazole-4- 1-methylpyridin-2(1H)-one, 3-methyl-2-(4-{[1-methyl-4-(pyridyl) Pyridin-4-yl)-1H-pyrazol-3-yl]methoxy}phenyl)quinoline, 3-methyl-2-[4-({[1-methyl-4-(pyridazine)- 4-yl)-1H-pyrazol-3-yl]oxy}methyl)phenyl]quinoline, 2-(4-{[(1,1'-dimethyl-1H,1'H-4 , 4'-bispyrazol-3-yl)oxy]methyl}phenyl)-3-methylquinoline, 1-methyl-5-(1-methyl-3-{[4-(quinolin-2-yl)benzyl)oxy}-1H-pyrazol-4-yl)pyridine-2 (1H) -keto, 1-ethyl-5-(1-methyl-3-{[4-(3-methylquinolin-2-yl)benzyl]oxy}-1H-pyrazol-4-yl Pyridine-2(1H)-one, 5-(1-methyl-3-{[4-(3-methylquinolin-2-yl)benzyl]oxy}-1H-pyrazole-4 -yl)-1-propylpyridine-2(1H)-one, 5-(3-{[4-(6-fluoro-3-methylquinolin-2-yl)benzyl)oxy}- 1-methyl-1H-pyrazol-4-yl)-1-methylpyridine-2(1H)-one, 1-methyl-5-(2-methyl-5-{[4-(3- Methylquinolin-2-yl)phenoxy]methyl}-2H-1,2,3-triazol-4-yl)pyridine-2(1H)-one, 3-methyl-2-(4 -{[1-methyl-4-(2-methylpyridin-4-yl)-1H-pyrazol-3-yl]methoxy}phenyl)quinoline, 2-(4-{[4- (2,6-Dimethylpyridin-4-yl)-1-methyl-1H-pyrazol-3-yl]methoxy}phenyl)-3-methylquinoline, 1-methyl-4 -(1-methyl-3-{2-[4-(3-methylquinolin-2-yl)phenyl]ethyl}-1H-pyrazol-4-yl)pyridine-2(1H)- Ketone, 1-methyl-4-(1-methyl-3-{[4-(3-methylquinolin-2-yl)phenoxy]methyl}-1H-pyrazol-4-yl) Pyridine-2(1H)-one, 1-methyl-4-(4-{[1-methyl-4-(2-methyl-1-oxide pyridine-4) -yl)-1H-pyrazol-3-yl]methoxy}phenyl)-1H-benzimidazole, 1-methyl-4-(4-{[1-methyl-4-(pyridazine)- 4-yl)-1H-pyrazol-3-yl]methoxy}phenyl)-1H-benzimidazole, 1-methyl-4-(1-methyl-3-{[4-(1- Methyl-1H-benzimidazol-4-yl)phenoxy]methyl}-1H-pyrazol-4-yl)pyridine-2(1H)-one, 1'-Ethyl-1-methyl-3-{[4-(1-methyl-1H-benzimidazol-4-yl)phenoxy]methyl}-1H,1'H-4,4 '-Dipyrazole, 1-methyl-5-(1-methyl-3-{[4-(quinolin-8-yl)phenoxy)methyl}-1H-pyrazol-4-yl) Pyridine-2(1H)-one, 5-(3-{[4-(6-methoxy-3-methylquinolin-2-yl)phenoxy]methyl}-1-methyl-1H -pyrazol-4-yl)-1-methylpyridine-2(1H)-one, 8-(4-{[1-methyl-4-(pyrazin-4-yl)-1H-pyrazole- 3-yl]methoxy}phenyl)quinoline, 1-methyl-5-(1-methyl-3-{[4-(quinolin-2-yl)phenoxy]methyl}-1H -pyrazol-4-yl)pyridine-2(1H)-one, 5-(3-{[4-(3-methoxyquinolin-2-yl)phenoxy]methyl}-1-methyl -1H-pyrazol-4-yl)-1-methylpyridine-2(1H)-one, 5-(3-{[4-(6-fluoroquinolin-2-yl)phenoxy]- -1-methyl-1H-pyrazol-4-yl)-1-methylpyridine-2(1H)-one, 5-(3-{[4-(6-methoxyquinoline-2) -yl)phenoxy]methyl}-1-methyl-1H-pyrazol-4-yl)-1-methylpyridine-2(1H)-one, 3-methyl-8-(4-{ [1-Methyl-4-(2-methylpyridin-4-yl)-1H-pyrazol-3-yl]methoxy}phenyl)imidazo[1,2-a]pyridine, 1,1 '-Dimethyl-3-{[4-(3-methylimidazo[1,2-a]pyridin-8-yl) Oxy]methyl}-1H, 1'H-4,4'-bispyrazole, 2-(4-{[1-methyl-4-(2-methylpyridin-4-yl)-1H- Pyrazol-3-yl]methoxy}phenyl)quinoline and the salts thereof.

When the binding pattern of L ¹ is, for example, described as -C _1-6 alkyl-T-, T is bonded to a 5-membered ring heterocyclic ring containing two nitrogen atoms and X as a ring-constituting atom, and represents -C _1-6 The meaning of alkyl-in combination with (B) _n or ring A. As an example, Ex. 1 described in Table 58 which will be described later. Further, when it is described as -TC _1-6 alkylene group, -C _1-6 alkylene group-bonds to a 5-membered ring heterocyclic ring containing two nitrogen atoms and X as a ring-constituting atom, indicating T and (B). _n or the meaning of ring A binding. For example, it is Ex. 12 described in Table 60 mentioned later.

Among the compounds of the formula (I), tautomers or geometric isomers exist depending on the kind of the substituent. In the present specification, only one isomeric form of the compound of the formula (I) is described, and the present invention also includes the other isomers, the isomers are separated, or these mixtures are also included.

Further, when the compound of the formula (I) has an asymmetric carbon atom or an asymmetrical axis, an optical isomer is present in accordance therewith. The invention also encompasses optical isomers of the compounds of formula (I), or mixtures thereof.

Moreover, the invention also encompasses pharmaceutically acceptable prodrugs of a compound of formula (I). The pharmaceutically acceptable prodrug is a compound which can be converted into an amine group, a hydroxyl group, a carboxyl group or the like by decomposition with a solvent or under physiological conditions. Examples of the base for forming a prodrug include those described in Prog. Med., 5, 2157-2161 (1985) or "Development of Pharmaceutical Products" (Guangchuan Bookstore, 1990), Volume 7, Molecular Designs 163-198. base.

Further, the compound of the formula (I) may form an acid addition salt or a salt with a base depending on the kind of the substituent, and the salt is a pharmaceutically acceptable salt, and is included in the present invention. Specific examples thereof include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, or with formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, and lactic acid. Malic acid, flat Peach acid, tartaric acid, benzoyl tartaric acid, toluyl tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid, etc. Acid acid addition salt, inorganic base such as sodium, potassium, magnesium, calcium, aluminum, salt with organic base such as methylamine, ethylamine, ethanolamine, lysine, ornithic acid, and ethionylamine A salt or an ammonium salt of various amino acids and amino acid derivatives such as an acid.

Further, the present invention also encompasses various hydrates or solvates of the compound of the formula (I) and pharmaceutically acceptable salts thereof, and a crystalline polymorph. Further, the invention also encompasses a variety of compounds identified by radioactive or non-radioactive isomers.

(manufacturing method)

The compound of the formula (I) and a pharmaceutically acceptable salt thereof can be produced by using various basic synthetic methods depending on the basic skeleton or depending on the kind of the substituent. In this case, when the functional group is substituted with a suitable protecting group (which can be easily converted into a group of the functional group) from the raw material to the intermediate by the kind of the functional group, it may have an effect in terms of manufacturing technology. Examples of such a functional group include an amine group, a hydroxyl group, and a carboxyl group. Examples of the protective group include a protective group described in "Protective Groups in Organic Synthesis (3rd edition, 1999)" by Greene and Wuts. Etc., it can be selected and used only in accordance with these reaction conditions. In such a method, after the protective group is introduced and reacted, the desired compound can be obtained by removing the protective group as necessary.

Further, the prodrug of the compound of the formula (I) is the same as the above protecting group The specific group is introduced at the stage of the raw material to the intermediate, or the obtained compound of the formula (I) is used, and further, the reaction can be carried out. The reaction is generally carried out by a method known to those skilled in the art of esterification, guanidation or dehydration.

A representative production method of the compound of the formula (I) is explained below. Each method can be carried out with reference to the references mentioned in the description. Further, the manufacturing method of each invention is not limited to the examples shown below.

(the first method)

(wherein, R ^2A and R ^2B represent -OH, the other represents -C _1-6 alkyl-OH, and L ² represents -C _1-6 alkyl-O- or -OC _1-6 Alkyl-. The same as below.)

The compound (I-1) of the present invention can be obtained by a reaction of the compound 1a with the compound 1b.

In the present reaction, when the equivalent amount or the excess amount of the compound 1a and the compound 1b is used, in the presence of a phosphine reagent or diethyl azodicarboxylate (DEAD) in a solvent inert to the reaction or in the absence of a solvent, The stirring is generally carried out for 0.1 hour to 5 days under cooling from heating to reflux, preferably from 0 ° C to 100 ° C. Examples of the solvent to be used therein are not particularly limited, and examples thereof include aromatic hydrocarbon groups such as benzene, toluene, and xylene, and diethyl ether. An ether such as tetrahydrofuran, dioxane or dimethoxyethane. The phosphine reagent is not particularly limited, and examples thereof include triphenylphosphine and tributylphosphine. When 1,1'-(azodicarbonyl)dipiperidine is used instead of DEAD, the reaction can be carried out smoothly, which is sometimes advantageous. It is sometimes advantageous for the cyanide methyltributylphosphine to be reacted smoothly.

In addition to the above method, an equivalent or one excess amount of a hydroxyl group of -C _1-6 alkyl-OH of R ^2A or R ^2B is converted into a predetermined leaving group, for example, converted into a compound such as a halogen, in the presence of a base, The solvent is inert to the reaction or in the absence of a solvent, and is preferably stirred at a temperature of from 0 ° C to 100 ° C under cooling to reflux at from 0.1 ° to 5 ° C. The example of the solvent to be used is not particularly limited, and examples thereof include N,N-dimethylformamide and the like. The base may, for example, be an inorganic base such as potassium carbonate.

(the second method)

(wherein R ³ represents -C _0-5 alkylene-C(O)H, and L ³ represents -C _1-6 alkylene group. The same applies hereinafter.)

The compound (I-2) of the present invention can be obtained by amination reaction of the compound 1c with the reduction of the compound 1d.

This reaction uses the equivalent or one of the compound 1c and the compound 1d. The remaining amount is stirred in the presence of a reducing agent in a solvent inert to the reaction from -45 ° C to reflux under heating, usually for 0.1 to 5 days. The solvent to be used herein is not particularly limited, and examples thereof include alcohols such as methanol and ethanol, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, and mixtures thereof. Examples of the reducing agent include sodium cyanoborohydride, sodium triethoxy hydride borohydride, and sodium borohydride. It is preferred to carry out the reaction in the presence of a dehydrating agent such as a molecular sieve or an acid such as acetic acid, hydrochloric acid or titanium (IV) isopropoxide. By reacting, the compound 1c is condensed with the compound 1d to form an imine, which can be isolated as a stable intermediate. At this time, the compound (I-2) can be obtained by a reduction reaction of the imine intermediate. Further, instead of the treatment with the reducing agent, a reducing catalyst (for example, palladium carbon, Raney nickel, etc.) may be used in a solvent such as methanol, ethanol or ethyl acetate, or in the presence or absence of an acid such as acetic acid or hydrochloric acid. Carry out the reaction. At this time, it is preferred to carry out the reaction under a hydrogen atmosphere at a normal pressure to 50 atmospheres under cooling to heating.

〔literature〕

A. R. Katritzky and R. J. K. Taylor, "Comprehensive Organic Functional Group Transformations II", Volume 2, Elsevier Pergamon, 2005

The Chemical Society of Japan, "Experimental Chemistry Lecture (5th Edition)", Volume 14 (2005) (Maruzen)

(the third method)

(wherein m represents an integer of 0 to 4, p represents an integer of 1 to 5, and L ⁴ represents a -C _2-6 alkylene group -. However, the total of m and p is 1 to 5)

The compound (I-3) of the present invention can be obtained by a Wittig reaction of the compound 1e with the compound 1f followed by hydrogenation. But B is other than -C≡C-.

First, using an equivalent amount or a excess amount of the compound 1e and the compound 1f, in a solvent inert to the reaction or in the absence of a solvent, in the presence of a base, from cooling to heating under reflux, preferably from 0 ° C to 100 ° C In general, stirring is carried out for 0.1 hour to 5 days. The solvent to be used is not particularly limited, and examples thereof include ethers such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane. Further, the base is not particularly limited, and examples thereof include an organic base such as diazabicycloundecene.

Next, the obtained compound having a double bond is stirred in a hydrogen atmosphere in a solvent inert to the reaction in the presence of a metal catalyst for 1 hour to 5 days. The reaction is generally carried out from cooling to heating, preferably at room temperature. Examples of the solvent to be used therein are not particularly limited, and examples thereof include alcohols such as methanol, ethanol, and 2-propanol, and ethers such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane, and water. Ethyl acetate, N,N-dimethylformamide, dimethylhydrazine and mixtures thereof. As the metal catalyst, a palladium catalyst such as palladium carbon, palladium black or palladium hydroxide, a platinum catalyst such as a platinum plate or platinum oxide, a nickel catalyst such as reduced nickel or Raney nickel, or a triphenylphosphine chloride or the like can be used. catalyst It is preferable to reduce iron or the like such as iron. Instead of hydrogen, an equivalent to an excess amount of formic acid or ammonium formate can be used as a hydrogen source for a compound having a double bond.

〔literature〕

M. Hudlicky, "Reductions in Organic Chemistry, 2nd ed (ACS Monograph: 188)", ACS, 1996

The Chemical Society of Japan, "Experimental Chemistry Lecture (5th Edition)", Vol. 19 (2005) (Maruzen)

(the fourth method)

(wherein, either of LG ^1A and LG ^1B represents a leaving group, and the other represents -B(OH) ₂ or -B(OZ) OW. wherein Z and W may be the same or different C _1-6 alkane The group or Z and W are integrated to represent a C _1-6 alkyl group.)

The compound (I-4) of the present invention can be obtained by a coupling reaction of the compound 1g with the compound 1h.

The reaction is carried out by using an equivalent amount or a excess amount of the compound 1g and the compound 1h, and stirring in a solvent inert to the reaction in the presence of a base and a palladium catalyst from room temperature to heating under reflux, generally for 0.1 to 5 days. . The reaction is preferably carried out under an inert gas atmosphere. The solvent to be used is not particularly limited, and examples thereof include an aromatic hydrocarbon group such as benzene, toluene or xylene, and an ether such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane. Halogenated hydrocarbon groups such as methyl chloride, 1,2-dichloroethane or chloroform; alcohols such as methanol, ethanol, 2-propanol and butanol, N,N-dimethylformamide, dimethyl alum, And these mixed solvents. As the base, an inorganic base such as Na ₂ CO ₃ , K ₂ CO ₃ or sodium hydroxide is preferred. As the palladium catalyst, palladium (triphenylphosphine) palladium, dichlorobis(triphenylphosphine)palladium, palladium chloride-1,1'-bis(diphenylphosphino)ferrocene or the like is preferred. Further, examples of the leaving group include a halogen and a trifluoromethanesulfonate group.

〔literature〕

A. d. Edited by Meijere and F. Diederich, "Metal-Catalyzed Cross-Coupling Reactions", 1st edition, VCH Publishers Inc., 1997

The Chemical Society of Japan, "Experimental Chemistry Lecture (5th Edition)", Vol. 13 (2005) (Maruzen)

(the fifth method)

(wherein LG ² represents a halogen, and LG ³ represents -B(OH) ₂ or -B(OZ)OW.)

The compound (I-5) of the present invention can be obtained by a coupling reaction of the compound 1i with the halogenated compound 1j and the compound 1k.

(Step 1)

This step is a step of halogenating compound 1i to give compound 1j.

This step is carried out by using an equivalent amount or a excess amount of the compound 1i and the halogenating agent, and stirring in a solvent inert to the reaction from room temperature to heating under reflux, generally for 0.1 to 5 days. The solvent used herein is not particularly limited, and examples thereof include acetonitrile and the like. Examples of the halogenating agent include N-bromosuccinimide, N-iodosuccinimide, iodine, and the like.

(Step 2)

This step is a step of obtaining a compound (I-5) of the present invention by a coupling reaction of the compound 1j with the compound 1k.

The reaction conditions were the same as in the fourth method.

Among the compounds of the formula (I), various substituents on R ¹ , ring A, ring B and ring E are known, and the compound of the formula (I) is used as a raw material, and is known by the use of the reaction described in the examples described later. The reaction or these modifications can be easily converted to other functional groups. For example, O-alkylation, N-alkylation, oxidation, reduction, reduction of alkylation, cyclization, hydrolysis, amide, thiolation, deprotection, etc. get on.

(Manufacture of raw material compounds)

The raw material compound in the above production method can be produced, for example, by the following method, a method described in the production examples described below, a known method, or a modification thereof.

(Material synthesis 1)

Wherein R ⁴ represents -CN or -C(O)OC _1-6 alkyl, and R ⁵ represents -NH ₂ or -OH. However, when R ⁴ of compound 2a is -CN, R ⁵ of compound 2b is -NH ₂ , when R ⁴ of the compound 2a is -C(O)OC _1-6 alkyl, R ⁵ of the compound 2b is -OH.)

In the present process, each of the raw material compounds 1a of the first production method is a method in which R ^2A is -OH, X is a compound of CH, and the raw material compound 1c of the second production method is a compound 2b wherein X is CH.

Compound 2b can be produced by cyclization of compound 2a.

The reaction is carried out by using the equivalent amount or one excess of the compound 2a and, for example, N,N-dimethylformamide dimethyl acetal and R ¹ NH-NH ₂ in a solvent inert to the reaction, from room temperature to heating. Under reflux, it is usually carried out by stirring for 0.1 to 5 days. The example of the solvent used herein is not particularly limited, and examples thereof include N,N-dimethylformamide and the like.

(Material Synthesis 2)

This production method is a method for producing the compound 3d wherein R ^2A is -OH in the starting material compound 1a of the first production method.

The compound 3d can be obtained by subjecting the halogen moiety of the compound 3a to boronization, followed by coupling reaction of the obtained compound 3b with the compound 3c.

(Step 1)

This step is a step of subjecting compound 3a to boronization to obtain compound 3b.

Using the equivalent or one excess of the compound 3a and the predetermined boron reagent, in a solvent inert to the reaction, in the presence of the determined base and the palladium reagent, from room temperature to heating under reflux, generally from 0.1 to 5 days Stirring get on. The solvent used in the example is not particularly limited, and examples thereof include dioxane and the like. Examples of the predetermined boron reagent include boronic acid pinacol ester and the like. As a predetermined base, potassium acetate etc. are mentioned. Examples of the palladium reagent include 1,1'-bis(diphenylphosphino)ferrocene-palladium (II) dichloride.

(Step 2)

This step is a step of obtaining a compound 3d by a coupling reaction of the compound 3b and the compound 3c.

The reaction conditions were the same as in the fourth method.

(Material Synthesis 3)

(wherein R ⁶ represents a C _1-6 alkyl group)

This production method is a method of producing the compound 4d wherein R ^2A is -C _1-6 alkyl-OH in the raw material compound 1a of the first production method, and the raw material compound 1e of the third production method.

(Step 1)

This step is a step of obtaining a compound 4b by halogenating the compound 4a.

The reaction conditions are the same as in the first step of the fifth production method.

(Step 2)

This step is a step of obtaining a compound 4c by a coupling reaction of the compound 4b with the compound 1k.

The reaction conditions were the same as in the fourth method.

(Step 3)

This step is a step of reducing compound 4c to give compound 4d.

The equivalent amount or the excess amount of the compound 4c and the predetermined reducing agent is used, and the solvent which is inert to the reaction is usually stirred from 0.1 to 5 days from ice-cooling to heating under reflux. Examples of the predetermined reducing agent include lithium aluminum hydride, diisobutylaluminum hydride, lithium borohydride, and sodium borohydride. The solvent used herein is not particularly limited, and examples thereof include ethers such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane.

(Step 4)

This step is a step of obtaining a compound 1e by oxidizing the compound 4d.

Using the equivalent of compound 4d and the given oxidant, or excess amount, The solvent which is inert to the reaction is usually carried out by stirring from 0.1 to 5 days from ice cooling to heating under reflux. As a predetermined oxidizing agent, manganese oxide etc. are mentioned. The solvent used herein is not particularly limited, and examples thereof include halogenated hydrocarbon groups such as dichloromethane, 1,2-dichloroethane, chloroform, and carbon tetrachloride.

(Material Synthesis 4)

The present process is a process for producing a compound 5c wherein n is 1 in the starting compound 1b of the first process.

The reaction conditions were the same as in the fourth method.

(Material synthesis 5)

The present process is a process for producing a compound 6b wherein L ¹ is -C _1-6 alkyl-O- or -OC _1-6 alkyl-alkyl group in ¹ g of the starting material compound of the fourth process.

The reaction conditions were the same as in the first method.

(Material synthesis 6)

The present process is a process for producing a compound 7c in which the L ¹ is -C _1-6 alkyl-O- or -OC _1-6 alkyl-, and n is 1 in the starting compound 1i of the fifth process.

The reaction conditions were the same as in the first method.

The compound of the formula (I) is isolated and purified as a free compound, a pharmaceutically acceptable salt, hydrate, solvate or crystalline polymorph. The pharmaceutically acceptable salt of the compound of the formula (I) can be produced by a conventional salt-forming reaction.

The separation and purification can be carried out by a general chemical operation such as extraction, separate crystallization, and various partial chromatography.

The various isomers can be produced by selecting an appropriate starting compound or by utilizing the difference in physicochemical properties between the isomers. For example, an optical isomer is a general optical splitting method by a racemic body (for example, a separate crystallisation of a diastereomeric salt which can be derived from an optically active base or an acid, or a layer of an isomer separation column) The method of analysis, etc.) can also be produced from a suitable optically active starting material compound.

The pharmacological activity of the compound of formula (I) can be confirmed by the following experiment.

1. PDE10A enzyme blocking activity

To determine the PDE10A enzyme blocking activity of the test drug, the human PDE10A gene was selected, and the enzyme was obtained in the form of a baculovirus expressed in Sf9 cells.

The measurement was carried out using a cAMP assay kit (SCETI, cAMP femto 2 kit) and extraction, the above human PDE10A enzyme (Reference: Eur. J. Biochem. 266, 1118-1127 (1999)). The method of measurement is based on the instructions added. The following is a brief description.

The PDE10A enzyme and the test compound were mixed in a reaction buffer (40 mM Tris-HCl, 5 mM MgCl ₂ , pH 7.5) in a 384-well plate (total 8 μL), and cultured at room temperature for 30 minutes under constant temperature. The cAMP of the mixed medium (final concentration: 100 nM, 4 μL/well) was further cultured at room temperature for 1 hour at a constant temperature. 4 μL of cAMP-d2 solution and anti cAMP-cryptate solution of cAMP femto 2 kit reagent were added to stop the reaction. After the incubation was carried out at room temperature for 1 hour or more, the measurement was carried out using a fluorescence measuring machine (manufactured by PerkinElmer Co., Ltd., multi-label ‧ disc analyzer: EnVision). The reaction rate when the enzyme was not added was 0%, the reaction rate when the enzyme was added and the test compound was not added was taken as 100%, and the IC ₅₀ value (nM) of the compound was calculated according to the logistic method.

Table 1 shows the results of this test for several compounds of the formula (I). Ex in the table indicates the embodiment number.

2. Little mouse ‧ Phencyclidine induced activity inhibition test

In the experiment, a male ICR mouse (Japan SLC Co., Ltd.) (5 weeks old, about 30 g) was used. The test compound was suspended in a 0.5% methylcellulose solution, and 10 mL/kg of the test compound or solvent was orally administered. After the administration, the animals were placed in an exercise amount measuring device (spontaneous exercise amount measuring system ‧ SuperMex manufactured by Muromachi Machinery Co., Ltd.), and measurement was started. The activity was measured 1 hour after the start of the measurement, and each animal was induced by subcutaneous administration with Phencyclidine (2.5 mg/10 mL/kg), and the inhibitory effect on the active compound was measured and evaluated in 1 hour. Drug effect. The amount of exercise of the solvent-solvent administration group was taken as 0%, and the amount of exercise of the solvent-Phencyclidine administration group was taken as 100%, and the ED ₅₀ value of the test compound was calculated by linear regression. The test results as representative compounds in the compounds of the present invention are shown in the following table. Further, the results of the test were based on the inhibitory effect (%) of 30 mg/kg.

For the above-mentioned small mouse ‧ phencycline induced (Phencvclidine) induced activity inhibition test, several compounds of the compound of formula (I) can inhibit benzene Phencyclidine induced activity.

As a result of the above test, the compound of the formula (I) was confirmed to have PDE10A inhibitory activity and can be used for the prevention and/or treatment of schizophrenia.

In the Cytochrome P450 (CYP) 3A4 enzyme inhibition test, a compound of the formula (I) or a salt thereof was used as a pharmaceutical product, and it was confirmed that it was a compound having a small inhibitory energy of the metabolic enzyme of Cytochrome P450.

Further, for the Cytochrome P450 (CYP) 1A2, 2C9, 2C19, and 2D6 enzyme inhibition tests, a compound of the formula (I) or a salt thereof was confirmed to be a hindrance to the metabolic enzyme of Cytochrome P450 to the extent that it can be used as a pharmaceutical product. Can be smaller compounds. The results (IC ₅₀ (μM)) are shown in the following table.

The pharmaceutical composition containing one or two or more kinds of the compound of the formula (I) or a salt thereof as an active ingredient can be used by using an excipient which is generally used in the field, that is, a pharmaceutical excipient or a pharmaceutical carrier. The general method is modulated.

The administration is by oral administration of a tablet, a pill, a capsule, a granule, a powder, a liquid, or the like, or an intra-articular, intravenous, intramuscular injection, a suppository, an eye drop, an ophthalmic ointment, a Liquid preparation for ointment, ointment, percutaneous patch, transmucosal solution, transmucosal patch, inhalant, etc. Any form is acceptable.

As a solid composition for oral administration, a tablet, a powder, a granule, or the like is used. For such a solid composition, one or more active ingredients and at least one inert excipient, for example, with lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinyl Pyrrolidone, and/or magnesium metasilicate aluminate are mixed. The composition may contain an inert additive according to a usual method, for example, a slip agent such as a magnesium stearate or a sodium carboxymethyl starch, a stabilizer, a dissolution aid, and a dissolution aid. Tablets or pills may optionally be coated with a film of sugar-coated or gastric-soluble or enteric material.

The liquid composition for oral administration contains a pharmaceutically acceptable emulsion, a solution, a suspension, a syrup or an elixir, and the like, and contains an inert diluent which is generally used, such as purified water or ethanol. The liquid composition may contain, in addition to an inert diluent, a solubilizing agent, a wetting agent, a suspending agent, a sweetener, a flavoring agent, a flavoring agent, and a preservative.

The injection to be used for parenteral administration contains a sterile aqueous or nonaqueous solvent, suspending agent or opacifying agent. The aqueous solvent contains, for example, distilled water for injection or physiological saline. As the nonaqueous solvent, for example, a vegetable oil such as propylene glycol, polyethylene glycol or olive oil, an alcohol such as ethanol, or Polysorbate 80 (the name of the party) may be mentioned. Such a composition may further contain an isotonic agent, a preservative, a wetting agent, an emulsifier, a dispersing agent, a stabilizer, or a dissolution aid. These can be sterilized by, for example, filtration through a bacteria-retaining filter, mixing of a bactericide, or irradiation. Also, these can also be used to make sterile solid compositions which are dissolved or suspended in sterile water or sterile prior to use. It is used after the solvent for injection.

The external preparation includes an ointment, a plaster, a cream, a jelly, a patch, a spray, an emulsion, an eye drop, an eye ointment, and the like. Contains commonly used ointment bases, emulsion bases, aqueous or non-aqueous liquids, suspensions, emulsions, and the like. For example, as an ointment or emulsion base, polyethylene glycol, propylene glycol, white petrolatum, beeswax, polyepoxy hardened castor oil, glyceryl monostearate, stearyl alcohol, cetyl alcohol, polyglycerol may be mentioned. (Lauromacrogol), sorbitol hemioleate, and the like.

A solid, liquid or semi-solid form of a transmucosal agent such as an inhalant or a nasal spray can be produced according to a conventionally known method. For example, a known excipient or a pH adjusting agent, a preservative, a surfactant, a slip agent, a stabilizer or a tackifier may be added as appropriate. A device that can be properly inhaled or blown can be used for administration. For example, a known device or a nebulizer such as a metered administration inhalation device is used as a powder or a mixture of a prescribed compound, or a pharmaceutically acceptable carrier, and then administered as a solution or suspension. A dry powder inhaler or the like may be administered to a single or a plurality of times, and a dry powder or a capsule containing a powder may also be used. Alternatively, a suitable expelling agent such as a pressurized gas-capacitor spray of a preferred gas such as chlorofluoroalkane, hydrofluoroalkane or carbon dioxide may be used.

Generally, when administered orally, the dosage for one day is about 0.001 to 100 mg/kg, preferably 0.1 to 30 mg/kg, more preferably 0.1 to 10 mg/kg, depending on the body weight. It is administered once or twice to 4 times. For intravenous administration, the daily dose is about 0.0001 to 10 mg/kg, which is appropriate for the body weight, and is divided into 1 day to several times. versus. Further, as a transmucosal agent, about 0.001 to 100 mg/kg is divided into one to several times and administered in a plurality of times. The amount of administration can be determined by taking into account the symptoms, age, gender, etc., in accordance with the individual circumstances.

Although it is different depending on the administration route, the dosage form, the administration site, the excipient or the type of the additive, the pharmaceutical composition of the present invention contains 0.01 to 100% by weight, and as a certain aspect, it contains 0.01 to 50% by weight. One or more of the active ingredients or a salt of the compound of the formula (I).

The compound of the formula (I) can be used in combination with various therapeutic or prophylactic agents for the disease of the compound of the above formula (I) which exhibits effectiveness. The combined use may be administered simultaneously, or may be continuous, or may be administered at desired intervals. Simultaneous administration of the preparation may be a compounding agent or a separate formulation.

(Example)

Hereinafter, the production method of the compound of the formula (I) and a raw material compound thereof will be explained in more detail based on the examples. Further, the present invention is not limited to the compounds described in the following examples. Further, the production method of the raw material compound is represented by a production example. Further, the production method of the compound of the formula (I) is not limited to the production method of the specific examples shown below, and the compound of the formula (I) can be produced by a combination of these production methods or a method well known to those skilled in the art.

Further, the following abbreviations may be used in the production examples, the examples, and the tables to be described later.

PEx: manufacturing example number, Ex: example number, Syn: example number manufactured by the same method, PSyn: manufacturing example number manufactured by the same method, Str: structural formula, Data: physicochemical data, ESI+: quality analysis m/z value (ionization method ESI, if no special condition (M+H) ⁺ ), ESI-:m/z value (ionization method ESI, if no special condition indicates (MH) ^- ), EI+: mass The m/z value in the analysis (ionization method EI, if there is no special condition (M)+), CI+: m/z value in mass analysis (chemical ionization method CI, if there is no special condition (M)+ NMR1: δ (ppm) in ¹ H NMR in dimethyl sulfonium-d ₆ , [M]: [mol/L] in the production example and the examples, and WSC represents 1-ethyl-3 -(3-Dimethylaminopropyl)carbodiimide hydrochloride, tBu represents tert-butyl, TIPS represents triisopropylsulfonium, and TBS represents tert-butyldimethylhydrazine.

Further, the PEx number may be described in the Syn portion of the examples, and the compound of this example is produced by the same method as the compound of the PEx number (for example, Ex. 131 indicates the same method as that of PEx. 60).

Further, HCl in the formula represents a hydrochloride, Oxa represents an oxalate, Suc represents a succinate, TFA represents a trifluoroacetate, Fum represents a fumarate, Pho represents a phosphate, and Tar represents L-(+). - Tartrate, Mal stands for L-(-)-malate, and the former number of HCl indicates Morabi. For example, 2HCl means dihydrochloride, 0.5Oxa and 0.5Suc each represent hemi-oxalate, hemisuccinate, and 1.5Pho means sesquiphosphate.

Further, the compound in which the double bond partially intersects in the structural formula represents a mixture of an cis and a trans.

Further, depending on the compound, for example, a compound which is a final form by a free-body synthesis method (for example, Ex. 201 or the like) may be omitted.

Manufacturing example 1

A mixture of 4-pyridylacetonitrile hydrochloride (2.01 g), tetrahydrofuran (30 mL) and ethanol (30 mL) was evaporated. A solution of N,N-dimethylformamide dimethyl acetal in N,N-dimethylformamide (10 mL) was added to the residue, and the mixture was stirred at 80 ° C for 1 hour, and then the mixture was concentrated under reduced pressure. . Methanol (20 mL), acetic acid (780 mg), and methyl hydrazine (718 mg) were added to the residue, and the mixture was stirred at 60 ° C for 12 hours. After concentrating the reaction mixture, the residue was purified by silica gel column chromatography (chloroform/methanol) to give 1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-amine (400 mg) .

Manufacturing Example 2

Add high propargyl alcohol (1.54g), triethylamine (5.1mL), copper iodide in a solution of 2-chloroquinoline (3.0g) in N,N-dimethylformamide (30mL) under argon. (I) (173 mg) and bistriphenylphosphine palladium dichloride (257 mg) were stirred at room temperature for 5 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen sulfate. The aqueous layer was extracted again with ethyl acetate. EtOAc (EtOAc m.). Quinoline-2-yl)but-3-yn-1-ol (4.2 g).

Manufacturing Example 3

Under a stream of argon, 55% sodium hydride (203 mg) was added to a mixture of 4-iodo-1H-pyrazole-3-carboxylic acid methyl (980 mg) in tetrahydrofuran (20 mL). Methyl iodide (830 mg) was added, and the mixture was stirred at room temperature for 14 hours. Saturated aqueous sodium hydrogencarbonate solution and saturated brine were added under ice-cooling, and ethyl acetate was evaporated. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate / chloroform) to afford 4-iodo-1-methyl-1H-pyrazole-3-carboxylic acid methyl (915 mg).

Manufacturing Example 4

To a solution of 4-(quinolin-2-yl)but-3-yn-1-ol (3.65 g) in ethanol (36 mL) was added 10% palladium-carbon (788 mg), and under a hydrogen atmosphere for 22 hours under normal pressure. Stir. After filtering the diatomaceous earth, the filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / chloroform) to afford 4-(quinolin-2-yl)butane-1-ol (2.90 g).

Manufacturing Example 5

To 1-methyl-3-{[4-(quinolin-2-yl)benzyl]oxy}-1H-pyrazole-4-carboxylic acid ethyl (257 mg), ethanol (2.6 mL), A 1 M aqueous sodium hydroxide solution (1.3 mL) was added to a mixture of tetrahydrofuran (1.3 mL), and stirred at 70 ° C for 11 hours. After the reaction solution was allowed to cool, it was neutralized with 1 M hydrochloric acid. The resulting precipitate was filtered off and dried under reduced pressure to give 1-methyl-3-{[4-(quinolin-2-yl)benzyloxy}-1H-pyrazole-4-carboxylic acid (137 mg) ).

Manufacturing Example 6

4-{3-[(4-Bromobenzyl)oxy]-1-methyl-1H-pyrazol-4-yl}pyridine (292 mg), boronic acid pinacol ester (259 mg), Add 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex (69 mg) to a mixture of potassium acetate (250 mg) and dioxane (3 mL) The mixture was stirred at 100 ° C for 3 hours under an argon atmosphere. After cooling, it was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / chloroform) to give 4-(1-methyl-3-{[4-(4,4,5,5-tetramethyl-1,3,2) -Dioxaborolan-2-yl)benzyloxy]-1H-pyrazol-4-yl)pyridine (135 mg).

Manufacturing Example 7

A mixture of tetrafluorofuran (10 mL) of methyl 2-fluoro-4-(quinolin-2-yl)benzoate (515 mg) was added dropwise to a mixture of lithium aluminum hydride (104 mg) in tetrahydrofuran (10 mL). Stir at 2 hours with the same temperature. At the same temperature, a small amount of 28% ammonia water was slowly added dropwise so as not to be shot, and a mixed solvent of methanol and chloroform (1:9) (100 mL) was added thereto, and the mixture was stirred at room temperature for 2 hours. After adding anhydrous magnesium sulfate and diatomaceous earth, the insoluble matter was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / chloroform) to afford [2-fluoro-4-(quinolin-2-yl)phenyl]methanol (460 mg).

Manufacturing Example 8

A mixture of 4-(bromoethenyl)benzoic acid ethyl (1.11 g) and 2-aminopyridine (385 mg) in ethanol (10 mL) was evaporated. After allowing to cool, the reaction mixture was concentrated under reduced pressure. The resulting precipitate was taken by filtration, washed with water, and then the obtained solid was purified by silica gel column chromatography (ethyl acetate/hexane) to give 4-(imidazo[1,2-a]pyridine- 2-based) benzoic acid ethyl (1.09 g).

Manufacturing Example 9

Acetic anhydride (4.8 mL) was added to a mixture of 4-(pyridin-4-yl)-1H-pyrazol-3-ol (7.84 g) in pyridine (78 mL), and stirred at 100 ° C for 2 hours. The reaction liquid was concentrated under reduced pressure, water was added to the residue, and the resulting precipitate was filtered. The solid was washed with hexane and dried under reduced pressure to give 1-[3-hydroxy-4-(pyridin-4-yl)-1H-pyrazol-1-yl]ethanone (10 g).

Manufacturing Example 10

Add N,N-dimethylformamide dimethyl acetal (50 mL) to a solution of ethyl 4-pyridylacetate (25 g) in N,N-dimethylformamide (100 mL) at 80 ° C Stir for 2 hours. The reaction solution was allowed to cool and concentrated under reduced pressure. Ethanol (250 mL), methyl hydrazine (16 mL), and acetic acid (60 mL) were added under ice cooling, and stirred at room temperature for 16 hours. After the reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (methanol / chloroform). The crude product was washed with a mixed solvent of ethyl acetate and hexane to give 1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-ol (15.3 g).

Manufacturing Example 11

Sodium borohydride (100 mg) was added to a mixture of 5-(quinolin-2-yl)thiophene-2-carbaldehyde (630 mg) in ethanol (19 mL), and the mixture was stirred at room temperature for 2 hours. Water and saturated brine were added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate (MgSO4).

Manufacturing Example 12

Methyl 4-iodobenzoate (700 mg), hydrazine (376 mg), copper (I) iodide (254 mg), DL-proline (308 mg), potassium carbonate (1.11 g) The mixture of guanidine (3 mL) was stirred at 100 ° C for 20 hours under an argon atmosphere. After cooling, water was added and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and then purified to ethylamine (hexane) .

Manufacturing Example 13

4-(3-methylquinolin-2-yl)phenol (170 mg), 4-bromo-5-(bromomethyl)-2-methyl-2H-1,2,3-triazole (184 mg) Potassium carbonate (250 mg) was added to a mixture of N,N-dimethylformamide (3.4 mL), and the mixture was stirred at 60 ° C for 4 hours. After cooling, water and saturated brine were added, and extraction was performed with chloroform. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (methanol / chloroform), 2- {4-[(5-Bromo-2-methyl-2H-1,2,3-triazol-4-yl)methoxy]phenyl}-3-methylquinoline (295 mg).

Manufacturing Example 14

Add ammonium chloride (232 mg) to a mixture of {4-[(3-nitropyridin-2-yl)amino]phenyl}methanol (2.13 g) in ethanol (30 mL) and water (7.5 mL) Iron (2.42 g), heated to reflux for 30 minutes. After cooling, chloroform and water were added, and the mixture was filtered through Celite. The filtrate was extracted with chloroform, and the organic layer was concentrated under reduced pressure to yield crude crystals of (4-[(3-aminopyridin-2-yl)amino]phenyl}methanol (2.42 g). p-Toluenesulfonic acid monohydrate (149 mg) was added to a mixture of the crude product (2.42 g), triethyl acetate (3.3 mL), and tetrahydrofuran (25 mL), and stirred at 60 ° C for 15 minutes. After cooling, ethyl acetate was added, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution and brine. After the organic layer was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (methanol/chloroform) to give [4-(3H-imidazo[4,5-b]pyridin-3-yl)benzene. Methyl methoxide (639 mg).

Manufacturing Example 15

a mixture of 1-methyl-1H-pyrazol-3-ol (8.1 g), benzyl bromide (16.9 g) and potassium carbonate (13.7 g) in N,N-dimethylformamide (100 mL) The mixture was stirred at room temperature for 1.5 hours and at 50 ° C for 4 hours. After adding water and ethyl acetate, the organic layer was washed with brine, dried over anhydrous magnesium sulfate The residue is subjected to gel column chromatography (B Purification with ethyl acetate/hexanes gave 3-(benzyloxy)-1-methyl-1H-pyrazole (13.0 g).

Manufacturing Example 16

To a solution of 2-(4-methoxyphenyl)imidazo[1,2-a]pyridine (4.89 g) in dichloromethane (120 mL), 1 m. 65 mL) was stirred at room temperature for 18 hours. The precipitate obtained by adding the reaction solution to a saturated aqueous sodium hydrogencarbonate solution was taken out by filtration. The filtrate was extracted with 10% methanol-chloroform. The organic layer and the solid were combined, and the residue was evaporated to ethylamine.

Manufacturing Example 17

In a mixture of 2-(4-{[(4-iodo-1-methyl-1H-pyrazol-3-yl)oxy]methyl}phenyl)quinoline (2.0 g) in tetrahydrofuran (40 mL) A solution of 2M isopropylmagnesium chloride in tetrahydrofuran (0.5 mL) was added below -10 °C. 45 minutes stirring at -18 ° C to -10 ° C, adding propoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.6 mL), in the room Stir for 1.5 hours at a temperature. Cool again to -15 ° C, add 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.0 mL), at room temperature 1 Stir for hours. A saturated aqueous solution of ammonium chloride and ethyl acetate were added to the mixture, and the organic layer was washed with brine, The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 2-[4-({[1-methyl-4-(4,4,5,5- Base-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-3-yl]oxy}methyl)phenyl]quinoline (1.67 g).

Manufacturing Example 18

Add lithium borohydride (806 mg) and ethanol (2.2 mL) to a mixture of 4-(imidazo[1,2-a]pyridin-2-yl)benzoic acid ethyl (3.11 g) in tetrahydrofuran (50 mL). , heating and refluxing for 2 hours. After the reaction solution was allowed to cool, a saturated aqueous solution of sodium hydrogencarbonate was added. The reaction mixture was extracted with EtOAc. The residue was purified by silica gel column chromatography (methanol / chloroform) to afford [4-(imidazo[1,2-a]pyridin-2-yl)phenyl]methanol (2.46 g).

Manufacturing Example 19

a suspension of 2-chloro-3-methylquinoline (533 mg), [4-(hydroxymethyl)phenyl]boronic acid (501 mg) in 1,2-dimethoxyethane (20 mL) A solution of ruthenium (triphenylphosphine)palladium (173 mg) and 1 M aqueous sodium carbonate (7.5 mL) was added thereto, and the mixture was stirred at 90 ° C for 19 hours under an argon atmosphere. After cooling, water was added to the reaction mixture, and extracted with ethyl acetate. The residue was purified by silica gel column chromatography (methanol / chloroform) to afford [4-(3-methylquinolin-2-yl)phenyl]methanol (696 mg).

Manufacturing Example 20

Add diammonium nitrate to a solution of 2-(4-{[(1-methyl-1H-pyrazol-3-yl)oxy]methyl}phenyl)quinoline (5.32 g) in acetonitrile (140 mL) 铈 (5.55 g) and iodine (2.57 g) were stirred at room temperature for 10 minutes. The reaction mixture was washed with EtOAc EtOAc. The residue was purified by silica gel column chromatography (ethyl acetate /hexane) to give 2-(4-{[(4-iodo-1-methyl-1H-pyrazol-3-yl)oxy] Methyl}phenyl)quinoline (4.94 g).

Manufacturing Example 21

Pyrithion bromide perbromide (1.45 g) was added to a solution of 1-[4-(hydroxymethyl)phenyl]propan-1-one (710 mg) in tetrahydrofuran (10 mL). Stir for hours. After filtration and concentration under reduced pressure, a crude purified material (yield, 2-bromo-1-[4-(hydroxymethyl)phenyl)propan-1-one (2.02 g).

Manufacturing Example 22

A 1 M solution of lithium hexamethyldiguanidinium chloride in tetrahydrofuran (30 mL) was added to tetrahydrofuran (45 mL), 1,4-dioxaspiro[4.5]hydrazin-8-ylacetic acid ethyl ester (6.55 g) in THF (20 mL) The solution was added at -78 °C. After stirring for 50 minutes at the same temperature, methyl formate (3.5 mL) was added. After stirring at the same temperature for 10 minutes, the mixture was stirred at room temperature for 3 hours. After ice-cooling, 1 M hydrochloric acid and saturated brine were added, and the mixture was extracted with chloroform. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure to give ethyl 2-(1,4-dioxaspiro[4.5]indole-8-yl)-3-hydroxy acrylate. Ethanol (60 mL) of 2-(1,4-dioxospiro[4.5]癸-8-yl)-3-hydroxyethyl acrylate obtained Methyl hydrazine (3.0 mL) was added to the solution, and the mixture was stirred at 100 ° C for 3 hours. After cooling, it was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / chloroform) to give 4-(1,4-dioxaspiro[4.5] 癸-8-yl)-1-methyl- 1H-pyrazol-3-ol positional isomer mixture (2.91 g).

Production Example 23

Adding trifluoromethanesulfonate to a solution of 5,6,7,8-tetrahydroquinolin-2(1H)-one (1.03 g), triethylamine (1.9 mL) in dichloromethane (20 mL) The acid anhydride (1.7 mL) was stirred at the same temperature for 1 hour. The reaction solution was neutralized with a saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer was concentrated under reduced pressure to give 5,6,7,8-tetrahydroquinolin-2-yltrifluoromethanesulfonate (2.653 g).

Manufacturing Example 24

Add manganese dioxide (10.0 g) to a solution of [1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]methanol (1.00 g) in chloroform (30 mL) at 50 ° C Stir for 12 hours. The reaction mixture was filtered through Celite, and the residue was evaporated.

Manufacturing Example 25

Triphenylphosphine (2.62 g) was added to a solution of 2-[4-(chloromethyl)phenyl]-3-methylquinoline (1.78 g) in EtOAc (EtOAc) The reaction solution was concentrated under reduced pressure and the residue was washed with diethyl ether. Net, [4-(3-methylquinolin-2-yl)benzyl]triphenylphosphonium chloride (2.66 g).

Manufacturing Example 26

Add chlorinated [4-(3-methylquinolin-2-) to a solution of 1-methyl-4-(pyridin-4-yl)-1H-pyrazole-3-carbaldehyde (576 mg) in tetrahydrofuran (20 mL) Benzophenyl]triphenylphosphonium (1.63 g) and diazabicycloundecene (703 mg) were stirred at room temperature for 48 hours. The reaction mixture was concentrated under reduced pressure, and then purified and purified, m. m. 4-yl)-1H-pyrazol-3-yl]vinyl}phenyl)quinoline (967 mg).

Manufacturing Example 27

Add 9.8 M methylamine methanol to a mixture of 1-bromo-3-fluoro-2-nitrobenzene (1.00 g) and potassium carbonate (942 mg) in N,N-dimethylformamide (3 mL) The solution (2.3 mL) was stirred at room temperature for 3 hours. Ethyl acetate was added to the reaction mixture, and the organic layer was washed with saturated aqueous sodium hydrogen sulfate and brine, and evaporated.

Manufacturing Example 28

Ammonium chloride (122 mg) and iron (1.27 g) were added to a mixture of 3-bromo-N-methyl-2-nitroaniline (1.05 g), ethanol (8 mL), and water (2 mL). It was heated to reflux over 2 hours. After cooling, add chloroform and water. Filter with diatomaceous earth. The filtrate was extracted with chloroform, and the organic layer was concentrated under reduced pressure to give 2-amino-3-bromo-N-methylaniline (914 mg).

Manufacturing Example 29

To a solution of 2-amino-3-bromo-N-methylaniline (914 mg), triethyl orthoformate (1.9 mL) in tetrahydrofuran (10 mL). It was heated to reflux over 1 hour. After cooling, ethyl acetate was added to the reaction mixture, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution and brine. The organic layer was concentrated under reduced pressure, and then purified, mjjjjjjj

Manufacturing Example 30

5-(3-Hydroxy-1-methyl-1H-pyrazol-4-yl)-1-methylpyridine-2(1H)-one (285 mg), platinum oxide (50 mg), and acetic acid (10 mL) The mixture was stirred under a hydrogen atmosphere at room temperature for 3 hours at 3 atmospheres. The reaction solution was filtered through Celite, and the filtrate was evaporated. The residue was purified by silica gel column chromatography (methanol / chloroform) to give 5-(3-hydroxy-1-methyl-1H-pyrazol-4-yl)-1-methylpiperidine-2 (1H )-ketone (193 mg).

Manufacturing Example 31

5-Bromo-2(1H)-pyridone (2.0 g), cesium carbonate (11.24 g), 2-chloro-N,N-dimethylethaneamine hydrochloride (2.06 g), and N,N -dimethyl A mixture of carbamide (40 mL) was stirred at 60 ° C for 20 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was washed with brine, dried over anhydrous The residue was purified by silica gel column chromatography (methanol / chloroform) to afford 5-bromo-1-[2-(dimethylamino)ethyl]pyridin-2 (1H)-one (1.63 g).

Manufacturing Example 32

(1-Methyl-1H-pyrazol-3-yl)methanol (4.00 g), 4-(3-methylquinolin-2-yl)phenol (8.53 g), cyanide methyltributylphosphine A mixture of (13.1 g) and toluene (120 mL) was stirred at 100 ° C for 8 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified to silica gel column chromatography (methanol / chloroform). Add acetonitrile (250 mL) and cerium ammonium nitrate (16.0) to the obtained 3-methyl-2-{4-[(1-methyl-1H-pyrazol-3-yl)methoxy]phenyl}quinoline. g), iodine (14.9 g), stirred at room temperature for 45 minutes. The reaction mixture was concentrated under reduced pressure. EtOAc was evaporated. After the organic layer was concentrated under reduced pressure, the residue was purified, m. The obtained solid was washed with ethyl acetate-hexane to give 2-{4-[(4-iodo-1-methyl-1H-pyrazol-3-yl)methoxy]phenyl}-3- Methylquinoline (10.63 g).

Manufacturing Example 33

Add a solution of (2-methoxyquinolin-3-yl)boronic acid (300 mg) in methanol (10 mL) in a mixture of copper (II) chloride (795 mg) and water (10 mL). The mixture was stirred at ° C for 1 hour. Add acetic acid after cooling Ethyl acetate and water, the organic layer was washed with saturated brine. The residue was purified by silica gel column chromatography (chloroform/hexane) to afford 3-chloro-2-methoxyquinoline (246 mg).

Manufacturing Example 34

To a mixture of 6-[4-(hydroxymethyl)phenyl]nicotinic acid (2.91 g) in methanol (50 mL). The reaction solution was poured into ice water, neutralized with sodium hydrogen sulfate, and ethyl acetate. The organic layer was concentrated under reduced pressure, and then purified, mjjjjjjjj

Manufacturing Example 35

Add sodium iodide (1.56 g) and trimethylchlorosilane (1.3 mL) to a solution of 3-chloro-2-methoxyquinoline (804 mg) in acetonitrile (20 mL) and stir at 50 ° C for 1 hour. . After cooling, a saturated aqueous solution of sodium hydrogencarbonate was added and ethyl acetate was evaporated. The organic layer was washed with water and saturated brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate /hexane) to afford 3-chloroquinolin-2-ol (603 mg).

Manufacturing Example 36

3-(Benzyloxy)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyridyl Azole (4.66 g), 5-bromo-1-methylpyridine-2(1H)-one (3.37 g), 1,1'-bis(diphenylphosphino)ferrocene-palladium II A mixture of chloride-dichloromethane (723 mg), sodium carbonate (4.72 g), N,N-dimethylformamide (56 mL), and water (11 mL) was taken at 100 ° C under argon. Stir for hours. Ethyl acetate and water were added to the reaction mixture, and the resulting insoluble material was separated by filtration over Celite. The organic layer was washed with brine, dried over anhydrous magnesium sulfate The residue was purified by silica gel column chromatography (methanol / chloroform) to give 5-[3-(benzyloxy)-1-methyl-1H-pyrazol-4-yl]-1-methylpyridine. -2(1H)-one (2.57 g).

Manufacturing Example 37

Add methyl iodide (0.485 mL) to a mixture of 2-chloroquinolin-3-ol (1.27 g), potassium carbonate (2.44 g) in N,N-dimethylformamide (20 mL) at room temperature Stir for 15 minutes. Ethyl acetate was added and washed with saturated brine. The organic layer was concentrated under reduced pressure, and then purified, m.j.

Manufacturing Example 38

5-[3-(Benzyloxy)-1-methyl-1H-pyrazol-4-yl]-1-methylpyridine-2(1H)-one (2.57 g), 20% palladium hydroxide A mixture of (350 mg) and ethanol (40 mL) was stirred overnight under a hydrogen atmosphere at room temperature under 3 atmospheres. The reaction solution was filtered using diatomaceous earth. The filtrate was concentrated under reduced pressure to give 5-(3-hydroxy-1-methyl-1H-pyrazol-4-yl)-1-methylpyridine-2(1H)-one (1.49 g).

Manufacturing Example 39

3-(Benzyloxy)-4-iodo-1-methyl-1H-pyrazole (7g), ethyl acrylate (7.3mL), palladium acetate (250mg), N,N-di A mixture of isopropylethylamine (19 mL) and N,N-dimethylformamide (28 mL) was stirred at 100 ° C for 24 hours. After the reaction mixture was cooled to room temperature, it was filtered over Celite, and the filtrate was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to afford (2E)-3-[3-(benzyloxy)-1-methyl-1H-pyrazol-4-yl Ethyl acrylate (5.217 g).

Manufacturing Example 40

To a suspension of [4-(3-methylquinolin-2-yl)phenyl]methanol (12 g) in dichloromethane (200 mL) was added EtOAc (10 mL) and stirred at room temperature for 1 hour. . The reaction mixture was concentrated under reduced vacuo. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate (MgSO4).

Manufacturing Example 41

Add to a solution of ethyl (2E)-3-[3-(benzyloxy)-1-methyl-1H-pyrazol-4-yl]acrylate (2.6 g) in tetrahydrofuran (20 mL) Nitromethane (2.5 mL), diazabicycloundecene ( 1.7 mL) was stirred at 60 ° C for 17 hours. Nitromethane (2.5 mL) and diazabicycloundecene (1.7 mL) were added, and the mixture was stirred at 70 ° C for 19 hours. The reaction mixture was concentrated under reduced pressure and purified residue purified eluted eluted eluted eluted elut elut 4-[4-]-4-nitrobutanoic acid ethyl (2.266 g).

Manufacturing Example 42

3-[3-(Benzyloxy)-1-methyl-1H-pyrazol-4-yl]-4-nitrobutanoic acid ethyl (2.246 g), iron (1.81 g), chlorinated A mixture of ammonium (1.73 g), ethanol (19 mL), and water (7.2 mL) was stirred at 90 ° C for 6 hours. Iron (1.81 g) and ammonium chloride (1.73 g) were added, and the mixture was stirred at 90 ° C for 2 hours. It was filtered through celite and concentrated under reduced pressure. Triethylamine (2.7 mL) and toluene (100 mL) were added to the residue, and the mixture was heated under reflux for 5 hours. The reaction solution was concentrated under reduced pressure and the residue was purified mjjjjjjjjjjjjj Pyrrolidin-2-one (1.41 g).

Manufacturing Example 43

Tetrahydrofuran (15 mL) was ice-cooled under a nitrogen stream, and lithium aluminum hydride (325 mg) was added. Next, a solution of 4-[3-(benzyloxy)-1-methyl-1H-pyrazol-4-ylpyrrolidin-2-one (1.161 g) in tetrahydrofuran (8 mL) was added and Stir for hours. After the reaction solution was ice-cooled, sodium sulfate 10 hydrate was added and stirred. After filtering with diatomaceous earth, add two to the filtrate. A solution of tert-butyl dicarbonate (1.12 g) in tetrahydrofuran was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and purified residue purified eluted eluted eluted eluted elut elut Pyrazol-4-ylpyrrolidin-1-carboxylate (1.08 g).

Manufacturing Example 44

(4-Bromophenyl)methanol (1.60 g), tetrahydrofuran (100 mL), 1,1' was added to 1-methyl-4-pyridin-4-yl-1H-pyrazol-3-ol (1.00 g). -(Azodicarbonyl)dipiperidine (2.88 g) and tri-n-butylphosphine (2.31 g) were stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified to silica gel column chromatography (methanol / chloroform). The obtained crude product was washed with hexane to give 4-{3-[(4-bromophenylmethyl)oxy]-1-methyl-1H-pyrazol-4-yl}pyridine (1.26 g). .

Manufacturing Example 45

Add N-bromosuccinimide (606 mg) and 2 to a solution of 4-bromo-2,5-dimethyl-2H-1,2,3-triazole (545 mg) in carbon tetrachloride (10 mL) 2'-Azobis(isobutyronitrile) (51 mg) was stirred at 90 ° C for 19 hours. The precipitate was separated by filtration and concentrated under reduced pressure. EtOAc EtOAc EtOAc -1,2,3-triazole (185 mg).

Manufacturing Example 46

2-Aminopyridine (4.82 g), p-tolyl cyanide (5.00 g), copper (I) bromide (306 mg), zinc iodide (681 mg), 1,10-diazaphenanthrene (770 mg), The mixture of toluene (100 mL) was stirred at 110 ° C for 24 hours. The reaction mixture was concentrated under reduced pressure. The filtrate was washed with water, and the organic layer was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 2-(4-methylphenyl)[1,2,4 Triazolo[1,5-a]pyridine (1.00 g).

Manufacturing Example 47

To a solution of methyl 2-fluoro-4-(3-methylquinolin-2-yl)benzoate (700 mg) in dimethyl hydrazine (5.0 mL), morpholine (0.25 mL) Diisopropylethylamine (0.61 mL) was stirred at 80 ° C for 15 hours. Further, morpholine (0.5 mL) and diisopropylethylamine (1.2 mL) were added, and the mixture was stirred at 100 ° C for 48 hours. Water was added and extracted with ethyl acetate. The organic layer was separated, washed with brine and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure and the residue was purified mjjjjjjjjjjj Methyl benzoate (467 mg).

Manufacturing Example 48

Tetrahydrofuran under 1-cold 1-methyl-4-(1-methyl-6-oxo-oxy-1,6-dihydropyridin-3-yl)-1H-pyrazole-3-carboxylic acid methyl (812 mg) Add lithium borohydride (143 mg) and ethanol (0.57 mL) to the mixture (20 mL). The mixture was heated to reflux for 2 hours. After the reaction mixture was allowed to cool, 1M hydrochloric acid (10 mL) was added. The reaction was neutralized with a saturated aqueous sodium hydrogencarbonate solution and concentrated. The residue was purified by silica gel column chromatography (methanol / chloroform) to give 5-[3-(hydroxymethyl)-1-methyl-1H-pyrazol-4-yl]-1-methylpyridine- 2(1H)-one (205 mg).

Manufacturing Example 49

a mixture of 5-(3-methylquinolin-2-yl)pyridine-2-carboxylic acid methyl (182 mg), tetrahydrofuran (4.0 mL), and methanol (4.0 mL). The aqueous solution (1.5 mL) was stirred at the same temperature for 7 hours. After neutralizing with 1 M hydrochloric acid (1.5 mL), the mixture was evaporated. Water was added to the residue and the precipitated solid was taken out by filtration. Tetrahydrofuran (5.0 m) was added to the obtained solid, and carbonyldiimidazole (130 mg) was added thereto under ice cooling, and the mixture was stirred at room temperature for 2 hours. An aqueous solution (0.5 mL) of sodium borohydride (60 mg) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 15 minutes, and then stirred at room temperature overnight. Water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to afford (5-(3-methylquinolin-2-yl)pyridin-2-yl]methanol (70 mg).

Manufacturing Example 50

To N,N-dimethylformamide (1.4 mL), phosphorus oxychloride (3.3 mL) was added under ice cooling, and stirred at the same temperature for 30 minutes. Add to the mixture N-(4-fluorophenyl)propane decylamine (2 g), cetyltrimethylammonium bromide (436 mg), and acetonitrile (20 mL) were stirred at 80 ° C for 8 hours and then at 100 ° C. Stir for hours. The reaction mixture was concentrated under reduced pressure. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to afford 2-chloro-6-fluoro-3-methylquinoline (558 mg).

Manufacturing Example 51

To a solution of (1,5-dimethyl-1H-pyrazol-3-yl)methanol (2.0 g) in dichloromethane (100 mL) Stir for hours. The reaction solution was concentrated under reduced pressure and the residue was evaporated. N,N-dimethylformamide (180 mL), 4-(3-methylquinolin-2-yl)phenol (3.53 g), and potassium carbonate (5.18 g) were added, and stirred at 70 ° C for 8 hours. . The reaction mixture was concentrated under reduced pressure. The organic layer was concentrated under reduced pressure and the residue was purified to silica gel column chromatography (methanol/chloroform) to afford 2-{4-[(1,5-dimethyl-1H-pyrazol-3-yl). Oxy]phenyl}-3-methylquinoline (5.05 g).

Manufacturing Example 52

To a mixture of 3-bromo-1-N-methylbenzene-1,2-diamine (970 mg) in 4M hydrochloric acid (3.0 mL), acetic acid (0.35 mL) was added at room temperature and stirred at 120 ° C for 18 hours. It was neutralized with a saturated aqueous sodium hydrogencarbonate solution and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. go with. The residue was purified by silica gel column chromatography (methanol / chloroform) to afford 4-bromo-1,2-dimethyl-1H-benzimidazole (549 mg).

Manufacturing Example 53

Methyl 6-[4-(hydroxymethyl)phenyl]nicotinic acid (1.72 g) was added to dichloromethane (60 mL) and EtOAc (1. The reaction liquid was concentrated under reduced pressure, and the residue was dried under reduced pressure. To the obtained solid was added N,N-dimethylformamide (50 mL), 5-(3-hydroxy-1-methyl-1H-pyrazol-4-yl)-1-methylpyridine-2 ( 1H)-ketone (1.00 g) and potassium carbonate (1.68 g) were stirred at 70 ° C for 8 hours. After the reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with a mixture of methanol and chloroform (1:10). After the organic layer was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (methanol / chloroform). The obtained crude purified product was washed in the order of ethyl acetate and hexane to give 6-[4-({[1-methyl-4-(1-methyl-6- s. Methyl hydropyridine-3-yl)-1H-pyrazol-3-yloxy}methyl)phenyl]nicotinic acid (1.48 g).

Manufacturing Example 54

A mixture of 3,4-difluoroaniline (6.46 g), potassium carbonate (6.91 g), and dichloromethane (200 mL) was added at -15 ° C to a solution of bromo (7.99 g) in dichloromethane (50 mL) Stir at the same temperature for 15 minutes. The reaction solution was added to ice and extracted with chloroform. The organic layer was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (ethyl acetate /hexane) To 2-bromo-4,5-difluoroaniline (9.84 g).

Manufacturing Example 55

To a mixture of (5-bromopyridin-2-yl)methanol (2.77 g), dimethylpyridine (4.7 mL), and tetrahydrofuran (30 mL), triisopropyltrifluoromethanesulfonic acid (2.0 mL), Stirring was carried out for 1 hour at room temperature. Water and ethyl acetate were added to the reaction mixture, and the organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by basic EtOAc EtOAc EtOAc (EtOAc)

Manufacturing Example 56

Add to a solution of 1-methyl-4-(6-{[(triisopropylsulfonyl)oxy)methyl}pyridin-3-yl)-1H-benzimidazole (2.37 g) in tetrahydrofuran (20 mL) Tetrabutylammonium fluoride (9.0 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and purified residue purified m. Methanol (0.974 g).

Manufacturing Example 57

2-Bromo-4,5-dimethoxyaniline (4.73 g), methyl methacrylate (6.5 mL), palladium acetate (229 mg), ginseng (2-methylphenyl) phosphine (under argon) a mixture of 620 mg), N,N-diisopropylethylamine (11 mL), and N,N-dimethylformamide (50 mL) at 48 ° C for 48 hours Stir when. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated. 6M Hydrochloric acid (70 mL) was added to the residue, and the mixture was stirred at 100 ° C for 1 hour. The reaction liquid was ice-cooled, and the precipitated solid was filtered and dried under reduced pressure to give 6,7-dimethoxy-3-methylquinoline-2(1H)-one (0.85 g).

Manufacturing Example 58

To 6,7-dimethoxy-3-methylquinolin-2(1H)-one (840 mg), phosphorus oxychloride (4 mL) was added under ice cooling, and the mixture was stirred at 100 ° C for 1 hour. The reaction liquid was concentrated under reduced pressure, and the residue was diluted with chloroform, and then poured into ice. After adding a saturated aqueous solution of sodium hydrogencarbonate and extracting with chloroform, the organic layer was washed with saturated sodium hydrogen carbonate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified to silica gel column chromatography (hexane/ethyl acetate) to give 2-chloro-6,7-dimethoxy-3-methylquine. Porphyrin (569 mg).

Manufacturing Example 59

To a solution of 1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-ol (5 g) in methanol (250 mL), EtOAc (EtOAc) Stirring was carried out for 24 hours at room temperature. Sodium thiosulfate (2.25 g) dissolved in water (25 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 5 minutes. The reaction solution was concentrated under reduced pressure and the residue was purified to silica gel column chromatography (chloroform/methanol) to give 1-methyl-4-(1-oxide pyridin-4-yl)-1H-pyrazole-3 - Alcohol (3.957 g).

Manufacturing Example 60

4-Iodo-1-methyl-1H-pyrazole-3-carboxylic acid methyl (9.00 g), 1-methyl-5-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl)pyridine-2(1H)-one (11.9 g), N,N-dimethylformamide (240 mL), and water (72 mL) were added cesium carbonate (22.0) g), triphenylphosphine palladium (3.65 g), stirred at 80 ° C for 9 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified to silica gel column chromatography (methanol / chloroform) to give 1-methyl-4-(1-methyl-6-s-oxo-1,6-dihydropyridine. 3-yl)-1H-pyrazole-3-carboxylic acid methyl (8.24 g).

Manufacturing Example 61

4-Bromo-1-methyl-1H-benzimidazole (920 mg), ethyl acrylate (1.4 mL), bis(tri-tert-butylphosphine)palladium (111 mg), N,N- under argon atmosphere A mixture of dicyclohexylmethylamine (936 mg) and dioxane (4.6 mL) was stirred at 100 ° C for 12 hours. Bis(tri-tert-butylphosphine)palladium (111 mg) was added, and the mixture was stirred at 100 ° C for 3 hours. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to afford ethyl (2E)-3-(1-methyl-1H-benzimidazol-4-yl) (600mg).

Manufacturing Example 62

Addition of 1.01M hydrogenation at -50 ° C in a solution of ethyl (2E)-3-(1-methyl-1H-benzimidazol-4-yl)acrylate (568 mg) in tetrahydrofuran (12 mL) Diisobutyl aluminum toluene solution (7.4mL ). After heating to -30 ° C over 3 hours, a saturated aqueous solution of Lodil brine and ethyl acetate were added and stirred temporarily. After extracting with ethyl acetate, the org. The residue was purified by silica gel column chromatography (chloroform/methanol) to give (2E)-3-(1-methyl-1H-benzimidazol-4-yl)prop-2-en-1-ol ( 241 mg).

Manufacturing Example 63

3-(Benzyloxy)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl under argon -1H-pyrazole (2g), 4-chloro-3-fluoropyridine (925mg), ginseng (diphenylmethyleneacetone) dipalladium (290mg), tricyclohexylphosphine (215mg), potassium phosphate (4.06g) The mixture of dioxane (30 mL) and water (15 mL) was stirred at 100 ° C for 5 hours. After the reaction solution was returned to room temperature, ethyl acetate was added and the mixture was washed with brine. After the organic layer was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 4-[3-(benzyloxy)-1-methyl-1H-pyrazole. 4-yl]-3-fluoropyridine (830 mg).

Manufacturing Example 64

4-[3-(Benzyloxy)-1-methyl-1H-pyrazol-4-yl]-3-fluoropyridine (820 mg), pentamethylbenzene (858 mg), and trifluoroacetic acid (4.5 The mixture of mL) was stirred at room temperature for 12 hours. Ethyl acetate was added, and the solid was filtered and dried under reduced pressure to give 4-(3-fluoropyridin-4-yl)-1-methyl-1H-pyrazol-3-ol trifluoroacetate ( 713 mg).

Manufacturing Example 65

Add tert to a mixture of (4-iodo-1-methyl-1H-pyrazol-3-yl)methanol (1.284 g), imidazole (1.06 g), N,N-dimethylformamide (13 mL) Butyldimethylchloromethane (1 g) was stirred at room temperature for 1 hour. Water was added and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 3-({[tert-butyl(dimethyl)methyl)oxy}methyl)-4-io -Methyl-1H-pyrazole (1.564 g).

Manufacturing Example 66

Potassium carbonate (16.8 g), benzyl bromide (20.8 g) was added to a solution of 1-methyl-1H-pyrazol-3-ol (9.92 g) in N,N-dimethylformamide (120 mL). ), heating and stirring at 50 ° C for 4 hours. The reaction mixture was concentrated under reduced vacuo. The organic phase was concentrated under reduced pressure, and the residue was purified and purified eluted eluted eluted eluting eluting g).

Manufacturing Example 371

In a mixture of 1-methyl-1H-benzotriazol-4-amine (333 mg) and acetonitrile (8 ml), copper (II) bromide (552 mg) and isoamyl nitrite (319 mg) were added to the chamber. Stirring was carried out for 2 hours at a temperature. The reaction mixture was filtered through Celite, washed with ethyl acetate, and evaporated. will The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to afford 4-bromo-1-methyl-1H-benzotriazole (181 mg).

Manufacturing Example 372

8-[4-(Tetrahydro-2H-pyran-2-oxy)phenyl]imidazo[1,2-a]pyridine (535 mg), sodium hydrogencarbonate (679 mg), N-bromosuccinate A mixture of the imine (324 mg) and chloroform (10 ml) was stirred at room temperature for 4 hours. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, and ethyl acetate was evaporated. The organic layer was washed with brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 3-bromo-8-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]imidazo[ 1,2-a]pyridine (540 mg).

Manufacturing Example 385

4-methoxybenzoic acid (1.52g), N-methyl-1,2-phenylenediamine hydrochloride (2.52g), 1-hydroxybenzotriazole (1.62g), triethylamine (3.48 mL) of N,N-dimethylformamide (50 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide ‧ hydrochloride (2.30) g), stirring was carried out for 12 hours at room temperature. Ethyl acetate was added to the reaction mixture, and the organic phase was washed with water and brine, and evaporated. The obtained crude purified product was dissolved in acetic acid (46 mL), and stirred at 90 ° C for 12 hours. After allowing to cool, the reaction mixture was evaporated to dryness. After the organic layer was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (methanol / chloroform). To 2-(4-methoxyphenyl)-1-methyl-1H-benzimidazole (1.98 g).

Manufacturing Example 387

3-Bromo-N-1-methylbenzene-1,2-diamine dihydrochloride (350 mg) was dissolved in toluene (5.9 ml), trifluoroacetic acid (2.9 ml) was added at room temperature at 80 ° C Heat and stir for 6 hours. The reaction solution was cooled, concentrated under reduced pressure, and the residue was purified by column chromatography (hexane/ethyl acetate) to give 4-bromo-1-methyl-2-(trifluoromethyl)- 1H-benzimidazole (388 mg).

Manufacturing Example 389

To a solution of 3-bromo-N-1-methylbenzene-1,2-diamine dihydrochloride (350 mg) in tetrahydrofuran (5.0 ml), pyridine (0.36 ml) The base chloride (0.12 ml) was added in order and stirred at room temperature for 1 hour. 1M Hydrochloric acid (2.0 ml) was added to the reaction solution, and ethyl acetate was evaporated. The separated organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and then evaporated to ethyl acetate (3.5 ml), and the mixture was stirred at 90 ° C for 15 hours. After allowing to cool at room temperature, the reaction solution was concentrated, and the residue was separated and purified by silica gel column chromatography (basic silica gel; ethyl acetate-hexane=70:30→50:50) to give 4-bromo- 2-(Methoxymethyl)-1-methyl-1H-benzimidazole (165 mg).

Manufacturing Example 391

Under ice cooling in methanol (1.2 ml) in tetrahydrofuran (12.0 ml) 60% of an oily sodium hydride (200 mg) was added, and after stirring at the same temperature for 15 minutes, 8-bromo-4-chloroquinoline (600 mg) was added thereto, and the mixture was returned to room temperature, followed by heating and stirring at 80 ° C for 2 hours. After adding acetic acid (0.28 ml) to the reaction mixture under ice cooling and neutralizing, ethyl acetate and water were added, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, and then evaporated. mjjjjjjjj .

Manufacturing Example 398

6-Chloro-8-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]imidazo[1,2-b]pyridazine (304 mg), 10% palladium on carbon (100 mg; A mixture of 55% aqueous) and ethanol (20 ml) was stirred at room temperature for 2 hours under a hydrogen atmosphere at normal pressure. The reaction solution was filtered through Celite, and concentrated. The residue was suspended in tetrahydrofuran (10 ml), and 1M hydrochloric acid (2 ml) was added and stirred at room temperature for 2 hours. A 1 M aqueous sodium hydroxide solution (2 ml) was added to the mixture and the mixture was evaporated. The organic layer was dried and concentrated under reduced pressure to give 4-(im[rho]-[l,2-b]pyridazin-8-yl) phenol (169 mg).

Manufacturing Example 409

A solution of 2-methyl-3-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]quinoxaline (1.345 g) in tetrahydrofuran (10 mL) was evaporated. Stir for 5 hours. The reaction solution was neutralized with a 1 mol/l aqueous sodium hydroxide solution (9 mL) and ethyl acetate. Reaction solution It was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was washed with ethyl acetate-hexane to give 4-(3-methylquinoxalin-2-yl)phenol (960 mg).

Manufacturing Example 432

4-[4-(Tetrahydro-2H-pyran-2-oxy)phenyl-1,3-benzoxazole (359 mg), pyridinium p-toluenesulfonate (31 mg) and ethanol (12 ml) The mixture was heated and stirred at an oil temperature of 80 ° C for 30 minutes. After cooling at room temperature, saturated sodium bicarbonate was added and ethyl acetate was evaporated. The organic layer was washed with saturated brine, dried and evaporated, evaporated, evaporated

Manufacturing Example 461

4-Bromo-1-methyl-1H-benzimidazole (300 mg), 2,6-difluoro-4-methoxyphenylboronic acid (267 mg), ginseng (diphenylmethyleneacetone) dipalladium A mixture of (0) (65 mg), tri-t-butylhydrazine tetrafluoroborate (52 mg), potassium fluoride (273 mg), tetrahydrofuran (4 ml) and water (0.4 ml) was taken at an oil temperature of 65 ° C. Stir under heating. After cooling at room temperature, the reaction mixture was diluted with EtOAc. The residue was purified by column chromatography (chloroform/methanol) to give 4-(2,6-difluoro-4-methoxyphenyl)-1-methyl-1H-benzimidazole (31 mg) .

Manufacturing example 462

1,2-O-chloro-8-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]quinoline (200 mg), trimethylboroxine (0.1 ml) To a suspension of dimethoxyethane (2.0 ml), hydrazine (triphenylphosphine) palladium (0) (70 mg), 2 M aqueous sodium carbonate (0.4 ml) was added, and the mixture was stirred at 120 ° C for one hour. reaction. After cooling, the insoluble material was filtered over Celite, and water was added to the filtrate, and ethyl acetate was evaporated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to afford 4-methyl-8-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl] Porphyrin (164 mg).

Manufacturing Example 463

In a mixture of 3-bromo-8-[4-(tetrahydro-2H-pyran-2-oxy)phenyl]imidazo[1,2-a]pyridine (284 mg) and toluene (6.3 ml), Water (0.43 ml), trimethylboroxine (96 mg), tripotassium phosphate (291 mg), palladium(II) acetate (17 mg) and tricyclohexylphosphine (43 mg) were added at an oil temperature of 110 ° C. Heat and stir for hours. After cooling at room temperature, ethyl acetate was added and washed with water. The organic layer was washed with brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) 4-(Tetrahydro-2H-pyran-2-yloxy)phenyl]imidazo[1,2-a]pyridine (102 mg).

Manufacturing example 466

2-Amino-4'-methoxybiphenyl-3-carboxylic acid (975 mg), formazan A mixture of acetate (1.3 g) and ethanol (10 ml) was heated and stirred at an oil temperature of 75 ° C for 16 hours. After cooling at room temperature, the precipitate was filtered off to give 8-(4-methoxyphenyl)quinazolin-4-ol (852 mg).

Manufacturing Example 467

A mixture of 8-(4-methoxyphenyl)quinazolin-4-ol (300 mg), phosphorus pentachloride (500 mg) and phosphorus oxychloride (1.8 ml) was carried out at an oil temperature of 105 ° C. Heat and stir for hours. After cooling at room temperature, it was concentrated under reduced pressure. After the residue was added to chloroform, the mixture was washed with saturated aqueous sodium hydrogen sulfate and brine and evaporated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to afford 4-chloro-8-(4-methoxyphenyl) quinazoline (142 mg).

Manufacturing Example 469

To a solution of 4-chloro-8-(4-methoxyphenyl)quinazoline (177 mg) in dichloromethane (5 ml), p-toluenesulfonate (125 mg) Stir for hours. The reaction mixture was concentrated under reduced pressure. ethyl acetate (2 ml) and 1M aqueous sodium hydroxide (2 ml) was added to the residue, and the mixture was stirred and stirred at an oil temperature of 85 ° C for 4 hours. After cooling at room temperature, water was added and the mixture was extracted with diethyl ether. The organic layer was dried, filtered, evaporated, evaporated, evaporated, mjjjjjjjjjjjjj .

Manufacturing Example 481

Dichloromethane in 5-[3-(hydroxymethyl)-1-methyl-1H-pyrazol-4-yl]-1-methylpyridine-2(1H)-one (33.3g) under ice cooling (330 mL) To the mixture was added hydrazine chloride (16.6 mL), and the mixture was stirred at room temperature for 5 hours. After ethyl acetate was added to the reaction mixture, the precipitated solid was filtered and dried under reduced pressure to give 5-[3-(chloromethyl)-1-methyl-1H-pyrazol-4-yl]-1 -methylpyridine-2(1H)-one hydrochloride (36.1 g).

The compound of the production example shown in the following table was produced in the same manner as in the method of the above production example. The chemical structural formula, physicochemical data and manufacturing method of the compound of the production example are shown in Tables 6 to 57 and Tables 148 to 166.

Example 1

1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-amine (177 mg), 4-(quinolin-2-yl)benzaldehyde (284 mg), and 1,2-di To a mixture of ethyl chloride (1 mL), tetraisopropyl orthotitanate (0.45 mL) was added, and the mixture was stirred at 85 ° C for 2 hours. After the reaction mixture was ice-cooled, methanol (5 mL) and sodium borohydride (130 mg) were added, and the mixture was stirred at room temperature for 3 hours. Sodium borohydride (140 mg) was added, followed by stirring for 2 hours. After adding sodium bicarbonate solution, diluting with chloroform, filtering with diatomaceous earth, the organic layer of the filtrate was purified by column chromatography (chloroform/methanol) to give 1-methyl-4-(pyridine-4- -N-[4-quinolin-2-yl)benzyl]-1H-pyrazol-3-amine (138 mg).

Example 2

1-methyl-4-(pyridin-4-yl)-N-[4-(quinolin-2-yl)benzyl]-1H-pyrazol-3-amine (77 mg), methylene chloride Formaldehyde (164 mg) was added to a mixture of 4 mL) and acetic acid (0.80 mL), and stirred for 10 minutes. Sodium triethoxy hydride borohydride (167 mg) was added, and the mixture was stirred at room temperature for 2 hours. Addition of formaldehyde (164 mg) and sodium triethoxyphosphonium hydride (167 mg) was carried out overnight at room temperature. Further, formaldehyde (164 mg) and sodium triethoxyphosphonium hydride (167 mg) were added, and the mixture was stirred at room temperature for 12 hours. A sodium hydrogen carbonate solution was added and extracted with chloroform. The organic layer was purified by EtOAc EtOAc (EtOAc) elute The residue was washed with diisopropyl ether/2-propanol to give N,1-dimethyl-4-(pyridin-4-yl)-N-[4-(quinolin-2-yl)benzene. -1H-pyrazol-3-amine dihydrochloride (21 mg).

Example 3

In a solution of 1-methyl-3-{[4-(quinolin-2-yl)benzyl]oxy}-1H-pyrazole-4-carboxylic acid (137 mg) in dichloromethane (4 mL) Carbonyldiimidazole (105 mg) was added at room temperature and stirred at 15 minutes with the same temperature. Further, N-hydroxyacetamidine (48 mg) was added, and the mixture was stirred at room temperature for 0.5 hr. Toluene was added to the residue, and after stirring at 110 ° C for 12 hours, p-toluenesulfonate monohydrate (7 mg) was added, and stirred at the same temperature for 4 hours. Further, N-methylpyrrolidone (2 mL) was added, and the mixture was further stirred at the same temperature for 4 hours. Add water after cooling Saturated brine and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was evaporated from ethyl acetate and ethyl acetate (4:1). After stirring for an hour, 2-[4-({[1-methyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)-1H-pyrazol-3-yl]oxy) was obtained. Methyl)phenyl]quinoline monohydrochloride (70 mg).

Example 4

4-{3-[(4-Bromobenzyl)oxy]-1-methyl-1H-pyrazol-4-yl}pyridine (137 mg), 0.5 M 2-pyridyl zinc bromide in tetrahydrofuran To a mixture of the solution (1.6 mL) and tetrahydrofuran (1 mL), hydrazine (triphenylphosphine)palladium (92 mg) was added, and the mixture was subjected to microwave irradiation at 120 ° C for 1 hour in a sealed tube. After cooling, water was added to the reaction solution and the reaction was stopped. The mixture was filtered over celite, and ethyl acetate was added to the residue. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (chloroform/hexane). The obtained crude purified product was dissolved in ethanol, and a 4 M solution of hydrogen chloride in ethyl acetate was added thereto, and the mixture was stirred at room temperature for 1 hour. Diethyl ether was added, and the resulting precipitate was filtered off and washed with diethyl ether to give 2-[4-({[1-methyl-4-(pyridin-4-yl)-1H-pyrazole)- 3-yl]oxy}methyl)phenyl]pyridine dihydrochloride (30 mg).

Example 5

4-({[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]oxy Benzoic acid (400 mg), 1,2-phenylenediamine (154 mg), 1-hydroxybenzotriazole (210 mg), triethylamine (0.27 mL), and N, WSC hydrochloride (296 mg) was added to a mixture of N-dimethylformamide (5 mL), and stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, and the organic layer was washed with water and brine, and evaporated. The obtained crude purified product was dissolved in acetic acid, and stirred at 90 ° C for 12 hours. After the reaction mixture was cooled, the reaction mixture was evaporated, evaporated, evaporated,,,,,,,,,,,,,,, After extracting with chloroform, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / ethyl acetate). The obtained crude purified product was dissolved in ethanol, and a 4M solution of hydrogen chloride in ethyl acetate was added and stirred at room temperature for 15 hours. Diethyl ether was added to the reaction mixture, and the resulting precipitate was filtered off and washed with diethyl ether to give 2-[4-({[1-methyl-4-(pyridin-4-yl)-1H-) Pyrazol-3-yloxy}methyl)phenyl]-1H-benzimidazole dihydrochloride (148 mg).

Example 6

2-[4-({[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)oxy}methyl)phenyl]-1H-benzimidazole (124 To a mixture of potassium carbonate (135 mg) and N,N-dimethylformamide (3 mL), methyl iodide (0.041 mL) was added and stirred at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture, and the organic layer was washed with brine and evaporated. The residue was purified by silica gel column chromatography (chloroform). The obtained crude purified product was dissolved in ethanol, and 4 M of hydrogen chloride was added thereto. The acid ethyl ester solution was stirred at room temperature for 15 hours. The resulting precipitate was filtered off and washed with diethyl ether to give 1-methyl-2-[4-({[1-methyl-4-(pyridin-4-yl)-1H-pyrazole-3). -yloxy}methyl)phenyl]-1H-benzimidazole dihydrochloride (76 mg).

Example 7

4-{3-[(4-Bromobenzyl)oxy]-1-methyl-1H-pyrazol-4-yl}pyridine (413 mg), quinoline-8-ylboronic acid (311 mg), To a mixture of 1,2-dimethoxyethane (30 mL), hydrazine (triphenylphosphine)palladium (277 mg) and 1 M aqueous sodium carbonate (3 mL) were added, and stirred at 90 ° C for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified to silica gel column chromatography (methanol / chloroform). The obtained crude purified product was dissolved in ethyl acetate, and a 4M solution of hydrogen chloride in ethyl acetate was added and stirred for 30 minutes. The resulting precipitate was filtered off and washed with ethyl acetate to give 8-[4-({[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)oxy} Methyl)phenyl]quinoline dihydrochloride (468 mg).

Example 8

N,N-dimethyl at 2-[4-({[4-(pyridin-4-yl)-1H-pyrazol-3-yl)oxy}methyl)phenyl]quinoline (567 mg) To a solution of tolamine (20 mL), 1,1,1-trifluoro-2-iodoethane (630 mg) and cesium carbonate (1.46 g) were added, and the mixture was stirred at 60 ° C for 5 hours. The reaction mixture was concentrated under reduced pressure. The organic layer was purified by column chromatography (methanol / chloroform). Dissolve the crude extract To a solution of ethyl acetate, a 4M solution of hydrogen chloride in ethyl acetate was added and stirred for 30 min. The resulting precipitate was filtered and washed with ethyl acetate to give 2-[4-({[4-(pyridin-4-yl)-1-(2,2,2-trifluoromethyl)-1H- Pyrazol-3-yloxy}methyl)phenyl]quinoline dihydrochloride (650 mg).

Example 9

Ethyl [4-(pyridin-4-yl)-3-{[4-(quinolin-2-yl)benzyl]oxy}-1H-pyrazol-1-yl]acetate (380 mg) A solution of ethanol (15 mL) was added to a 1M aqueous sodium hydroxide solution (2.5 mL), and stirred at 60 ° C for 5 hours. The reaction solution was concentrated under reduced pressure and neutralized with 1N hydrochloric acid. The resulting precipitate was taken out by filtration, and the filtrate was extracted with ethyl acetate. The organic layer and the precipitate were combined and purified by silica gel column chromatography (methanol / chloroform). The obtained crude product was washed with ethyl acetate-hexane to give [4-(pyridin-4-yl)-3-{[4-(quinolin-2-yl)phenylmethyl]oxy}- 1H-pyrazol-1-yl]acetic acid (57 mg).

Example 10

2-[4-({[1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole) 3-yl]oxy}methyl)phenyl]quinoline (300 mg), 3-chloropyridazine hydrochloride (228 mg), 1,1'-bis(diphenylphosphino)ferrocene-palladium ( II) a mixture of dichloride-dichloromethane (33 mg), sodium carbonate (288 mg), N,N-dimethylformamide (3 mL), and water (1 mL) under argon at 100 ° C Stir for 12 hours. Ethyl acetate and water were added, and the resulting insoluble material was separated by filtration from celite. will The organic layer was washed with brine, dried over anhydrous magnesium The residue was purified by silica gel column chromatography (methanol / chloroform). The obtained crude purified product was dissolved in ethyl acetate-ethyl acetate. The resulting solid was washed with ethanol-ether and filtered to give 2-[4-({[1-methyl-4-(pyridazin-3-yl)-1H-pyrazol-3-yl)oxy Methyl)phenyl]quinoline dihydrochloride (56 mg).

Example 11

Ethyl acetate [4-(pyridin-4-yl)-3-{[4-(quinolin-2-yl)benzyl]oxy}-1H-pyrazol-1-yl] (600 mg) A 1 M solution of diisobutylaluminum hydride in toluene (3.9 mL) was added to a mixture of tetrahydrofuran (40 mL), and stirred at room temperature for 1 hour. The reaction solution was ice-cooled, and methanol was added to stop the reaction. The resulting gel was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / chloroform). The obtained crude purified product was dissolved in ethanol, and then ethylamine sulfate The residue was washed with ethyl acetate to give [4-(pyridin-4-yl)-3-{[4-(quinolin-2-yl)benzyl]oxy}-1H-pyrazole-1- Ethyl alcohol dihydrochloride (189 mg).

Example 12

4-(Imidazo[1,2-a]pyridin-2-yl)phenol (330 mg), [1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]methanol (330 mg) of a mixture of toluene (10 mL) was added with cyanide methyltributylphosphine ( 570 mg), stirred at 100 ° C for 8 hours. The reaction mixture was concentrated under reduced pressure and purified residue purified eluting eluting eluting eluting Ethyl alcohol and 4 M hydrogen chloride in ethyl acetate solution were added to the obtained crude purified product, and the mixture was stirred at room temperature for 30 minutes. After the reaction mixture was concentrated under reduced pressure, the residue was purified eluting ethyl acetate to afford 2-(4-{[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl] Methoxy}phenyl)imidazo[1,2-a]pyridine dihydrochloride (459 mg).

Example 13

N,N-dimethylformamidine of 1-methyl-3-{[4-(quinolin-2-yl)benzyl]oxy}-1H-pyrazole-4-carboxylic acid (246 mg) To the amine (7 mL) solution was added carbonyldiimidazole (166 mg), and the mixture was stirred at room temperature for 15 hours. Ethyl hydrazide (0.40 mL) was added and stirred at 60 ° C for 18 hours. Saturated aqueous sodium hydrogencarbonate solution and saturated brine were added under ice-cooling, and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and evaporated, evaporated, evaporated,,,,,,,,,, {[4-(Quinolin-2-yl)benzyl)oxy}-1H-pyrazole-4-carboindole (198 mg). The resulting N'-ethinyl-1-methyl-3-{[4-(quinolin-2-yl)benzyl]oxy}-1H-pyrazole-4-carboquinone (267 mg) A mixture of Burgess test (459 mg) and dichloroethane (8 mL) was placed in a sealed tube and subjected to microwave irradiation at 130 ° C for 20 minutes. After cooling, a saturated aqueous solution of sodium hydrogencarbonate and saturated brine were added, and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / chloroform). After the obtained solid was suspended in ethanol, a 4 M solution of hydrogen chloride in ethyl acetate was added, and the mixture was stirred for 30 minutes, and the resulting solid was collected by filtration to give 2-[4-({[1-methyl-4-(5- Methyl-1,3,4-oxadiazol-2-yl)-1H-pyrazol-3-yl]oxy}methyl)phenyl]quinoline monohydrochloride (219 mg).

Example 14

1-methyl-4-pyridin-4-yl-1H-pyrazol-3-ol (200 mg), [4-(imidazo[1,2-a]pyridin-3-yl)phenyl]methanol To a mixture of (300 mg) and toluene (15 mL), cyanide methyltributylphosphine (413 mg) was added, and the mixture was stirred at 100 ° C for 24 hours. After allowing to cool, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / chloroform). The obtained crude purified product was dissolved in ethanol, and a 4 M solution of hydrogen chloride in ethyl acetate was added thereto, and the mixture was stirred at room temperature for 2 hours. Diethyl ether was added to the reaction mixture, and the resulting precipitate was filtered and washed with diethyl ether to give 3-[4-({[1-methyl-4-(pyridin-4-yl)-1H-) Pyrazol-3-yloxy}methyl)phenyl]imidazo[1,2-a]pyridine dihydrochloride (117 mg).

Example 15

2-[4-(Chloromethyl)phenyl]quinoline hydrochloride (950 mg), 4-(1,4-dioxo[4.5]癸-8-yl)-1-methyl-1H- A mixture of pyrazole-3-ol (819 mg) and N,N-dimethylformamide (9.5 mL) was added to potassium carbonate (1.13 g), and stirred at 60 ° C for 1 hour. Join after cooling Water and saturated brine were extracted with a mixed solvent of methanol and chloroform, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (methanol / chloroform - ethyl acetate /hexane) to give 2-[4-({[4-(1,4-dioxos[4.5]]-8- ))-1-methyl-1H-pyrazol-3-yl]oxy}methyl)phenyl]quinoline (738 mg). 2-[4-({[4-(1,4-Dioxaspiro[4.5]癸-8-yl)-1-methyl-1H-pyrazol-3-yl)oxy}methyl) A mixture of phenyl]quinoline (1.095 g), tetrahydrofuran (11 mL) and water (11 mL) was added to p-toluenesulfonate (229 mg), and stirred at room temperature for 3 days. Saturated aqueous sodium hydrogencarbonate solution and saturated brine were added to the mixture, and the mixture was evaporated. It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / chloroform). The obtained crude purified product was dissolved in ethyl acetate, and a 4M aqueous solution of hydrogen chloride was added, and the mixture was stirred at the same temperature for 15 minutes. The resulting solid was removed by filtration to give 4-(1-methyl-3-{[4-(quinolin-2-yl)benzyl]oxy}-1H-pyrazol-4-yl)cyclohexanone. Monohydrochloride (105 mg).

Example 16

Under a stream of argon, potassium tert-butoxide was added to a mixture of dimethylidene iodide (94 mg) in dimethyl hydrazine (1.3 mL) and stirred at room temperature for 1.5 hours. 4-(1-Methyl-3-{[4-(quinolin-2-yl)benzyl)oxy}-1H-pyrazol-4-yl)cyclohexanone (160 mg) was added to the reaction mixture. A solution of toluene (3 mL) was stirred at room temperature for 9 hours. Water was added and extracted with chloroform. Wash the organic layer with water and saturated brine. After drying over anhydrous magnesium sulfate and concentration under reduced pressure afforded 2-[4-({[1-methyl-4-(1-oxaspiro[2.5]oct-6-yl)-1H-pyrazole- 3-yl]oxy}methyl)phenyl]quinoline (150 mg). Under a stream of argon, a mixture of lithium aluminum hydride (40 mg) in tetrahydrofuran (3 mL) was added with 2-[4-({[1-methyl-4-(1-oxaspiro[2.5]oct-6-yl) A solution of -1H-pyrazol-3-yl]oxy}methyl)phenyl]quinoline (150 mg) in tetrahydrofuran (4.5 mL) was stirred at room temperature for 1 hour. Ammonia water was added under ice cooling, diluted with a mixed solvent of methanol and chloroform (1:9), and stirred at room temperature for 1 hour. The resulting solid was separated by filtration through celite, and the residue was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / chloroform) to give 1-methyl-4-(1-methyl- 3-{[4-(Quinolin-2-yl)benzyl]oxy}-1H-pyrazol-4-yl)cyclohexanol (97 mg). 1-Methyl-4-(1-methyl-3-{[4-(quinolin-2-yl)benzyl]oxy}-1H-pyrazol-4-yl)cyclohexanol obtained (56 mg) of N,N-dimethylformamide (2 mL) was added with imidazole (45 mg) and tert-butyldimethylchloromethane (49 mg), stirred at room temperature for 15 hours, followed by 50 Stirring was carried out for 24 hours at °C. The reaction solution was directly purified by silica gel column chromatography (methanol / chloroform), and ethyl acetate was dissolved in ethyl acetate. The resulting solid was removed by filtration to give 1-methyl-4-(1-methyl-3-{[4-(quinolin-2-yl)benzyl]oxy}-1H-pyrazole-4- Cyclohexanol dihydrochloride (25 mg).

Example 17

4-(1-methyl-3-{[4-(quinolin-2-yl)benzyl]oxy}-1H-pyrazol-4-yl)cyclohexanone (300 mg), ethanol (6 mL) Hydroxylamine hydrochloride (61 mg) and sodium acetate (78 mg) were added to a mixture of water and water (1.2 mL), and stirred at room temperature for 1 hour. Saturated brine was added and extracted with chloroform. After drying over anhydrous magnesium sulfate and concentration under reduced pressure to give N-hydroxy-4-(1-methyl-3-{[4-(quinolin-2-yl)phenylmethyl]oxy}-1H-pyrazole- 4-yl)cyclohexaneimine (310 mg). N-Hydroxy-4-(1-methyl-3-{[4-(quinolin-2-yl)benzyl]oxy}-1H-pyrazol-4-yl)cyclohexaneimine ( A solution of 310 mg of tetrahydrofuran (3 mL) was added 3M aqueous sodium hydroxide (606 μL), and a solution of 4-methylbenzenesulfonium chloride (166 mg) in tetrahydrofuran (3.2 mL) was added. After stirring at 50 ° C for 6 hours, saturated brine was added and extracted with chloroform. The organic layer was dried over anhydrous MgSO.sub.sub.sub.sub.sub.sub.sub.sub.sub. -2-yl)benzyloxy]-1H-pyrazol-4-yl)azepane-2-one (288 mg). 5-(1-methyl-3-{[4-(quinolin-2-yl)benzyl}oxy}-1H-pyrazol-4-yl)azepane-2- A solution of the ketone (116 mg) in ethyl acetate (4.6 mL) was then evaporated. The resulting solid was removed by filtration to give 5-(1-methyl-3-{[4-(quinolin-2-yl)benzyl]oxy}-1H-pyrazol-4-yl)azacyclohexane. Heptan-2-one dihydrochloride (102 mg).

Example 18

4-(1-methyl-3-{[4-(quinolin-2-yl)benzyl)oxy}-1H-pyrazol-4-yl)cyclohexanone (462 mg) under argon In a mixture of 1,2-dimethoxyethane (7 mL) and tert-butanol (2.8 mL), p-toluenesulfonylmethyl isocyanide (329 mg) and potassium tert-butoxide were added under ice cooling. (227 mg), stirred at the same temperature for 30 minutes. And stirring was carried out for 7 hours at room temperature. Water and saturated brine were added, and the mixture was extracted with ethyl acetate. It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / chloroform) to give 4-(1-methyl-3-{[4-(quinolin-2-yl)phenylmethyl)oxy}-1H- Pyrazol-4-yl)cyclohexanecarbonitrile (167 mg).

Example 19

4-(1-methyl-3-{[4-(quinolin-2-yl)benzyl}oxy}-1H-pyrazol-4-yl)cyclohexanecarbonitrile (166 mg, anti-body and A solution of the cis-mixed mixture in ethanol (8.3 mL) was added 1M aqueous sodium hydroxide (1. 38 mL) and 30% aqueous hydrogen peroxide (0.28 mL) under ice cooling, and stirred at room temperature for 4 days. Water was added and the mixture was extracted with ethyl acetate, and the organic layer was washed with aqueous sodium sulfate aqueous solution and brine. The aqueous layer was extracted with EtOAc. The residue was purified by column chromatography (methanol / ethyl acetate). The obtained transester was dissolved in ethyl acetate, and a 4 M solution of hydrogen chloride in ethyl acetate was added thereto, and the mixture was stirred at room temperature, and the resulting solid was removed by filtration to give trans-4-(1-methyl-3- {[4-(Quinolin-2-yl)benzyl]oxy}-1H-pyrazol-4-yl)cyclohexaneamine formazan dihydrochloride (26 mg, mp. Shun The same treatment was carried out to give cis-4-(1-methyl-3-{[4-(quinolin-2-yl)benzyl]oxy}-1H-pyrazol-4-yl)cyclohexaneamine A Bismuth hydrochloride (58 mg, Ex. 149).

Example 20

3-methyl-2-(4-{2-[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]vinyl}phenyl)quinoline (950mg) To a solution of ethanol (10 mL), 10% palladium hydroxide-carbon (200 mg) was added, and the mixture was pressurized under a hydrogen atmosphere, and stirred at room temperature for 5 days. It was filtered through celite and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / chloroform). The obtained crude purified product was dissolved in ethyl acetate, and then a solution of 4M hydrogen chloride in ethyl acetate was added, and the mixture was stirred at room temperature for 15 minutes. The solvent was concentrated under reduced pressure, and the residue was added 2-propanol-diisopropyl ether and solidified to give 3-methyl-2-(4-{2-[1-methyl-4-(pyridine-4- -1H-pyrazol-3-yl]ethyl}phenyl)quinoline dihydrochloride (27 mg).

Example 21

4-(1-methyl-3-{[4-(quinolin-2-yl)benzyl]oxy}-1H-pyrazol-4-yl)cyclohexanone (183 mg), ethanol (3.7 A mixture of mL) and water (0.7 mL) was added with aminooxymethane hydrochloride (45 mg) and sodium acetate (47 mg), and stirred at room temperature for 2 hours. Saturated brine was added and extracted with chloroform. It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc/hexane). The solution was stirred at room temperature for 1 hour, and the resulting solid was filtered off to give N-methoxy-4-(1-methyl-3-{[4-(quinolin-2-yl)benzene. Methyl]oxy}-1H-pyrazol-4-yl)cyclohexaneimine dihydrochloride (157 mg).

Example 22

Ethanol in 4-(1-methyl-3-{[4-(quinolin-2-yl)benzyl)oxy}-1H-pyrazol-4-yl)cyclohexanone (203 mg) under ice cooling (4 mL) solution, sodium borohydride (22 mg) was added, and the mixture was stirred for 1 hour. Water and saturated brine were added, and the mixture was extracted with chloroform. After drying over anhydrous magnesium sulfate and concentrating under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give trans-4-(1-methyl-3-{[4- a colorless oil of oxa-4-yl)benzyloxy]-1H-pyrazol-4-yl)cyclohexanol (150 mg), further cis-4-(1-methyl-3-{ [4-(quinolin-2-yl)benzyl]oxy}-1H-pyrazol-4-yl)cyclohexanol (25 mg) as a white solid. The trans-body was dissolved in ethanol (4 mL), and oxalic acid (22 mg) was added and stirred for 30 minutes. After concentration under reduced pressure, the solid was combined with ethyl acetate and ethyl acetate to give trans-4-(1-methyl-3-{[4-(quinolin-2-yl)benzyl)oxy} -1H-pyrazol-4-yl)cyclohexanol oxalate (74 mg, Ex. 22). The solution was dissolved in ethyl acetate (6 mL), and then 4M hydrogen chloride in ethyl acetate was added and stirred at room temperature for 1 hour to give cis-4-(1-methyl-3-{[4-( Phenyl-2-yl)benzyloxy]-1H-pyrazol-4-yl)cyclohexanol dihydrochloride (28 mg, Ex. 154).

Example 23

1-(2-{[tert-butyl(dimethyl)indolyl)oxy}ethyl)-5-(1-methyl-3-{[4-(3-methylquinoline-2) To a solution of 4-benzyloxy]-1H-pyrazol-4-yl)pyridine-2(1H)-one (143 mg) in tetrahydrofuran (3 mL) was added tetrabutylammonium fluoride (0.4 mL). Stirring was carried out for 3 hours at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified to silica gel column chromatography (methanol / chloroform). The obtained crude purified product was dissolved in ethyl acetate, and then 4M hydrogen chloride ethyl acetate was added. The resulting precipitate was filtered off and washed with ethyl acetate to give 1-(2-hydroxyethyl)-5-(1-methyl-3-{[4-(3-methylquinolin-2-yl) Benzyl]oxy}-1H-pyrazol-4-yl)pyridine-2(1H)-one dihydrochloride (80 mg).

Example 24

2-[4-({[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)oxy}methyl)phenyl]quinolin-3-carbaldehyde (175) To a mixture of mg), dimethylamine hydrochloride (68 mg), and dichloromethane (5 mL), triethylamine (116 μL) and sodium triethyloxyborohydride (264 mg) at room temperature The mixture was stirred for 22 hours. The reaction solution was neutralized with a saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer was concentrated under reduced pressure and the residue was purified mjjjjjd The obtained crude purified product was dissolved in ethanol, and a 4M solution of hydrogen chloride in ethyl acetate was added, and the mixture was stirred at room temperature for 13 hours. Diethyl ether was added to the reaction mixture, and the resulting precipitate was filtered off and further washed with diethyl ether to give N,N-dimethyl-1-{2-[4-({[1-methyl- 4-(pyridin-4-yl)-1H-pyrazol-3-yl Oxy]methyl)phenyl]quinolin-3-yl}methaneamine trihydrochloride (118 mg).

Example 25

Under ice cooling, {2-[4-({[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)oxy}methyl)phenyl]quinoline-3 To a solution of methanol (270 mg) in N,N-dimethylformamide (5 mL), 55% sodium hydride (42 mg) was added and stirred at the same temperature for 15 min. After adding methyl iodide (60 μL), the temperature was raised to room temperature, and the mixture was stirred for 12 hours. The reaction solution was ice-cooled, and 55% sodium hydride (42 mg) and methyl iodide (60 μL) were added, and the mixture was warmed to room temperature, and then stirred for 1 hour. Water was added to the reaction mixture to stop the reaction, and ethyl acetate was added thereto, and the organic layer was washed with saturated brine. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (methanol / chloroform). The obtained crude purified product was dissolved in ethanol, and a 4 M solution of hydrogen chloride in ethyl acetate was added thereto, and the mixture was stirred at room temperature for 1 hour. Diethyl ether was added to the reaction mixture, and the resulting precipitate was filtered off and washed with diethyl ether to give 3-(methoxymethyl)-2-[4-({[1-methyl-4-) (Pyridin-4-yl)-1H-pyrazol-3-yl]oxy}methyl)phenyl]quinoline dihydrochloride (84 mg).

Example 26

2-(4-{[(4-Iodo-1-methyl-1H-pyrazol-3-yl)oxy]methyl}phenyl)-3-methylquinoline (338 mg), morpholine ( 2.7 mL), copper (142 mg), tripotassium phosphate (473 mg), 2-(dimethylamino)ethanol ( The mixture of 2.7 mL) was stirred at 110 ° C for 15 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure. Ethyl acetate, ethanol, 4M hydrogen chloride in ethyl acetate solution was added to the crude material, and stirred at room temperature for 30 minutes. The resulting solid was taken by filtration and washed with ethyl acetate to give 3-methyl-2-[4-({[1-methyl-4-(morpholin-4-yl)-1H-pyrazole-3 -yloxy}methyl)phenyl]quinoline dihydrochloride (164 mg).

Example 27

Cooling solution of 2-{4-[(4-iodo-1-methyl-1H-pyrazol-3-yl)methoxy]phenyl}-3-methylquinoline (6.00 g) in tetrahydrofuran (120 mL) A 2M solution of isopropylmagnesium chloride in tetrahydrofuran (16.5 mL) was added. Stirring was carried out for 45 minutes at the same temperature, and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.30 mL) was added. After stirring at room temperature for 2 hours, an aqueous solution of ammonium chloride was added and the mixture was extracted with ethyl acetate. After the organic layer was concentrated under reduced pressure, the residue was purified to silica gel column chromatography (ethyl acetate/hexane) to give 3-methyl-2-(4-{[1-methyl-4-( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-3-yl]methoxy}phenyl)quinoline (2.32 g).

3-methyl-2-(4-{[1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazol-3-yl]methoxy}phenyl)quinoline (500 mg), 5-bromo-1-methylpyridine-2(1H)-one (413 mg), N,N-dimethyl a mixture of methotrexate (5 mL) and water (1 mL) A dichloromethane adduct (54 mg) of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) and sodium carbonate (349 mg) were added, and the mixture was stirred at 100 ° C for 1 hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate. After the organic layer was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (methanol / chloroform). The obtained crude purified product was dissolved in ethanol, and a 4M solution of hydrogen chloride in ethyl acetate was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. Oxy]methyl}-1H-pyrazol-4-yl)pyridine-2(1H)-one dihydrochloride (80 mg).

Example 28

Addition of thallium chloride (1.1 mL) to a mixture of 1-[4-(hydroxymethyl)phenyl]-2-methyl-1H-benzimidazole (1.19 g) in dichloromethane (50 mL) Stir at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and the residue was evaporated. To the obtained solid (483 mg) was added 1-methyl-4-pyridin-4-yl-1H-pyrazol-3-ol (263 mg), potassium carbonate (520 mg), N,N-dimethylformamide (15 mL) was stirred at 70 ° C for 8 hours. The reaction mixture was concentrated under reduced pressure. The organic layer was concentrated under reduced pressure and the residue was purified mjjjjjd The obtained crude purified product was dissolved in ethanol, and a 4M solution of hydrogen chloride in ethyl acetate was added, and the mixture was stirred at room temperature for 15 minutes. The resulting precipitate was filtered off and washed with ethyl acetate to give 2-methyl-1-[4-({[1-methyl-4-(pyridin-4-yl)-1H-pyrazole-3- Alkyloxy}methyl)phenyl]-1H-benzimidazole dihydrochloride ( 445 mg).

Example 29

Under ice cooling, 4-(1-methyl-3-{[4-(quinolin-2-yl)benzyl)oxy}-1H-pyrazol-4-yl)cyclohexanone (213 mg) To the ethanol solution (8.5 mL), sodium borohydride (23 mg) was added, followed by stirring for 1 hour. Water and saturated brine were added, and the mixture was extracted with chloroform. After drying over anhydrous magnesium sulfate, the residue was evaporated. mjjjjjjjj Methylquinolin-2-yl)benzyloxy]-1H-pyrazol-4-yl)cyclohexanol (214 mg). 4-(1-methyl-3-{[4-(3-methylquinolin-2-yl)benzyl]oxy}-1H-pyrazol-4-yl)cyclohexanol obtained ( 214 mg) of N,N-dimethylformamide (3.2 mL) was added with imidazole (136 mg), tert-butyldimethylchloromethane (151 mg) and N,N-dimethyl-4-amino group. Pyridine (18 mg) was stirred at room temperature for 14 hours. After adding water, it was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (ethyl acetate /hexane) to give 2-[4-({[4-(trans)-4-{[tert-butyl(dimethyl)) Mercapto]oxy}cyclohexyl)-1-methyl-1H-pyrazol-3-yl]oxy}methyl)phenyl]-3-methylquinoline (160 mg). 2-[4-({[4-(trans-4-{[tert-butyl(dimethyl)indenyl)oxy}cyclohexyl)-1-methyl-1H-pyrazole) To a solution of 3-methyl]oxy}methyl)phenyl]-3-methylquinoline (160 mg) in tetrahydrofuran (3.2 mL), tetra-N-butylammonium fluoride (886 μL) was added at room temperature Carry out 7 small Stir when. After concentrating, the residue was purified by silica gel column chromatography (methanol / chloroform), and the residue was dissolved in ethyl acetate (6.4 mL). Stir for hours. The resulting solid was removed by filtration to give trans-4-(1-methyl-3-{[4-(3-methylquinolin-2-yl)benzyl]oxy}-1H-pyrazole- 4-yl)cyclohexanol dihydrochloride (104 mg).

Example 30

3-methyl-2-[4-({[1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazol-3-yloxy}methyl)phenyl]quinoline (507 mg), 5-bromo-2-(tert-butoxy)pyridine (384 mg), 1,1'-double (diphenylphosphine)ferrocene-palladium(II) dichloride-dichloromethane (54 mg), sodium carbonate (354 mg), N,N-dimethylformamide (7.5 mL), and water The mixture (1.5 mL) was stirred at 100 ° C for 1 hour under an argon atmosphere. Ethyl acetate and water were added, and the resulting insoluble material was filtered over Celite. The organic layer was washed with brine, dried over anhydrous magnesium sulfate The residue was purified by silica gel column chromatography (methanol / chloroform). After dissolving the obtained compound in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and saturated aqueous sodium hydrogen sulfate and ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (methanol / chloroform). The obtained crude purified product was dissolved in ethanol, and then a solution of 4 M hydrogen chloride in ethyl acetate. The solution was concentrated under reduced pressure. filter The resulting precipitate was taken out and washed with ether to give 6-(1-methyl-3-{[4-(3-methylquinolin-2-yl)benzyl]oxy}-1H-pyrazole. 4-yl)pyridine-2(1H)-one dihydrochloride (160 mg).

Example 31

2-{4-[(5-Bromo-2-methyl-2H-1,2,3-triazol-4-yl)methoxy]phenyl}-3-methylquinoline (290 mg), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (436 mg), N,N-dimethylformamide (2.9 mL) To a mixture of water and water (1.2 mL), cesium carbonate (462 mg) and triphenylphosphine palladium (123 mg) were added, and the mixture was stirred at 80 ° C for 18 hours. After cooling, water was added and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate The residue was purified by silica gel column chromatography (ethyl acetate / hexane), and the residue was dissolved in ethyl acetate (12 mL), and 4M hydrogen chloride in dioxane was added and stirred at room temperature for 1 hour. . The resulting solid was removed by filtration to give 3-methyl-2-(4-{[2-methyl-5-(pyridin-4-yl)-2H-1,2,3-triazol-4-yl] Methoxy}phenyl)quinoline dihydrochloride (99 mg).

Example 32

Under ice-cooling, dichloromethane in 5-[3-(hydroxymethyl)-1-methyl-1H-pyrazol-4-yl]-1-methylpyridine-2(1H)-one (394 mg) To a mixture of 20 mL), hydrazine chloride (0.4 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and the residue was evaporated. Join N,N-dimethylformamide (16 mL), 4-(1-methyl-1H-benzimidazol-4-yl)phenol (270 mg), and potassium carbonate (414 mg) at 80 ° C for 8 hours Stir. After the reaction mixture was concentrated under reduced pressure, water was evaporated and evaporated. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (methanol / chloroform). The obtained crude purified product was dissolved in ethyl acetate, and then a 4M aqueous solution of hydrogen chloride was added, and the mixture was stirred at room temperature for 10 minutes. After the solvent was concentrated under reduced pressure, the residue was purified ethyl ethyl acetate ethyldiethyldiethylethylethylethylethylethylethylethylethylethylethylethylethylethylethylethylethylethyldiethylethyl Phenyloxy]methyl}-1H-pyrazol-4-yl)pyridine-2(1H)-one dihydrochloride (206 mg).

Example 33

3-(1-methyl-3-{[4-(3-methylquinolin-2-yl)benzyl]oxy}-1H-pyrazol-4-yl)pyrrolidine-1-carboxyl To a solution of the acid tert-butyl (152 mg) in dichloromethane (0.3 mL) was added trifluoroacetic acid (0.3 mL), and the mixture was stirred at room temperature for 2 hours. After the reaction mixture was ice-cooled, a saturated aqueous The organic layer was dried with anhydrous sodium sulfate, filtered and evaporated. The residue was dissolved in dichloromethane (3 mL), and then ice-cooled. Triethylamine (51 μL) and ethyl acetate (24 μL) were added, and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture and the mixture was evaporated. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol). The obtained crude purified product was dissolved in ethyl acetate, and a 4M aqueous solution of hydrogen chloride was added, and the mixture was stirred at room temperature for 30 minutes. Filter out and take out The solid was washed with ethyl acetate to give 1-[3-(1-methyl-3-{[4-(3-methylquinolin-2-yl)benzyl]oxy}-1H. Pyrazol-4-yl)pyrrolidin-1-yl]ethanone dihydrochloride (125 mg).

Example 34

2-[4-({[1-methyl-4-(1-methyl-6-oxo-oxy-1,6-dihydropyridin-3-yl)-1H-pyrazol-3-yl]oxy) Sodium borohydride (96 mg) was added to a mixture of benzyl]methyl]phenyl]quinoline-3-carbaldehyde (569 mg), methanol (5 mL) and THF (5 mL), and the mixture was stirred at room temperature for 22 hours. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (methanol / chloroform). The obtained crude purified product was dissolved in methanol, 4M hydrogen chloride in dioxane solution was added, and the solution was concentrated under reduced pressure. The resulting solid was washed with methanol-ether and filtered to give 5-[3-({4-[3-(hydroxymethyl)quinolin-2-yl]phenylmethyl}oxy)-1 -Methyl-1H-pyrazol-4-yl]-1-methylpyridine-2(1H)-one monohydrochloride (74 mg).

Example 35

2-[4-({[1-methyl-4-(1-methyl-6-oxo-oxy-1,6-dihydropyridin-3-yl)-1H-pyrazol-3-yl]oxy) Add bis(2-methoxyethyl)aminosulfur trifluoride (0.1 mL) to a solution of methylene (methyl)phenyl]quinolin-3-carbaldehyde (150 mg) in dichloromethane (3 mL) Stir for one night under warm conditions. Water was added and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. Residue as alkali Purification by column chromatography (chloroform/hexane). The obtained crude purified product was dissolved in ethyl acetate, and then 4M hydrogen chloride ethyl acetate was added. The resulting precipitate was filtered off and washed with ethyl acetate to give 5-[3-({4-[3-(difluoromethyl)quinolin-2-yl]benzyl}oxy)-1- Methyl-1H-pyrazol-4-yl]-1-methylpyridine-2(1H)-one dihydrochloride (83 mg).

Example 36

2-[4-({[1-methyl-4-(1-methyl-6-oxo-oxy-1,6-dihydropyridin-3-yl)-1H-pyrazol-3-yl]oxy) Hydroxyamine hydrochloride (48 mg) and powdered potassium carbonate (143 mg) were added to a mixture of methyl}methyl)phenyl]quinolin-3-carbaldehyde (155 mg), tetrahydrofuran (3.5 mL), and methanol (0.4 mL). Stirring was carried out for 0.5 hour at room temperature. After concentration under reduced pressure, water was added and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated. Triethylamine (0.056 mL) and trifluoroacetic anhydride (0.052 mL) were added to a solution of the obtained compound in dichloromethane (3 mL), and the mixture was stirred at room temperature for 2 hours. Triethylamine (0.216 mL) and trifluoroacetic anhydride (0.219 mL) were added, and stirred at room temperature for 5 hours. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (methanol / chloroform). The obtained solid was washed with ethanol, and then filtered to give 2-[4-({[1-methyl-4-(1-methyl-6-oxooxy-1,6-dihydropyridin-3-yl). -1H-pyrazol-3-yloxy}methyl)phenyl]quinolin-3-carbonitrile (83 mg).

Example 37

Under ice cooling, 6-[4-({[1-methyl-4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-pyrazole-3- To a mixture of methyl oxy)methyl)phenyl]nicotinic acid methyl ester (1.47 g) in tetrahydrofuran (50 mL) was added lithium borohydride (148 mg) and ethanol (0.60 mL). The reaction solution was cooled, and a saturated aqueous The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / chloroform). The obtained crude purified product was washed with ethyl acetate and hexane to give 5-[3-({4-[5-(hydroxymethyl)pyridin-2-yl]phenylmethyl}oxy) 1-Methyl-1H-pyrazol-4-yl]-1-methylpyridine-2(1H)-one (770 mg).

Example 38

4-[4-(Chloromethyl)phenyl]-1-methyl-1H-benzimidazole hydrochloride (143 mg), 5-(3-hydroxy-1-methyl-1H-pyrazole-4 A mixture of 1-methylpyridin-2(1H)-one (100 mg), potassium carbonate (168 mg), and N,N-dimethylformamide (2 mL) was stirred at 60 ° C for 5 hours. Water was added, and the resulting solid was taken out by filtration and purified by silica gel column chromatography (methanol / chloroform). The obtained crude purified product was dissolved in ethyl acetate, and the resulting precipitate was filtered to give 1-methyl-5-(1-methyl-3-{[4-(1-methyl-1H-benzimidazole). 4-yl)benzylmethyloxy}-1H-pyrazol-4-yl)pyridine-2(1H)-one (75 mg).

Example 39

1-methyl-4-pyridin-4-yl-1H-pyrazol-3-ol (90 mg), [4-(imidazo[1,2-a]pyridin-2-yl)phenyl]methanol ( 1,1'-(Azodicarbonyl)dipiperidine (259 mg) and tri-n-butylphosphine (208 mg) were added to a mixture of 174 mg of tetrahydrofuran (9 mL), and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure and purified residue purified eluting eluting eluting eluting The obtained crude purified product was added with ethanol, 4M aqueous solution of hydrogen chloride, and stirred at room temperature for 30 minutes. After the reaction mixture was concentrated under reduced pressure, the residue was purified ethyl ether ethyl acetate to afford 2-[4-({[1-methyl-4-(pyridin-4-yl)-1H-pyrazole-3 -yloxy}methyl)phenyl]imidazo[1,2-a]pyridine dihydrochloride (122 mg).

Example 40

1-methyl-4-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-3-ol (250 mg) and 4-(quinolin-2-yl)butan-1-ol Cyanide methyltributylphosphine (497 mg) was added to a solution of (360 mg) in toluene (18 ml), and the mixture was stirred under heating at 100 ° C for 2.5 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified mjjjjjlilililililililili This was dissolved in ethyl acetate, and oxalic acid (62 mg) was added and stirred at room temperature. The solid obtained after concentration under reduced pressure was filtered to give 2-(4-{[1-methyl-4-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-3-yl. Oxyoxy}butyl)quinoline oxalate (250mg).

Example 41

To a solution of [5-(quinolin-2-yl)-2-thienyl]methanol (320 mg) in dichloromethane (6 mL) was then evaporated. Toluene was added, and the resulting solid was taken out by filtration. 2-[5-(Chloromethyl)-2-thienyl]quinoline hydrochloride (302 mg) and 1-methyl-4-(pyridin-4-yl)-1H-pyrazole-3- Potassium carbonate (352 mg) was added to a suspension of alcohol (179 mg) in N,N-dimethylformamide (6 mL), and the mixture was stirred at room temperature for 20 minutes, and then the mixture was heated to 60 ° C and stirred for 7 hours. After cooling, water and a saturated brine were added, and ethyl acetate was evaporated. The residue thus obtained was purified by silica gel column chromatography (methanol / chloroform). After dissolving this in ethyl acetate, succinic acid (35 mg) was added and stirred at room temperature for 1 hour. The resulting solid was removed by filtration to give 2-[5-({[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)oxy}methyl)-2-thiophene Quinoline 0.5 succinate (205 mg).

Example 42

Toluene of 1-methyl-4-pyridin-4-yl-1H-pyrazol-3-ol (550 mg) and 3-(quinolin-2-yl)prop-2-yn-1-ol (603 mg) Cyanide methyltributylphosphine (953 mg) was added to the solution (55 mL), and the mixture was stirred under heating at 100 ° C for 2.5 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified mjjjd Dissolve this in ethanol (3 mL), succinic acid (13 mg) was added, and the mixture was stirred under heating for 5 minutes. After cooling, it was concentrated under reduced pressure and the residue was solidified ethyl acetate to give 2-(3-{[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]oxy }}prop-1-yn-1-yl)quinoline succinate (59 mg).

Example 43

1-[3-Hydroxy-4-(pyridin-4-yl)-1H-pyrazol-1-yl]ethanone (3.19 g), 2-[4-(chloromethyl)phenyl]quinoline salt A mixture of the acid salt (4.15 g) and potassium carbonate in N,N-dimethylformamide (80 mL) was stirred at 60 ° C for 3 hours. After the reaction mixture was concentrated under reduced pressure, methanol (80 mL) and water (20 mL) were added to the residue, and the mixture was stirred at 60 ° C for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting precipitate was filtered and evaporated. The solid was purified by column chromatography (methanol / chloroform) to give 2-[4-({[4-(pyridin-4-yl)-1H-pyrazol-3-yl)oxy}methyl Phenyl]quinoline (1.52 g).

Example 44

3-(1-methyl-3-{[4-(3-methylquinolin-2-yl)benzyloxy}-1H-pyrazol-4-yl)pyrrolidine-1-carboxylic acid tert To a solution of butyl (916 mg) in dichloromethane (1.8 mL), trifluoroacetic acid (1.8 mL) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction mixture was ice-cooled, a saturated aqueous The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 3-methyl-2-[4-({[1-methyl-4-(pyrrolidin-3-yl)-1H-pyrazole-3- Ethyloxy}methyl)phenyl]quinoline (806 mg).

Example 45

Under ice cooling, 1-methyl-4-(4-{[1-methyl-4-(2-methylpyridin-4-yl)-1H-pyrazol-3-yl]methoxy}phenyl To a solution of -1H-benzimidazole (731 mg) in chloroform (30 mL), 75% of m-chloro-benzoic acid (534 mg) was added and stirred at room temperature for 24 hours. To the reaction mixture, sodium thiosulfate (570 mg) dissolved in water (5 mL) was added and stirred for 5 minutes. The reaction solution was concentrated under reduced pressure and purified residue purified eluted eluted eluted eluted eluted eluted eluted eluted eluted 1-Oxylpyridin-4-yl)-1H-pyrazol-3-yl]methoxy}phenyl)-1H-benzimidazole (503 mg).

Example 46

A mixture of 3-(1-methyl-1H-benzimidazol-4-yl)propan-1-ol (62 mg) in dichloromethane (1.5 mL) was iced cold, and triethylamine (82 μL) and methane. Chlorohydrazine (38 μL) was stirred at the same temperature for 30 minutes. After adding a saturated aqueous solution of sodium hydrogencarbonate and EtOAc (EtOAc) Add 5-(3-hydroxy-1-methyl-1H-pyrazol-4-yl)-1-methylpyridine-2(1H)-one trifluoroacetate (115 mg) and potassium carbonate (135 mg) to the residue. N,N-dimethylformamide (1.5 mL) was stirred at 60 ° C for 12 hours. A saturated aqueous solution of sodium chloride was added and the mixture was extracted with chloroform. The organic layer was dried with anhydrous sodium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography (chloroform / methanol). The obtained crude purified product was dissolved in ethyl acetate and added A 4 M solution of hydrogen chloride in ethyl acetate was stirred at room temperature for 30 minutes. The precipitated solid was filtered and dried under reduced pressure to give 1-methyl-5-{1-methyl-3-[3-(1-methyl-1H-benzimidazol-4-yl)propoxy. -1H-pyrazol-4-yl}pyridine-2(1H)-one trihydrochloride (16 mg).

Example 47

1-methyl-5-(1-methyl-3-{[4-(1-trityl-1H-benzimidazol-4-yl)phenoxy]methyl}-1H-pyrazole To a solution of -4-yl)pyridine-2(1H)-one (311 mg) in dioxane (8 mL) was added 4M hydrogen chloride in dioxane (0.6 mL) and stirred at 70 ° C for 1.5 hours. The reaction solution was concentrated under reduced pressure. Saturated sodium chloride was added and extracted with chloroform. The organic layer was dried with anhydrous sodium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography (chloroform / methanol). The obtained crude purified product was dissolved in ethanol, and a 4 M solution of hydrogen chloride in ethyl acetate was added thereto, and the mixture was stirred at room temperature for 30 minutes. Ethyl acetate was added, and the precipitated solid was filtered and dried under reduced pressure to give 5-(3-{[4-(1H-benzimidazol-4-yl)phenoxy]methyl}-1-methyl -1H-pyrazol-4-yl)-1-methylpyridine-2(1H)-one trihydrochloride (160 mg).

Example 338

Toluene in 2-{4-[(4-iodo-1-methyl-1H-pyrazol-3-yl)methoxy]phenyl}-3-methylquinoline (500 mg) under argon (10 mL) solution was added 4-(tributylstannyl)pyridazine (500 mg), ginseng ( Diphenylmethyleneacetone) dipalladium (0) (50 mg), 2-dicyclohexylphosphine-2', 4',6'-triisopropylbiphenyl (52 mg), 12 at 110 ° C Heat and stir for hours. The reaction solution was concentrated under reduced pressure, and the residue was purified and purified by silica gel column chromatography (methanol / chloroform). The obtained crude purified product was washed with ethyl acetate-hexane to give 3-methyl-2-(4-{[1-methyl-4-(pyridazin-4-yl)-1H-pyrazole- 3-yl]methoxy}phenyl)quinoline (255 mg).

Example 397

2-{4-[(4-Iodo-1-methyl-1H-pyrazol-3-yl)methoxy]phenyl}-3-methylquinoline (200 mg), 5-methylpyridazine -3-boronic acid pinacol ester (116 mg), tri-t-butyl phosphonium tetrafluoroborate (16 mg), ginseng (diphenylmethyleneacetone) dipalladium (0) (20 mg), tripotassium phosphate ( A mixture of 308 mg) and acetonitrile (3 ml) was heated and stirred at an oil temperature of 80 ° C for 4 hours, then N,N-dimethylformamide (2 ml) was added, and the mixture was heated and stirred at an oil temperature of 90 ° C for an additional 18 hours. . After cooling at room temperature, the reaction mixture was diluted with ethyl acetate, washed with brine, dried, evaporated, evaporated, evaporated. Benzyl-2-(4-{[1-methyl-4-(6-methylpyridazin-4-yl)-1H-pyrazol-3-yl]methoxy}phenyl)quinoline (9mg) .

Example 404

5-[3-(Chloromethyl)-1-methyl-1H-pyrazol-4-yl]-1-methylpyridine-2(1H)-one hydrochloride (180 mg), 4-(quin Oxalin-2-yl)phenol (120 mg), potassium carbonate (205 mg) and N,N-dimethylformamide ( The mixture of 13 mL) was stirred at 70 ° C for 8 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / chloroform) and basic hexanes column chromatography (methanol / chloroform) to give 1-methyl-5-(1- Methyl-3-{[4-(quinolin-2-yl)phenoxy]methyl}-1H-pyrazol-4-yl)pyridine-2(1H)-one (90 mg).

Example 412

1-Methyl-5-(1-methyl-3-{[4-(1-methyl-1H-benzimidazol-4-yl)phenoxy]methyl}-1H-pyrazole-4 A suspension of -pyridine)-2(1H)-one (2.5 g) in methanol (30 mL) was heated and dissolved in a water bath at 60 °C. At this temperature, 118 mL of a 0.1 M phosphoric acid-ethanol solution was added, and the mixture was stirred at the same temperature for 30 minutes. After returning the reaction mixture to room temperature, it was concentrated under reduced pressure. Ethanol (500 mL) and water (50 mL) were added to the residue, and the mixture was stirred at a water bath temperature of 90 ° C for 2 hours. After returning to room temperature and stirring for 1 hour, the solid was taken out by filtration and washed with ethanol. After drying under reduced pressure at 50 ° C overnight, 1-methyl-5-(1-methyl-3-{[4-(1-methyl-1H-benzimidazol-4-yl)phenoxy]- Base}-1H-pyrazol-4-yl)pyridine-2(1H)-one ‧ phosphate 2.96 g.

The compound of the examples shown in the following Table was produced in the same manner as in the above examples. The chemical structural formulas of the example compounds are shown in Tables 58 to 125 and Tables 167 to 182, and the physicochemical data and the manufacturing methods are shown in Tables 126 to 147 and Tables 183 to 188, respectively.

Industrial availability

The compound of the formula (I) or a salt thereof has a PDE10A inhibitory action and can be used as a prophylactic and/or therapeutic agent for schizophrenia, anxiety, Huntington's disease, drug dependence and/or Alzheimer's disease.

Claims (26)

a compound of the following formula (I) or a salt thereof, (wherein, ring A is an aromatic heterocyclic ring which may be substituted, and B is a cycloalkyl group which may be substituted by a C _1-6 alkyl group, a halogen, -OC _1-6 alkyl group, and may be substituted a non-aromatic heterocyclic group in which the same or different one or more substituents are substituted with a phenyl, pyridyldiyl, or thiophenediyl group, or -C≡C-, n is an integer of 0 or 1. , L ¹ is -C _1-6 alkylene -, - C _1-6 alkylene the -T-, or -TC _1-6 alkylene -, but when n is 0, L ¹ is - A three extension a radical -T- or -tetramethyl-T-, X is CR ⁰ or N, and R ¹ is halogen, -OH, -OC _1-6 alkyl, -CN, -C(O)OH, and - a C _1-6 alkyl group or H in which a C(O)OC _1-6 alkyl group is substituted by the same or different one or more groups, and the ring E is a cycloalkyl group which may be substituted and may be substituted. An aryl group, an aromatic hetero ring which may be substituted, or a non-aromatic heterocyclic ring which may be substituted, T is O, S, -NH-, or -N(C _1-6 alkyl)-, R ⁰ is H or C _1-6 alkyl). The compound of claim 1 or a salt thereof, wherein ring A is selected from (i) may be selected from the group consisting of halogen, -OH, -OC _1-6 alkyl, and -N(C _1-6 alkyl) ₂ groups of C _1-6 alkyl groups substituted with the same or different one or more groups, (ii) halogen, (iii)-O- (substituted by the same or different one or more halogens) C _1-6 alkyl), (iv)-N(C _1-6 alkyl) ₂ , (v)-CN, (vi) cycloalkyl, (vii)-C(O)H, in groups An aromatic heterocyclic ring substituted with the same or different one or more groups, and B is an alkyl group selected from C _1-6 alkyl, halogen, -OC _1-6 alkyl, cycloalkyl, and non-aromatic a phenyl, pyridyldiyl or thiophenediyl group substituted by the same or different one or more groups of the ring, or -C≡C-, n is an integer of 0 or 1, and L ¹ is - C _1-6 alkylene-, -C _1-6 alkyl-T-, or -TC _1-6 alkyl-, but when n is 0, L ¹ is -tri-methyl-T- or - tetramethyl-T-, X is CR ⁰ or N, and R ¹ may be selected from the group consisting of halogen, -OH, -OC _1-6 alkyl, -CN, -C(O)OH, and -C(O a C _1-6 alkyl group or H, which is substituted by the same or different one or more groups of OC _1-6 alkyl groups, may be selected from C _1-6 alkane , -OH, -C(O)NH ₂ , -C(O)NH(C _1-6 alkyl), -C(O)N(C _1-6 alkyl) ₂ , -CN, =NOC ₁ a cycloalkyl group substituted with the same or different one or more groups of a group of _-6 alkyl groups and side oxygen groups, an aryl group, which may be selected from the group consisting of halogen, -OH, -OC _1-6 alkyl, -O- (tert- butyldimethyl silicon), and -N (C _1-6 alkyl) ₂ or more groups of the same or different groups of the substituted C _1-6 An aromatic heterocycle substituted with an alkyl group, ii) halogen, iii) -OC _1-6 alkyl group, iv)-OH, and v) a group of the same or different ones of the cycloalkyl group, Or C which may be substituted by the same or different one or more groups selected from the group consisting of i) halogen, -OH, -OC _1-6 alkyl, and -N(C _1-6 alkyl) _{2 1-6} alkyl, ii)-OH, iii)-S(O) ₂ -C _1-6 alkyl, iv)-C(O)- (C _1- substituted by -OC _1-6 alkyl ₆ alkyl), v)-C(O)-N(C _1-6 alkyl) ₂ , vi)-C(O)OC _1-6 alkyl, and vii) the same or phase of the side oxygen group A non-aromatic heterocyclic ring substituted with one or more different groups. The compound of claim 2 or a salt thereof, wherein ring E is selected from the group consisting of halogen, -OH, -OC _1-6 alkyl, and -N(C _1-6 alkyl) ₂ A group of C _1-6 alkyl groups substituted with the same or different one or more groups, and a non-aromatic heterocyclic ring substituted with the same or different one or more groups in which the side oxygen groups are grouped. The compound of claim 3 or a salt thereof, wherein ring A is selected from the group consisting of halogen, -OH, -OC _1-6 alkyl, and -N(C _1-6 alkyl) ₂ a group of C _1-6 alkyl groups substituted by the same or different one or more groups, ii) halogen, iii)-O- (C ₁ substituted by the same or different one or more halogens) _a quinolyl group substituted with the same or different one or more groups of a group of _-6 alkyl), iv)-CN, v) cycloalkyl, and vi)-C(O)H, which may be selected from i) a C _1-6 alkyl group, ii)-O-(C _1-6 alkane) which may be substituted by the same or different one or more groups selected from the group consisting of -OH and -OC _1-6 alkyl groups a pyridyl group substituted with the same or different one or more groups of iii)-N(C _1-6 alkyl) ₂ or may be selected from the group consisting of halogens and a C _1-6 alkyl group substituted with the same or different one or more groups of OC _1-6 alkyl groups, ii) a cycloalkyl group, and iii) a group of the same or different halogens a benzimidazolyl group substituted with one or more groups, and B is a group of the same or different groups which may be grouped by a C _1-6 alkyl group, a halogen group, and a —OC _1-6 alkyl group. Substituted benzene The group, n is 1, L ¹ is -C _1-6 alkyl-O- or -OC _1-6 alkyl, X is CH, and R ¹ is C _1-6 alkyl. The compound of claim 4 or a salt thereof, wherein the ring E is 1,2-substituted by the same or different one or more groups selected from the group consisting of a C _1-6 alkyl group and a side oxygen group. Dihydropyridyl. The compound of claim 5 or a salt thereof, wherein ring E is 1-methyl-6-oxo-oxy-1,6-dihydropyridin-3-yl. The compound of claim 6 or a salt thereof, wherein ring A is selected from the group consisting of halogen, -OH, -OC _1-6 alkyl, and -N(C _1-6 alkyl) ₂ a group of C _1-6 alkyl groups substituted by the same or different one or more groups, ii) halogen, iii)-O- (C ₁ substituted by the same or different one or more halogens) _a quinolyl group substituted with the same or different one or more groups of _-6 alkyl), iv)-CN, v) cycloalkyl, and vi)-C(O)H, or may be selected since i) may be selected from halogen, and -OC one or more groups of the same or different groups of _1-6 alkyl substituted with C _1-6 alkyl, ii) cycloalkyl, and, III) A benzimidazolyl group substituted with one or more of the same or different groups of halogens. The compound of claim 7 or a salt thereof, wherein ring A is one or more groups selected from i) which may be the same or different groups selected from the group consisting of halogen and -OC _1-6 alkyl group. Substituted C _1-6 alkyl, ii) cycloalkyl, and iii) benzimidazolyl substituted with the same or different one or more groups of the halogen group. The compound of claim 8 or a salt thereof, wherein ring A is a benzimidazol-4-yl group substituted by a C _1-6 alkyl group. The compound of claim 9 or a salt thereof, wherein ring A is 1-methylbenzimidazol-4-yl. The compound of claim 10 or a salt thereof, wherein B is 1,4-phenylene. The compound of claim 7 or a salt thereof, wherein ring A is selected from the group consisting of halogen, -OH, -OC _1-6 alkyl, and -N(C _1-6 alkyl) ₂ a group of C _1-6 alkyl groups substituted by the same or different one or more groups, ii) halogen, iii)-O- (C ₁ substituted by the same or different one or more halogens) _a quinolyl group substituted with the same or different one or more groups of a group of _-6 alkyl), iv)-CN, v) cycloalkyl, and vi)-C(O)H. The compound of claim 12 or a salt thereof, wherein ring A is selected from the group consisting of halogen, -OH, -OC _1-6 alkyl, and -N(C _1-6 alkyl) ₂ a group of C _1-6 alkyl groups substituted by the same or different one or more groups, ii) halogen, iii)-O- (C ₁ substituted by the same or different one or more halogens) _-6 alkyl), iv)-CN, v) cycloalkyl, and vi)-C(O)H group of the same or different one or more substituted quinolin-2-yl groups, Or a quinoline-8-yl group substituted with the same or different one or more groups selected from the group consisting of a C _1-6 alkyl group and a -OC _1-6 alkyl group. The compound of claim 13 or a salt thereof, wherein ring A is quinolin-2-yl, 3-methylquinolin-2-yl, 3-hydroxymethylquinolin-2-yl, 3-methyl Oxyquinolin-2-yl, 6-fluoroquinolin-2-yl, 6-methoxyquinolin-2- Base, 6-methoxy-3-methylquinolin-2-yl, or quinoline-8-yl. A compound according to claim 14 or a salt thereof, wherein B is 1,4-phenylene. The compound of claim 2 or a salt thereof, wherein the ring E is a group selected from the group consisting of halogen, -OH, -OC _1-6 alkyl, and -N(C _1-6 alkyl) ₂ An aromatic heterocyclic ring substituted with a C _1-6 alkyl group substituted by the same or different one or more groups. The compound of claim 16 or a salt thereof, wherein ring A is selected from the group consisting of halogen, -OH, -OC _1-6 alkyl, and -N(C _1-6 alkyl) ₂ a group of C _1-6 alkyl groups substituted by the same or different one or more groups, ii) halogen, iii)-O- (C ₁ substituted by the same or different one or more halogens) _a quinolyl group substituted with the same or different one or more groups of _-6 alkyl), iv)-CN, v) cycloalkyl, and vi)-C(O)H may be selected from i) a C _1-6 alkyl group, ii)-O-(C _1-6 alkane) which may be substituted by the same or different one or more groups selected from the group consisting of -OH and -OC _1-6 alkyl groups a pyridyl group substituted with the same or different one or more groups of iii)-N(C _1-6 alkyl) ₂ or may be selected from the group consisting of halogens and a C _1-6 alkyl group substituted with the same or different one or more groups of OC _1-6 alkyl groups, ii) a cycloalkyl group, and iii) a group of the same or different halogens a benzimidazolyl group substituted with one or more groups, and B is a group of the same or different groups which may be grouped by a C _1-6 alkyl group, a halogen group, and a —OC _1-6 alkyl group. Substituted extension Group, n is to 1, L ¹ is -C _1-6 alkylene -O- or -OC _1-6 alkylene, X is CH, R ¹ is a C _1-6 alkyl group, E is a ring may be, by -C _1-6 alkyl group substituted with the same or different one or more groups of -OC _1-6 alkyl group and -OH group, substituted pyridyl group. The compound of claim 17 or a salt thereof, wherein ring E is 2-methylpyridin-4-yl. The compound of claim 18, wherein the ring A is the same or different one or more groups selected from the group consisting of halogen, C _1-6 alkyl and -OC _1-6 alkyl, or a salt thereof. a substituted quinolyl group, a pyridyl group substituted with the same or different one or more C _1-6 alkyl groups, or a benzene substituted with the same or different one or more C _1-6 alkyl groups And imidazolyl, B is 1,4-phenylene. The compound of claim 1 or a salt thereof, wherein 8-[4-({[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)oxy} A Phenyl]quinoline, 1-methyl-5-(1-methyl-3-{[4-(3-methylquinolin-2-yl)phenoxy]methyl}-1H-pyridyl Zin-4-yl)pyridine-2(1H)-one, 1-methyl-5-(1-methyl-3-{[4-(1-methyl-1H-benzimidazol-4-yl) Phenoxy]methyl}-1H-pyrazol-4-yl)pyridine-2(1H)-one, 1-methyl-5-(1-methyl-3-{[4-(1-methyl) -1H-benzimidazol-4-yl)benzyloxy]-1H-pyrazol-4-yl)pyridine-2(1H)-one, 2-(3-{[1-methyl-4 -(pyridin-4-yl)-1H-pyrazol-3-yl]oxy}prop-1-yn-1-yl)quinoline, 1-methyl-5-(1-methyl-3-{ [4-(3-methylquinolin-2-yl)benzyl]oxy}-1H-pyrazol-4-yl)piperidin-2-one, 4-(3-{[4-(6 -fluoro-3-methylquinolin-2-yl)benzyloxy]-1-methyl-1H-pyrazol-4-yl)-1-methylpyridine-2(1H)-one, 5-(3-{[4-(6-methoxy-3-methylquinolin-2-yl)benzyl]oxy}-1-methyl-1H-pyrazol-4-yl)- 1-methylpyridine-2(1H)-one, 1-methyl-4-(4-{[1-methyl-4-(2-methylpyridin-4-yl)-1H-pyrazole-3 -yl]methoxy}phenyl)-1H-benzo Oxazole, 5-(3-{[4-(3-ethylquinolin-2-yl)benzyl]oxy}-1-methyl-1H-pyrazol-4-yl)-1-methyl Pyridine-2(1H)-one, 3-methyl-2-(4-{[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]methoxy}benzene Quinoline, 3-methyl-2-[4-({[1-methyl-4-(pyridazin-4-yl)-1H-pyrazol-3-yl)oxy}methyl)phenyl]quinoline, 2-(4-{[(1,1'-dimethyl-1H,1'H-4,4'-bispyrazol-3-yl)oxy]methyl}phenyl)-3-methyl Quinoline, 1-methyl-5-(1-methyl-3-{[4-(quinolin-2-yl)benzyl)oxy}-1H-pyrazol-4-yl)pyridine-2 (1H)-keto, 1-ethyl-5-(1-methyl-3-{[4-(3-methylquinolin-2-yl)benzyl]oxy}-1H-pyrazole- 4-yl)pyridine-2(1H)-one, 5-(1-methyl-3-{[4-(3-methylquinolin-2-yl)benzyl]oxy}-1H-pyridyl Zin-4-yl)-1-propylpyridine-2(1H)-one, 5-(3-{[4-(6-fluoro-3-methylquinolin-2-yl)benzyl]oxy -1-methyl-1H-pyrazol-4-yl)-1-methylpyridine-2(1H)-one, 1-methyl-5-(2-methyl-5-{[4- (3-methylquinolin-2-yl)phenoxy]methyl}-2H-1,2,3-triazol-4-yl)pyridine-2(1H)-one, 3-methyl-2 -(4-{[1-methyl-4-(2-methylpyridin-4-yl)-1H-pyrazol-3-yl]methoxy}phenyl)quinoline, 2-(4-{ [4-(2,6-Dimethylpyridin-4-yl)-1-methyl-1H-pyrazol-3-yl]methoxy}phenyl)-3-methylquinoline, 1-methyl 4-(1-methyl-3-{2-[4-(3-methylquinolin-2-yl)phenyl]ethyl}-1H-pyridyl 4-yl)pyridine-2(1H)-one, 1-methyl-4-(1-methyl-3-{[4-(3-methylquinolin-2-yl)phenoxy]- -1}-1H-pyrazol-4-yl)pyridine-2(1H)-one, 1-methyl-4-(4-{[1-methyl-4-(2-methyl-1-oxide) Pyridin-4-yl)-1H-pyrazol-3-yl]methoxy}phenyl)-1H-benzimidazole, 1-Methyl-4-(4-{[1-methyl-4-(pyridazin-4-yl)-1H-pyrazol-3-yl]methoxy}phenyl)-1H-benzimidazole , 1-methyl-4-(1-methyl-3-{[4-(1-methyl-1H-benzimidazol-4-yl)phenoxy]methyl}-1H-pyrazole-4 -yl)pyridine-2(1H)-one, 1'-ethyl-1-methyl-3-{[4-(1-methyl-1H-benzimidazol-4-yl)phenoxy]- }}-1H,1'H-4,4'-bispyrazole, 1-methyl-5-(1-methyl-3-{[4-(quinolin-8-yl)phenoxy)- -1--1H-pyrazol-4-yl)pyridine-2(1H)-one, 5-(3-{[4-(6-methoxy-3-methylquinolin-2-yl)phenoxy Methyl}-1-methyl-1H-pyrazol-4-yl)-1-methylpyridine-2(1H)-one, 8-(4-{[1-methyl-4-(pyridyl) Pyrazin-4-yl)-1H-pyrazol-3-yl]methoxy}phenyl)quinoline, 1-methyl-5-(1-methyl-3-{[4-(quinoline-2) -yl)phenoxy]methyl}-1H-pyrazol-4-yl)pyridine-2(1H)-one, 5-(3-{[4-(3-methoxyquinolin-2-yl) Phenoxy]methyl}-1-methyl-1H-pyrazol-4-yl)-1-methylpyridine-2(1H)-one, 5-(3-{[4-(6-fluoro) Quinoline-2-yl)phenoxy]methyl}-1-methyl-1H-pyrazol-4-yl)-1-methylpyridine-2(1H)-one, 5-(3-{[ 4-(6-methoxyquinolin-2-yl)phenoxy]methyl}-1-methyl-1H-pyrazole-4- -1-methylpyridine-2(1H)-one, 3-methyl-8-(4-{[1-methyl-4-(2-methylpyridin-4-yl)-1H-pyrazole 3-yl]methoxy}phenyl)imidazo[1,2-a]pyridine, 1,1'-dimethyl-3-{[4-(3-methylimidazo[1,2- a]pyridin-8-yl)phenoxy]methyl}-1H,1'H-4,4'-dipyrazole, or 2-(4-{[1-Methyl-4-(2-methylpyridin-4-yl)-1H-pyrazol-3-yl]methoxy}phenyl)quinoline. A pharmaceutical composition comprising a compound as claimed in claim 1 or a salt thereof, and a pharmaceutically acceptable excipient. A schizophrenia, anxiety disorder, Huntington's disease, drug dependence, and/or a prophylactic and/or therapeutic agent for Alzheimer's disease, characterized by containing a compound of the first aspect of the patent application or a salt thereof. Use of a compound or a salt thereof as claimed in claim 1 for use in the prevention and/or prevention of schizophrenia, anxiety, Huntington's disease, drug dependence, and/or Alzheimer's disease The manufacture of therapeutic pharmaceutical compositions. Use of a compound or a salt thereof as claimed in claim 1 for use in the prevention and/or prevention of schizophrenia, anxiety, Huntington's disease, drug dependence, and/or Alzheimer's disease Treatment. A method for preventing and/or treating schizophrenia, anxiety, Huntington's disease, drug dependence, and/or Alzheimer's disease, characterized by the compound of the first aspect of the patent application or a salt thereof The effective amount is given to the person who is the subject. The compound of claim 1 or a salt thereof for use in the prevention and/or treatment of schizophrenia, anxiety, Huntington's disease, drug dependence, and/or Alzheimer's disease.