HK1180955B - Heterocyclyl compounds as histamine h3 receptor ligands - Google Patents

Description

Heterocyclyl compounds as histamine H3 receptor ligands

Technical Field

The present invention relates to heterocyclyl compounds of formula (I) and their pharmaceutically acceptable salts, processes for their preparation and compositions containing them for the treatment of histamine H₃Various diseases related to the receptor.

Background

Histamine H₃The recipient being a G eggThe white coupled receptor (GPCR) is one of the four receptors of the histamine family. Histamine H₃The receptor was identified in 1983, and its cloning and characterization was performed in 1999. Histamine H₃Receptors are expressed to a greater extent in the central nervous system and to a lesser extent in the peripheral nervous system.

Literature evidence suggests that histamine H can be converted₃The receptors are useful in the treatment of cognitive disorders (British Journal of Pharmacology, 2008, 154(6), 1166-.

Patent/patent applications US4695575, EP0151826, WO2010026113, WO2004022060 and WO2003004480 disclose histamine H as histamine₃A series of compounds that are ligands for receptors. Although some histamine H has been disclosed₃Receptor ligands, but no compounds have been introduced on the market in this field of research to date, so that there is still a need and the eye for the discovery of new drugs with a new chemical structure for the treatment of histamine H₃A receptor-affected disease.

Disclosure of Invention

The invention relates to novel histamine H of formula (I)₃A receptor ligand or a pharmaceutically acceptable salt thereof;

wherein the content of the first and second substances,

R₁is-C (O) -R₄、-S(O)₂-R₄、Substituted or unsubstituted cycloalkyl, aryl or heteroaryl; wherein the substituents may be one or moreAnd is independently selected from hydrogen, hydroxy, halogen, alkyl, alkoxy, haloalkyl or haloalkoxy;

R₄is a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl or heterocyclylalkyl group; wherein the substituents may be one or more and are independently selected from hydrogen, hydroxy, halogen, alkyl, alkoxy, haloalkyl or haloalkoxy;

R₅is hydrogen, alkyl or cycloalkyl;

in each case, R₃Independently selected from hydrogen, halogen, alkyl or alkoxy;

R₂is hydrogen, substituted or unsubstituted alkyl or cycloalkyl; wherein the substituents may be one or more and are independently selected from hydrogen, hydroxy, halogen, alkyl, alkoxy, haloalkyl or haloalkoxy;

x is S, N or O;

y is C or N;

"p" is an integer from 0 to 2;

"q" is an integer from 0 to 2;

"r" is an integer of 0 to 1.

The present invention relates to the use of a therapeutically effective amount of a compound of formula (I) for the preparation of a medicament for the treatment of histamine H₃The application of the medicine in treating various diseases related to receptor.

In particular, the compounds of the present invention are useful for the treatment of various diseases, such as cognitive disorders, sleep disorders, obesity and pain.

In another aspect, the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of at least one compound of formula (I) and pharmaceutically acceptable salts thereof in admixture with pharmaceutically acceptable excipients.

In yet another aspect, the invention relates to methods for using compounds of formula (I).

In a further aspect, the invention also relates to processes for the preparation of compounds of formula (I) and pharmaceutically acceptable salts thereof.

Representative compounds of the invention include those detailed below and pharmaceutically acceptable salts thereof. The invention should not be construed as being limited thereto:

1- [2- (1-cyclobutyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -propan-1-one tartrate;

[2- (4-cyclobutyl-cyclohexyloxy) -4,5,7, 8-tetrahydro-thiazolo [5,4-d ]]Aza derivatives-6-yl]-cyclopropyl-methanone tartrate;

n- [2- (1-cyclobutyl-piperidin-4-yloxy) -4,5,6, 7-tetrahydro-benzothiazol-6-yl ] -propionamide;

[2- (1-cyclobutyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -cyclopropyl-methanone tartrate;

cyclobutyl- [2- (1-cyclobutyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -methanone tartrate;

[2- (1-cyclobutyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] - (2-fluoro-phenyl) -methanone tartrate;

1- [2- (1-cyclobutyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -3-methyl-butan-1-one tartrate;

cyclobutyl- [2- (1-isopropyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -methanone;

cyclopropyl- [2- (1-isopropyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -methanone tartrate;

cyclopropyl- [2- (1-cyclopropyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -methanone tartrate;

cyclobutyl- [2- (1-cyclopropyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -methanone tartrate;

1- [2- (1-cyclobutyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -2-morpholin-4-yl-ethanone tartrate;

[4- (5-cyclobutyl-6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-2-yloxy) -piperidin-1-yl ] -cyclopropyl-methanone tartrate;

[3- (5-cyclobutyl-6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-2-yloxy) -piperidin-1-yl ] -cyclopropyl-methanone tartrate;

[2- (1-cyclobutyl-piperidin-3-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -cyclopropyl-methanone tartrate;

[2- (1-cyclobutyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -pyridin-4-yl-methanone tartrate;

[2- (1-cyclobutyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] - (4-methoxy-phenyl) -methanone tartrate;

1- [2- (1-cyclobutyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -2-piperidin-1-yl-ethanone tartrate;

1- [2- (1-cyclobutyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -2-cyclopropyl-ethanone;

2- (1-cyclobutyl-piperidin-4-yloxy) -5- (2-fluoro-benzenesulfonyl) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridine tartrate;

2- (1-cyclobutyl-piperidin-4-yloxy) -5-methanesulfonyl-6, 7-dihydro-4H-thiazolo [5,4-c ] pyridine;

1- [2- (1-cyclobutyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -2-methyl-propan-1-one tartrate;

2- (1-cyclobutyl-piperidin-4-yloxy) -5- (2-trifluoromethyl-pyridin-5-yl) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridine;

cyclopropyl- [2- (1-isobutyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -methanone tartrate;

[2- (1-cyclobutyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] - (2-trifluoromethyl-pyridin-5-yl) -methanone;

[2- (1-cyclobutyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -pyridin-3-yl-methanone tartrate;

2- (1-cyclobutyl-piperidin-4-yloxy) -5-pyridin-3-yl-6, 7-dihydro-4H-thiazolo [5,4-c ] pyridine tartrate;

[2- (1-cyclobutyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] - (tetrahydro-pyran-4-yl) -methanone;

[2- (1-cyclobutyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -morpholin-4-yl-methanone tartrate;

[2- (1-cyclobutyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -piperidin-1-yl-methanone hydrochloride;

6- [2- (1-cyclobutyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -nicotinamide;

[2- (1-cyclobutyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -cyclopentyl-methanone tartrate;

[2- (1-cyclobutyl-piperidin-4-yloxy) -6, 7-dihydro-5H-thiazolo [5,4-b ] pyridin-4-yl ] -cyclopropyl-methanone tartrate;

cyclopropyl- [2- (1-isopropyl-piperazine)Pyridin-4-yloxy) -4,5,7, 8-tetrahydro-thiazolo [5,4-d]Aza derivatives-6-yl]-methanone tartrate;

[2- (1-cyclobutyl-piperidin-4-yloxy) -6, 7-dihydro-5H-thiazolo [5,4-b ] pyridin-4-yl ] -cyclopropyl-methanone;

1- [2- (1-cyclobutyl-piperidin-4-yloxy) -6, 7-dihydro-5H-thiazolo [5,4-b ] pyridin-4-yl ] -propan-1-one;

cyclobutyl- [2- (1-cyclobutyl-piperidin-4-yloxy) -6, 7-dihydro-5H-thiazolo [5,4-b ] pyridin-4-yl ] -methanone;

n- [2- (1-cyclobutyl-piperidin-4-yloxy) -4,5,6, 7-tetrahydro-benzothiazol-7-yl ] -propionamide;

1- [2- (1-cyclobutyl-piperidin-4-yloxy) -6, 7-dihydro-4H-Azolo [5,4-c ] s]Pyridin-5-yl]-propan-1-one;

1- [2- (1-cyclobutyl-piperidin-4-yloxy) -4, 6-dihydro-pyrrolo [4, 3-d]Azol-5-yl]-propan-1-one;

n- [2- (1-cyclobutyl-piperidin-4-yloxy) -5, 6-dihydro-4H-cyclopentaAzol-5-yl]-propionamide;

n- [2- (1-cyclobutyl-piperidin-4-yloxy) -5, 6-dihydro-4H-cyclopenta-thiazol-5-yl ] -propionamide;

1- [2- (1-cyclobutyl-piperidin-4-yloxy) -4, 6-dihydro-pyrrolo [4, 3-d ] thiazol-5-yl ] -propan-1-one;

1- [2- (1-cyclobutyl-piperidin-4-yloxy) -5, 6-dihydro-pyrrolo [3, 2-d ] thiazol-4-yl ] -propan-1-one;

n- [2- (1-cyclobutyl-piperidin-4-yloxy) -5, 6-dihydro-4H-cyclopenta-thiazol-6-yl ] -propionamide;

n- [2- (1-cyclobutyl-piperidin-4-yloxy) -5, 6-dihydro-4H-cyclopentaAzol-6-yl]-propionamide;

1- [2- (1-cyclobutyl-piperidin-4-yloxy) -5, 6-dihydro-pyrrolo [3, 2-d]Azol-4-yl]]-propan-1-one;

1- [2- (1-cyclobutyl-piperidin-4-yloxy) -4, 6-dihydro-pyrrolo [4, 3-d]Azol-5-yl]-propan-1-one;

n- [2- (1-cyclobutyl-piperidin-4-yloxy) -5, 6-dihydro-4H-cyclopentaAzol-5-yl]-propionamide;

1- [2- (1-cyclobutyl-piperidin-4-yloxy) -4, 6,7, 8-tetrahydro-thiazolo [5,4-c]Aza derivatives-5-yl]-propan-1-one;

1- [2- (1-cyclobutyl-piperidin-4-yloxy) -4-methyl-6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -propan-1-one;

1- [2- (1-cyclobutyl-piperidin-4-yloxy) -7-fluoro-6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -propan-1-one;

1- [2- (1-cyclobutyl-piperidin-4-yloxy) -7-methyl-6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -propan-1-one;

1- [2- (1-cyclobutyl-piperidin-4-yloxy) -6-methyl-6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -propan-1-one;

1- [2- (1-cyclobutyl-3-methyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -propan-1-one;

1- [2- (1-cyclobutyl-3-fluoro-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -propan-1-one;

1-cyclobutyl-4- (5-propionyl-4, 5,6, 7-tetrahydro-thiazolo [5,4-c ] pyridin-2-yloxy) -piperidine-3-carbonitrile;

1- [2- (1-cyclobutyl-azepan-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -propan-1-one;

1- [2- (1-cyclobutyl-azepan-4-yloxy) -4,5,7, 8-tetrahydro-thiazolo [5,4-d ]]Aza derivatives-6-yl]-propan-1-one;

1- [2- (1-cyclobutyl-pyrrolidin-3-yloxy) -4,5,7, 8-tetrahydro-thiazolo [5,4-d ]]Aza derivatives-6-yl]-propan-1-one;

1- [2- (1-cyclobutyl-pyrrolidin-3-yloxy) -4, 6-dihydro-pyrrolo [4, 3-d ] thiazol-5-yl ] -propan-1-one;

1- [2- (1-cyclobutyl-azepan-4-yloxy) -4, 6-dihydro-pyrrolo [4, 3-d ] thiazol-5-yl ] -propan-1-one;

1- {2- [1- (2-hydroxy-ethyl) -piperidin-4-yloxy ] -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl } -propan-1-one;

1- [2- (1-ethoxymethyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -propan-1-one;

1- {2- [1- (2, 2, 2-trifluoro-ethyl) -piperidin-4-yloxy ] -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl } -propan-1-one;

1- [2- (1-cyclobutyl-azetidin-3-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -propan-1-one; and pharmaceutically acceptable salts thereof.

Detailed Description

Unless otherwise indicated, the following terms used in the specification and claims have the meanings given below:

the term "halogen" means fluorine, chlorine, bromine or iodine.

The term "alkyl" means a straight or branched hydrocarbon group consisting only of carbon and hydrogen atoms, excluding unsaturation, having from 1 to 8 carbon atoms and being connected to the remaining molecule by a single bond. Exemplary "alkyl" groups include methyl, ethyl, n-propyl, isopropyl, and the like.

The term "alkoxy" means an alkyl group attached to the rest of the molecule via an oxygen linkage. Exemplary "alkoxy" groups include methoxy, ethoxy, propoxy, isopropoxy, and the like.

The term "haloalkyl" means a straight or branched alkyl group containing 1 to 3 carbon atoms. Exemplary "haloalkyl" groups include fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, fluoroethyl, difluoroethyl and the like.

The term "haloalkoxy" means a straight or branched chain alkoxy group containing 1 to 3 carbon atoms. Exemplary "haloalkoxy" groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy, difluoroethoxy, and the like.

The term "cycloalkyl" means a non-aromatic monocyclic ring of 3 to 8 carbon atoms. Exemplary "cycloalkyl" groups include cyclopropyl, cyclobutyl, cyclopentyl, and the like.

The term "cycloalkylalkyl" means a cycloalkyl ring group bonded directly to an alkyl group.

The term "aryl" means any functional group or substituent derived from a simple aromatic ring, and exemplary "aryl" includes phenyl, naphthyl, and the like.

The term "heteroaryl" means an organic compound comprising a ring structure containing an atom other than carbon (e.g., sulfur, oxygen, or nitrogen) as part of the ring, which additional atom may be repeated more than once in the ring. These rings may be simple aromatic rings. Exemplary "heteroaryl" groups include pyridine, pyrimidine, benzofuranyl, benzothiophene, furanyl, dioxolanyl, pyrrolyl, and,Oxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, indolyl, and the like.

The term "heterocyclyl" means a non-aromatic monocyclic ring of 2 to 7 carbon atoms, the ring structure of which contains 1 to 3 heteroatoms, these additional atoms being repeated more than once in the ring. Exemplary "heterocyclyl" groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and the like.

The term "heterocyclylalkyl" means a heterocyclyl ring group directly bonded to an alkyl group.

The term "treatment" includes all meanings, such as prophylactic, protective and palliative.

The phrase "pharmaceutically acceptable salt" means that the material or composition must be chemically and/or toxicologically compatible with the other ingredients (including the formulation), the mammal being treated.

The phrase "therapeutically effective amount" is defined as the amount of a compound of the invention when used in: (i) treating or preventing a particular disease, condition, or disorder, (ii) attenuating, alleviating, or eliminating one or more symptoms of a particular disease, condition, or disorder, (iii) preventing or delaying the onset of one or more symptoms of a particular disease, condition, or disorder described herein.

Commercial reagents were used without further purification. The room temperature means 25-40 ℃. Unless otherwise indicated, all mass spectra were performed using ESI conditions. Recording at 400MHz using a Bruker instrument¹H-NMR spectrum. Deuterated chloroform (99.8% D), methanol or dimethylsulfoxide was used as solvent. TMS was used as an internal reference standard. Chemical shift values are expressed as parts per million () values. The following abbreviations are used for multiplicity of NMR signals: s ═ singlet, bs ═ broad singlet, d ═ doublet, t ═ triplet, q ═ quartet, qui ═ quintet, h ═ heptaplex, dd ═ doublet, dt ═ doublet, tt ═ triplet, m ═ multiplet. Chromatography refers to column chromatography performed using 100-200 mesh silica gel and performed under nitrogen pressure (flash chromatography).

The compound was named by using Chem Draw Ultra 7.0.

Pharmaceutical composition

For use in therapy, the compounds of formula (I) are generally formulated into pharmaceutical compositions according to standard pharmaceutical practice.

The pharmaceutical compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable excipients. The pharmaceutically acceptable excipient is a carrier or diluent. Thus, the active compounds of the present invention can be formulated for oral, intranasal, or parenteral (e.g., intravenous, intramuscular, or subcutaneous). Such pharmaceutical compositions and methods of making them are well known in The art (see, e.g., Remington: The Science and Practice of Pharmacy (D.B. Troy, eds.), 21 st edition, Lippincott, Williams & Wilkins, 2006).

The dosage of the active compound may vary depending on factors such as the route of administration, the age and weight of the patient, the nature and severity of the disease to be treated and the like. Thus, any reference herein to a pharmacologically effective amount of a compound of formula (I) refers to the aforementioned factors.

Preparation method

The compounds of formula (I) are prepared by scheme I below.

Scheme I

In scheme I above, p is 1; q is 1; r is 1; y is N; x is S; r₁is-C (O) -R₄、-S(O)₂-R₄Substituted or unsubstituted cycloalkyl, aryl or heteroaryl, and all other symbols are as described above.

Coupling a compound of formula (1) with a compound of formula (2) to form a compound of formula (3). Deprotecting the compound of formula (3) to form a compound of formula (4). Coupling a compound of formula (4) with a compound of formula (5) to form a compound of formula (I).

In the first step of the above preparation, the compound of formula (1) is coupled with the compound of formula (2) to form the compound of formula (3). The reaction is preferably carried out in a solvent (e.g., tetrahydrofuran, toluene, ethyl acetate, dichloromethane, triethylamine, dimethylformamide, etc., or a mixture thereof) and preferably by using tetrahydrofuran. The reaction may take place in the presence of a base (e.g. sodium hydride, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide or mixtures thereof) and preferably by using sodium hydride. The reaction was carried out at room temperature. The reaction may last for 4 to 8 hours, preferably 5 to 7 hours.

In the second step of the above preparation, the compound of formula (3) is deprotected to form the compound of formula (4). The reaction is preferably carried out in a solvent (e.g., tetrahydrofuran, toluene, ethyl acetate, dichloromethane, acetonitrile, 1, 4-diethyldione, dimethylformamide, etc., or a mixture thereof) and preferably by using dichloromethane. The reaction may take place in the presence of an acid (e.g., trifluoroacetic acid, sulfuric acid, acetic acid, perchloric acid, hydrochloric acid, and the like, or mixtures thereof) and preferably by using trifluoroacetic acid. The reaction is carried out at a temperature of 60 ℃ to 85 ℃ and preferably at a temperature of 65 ℃ to 75 ℃. The reaction may last for 2 to 6 hours, preferably 3 to 5 hours.

In the third step of the above preparation, the compound of formula (4) is coupled with the compound of formula (5) to form the compound of formula (I). The reaction is preferably carried out in a solvent (e.g., dichloromethane, tetrahydrofuran, toluene, ethyl acetate, dimethylformamide, and the like or a mixture thereof) and preferably by using dichloromethane. The reaction may take place in the presence of a base (e.g. triethylamine, potassium carbonate, diisopropylethylamine and pyridine) and is preferably by using triethylamine. The reaction was carried out at room temperature. The reaction may last for 15 to 45 minutes, preferably 25 to 35 minutes.

The compounds of formula (1), formula (2) and formula (5) are commercially available or can be prepared by conventional methods or by modification using known procedures.

The compounds of formula (I) can also be prepared by using scheme II below.

Scheme II

In scheme II above, p is 1; q is 2; r is 1; y is N; x is S; r₁is-C (O) -R₄、-S(O)₂-R₄Substituted or unsubstituted cycloalkyl, aryl or heteroaryl, and all other symbols are as described above.

Coupling a compound of formula (6) with a compound of formula (5) to form a compound of formula (7). Brominating the compound of formula (7) to form the compound of formula (8). Cyclizing the compound of formula (8) to form the compound of formula (9). Diazotizing the compound of formula (9) to form the compound of formula (10). Coupling a compound of formula (10) with a compound of formula (2) to form a compound of formula (I).

In the first step of the above preparation, the compound of formula (6) is coupled with the compound of formula (5) to form the compound of formula (7). The reaction is preferably carried out in a solvent (e.g., tetrahydrofuran, toluene, ethyl acetate, dichloromethane, dimethylformamide, and the like or a mixture thereof) and preferably by using dichloromethane. The reaction may take place in the presence of a base (e.g. triethylamine, potassium carbonate, diisopropylethylamine and pyridine) and is preferably by using triethylamine. The reaction was carried out at room temperature. The reaction may last for 15 to 45 minutes, preferably 25 to 35 minutes.

In the second step of the above preparation, the compound of formula (7) is brominated to form the compound of formula (8). The reaction may take place in the presence of an acid (e.g., sulfuric acid, acetic acid, perchloric acid, hydrochloric acid, and the like, or mixtures thereof) and is preferably by using acetic acid. The reaction may take place in the presence of a brominating agent (e.g., bromine, copper (II) bromide, hydrobromic acid, N-bromosuccinimide, pyridinium perbromide, tetrabromomethane, and the like, or mixtures thereof) and preferably by using bromine. The reaction was carried out at room temperature. The reaction may last for 16 to 20 hours, preferably 17 to 19 hours.

In the third step of the above preparation, the compound of formula (8) is cyclized to form the compound of formula (9). The reaction is preferably carried out in a solvent (e.g., isopropanol, tetrahydrofuran, toluene, ethyl acetate, dichloromethane, triethylamine, dimethylformamide, etc., or a mixture thereof) and preferably by using isopropanol. The reaction may take place in the presence of urea or thiourea. The reaction is carried out at a temperature of 60 ℃ to 85 ℃ and preferably at a temperature of 65 ℃ to 75 ℃. The reaction may last for 15 to 45 minutes, preferably 25 to 35 minutes.

In the fourth step of the above preparation, the compound of formula (9) is diazotized to form the compound of formula (10). The reaction is preferably carried out in a solvent (e.g., acetonitrile, tetrahydrofuran, isopropanol, toluene, ethyl acetate, dichloromethane, triethylamine, dimethylformamide, etc., or a mixture thereof) and preferably by using acetonitrile. The reaction may take place in the presence of a brominating agent (e.g., copper (II) bromide, hydrobromic acid, N-bromosuccinimide, pyridinium perbromide, tetrabromomethane, and the like, or mixtures thereof) and preferably by using copper (II) bromide. The reaction can take place in the presence of alkyl nitrites and preferably by using tert-butyl nitrite. The reaction was carried out at room temperature. The reaction may last for 15 to 45 minutes, preferably 25 to 35 minutes.

In the fifth step of the above preparation, the compound of formula (10) is coupled with the compound of formula (2) to form the compound of formula (I). The reaction is preferably carried out in a solvent (e.g., tetrahydrofuran, toluene, ethyl acetate, dichloromethane, triethylamine, dimethylformamide, etc., or a mixture thereof) and preferably by using tetrahydrofuran. The reaction may take place in the presence of a base (e.g. sodium hydride, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide or mixtures thereof) and preferably by using sodium hydride. The reaction may take place in the presence of urea or thiourea. The reaction is carried out at a temperature of 60 ℃ to 85 ℃ and preferably at a temperature of 65 ℃ to 75 ℃. The reaction may last for 12 to 18 hours, preferably 14 to 16 hours.

The compounds of formula (2), formula (5) and formula (6) are commercially available or can be prepared by conventional methods or by modification using known procedures.

Compounds of formula (I) can also be prepared by using scheme III below

Scheme III

In scheme III above, p is 1; q is 1; r is 1; y is C; x is S; r₁Is thatAnd all other symbols are as described above.

Coupling a compound of formula (11) with a compound of formula (5) to form a compound of formula (12). Coupling a compound of formula (12) with a compound of formula (2) to form a compound of formula (I).

In the first step of the above preparation, a compound of formula (11) is coupled with a compound of formula (5) to form a compound of formula (12). The reaction is preferably carried out in a solvent (e.g., tetrahydrofuran, toluene, ethyl acetate, dichloromethane, dimethylformamide, and the like or a mixture thereof) and preferably by using dichloromethane. The reaction may take place in the presence of a base (e.g. triethylamine, potassium carbonate, diisopropylethylamine and pyridine) and is preferably by using triethylamine. The reaction was carried out at room temperature. The reaction may last for 15 to 45 minutes, preferably 25 to 35 minutes.

In the second step of the above preparation, the compound of formula (12) is coupled with the compound of formula (2) to form the compound of formula (I). The reaction is preferably carried out in a solvent (e.g., tetrahydrofuran, toluene, ethyl acetate, dichloromethane, triethylamine, dimethylformamide, etc., or a mixture thereof) and preferably by using dimethylformamide. The reaction may take place in the presence of a base (e.g. sodium hydride, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide or mixtures thereof) and preferably by using sodium hydride. The reaction was carried out at room temperature. The reaction may last for 45 to 51 hours, preferably 47 to 49 hours.

The compounds of formula (2), formula (5) and formula (11) are commercially available or can be prepared by conventional methods or by modification using known procedures.

If necessary, any one or more than one of the following steps may be performed,

i) converting a compound of formula (I) into another compound of formula (I) or

ii) forming a pharmaceutically acceptable salt.

Process (i) can be carried out by further chemical modification using well-known reactions such as oxidation, reduction, protection, deprotection, rearrangement, halogenation, hydroxylation, alkylation, alkylthio, demethylation, O-alkylation, O-acylation, N-alkylation, N-alkenylation, N-acylation, N-cyanation, N-sulfonylation, coupling reactions using transition metals, and the like.

In process (ii), the pharmaceutically acceptable salts can be conveniently prepared by reaction with the appropriate acid or acid derivative.

Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art and include those described in j.pharm.sci., 1977, 66, 1-19, for example, acid addition salts formed with inorganic acids (e.g., hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acids) and organic acids (e.g., succinic, maleic, acetic, fumaric, citric, malic, tartaric, benzoic, p-toluic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acids).

Pharmaceutically acceptable salts forming part of the invention may be prepared by treating a compound of formula (I) with 1 to 6 equivalents of a base such as sodium hydride, sodium methoxide, sodium ethoxide, sodium hydroxide, potassium tert-butoxide, calcium hydroxide, calcium acetate, calcium chloride, magnesium hydroxide, magnesium chloride and the like. Solvents which can be used are, for example, water, acetone, diethyl ether, THF, methanol, ethanol, tert-butanol, diAn alkane, isopropanol, isopropyl ether, or a mixture thereof.

Examples

The novel compounds of the present invention were prepared according to the following experimental procedures, using the appropriate materials and the appropriate conditions.

Preparation 1: preparation of tert-butyl 2-bromo-6, 7-dihydro-4H-thiazolo [5,4-c ] pyridine-5-carboxylate

Step (i): preparation of 3-bromo-4-oxo-piperidine-1-carboxylic acid tert-butyl ester

A solution of tert-butyl 4-oxo-piperidine-1-carboxylate (10 g, 50mmol) and aluminum chloride (0.67 g, 5mmol) in tetrahydrofuran (30mL) and diethyl ether (30mL) was cooled to 0 deg.C before treatment with bromine (2.6mL, 50mmol) for 30 min. The reaction mass was stirred at 0-5 ℃ for 24 hours. After completion of the reaction, the obtained solid was filtered, followed by concentrating the mother liquor under vacuum. The obtained crude material was pulverized with diethyl ether, and the solid was filtered and dried under vacuum to obtain the title compound (10 g).

¹H-NMR(ppm)：1.51(9H，s)，2.42-2.48(1H，m)，3.04(1H，m)，3.59-3.74(2H，m)，3.97(2H，m)，4.33(1H，m)；

Mass(m/z)：278(M+H)⁺，280(M+3H)⁺.

Step (ii): preparation of tert-butyl 2-amino-6, 7-dihydro-4H-thiazolo [5,4-c ] pyridine-5-carboxylate

A suspension of 3-bromo-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (10 g, 35mmol, obtained in the above step) and thiourea (3.28 g, 42mmol) in isopropanol (100mL) was refluxed for 1 hour. After completion of the reaction, the reaction mass was concentrated and the resulting crude material was triturated with ether (50mL), the solid was filtered and dried under vacuum to obtain the title compound (10 g).

¹H-NMR(ppm)：1.39(9H，s)，2.52(2H，m)，3.56-3.59(2H，t)，4.30(2H，s)，7.10(2H，bs)；Mass(m/z)：256(M+H)⁺.

Step (iii): preparation of tert-butyl 2-bromo-6, 7-hydro-4H-thiazolo [5,4-c ] pyridine-5-carboxylate

A solution of tert-butyl 2-amino-6, 7-dihydro-4H-thiazolo [5,4-c ] pyridine-5-carboxylate (10 g, 40mmol, obtained in the above step) and copper (II) bromide (9.6 g, 43mmol) in acetonitrile (50mL) was cooled to 0 ℃. Tert-butyl nitrite (5.1mL, 43mmol) was added dropwise over 30 min at 0 ℃. The reaction mass was allowed to stir for 30 minutes and then quenched with 6N hydrochloric acid solution. The product was extracted with ethyl acetate (3 × 100mL), and the combined organic layers were washed with water and then brine, followed by drying over anhydrous sodium sulfate. The organic volatiles were evaporated under vacuum. The obtained residue was purified by flash chromatography (ethyl acetate/n-hexane, 0.5/9.5) to obtain the title compound (3.0 g).

¹H-NMR(ppm)：1.49(9H，s)，2.85(2H，m)，3.72(2H，m)，4.56(2H，s)；

Mass(m/z)：319.3(M+H)⁺，321.3(M+H)⁺.

Preparation 2: preparation of (2-bromo-4, 5,6, 7-tetrahydro-benzothiazol-6-yl) -carbamic acid tert-butyl ester

Step (i): preparation of (3-bromo-4-oxo-cyclohexyl) -carbamic acid tert-butyl ester

A solution of (4-oxo-cyclohexyl) -carbamic acid tert-butyl ester (10 g, 46mmol) and aluminum chloride (0.25 g, 2mmol) in tetrahydrofuran (30mL) and diethyl ether (30mL) was cooled to 0 ℃ before treatment with bromine (2.4mL, 46mmol) for 30 min. The reaction mass was stirred at 0-5 ℃ for 24 hours. After completion of the reaction, the obtained solid was filtered, and then the lower filtrate was concentrated under vacuum. The obtained crude material was pulverized with diethyl ether, and the resulting solid was filtered and dried under vacuum to obtain the title compound (9.0 g).

Mass(m/z)：292.3(M+H)⁺，294.3(M+3H)⁺.

Step (ii): preparation of 2-amino-4, 5,6, 7-tetrahydro-benzothiazol-6-yl) -carbamic acid tert-butyl ester

A suspension of 3-bromo-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (9 g, 31mmol, obtained in the above step) and thiourea (2.4 g, 31mmol) in isopropanol (100mL) was refluxed for 1 hour. After completion of the reaction, the reaction mass was concentrated and the resulting crude material was triturated with ether (50mL), the solid was filtered and dried under vacuum to obtain the title compound (9 g).

¹H-NMR(ppm)：1.38(9H，s)，1.61-1.71(1H，m)，1.84-1.86(1H，m)，2.29-2.35(1H，m)，2.53-2.57(2H，m)，2.71-2.76(1H，m)，3.71-3.76(1H，m)，9.11(2H，s)，12.86-12.93(1H，bs)；

Mass(m/z)：270.3(M+H)⁺.

Step (iii): preparation of (2-bromo-4, 5,6, 7-tetrahydro-benzothiazol-6-yl) -carbamic acid tert-butyl ester

A solution of 2-amino-4, 5,6, 7-tetrahydro-benzothiazol-6-yl) -carbamic acid tert-butyl ester (9 g, 33mmol, obtained in the above step) and brominated ketone (II) (8.3 g, 37mmol) in acetonitrile (70mL) was cooled to 0 ℃. The resulting material was treated with tert-butyl nitrite (4.5mL, 37mmol) at 0 ℃ for 30 min. The reaction mass was stirred for 30 minutes and then quenched with 6N hydrochloric acid solution. The product was extracted with ethyl acetate (3 × 100mL), and the combined organic layers were washed with water and then brine, followed by drying over anhydrous sodium sulfate. The organic volatiles were evaporated under vacuum. The residue was purified by flash chromatography (ethyl acetate/n-hexane, 0.5/9.5) to obtain the title compound (2.3 g).

¹H-NMR(ppm)：1.45(9H，s)，1.89-1.93(1H，m)，2.03-2.07(1H，m)，2.59-2.63(1H，m)，2.85-2.91(1H，m)，3.09-3.13(1H，m)，4.05-4.09(1H，m)，4.63-4.66(1H，m)，12.36-12.42(1H，bs)；

Mass(m/z)：333.1(M+H)⁺，335.3(M+3H)⁺.

Example 1: preparation of 1- [2- (1-cyclobutyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -propan-1-one tartrate

Step (i): preparation of tert-butyl 2- (1-cyclobutyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridine-5-carboxylate

Slowly treat 1-cyclobutyl-piperidin-4-ol (1.6 g, 10mmol) in tetrahydrofuran (20mL) with a cooled and stirred suspension of sodium hydride (0.9 g, 18mmol) in tetrahydrofuran (20mL) for 30 min; the reaction mixture was stirred for 1 hour. A solution of tert-butyl 2-bromo-6, 7-dihydro-4H-thiazolo [5,4-c ] pyridine-5-carboxylate (3 g, 9mmol, obtained in preparation 1) in tetrahydrofuran (30mL) was added dropwise over 15 minutes and the reaction was refluxed for 6 hours. The reaction mass was quenched with ice-cold water and the product was extracted with ethyl acetate (3X 50 mL). The combined organic layers were washed with water and then brine, and then dried over anhydrous sodium sulfate. The organic volatiles were evaporated under vacuum. The residue was purified by flash chromatography (ethyl acetate/n-hexane, 1/1) to obtain the title compound (2.0 g).

¹H-NMR(ppm)：1.48(9H，s)，1.65-1.72(2H，m)，1.85-1.92(4H，m)，2.01-2.07(4H，m)，2.18-2.19(2H，m)，2.57(2H，m)，2.62-2.66(2H，m)，2.71-2.75(1H，m)，3.70(2H，m)，4.43(2H，m)，4.93(1H，m)；

Mass(m/z)：394.2(M+H)⁺.

Step (ii): preparation of 2- (1-cyclobutyl-piperidin-4-yloxy) -4,5,6, 7-tetrahydro-thiazolo [5,4-c ] pyridine

A solution of tert-butyl 2- (1-cyclobutyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridine-5-carboxylate (2.0 g, 5mmol, obtained in the above step) in dichloromethane (30mL) was treated with trifluoroacetic acid (5.0mL, 50mmol) at 0 ℃. The reaction mass was allowed to stir for 4 hours. After completion of the reaction, the reaction mass was quenched in ice-cold water and the pH was adjusted to 10 by using 40% aqueous sodium hydroxide solution. The product was extracted with dichloromethane (3 × 50mL), and the combined organic layers were washed with water and then brine, followed by drying over anhydrous sodium sulfate. The organic volatiles were evaporated under vacuum to give the title compound (1.3 g).

¹H-NMR(ppm)：1.68-1.74(2H，m)，1.85-1.93(4H，m)，2.06(4H，m)，2.19(2H，m)，2.60-2.61(4H，m)，2.73-2.80(1H，m)，2.90-3.10(1H，m)，3.13-3.16(2H，m)，3.85(2H，s)，4.90-4.93(1H，m)；

Mass(m/z)：294.2(M+H)⁺.

Step (iii): preparation of 1- [2- (1-cyclobutyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -propan-1-one

A solution of 2- (1-cyclobutyl-piperidin-4-yloxy) -4,5,6, 7-tetrahydro-thiazolo [5,4-c ] pyridine (1.3 g, 4mmol, obtained in the above step) and triethylamine (1.9mL, 13mmol) in dichloromethane (30mL) was cooled to 0 ℃. Propionyl chloride (0.4mL, 5mmol) in dichloromethane (5mL) was added dropwise over 15 min and the reaction was stirred for 30 min. The reaction mass was poured onto ice water and the product was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with water and then brine, and then dried over anhydrous sodium sulfate. The organic volatiles were evaporated under vacuum. The residue was purified by flash chromatography (methanol/chloroform, 2/98) to obtain the title compound (1.0 g).

¹H-NMR(ppm)：1.17-1.21(3H，m)，1.65-1.72(5H，m)，1.87-1.91(4H，m)，2.01-2.07(4H，m)，2.22(1H，m)，2.38-2.45(2H，m)，2.45(1H，m)，2.68-2.76(3H，m)，3.72-3.74(1H，m)，4.47-4.62(2H，m)，4.92-4.94(1H，m).

Mass(m/z)：350.4(M+H)⁺.

Step (iv): preparation of 1- [2- (1-cyclobutyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -propan-1-one tartrate

A solution of 1- [2- (1-cyclobutyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -propan-1-one (0.8 g, 2.3mmol, obtained in the above step) in methanol (10mL) was treated with L (+) -tartaric acid (0.34 g, 2.3mmol) at 0 ℃. The reaction mass was allowed to stir for about 1 hour, then the solvent was evaporated to dryness under vacuum. The solid was washed with diethyl ether and dried under vacuum to obtain the title compound (1.1 g).

¹H-NMR(ppm)：1.12-1.20(3H，m)，1.82-1.87(2H，m)，2.16-2.32(7H，m)，2.45-2.55(2H，m)，2.63-2.66(3H，m)，2.72(1H，m)，3.20(2H，m)，3.47-3.50(1H，m)，3.66-3.70(1H，m)，3.81-3.88(2H，m)，4.45(2H，s)，4.60(2H，s)，5.18(5H，m);

Mass(m/z)：350.4(M+H)⁺.

Example 2: [2- (4-cyclobutyl-cyclohexyloxy) -4,5,7, 8-tetrahydro-thiazolo [5,4-d ]]Aza derivatives-6-yl]Preparation of (E) -cyclopropyl-methanone tartrate

Step (i): preparation of 1-cyclopropylformyl-azepan-4-one

A solution of azepan-4-one (1.75 g, 15.3mmol) and triethylamine (6.45mL, 3.1mmol) in dichloromethane (15mL) was cooled to 0 ℃. Propionyl chloride (0.17mL, 1.8mmol) in dichloromethane (2mL) was added and the reaction stirred for 30 min. The reaction mass was poured onto ice-cold water and the product was extracted with dichloromethane (3 × 15 mL). The combined organic layers were washed with water and then brine, and then dried over anhydrous sodium sulfate. The organic volatiles were evaporated under vacuum to give the title compound (2.7 g).

¹H-NMR(ppm)：0.66-0.69(4H，m)，1.56-1.57(1H，m)，1.71-1.75(1H，m)，1.87-1.89(1H，m)，2.45-2.49(1H，m)，2.59-2.62(1H，m)，3.57-3.91(4H，m)；

Mass(m/z)：182(M+H)⁺.

Step (ii): preparation of 5-bromo-1-cyclopropylformyl-azepan-4-one

A solution of 1-cyclopropylformyl-azepin-4-one (2.7 g, 14.9mmol, obtained in the above step) in acetic acid (30mL) was cooled to 10 ℃ and then treated with bromine (0.71mL, 14.9mmol) for 15 min. The resulting slurry was stirred under nitrogen for 18 hours. After completion of the reaction, the material was concentrated to dryness to obtain the title compound (3.87 g).

Mass(m/z)：260，262(M+H)⁺.

Step (iii):(2-amino-4, 5,7, 8-tetrahydro-thiazolo [5, 4-d)]Aza derivativesPreparation of (E) -6-yl-cyclopropyl-methanone

A suspension of 5-bromo-1-cyclopropylformyl-azepin-4-one (3.87 g, 14.8mmol, obtained in the above step) and thiourea (1.13 g, 14.8mmol) in isopropanol (40mL) was refluxed for 6 hours. After completion of the reaction, the reaction mass was concentrated, and the obtained residue was purified by flash chromatography (methanol/chloroform, 3/97) to obtain the title compound (0.4 g).

¹H-NMR(ppm)：0.66-0.73(4H，m)，1.95(1H，m)，2.66-2.69(2H，m)，2.75-2.76(2H，m)，3.55-3.62(2H，m)，3.79-3.86(2H，m)，6.61(2H，bs)；

Mass(m/z)：238(M+H)⁺.

Step (vi): (2-bromo-4, 5,7, 8-tetrahydro-thiazolo [5, 4-d)]Aza derivativesPreparation of (E) -6-yl-cyclopropyl-methanone

Reacting (2-amino-4, 5,7, 8-tetrahydro-thiazolo [5,4-d ]]Aza derivativesA solution of-6-yl) -cyclopropyl-methanone (0.4 g, 1.68mmol, obtained in the above step) and copper (II) bromide (0.37 g, 1.68mmol) in acetonitrile (40mL) was cooled to 0 ℃. Tert-butyl nitrite (0.2mL, 1.68mmol) was added dropwise over 10 min at 0 ℃. The reaction mass was allowed to stir for 30 minutes and then quenched with 3N hydrochloric acid solution. The product was extracted with ethyl acetate (3 × 15mL), and the combined organic layers were washed with water and then brine, followed by drying over sodium sulfate. The organic volatiles were evaporated under vacuum. The residue thus obtained was purified by flash chromatography (ethyl acetate/n-hexane, 7/3) to obtain the title compound (0.053 g).

¹H-NMR(ppm)：0.71-0.75(4H，m)，1.97(1H，m)，2.86-2.92(2H，m)，2.99-3.08(2H，m)，3.61-3.86(2H，m)，3.86-3.90(2H，m)；

Mass(m/z)：301(M+H)⁺.

Step (v): [2- (4-Cyclobutylpiperidin-4-yl-oxy) -4,5,7, 8-tetrahydro-thiazolo [5,4-d ]]Aza derivatives-6-yl]Preparation of-cyclopropyl-methanone

1-cyclobutyl-piperidin-4-ol (0.04 g, 0.26mmol) in tetrahydrofuran (3mL) was slowly treated with a cooled and stirred suspension of sodium hydride (0.021 g, 0.51mmol) in tetrahydrofuran (8mL) for 5 min, and then the reaction mixture was stirred at room temperature for 2 h. (2-bromo-4, 5,7, 8-tetrahydro-thiazolo [5,4-d ] was added dropwise over 5 minutes]Aza derivatives-6-yl) -cyclopropyl-methanone (0.053 g, 0.17mmol, obtained in the above step) in tetrahydrofuran (3mL) and refluxed for 15 hours. The reaction mass was quenched on ice-cold water and the product was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with water and then brine, and then dried over anhydrous sodium sulfate. The organic volatiles were evaporated under vacuum. The obtained residue was purified by flash chromatography (methanol/chloroform, 3/97) to obtain the title compound (0.05 g).

¹H-NMR(ppm)：0.84-0.86(4H，m)，0.91(1H，m)，1.73-1.76(2H，m)，1.86-1.93(4H，m)，2.07-2.08(5H，m)，2.63(2H，m)，2.80-2.84(2H，m)，2.93-2.99(3H，m)，3.74-3.79(2H，m)，3.94-4.00(2H，m).

Mass(m/z)：376.4(M+H)⁺.

Step (vi): [2- (1-cyclobutyl-piperidin-4-yloxy) -4,5,7, 8-tetrahydro-thiazolo [5,4-d ]]Aza derivatives-6-yl]Preparation of (E) -cyclopropyl-methanone tartrate

Treatment of [2- (4-cyclobutyl-cyclohexyloxy) -4,5,7, 8-tetrahydro-thiazolo [5,4-d ] with L (+) -tartaric acid (0.031 g, 0.208mmol) at 0 deg.C]Aza derivatives-6-yl]-a solution of cyclopropyl-methanone (0.078 g, 0.208mmol, obtained in the above step) in methanol (5 mL). The reaction mass was allowed to stir for about 1 hour, then the solvent was evaporated to dryness under vacuum. The solid was washed with diethyl ether and dried under vacuum to obtain the title compound (0.1 g).

¹H-NMR(ppm)：0.84-0.99(4H，m)，1.83-1.90(2H，m)，2.00-2.02(1H，m)，2.18-2.23(5H，m)，2.32-2.41(2H，m)，2.82-2.87(2H，m)，2.95-2.99(2H，m)，3.13-3.20(5H，m)，3.62-3.66(1H，m)，3.74-3.79(2H，m)，3.95-3.99(2H，m)，4.43(2H，s)，5.13(1H，s).

Mass(m/z)：376.4(M+H)⁺.

Example 3: preparation of N- [2- (1-cyclobutyl-piperidin-4-yloxy) -4,5,6, 7-tetrahydro-benzothiazol-6-yl ] -propionamide

Step (i): preparation of 2-bromo-4, 5,6, 7-tetrahydro-benzothiazol-6-ylamine

A solution of (2-bromo-4, 5,6, 7-tetrahydro-benzothiazol-6-yl) -carbamic acid tert-butyl ester (0.50 g, 1.5mmol, obtained in preparation 2) in dichloromethane (30mL) was treated with trifluoroacetic acid (1.1mL, 15mmol) at 0 ℃. The reaction mass was allowed to stir for 4 hours. After completion of the reaction, the mass was quenched with ice-cold water, and then the pH was adjusted to 10 by using 40% aqueous sodium hydroxide solution. The product was extracted with dichloromethane (3 × 50mL), and the combined organic layers were washed with water and then brine, followed by drying over anhydrous sodium sulfate. The organic volatiles were evaporated under vacuum to give the title compound (0.36 g).

Mass(m/z)：233.0(M+H)⁺，235.0(M+3H)⁺.

Step (ii): preparation of N- (2-bromo-4, 5,6, 7-tetrahydro-benzothiazol-6-yl) -propionamide

A solution of 2-bromo-4, 5,6, 7-tetrahydro-benzothiazol-6-ylamine (0.36 g, 1.5mmol, obtained in the above step) and triethylamine (0.43mL, mmol) in dichloromethane (15mL) was cooled to 0 ℃. Propionyl chloride (0.17mL, 1.8mmol) in dichloromethane (2mL) was added, then the reaction mass was stirred for 30 min. After completion of the reaction, the material was poured onto ice-cold water and the product was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were washed with water and then brine, dried over anhydrous sodium sulfate, and the organic volatiles were evaporated under vacuum. The residue was purified by flash chromatography (methanol/chloroform, 2/98) to obtain the title compound (0.4 g).

¹H-NMR(ppm)：0.81-0.85(1H，m)，1.14-1.18(3H，m)，1.20-1.28(2H，m)，1.90-1.96(1H，m)，2.02-2.05(1H，m)，2.18-2.23(2H，m)，2.57-2.63(1H，m)，2.86-2.91(1H，m)，3.10-3.15(1H，m)；

Mass(m/z)：289.2(M+H)⁺，291.2(M+3H)⁺.

Step (iii): preparation of N- [2- (1-cyclobutyl-piperidin-4-yloxy) -4,5,6, 7-tetrahydro-benzothiazol-6-yl ] -propionamide

1-cyclobutyl-piperidin-4-ol (0.25 g, 1.6mmol) in N, N-dimethylformamide (5mL) was slowly treated with a cooled and stirred suspension of sodium hydride (0.1 g, 2.08mmol) in N, N-dimethylformamide (10mL) for 30 min, after which the reaction mixture was stirred for an additional 1 h. A solution of N-2-bromo-4, 5,6, 7-tetrahydro-benzothiazol-6-yl) -propionamide (0.4 g, 1.3mmol, obtained in the above step) in N, N-dimethylformamide (5mL) was added dropwise over 10 minutes and the resulting mass was stirred for 48 hours. After completion of the reaction, the mass was quenched on ice-cold water and the product was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were washed with water and then brine, dried over anhydrous sodium sulfate, and the organic volatiles were evaporated under vacuum. The residue was purified by flash chromatography (ethyl acetate/n-hexane, 1/1) to obtain the title compound (0.068 g).

¹H-NMR(ppm)：0.81-0.88(2H，m)，1.14-1.18(3H，m)，1.65-1.70(2H，m)，1.89-1.91(5H，m)，2.03-2.05(5H，m)，2.17-2.23(3H，m)，2.49-2.75(4H，m)，2.96-3.01(2H，m)，4.35-4.39(1H，m)，4.90-3.96(1H，m)，5.50-5.53(1H，m)；

Mass(m/z)：364.3(M+H)⁺.

Examples 4 to 34:

the compounds of examples 4-34 were prepared by following the procedures described in examples 1-3 with some non-critical variations.

Examples 35 to 66:

the compounds of examples 35-66 can be prepared by one skilled in the art according to the procedures described above.

Biological assay

Example 67: human or rat histamine H₃Receptor binding and functional assays

Compounds can be evaluated according to the following procedure.

Materials and methods:

the receptor source is as follows: recombinant human cDNA expressed in rat brain frontal cortex or CHO cell

A radioligand: [³H]R-alpha-methyl histamine

Final ligand concentration- [3.0nM ]

Non-specific determinants: r-alpha-methyl histamine (100. mu.M)

Reference compound: r-alpha-methyl histamine

Positive control: r-alpha-methyl histamine

Incubation conditions were as follows:

test compounds or standards were mixed with 5mM MgCl at room temperature₂And membrane receptor and release in 50mM TRIS-HCl (pH7.4)The radioligands were incubated for 60 min. The reaction was terminated by rapid vacuum filtration onto a glass fiber filter. The radioactivity trapped on the filter is determined and compared to control values to determine any interaction of the test compound with the cloned human or rat receptor binding site.

Example numbering	Ki(nM)
		1.	3.83
2.	2.0
		3.	26.67
4.	7.2
		5.	3.3
6.	13.4
		7.	10.5
8.	7.69
		9.	9.94
10.	5.43
		11.	11.98
12.	8.44
		14.	23.6
16.	33.55
		17.	21.2
18.	6.96
		19.	12.28

20.	7.4
		21.	22.6
22.	9.5
		23.	0.3
25.	35.33
		26.	32.54
27.	0.75
		28.	38.96
29.	11.3
		30.	4.19
31.	1.62
		32.	4.6
33.	15.45
		34.	15.6

Reference to the literature: millipore data sheet

Example 68: pharmacokinetic Studies in rodents

Male Wistar rats (230- & 280g) obtained from NIN (National Institute of Nutrition), Hyderabad, India were used as experimental animals. Each cage contained 3 animals. Animals were kept fasted overnight and maintained with a 12 hour light/dark cycle. Three rats were dosed orally (3 or 10mg/kg) and intravenously (1 or 5mg/kg) with the New Chemical Entity (NCE) on days 0 and 2.

At each time point, blood was collected via the jugular vein. The blood was stored at 2-8 ℃ until analysis. The concentration of NCE compounds in blood was determined using LC-MS/MS method. The preset time point is as follows: before administration, 0.08, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after administration (n ═ 3). NCE compounds were quantified in blood by partially validated LC-MS/MS method using acetonitrile precipitation technique. In blood, NCE compounds were quantified in a calibrated range of 1-2000 ng/mL. The study samples were analyzed using an intra-lot calibration sample and an inter-lot quality control sample.

Pharmacokinetic parameters were calculated by a non-compartmental model (non-comparative model) using software WinNonlin version 5.0.1.

Example 69: brain penetration study in rodents

Male Wistar rats (230- "280 g") obtained from NIN (national academy of Nutrition, Hyderabad, India) were used as experimental animals. Each cage contained 3 animals. Animal water and food were given ad libitum throughout the experiment and maintained for a 12 hour light-dark period.

The New Chemical Entity (NCE) was dissolved in a suitable vehicle and administered orally (3 or 10 mg/kg). At about T_max(i.e., 0.5 hours, 1.0 hour, and 2.0 hours) animals were sacrificed. Blood and brain tissue were collected and the brain was homogenized to yield 20% w/v. Blood was stored at 2-8 ℃ and brain homogenate was frozen at-20 ℃ until analysis. The concentration of NCE in blood and brain was quantified using the LC-MS/MS method.

NCE was quantified in blood and brain homogenates by a partially validated LC-MS/MS method using acetonitrile precipitation technique. NCE compounds were quantified in blood and brain homogenates over a calibrated range of 1-500 ng/mL. The study samples were analyzed using an intra-lot calibration sample and an inter-lot quality control sample. Calculating the range of brain-blood ratios (C)_b/C_p)。

Example 70: object recognition task model

The cognitive enhancing properties of the compounds of the invention were evaluated by using this model.

Male Wistar rats (230-. Each cage contained 4 animals. Animals were kept 20% food deprived a day before and given ad libitum throughout the experiment with water and maintained for a 12 hour light-dark period. In addition, rat animals were habituated to each field (arena) for 1 hour without any object present.

One group of 12 rats received vehicle (1mL/Kg) orally and another group of animals received compound of formula (I) orally or intraperitoneally (i.p.) 1 hour prior to familiarity (T1) and selection trial (T2).

The experiments were performed in a 50X 50cm open field (open field) made of acrylic acid. In the familiarity phase (T1), rats were each placed in an open field for 3 minutes, with two identical objects (plastic bottles, 12.5cm height x 5.5cm diameter) (a1 and a2) individually covered with yellow masking tape placed at two adjacent corners, 10cm from the wall. After 24 hours of the (T1) test of the long-term memory test, the same batch of rats was placed in the same field as they were placed in the T1 test. The phase (T2) was chosen such that the rat probed the agoraph for 3 minutes in the presence of a familiar object (a3) and a new object (b) (amber glass bottle, 12cm high and 5cm diameter). Familiar objects exhibit similar texture, color and size. During the T1 and T2 trials, the exploration of each object (defined as sniffing, licking, chewing, or moving the whisker while directing the nose toward the object at a distance of less than 1 cm) was recorded separately by a stopwatch. Sitting on an object is not considered an exploratory act, but is rarely observed.

T1 is the total time it takes to explore the familiar object (a1+ a 2).

T2 is the total time it takes to explore familiar objects and new objects (a3+ b).

Object recognition tests were performed as described by Ennaceur, A., Delaour, J., 1988, A new one-tertiary test for neurological students of memory in rates-Behavioural data, Behav. Brain Res., 31, 47-59.

Example 71: morris (Morris) water maze

The cognitive enhancing properties of the compounds of the invention were evaluated by using this model.

A water maze set up of a circulating pool (1.8m diameter, 0.6m height) constructed in plexiglas black (Perspex) was filled with water (24. + -. 2 ℃) and placed under a wide angle camera (TSE systems, Germany) to track the animals. Will be located 1cm below the water surface by 10cm²The plexiglass platform was placed in the center of one of the four imaginary quadrants (imaginary quadrants), which remained stationary for all rats. The black perspex used to construct the maze and platform did not provide an in-maze cue to guide escape behavior. In contrast, the training room provides several strong extramaze visual cues to help form the spatial map necessary for escape learning. Using an automatic tracking System [ Videomoto 2(5.51), TSE systems, Germany]. The program analyzes the video images taken via the digital camera and image capture board to determine the path length, swim speed and number of entries and swim duration spent in each quadrant of the water maze.

Example numbering	Reversal of scopolamine-induced amnesia
		1.	Less than or equal to 10mg/kg, orally taken
4.	Less than or equal to 10mmg/kg, is taken orally
		5.	Less than or equal to 3mmg/kg, is taken orally
12.	Not less than 20mg/kg, and can be administered orally
		28.	Not less than 10mg/kg, orally administered

Example 72: inhibition of food intake

The anti-obesity properties of the compounds of the invention were assessed by using this model.

The experiment consisted of 6 days. Rats were acclimatized to an 18 hour fasting and 6 hour feeding regimen. Animals were loaded in groups of 3 in cages fitted with a fasting grid (fasting grill) and fasted for 18 hours. After 18 hours fasting, rats were divided and individually placed in cages. The rats were provided with a weighed amount of food for 6 hours, and food intake was measured at 1 hour, 2 hours, 4 hours, and 6 hours.

Rats were regrouped and fasted for 18 hours. The procedure was followed for 5 days. The average cumulative food intake of the rats on the last 3 days was calculated. Animals were randomized on the basis of their food intake 3 days prior. On the day of the experiment, rats were treated orally with test compound or vehicle. After 60 minutes, rats were provided with food and food intake was measured at 1 hour, 2 hours, 4 hours and 6 hours. Food intake of rats treated with test compounds was compared to vehicle treated groups by using Unpaired t-test (Unpaired Student's t test).

Example numbering	Inhibition of food intake
		4.	20mmg/kg，p.o.

Claims (12)

1. A compound of the general formula (I):

wherein the content of the first and second substances,

R₁is that

R₂Is isopropyl, isobutyl, cyclopropyl or cyclobutyl;

R₃is hydrogen;

x is S;

y is N;

"p" is the integer 1;

"q" is an integer from 1 to 2;

"r" is an integer of 1.

2. The compound according to claim 1, selected from:

1- [2- (1-cyclobutyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -propan-1-one tartrate;

[2- (4-cyclobutyl-cyclohexyloxy) -4,5,7, 8-tetrahydro-thiazolo [5,4-d ]]Aza derivatives-6-yl]-cyclopropyl-methanone tartrate;

[2- (1-cyclobutyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -cyclopropyl-methanone tartrate;

cyclobutyl- [2- (1-cyclobutyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -methanone tartrate;

[2- (1-cyclobutyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] - (2-fluoro-phenyl) -methanone tartrate;

1- [2- (1-cyclobutyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -3-methyl-butan-1-one tartrate;

cyclobutyl- [2- (1-isopropyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -methanone;

cyclopropyl- [2- (1-isopropyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -methanone tartrate;

cyclopropyl- [2- (1-cyclopropyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -methanone tartrate;

cyclobutyl- [2- (1-cyclopropyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -methanone tartrate;

1- [2- (1-cyclobutyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -2-morpholin-4-yl-ethanone tartrate;

[4- (5-cyclobutyl-4, 5,6, 7-tetrahydro-4H-thiazolo [5,4-c ] pyridin-2-yloxy) -piperidin-1-yl ] -cyclopropyl-methanone tartrate;

[3- (5-cyclobutyl-4, 5,6, 7-tetrahydro-4H-thiazolo [5,4-c ] pyridin-2-yloxy) -piperidin-1-yl ] -cyclopropyl-methanone tartrate;

[2- (1-cyclobutyl-piperidin-3-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -cyclopropyl-methanone tartrate;

[2- (1-cyclobutyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -pyridin-4-yl-methanone tartrate;

[2- (1-cyclobutyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] - (4-methoxy-phenyl) -methanone tartrate;

1- [2- (1-cyclobutyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -2-piperidin-1-yl-ethanone tartrate;

1- [2- (1-cyclobutyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -2-cyclopropyl-ethanone;

2- (1-cyclobutyl-piperidin-4-yloxy) -5- (2-fluoro-benzenesulfonyl) -4,5,6, 7-tetrahydro-thiazolo [5,4-c ] pyridine tartrate;

2- (1-cyclobutyl-piperidin-4-yloxy) -5-methanesulfonyl-4, 5,6, 7-tetrahydro-thiazolo [5,4-c ] pyridine;

1- [2- (1-cyclobutyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -2-methyl-propan-1-one tartrate;

2- (1-cyclobutyl-piperidin-4-yloxy) -5- (6-trifluoromethyl-pyridin-3-yl) -4,5,6, 7-tetrahydro-thiazolo [5,4-c ] pyridine;

cyclopropyl- [2- (1-isobutyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -methanone tartrate;

[2- (1-cyclobutyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] - (6-trifluoromethyl-pyridin-3-yl) -methanone;

[2- (1-cyclobutyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -pyridin-3-yl-methanone tartrate;

2- (1-cyclobutyl-piperidin-4-yloxy) -5-pyridin-3-yl-4, 5,6, 7-tetrahydro-thiazolo [5,4-c ] pyridine tartrate;

[2- (1-cyclobutyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] - (tetrahydro-pyran-4-yl) -methanone;

[2- (1-cyclobutyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -morpholin-4-yl-methanone tartrate;

[2- (1-cyclobutyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -piperidin-1-yl-methanone hydrochloride;

[2- (1-cyclobutyl-piperidin-4-yloxy) -6, 7-dihydro-4H-thiazolo [5,4-c ] pyridin-5-yl ] -cyclopentyl-methanone tartrate;

[2- (1-cyclobutyl-piperidin-4-yloxy) -6, 7-dihydro-5H-thiazolo [5,4-b ] pyridin-4-yl ] -cyclopropyl-methanone tartrate; and

cyclopropyl- [2- (1-isopropyl-piperidin-4-yloxy) -4,5,7, 8-tetrahydro-thiazolo [5,4-d]Aza derivatives-6-yl]-methanone tartrate.

3. A pharmaceutical composition comprising a compound of claim 1 or 2 and a pharmaceutically acceptable excipient.

4. The pharmaceutical composition according to claim 3, for use in the treatment of a clinical condition.

5. The pharmaceutical composition according to claim 4, wherein the clinical condition is selected from cognitive disorders, sleep disorders, obesity and pain.

6. A process for the preparation of a compound of formula (I) according to claim 1, which comprises (a) coupling a compound of formula (1) with a compound of formula (2)

To form a compound of formula (3),

(b) deprotecting the compound of formula (3) to form a compound of formula (4),

(c) coupling a compound of formula (4) with a compound of formula (5)

R₁-Cl

(5)

To form compounds of formula (I) wherein all substituents are as defined in claim 1,

(d) optionally converting the compound of formula (I) into a pharmaceutically acceptable salt thereof.

7. A process for the preparation of a compound of formula (I) according to claim 1, which comprises:

(a) coupling of a Compound of formula (6) with a Compound of formula (5)

To form a compound of formula (7),

(b) brominating the compound of formula (7) to form a compound of formula (8),

(c) cyclizing the compound of formula (8) to form a compound of formula (9),

(d) diazotizing the compound of formula (9) to form the compound of formula (10),

(e) coupling of a Compound of formula (10) with a Compound of formula (2)

To form compounds of formula (I) wherein all substituents are as defined in claim 1,

(f) optionally, converting the compound of formula (I) into a pharmaceutically acceptable salt thereof.

8. A process for the preparation of a compound of formula (I) according to claim 1, which comprises:

(a) coupling a compound of formula (11) with a compound of formula (5),

to form a compound of formula (12),

(b) coupling a Compound of formula (12) with a Compound of formula (2)

To form compounds of formula (I) wherein all substituents are as defined in claim 1,

(c) optionally, converting the compound of formula (I) into a pharmaceutically acceptable salt thereof.

9. A compound according to claim 1 for the preparation of a medicament for the treatment of histamine H₃A drug for a receptor-related disease.

10. Use of a compound according to claim 1 or 2 for the preparation of a medicament for the treatment of histamine H₃The use in the preparation of medicaments for treating receptor-related diseases.

11. Use of a compound according to claim 10 for the treatment of a clinical condition.

12. The use of a compound according to claim 11, wherein the clinical condition is selected from cognitive disorders, sleep disorders, obesity and pain.