EP2201007A1

EP2201007A1 - Cannabinoid receptor ligands

Info

Publication number: EP2201007A1
Application number: EP08858116A
Authority: EP
Inventors: Jérémiah HARNETT
Original assignee: Ipsen Pharma SAS
Current assignee: Ipsen Pharma SAS
Priority date: 2007-09-13
Filing date: 2008-09-11
Publication date: 2010-06-30
Also published as: US20110059970A1; WO2009071753A1; JP2010539145A; WO2009071753A8; FR2921063A1; FR2921063B1

Abstract

The subject of the present invention is novel 4-phenyl-1,3-azole derivatives of general formula (I) in which R1, R2, R3, R4, X, A, B and n are variable, in racemic or enantiomer form or any combinations of these forms. These compounds exhibit an affinity for cannabinoid receptors and are therefore capable of being used as medicaments for treating or preventing pathological states and diseases in which one or more of these receptors is (are) involved. The invention also concerns pharmaceutical compositions containing said products and the use thereof for the preparation of a medicament.

Description

DERIVATIVES OF 4-PHENYL-1,3-THIAZOLES AND 4-PHENYL-1,3-OXAZOLES AS LIGANDS OF CANNABINOID RECEPTORS

The present application relates to novel derivatives of 4-phenyl-1,3-azoles. These products have good affinity for certain cannabinoid receptor subtypes, particularly CB2 receptors. They are particularly useful for treating disease states and diseases in which one or more cannabinoid receptors are involved. The invention also relates to pharmaceutical compositions containing said products and their use for the preparation of a medicament.

Cannabinoids found in Indian cannabis (Cannabis sativa) are

10 psychoactive components including nearly 6 different molecules, the most represented is delta-9-tetrahydrocannabinol. The knowledge of the therapeutic activity of cannabis goes back to the ancient Chinese dynasties in which, 5000 years ago, cannabis was used for the treatment of asthma, migraines and gynecological disorders. It was in 1850 that cannabis extracts were

15 recognized and included in the American Pharmacopoeia.

Cannabinoids are known to have effects on the central nervous system and / or the cardiovascular system. These effects include impaired memory, euphoria, and sedation. Cannabinoids also increase heart rate and alter systemic blood pressure. Peripheral effects related to bronchial constriction, immunomodulation and inflammation were also observed. More recently, cannabinoids have been shown to modulate cellular and humoral immune responses and have anti-inflammatory properties.

However, despite all these properties, the therapeutic use of cannabinoids is controversial for its psychoactive effects (cause of dependence) but also for its multiple side effects not yet fully characterized.

In addition, two cannabinoid receptors have been identified and cloned, CB1 and CB2. CB1 is expressed predominantly in the central nervous system while CB2 is expressed in peripheral tissues, mainly in the immune system. These two receptors are members of the G-protein coupled receptor family and their inhibition is related to the activity of adenylate cyclase. Also, in order to meet the requirements of industry, it has become necessary to find compounds capable of selectively modulating the activity of cannabinoid receptors that is to say, selective products of a particular receptor subtype.

Thus, there is considerable interest in compounds with high selective affinity for the CB2 receptor. Indeed compounds that specifically modulate CB2 receptor activity, directly or indirectly, can produce clinically useful effects without binding to CB1 receptors and thus without affecting the central nervous system, thus providing a rational therapeutic approach for a wide variety of pathological conditions such as immune disorders, inflammation, osteoporosis, renal ischemia.

The problem to be solved by the invention is to provide products having an affinity for cannabinoid receptors and more particularly selective products of the CB2 receptor subtype.

The invention also provides the use of the compounds of general formula (I) for the treatment and prevention of disease states and diseases associated with cannabinoid receptor activity such as, but not limited to, cell proliferation disorders such as cancer, immune disorders and autoimmune diseases, allergic diseases, inflammation, pain, eye diseases, lung diseases, osteoporosis, gastrointestinal disorders, neurodegenerative diseases, cardiovascular diseases. These diseases include, for example, the following diseases or conditions: disorders of the immune system, including autoimmune diseases: psoriasis, lupus erythematosus, connective tissue diseases or connective tissue diseases, Sjόgren's syndrome, ankylosing spondylitis, rheumatoid arthritis, reactive arthritis , undifferentiated spondyloarthritis, Behcet's disease, hemolytic autoimmune anemias, multiple sclerosis, amyotrophic lateral sclerosis, amyloidosis, transplant rejection, diseases affecting the plasma cell line; allergic diseases: delayed or immediate hypersensitivity, allergic rhinitis, contact dermatitis, allergic conjunctivitis; parasitic, viral or bacterial infectious diseases: AIDS, meningitis; amyloidosis, diseases affecting lineages of the lympho-hematopoietic system; chronic diseases of the liver of alcoholic, viral and toxic origin as well as stéato hepatitis of non-alcoholic origin and primary cancer of the liver; inflammatory diseases, including joint diseases: arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, Crohn's disease, irritable bowel disease irritable bowel syndrome and IBS: irritable bowel syndrome syndrome), pancreatitis; osteoporosis; pain: chronic inflammatory pain, neuropathic pain, acute peripheral pain; eye conditions: ocular hypertension, glaucoma; lung diseases: respiratory diseases, asthma, fibrosis, chronic bronchitis, chronic obstructive pulmonary disease (COPD), emphysema; central nervous system diseases and neurogenerative diseases: Tourette's syndrome, Parkinson's disease, Alzheimer's disease, senile dementia, chorea, Huntington's chorea, epilepsy, psychosis, depression, spinal cord injury; migraine, vertigo, vomiting, nausea especially those following chemotherapy; cardiovascular diseases especially hypertension, arteriosclerosis, heart attack, cardiac ischemia; renal ischemia; cancers: benign tumors of the skin, papillomas and cancerous tumors, prostate tumors, brain tumors (glioblastomas, medullo-epitheliomas, medulloblastomas, neuroblastomas, embryonic origin tumors, astrocytomas, astroblastomas, ependymomas, oligodendrogliomas, tumors plexus, neuroepitheliomas, epiphysis tumor, ependymoblastomas, neuroectodermal, malignant meningiomas, sarcomatoses, malignant melanomas, schwannomas); gastrointestinal diseases; obesity; diabetes.

Other advantages and characteristics of the invention will become clear from reading the description and examples given by way of purely illustrative and nonlimiting that will follow.

Unexpectedly, the inventors have demonstrated that it is possible to use the compounds of general formula (I) to modulate the activity of CB2.

The subject of the invention is therefore compounds of general formula (I)

(I) in racemic, enantiomeric or any combination of these forms and wherein: A represents a radical -NR5R6, -CR5R6R7, or -OR5 with R5, R6, R7 independently representing a hydrogen atom, an alkyl or cycloalkyl radical;

or A represents -NR5R6, with R5 and R6 forming together with the nitrogen atom to which they are attached a heterocycloalkyl;

or A represents -CR5R6R7, with R5, R6 and R7 forming together with the carbon atom to which they are attached a cycloalkyl;

n represents an integer from 1 to 3 inclusive;

B represents an oxygen atom, sulfur, a methylene radical or a radical -NR9-;

X represents an oxygen or sulfur atom;

R4 represents a hydrogen atom or an alkyl radical;

R1, R2, R3 independently represent a hydrogen atom, a halogen atom, an alkyl radical, -CH ₂ RH, -SR11, haloalkyl, -N (R9) ₂ , -OR10;

R9 represents a hydrogen atom or an alkyl radical;

R10 represents a hydrogen atom, an alkyl radical, or aryl optionally substituted with one or more identical or different radicals independently selected from halo, nitro, cyano, or alkoxy;

R 1 represents an aryl radical;

or a pharmaceutically acceptable salt thereof;

it being understood that when A represents -NH ₂ , B does not represent a methylene radical. By alkyl, when no more details are given, is meant a linear or branched alkyl radical containing from 1 to 8 carbon atoms, and preferably from 1 to 6 carbon atoms, even more preferably from 1 to 4 carbon atoms. carbon atoms. By linear or branched alkyl having from 1 to 6 carbon atoms is meant, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl, neopentyl, isopentyl, hexyl and isohexyl radicals.

Haloalkyl means an alkyl radical as defined above, at least one of the hydrogen atoms is substituted by a halogen atom such as the -CF ₃ radical. Alkoxy, when no further details are given, means an -O-alkyl radical in which the term alkyl is as defined above. Preferentially, the term alkoxy represents a radical such as methoxy, ethoxy, propyloxy, isopropyloxy and very preferably the methoxy radical.

By cycloalkyl, when not given more details is meant a saturated carbocyclic radical having 3 to 7 carbon atoms such as for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

By heterocycloalkyl (or heterocyclic) is meant in the sense of the present invention a non-aromatic cyclic radical comprising from 4 to 7 atoms, these atoms being chosen from carbon, nitrogen, oxygen or sulfur, or one of their combinations such as, for example, piperidine, pyrrolidine, azetidine, morpholine, thiomorpholine, piperazine and homopiperazine radicals.

In particular, piperazine means a radical

in which R8 represents a hydrogen atom or an alkyl radical.

In particular by homopiperazine, we mean a radical

in which R8 represents a hydrogen atom or an alkyl radical.

By aryl is meant an unsaturated carbocyclic system comprising at least one aromatic ring, preferably a radical chosen from phenyl, naphthyl and fluorenyl and very preferably a phenyl radical.

Preferably, the subject of the invention is a compound of general formula (I) in which R 1, R 2, R 3 independently represent a hydrogen atom, a halogen atom, an alkyl radical, -CH ₂ RH, -SR 11, haloalkyl N (R9) ₂ , -OR10; R10 represents a hydrogen atom, an alkyl or phenyl radical optionally substituted with one or more identical or different radicals independently chosen from halo, nitro, cyano or alkoxy; and R11 represents a phenyl radical.

Very preferably, the subject of the invention is a compound of general formula (I) in which R1, R2, R3 independently represent a hydrogen atom, a halogen atom, an alkyl radical, -CH ₂ RH, -SR11, haloalkyl, -N (R9) ₂ , -OR10; R10 represents a hydrogen atom, an alkyl or phenyl radical optionally substituted with one or more identical or different radicals independently chosen from halo, nitro, cyano, or methoxy; and R11 represents a phenyl radical.

Preferably, the subject of the invention is a compound of general formula (I) in which X represents the sulfur atom.

Also preferably, the subject of the invention is a compound of general formula (I) in which X represents the oxygen atom.

Preferably, the compound according to the invention has radicals R1, R2, R3 independently representing a hydrogen atom, a halogen atom, an alkyl radical or -OR10.

Preferably, the compound according to the invention has radicals R1, R2, R3 which independently represent an alkyl radical or -OR10, in which R10 represents a hydrogen atom or an alkyl radical.

Preferably, the compound according to the invention has a radical A which represents a radical -NR5R6 in which R5 and R6 independently represent a hydrogen atom or an alkyl radical.

Preferably, the compound according to the invention has a radical A which represents -NR5R6 in which R5 and R6 together with the nitrogen atom to which they are attached form a heterocycloalkyl.

Preferably, the compound according to the invention has a radical B which represents an oxygen or sulfur atom.

Also preferably, the compound according to the invention can correspond to the general formula (I) in which:

A independently represents a -NR5R6 radical, with R5, R6, independently representing a hydrogen atom, an alkyl or cycloalkyl radical; or A represents -NR5R6, with R5 and R6 forming together with the nitrogen atom to which they are attached a heterocycloalkyl;

n represents an integer from 1 to 3 inclusive;

B represents an oxygen atom, sulfur, a methylene radical, or a radical -NR9;

X represents an oxygen or sulfur atom;

R4 represents a hydrogen atom or an alkyl radical;

R1, R2, R3 independently represent a hydrogen atom, a halogen atom, an alkyl radical, -OR10;

R9 represents a hydrogen atom or an alkyl radical;

R10 represents a hydrogen atom, an alkyl or aryl radical optionally substituted with one or more identical or different radicals independently chosen from halo, nitro, cyano or alkoxy;

or a pharmaceutically acceptable salt thereof; it being understood that when A represents -NH ₂ , B does not represent a methylene radical.

A represents a radical -NR5R6, wherein R5 and R6 independently represent a hydrogen atom, an alkyl or cycloalkyl radical;

n represents an integer from 1 to 3 inclusive;

B represents an oxygen atom, or sulfur;

X represents an oxygen or sulfur atom;

R4 represents a hydrogen atom or an alkyl radical; R1, R2, R3 independently represent a hydrogen atom, a halogen atom, an alkyl radical, -CH ₂ RH, -SR11, haloalkyl, -N (R9) ₂ , -OR10;

R10 represents a hydrogen atom, alkyl, or an aryl radical optionally substituted with one or more identical or different radicals independently selected from halo, nitro, cyano, or alkoxy;

R11 represents an aryl radical; or a pharmaceutically acceptable salt thereof.

Preferably, the compound according to the invention can correspond to the general formula (I) in which:

n represents an integer from 1 to 3 inclusive;

B represents an oxygen or sulfur atom;

X represents an oxygen or sulfur atom;

R4 represents a hydrogen atom or an alkyl radical;

R1, R2, R3 independently represent a hydrogen atom, a halogen atom, an alkyl radical or -OR10;

R10 represents a hydrogen atom, alkyl, or an aryl radical optionally substituted with one or more identical or different radicals independently selected from halo, nitro, cyano, or alkoxy; or a pharmaceutically acceptable salt thereof.

Preferably, the compound according to the invention is chosen from the following compounds or their salts:

{4- [4- (3,5-Di-tert-butyl-4-methoxyphenyl) -1,3-thiazol-2-yl] tetrahydro-2H-pyran-4-yl} amine • {4- [4- (3,5-Di-tert-butyl-4-methoxyphenyl) -1,3-thiazol-2-yl] tetrahydro-2H-pyran-4-yl} dimethylamine hydrochloride

4- [2- (4-Aminotetrahydro-2H-pyran-4-yl) -1,3-thiazol-4-yl] -2,6-di-tert-butylphenol

• 2,6-Di-tert-Butyl-4- {2- [4- (dimethylamino) tetrahydro-2H-pyran-4-yl] -1,3-thiazol-4-yl} phenol hydrochloride

4- [2- (4-Aminotetrahydro-2H-thiopyran-4-yl) -1,3-thiazol-4-yl] -2,6-di-tert-butylphenol

• 2,6-Di-tert-Butyl-4- {2- [4- (dimethylamino) tetrahydro-2H-thiopyran-4-yl] -1,3-thiazol-4-yl} phenol hydrochloride • Hydrochloride of 2 6-di-tert-butyl-4- {2- [3- (dimethylamino) tetrahydrofuran-3-yl]

1, 3-thiazol-4-yl} phenol

• {4- [4- (4-tert-Butylphenyl) -1,3-thiazol-2-yl] tetrahydro-2H-pyran-4-yl} dimethylamine hydrochloride

• (4- {4- [3,5-Bis (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} tetrahydro-2H-pyran-4-yl) dimethylamine hydrochloride

{4- [4- (3,5-Di-tert-butylphenyl) -1,3-thiazol-2-yl] tetrahydro-2H-pyran-4-yl} amine

• {4- [4- (3,5-Di-tert-butylphenyl) -1,3-thiazol-2-yl] tetrahydro-2H-pyran-4-yl} dimethylamine hydrochloride

• {4- [4- (4-Methoxy-3,5-dimethylphenyl) -1,3-thiazol-2-yl] tetrahydro-2H-pyran-4-yl} dimethylamine hydrochloride

• {4- [4- (3-tert-Butyl-5-chloro-4-methoxyphenyl) -1,3-thiazol-2-yl] tetrahydro-2H-pyran-4-yl} dimethylamine Hydrochloride

• {4- [4- (3-tert-Butyl-4-methoxyphenyl) -1,3-thiazol-2-yl] tetrahydro-2H-pyran-4-yl} dimethylamine Hydrochloride • 2,6-di Hydrochloride -tert-butyl-4- {2- [4- (dimethylamino) tetrahydro-2H-pyran-4-yl] -1,3-oxazol-4-yl} phenol

• N, N-dimethyl-4- [4- (4-phenoxyphenyl) -1,3-thiazol-2-yl] tetrahydro-2H-pyran-4-amine hydrochloride

2,6-di-tert-butyl-4- {2- [4- (ethylamino) tetrahydro-2H-pyran-4-yl] -1,3-thiazol-4-yl] phenol

• 2,6-Di-tert-Butyl-4- {2- [4- (diethylamino) tetrahydro-2H-pyran-4-yl] -1,3-thiazol-4-yl} phenol hydrochloride • 2,6-Di-tert-Butyl-4- {2- [4- (methylamino) tetrahydro-2H-pyran-4-yl] -1,3-thiazol-4-yl} phenol hydrochloride

2,6-di-tert-butyl-4- [2- (4-piperidin-1-yltetrahydro-2H-pyran-4-yl) -1,3-thiazol-4-yl] phenol-2 hydrochloride, 6-di-tert-butyl-4- [2- (4-morpholin-4-yltetrahydro-2H-pyran-4-yl) -1,3-thiazol-4-yl] phenol

• 2,6-Di-tert-Butyl-4- {2- [4- (4-methylpiperazin-1-yl) tetrahydro-2H-pyran-4-yl] -1,3-thiazol-4-yl hydrochloride }phenol

• 2,6-Di-tert-Butyl-4- {2- [4- (dimethylamino) -1-methylpiperidin-4-yl] -1,3-thiazol-4-yl} phenol hydrochloride

2,6-di-tert-butyl-4- {2- [4- (dimethylamino) piperidin-4-yl] -1,3-thiazol-4-yl} phenol trifluoroacetate

• {4- [4- (3,5-Di-tert-butyl-4-methoxyphenyl) -5-methyl-1,3-thiazol-2-yl] tetrahydro-2H-pyran-4-yl} dimethylamine hydrochloride 2,6-di-tert-butyl-4- [2- (1-methoxycyclopentyl) -1,3-thiazol-4-yl] phenol

2,6-di-tert-butyl-4- [2- (1-ethylcyclopentyl) -1,3-thiazol-4-yl] phenol

• (4- {4- [4- (Diethylamino) phenyl] -1,3-thiazol-2-yl} tetrahydro-2H-pyran-4-yl) dimethylamine hydrochloride

• {4- [4- (4-Benzylphenyl) -1,3-thiazol-2-yl] tetrahydro-2H-pyran-4-yl] dimethylamine hydrochloride

• 2-Chloro-6- (4- {2- [4- (dimethylamino) tetrahydro-2H-pyran-4-yl] -1,3-thiazol-4-yl} phenoxy) benzonitrile hydrochloride

• (4- {4- [2-Chloro-4- (4-chlorophenoxy) phenyl] -1,3-thiazol-2-yl} tetrahydro-2H-pyran-4-yl) dimethylamine hydrochloride • N-Hydrochloride, N-dimethyl-4- {4- [4- (4-nitrophenoxy) phenyl] -1,3-thiazol-2-yl} tetrahydro-2H-pyran-4-amine

• N, N-dimethyl-4- {4- [4- (phenylthio) phenyl] -1,3-thiazol-2-yl} tetrahydro-2H-pyran-4-amine hydrochloride

• (4- {4- [4- (4-methoxyphenoxy) phenyl] -1,3-thiazol-2-yl} tetrahydro-2H-pyran-4-yl) dimethylamine hydrochloride

• {4- [4- (3,5-Di-tert-butyl-2-methoxyphenyl) -1,3-thiazol-2-yl] tetrahydro-2H-pyran-4-yl} dimethylamine hydrochloride More preferably, the compound according to the invention is chosen from the following compounds or their salts:

• {4- [4- (3,5-Di-tert-butyl-4-methoxyphenyl) -1,3-thiazol-2-yl] tetrahydro-2H-pyran-4-yl} dimethylamine hydrochloride • Hydrochloride 2 6-Di-tert-butyl-4- {2- [4- (dimethylamino) tetrahydro-2H-pyran-4-yl] -1,3-thiazol-4-yl} phenol

• 2,6-Di-tert-Butyl-4- {2- [4- (dimethylamino) tetrahydro-2H-thiopyran-4-yl] -1,3-thiazol-4-yl} phenol hydrochloride

• 2,6-Di-tert-Butyl-4- {2- [4- (dimethylamino) tetrahydro-2H-pyran-4-yl] -1,3-oxazol-4-yl} phenol hydrochloride

• 2,6-Di-tert-Butyl-4- {2- [4- (diethylamino) tetrahydro-2H-pyran-4-yl] -1,3-thiazol-4-yl} phenol hydrochloride

• 2,6-Di-tert-butyl-4- [2- (4-piperidin-1-yltetrahydro-2H-pyran-4-yl) -1,3-thiazol-4-yl] phenol hydrochloride

The compounds according to the invention can be prepared according to the methods described below, of course, these methods are given for illustrative purposes and the skilled person can subject them to the variations that he judges useful, as well as to relates to the reagents that the conditions and techniques of the reactions.

In the description of these processes, the term "ambient temperature" indicates a temperature of between 20 ^° C. and 25 ° C .; the yields of the reactions are indicated in molar percentage and the definition of the radicals is that given previously.

The different synthetic routes are envisaged and presented here according to the nature of the group A, which may be a substituted nitrogen atom -NR5R6, a substituted carbon atom -CR5R6R7 or a substituted oxygen atom - OR5.

1 / Synthesis of the compounds in which A represents -NR5R6:

These compounds are obtained according to a method presented in diagrams 1 to 4 below.

(5) (6) X = O (6a) X = O

B = N (Gp 2), CH ₂ , O, S. W (6b) X = S

Diagram 1

According to Scheme 1, the ketone derivatives (3) are converted into the corresponding α-haloketones of general formula (4) such as, for example, α-bromo-ketones by reaction with a halogenating agent such as, for example, CuBr ₂ in ethyl acetate (J. Org Chem (1964), 29, 3459), or bromine (J. Het Chem (1988), 25, 337), or N-bromosuccinimide (J. Amer. Chem Soc. (1980), 102, 2838) in the presence of acetic acid in a solvent such as ethyl acetate or dichloromethane. The ketone derivatives (3) can also be converted into the corresponding α-halogenoketones of the general formula (4) by reaction with other halogenating agents such as HBr or Br ₂ in ether or acetic acid (Bioorg Chem Chem Lett (1996), 6 (3), 253-258, J. Med Chem (1988), 31 (10), 1910-1918) or with the aid of a resin of bromation (J. Macromol Sci Chem (1977), A11, (3) 507-514). Ketones (3) which are not commercially available are prepared from carboxylic acids (1) converted into Weinreb carboxamides (2) by reacting the carboxylic acids of general formula (1) with O, N-dimethylhydroxylamine hydrochloride in the presence of EDC and HOBT. Then the Weinreb carboxamides (2) are converted into ketones of general formula (3) by reaction with organometallic reagents R4-CH ₂ -M, where M is a metal radical and in particular Li or MgCl or MgBr.

The compounds of general formula (6) comprising carboxamides (6a) and thiocarboxamides (6b) are prepared from amino acids (5) whose amino functions are protected by protective groups Gp1 and Gp2 such as Boc, Fmoc, CBZ , Bn. Amino acids (5) are treated with ammonia-HOBT (NH ₃ -HOBT, see experimental part) in a solvent such as DMF in the presence of BOP to form carboxamides (6a). These carboxamides (6a) react with (P ₂ S ₅ J ₂ or Lawesson's reagent in an organic solvent such as dioxane or benzene at a temperature preferably between room temperature and that of the reflux of the mixture to yield thiocarboxamides of general formula (6b).

According to Scheme 2 below, the compounds of general formula (8) are prepared from the compounds of general formula (6). The conditions differ according to the nature of the chain X. Thus, the thiazoles of general formula (8) where X represents S, are prepared from thiocarboxamides (6b), treated with α-haloketones (4) in an organic solvent such as acetone, ethanol or toluene at a temperature preferably between room temperature and that of the reflux of the mixture to yield thiazole compounds of general formula (8). The oxazoles of general formula (8) wherein X is O are prepared from carboxamides (6a). These carboxamides are treated with α-haloketones (4) in a polar solvent such as, for example, in DMF heated in a microwave at a temperature of between 100 ^° C. and 150 ° C. (Biotage® equipment), in a sealed tube. for 45 to 90 minutes, to give the oxazoles of general formula (8).

When B represents a methylene, an oxygen or sulfur atom (see scheme 2), the compounds of general formula (8) are deprotected to give the corresponding amines of general formula (9) according to methods known to those skilled in the art. job. Gp1 can be CBZ, Boc, Fmoc, Bn. For example when Gp1 is the Fmoc protecting group, it is cleaved with an excess of dimethylamine in an organic solvent such as tetrahydrofuran, at a reaction temperature of between room temperature and 55 ° C. The substituted amines of the general formula (10, 12, 13, 14, 15) are prepared from the compounds (9) according to one of the following methods:

i) Condensation with corresponding aldehydes under Eschweiler-Clark conditions (Harding, JR, Jones, JR, Lu, SY, Wood, R. Tetrahedron Letters 2002, 43, 9487-9488, Torchy, S. Barby, DJ Chem Res (S) 2001, 292-293). The primary amines of general formula (9), formic acid and the corresponding aldehydes are heated in DMSO under microwaves at a temperature of between 130 and 200 ^° C. (Biotage® equipment), in a sealed tube, for 4 to 20 minutes to form secondary (10) and / or tertiary amines (12) substituted with R 5 'and / or R 6' groups, it being understood that R 5 'and R 6' independently represent a hydrogen atom or an alkyl radical .

ii) Condensation with corresponding aldehydes in the presence of a reducing agent (reductive amination) such as sodium triacetoxyborohydride or sodium borohydride, in a lower aliphatic alcohol such as methanol and optionally in the presence of molecular sieves, the reaction temperature being between room temperature and that of the reflux of the mixture, the reductive amination can also be done by heating under a waves (Biotage® equipment) to form secondary (10) and / or tertiary amines (12) substituted with R5 'and / or R6' groups, it being understood that R5 'and R6' independently represent a hydrogen atom or a alkyl radical.

iii) The amines of general formula (13) and (14) according to scheme 2, are prepared from the halogenated derivatives (RS-HaI and R6-Hal where HaI is a halogen) to form secondary amines (13) and / or tertiary (14).

iv) When R5 and R6 taken together form a 4- to 7-membered ring, the amines of general formula (15) are prepared using dihaloalkyl (11) wherein B2 is NR8, NGp3, O, S or methylene. The dihaloalkyl (11) and the compounds (9) react in a polar solvent such as, for example, ethanol in the presence of a base such as, for example, sodium bicarbonate, triethylamine, with or without sodium iodide, at a temperature of of reaction between the ambient temperature and that of the reflux of the mixture. The reaction may also be carried out by heating under microwaves (equipment Biotage) at a temperature between 100 ^c C and 200 ⁰ C for 4 to 60 minutes to complete heterocyclic general formula (15). When B2 represents a protected nitrogen atom NGp3, the compounds of general formula (15) are deprotected to give the corresponding amines of general formula (16) according to methods known to those skilled in the art, Gp3 may be CBZ, Boc, Fmoc or Bn. Then compounds (16) are alkylated according to method i, ii or iii to yield compounds (17).

When B2 = N (Gp3)

Figure 2

In the case of azoles (18) when B is a protected nitrogen NGp2, the protective groups (Gp1 and Gp2) can be deprotected selectively or non-selectively under conditions known to those skilled in the art to yield compounds of general formula ( 21); by channel 1 if R5, R6 and R9 are identical (see diagram 3), or by channels 2 or 3 if R5, R6 and R9 are not identical (see diagram 4).

Lane 1:

In cases where A is NR5R6, and R5, R6, and R9 are the same, Gp1 and Gp2 can be selected from CBZ, Boc, Fmoc, or Bn. For example, when Gp1 and Gp2 are the Fmoc protective groups, they can be deprotected by an excess dimethylamine in an organic solvent such as, for example, tetrahydrofuran, at a reaction temperature between room temperature and 55 ° C. When Gp1 and Gp2 are Boc protecting groups they are deprotected by gaseous HCl bubbling in a solvent such as for example ethyl acetate to access the amines (20).

In cases where Gp1 is not identical to Gp2, the amino functions can be deprotected selectively under conditions known to those skilled in the art. For example, when Gp1 represents a Fmoc group and Gp2 represents a Boc group, then the Fmoc group is cleaved to release the amines (19) as free bases under basic conditions (for example dimethylamine in THF), then the Boc group is cleaved in acidic medium to lead to amines (20) or vice versa. The amines (20) are then trialkylated by methods i, ii or Mi to form the compounds of general formula (21).

PATH 1 (R5 = R6 = R9>

Figure 3

Paths 2 and 3

In cases where A represents NR5R6, and R5, R6 and R9 are not identical (scheme 4), the compounds of general formula (27) are prepared according to the procedures described in scheme 4. The protective groups Gp1 and Gp2 are cleaved selectively under conditions known to those skilled in the art. For example, when Gp1 represents a group Fmoc and Gp2 represents a group Boc, the grouping Fmoc can be cleaved to liberate the amines (19) as free bases under basic conditions (eg dimethylamine in THF), to initiate pathway 2, or the protecting group Gp2 can be selectively cleaved in an acid medium to form the amines (22) to initiate the pathway 3.

Figure 4 According to Route 2: After the selective deprotection of the compounds of the general formula (18), the primary amines (19) are alkylated by the methods i, ii, iii or iv described above to form the compounds (23). These compounds (23) are then deprotected to release secondary amines (25) which are in turn alkylated according to methods i, ii or iii to yield compounds (27).

According to Route 3: After the selective deprotection of the compounds of general formula (18) the secondary amines (22) are alkylated by methods i, ii or iii to form the compounds of general formula (24). The Gp1 group of the compounds (24) is then cleaved to form the primary amines (26) which are in turn alkylated by the methods i, ii, iii or iv to yield the compounds (27).

2 / Synthesis of the compounds in which A represents -CR 5 R 6 R 7

B = N (R9), N (Gp2), O, S, CH ₂

When B = N (Gp2)

Figure 5

These compounds are obtained according to a method summarized in Scheme 5 above.

Compounds of general formula (30), including carboxamides (30a) where X is O and thiocarboxamides (30b) where X is S are prepared from carboxylic acids (28). The dianion of the carboxylic acids (28) can be prepared by treatment with an excess of LDA (at least two eq.) At a temperature between 0 ° C and -78 ° C in tetrahydrofuran. This dianion is reacted with the halogenated derivatives CR5R6R7-Hal where HaI is a halogen atom to produce the compounds of general formula (29), from which the compounds of general formula (30) including carboxamides and thiocarboxamides ( 30a) and (30b) are prepared in the same way as the compounds of the general formula (6) in Scheme 1. The compounds of the general formula (30) are reacted with the halogenated derivatives of the general formula (4) of same as in Scheme 2 to provide the compounds of general formula (32).

When B is a protected nitrogen atom NGp2, the amine (32a) is deprotected under standard conditions known to those skilled in the art, Gp2 being selected from the groups CBZ, Boc, Fmoc or Bn. For example, when Gp2 is the Fmoc protecting group, it is deprotected by an excess of dimethylamine in a solvent such as tetrahydrofuran, at a reaction temperature between room temperature and 55 ° C to provide the compounds (33). . These compounds of general formula (33) may be alkylated according to procedures (i) ii) or (iii) to provide the compounds of general formula (34).

3 / Synthesis of the compounds in which A represents -OR5:

(35) (36) (37) (38)

(42a) (43) (44) Figure 6

These compounds are obtained according to a method summarized in Scheme 6 above.

Compounds of general formula (40), including carboxamides (40a) where X is O and thiocarboxamides (40b) where X is S are prepared from ketones of general formula (35) via trimethylsilyl ether cyanohydrins (36) . The ketones (35) react with cyanotrimethylsilyl ether in the presence of a catalyst such as zinc iodide in an anhydrous solvent such as THF, to form the trimethylsilyl-ether cyanohydrins (36) which are not isolated but hydrolyzed by HCI solution to form the hydroxy acids (37). The acids (37) are converted to ethyl or methyl esters and the hydroxyl group is alkylated by reaction with the halogenated derivatives R5-Hal (HaI being a halogen atom) in the presence of a base such as NaH in an anhydrous solvent such as than THF to form the compounds (38). The esters obtained are then saponified by the action of a base such as for example LiOH in tetrahydrofuran to form the acids (39) which are subsequently converted into compounds of general formula (40), including carboxamides (40a) where X represents O and the thiocarboxamides (40b) where X represents S by the methods previously described for the compounds of general formula (6), as illustrated in scheme 1. The compounds of general formula (40) are reacted with the halogenated derivatives of formula general (4) to yield compounds (42) by the previously described methods for compounds (8), as shown in Scheme 2.

In cases where B is a protected nitrogen atom NGp2, the compounds (42a) are deprotected under standard conditions known to those skilled in the art to yield amines of the general formula (43) which are then alkylated according to the procedures ( i) (ii) or (iii) to provide the compounds of general formula (44) according to the methods previously described for compounds (33) and (34) scheme 5.

The subject of the present invention is also a process for the preparation of a compound of general formula (I) as described above, characterized in that an α-haloketone of general formula (4) is reacted.

(4) wherein R 1, R 2, R 3 and R 4 are as previously defined, wherein Hal represents a halogen atom, with a compound of the general formula (30)

(30)

wherein X, B, R5, R6, R7 and n are as defined above, to yield the compound of general formula (32), i.e. a compound of general formula (I) wherein A represents a radical -CR5R6R7,

(32)

wherein R1, R2, R3, R4, X, B, n, R5, R6 and R7 are as defined above;

with a compound of the general formula (40)

in which X, B, R5 and n are as defined above, to yield the compound of general formula (42), that is to say a compound of general formula (I) in which A represents a radical -OR5,

wherein R1, R2, R3, R4, X, B, n and R5 are as defined above;

- with a compound of general formula (6) wherein X, B and n are as defined above, Gp1 representing a protecting group, to give the compound of the general formula (8)

(8) wherein R1, R2, R3, R4, X, B, n and Gp1 are as defined above, compound of the general formula (8), the protecting group of which is cleaved to yield the compound of the general formula (9) ), that is to say a compound of general formula (I) in which A represents a radical -NR5R6, R5 and R6 representing a hydrogen atom,

compound of general formula (I) wherein R 1, R 2, R 3, R 4, X, B, and n are as defined above and A represents a radical -NR 5 R 6, R 5 and R 6 represent a hydrogen atom, which as an intermediate for the synthesis of the compound of general formula (14), that is to say a compound of general formula (I) in which A represents a radical -NR5R6, R5 and / or R6 not representing an atom hydrogen,

wherein R 1, R 2, R 3, R 4, X, B ₁ n, R 5 and R 6 are as defined above and R 5 and / or R 6 is not hydrogen.

The present invention also relates to the compounds of general formula (I) as described above or a pharmaceutically acceptable salt of such a compound, as a drug. The subject of the present invention is also pharmaceutical compositions comprising, as active ingredient, a compound of general formula (I) as described above or a pharmaceutically acceptable salt of such a compound, with at least one pharmaceutically acceptable excipient. acceptable.

The present invention also relates to the use of at least one compound of general formula (I) as described above, or a pharmaceutically acceptable salt thereof, for preparing a medicament for treating or preventing a disease or a disease. disorder selected from the following diseases or disorders: cell proliferative disorders such as cancer, immune disorders and autoimmune diseases, allergic diseases, inflammation, pain, eye conditions, lung diseases, osteoporosis , gastrointestinal disorders, neurodegenerative diseases, cardiovascular diseases.

Preferably, the subject of the present invention is also the use of the compounds of general formula (I) as described above or a pharmaceutically acceptable salt of such a compound, for preparing a medicament intended to treat or prevent cancers. .

Preferably, the present invention also relates to the use of at least one compound of general formula (I) as described above, or a pharmaceutically acceptable salt thereof, for preparing a medicament for treating or preventing the cancer, characterized in that the cancers intended to be treated or prevented are chosen from cancers of the colon, rectum, stomach, lungs, pancreas, kidney, testes, breast, uterus, ovarian, prostate, skin, bones, spinal cord, neck, tongue, head as well as sarcomas, carcinomas, fibroadenomas, neuroblastomas, leukemias, melanomas .

Moreover, some of the compounds of general formula (I) can be in the form of enantiomers. The present invention includes both enantiomeric forms and any combinations of these forms, including racemic "R, S" mixtures. For the sake of simplicity, when no specific configuration is indicated in the structural formulas, it should be understood that the two enantiomeric forms and their mixtures are represented.

The compound of general formula (I) or its salt used according to the invention or the combination according to the invention may be in the form of a solid, for example powders, granules, tablets, capsules, liposomes or suppositories. The Suitable solid carriers may be, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, carboxymethyl cellulose, and the like. sodium, polyvinylpyrrolidine and wax.

The compound of general formula (I) or its salt used according to the invention or the combination according to the invention may also be in liquid form, for example solutions, emulsions, suspensions or syrups. Suitable liquid carriers may be, for example, water, organic solvents such as glycerol or glycols, as well as their mixtures, in varying proportions, in water.

The administration of a compound of general formula (I) or its salt used according to the invention or the combination according to the invention may be carried out topically, orally, parenterally, by intramuscular injection, subcutaneously, etc.

The dose of a product according to the present invention, to be provided for the treatment of the diseases or disorders mentioned above, varies according to the mode of administration, the age and the body weight of the subject to be treated as well as the state of the latter, and it will ultimately be decided by the attending physician or veterinarian. Such a quantity determined by the attending physician or veterinarian is referred to herein as a "therapeutically effective amount".

As an indication, the envisaged administration dose for a drug according to the invention is between 0.1 mg and 10 g depending on the type of active compound used.

The following examples illustrate the invention without limiting its scope.

EXAMPLES

Melting points were measured using a Bϋchi B-545 capillary device or a Leica VMHB kofler system.

The compounds are characterized by their molecular peak (MH +) determined by mass spectrometry (MS), using a simple quadrupole mass spectrometer (Micromass, Platform model) equipped with an electrospray source, used with a resolution of 0.8 da at 50% of valley.

Example 1: {4- [4- (3,5-Di-tert-butyl-4-methoxyphenyl) -1,3-thiazol-2-yl] tetrahydro-2H-pyran-4-yl} amine

1.1 1- (3,5-di-tert-butyl-4-methoxyphenyl) ethanone

In a solution at 0 ^° C. of 3,5-di-tert-butyl-4-hydroxyacetophenone (1.24 g, 5.0 mmol) in anhydrous tetrahydrofuran (30 ml) under argon, a small portion of the hydride of sodium (0.240 g, 6.10 mmol) and the mixture is allowed to stand at room temperature. Methyl iodide (0.47 ml, 7.5 mmol) is added dropwise with stirring at room temperature, followed by refluxing for 8 hours. A water / THF mixture is added dropwise. The extraction is carried out with ethyl acetate and after decantation, the organic phase is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then evaporated under vacuum. The solvent is evaporated and then purified on a silica column (eluent: ethyl acetate-heptane: 95-5). A purplish oil is obtained with a yield of 76%.

MH + = 263.4

NB: The sodium hydride can also be changed to potassium carbonate and the solvent to DMF to provide the type I intermediates.

1.2 2-bromo-1- (3,5-di-tert-butyl-4-methoxyphenyl) ethanone

In a solution of intermediate 1.1 (1 g, 3.81 mmol) in ethyl acetate (30 ml), copper bromide (CuBr ₂ ) is added and the mixture is refluxed for 5 hours. Then filtered through a layer of celite and washed with ethyl acetate. The solvents are evaporated to give a brown oil which crystallizes, the product is used directly in the next step.

MH + = 341.2

1.3 9H-Fluoren-9-ylmethyl [4- (aminocarbonyl) tetrahydro-2H-pyran-4-yl] carbamate

The 4 - {[(9H-fluoren-9-ylmethoxy) carbonyl] amino} tetrahydro-2H-pyran-4-carboxylic acid (0.5 g, 1.365 mmol) is dissolved in DMF, the HOBT- reagent is added to it. NH ₃ * (0.253 g, 1.633 mmol) then BOP (0.602 g, 1.36 mmol) and diisopropyl ethylamine (0.7 ml, 4.083 mmol) and stirred for 12 hours. The product obtained is then extracted with ethyl acetate and water, and after decantation, the organic phase is washed with a saturated aqueous solution of sodium bicarbonate and with a saturated aqueous sodium chloride solution, dried on magnesium sulfate and filtered. The filtrate is concentrated to dryness to give a white solid, the solid is triturated with ethyl ether and filtered. The solid is washed with ether to provide the intermediate

1.3 with a yield of 68%. The product is used directly in the next step.

Melting point: 154 ° C, MH + = 367.3.

* Method for preparing the HOBT-NH ₃ reagent used to synthesize Intermediate 1.3: HOBT (20 g, 0.148 mol) is dissolved in methanol (100 ml), ammonium hydroxide (12 ml, NH ₄ ) is added thereto 28% ammonia) and then stirred at room temperature for 12 hours. Three quarters of the volume of solvent is evaporated and the solid which precipitates is filtered off. The solid is washed with diisopropyl ether and then dried to give a white solid in quantitative yield.

1.4 9H-Fluoren-9-ylmethyl [4- (aminocarbonothioyl) tetrahydro-2H-pyran-4yl] carbamate

1.91 g (5.213 mmol) of Intermediate 1.3 is dissolved in dimethoxyethane (30 ml). Sodium bicarbonate (1.752 g, 20.85 mmol) and then (P ₂ S ₅ J ₂ (4.634 g, 10.43 mmol)) are added in small portions and the reaction medium is stirred for 24 hours. At 0 ° C., a saturated aqueous solution of sodium bicarbonate is then added and the solution is extracted with ethyl ether The organic phase is then dried over magnesium sulphate, filtered and concentrated in vacuo to give a white solid with a yield of 90%, MH + = 383.2.

1.5H-fluoren-9-ylmethyl {4- [4- (3,5-di-tert-butyl-4-methoxyphenyl) -1,3-thiazol-2-yl] tetrahydro-2H-pyran-4-yl} carbamate

Intermediate 1.4 (0.5 g, 1.3 mmol) and intermediate 1.2 (0.446 g, 1.3 mmol) are dissolved in acetone (20 ml) under an argon atmosphere and the mixture is then heated at 50 ^° C. for 5 hours. hours and then left stirring at room temperature for 12 hours. Then it is taken up with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of sodium chloride. The organic phase is separated, dried over magnesium sulphate, filtered and conquered under vacuum and then purified on a silica column (eluent: gradient ethyl acetate in heptane: from 10% to 30% ethyl acetate). A pale yellow foam is obtained with a yield of 77%. MH + = 625.43

1.6 {4- [4- (3,5-di-tert-butyl-4-methoxyphenyl) -1,3-thiazol-2-yl] tetrahydro-2H-pyran-4-yljamine (Example 1)

Intermediate 1.5 (0.6 g, 0.96 mmol) is dissolved in tetrahydrofuran (20 ml). Diethylamine (0.5 mL, 4.8 mmol) is added and the reaction mixture is first heated to reflux and then allowed to stir at room temperature for 12 hours. It is extracted with ethyl acetate and the organic phase is washed with a saturated aqueous solution of sodium chloride. The organic phase is separated, dried over magnesium sulphate, filtered and concentrated in vacuo and then purified on a silica column (eluent: ethyl acetate-heptane: 50-50). A white solid is obtained with a yield of 52%.

Melting point: 128.4 - 129.7 ° C. MH + = 403.3

Example 2: {4- [4- (3,5-Di-tert-butyl-4-methoxyphenyl) -1,3-thiazol-2-yl] tetrahydro-2H-pyran-4-yl} dimethylamine hydrochloride

The product 1.6 of Example 1 (0.180 g, 0.447 mmol) is solubilized in DMSO (2 ml) and formaldehyde (72 μl, 0.894 mmol) is added thereto, followed by formic acid (47 μl, 0.894 mmol). . The reaction mixture is heated under microwaves (Biotage® equipment) at 190 ^° C. for 10 minutes. It is diluted with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic phase is then washed with a saturated aqueous solution of sodium chloride. Then it is dried over magnesium sulfate. Filtered and then evaporated. Then purification is carried out on a silica column (eluent: ethyl acetate-heptane: 50-50). A colorless oil is obtained which is salified directly. The amine is dissolved in ether (5ml) and HCl (0.6 ml, 1M in ether) is added thereto, the solid obtained is filtered and washed with ethyl ether and then with isopentane and then dried under vacuum. A white solid is obtained with a yield of 38%.

Melting point: 215.0 - 216.7 ° C. MH + = 431.29

Example 3 4- [2- (4-Aminotetrahydro-2H-pyran-4-yl) -1,3-thiazol-4-yl] -2,6-di-tert-butylphenol

3.1H-Fluoren-9-ylmethyl {4- [4- (3,5-di-tert-butyl-4-hydroxyphenyl) -1,3-thiazol-2-yl] tetrahydro-2H-pyran-4-yl} carbamate

The experimental protocol used is the same as that described for Intermediate 1.5, where commercially available 3,5-di-tert-butyl-4-hydroxy-phenacyl bromide replaces Intermediate 1.2. Intermediate 3.1 is obtained in the form of a white foam after purification on a silica column (eluent: gradient of 10% to 40% of ethyl acetate in heptane) with a yield of 67.3%. MH + = 611.3

3.2 4- [2- (4-Aminotetrahydro-2H-pyran-4-yl) -1,3-thiazol-4-yl] -2,6-di-tert-butylphenol (Example 3)

The experimental protocol used is the same as that described for example 1, where intermediate 3.1 replaces intermediate 1.5. Example 3 is obtained in the form of a white solid after purification on a silica column (eluent: gradient of 10% to 40% of ethyl acetate in heptane) with a yield of 81.7%.

Melting point: 123.0-126.5 ⁰ C. MH + = 389.3

Example 4: 2,6-Di-tert-Butyl-4- {2- [4- (dimethylamino) tetrahydro-2H-pyran-4-yl] -1,3-thiazol-4-yl} phenol hydrochloride

The experimental protocol used is the same as that described for Example 2, in which Example 3 replaces Example 1. Example 4 is obtained in the form of a white solid with a yield of 86.8%.

Melting point: 255.0-257.7 ⁰ C. MH + = 417.3

Example 5: 4- [2- (4-Aminotetrahydro-2H-thiopyran-4-yl) -1,3-thiazol-4-yl] -2,6-di-tert-butylphenol

The experimental protocol used is the same as that described for Example 1, with the difference that the synthesis starts in step 1.3 where 4 - {[(9H-fluoren-9-ylmethoxy) carbonyl] amino} tetrahydro-2H -thiopyran-4-carboxylic acid replaces 4-

{[(9H-fluoren-9-ylmethoxy) carbonyl] amino} tetrahydro-2H-pyran-4-carboxylic acid and the

Commercially available 3,5-di-tert-butyl-4-hydroxy phenacyl bromide replaces intermediate 1.2 in step 1.5. Using the experimental deprotection protocol described for Example 1 (step 1.6), Example 5 is obtained in the form of a yellow solid.

Melting point: 148.8-150.8 ⁰ C. MH + = 405.20

Example 6 2,6-Di-tert-Butyl-4- {2- [4- (dimethylamino) tetrahydro-2H-thiopyran-4-yl] -1,3-thiazol-4-yl} phenol hydrochloride

The experimental protocol used is the same as that described for Example 2, in which Example 5 replaces Example 1. Example 6 is obtained in the form of a white solid.

Melting point: 247.2-250.0 ⁰ C. MH + = 433.2

Example 7: 2,6-Di-tert-Butyl-4- {2- [3- (dimethylamino) tetrahydrofuran-3-yl] -1,3-thiazol-4-yl} phenol hydrochloride

The experimental protocol used is the same as that described for Examples 1 and 2, the synthesis starts from step 1.3 where 3 - {[(9H-fluoren-9-ylmethoxy) carbonyl] amino} tetrahydrofuran-3-carboxylic acid replaces 4 - {[(9H-fluoren-9-ylmethoxy) carbonyl] amino} tetrahydro-2H-pyran-4-carboxylic acid in step 1.3 and 3,5-di-tert-butyl-4-hydroxy phenacyl bromide commercially available replaces intermediate 1.2 in step 1.5. The expected final product is obtained in the form of a white solid. Melting point: 239.0 - 231.0 ⁰ C. MH + = 403.2

Example 8: {4- [4- (4-tert-Butylphenyl) -1,3-thiazol-2-yl] tetrahydro-2H-pyran-4-yl} dimethylamine Hydrochloride

The experimental protocol used is the same as that described for Examples 1 and 2, the synthesis starts from Step 1.3 where the commercially available 4-tert-butyl phenacyl chloride replaces Intermediate 1.2 in Step 1.5. The expected final product is obtained in the form of a yellowish solid. Melting point: 205.0 - 207.0 ⁰ C. MH + = 345.36

Example 9: (4- {4- [3,5-Bis (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} tetrahydro-2H-pyran-4-yl) dimethylamine hydrochloride

The experimental protocol used is the same as that described for Examples 1 and 2, the synthesis starts in step 1.3 where commercially available 3,5-bis (trifluoromethyl) phenacyl bromide replaces intermediate 1.2 in step 1.5. The expected final product is obtained in the form of a white solid.

Melting point: 232.2 - 233.0 ⁰ C. MH + = 425.2

Example 10: {4- [4- (3,5-di-tert-butylphenyl) -1,3-thiazol-2-yl] tetrahydro-2H-pyran-4-yl} amine

10.1 3, 5-di-tert-butyl-N-methoxy-N-methylbenzamide

In a solution of 3,5-di-tert-butylbenzoic acid (10 g, 42.7 mmol) in anhydrous DMF (30 ml) under argon was added triethylamine (15 ml). The mixture is left stirring at room temperature. Then after a few minutes, ₁ N-dimethylhydroxylamine hydrochloride (4.55 g, 46.9 mmol) is added, followed by EDC (quantity) and HOBT (quantity), and stirring is continued at room temperature for 24 hours. Then poured on ice water and extracted with ethyl acetate. After decantation, the organic phase is washed with a 10% aqueous solution of sodium bicarbonate followed by a saturated aqueous solution of sodium chloride, then dried over magnesium sulfate and then evaporated under vacuum. A pale yellow oil is obtained in quantitative yield, the product is used directly in the next step.

MH + = 278.2

10.2 1- (3,5-di-tert-butylphenyl) ethanone

Intermediate 10.1 (11.83 g, 42.7 mmol), dissolved in anhydrous THF (150 ml) is cooled to -30 ^° C. and then methyl lithium (42.7 ml, 1.6M in ether) is added dropwise and the The reaction mixture is stirred, returning to -10 ^° C. for 3 hours. A saturated aqueous solution of ammonium chloride is poured, the organic phase is extracted with ethyl acetate and after decantation, washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate and then evaporated under vacuum. A pale yellow oil is obtained which becomes orange with time with a quantitative yield, the product is engaged directly in the next step.

MH + = 233.2

10.3 2-bromo-1- (3,5-di-tert-butylphenyl) ethanone

The experimental protocol used is the same as that described for intermediate 1.2, in which intermediate 10.2 replaces intermediate 1.1, intermediate 10.3 is obtained in the form of a light brown oil after purification on a silica column (eluent: sodium acetate). ethyl-heptane: 5-95) with a yield of 63%.

MH + = 277.6

10.4 9H-Fluoren-9-ylmethyl {4- [4- (3,5-di-tert-butylphenyl) -1,3-thiazol-2-yl] tetrahydro-2H-pyran-4-yl} carbamate

The experimental protocol used is the same as that described for intermediate 1.5, where intermediate 10.3 replaces intermediate 1.4, intermediate 10.4 is obtained in the form of a white foam after purification on a silica column (eluent: ethyl acetate heptane: 20-80) with a yield of 73%.

MH + = 595.4 10.5 {4- [4- (3,5-di-tert-butylphenyl) -1,3-thiazol-2-yl] tetrahydro-2H-pyran-4-yl} amine (Example 10)

The experimental protocol used is the same as that described for Example 1 (step 1.6) where intermediate 10.4 replaces intermediate 1.5, Example 10 is obtained in the form of a white crystalline solid after purification on a silica column (eluent ethyl acetate-heptane: 30-70) in quantitative yield.

Melting point: 114.0 - 114.4 ⁰ C. MH + = 373.3

Example 11: {4- [4- (3,5-Di-tert-butylphenyl) -1,3-thiazol-2-yl] tetrahydro-2H-pyran-4-yl} dimethylamine hydrochloride

The experimental protocol used is the same as that described for Example 2 in which the amine example 10 replaces Example 1, Example 11 is obtained in the form of a pale yellow solid with a yield of 14%.

MH + = 401.3

Example 12: {4- [4- (4-Methoxy-3,5-dimethylphenyl) -1,3-thiazol-2-yl] tetrahydro-2H-pyran-4-yl} dimethylamine Hydrochloride

The experimental protocol used is the same as that described for Examples 1 and 2, in which 3,5-dimethyl-4-hydroxyacetophenone replaces 3,5-di-tert-butyl-4-hydroxyacetophenone. The expected final product is obtained in the form of a white solid.

Melting point: 237.5 - 239.O ⁰ C. MH + = 347.36 Example 13: {4- [4- (3-tert-Butyl-5-chloro-4-methoxyphenyl) -1,3-thiazol-2-yl] tetrahydro-2H-pyran-4-yl} dimethylamine Hydrochloride

The experimental protocol used is the same as that described for Examples 1 and 2, where 1- (3-tert-Butyl-5-chloro-4-methoxyphenyl) ethanone (the method of synthesis of which is described in US2006 / 0058370 A1) replaces 3,5-di-tert-butyl-4-hydroxyacetophenone. The expected final product is obtained in the form of a white solid.

Melting point: 219.7 - 222.2 ⁰ C. MH + = 409.27

Example 14: {4- [4- (3-tert-Butyl-4-methoxyphenyl) -1,3-thiazol-2-yl] tetrahydro-2H-pyran-4-yl} dimethylamine Hydrochloride

The experimental protocol used is the same as that described for Examples 1 and 2 in which 1- (3-tert-Butyl-4-methoxyphenyl) ethanone (the method of synthesis of which is described in patent US2006 / 0058370 A1) replaces the 3,5-di-tert-butyl-4-hydroxyacetophenone. The expected final product is obtained in the form of a white solid.

Melting point: 232.7 - 233.5 ° C. MH + = 375.35

Example 15: 2,6-Di-tert-Butyl-4- {2- [4- (dimethylamino) tetrahydro-2H-pyran-4-yl] -1,3-oxazol-4-yl} phenol hydrochloride

15.1 9H-fluoren-9-ylmethyl {4- [4- (3,5-di-tert-butyl-4-hydroxyphenyl) -1,3-oxazol-2-yl] tetrahydro-2H-pyran-4-yl} carbamate

3,5-Di-tert-butyl-4-hydroxyphenacyl bromide (327 mg, 1 mmol) and Intermediate 1.4 are dissolved in anhydrous DMF (2 mL) in a Biotage ^® reaction tube, a spatula tip. molecular sieve (approximately 40mg) is added and the tube is sealed, and heated under microwave with magnetic stirring at 150 ° C for

1 hour and 30 minutes. The mixture is diluted with water and after decantation, the organic phase is washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate, then filtered and evaporated in vacuo. A pale brown oil is obtained which is purified on a silica column (eluent: ethyl acetate-heptane: 20-80) and a yellow-brown solid is obtained with a yield of 12%.

15.2 4- [2- (4-Aminotetrahydro-2H-pyran-4-yl) -1,3-oxazol-4-yl] -2,6-di-tert-butylphenol

The experimental protocol used is the same as that described for Example 1, in which intermediate 15.1 replaces intermediate 1.5, intermediate 15.2 is obtained in the form of a brown oil after purification on a silica column (eluent: chloroform). ethanol: 97-3) with a quantitative yield.

MH + = 373.32

15.3 2,6-Di-tert-butyl-4- {2- [4- (dimethylamino) tetrahydro-2H-pyran-4-yl] -1,3-oxazol-4-yl} phenol hydrochloride (Example 15)

The experimental protocol used is the same as that described for Example 2, in which Intermediate 15.2 replaces Example 1, Example 15 is obtained in the form of a white solid with a yield of 12%.

Melting point: 233.0 - 235.O ⁰ C. MH + = 401.33

Example 16: N, N-dimethyl-4- [4- (4-phenoxyphenyl) -1,3-thiazol-2-yl] tetrahydro-2H-pyran-4-amine hydrochloride

16.1 2-bromo-1- (4-phenoxyphenyl) ethanone

2-Bromo-1- (4-phenoxyphenyl) ethanone is prepared according to the method described above for Intermediate 1.2, where 4-phenoxyacetophenone replaces Intermediate 1.1. Α-Bromocetone is obtained as a red oil, and used directly in the next step.

16.2 N, N-dimethyl-4- [4- (4-phenoxyphenyl) -1,3-thiazol-2-yl] tetrahydro-2H-pyran-4-amine hydrochloride (Example 16)

For the preparation of Example 16, the experimental protocol used is the same as that described for Examples 1 and 2, the synthesis starting in step 1.5 and α-bromoketone 16.1 replacing intermediate 1.2. The expected final product is obtained in the form of a white solid.

Melting point: 213.0-223.2 ⁰ C. MH + = 381.32

Example 17: 2,6-Di-tert-butyl-4- {2- [4- (ethylamino) tetrahydro-2H-pyran-4-yl] -1,3-thiazol-4-yl} phenol

For the preparation of Example 17, the experimental protocol used is the same as that described for Example 2 in which Example 3 replaces Example 1, acetaldehyde replaces formaldehyde and the reaction mixture is heated under micro -ondes (Biotage® equipment) at 140 ⁰ C for 4 minutes. The expected product in free base form is a pale yellow solid.

MH + = 417.3 Example 18: 2,6-Di-tert-Butyl-4- {2- [4- (diethylamino) tetrahydro-2H-pyran-4-yl] -1,3-thiazol-4-yl} phenol hydrochloride

For the preparation of Example 18 the experimental protocol used is the same as that described for Example 2 in which Example 3 replaces Example 1, acetaldehyde replaces formaldehyde (a large excess of acetaldehyde is used approximately 20 eq.), and the reaction mixture is heated under microwaves (Biotage® equipment) at 140 ^° C. for 16 minutes. The expected product in hydrochloride form is a white solid. Melting point: 208.0 - 211.5 ^° C. MH + = 445.3

Example 19: 2,6-Di-tert-Butyl-4- {2- [4- (methylamino) tetrahydro-2H-pyran-4-yl] -1,3-thiazol-4-yl} phenol hydrochloride

Example 3 (50 mg, 0.13 mmol) and paraformaldehyde (5 mg, 0.17 mmmol) is dissolved in methanol (1 mL) in a Biotage ^® reaction tube and the molecular sieve (50 mg) followed by NaBH4 (10 mg, 0.26 mmol) are added. The tube is sealed by a capsule, placed under microwave (Biotage ^® ) and then heated with magnetic stirring at 120 ° C for 6 minutes. The mixture is diluted with water and then extracted with ethyl acetate. After decantation, the organic phase is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and then evaporated under vacuum. The residue is purified on a silica column (eluent: 10% acetone in dichloromethane) and is salified directly. The secondary amine (0.010 g, 0.025 mmol) is dissolved in ether (2 ml) and then HCl (0.1 ml, 1M in ether). The solid formed is filtered and washed with ethyl ether and then dried under vacuum. A white solid is obtained with a yield of 21.1%.

Melting point: 250.0 - 252.0 ⁰ C. MH + = 403.3

Example 20: 2,6-Di-tert-Butyl-4- [2- (4-piperidin-1-yltetrahydro-2H-pyran-4-yl) -1,3-thiazol-4-yl] phenol hydrochloride

Example 3 (50 mg, 0.13 mmol) and 1, 5-dibromopentane (201.4 mg, 0.876 mmmol) are dissolved in ethanol (1.5 mL) in a reaction tube Biotage ^®. Sodium bicarbonate (38 mg, 0.450 mmol) is added and the tube is sealed with a capsule and heated under Biotage ^® microwaves at 150 ° C for 15 minutes. The mixture is diluted with water and then extracted with ethyl acetate. After decantation, the organic phase is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and then evaporated under vacuum. The residue is purified on a silica column (eluent: 20% ethyl acetate in heptane) and a colorless oil (0.03 g, 0.066 mmol) is obtained which is dissolved in ether (3 ml), then HCl (0.3 ml, 1M in ether) is added. The solid formed is filtered and then washed with ether and dried under vacuum. A white solid is obtained with a yield of 31.6%.

Melting point 230.0 - 231.8 ⁰ C. MH + = 457.4.

Example 21 2,6-Di-tert-butyl-4- [2- (4-morpholin-4-yltetrahydro-2H-pyran-4-yl) -1,3-thiazol-4-yl] phenol

For the preparation of Example 21, the experimental protocol used is the same as that described for Example 20 in which the bis (2-bromoethylether) (12 eq.) Replaces 1, 5-dibromopentane in the presence of an excess of sodium bicarbonate (14 eq.) - The reaction mixture is heated under microwaves (Biotage® equipment) at 160 ^° C. for 45 minutes. The expected product is obtained in the form of a base, in the form of a white solid with a yield of 68.8%.

Melting Point: 172.0 - 174.0 ⁰ C. MH + = 459.3

Example 22 2,6-Di-tert-Butyl-4- {2- [4- (4-methylpiperazin-1-yl) tetrahydro-2H-pyran-4-yl] -1,3-thiazol-4 hydrochloride yl} phenol

For the preparation of Example 22, the experimental protocol used is the same as that described for Example 20 in which mechlorethamine (6 eq.) Replaces 1,5-dibromopentane. An excess of sodium bicarbonate is used (14 eq.), As well as triethylamine (6 eq.) And sodium iodide (12 eq.). The reaction mixture is heated under microwaves (Biotage® equipment) at 155 ^° C. for 60 minutes. After treatment and purification on a silica column (eluent: 2% ethanol in dichloromethane), it is salified directly as in Example 20 and the expected product is obtained in the form of a white solid with a yield of 68.8%.

MH + = 472.4

Example 23 2,6-Di-tert-Butyl-4- {2- [4- (dimethylamino) -1-methylpiperidin-4-yl] -1,3-thiazol-4-yl} phenol hydrochloride

23.1 9H-fluoren-9-ylmethyl 4- (aminocarbonyl) -4 - [(tert-butoxycarbonyl) amino] piperidine -1-carboxylate The experimental protocol used is the same as that described for Example 1 (step 1.3), where 4 - [(tert-butoxycarbonyl) amino] -1 - [(9H-fluoren-9-ylmethoxy) carbonyl] piperidine -4 Carboxylic acid replaces 4 - {[(9H-fluoren-9-ylmethoxy) carbonyl] amino} tetrahydro-2H-pyran-4-carboxylic acid. The product 23.1 is obtained in the form of a white solid with a quantitative yield, used directly in the next step.

Melting Point: 13O ⁰ C. MH + = 466.3

23.2 9H-fluoren-9-ylmethyl 4- (aminocarbonothioyl) -4 - [(tert-butoxycarbonyl) amino] piperidine -1-carboxylate

The experimental protocol used is the same as that described for example 1 (step 1.4), intermediate 23.1 replacing intermediate 1.3. The product 23.2 is obtained in the form of a white solid with a yield of 30%.

MH + = 482.3

23.3 9H-fluoren-9-ylmethyl 4 - [(tert-butoxycarbonyl) amino] -4- [4- (3,5-di-tert-butyl-4-hydroxyphenyl) -1,3-thiazol-2-yl] piperidine-1-carboxylate

The experimental protocol used is the same as that described for example 1 (step 1.5), intermediate 23.2 replacing intermediate 1.4. Intermediate 23.3 is obtained in the form of a white foam with a yield of 65%.

MH + = 710.5

23.4 9H-fluoren-9-ylmethyl-4-amino-4- [4- (3,5-di-tert-butyl-4-hydroxyphenyl) -1,3-thiazol-2-yl] piperidine-1-carboxylate

Intermediate 23.3 (0.710 g, 1 mmol) is dissolved in ethyl acetate (20 ml) in which gaseous HCl is bubbled for 10 minutes. The reaction mixture is concentrated to dryness, taken up in water and extracted with ethyl acetate. After decantation, the organic phase is washed with a saturated aqueous solution of sodium bicarbonate and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and then evaporated under vacuum. The residue is purified on a silica column (eluent: 50% ethyl acetate in heptane) and a white foam is obtained with a yield of 94%.

MH + = 610.4

23.5 4- [2- (4-aminopiperidin-4-yl) -1,3-thiazol-4-yl] -2,6-di-tert-butylphenol The experimental protocol used is the same as that described for example 1 (step 1.6), intermediate 23.4 replacing intermediate 1.5. The product 23.5 is obtained in the form of a light brown paste with a yield of 66%.

MH + = 388.3

23.6 2,6-Di-tert-butyl-4- {2- [4- (dimethylamino) -1-methylpiperidin-4-yl] -1,3-thiazol-4-yl} phenol hydrochloride (Example 23)

The experimental protocol used is the same as that described for Example 2, Intermediate 23.5 replacing Example 1. Example 23 is obtained in the form of a beige solid with a yield of 41%. Melting point: 236.0 - 238.0 ⁰ C. MH + = 430.3

Example 24 2,6-Di-tert-butyl-4- {2- [4- (dimethylamino) piperidin-4-yl] -1,3-thiazol-4-yl} phenol trifluoroacetate

Intermediate 23.4 (280 mg, 0.459 mmol) and formaldehyde (32 mg, 1.066 mmol) are dissolved in methanol (15 ml) in the presence of molecular sieve (50 mg) and the mixture is refluxed for 5 minutes. hours and then stirred at room temperature for 12 hours. NaBH4 (20 mg, 1.066 mmol) is added in small portions and then the reaction mixture is refluxed again for 5 hours (the product obtained is the di-alkylated product and deprotected). The mixture is diluted with water and extracted with ethyl acetate. After decantation, the organic phase is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and then concentrated to dryness. The residue is purified by reverse phase preparative HPLC on C18 grafted silica (gradient: water + TFA 0.2 M-acetonitrile = 80-20 to 60-40), an oil is obtained with a yield of 4%. MH + = 416.3

Example 25 {4- [4- (3,5-Di-tert-butyl-4-methoxyphenyl) -5-methyl-1,3-thiazol-2-yl] tetrahydro-2H-pyran-4-yl hydrochloride } dimethylamine

The experimental protocol used is the same as that described for Examples 1 and 2, where 1- (3,5-ditert-butyl-4-hydroxyphenyl) propanone (Russ J. Org Chem 33 (10) 1409-1416 , 1997) replaces 3,5-di-tert-butyl-4-hydroxy acetophenone in step 1.1. The expected final product is obtained in the form of a white solid.

MH + = 445.3

Example 26 2,6-Di-tert-butyl-4- [2- (1-methoxycyclopentyl) -1,3-thiazol-4-yl] phenol

26.1 Methyl 1-methoxycyclopentanecarboxylate

The experimental protocol used is the same as that described for Example 1, where the 1-cyclopentanol-1-methylcarboxylate ester replaces 3,5-di-tert-butyl-4-hydroxyacetophenone. Intermediate 26.1 is obtained in the form of a yellow oil with a yield of 54%.

26.2 1-Methoxycyclopentanecarboxylic acid

The ester 26.1 (5.85 g, 0.0367 mol) is dissolved in THF (50 ml) and then an aqueous solution of 1N LiOH (55 ml, 0.055 mol) is added dropwise. The mixture is stirred for 12 hours at room temperature and then poured into ice-water and acidified with an aqueous solution of 1N HCl to pH = 1, extracted with ethyl acetate. After decantation, the organic phase is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and then evaporated under vacuum to form the product as a pale yellow oil with a yield of 73%. 26.3 1-methoxycyclopentanecarboxamide

The experimental protocol used is the same as that described for intermediate 1.3, where intermediate 26.2 replaces 4 - {[(9H-fluoren-9-ylmethoxy) carbonyl] amino} tetrahydro-2H-pyran-4-carboxylic acid. The reaction mixture is heated under microwaves (Biotage® equipment) at 60 ^° C. for 30 minutes. After treatment the product is used directly in the next step.

MH + = 287.1

26.4 1-methoxycyclopentanecarbothioamide

The experimental protocol used is the same as that described for intermediate 1.4, intermediate 26.3 replacing intermediate 1.3. The product is obtained as a fluffy white solid with a yield of 77%.

Fusion Point: 140 ⁰ C, MH + = 320.3

26.5 2,6-di-tert-butyl-4- [2- (1-methoxycyclopentyl) -1,3-thiazol-4-yl] phenol (Example 26)

The experimental protocol used is the same as that described for Intermediate 1. Intermediate 26.4 replacing Intermediate 4 gives Example 26 as a white solid with a 21% yield. Melting point: 121.1 - 122.4 ° C.

Example 27 2,6-Di-tert-butyl-4- [2- (1-ethylcyclopentyl) -1,3-thiazol-4-yl] phenol

27.1 1-ethylcyclopentanecarboxylic acid

The di-isopropylethylamine (5.874 g, 0.058 mol) is dissolved in anhydrous THF (100 ml) at 0 ^° C., then a solution of BuLi 1.6M in heptane (33 ml) is added dropwise and the mixture is stirred for 15 minutes. minutes. The cyclopentanecarboxylic acid (2.738 g, 0.024 mol) in anhydrous THF is added at 0 ^° C. and then stirred for 1 hour. Iodoethane (3.928 g, 0.0252 mol) is added at -55 ° C. and then the mixture is allowed to rise to -100 ^° C. for 12 hours. The reaction is cooled to -55 ° C and the reaction mixture is diluted with aqueous HCl (1N), extracted with ether. After decantation, the organic phase is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and then evaporated under vacuum. A red oil is obtained with a yield of 92%. The product is used directly in the next step.

27.2 1-ethylcyclopentanecarboxamide

The experimental protocol used is the same as that described for intermediate 1.3, intermediate 27.1 replacing 4 - {[(9H-fluoren-9-ylmethoxy) carbonyl] amino} tetrahydro-2H-pyran-4-carboxylic acid. Intermediate 27.2 is obtained in the form of a beige solid with a yield of 77.4%. Melting point: 95 ° C.

27.3 1-ethylcyclopentanecarbothioamide

The experimental protocol used is the same as that described for intermediate 1.4, intermediate 27.2 replacing intermediate 1.3. The product is obtained in the form of pearlescent white pearlescent solid with a yield of 13%. Melting point: 130 ^° C.

27.4 2,6-di-tert-butyl-4- [2- (1-ethylcyclopentyl) -1,3-thiazol-4-yl] phenol (Example 27)

The experimental protocol used is the same as that described for intermediate 1.5, intermediate 27.3 replacing intermediate 1.4. Example 27 is obtained as a yellow oil in quantitative yield. MH + = 386.3.

Example 28: (4- {4- [4- (Diethylamino) phenyl] -1,3-thiazol-2-yl} tetrahydro-2H-pyran-4-yl) dimethylamine hydrochloride

The experimental protocol used is the same as that described for Examples 1 and 2, the synthesis beginning in step 1.3 where α-bromo-4- (diethylamino) acetophenone commercially available replaces intermediate 1.2 in step 1.5. The expected final product is obtained in the form of a brown foam solid.

MH + = 360.26.

Example 29: {4- [4- (4-Benzylphenyl) -1,3-thiazol-2-yl] tetrahydro-2H-pyran-4-yl} dimethylamine hydrochloride

29.1 1- (4-benzylphenyl) -2-bromoethanone

1- (4-Benzylphenyl) -2-bromoethanone is prepared according to the method described for Intermediate 1.2 where (4-acetylphenyl) phenylmethane replaces Intermediate 1.1. 1- (4-Benzylphenyl) -2-bromoethanone is obtained as a brown oil in quantitative yield and is used directly in the next step.

29.2 {4- [4- (4-Benzylphenyl) -1,3-thiazol-2-yl] tetrahydro-2H-pyran-4-yl} dimethylamine hydrochloride (Example 29)

For the preparation of Example 29, the experimental protocol used is the same as that described for Examples 1 and 2, the synthesis starting in Step 1.5 where 1- (4-benzylphenyl) -2-bromoethanone replaces the intermediate 1.2 in step 1.5. The expected final product is obtained in the form of a white solid.

Melting point: 228.4-222.5 ° C. MH + = 379.20.

Example 30: 2-Chloro-6- (4- {2- [4- (dimethylamino) tetrahydro-2H-pyran-4-yl] -1,3-thiazol-4-yl} phenoxy) benzonitrile hydrochloride

30.1 2- [4- (Bromoacetyl) phenoxy] -6-chlorobenzonitrile.

2- [4- (Bromoacetyl) phenoxy] -6-chlorobenzonitrile is prepared according to the method described for Intermediate 1.2, where 2- (4-acetylphenoxy) -6-chlorobenzene carbonitrile replaces Intermediate 1.1. 2- [4- (Bromoacetyl) phenoxy] -6-chlorobenzonitrile is obtained in the form of a gray solid by crystallization from ether in quantitative yield.

Melting point: 86 ° C.

30.2 2-Chloro-6- (4- {2- [4- (dimethylamino) tetrahydro-2H-pyran-4-yl] -1,3-thiazol-4-yl} denenyl) benzonitrile hydrochloride (Example 30)

For the preparation of Example 30, the experimental protocol used is the same as that described for Examples 1 and 2, the synthesis starting in Step 1.5 where 2- [4- (bromoacetyl) phenoxy] -6-chlorobenzonitrile replaces intermediate 1.2 in step 1.5. The expected final product is obtained in the form of a yellow solid.

Melting point: 127-130 ⁰ C. MH + = 440.03.

Example 31: (4- {4- [2-Chloro-4- (4-chlorophenoxy) phenyl] -1,3-thiazol-2-yl} tetrahydro-2H-pyran-4-yl) dimethylamine hydrochloride

31.1 2-Bromo-1- [2-chloro-4- (4-chlorophenoxy) phenyl] ethanone.

2-Bromo-1- [2-chloro-4- (4-chlorophenoxy) phenyl] ethanone is prepared according to the method described for Intermediate 1.2 where 1- [2-chloro-4- (4-chlorophenoxy) phenyl] ethanone-1-one replaces intermediate 1.1. 2-Bromo-1- [2-chloro-4- (4-chlorophenoxy) phenyl] ethanone is obtained as a yellow oil in quantitative yield, and is used directly in the next step.

31.2 (4- {4- [2-Chloro-4- (4-chlorophenoxy) phenyl] -1,3-thiazol-2-yl} tetrahydro-2H-pyran-4-yl) dimethylamine hydrochloride (Example 31) For the preparation of Example 31 the experimental protocol used is the same as that described for Examples 1 and 2, the synthesis starting at Step 1.5 where 2-bromo-1- [2-chloro-4- (4) -chlorophenoxy) phenyl] ethanone replaces intermediate 1.2 in step 1.5. The expected final product is obtained in the form of a white solid.

> Melting point: 226.7 - 228.0 ⁰ C.

Example 32: N, N-dimethyl-4- {4- [4- (4-nitrophenoxy) phenyl] -1,3-thiazol-2-yl} tetrahydro-2H-pyran-4-amine hydrochloride

32.1 2-Bromo-1- [4- (4-nitrophenoxy) phenyl] ethanone.

2-Bromo-1- [4- (4-nitrophenoxy) phenyl] ethanone is prepared according to the method described for Intermediate 1.2, where 4-acetyl-4'-nitrodiphenyl ether replaces Intermediate 1.1. 2-Bromo-1- [4- (4-nitrophenoxy) phenyl] ethanone is obtained as a pale yellow solid with a yield of 53%.

Melting point: 94 ° C.

32.2 N, N-dimethyl-4- {4- [4- (4-nitrophenoxy) phenyl] -1,3-thiazol-2-yl} tetrahydro-2H-pyran-4-amine hydrochloride (Example 32)

For the preparation of Example 32, the experimental protocol used is the same as that described for Examples 1 and 2, the synthesis starting at step 1.5 where 2-bromo-1- [4- (4-nitrophenoxy) phenyl) ] ethanone replaces intermediate 1.2 in step 1.5. The expected final product is obtained in the form of a pale yellow solid.

Melting point: 167-169 ° C. MH + = 426.16.

Example 33: N, N-dimethyl-4- {4- [4- (phenylthio) phenyl] -1,3-thiazol-2-yl} tetrahydro-2H-pyran-4-amine hydrochloride

33.1 2-Bromo-1- [4- (phenylthio) phenyl] ethanone.

2-Bromo-1- [4- (phenylthio) phenyl] ethanone is prepared according to the method described for Intermediate 1.2, where 4-acetyldiphenylsulfide replaces Intermediate 1.1. 2-Bromo-1- [4- (phenylthio) phenyl] ethanone is obtained in the form of a yellow oil after purification on a silica column (eluent: ethyl acetate-heptane: 20-80) with a yield of 71% .

33.2 N, N-dimethyl-4- {4- [4- (phenylthio) phenyl] -1,3-thiazol-2-yl} tetrahydro-2H-pyran-4-amine hydrochloride (Example 33)

For the preparation of Example 33, the experimental protocol used is the same as that described for Examples 1 and 2, the synthesis starting in Step 1.5 where 2-bromo-1- [4- (phenylthio) phenyl] ethanone replaces intermediate 1.2 in step 1.5. The expected final product is obtained in the form of a pale yellow solid.

Melting point: 215.0 - 218.8 ^° C. MH + = 397.18.

Example 34: (4- {4- [4- (4-methoxyphenoxy) phenyl] -1,3-thiazol-2-yl} tetrahydro-2H-pyran-4-yl) dimethylamine hydrochloride

34.1 2-Bromo-1- [4- (4-methoxyphenoxy) phenyl] ethanone. 2-Bromo-1- [4- (4-methoxyphenoxy) phenyl] ethanone is prepared according to the method described for Intermediate 1.2, where 1- [4- (4-methoxyphenoxy) phenyl] ethan-1-one replaces l Intermediate 1.1. 2-Bromo-1- [4- (4-methoxyphenoxy) phenyl] ethanone is obtained in the form of a brown oil which crystallizes slowly with a yield of 56%.

Melting Point: 58 ° C.

34.2 (4- {4- [4- (4-Methoxyphenoxy) phenyl] -1,3-thiazol-2-yl} tetrahydro-2H-pyran-4-yl) dimethylamine hydrochloride (Example 34)

For the preparation of Example 34 the experimental protocol used is the same as that described for Examples 1 and 2, the synthesis starting in Step 1.5 where 2-bromo-1- [4- (4-methoxyphenoxy) phenyl) ] ethanone replaces intermediate 1.2 in step 1.5. The expected final product is obtained in the form of a light brown solid. Melting point: 120.0 - 121.0. MH + = 411.22.

Example 35: {4- [4- (3,5-Di-tert-butyl-2-methoxyphenyl) -1,3-thiazol-2-yl] tetrahydro-2H-pyran-4-yl} dimethylamine hydrochloride

The experimental protocol used is the same as that described for Examples 1 and 2, in which 3,5-di-tert-butyl-2-methoxyacetophenone replaces 3,5-di-tert-butyl-4-hydroxyacetophenone. The expected final product is obtained in the form of a light yellow solid.

Melting point: 199.4 - 200.7 ^° C. MH + = 431.22.

PHARMACOLOGICAL STUDY OF THE PRODUCTS OF THE INVENTION The affinity of the compounds of the present invention for the different cannabinoid receptor subtypes was measured according to the procedures analogous to those described hereinafter for the human CB2 receptor.

Study of the affinity of the compounds for CB2 human cannabinoid receptors

The affinity of the compounds of the invention for CB2 human receptors is determined by measuring the inhibition of [ ³ H] -CP55940 binding to membrane preparations of transfected CHO-K1 cells.

CHO-K1 cells stably expressing human CB2 receptors are cultured in RPMI 1640 medium containing 10% fetal calf serum, 2 mM glutamine, 100 U / ml penicillin, 0.1 mg / ml streptomycin and 0.5 mg / ml G418. The cells are collected with 0.5 mM EDTA and centrifuged at 500 g for 5 min at 4 ° C. The pellet is resuspended in phosphate buffered saline (PBS) and centrifuged at 500 g for 5 min at 4 ° C. The pellet is resuspended in a 50 mM Tris buffer medium at pH 7.4 and centrifuged at 500 g for 5 min at 4 ° C. The cells are lysed by sonication and centrifuged at 39,000 g for 10 min. at 4 ° C. The pellet is resuspended in 50 mM Tris buffer medium at pH 7.4 and centrifuged at 50,000 g for 10 min at 4 ° C. The membranes obtained in this latter pellet are stored at -80 ° C. vs.

The measurement of competitive inhibition of [ ³ H] -CP55940 binding to CB2 receptors is performed in duplicate using 96-well polypropylene plates. The cell membranes (10 μg protein / well) are incubated with [ ³ H] -CP55940 (1 nM) for 60 min at 25 ° C. in a 50 mM Tris-HCl buffer medium, pH 7.4, comprising 0, 1% bovine serum albumin (BSA), 5 mM MgCl ₂ , and 50 μg / ml bacitracin.

The bound [ ³ H] -CP55940 is separated from free [ ³ H] -CP55940 by filtration through GF / C fiberglass filter plates (Unifilter, Packard) preimpregnated with 0.1% polyethyleneimine (PEI). ), using a Filtermate 196 (Packard). The filters are washed with 50 mM Tris-HCl buffer, pH 7.4 at 0-4 ° C and the radioactivity present is determined using a counter (Packard Top Count).

The specific binding is obtained by subtracting the non-specific binding (determined in the presence of 0.1 μM of WIN55212-2 from the total binding). The data are analyzed by computer-assisted nonlinear regression (MDL). For each test, a Cheng-Prusoff correction is made to convert the IC50 to a constant of inhibition Ki. IC50

So, Ki =

1 + [L] / Kd

where [L] is the concentration of the radioligand used in the assay and Kd is the equilibrium radioligand dissociation constant. The CB2 receptor agonist or antagonist activity of the compounds of the present invention was determined by measuring the cyclic AMP production by CHO-K1 cells transfected with the CB2 receptor. Measurement of intracellular cyclic AMP production via CB2 receptors:

CHO-K1 cells expressing cannabinoid CB2 receptors are cultured in 384-well plates in RPMI 1640 medium with 10% fetal calf serum and 0.5 mg / ml G418. The cells are washed twice with 50 μl of RPMI medium comprising 0.2% BSA and 0.5 mM of 3-isobutyl-1-methylxanthine (IBMX).

To measure the agonist effect of a compound, the cells are incubated for 5 min at 37 ° C. in the presence of 0.5 mM of IBMX, then the stimulation of cyclic AMP production is obtained by adding 5 μM of Forskolin and inhibition is measured by adding the compound at concentrations of between 1 μM and 10 μM in duplicate for 20 min at 37 ° C. The antagonistic effect of a compound is measured by inhibiting the inhibition of the production of Cyclic AMP induced by WIN55212-2 in the presence of 5 μM Forskolin, at concentrations of between 1 μM and 10 μM, in the presence of the test compound, at concentrations of between 1 nM and 10 μM, in duplicate for 20 min at 37 ° C.

The reaction medium is removed and 80 .mu.l of lysis buffer are added. The level of intracellular cyclic AMP is measured by a competition test with fluorescent cyclic AMP (CatchPoint, Molecular Devices).

Results of pharmacological studies:

a) All the compounds of Examples 1 to 35 are selective with respect to the CB2 receptor relative to the CB1 receptor. For the purposes of the present invention, the term "selective" means that the compounds have a better affinity for the CB2 receptor than for the CB1 receptor.

b) In general, all the compounds of Examples 1 to 35 have an affinity for the CB2 receptor of less than 10,000 nM.

Examples 5, 14, 28, 29 and 33 have an affinity of between 1000 nM and 500 nM.

Examples 7, 8, 11, 13, 16, 17, 19, 21, 23, 25 and 32 have affinity between 500 nM and 100 nM. Examples 2, 4, 6, 15, 18 and 20 have an affinity of even less than or equal to 100 nM.

Claims

1. Compound of general formula (I)

(I) in racemic, enantiomeric or any combination of these forms and wherein:

A represents a radical -NR5R6, -CR5R6R7, or -OR5 with R5, R6, R7 independently representing a hydrogen atom, an alkyl or cycloalkyl radical;

n represents an integer from 1 to 3 inclusive;

B represents an oxygen atom, sulfur, a methylene radical, or a radical -NR9;

X represents an oxygen or sulfur atom;

R4 represents a hydrogen atom or an alkyl radical;

R1, R2, R3 independently represent a hydrogen atom, a halogen atom, an alkyl radical, -CH ₂ R11, -SR11, haloalkyl, -N (R9) ₂ , -OR10;

R9 represents a hydrogen atom or an alkyl radical;

R11 represents an aryl radical; or a pharmaceutically acceptable salt thereof;

it being understood that when A represents -NH ₂ , B does not represent a methylene radical.

2. Compound according to claim 1 characterized in that R1, R2, R3 independently represent a hydrogen atom, a halogen atom, an alkyl radical, - CH ₂ RH, -SR11, haloalkyl, -N (R9) _{2 )} -OR10; R10 represents a hydrogen atom, an alkyl or phenyl radical optionally substituted with one or more identical or different radicals independently chosen from halo, nitro, cyano or alkoxy; and R11 represents a phenyl radical.

3. Compound according to one of claims 1 or 2 characterized in that R1, R2, R3 independently represent a hydrogen atom, a halogen atom, an alkyl radical, -CH ₂ RH, -SR11, haloalkyl, N (R9) ₂ , -OR10; R10 represents a hydrogen atom, an alkyl or phenyl radical optionally substituted with one or more identical or different radicals independently chosen from halo, nitro, cyano, or methoxy; and R11 represents a phenyl radical.

4. Compound according to claim 1 characterized in that X represents the sulfur atom.

5. Compound according to claim 1 characterized in that X represents the oxygen atom.

6. Compound according to claim 1 characterized in that R1, R2, R3 independently represent a hydrogen atom, a halogen atom, an alkyl radical or

-OR10.

7. Compound according to claim 1 characterized in that R1, R2, R3 independently represent an alkyl radical or -OR10, it being understood that R10 represents a hydrogen atom or an alkyl radical.

8. Compound according to claim 1 characterized in that A represents a -NR5R6 radical in which R5 and R6 independently represent a hydrogen atom or an alkyl radical.

9. Compound according to claim 1 characterized in that A represents -NR5R6 wherein R5 and R6 together with the nitrogen atom to which they are attached a heterocycloalkyl.

10. Compound according to claim 1 characterized in that B represents an oxygen or sulfur atom.

11. Compound according to claim 1, characterized in that A represents, independently, a radical -NR5R6, with R5, R6, independently representing a hydrogen atom, an alkyl or cycloalkyl radical;

n represents an integer from 1 to 3 inclusive;

B represents an oxygen atom, sulfur, a methylene radical, or a radical -NR9;

X represents an oxygen or sulfur atom;

R4 represents a hydrogen atom or an alkyl radical;

R9 represents a hydrogen atom or an alkyl radical;

or a pharmaceutically acceptable salt thereof;

12. Compound according to claim 1 characterized in that A represents a radical - NR5R6, wherein R5 and R6 independently represent a hydrogen atom, an alkyl or cycloalkyl radical;

or A represents -NR5R6, with R5 and R6 forming together with the nitrogen atom to which they are attached a heterocycloalkyl; n represents an integer from 1 to 3 inclusive;

B represents an oxygen atom, or sulfur;

X represents an oxygen or sulfur atom;

R4 represents a hydrogen atom or an alkyl radical;

R11 represents an aryl radical;

or a pharmaceutically acceptable salt thereof.

13. A compound according to claim 1 characterized in that A represents a radical - NR5R6, wherein R5 and R6 independently represent a hydrogen atom, an alkyl or cycloalkyl radical;

n represents an integer from 1 to 3 inclusive;

B represents an oxygen or sulfur atom;

X represents an oxygen or sulfur atom;

R4 represents a hydrogen atom or an alkyl radical;

or a pharmaceutically acceptable salt thereof.

14. Compound according to claim 1 characterized in that said compound is chosen from the following compounds or a salt thereof:

• {4- [4- (3,5-di-tert-butyl-4-methoxyphenyl) -1,3-thiazol-2-yl] tetrahydro-2H-pyran-4-yljamine • Hydrochloride of {4- [4 - (3,5-di-tert-butyl-4-methoxyphenyl) -1,3-thiazol-2-yl] tetrahydro-2H-pyran-4-yl} dimethylamine

2,6-di-tert-butyl-4- {2- [4- (dimethylamino) tetrahydro-2H-pyran-4-yl] -1,3-thiazol-4-yl} phenol hydrochloride; 2- (4-Aminotetrahydro-2H-thiopyran-4-yl) -1,3-thiazol-4-yl] -2,6-di-tert-butylphenol

• 2,6-Di-tert-Butyl-4- {2- [3- (dimethylamino) tetrahydrofuran-3-yl] -1,3-thiazol-4-yl} phenol hydrochloride

• (4- {4- [3,5-Bis (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} tetrahydro-2H-pyran-4-yl) dimethylamine hydrochloride • {4- [4- ( 3,5-di-tert-butylphenyl) -1,3-thiazol-2-yl] tetrahydro-2H-pyran-4-yl} amine

• {4- [4- (4-Methoxy-3,5-dimethylphenyl) -1,3-thiazol-2-yl] tetrahydro-2H-pyran-4-yl} dimethylamine Hydrochloride • {4- [4] Hydrochloride - (3-tert-Butyl-5-chloro-4-methoxyphenyl) -1,3-thiazol-2-yl] tetrahydro-2H-pyran-4-yl} dimethylamine

• {4- [4- (3-tert-Butyl-4-methoxyphenyl) -1,3-thiazol-2-yl] tetrahydro-2H-pyran-4-yl} dimethylamine Hydrochloride

• N, N-dimethyl-4- [4- (4-phenoxyphenyl) -1,3-thiazol-2-yl] tetrahydro-2H-pyran-4-amine hydrochloride 2,6-di-tert-butyl-4- {2- [4- (ethylamino) tetrahydro-2H-pyran-4-yl] -1,3-thiazol-4-yl} phenol

• 2,6-Di-tert-Butyl-4- {2- [4- (diethylamino) tetrahydro-2H-pyran-4-yl] -1,3-thiazol-4-yl} phenol hydrochloride • Hydrochloride 2 , 6-di-tert-butyl-4- {2- [4- (methylamino) tetrahydro-2H-pyran-4-yl] -

1, 3-thiazol-4-yl} phenol

2,6-di-tert-butyl-4- [2- (4-morpholin-4-yltetrahydro-2H-pyran-4-yl) -1,3-thiazol-4-yl] phenol

2,6-di-tert-butyl-4- {2- [4- (dimethylamino) -1-methylpiperidin-4-yl] -1,3-thiazol-4-yl} phenol hydrochloride; trifluoroacetate of 2, 6-di-tert-butyl-4- {2- [4- (dimethylamino) piperidin-4-yl] -1,3-thiazol-4-yl} phenol

• {4- [4- (3,5-Di-tert-butyl-4-methoxyphenyl) -5-methyl-1,3-thiazol-2-yl] tetrahydro-2H-pyran-4-yl} dimethylamine hydrochloride

2,6-di-tert-butyl-4- [2- (1-methoxycyclopentyl) -1,3-thiazol-4-yl] phenol • 2,6-di-tert-butyl-4- [2- ( 1-ethylcyclopentyl) -1,3-thiazol-4-yl] phenol

• {4- [4- (4-Benzylphenyl) -1,3-thiazol-2-yl] tetrahydro-2H-pyran-4-yl} dimethylamine hydrochloride • 2-Chloro-6- (4- {2H hydrochloride - [4- (dimethylamino) tetrahydro-2H-pyran-4-yl] -

1,3-thiazol-4-yl} phenoxy) benzonitrile

• (4- {4- [2-Chloro-4- (4-chlorophenoxy) phenyl] -1,3-thiazol-2-yl} tetrahydro-2H-pyran-4-yl) dimethylamine hydrochloride

• N, N-dimethyl-4- {4- [4- (4-nitrophenoxy) phenyl] -1,3-thiazol-2-yl} tetrahydro-2H-pyran-4-amine hydrochloride

• N, N-dimethyl-4- {4- [4- (phenylthio) phenyl] -1,3-thiazol-2-yl} tetrahydro-2H-pyran-4-amine hydrochloride • (4- {4- [4- (4-methoxyphenoxy) phenyl] -1,3-thiazol-2-yl} tetrahydro-2H-pyran-4-yl) dimethylamine hydrochloride

• {4- [4- (3,5-Di-tert-butyl-2-methoxyphenyl) -1,3-thiazol-2-yl] tetrahydro-2H-pyran-4-yl} dimethylamine hydrochloride.

15. Compound according to claim 1 characterized in that said compound is chosen from the following compounds or a salt thereof:

• {4- [4- (3,5-Di-tert-butyl-4-methoxyphenyl) -1,3-thiazol-2-yl] tetrahydro-2H-pyran-4-yl} dimethylamine hydrochloride

• 2,6-Di-tert-Butyl-4- {2- [4- (dimethylamino) tetrahydro-2H-pyran-4-yl] -1,3-oxazol-4-yl} phenol hydrochloride • Hydrochloride 2 6-di-tert-butyl-4- {2- [4- (diethylamino) tetrahydro-2H-pyran-4-yl]

1, 3-thiazol-4-yl} phenol

2,6-di-tert-butyl-4- [2- (4-piperidin-1-yltetrahydro-2H-pyran-4-yl) -1,3-thiazol-4-yl] phenol hydrochloride.

16. Process for the preparation of a compound of general formula (I) according to claim 1, characterized in that an α-haloketone of general formula (4) is reacted.

in which R1, R2, R3 and R4 are as defined above, HaI representing a halogen atom,

- with a compound of general formula (30) wherein X, B, R5, R6, R7 and n are as defined above, to yield the compound of the general formula (32), i.e. a compound of the general formula (I) wherein A represents a radical -CR5R6R7

wherein R1, R2, R3, R4, X, B, n, R5, R6 and R7 are as defined in claim 1;

with a compound of the general formula (40)

(40)

in which X, B, R5 and n are as defined above, to yield the compound of general formula (42), that is to say a compound of general formula (I) in which A represents a radical -OR5

(42)

wherein R1, R2, R3, R4, X, B, n and R5 are as defined in claim 1;

- with a compound of general formula (6)

(6) in which X ₁ B and n are as defined above, Gp 1 representing a protecting group, to give the compound of the general formula (8)

(8) wherein R1, R2, R3, R4, X, B, n and Gp1 are as defined above, compound of the general formula (8), the protecting group of which is cleaved to yield the compound of the general formula (9) ), that is to say a compound of general formula (I) in which A represents a radical -NR5R6, R5 and R6 representing a hydrogen atom

compound of general formula (I) wherein R 1, R 2, R 3, R 4, X, B, and n are as defined above and A represents a radical -NR 5 R 6, R 5 and R 6 represent a hydrogen atom, which as an intermediate for the synthesis of the compound of general formula (14), that is to say a compound of general formula (I) in which A represents a radical -NR5R6, R5 and / or R6 not representing an atom hydrogen

wherein R1, R2, R3, R4, X, B, n, R5 and R6 are as defined above and R5 and / or R6 is not hydrogen.

17. As a medicament, a compound of general formula (I) according to one of claims 1 to 15, or a pharmaceutically acceptable salt of such a compound.

18. A pharmaceutical composition comprising, as active ingredient, a compound of general formula (I) according to one of claims 1 to 15, or a pharmaceutically acceptable salt of such a compound, with at least one pharmaceutically acceptable excipient.

19. Use of at least one compound of general formula (I) according to one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, for preparing a medicament for treating or preventing a disease or a disorder selected from the group consisting of following diseases or disorders: cell proliferation disorders such as cancer, immune disorders and autoimmune diseases, allergic diseases, inflammation, pain, eye conditions, lung diseases, osteoporosis, gastrointestinal disorders -intestinal, neurodegenerative diseases, cardiovascular diseases.

20. Use according to claim 19, characterized in that the medicament prepared is intended to treat or prevent cancers.

21. Use according to claim 20, characterized in that the cancers to be treated or prevented are selected from cancers of the colon, rectum, stomach, lungs, pancreas, kidney, testes, breast. , uterus, ovary, prostate, skin, bones, spinal cord, neck, tongue, head as well as sarcomas, carcinomas, fibroadenomas, neuroblastomas , leukemias, melanomas.