BRPI0607439A2 - compounds, pharmaceutical composition, method of preparing pharmaceutical compositions, and use of a compound - Google Patents

Abstract

COMPOUNDS, PHARMACEUTICAL COMPOSITION, METHOD FOR PREPARING PHARMACEUTICAL COMPOSITIONS, AND USE OF A COMPOUND. The invention relates to a group of qH-imidazole derivatives which are CB-2-cannabinoid receptor modulators to methods for the preparation of these compounds, to novel intermediates useful for the synthesis of said imidazole derivatives, to methods for the preparation of these compounds. of these intermediates, to pharmaceutical compositions containing one or more of these 1H-imidazole derivatives as an active ingredient, as well as to the use of these pharmaceutical compositions for the treatment of disorders in which CB2-2 cannabinoid receptors are involved. The compounds have the general formula (I) wherein R 1 -R-4 have the meanings given in the descriptive report.

Description

"COMPOUNDS, PHARMACEUTICAL COMPOSITION, METHOD OF PREPARING PHARMACEUTICAL COMPOSITIONS, AND USE OF A COMPOUND"

The present invention relates to a group of 1H-imidazole derivatives which are CB2 cannabinoid receptor modulators to the methods for preparing these compounds, to novel intermediates useful for the synthesis of said imidazole derivatives. The invention also relates to the use of a compound disclosed herein for the manufacture of a medicament which provides a beneficial effect. A beneficial effect is presented herein or evident to a person skilled in the art from the descriptive report and general knowledge in the art. The invention also relates to the use of a compound of the invention for the manufacture of a medicament for treating or preventing a disease or condition. More particularly, the invention relates to a novel use for the treatment of a disease or condition set forth herein or apparent to a person skilled in the art from the descriptive report and general knowledge in the art. In embodiments of the invention the specific compounds disclosed herein are used for the manufacture of a medicament useful in the treatment of disorders in which CB2 cannabinoid receptors are involved, or which can be treated by manipulation of these receptors.

1H-imidazole derivatives as CBj receptor modulators are known from WO 03/027076, WO 03/063781, WO 03/040107 and WO 03/007887. (Morpholin-4-yl) alkyl (1H) -imidazole derivatives have been claimed as CB2 receptor modulators in WO 01/58869 which disclose three specific imidazoles (examples 64, 65 and 66) all containing a group of carboxamide derived from n L-phenylalanine at position 4 of its (1H) -imidazole component. 1-Aryl- (1H) -imidazole derivatives have been claimed in US 4,952,698 as CNS active compounds. Recent advances in the field of CB2 receptor selective ligands have been reviewed by K.H. Raitio et al. (Curr. Med. Chem. 2005, 12, 1217-1237).

Surprisingly, novel 1H-imidazole derivatives have been observed which bind to the CB2 receptor, including compounds having approximately 100-fold higher CB2 receptor affinities as compared to prior art compounds which were exemplified in WO 01/58869. Moreover, many of the compounds within this invention are highly selective of the CB2 receptor subtype meaning that they bind much higher affinity to the CB2 receptor than to the CBi receptor.

The compounds within this invention are CB2 receptor agonists, CB2 receptor partial agonists, CB2 receptor antagonists or inverse CB2 receptor antagonists.

The invention relates to compounds of general formula (I)

<formula> formula see original document page 3 </formula>

on what:

R1 represents a hydrogen or halogen atom or a C1-3 alkyl group, wherein C1-3 alkyl group may contain from 1 to 3 fluorine atoms or a hydroxy or amino group, or R1 represents a C2-3 alkynyl group, a C2.3-alkenyl group, wherein the C2.3-alkynyl group or C2.3-alkenyl group may contain from 1 to 3 fluorine atoms, or R1 represents an acetyl, cyclopropyl, cyano, methylsulfonyl group, ethylsulfonyl, methylsulfinyl, ethylsulfinyl trifluoromethylsulfanyl, methylsulfanyl, ethylsulfanyl, formyl group or a C 2-4 heteroalkyl group,

R 2 represents a phenyl group which may be substituted with 1, 2, 3, 4 or 5 Y substituents, which may be the same or different, selected from the group consisting of methyl, ethyl, propyl, methoxy, ethoxy, hydroxy, chlorine, iodine , bromo, fluoro, trifluoromethyl, trifluoromethoxy, methylsulfonyl, carbamoyl, phenyl and cyano, or R2 represents a heteroaryl group wherein the heteroaryl group may be substituted with 1, 2 or 3 substituents Y, wherein Y has the meaning as defined above, provided that R2 is not a group of 6-methyl-2-pyridyl, or

R 2 represents a fused monocyclic, fused bicyclic or fused tricyclic 4- to 10-membered monocyclic or fully saturated carbocyclic ring system, or

R2 represents a monocyclic, fused bicyclic fused monocyclic or fused tricyclic 4- to 10-membered saturated or fully saturated heterocyclic ring system wherein the carbocyclic or heterocyclic ring system may be substituted with 1 to 5 substituents selected from methyl, ethyl, amino, hydroxy or fluorine , or

R 2 represents a group of formula CH 2 -R 5 wherein R 5 represents a phenyl group which is substituted with 1, 2, 3, 4 or 5 substituents Y as defined above, or R 5 represents a heteroaryl group or a group of 1,2,3 4-tetrahydronaphthyl or indanyl, wherein the heteroaryl group or group of 1,2,3,4-tetrahydronaphthyl or indanyl may be substituted with 1, 2 or 3 Y substituents as defined above or R 5 represents a carbocyclic ring system of 4 to 10 fused monocyclic, fused bicyclic or monounsaturated or fully fused monocyclic fused tricyclic members, or R5 represents a fused monocyclic, fused bicyclic monocyclic or fused monocyclic ring system of 4-10 membered monocyclic or fully saturated heterocyclic ring systems substituted with 1 to 5 selected substituents from the group consisting of methyl, ethyl, amino, hydroxy or fluorine, or

R2 represents a methylsulfonylaminoalkyl, methylsulfonylalkyl group or an acetamidoalkyl group,

R3 represents a hydrogen or halogen atom or a group of formyl, C1-6 alkylsulfonyl, C1-6 alkylsulfinyl, C1-6 alkylsulfanyl, trifluoromethylsulfanyl, benzylsulfanyl or cyano, or R3 represents C1-6 alkyl group, wherein the group C 1-6 alkyl may be substituted with 1 to 5 substituents selected from the group consisting of fluoro, hydroxy or amino, or R 3 represents a C 2-6 alkynyl, C 2-6 alkenyl, C 1-6 alkanoyl, C 3 group.

8-cycloalkyl, C5.8-heterocycloalkyl or a C2-6-heteroalkyl group, wherein the groups are optionally substituted with 1 to 3 methyl groups, an ethyl, amino or hydroxy group or 1 to 3 fluorine atoms, or R 3 represents a phenyl group which is substituted with 1 to 5 Y substituents, wherein Y has the meaning as defined above, or R 3 represents a heteroaryl group wherein the heteroaryl group may be substituted with 1, 2 or 3 Y substituents, wherein Y has the meaning as defined above or R 3 represents a benzyl or heteroaryl methyl group wherein the debenzyl or heteroaryl methyl group may be substituted with 1, 2 or 3 substituents YR 4 represents one of subgroups (i) or (ii)

<formula> formula see original document page 5 </formula>

on what

R5 represents a branched or linear C4.8 alkyl group, C3.g cycloalkyl group, C3.8-cycloalkyl-C1-2 alkyl group, C5-7-heterocycloalkyl-C1-2 alkyl group, C5-10 bicycloalkyl group of C5] O-bicycloalkyl C1 -C4 alkyl group of C5-10 heterobicycloalkyl C1-6 group C10-10 tricycloalkyl group C6-10 tricycloalkyl group alkyl, C6-10-hetero-tricycloalkyl-C1-6 alkyl group wherein the groups may be substituted with 1 to 5 substituents selected from methyl, hydroxy, ethyl, trifluoromethyl or fluoro, or R 1 represents a group of phenyl, benzyl, naphthyl or phenethyl wherein groups may be substituted on their ring aromatic system with 1 to 3 Y substituents as defined above, provided that R 6 is not a 2-methylphenyl group, or R 6 represents a depyridyl or thienyl group,

R7 represents a hydrogen atom or a linear C1-6 alkyl group wherein the linear C1-6 alkyl group may be substituted with 1 to 3 fluorine atoms or R7 represents an isopropyl group,

R 8 represents a C 2-6 alkyl group wherein the group is substituted with a hydroxy or amino group or 1 to 3 fluorine atoms, or R 8 represents a branched C 7-10 alkyl group, C 3-8 cycloalkyl group, C5.8 heterocycloalkyl, C3.8-cycloalkyl-C1-2 alkyl group, C5.7-heterocycloalkyl-C1-2 alkyl group, C5.10bicycloalkyl group, C5-10-bicycloalkyl group C5-10-heterobicycloalkyl-C1-6 alkyl group, C10-10 tricycloalkyl group, C10-10-tricycloalkyl-C1-4 alkyl group, C0-10-heterotriccycloalkyl-C1-4 alkyl group in which groups may be substituted with 1 to 5 substituents selected from methyl, hydroxy, ethyl, amino, hydroxymethyl, trifluoromethyl or fluorine, or R 8 represents a phenyl group wherein the group is substituted with 1 to 5 Y substituents as defined above, or R 5 represents a naphthyl group, 1,2,3,4-tetrahydronaphthyl or indanyl wherein the naphthyl, 1,2,3,4-tetrahydronaphthyl or indanyl groups may be being substituted with 1 to 3 substituents Y, or R 6 represents a phenyl-C 1-3 alkyl group, a diphenyl-C 1-3 alkyl group, wherein the groups may be substituted on their phenyl ring with 1 to 5 Y substituents, wherein Y has the above meaning, or R 8 represents a benzyl group, wherein the benzyl group is substituted with 1 to 5 Y substituents, or R 8 represents a heteroaryl, heteroarylmethyl, naphthylmethyl or heteroarylethyl group, wherein heteroaryl, heteroarylmethyl, naphthylmethyl or heteroarylethyl group may be substituted with 1 to 3 substituents Y, wherein Y has the above-mentioned meaning, or Rg represents a group of piperidinyl, azepanyl, morpholinyl, azabicyclo [3.3.0] octanyl, 4-hydroxypiperidinyl or pyrrolidinyl, provided that R 8 is neither a group of 6-methoxy-benzothiazol-2-ylan or a group of [3-chloro-5- (trifluoromethyl) pyrid-2-yl] methyl,

or R7 and R8 - together with the nitrogen atom to which they are attached - form a non-aromatic or partially aromatic saturated or unsaturated monocyclic, bicyclic or unsaturated heterocyclic group having from 7 to 10 ring atoms, wherein the monocyclic, bicyclic or tricyclic monocyclic heterocyclic group Non-aromatic or partially saturated or unsaturated aromatic may be substituted with 1 to 5 substituents selected from the group consisting of C1.3 alkyl, hydroxy, methoxy, cyano, phenyl, trifluoromethyl or halogen,

or R7 and Rg - together with the nitrogen atom to which they are attached - form a saturated monocyclic heterocyclic group, optionally containing another heteroatom (selected from N, O, S), having from 5 to 6 ring atoms, wherein the heterocyclic group is substituted with 1 to 5 substituents selected from the group consisting of C1-3 alkyl, hydroxy, amino, phenyl, benzyl, or fluoro,

with the proviso that R7 and R8 - together with the denitrogen atom to which they are attached - do not form a trimethyl substituted aza-bicyclo [3.2.1] octanyl group,

and tautomers, stereoisomers and N-oxides thereof, as well as pharmaceutically acceptable salts, hydrates and solvates of said compounds of formula (I) and their tautomers, stereoisomers and N-oxides.

The invention relates to racemates, mixtures of diisomeres as well as the individual stereoisomers of the compounds of formula (I).

In the description of the substituents the abbreviation 'alkyl' means a straight or branched alkyl group. For example, C 1-3 alkyl means methyl, ethyl, n-propyl or isopropyl. The abbreviation 'heteroaryl' means fused monocyclic or bicyclic heteroaromatic groups including, but not limited to, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazin 1, -triazinyl, indazolyl, indolyl, indolizinyl, isoindolyl, benzo [bjfuranyl, benzo [b] thiophenyl, 1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl,

isoquinolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, quinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, with the exclusion of the quinolin-2-one group. The abbreviation 'halogen' means chlorine, fluoro, bromine or iodine. The abbreviation 'Cs.g-cycloalkyl' means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

The abbreviation 'C5.8 heterocycloalkyl' refers to rings containing heteroatom (N, O, S) including, but not limited to, piperidinyl, morpholinyl, azepanyl, pyrrolidinyl, thiomorpholinyl, piperazinyl, tetrahydrofuran, tetrahydropyranyl. The abbreviation 'group C5.10 bicycloalkyl' refers to carbo-bicyclic ring systems including, but not limited to, bicyclo [2.2.1] heptanil, bicyclo [3.3.0] octanyl or debicyclo [3.1.1] heptanil group . The abbreviation "C10-10 tricycloalkyl group" refers to carbo-tricyclic ring systems such as the 1-adamantyl, noradamantyl or 2-adamantyl group. The abbreviation 'C 2-4 heteroalkyl' refers to the heteroatom (N, O, S) containing linear or branched C 2-4 alkyl groups including, but not limited to, methoxy methyl, dimethylaminomethyl and ethylsulfanylmethyl.

Prodrugs of the above-mentioned compounds are within the scope of the present invention. Prodrugs are therapeutic agents that are inactive per se, but are transformed into one or more active metabolites. Prodrugs are bioreversible derivatives of drug demolecules used to overcome certain barriers with autonomy of the parent drug molecule. These barriers include, but are not limited to, solubility, permeability, stability, presystemic metabolism, and targeting limitations (MedicinalChemistry: Principies and Practice, 1994, ISBN 0-85186-494-5, Ed .: FDKing, p. 215; J. Stella, "Prodrugs as therapeutics", Expert Opin. Ther. Patents, 14 (3), 277-280, 2004; P. Ettmayer et al., "Lessons Learned from Marketed and Investigational Prodrugs", J. Med. Chem., 47, 2393-2404, 2004). Prodrugs, that is, compounds which when administered to humans by any known route of administration, are metabolized to compounds having formula (I), belong to the invention. In particular this concerns compounds with primary or secondary amino or hydroxy groups. Such compounds may be reacted with organic acids to produce compounds having formula (I) wherein an additional group is present which is readily removed after administration, for example, but not limited to, amidine, enamine, a Mannich base, a derivative of hydroxy methylene, a derivative of 0- (acyloxymethylene carbamate), carbamate, ester, amide or enaminone.

N-oxides of the above mentioned compounds are within the scope of the present invention. Tertiary amines may or may not give rise to N-oxide metabolites. The extent to which N-oxidation would occur from trace amounts to a close quantitative conversion. N-oxides may be more active than their corresponding tertiary amines or less active. Although N-oxides are easily reduced in their corresponding tertiary amines by chemical means, in the human body this happens to varying degrees. Some N-oxides undergo quantitative reductive conversion to almost the corresponding tertiary amines, in others case conversion is a simple trace reaction or even completely absent. (MH Bickel: "The Pharmacology and Biochemistry of N-oxides", Pharmacological Reviews, 21 ( 4), 325-355, 1969).

The invention particularly relates to the compounds of general formula (1): <formula> formula see original document page 10 </formula>

on what:

represents a halogen atom or a C1-3 alkyl group, wherein the C1-3 alkyl group may contain from 1 to 3 fluorine atoms or a hydroxy or amino group, or R1 represents a C2-3 alkynyl group a C2-3 alkenyl group, wherein the C2-3 alkynyl group or C2-3 alkenyl group may contain from 1 to 3 fluorine atoms, or R1 represents an acetyl, cyclopropyl, cyano, methylsulfonyl, ethylsulfonyl group, methylsulfinyl, ethylsulfinyl trifluoromethylsulfanyl, methylsulfanyl, ethylsulfanyl, formyl group or a C 2-4 -heteroalkyl group, and R2, R3 and R4 have the meanings as given above.

More particularly, the invention relates to the compounds of formula (I):

<formula> formula see original document page 10 </formula>

on what:

R3 represents a hydrogen or halogen atom or a group of formyl, methylsulfonyl, ethylsulfonyl, methylsulfinyl, ethylsulfinyl, trifluoromethylsulfanyl, methylsulfanyl, ethylsulfanyl or cyano, or R3 represents C1-6 alkyl group, wherein the C1-6 alkyl group may contain de 1 to 3 fluorine atoms or a hydroxy or amino group, or R 3 represents a C 2-6 alkynyl, C 2-6 alkenyl, C 1-6 alkanoyl, C 3-8 cycloalkyl, C 5-8 heterocycloalkyl or C 2-6 heteroalkyl group, wherein the groups are optionally substituted with 1 to 3 methyl groups, an ethyl, amino or hydroxy group with 1 to 3 fluorine atoms, or R 3 represents a phenyl group which is substituted with 1 to 5 Y substituents, wherein Y has the meaning as defined above, or R 3 represents a heteroaryl group wherein the heteroaryl group may be substituted with 1, 2 or 3 Y substituents, wherein Y has the meaning as defined above or R 3 represents a debenzyl or heteroaryl methyl group wherein the benzyl or heteroaryl methyl group may be substituted with 1, 2 or 3 substituents YR4 represents subgroup (ii)

<formula> formula see original document page 11 </formula>

on what

R7 represents a hydrogen atom or a linear C1-6 alkyl group or an isopropyl group,

R 8 represents a C 2-6 alkyl group wherein the group is substituted with a hydroxy or amino group or with 1 to 3 fluorine atoms, or R 8 represents a branched C 7-10 alkyl group, C 3-8 cycloalkyl group, C 5,8 heterocycloalkyl group C3-8-cycloalkyl-C1-6 alkyl group, C5-7-heterocycloalkyl-C1-4 alkyl group, C5-10-bicycloalkyl group, C5-10-bicycloalkyl-C1-4 alkyl group -heterobicyclo-C1-2 alkyl-alkyl group of C6-10 tricycloalkyl, group of C6-10-tricyclo-C1-2 alkyl-group of C6-10heterotrylcyclo-C1-6 alkyl wherein the groups may be substituted with 1 to 5 substituents selected from demethyl, hydroxy, ethyl, amino, hydroxy methyl, trifluoromethyl, or fluoro, or R 8 represents a phenyl group wherein the group is substituted with 1 to 5 Y substituents as defined above, or R 8 represents a naphthyl or a group of 1,2, 3,4-tetrahydronaphthyl or indanyl wherein the groups may be substituted with 1 to 3 Y, or R 8 represents a phenyl-C 1-3 alkyl group, a diphenyl-C 1-3 alkyl group, wherein the groups may be substituted on their phenyl ring with 1 to 5 Y substituents, wherein Y has meaning above, or R 8 represents a benzyl group, wherein the benzyl group is substituted with 1 to 5 Y substituents, or R 8 represents a heteroaryl, heteroarylmethyl or heteroarylethyl group, wherein the heteroaryl, heteroarylmethyl or heteroarylethyl group may be substituted with 1 to 3 substituents Y, as defined above, or R 8 represents a group of piperidinyl, azepanyl, morpholinyl, azabicyclo [3.3.0] octanyl, 4-hydroxypiperidinyl or pyrrolidinyl, provided that Rg is not a group of 6-methoxy-benzothiazole -2-yl or a group of [3-chloro-5- (trifluoromethyl) pyrid-2-yl] methyl,

or R7 and Rg - together with the nitrogen atom to which they are attached - form a saturated or unsaturated monocyclic, bicyclic, nonaromatic or saturated aromatic heterocyclic group having from 7 to 10 ring atoms, wherein the heterocyclic group may be substituted with one or two C1.3 alkyl groups, one hydroxy group, one phenyl group, one trimethylfluoromethyl group, one benzyl group, one diphenyl methyl group or one halogen atom,

or R7 and R8 - together with the nitrogen atom to which they are attached - form a saturated monocyclic heterocyclic group, optionally containing another heteroatom (selected from N, O, S), having from 5 to 6 ring atoms, wherein the heterocyclic group is substituted with 1 to 3 groups of C 1-3 alkyl, a hydroxy group or 1 to 2 fluorine atoms,

with the proviso that R7 and R8 - together with the denitrogen atom to which they are attached - do not form a trimethyl substituted aza-bicyclo [3.2.1] octanyl group,

and R 1 and R 2 have the meanings as given above.

Also more particularly the invention relates to the compounds of formula (I)

<formula> formula see original document page 12 </formula> where:

R1 represents a halogen atom or a C1.3-alkyl group, wherein the C1-3 alkyl group may contain from 1 to 3 fluorine atoms or a hydroxy group, or represents a C2-3-alkynyl group, a group of C2-3-alkenyl, an acetyl, cyclopropyl, cyano, methylsulfonyl, methylsulfinyl group, or a C2-4-heteroalkyl group,

R 2 represents a phenyl group which may be substituted with 1, 2, 3, 4 or 5 Y substituents, which may be the same or different, selected from the group consisting of methyl, ethyl, propyl, methoxy, ethoxy, hydroxy, chlorine, iodine , bromine, fluoro, trifluoromethyl, trifluoromethoxy, methylsulfonyl, carbamoyl, phenyl and cyano, or R2 represents a monocyclic heteroaryl group wherein the heteroaryl group may be substituted with 1, 2 or 3 Y substituents, wherein Y has the meaning as defined above, provided that R2 is not a group of 6-methyl-2-pyridyl, or

R2 represents a fused monocyclic, fused bicyclic or fused tricyclic monocyclic 4- to 10-membered carbocyclic ring system, or

R2 represents a monocyclic, fused bicyclic fused monocyclic or fused tricyclic 4- to 10-membered saturated or fully saturated heterocyclic ring system wherein the carbocyclic or heterocyclic ring system may be substituted with 1 to 5 substituents selected from methyl, ethyl, amino, hydroxy or fluorine , or

R 2 represents a group of formula CH 2 -R 5 wherein R 5 represents a phenyl group which is substituted with 1, 2, 3, 4 or 5 substituents Y as defined above, or R 5 represents a heteroaryl group or a group of 1,2,3 4-tetrahydronaphthyl or indanyl, wherein the heteroaryl group or group of 1,2,3,4-tetrahydronaphthyl or indanyl may be substituted with 1, 2 or 3 Y substituents as defined above or R 5 represents a carbocyclic ring system of 4 to 10 fused monocyclic, fused bicyclic or monounsaturated or fully fused monocyclic fused tricyclic members, or R5 represents a fused monocyclic, fused bicyclic monocyclic or fused monocyclic ring system of 4-10 membered monocyclic or fully saturated heterocyclic ring systems substituted with 1 to 3 metal groups, an ethyl, amino or hydroxy group or a fluorine atom,

R3 represents a hydrogen or halogen atom or a cyano group, or R3 represents C1-6 alkyl group, wherein the C1-6 alkyl group may contain from 1 to 3 fluorine atoms or a hydroxy or amino group, or R3 represents a C 2-6 alkynyl or C 2-6 alkenyl group, wherein those groups are optionally substituted with 1 to 3 fluorine atoms,

R4 represents subgroup (ii)

<formula> formula see original document page 14 </formula>

on what

R 7 represents a hydrogen atom or a linear d 3 alkyl group,

R 8 represents a C 2-6 alkyl group wherein the group is substituted with a hydroxy or amino group or with 1 to 3 fluorine atoms, or R 8 represents a branched C 7-10 alkyl group, C 3-8 cycloalkyl group, C 5 group. 8 heterocycloalkyl, C 3-6 -cycloalkyl-C 1-2 alkyl group, C 5-7 -cycloalkyl-C 1-2 alkyl group, C 5-10 -cycloalkyl group, C 5-10 -cycloalkyl-C 1-2 alkyl group , C5-10-heterobicyclo-C1-6 alkyl group, C6-10-tricycloalkyl group, C6-10-tricycloalkyl-C1-6 alkyl group, C6-10-heterotriccyclo-C1-6 alkyl group wherein groups may be substituted with 1 to 5 substituents selected from methyl, hydroxy, ethyl, amino, hydroxymethyl, trifluoromethyl, or fluorine, or R 8 represents a phenyl group wherein the group is substituted with 1 to 5 Y substituents as defined above, or R 6 represents a naphthyl or a 1,2,3,4-tetrahydronaphthyl or indanyl group wherein the groups may be substituted with 1 to 3 Y substituents, or R g represents a phenyl-C 1-3 alkyl group, a diphenyl-C 1-3 alkyl group, wherein the groups may be substituted on their phenyl ring with 1 to 5 Y substituents, wherein Y has the aforementioned meaning, or R 8 represents a benzyl group, wherein the benzyl group is substituted with 1 to 5 Y substituents, or R 8 represents a heteroaryl, heteroarylmethyl or heteroarylethyl group, wherein the heteroaryl, heteroarylmethyl or heteroarylethyl group may be substituted with 1 to 3 Y substituents, such as defined above, or R8 represents a group of piperidinyl, azepanyl, morpholinyl, azabicyclo [3.3.0] octanyl, 4-hydroxypiperidinyl or pyrrolidinyl, provided that R8 is neither a 6-methoxy-benzothiazol-2-yl group nor [3-chloro-5- (trifluoromethyl) pyrid-2-yl] methyl group,

Even more particularly the invention relates to the compounds of formula (I)

<formula> formula see original document page 15 </formula>

on what:

R 1 represents a halogen atom or a C 1-3 alkyl group, wherein the C 1-3 alkyl group may contain from 1 to 3 fluorine atoms or a hydroxy group, or R 1 represents a cyano or methylsulfanyl group,

R2 represents a monounsaturated or fully saturated 5- to 7-membered monocyclic carbocyclic ring system that may be substituted with 1 to 5 substituents selected from methyl, ethyl, amino, hydroxy or fluorine, or R2 represents a phenyl group that may be substituted with 1 , 2, 3, 4 or 5 Y substituents, which may be the same or different, selected from the group consisting of methyl, ethyl, propyl, methoxy, ethoxy, hydroxy, chlorine, iodine, bromine, fluorine, trifluoromethyl, trifluoromethoxy, methylsulfonyl, carbamoyl, phenyl and cyano,

R3 represents a hydrogen or halogen atom or a methylsulfanyl or cyano group, or R3 represents a C1-6 alkyl group, wherein the C1-6 alkyl group may contain from 1 to 3 fluorine atoms or a hydroxy or amino group ,

R4 represents subgroup (ii)

<formula> formula see original document page 16 </formula>

on what

R7 represents a hydrogen atom or a methyl group,

R 8 represents a C 2-6 alkyl group wherein the group is substituted with 1 to 3 fluorine atoms, or R 8 represents a branched C 7-10 alkyl group, C 3-8 cycloalkyl group, C 5,8 heterocycloalkyl group, C 3 group. 8-cyclo-C 1-2 alkylalkyl, C 5-7 -heterocycloalkyl-C 1-4 alkyl group, C 5-10 bicycloalkyl group, C 5-10 -cycloalkylC 1-2 alkyl group, C5-10-heterobicycloalkyl-C group .2-alkyl, C6-10 tricycloalkyl group, C6-10 tricycloalkyl-C1-6 alkyl group, C6-10 hetero-tricycloalkyl C1-2-alkyl group wherein the groups may be substituted with 1 to 5 selected substituents of methyl, hydroxy, ethyl, amino, hydroxymethyl, trifluoromethyl, or fluorine, or Rg represents a defenyl group wherein the group is substituted with 1 to 5 Y substituents as defined above, or R8 represents a naphthyl or a group of 1.2, 3,4-tetrahydronaphthyl or indanyl wherein the groups may be substituted with 1 to 3 substituents Y, or R 5 represents a phenyl-C 1-3 alkyl group. Quyl, a C1-3 alkyl-diphenyl group, wherein the groups may be substituted on their phenyl ring with 1 to 5 Y substituents, wherein Y has the above-mentioned meaning, or Rg represents a substituted benzyl group, wherein the benzyl group is substituted with 1 to 5 Y substituents, or Rg represents a deheteroaryl, heteroarylmethyl or heteroarylethyl group, wherein the heteroaryl, heteroarylmethyl or heteroarylethyl group may be substituted with 1 to 3Y substituents, as defined above, with the proviso that R 6 is neither a 6-methoxy-benzothiazol-2-yl group nor a [3-chloro-5- (trifluoromethyl) pyrid-2-yl] methyl group.

More particularly, the invention relates to the compounds of formula (I)

<formula> formula see original document page 17 </formula>

on what:

R 1 represents a halogen atom or a C 1-3 alkyl group, wherein the do-alkyl group may contain from 1 to 3 fluorine atoms, or R 1 represents a cyano or methylsulfanyl group,

R2 represents a saturated monocyclic carbocyclic ring of six-membered or R2 represents a phenyl group which may be substituted with 1, 2 or 3 Y substituents, which may be the same or different, selected from the group consisting of methyl, ethyl, propyl, methoxy, ethoxy, hydroxy, chlorine, iodine, bromine, fluoro, trifluoromethyl, trifluoromethoxy, methylsulfonyl, carbamoyl, phenyl and cyano,

R3 represents a hydrogen or halogen atom or a group of methylsulfanyl or cyano, or R3 represents a C1-4 alkyl group, wherein the C1-4 alkyl group may contain from 1 to 3 fluorine atoms,

R4 represents subgroup (ii)

<formula> formula see original document page 17 </formula> where

R7 represents a hydrogen atom or a methyl group, R8 represents a C2-6 alkyl group wherein the group is substituted with 1 to 3 fluorine atoms, or Rg represents a branched C7.10 alkyl group, C3.8 group cycloalkyl, C5.8heterocycloalkyl group, C3.8-cycloalkyl-C1-2 alkyl group, C5.7-heterocycloalkyl-C1.2-alkyl group, C5.10-bicycloalkyl group, C5.10-bicycloalkyl group -C1-2-alkyl, C5-10-heterobicyclo-C1-6 alkyl group, C6-10 tricycloalkyl group, C6- fricycloalkyl-C1-6 alkyl group, C6-10-heterotrycloalkyl-C1-4 group. 2-alkyl, wherein the groups may be substituted with 1 to 5 substituents selected from methyl, hydroxy, ethyl, amino, hydroxymethyl, trifluoromethyl, or fluorine, or Rg represents a defenyl group wherein the group is substituted with 1 to 3 Y substituents. wherein Y has the meaning as defined above, or R 8 represents a denaphtyl group wherein the group may be substituted with 1 to 3 substituents Y, or R 8 represents a phenyl-C 1-2 alkyl group, wherein the group may be substituted on the phenyl ring with 1 to 3 Y substituents, wherein Y has the above-mentioned meaning, or R 8 represents a substituted benzyl group, wherein the benzyl group is substituted with 1 to 5 Y substituents.

Finally, the invention also specifically relates to compounds having formula (I) wherein R2 represents a saturated six-membered carbocyclomonocyclic ring or R2 represents a phenyl group which may be substituted with 1, 2, 3, 4 or 5 Y substituents, which may be the same or different, selected from the group consisting of methyl, ethyl, propyl, methoxy, ethoxy, hydroxy, chlorine, iodine, bromine, fluorine, trifluoromethyl, trifluoromethoxy, methylsulfonyl, carbamoyl, phenyl and cyano, and all other symbols have the meanings as described above.

In another embodiment, the invention relates to the compounds of general formula (XIV)

<formula> formula see original document page 19 </formula>

on what:

R 1 represents a halogen atom or a C 1-3 alkyl group, wherein the C 1-6 alkyl group may contain from 1 to 3 fluorine atoms or a hydroxy or amino group, or R 1 represents a C 2-6 group. 3-alkynyl, a C2-3-alkenyl group, wherein the C2-3-alkynyl group or C2-3-alkenyl group may contain from 1 to 3 fluorine atoms, or R1 represents an acetyl, cyclopropyl, cyano, methylsulfonyl, ethylsulfonyl, methylsulfinyl, ethylsulfinyl trifluoromethylsulfanyl, methylsulfanyl, ethylsulfanyl, formyl group or a group of C 2-4 -heteroalkyl,

R 2 represents a phenyl group which may be substituted with 1, 2, 3, 4 or 5 Y substituents, which may be the same or different, selected from the group consisting of methyl, ethyl, propyl, methoxy, ethoxy, hydroxy, chlorine, iodine, bromine, fluorine, trifluoromethyl, trifluoromethoxy, methylsulfonyl, carbamoyl, phenyl and cyano, or R2 represents a heteroaryl group wherein the heteroaryl group may be substituted with 1, 2 or 3 Y substituents, wherein Y has the meaning as defined above, provided that R2 is not a group of 6-methyl-2-pyridyl, or

R2 represents a fused monocyclic, fused bicyclic or fused tricyclic 4- to 10-membered monocyclic carbocyclic ring system, or

R2 represents a monocyclic, fused bicyclic fused monocyclic or fused tricyclic monocyclic ring system of fused to 10-membered monounsaturated or fully saturated ring wherein the carbocyclic or heterocyclic ring system may be substituted with 1 to 5 substituents selected from methyl, ethyl, amino, hydroxy or fluorine, or

R 2 represents a group of formula wherein R 5 represents a phenyl group which is substituted with 1, 2, 3, 4 or Y substituents as defined above, or R 5 represents a group of 5 heteroaryl or a group of 1, 2,3,4-tetrahydronaphthyl or indanyl, wherein the heteroaryl group or 1,2,3,4-tetrahydronaphthyl or indanyl group may be substituted with 1, 2 or 3 Y substituents as defined above or R 5 represents a system of monocyclic, fused bicyclic fused monocyclic or fused tricyclic monocyclic ring, monounsaturated or fully saturated, or R5 represents a fused monocyclic, fused bicyclic monocyclic or fused tricyclic ring system, wherein carbocyclic or heterocyclic ring systems are optionally substituted with 1 to 5 substituents selected from the group consisting of methyl, ethyl, amino, hydroxy or fluorine, or

R2 represents a methylsulfonylaminoalkyl, methylsulfonylalkyl group or an acetamidoalkyl group, provided that R2 does not represent a phenyl, 4-methylphenyl or 4-methoxyphenyl group,

R3 represents a hydrogen or halogen atom or a group of formyl, C1-6 alkylsulfonyl, C1-6 alkylsulfmyl, C1-6 alkylsulfanyl, trifluoromethylsulfanyl, benzylsulfanyl or cyano, or R3 represents C1-8 alkyl group, where C1 α-alkyl may be substituted with 1 to 5 substituents selected from the group consisting of fluorine, hydroxy or amino, or R 3 represents a group of C 2-6 alkynyl, C 2-6 alkenyl, C 1-6 alkanoyl, C 3-8 C5.8-heterocycloalkyl or C2.6-heteroalkyl, wherein the groups are optionally substituted with 1 to 3 methyl groups, an ethyl, amino or hydroxy group or 1 to 3 fluorine atoms, or R3 represents a phenyl group which is substituted with 1 to 5 Y substituents, wherein Y has the meaning as defined above, or R 3 represents a heteroaryl group wherein the heteroaryl group may be substituted with 1, 2 or 3 Y substituents, wherein Y has the meaning as defined above or R3 represents a group of benzyl or heteroaryl methyl wherein the benzyl or heteroaryl methyl group may be substituted with 1, 2 or 3 substituents Y, Z represents a chlorine atom or a group of Q 3 alkyl,

a hydroxy group, or a group of -O-Na, -OK, -O-Li or -O-Cs, or Z represents a group of N-methoxy-N-methylamino, such compounds being useful in the synthesis of compounds of formula (I) wherein:

R1 represents an atom of or a C1-3 alkyl group, wherein the C1-3 alkyl group may contain from 1 to 3 fluorine atoms or a hydroxy or amino group, or R3 represents a C2-3 alkynyl group, a C2-3 alkenyl group, wherein the C2-3 alkynyl group or C2-3 alkenyl group may contain from 1 to 3 fluorine atoms, or R1 represents an acetyl, cyclopropyl, cyano, methylsulfonyl group , ethylsulfonyl, methylsulfinyl, ethylsulfinyl trifluoromethylsulfanyl, methylsulfanyl, ethylsulfanyl, formyl group or a C 2-4 -heteroalkyl group,

R 2 represents a phenyl group which may be substituted with 1, 2, 3, 4 or 5 Y substituents, which may be the same or different, selected from the group consisting of methyl, ethyl, propyl, methoxy, ethoxy, hydroxy, chlorine, iodine, bromine, fluorine, trifluoromethyl, trifluoromethoxy, methylsulfonyl, carbamoyl, phenyl and cyano, or R2 represents a heteroaryl group wherein the heteroaryl group may be substituted with 1, 2 or 3 Y substituents, wherein Y has the meaning as defined above, provided that R2 is not a group of 6-methyl-2-pyridyl, or

R2 represents a fused monocyclic, fused bicyclic or fused tricyclic 4- to 10-membered monocyclic carbocyclic ring system, or

R 2 represents a monocyclic, fused bicyclic fused monocyclic or fused tricyclic monocyclic ring system of 4 to 10 membered monounsaturated or fully saturated wherein the carbocyclic or heterocyclic ring system may be substituted with 1 to 5 substituents selected from methyl, ethyl, amino, hydroxy or fluorine, or

R-2 represents a group of formula wherein R 5 represents a phenyl group which is substituted with 1, 2, 3, 4 or 5 Y substituents as defined above, or R 5 represents a heteroaryl group or a group of 1,2,3,4-tetrahydronaphthyl or indanyl, wherein the heteroaryl group or 1,2,3,4-tetrahydronaphthyl or indanyl group may be substituted with 1, 2 or 3 Y substituents as defined above or R 5 represents a system monocyclic, fused bicyclic fused monocyclic or fused tricyclic monocyclic ring or fused monocyclic ring, or R 5 represents a fused monocyclic, fused bicyclic monocyclic or fused monocyclic ring system, wherein carbocyclic or heterocyclic ring systems are optionally substituted with 1 to 5 substituents selected from the group consisting of methyl, ethyl, amino, hydroxy or fluorine, or R2 represents a methylsulfonylaminoalkyl, methyl group sulfonylalkyl or a group of acetamidoalkyl,

R 3 represents a hydrogen or halogen atom or a formyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfinyl, C 1-6 alkylsulfanyl, trifluoromethylsulfanyl, benzylsulfanyl or cyano group, or R 3 represents a C 1-8 alkyl group, wherein the C 1 group α-alkyl may be substituted with 1 to 5 substituents selected from the group consisting of fluoro, hydroxy or amino, or R 3 represents a group of C 2-6 alkynyl, C 2,6-alkenyl, C 1-6 alkanoyl, C 3. 8-cycloalkyl, Cg-heterocycloalkyl or C2,6-heteroalkyl, wherein the groups are optionally substituted with 1 to 3 methyl groups, an ethyl, amino or hydroxy group or 1 to 3 fluorine atoms, or R 3 represents a phenyl group which is substituted with 1 to 5 Y substituents, wherein Y has the meaning as defined above, or R 3 represents a heteroaryl group wherein the heteroaryl group may be substituted with 1, 2 or 3 Y substituents, wherein wherein Y has the meaning as defined above or R 3 represents a benzyl or heteroaryl methyl group wherein the benzyl or heteroaryl methyl group may be substituted with 1, 2 or 3 Y substituents.

GENERAL SUMMARY ASPECTS

The compounds of formula (I) may be prepared by different methodologies. The selection of the particular method depends on factors such as the compatibility of the functional groups with the reagents used, the possibility of using protecting groups, catalysts, activation and coupling reagents and the last structural aspects present in the final compound being prepared.

Imidazole derivatives may be obtained according to known methods. Relevant articles are:

a) Gomez-Sanchez et al., J. Heterocyclic Chem. (1987) 24, 1757-1763.

b) Matsuura et al., J. Chem. Sound. Perkin Trans. I (1991), 11, 2821-2826

c) Ueda et al., Tetrahedron Lett. (1988), 29, 4607-4610

d) Gupta et al., Eur. J. Med. Chem. (2004), 39, 805-814

e) Van Berkel et al. Tetrahedron Lett. (2004), 45, 7659-7662

f) Haberhauer and Rominger, Tetrahedron Lett. (2002), 43, 6335-6338

g) Dell Erba et al., Tetrahedron (1997), 53, 2125-2136.

h) Lipshutz et al., Tetrahedron Lett. (1992), 33, 5865-5868

The compounds of formula (I) may be obtained according to the procedures outlined in Schemes 1 to 6.

R 1 to R 8 have the meanings as given above on pages 2 to 5, R 9 and R 10 represent alkyl (d_3) <formula> formula see original document page 24 </formula>

Nitroenamine derivatives of general formula (II) may be prepared according to the procedure published by Gomez-Sanchez et al., J. Heterocyclic Chem. (1987) 24, 1757-1763. Nitroenamine derivatives of formula (II) may be reacted with orthoesters of formula

(III) to provide imidazole derivatives of formula (IV) (Scheme 1). Subsequent basic ester hydrolysis, for example using lithium hydroxide (LiOH), NaOH, KOH or CsOH may provide intermediate imidazocarboxylic acid alkaline salts, which may be acidified by an acid such as aqueous hydrochloride (HCl) to provide acid derivatives. imidazolecarboxylic of formula (V). The compounds of general formula

(IV) may be subjected to amide with an amine of formula R 7 RgNH in a compound of formula (I) wherein X represents subgroup (ii) as defined above. Such amidations may be catalyzed by trimethylaluminum (CH3) 3A1. (For more information on aluminum-mediated conversion of esters to amides, see: J. I. Levin, E. Turos, S. M. Weinreb, Synth. Commun. (1982), 12, 989-993). Imidazole carboxylic acid derivatives of formula (V) or their corresponding alkaline salts may be reacted with an amine of formula R 7 RsNH in a compound of formula (I) wherein X represents subgroup (ii) as defined above. This particular reaction preferably proceeds through activation and coupling methods such as formation of an active ester, or in the presence of a so-called coupling reagent, such as for example DCC, HBTU (O-benzotriazol-1-yl-1-yl) hexafluorophosphate. N, N, N ', N'-tetramethyluronium), TB TU, HOAt (N-hydroxy-7-azabenzotriazole), PiBOP (benzotriazol-1-yloxytris (pyrrolidino) -phosphonium hexafluorophosphate), BOP, CIP (hexafluorophosphate) 2-chloro-1,3-dimethylimidazolium), 2-chloro-1,3-dimethylimidazolium chloride, PyAOP (7-azabenzotriazol-1-yloxytris (pyrrolidino) -phosphonium hexafluorophosphate) and others. (For more information on activation and coupling methods see a) M. Bodanszky, A. Bodanszky: The Practice of Peptide Synthesis, Springer-Verlag, New York, 1994; ISBN: 0-387-57505-7; b) K. Akaji et al., Tetrahedron Lett. (1994), 35, 3315-3318; c) F. Albericio et al., Tetrahedron Lett. (1997), 38, 4853-4856); d) C. Montalbetti and V. Falque, Tetrahedron (2005), 61, 10827-10852).

Alternatively, a compound having the general formula (V) or the corresponding alkaline salts may be reacted with a so-called halogenating agent such as for example thionyl chloride (SOCl 2) or oxalyl chloride. This reaction provides the corresponding carbonyl chloride (acid chloride) (Va) which may subsequently be reacted with a compound having the formula R7R8NH wherein R7 and R8 have the meanings as described above to provide a compound of formula (I) in where X represents subgroup (ii) as defined above. Such reactions may be catalyzed by pyridine or 4-dimethylaminopyridine (DMAP).

A compound having the general formula (V) may be reacted with N-methoxy-N-methylamine in the presence of a coupling reagent to produce the corresponding N-methoxy-N-methylarylide of general formula (VI) and subsequently reacted with a coupling reagent. lithium of formula R-Li or a Grignard reagent to provide a compound of formula (I) wherein X represents subgroup (i) as defined above.

R 1 to R 5 have the meanings as given above as on pages 2 to 5, R 9 represents (C 1-3) alkyl. In the compounds of formula R2-B (OH) 2, R2 represents an optionally substituted phenyl or heteroaryl group, a so-called Suzuki reagent.

<formula> formula see original document page 26 </formula>

Alternatively, a compound having the general formula (VII) may be reacted with a compound of the general formula (VIII), wherein L represents a so-called leaving group such as chlorine, bromine, iodine or mesyloxy (Scheme 2). A compound having general formula (VII) may likewise be reacted with a methylsulfonylaminoalkyl halogenide or methylsulfonylalkyl halogenide to add a methylsulfonylaminoalkyl group or methylsulfonylalkyl group at the 1-position of the imidazole nucleus. Such reactions are preferably performed in the presence of a base such as sodium hydride or potassium carbonate to facilitate nucleophilic attack of compound (VII) to produce a compound of formula (IV), wherein R2 represents a group -CH2 R5 and R5 Alternatively, a compound having the general formula (VII) may be reacted with the compound of formula R2-B (OH) 2 wherein R2 represents an optionally substituted phenyl or heteroaryl group, a so-called reagent. Suzuki, to produce a compound of formula (IV). Compounds of formula (IV) may be converted to compounds of formula (I) according to Scheme 1. Such reactions may be catalyzed with metal.

R 1 - R 3 have the meanings as given above on pages 2 to 5, R 9 represents (C 1-3) alkyl.

A compound having the general formula (IX) may be reacted with a nitrite derivative such as sodium nitrite (NaNO2) to provide a compound of the general formula (X). (Scheme 3). A compound having the general formula (X) may be reacted with an anhydride of the general formula (R 1 CO) 20 in the presence of a reducing agent such as hydrogen and a catalyst such as Pd on carbon (Pd / C) and others. in an inert organic solvent such as ethanol to provide a compound of formula (XI). A compound having formula (XI) may be reacted with an amine of formula R 2 NH 2 in an inert solvent such as butyronitrile to provide a compound of formula (IV). The compounds of formula (IV) may be converted to compounds of formula (I) according to Scheme 1.

Alternatively, a compound of formula (XI) may be obtained in a two-vessel reaction from a compound of formula (XII). A compound of formula (XII) may be deprotonated with a strong base such as potassium tert-butoxide (KO-t-Bu) and subsequently reacted with an acylation compound of formula R3COL, wherein L represents a leaving group. such as chloride, followed by treatment with an acid such as hydrochloric acid and the like. The resulting compound of formula (XIII) may be reacted with an anhydride of formula (R1CO) O to provide a compound of formula (XI). Alternatively, a compound having general formula (X) may be reacted with a reducing agent such as hydrogen and a catalyst such as Pd on carbon (Pd / C) and the like, in an inert organic solvent such as ethanol in the presence of a acid such as hydrochloric acid to provide a compound of formula (XIII).

R 4 through R 3 have the meanings as given above on pages 2 to 5, X represents subgroup (ii).

<formula> formula see original document page 28 </formula>

where X represents subgroup (ii) where X represents subgroup (ii)

A compound having general formula (I) wherein X represents subgroup (ii) and wherein position 5 of the imidazole component contains a hydrogen atom may be deprotonated with a strong non-nucleophilic base such as lithium diisopropylamide (LDA), followed by treatment with a group R3-L wherein L represents a leaving group to provide a compound of formula (I) wherein X represents subgroup (ii) and wherein apposition 5 of the imidazole component contains a substituent R3 (Scheme 4).

The symbols R2, R7, Rs and R9 have the meanings as given above on pages 2 to 5, E is derived from an electrophilic component, L represents a leaving group.

<formula> formula see original document page 29 </formula>

An imidazole derivative of formula (IV) wherein R 1 and R 3 represent hydrogen and where R 9 has the above meaning may be converted by ester hydrolysis, for example by use of lithium hydroxide (LiOH), NaOH , KOH or CsOH to provide alkaline salts of intermediate imidazocarboxylic acid, wherein the salts may be acidified by an acid such as aqueous hydrochloride (HCl) to provide imidazole carboxylic acid derivatives of formula (V). Imidazolecarboxylic acid derivatives of formula (V) may be subjected to amide to provide a compound of formula (I) wherein R1 and R3 represent hydrogen and R2, R7 and Rg have the above mentioned meanings. This compound of formula (I) wherein R 1 and R 3 represent hydrogen and R 2, R 7 and R 8 have the aforementioned meanings may be deprotonated with a strong non-nucleophilic base such as lithium diisopropylamide (LDA) or n-Buli, followed by treatment with an EL group wherein L represents a leaving group such as iodide, bromide, or S-alkyl and E represents an electrophilic group including, but not limited to, -S-alkyl, primary alkyl, chlorine, bromine, iodine or cyano to provide a compound of formula (I) wherein X represents subgroup (ii) and wherein position 2/5 of the imidazole component represents a substituent E and / or a hydrogen atom, depending on the type of E-L group applied in this reaction (Scheme 5). The definition of group E is part of the definition of Ri and R3 and does not exceed the definitions of Ri and R3 provided above. Mixtures of compounds that may be formed in the last reaction step in Scheme 5 may be separated and purified, for example by chromatographic methods or by crystallization techniques.

Scheme 6: The symbols R2, R7 and R8 have the meanings as given above as on pages 2 to 5.

<formula> formula see original document page 30 </formula>

A compound of formula (I) wherein R 1 and R 3 represent hydrogen and R 2, R 7 and R 6 have the above meanings may be reacted with a halogenating agent such as N-chlorosuccinimide (NCS) or bromine (Br 2) in a solvent inert organic such as dichloromethane to provide a compound of formula (I) wherein R 3 represents Cl or Br and R 3 represents a hydrogen atom. A compound of formula (I) wherein R 3 represents Cl or Br and K 3 represents a hydrogen atom may be reacted with a halogenating agent such as NCS or Br 2 in an inert organic solvent such as dichloromethane to provide a compound of formula general (I) wherein R3 represents Cl or Br and R1! represents Cl or Br (Scheme 6).

For more detailed information on nucleophiles, electrophiles and the leaving group concept see: M. B. Smith and J. March: Advanced organic chemistry, p. 275, 5th ed., (2001) John Wiley & Sons, New York, ISBN: 0-471-58589-0). More information on addition and subsequent removal of protecting groups in organic synthesis can be found at: T.W. Greene and P.G.M. Wuts, "Protective Groups with Organic Synthesis", third edition, John Wiley & Sons, Inc., New York, 1999.

Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by mixing a compound of the present invention with a suitable acid, for example an inorganic acid such as hydrochloric acid, or with an organic acid such as acid. smoking.

PHARMACEUTICAL PREPARATIONS

The compounds of the invention may be presented in forms suitable for administration by standard procedures using auxiliary substances such as liquid or solid carrier material. The pharmaceutical compositions of the invention may be administered enterally, orally, parenterally (intramuscularly or intravenously), rectally or locally (topically). They may be administered in the form of solutions, powders, capsule tablets (including microcapsules), ointments (creams or gel) or suppositories. Suitable excipients for such formulations are customary pharmaceutical or liquid fillers and diluents, solvents, emulsifiers, lubricants, flavorings, colorants and / or buffering substances. Commonly used auxiliary substances which may be mentioned are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars or sugar alcohols, talc, lactoprotein, gelatin, starch, cellulose and their derivatives, animal and vegetable oils such as fish liver, sunflower oil, peanut or sesame, polyethylene glycol and solvents such as, for example, sterile water and mono- or polyhydric alcohols such as glycerol.

The compounds of the present invention are generally administered as pharmaceutical compositions which are important and novel embodiments of the invention because of the presence of the compounds, more particularly the specific compounds disclosed herein. Types of pharmaceutical compositions that may be used include, but are not limited to, tablets, chewable tablets, capsules, solutions, parenteral solutions, suppositories, suspensions, and other types set forth herein or apparent to one skilled in the art from the report. descriptive and general knowledge in the art. In embodiments of the invention, a pharmaceutical patch or kit is provided comprising one or more containers provided with one or more of the ingredients of a pharmaceutical composition of the invention. Associated with such container (s) may be various written materials such as instructions for use, or a notice in the form prescribed by a government agency that regulates the manufacture, use, or sale of pharmaceutical products, where the notice depicts approval. by the agency of manufacture, use or sale for human or veterinary administration.

PHARMACOLOGICAL METHODS

In vivo and in vitro pharmacological assays related to CB2 cannabinoid receptor neurotransmission have been described in the literature. Some examples are: • Ibrahim, M.M. et al. (2003) Proc. Natl. Acad. Know. USA 100, 10529-10533 • Hanus, L. et al. (1999) Proc. Natl. Acad. Know. USA 96, 14228-14233 • Zhang, J. et al. (2003) Eur. J. Neuroscience 17, 2750-2754. • Klein, T.W. et al. (2003) J. Leukoc. Biol. 74, 486-496

• Shoemaker, J.L. et al. (2005), J. Pharmacol. Exp. Ther. 315, 828-838 • Iwamura, H. et al. (2001), J. Pharmacol. Exp. Ther. 296, 420-425. In vitro affinity for cannabinoid-CBi receptors

The affinity of the compounds of the invention for CB1 cannabinoid receptors can be determined using Chinese hamster ovary (CHO) cell membrane preparations in which the human CBj cannabinoid receptor is stably transfected together with [3H] CP-55,940 as radioliging. Following incubation of a freshly prepared cell membrane preparation with [3 H] ligand, with or without the addition of compounds of the invention, separation of bound and free ligand is performed by filtration through glass fiber filters. Radioactivity in the filter is measured by the liquid scintillation count. In vitro affinity for cannabinoid-CB2 receptors

The affinity of the compounds of the invention for CB2 cannabinoid receptors can be determined using Chinese hamster ovary (CHO) cell membrane preparations wherein the human CB2 cannabinoid receptor is stably transfected together with [3H] CP-55,940 as radioligand. Following incubation of a freshly prepared cell membrane preparation with [3 H] ligand, with or without the addition of compounds of the invention, separation of bound and free ligand is performed by filtration through glass fiber filters. Radioactivity in the filter is measured by the liquid scintillation count.

Due to their CB2 cannabinoid receptor modulating activity the compounds according to the invention are suitable for use in the treatment of immune system disorders, inflammatory disorders, allergies, pain, neuropathic pain, multiple sclerosis, neurodegenerative disorders, dementia, dystonia, muscle spasticity, tremor, epilepsy, traumatic brain damage, stroke, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease, cerebral ischemia, stroke, head injury, spinal cord injury, neuroinflammatory disorders, brain stem neurodegeneration , plaque sclerosis, viral encephalitis, demyelination-related disorders, and other neurological disorders, as well as in the treatment of cancers, diabetes, gastric diseases, lung diseases, asthma, and cardiovascular diseases, as well as other diseases in which neurotransmitter receptor transmission CB2 is involved life.

The compounds of the invention may be presented in forms suitable for administration by standard procedures using auxiliary substances and / or liquid or solid carrier materials. DOSE

The affinity of the compounds of the invention for cannabinoid CB2 receptors was determined as described above. From the binding affinity for a given compound of formula (I), a theoretical lower effective dose can be estimated. At a compound concentration equal to twice the measured Kj value, 100% of CB2 cannabinoid receptors are likely to be occupied by the compound. Converting this concentration to mg of compound per kg of the patient produces a theoretical lower effective dose that assumes optimal bioavailability. Pharmacokinetics, pharmacodynamics and other considerations may alter the generally administered dose to a higher or lower value. The conveniently administered dosage is from 0.001 to 1000 mg / kg, preferably from 0.1 to 100 mg / kg body weight of the patient.

TREATMENT

The term "treatment" as used herein refers to any treatment of a mammal, preferably human condition or disease, and includes: (1) preventing the disease or condition from occurring in an individual who may be predisposed to the disease, but has not yet been diagnosed as having it, (2) inhibiting the disease or condition, ie stopping its development, (3) relieving the disease or condition, ie causing the condition to regress, or (4) relieving the conditions caused by the disease, that is, stopping the symptoms of the disease.

EXAMPLES

EXAMPLE 1: MATERIALS AND METHODS All reactions involving moisture-sensitive compounds or conditions were performed under an anhydrous nitrogen atmosphere. Reactions were monitored by the use of thin layer chromatography (TLC) on silica coated plastic slides (Merck precoated silica gel 60 F245) with the indicated eluent. Dots were visualized by UV light (254 nm) or I2.

Scintillant chromatography refers to purification using the indicated eluent and Acros silica gel (0.030 to 0.075 mm). Petroleum ether (benzine) means petroleum ether 40-60. Nuclear magnetic resonance spectra (1 HNMR and 13 C NMR) were determined in the indicated solvent with tetramethylsilane as an internal standard. Chemical changes are given in ppm (scale 5) downstream of tetramethylsilane. Coupling constants J are given in hertz (Hz). Peak forms in the NMR spectra are indicated with the symbols 'q' (quartet), 'dq' (doublet quartet), 't' (triplet), 'dt' (doublet triplet), 'd' (doublet) ), 'dd' (doublet doublet), 's' (singlet), 'br s' (broad singlet) and 'm' (multiplet). Melting points were recorded on a Büchi B-545 melting point mechanism or determined by a differential scanning calorimetry (DSC) method. Yields refer to pure isolated products.

Preparative LC / MS Instrumentation and ProcedureSciex API 150 EX Electron Spray Mass Spectrometer, 2 Shimadzu LC8A LC Pump, Shimadzu SCL-10A VP System Controller, Shimadzu SPD-10A VP UV Meter, 25 Gilson 215 Injector / Collector

Column: Phenomenex Luna Cl8 (2)

: 150x21.2x5 u. Eluent: At 100% Water + 0.1% formic acid at pH

= 3: B 100% Acetonitrile + 0.1% formic acid

Injection: 2.5 ml

Divider: 1 to 50,000 with a preparation flow of 0.2 ml / min

: (25% H2 O / 75% ACN met 0.25% HCOOH)

MS Exam: step from 100 to 900 amu exam time from 1 amu 1 sec.

Method: Flow rates and gradient profiles.

<table> table see original document page 36 </column> </row> <table>

EXAMPLE 2: SUMMARY OF SPECIFIC COMPOUNDS

The specific compounds of which the synthesis is described below are intended to further illustrate the invention in greater detail, and therefore are not considered to narrow the scope of the invention in any way. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention presented herein. It is thus intended that the specification and the compounds be considered as exemplary only, with a true scope and spirit of the invention being indicated by the claims. Synthesis of compound 1

Part A: A magnetically stirred mixture of ethyl 5-methyl-1H-imidazole-4-carboxylate (13.875 g, 0.090 mol), phenylboronic acid (13.16 g, 0.108 mol) and Cul (0.85 g, 0, 0045 mol) in ethanol / water (900 ml, 1/1 (v / v)) was divided into 12 equal parts and reacted in parallel at 85 ° C for 60 hours. After cooling to room temperature the 12 parts were combined and concentrated in vacuo. The residue was purified by scintillation chromatography (Ethyl acetate / petroleum ether (benzine) 40 to 65 = 1/1 (v / v)) to provide ethyl 5-methyl-1-phenyl-1H-imidazole-4-carboxylate (5.88 g, 26% yield). 1 H NMR (400 MHz, CDCl 3): δ 1.42 (t, J = 7 Hz, 3H), 2.47 (s, 3H), 4.40 (q, J = 7 Hz, 2H), 7, 26 - 7.31 (m, 2H), 7.48 - 7.56 (m, 3H), 7.59 (s, 1H).

Part B: (-) - cis -Mirtanylamine (CAS 38235-68-6) (0.95 mL, 5.7 mmol) was dissolved in anhydrous dichloromethane (15 mL) and (CH3) 3A1 (2.9 mL of a 2 M solution in heptane, 5.8 mmol) was added. The resulting mixture was magnetically stirred for 10 minutes at room temperature and ethyl 5-methyl-1-phenyl-1H-imidazole-4-carboxylate (1.1 gram, 4.8 mmol) was added. The resulting mixture was stirred at 35 ° C for 16 hours, poured into an aqueous NaHCO 3 solution, stirred for 30 minutes and filtered through Hyflo. The filtrate was extracted twice with dichloromethane. The organic layers were dried by Na 2 SO 4, filtered and concentrated in vacuo. Subsequent purification with scintillation chromatography (ethyl acetate / petroleum ether (benzine) 40-65 = 1/2 (v / v)) provided N - [(1R, 2S, 5R) -rel-6,6-dimethylbicyclo [3.1 .1] heptan-2-methyl] -5-methyl-1-phenyl-1H-imidazole carboxamide, compound 1 (1.05 grams, 65% yield). Melting point: 85 to 89 ° C.

<formula> formula see original document page 37 </formula>

Similarly, the following compounds 2 through 7 were prepared:

<formula> formula see original document page 37 </formula>

Compound 2: Melting point: 214 to 219 ° C. <formula> formula see original document page 38 </formula>

Compound 3: Melting point: 167 to 169 ° C.

<formula> formula see original document page 38 </formula>

Compound 4: R - (+) - Bomylamine (CAS 32511-34-5). Melting point: 209 to 212 ° C.

<formula> formula see original document page 38 </formula>

Compound 5: endo- (1R) -1,33-trimethylbicyclo [2.2.1] heptan-2-amine. Melting point: 149 to 152 ° C.

<formula> formula see original document page 38 </formula>

Compound 6: Melting point: 198 to 200 ° C.

<formula> formula see original document page 38 </formula>

Compound 7: Melting point: 232 to 234 ° C. <formula> formula see original document page 39 </formula>

Synthesis of compound 8

Part A: Ethyl 2-methyl-1-phenyl-1H-imidazole-4-carboxylate (4.8 grams, 21% yield) was prepared according to the procedure described (in J. Heterocyclic Chem. 1987, 24, 1757-1763) from ethyl 3-anilino-2-nitroacrylate (23.6 grams, 0.01 mol) and triethylortoacetate (150 ml). The initially formed crude product was purified by scintillation chromatography (eluent: diethyl ether). Rf (diethyl ether ~ 0.15) to provide pure ethyl 2-methyl-1-phenyl-1H-imidazole-4-carboxylate as an oil.

Part B: Ethyl 2-methyl-1-phenyl-1H-imidazole-4-carboxylate (2.25 grams, 0.012 mol) was reacted (analogously to the procedure described above for compound 1) with AlMe3 (7.2 ml of a 2M solution in hexane, 0.0144 mol) and 1-adamantane amine. HCl (2.25 g, 0.012 mol). The initially formed crude product was purified by scintillation chromatography (eluent: diethyl ether) to afford N-adamantyl-2-methyl-1-phenyl-1H-imidazole-4-carboxamide (2.2 grams, 55% yield). Melting point: 207 to 210 ° C.

<formula> formula see original document page 39 </formula>

Compound 9 was prepared analogously to compound 6 from (-) - cis -mirtanylamine (CAS 38235-68-6). Melting point: 124 to 127 ° C. <formula> formula see original document page 40 </formula>

10

Compound 10: N-Adamantyl-2-methyl-1-phenyl-1H-imidazole carboxamide (0.33 grams, 0.001 mol) was dissolved in anhydrous tetrahydrofuran (25 ml). The resulting solution was slowly added to a solution of lithium diisopropylamide (1.25 ml of a 2 M solution in heptane / THF, 0.0025 mol LDA) under N 2 at -70 ° C. A solution of methyl iodide (0.14 grams, 0.001 mol) in anhydrous THF was added and the resulting solution was stirred for 1 hour at -70 ° C. The solution was allowed to reach room temperature and stirred for a further 2 hours and subsequently quenched with aqueous acetic acid. After concentration in vacuo the resulting residue was purified by scintillation chromatography (diethyl ether / petroleum ether (benzine) (40-60) = 3/1 (v / v)) to provide compound 10 and compound 11, respectively. Compound melting point 10: 180al83 ° C.

<formula> formula see original document page 40 </formula>

11

Compound 11: Compound 11 was prepared most efficiently by the reaction of ethyl 2,5-dimethyl-1-phenyl-1H-imidazole-4-carboxylate (cf. corresponding methyl ester 3j in J. Heterocyclic Chem. 1987, 24 1757-1763) with AlMe3 and 1-adamantane-amine.HCl according to the Weinreb amidation procedure described above for compound 1, Part B. Melting point: 201 to 204 ° C.

Synthesis of compound 12

Part A: Ethyl 2,5-dimethyl-1- (3-methoxyphenyl) -1H-imidazole-4-carboxylate was prepared analogously to the procedure described (in J. Heterocyclic Chem. 1987, 24, 1757-1763) from 3 - Ethyl (3-methoxyphenylamino) -3-methyl-2-nitroacrylate and triethylortoacetate.

Part B: Ethyl 2,5-dimethyl-1- (3-methoxyphenyl) -1H-imidazole-4-carboxylate was subjected to amide (analogously to the procedure described above for compound 1) (stirred at 70 ° C for 16 hours) with AlMe3 and (-) - cis-mirtanylamine (CAS 38235-68-6) to provide compound 12. Melting point: 153 to 155 ° C.

<formula> formula see original document page 41 </formula>

Similarly compounds 13 to 20 were prepared.

<formula> formula see original document page 41 </formula>

Synthesis of compound 21

Part A: To a magnetically stirred suspension of ethyl 4-methyl-1H-imidazole-5-carboxylate (15.42 grams, 0.100 mol) in anhydrous THF was slowly added sodium hydride (NaH) (4.88 g of a 60% suspension, 0.120 mol) and the resulting mixture was stirred at room temperature for 30 minutes. Benzyl bromide (13.8 mL, 0.120 mol) was slowly added and the resulting mixture was reacted for 16 hours. Water was added to the mixture. The organic layer was separated from the water layer. The water layer was extracted 3 times with ethyl acetate. The organic layer was dried by MgSO4, filtered and completely concentrated to afford an oil. The resulting residue was purified (to separate the two formed regioisomers) by scintillation chromatography (diethyl ether / ethyl acetate gradient) to afford ethyl N-benzyl-5-methyl-1H-imidazole-4-carboxylate (11, 4 grams, 47% yield). 1 H-NMR (400 MHz, CDCl 3): δ 1.40 (t, J = 7.3H), 2.45 (S, 3H), 4.37 (q, J = 7.2H), 5.10 (s, 2H), 7.03 - 7.08 (m, 2H), 7.28 - 7.38 (m, 3H), 7.48 (s, 1H).

Part B: Ethyl N-benzyl-5-methyl-1H-imidazole-4-carboxylate (1.5 grams, 0.0061 mol) was reacted with adamantyl-1-amine. HCl (1.72 g, 0.0092 mol) and A1 (CH3) 3 (4.6 mL, 2M in hexane, 0.0092 mol) in 1,2-dichloroethane (20 mL) at 70 ° C for 40 hours according to the procedure described for compound 1, part B. Purification by scintillation chromatography (ethyl acetate / petroleum ether (benzine) = 1/1 (v / v)) provided compound 21 (1.24 grams, 58 %). Melting point: 182 to 184 ° C.

<formula> formula see original document page 42 </formula>

21

Similarly compounds 22, 23 and 23A were prepared:

<formula> formula see original document page 42 </formula>

Compound 22Synthesis of compound 22

Compound 22 was prepared by coupling 3- (methylsulfonylamino) propyl chloride with ethyl 4-methyl-1H-imidazole-5-carboxylate using K 2 CO 3 as the base in DMF at 90 ° C for 20 hours, subsequent separation of the two. regioisomers formed by scintillation chromatography (ethyl acetate / methanol = 9/1 (v / v)), followed by catalyzed amidation of A1 (CH3) 3 with (-) - cis-mirtanylamine.

Compound 22. Melting point: 84 to 108 ° C. Rf 0.35 (EtOAc / MeOH = 4/1 (v / v)).

<formula> formula see original document page 43 </formula>

Compound 23. (from endo- (IR) -1,3,3-trimethylbicyclo [2.2.1] heptan-2-amine) Melting point: 149 to 156 ° C. Rf 0.4 (EtOAc / MeOH = 4/1 (v / v)).

<formula> formula see original document page 43 </formula>

Synthesis of compound 23A

Compound 23A was prepared by coupling 1-methyl-piperidin-2-ylmethyl ester of methanesulfonic acid HCl with ethyl 4-methyl-1H-imidazole-5-carboxylate using KOH as the base in DMSO at 60 ° C for 40 hours subsequent separation of the regioisomers formed by scintillation chromatography (dichloromethane / methanol = 95/5 (v / v)), followed by conversion of the resulting ester to the corresponding carboxylic acid (lithium hydroxide / THF / water; at 60 ° C for 20 hours) and coupling the carboxylic acid formed with (-) - cis-mirtanylamine using PyBOP (benzotriazol-1-yloxytris (pyrrolidine) -phosphonium hexafluorophosphate) as the coupling reagent in the presence of diisopropylethylamine in dichloromethane. Crude 23A was further purified by scintillation chromatography (dichloromethane / methanol = 95/5 (v / v)), followed by conversion of the isolated free base to the dihydrochloride salt.

Compound 23A. Melting point: 148 to 153 ° C.

Compound Synthesis 24

Part A: To a magnetically stirred solution of ethyl N-benzyl-5-methyl-1H-imidazole-4-carboxylate (8.4 grams, 0.0345 mol) in methanol (200 ml) was slowly added a solution of KOH. (7.3 grams, 85% graduation, 0.110 mol) and the resulting mixture was heated to 80 ° C for 2 hours. The solution was cooled to room temperature and concentrated HCl (9.2 mL) was subsequently added. The formed precipitate was collected by filtration to provide N-benzyl-5-methyl-1H-imidazole-4-carboxylic acid (6.77 grams, 91% yield). Melting point: 292 ° C (decomposed).

Part B: To a magnetically stirred solution of N-benzyl-5-methyl-1H-imidazole-4-carboxylic acid (6.77 grams, 0.031 mol) in anhydrous acetonitrile (35 ml) was successively added diisopropylethylamine (DIPEA) (17 2 ml, 0.0992 mol), HBTU (14.098 grams, 0.0372 mol) and methoxy methylamine (3.63 grams, 0.0372 mol). The resulting mixture was reacted at 20 ° C for 16 hours and subsequently concentrated in vacuo. The resulting residue was taken up in ethyl acetate and successively washed with 5% aqueous NaHCl 3 solution and water. The organic layer was dried by MgSO4, filtered and concentrated in vacuo. The resulting oily residue (18.45 grams) was purified by scintillation chromatography (ethyl acetate / acetone = 7/3 (v / v)) to afford N-methoxy-N-methyl-5-methyl-1-benzyl-1H -imidazol-4-carboxamide (10.77 grams, 82% yield). MH + = 260. 1 H NMR (400 MHz, CDCl3): δ 2.34 (s, 3H), 3.47 (s, 3H), 3.77 (s, 3H), 5.09 (s, 2H) , 7.05 - 7.10 (m, 2H), 7.18 - 7.28 (m, 3H), 7.48 (s, 1H).

Part C: To a magnetically stirred solution of 1-naphthylmagnesium bromide (49 ml, 0.25 M in THF, 0.00123 mol) was added a solution of N-methoxy-N-methyl-5-methyl-1-benzyl -1H-imidazole-4-carboxamide (2.69 grams, 0.0104 mol) in anhydrous THF (10 mL) and the resulting solution was stirred for 1 hour. The reaction mixture was quenched in 1N HCl (21 mL) and subsequently extracted with ethyl acetate (EtOAc). The EtOAc layer was twice washed with water, dried over MgSO4, filtered and concentrated in vacuo. The resulting crude residue was purified by scintillation chromatography (ethyl acetate / petroleum ether (benzine) = 1/1 (v / v)) followed by further scintillation chromatographic purification (dichloromethane / methanol = 99/1 (v / v)). ) to provide pure compound 24 (1.35 grams, 66% yield) as an oil. 1 H-NMR (400 MHz, CDCl 3): δ 2.58 (s, 3H), 5.12 (s, 2H), 7.08 - 7.13 (m, 2H), 7.31 - 7.40 (m, 3H), 7.44 - 7.56 (m, 4H), 7.78 - 7.82 (m, 1H), 7.84 - 7.89 (m, 1H), 7.92 - 7.96 (m, 1H), 8.16-8.22 (m, 1H).

<formula> formula see original document page 45 </formula>

24

Synthesis of compound 25

Similarly, compound 25 (from N-methoxy-N-methyl-5-methyl-1-phenyl-1H-imidazole-4-carboxamide and n-hexyl lithium in anhydrous diethyl ether) was prepared. Scintillation chromatographic purification (methyl tert-butyl ether / petroleum ether (benzine) = 1/3 (v / v)) of the initially isolated crude product provided compound 25 (24% yield) as a pale yellow oil. > formula see original document page 46 </formula>

Compound 25.] 1 H-NMR (400 MHz, CDCl 3): δ 0.86 - 0.94 (m, 3H), 1.25 - 1.47 (m, 6H), 1.70 - 1.80 (m , 2H), 2.50 (s, 3H), 3.04 - 3.11 (m, 2H), 7.26 - 7.32 (m, 2H), 7.50 - 7.59 (m, 4H ).

Similarly, compound 26 was prepared;

<formula> formula see original document page 46 </formula>

Compound 26; Rf (methanol / dichloromethane = 3/97 (v / v), silica gel) = 0.65.

Synthesis of compound 27

To a magnetically stirred solution of N- (adamant-1-yl) -1-phenyl-1H-imidazol-4-carboxylate (1.61 grams, 0.005 mol) in dichloromethane (20 ml) was added a solution of Br2 (0 , 52 mL, 0.010 mmol) in dichloromethane (5 mL). The resulting mixture was reacted at room temperature for 4 hours. Dichloromethane and 5% aqueous NaHCO3 solution were added to the reaction mixture. The separated organic layer was dried by MgSO 4, filtered and concentrated in vacuo. The resulting residue was purified by scintillation chromatography (dichloromethane / acetone = 19/1 (v / v)). Subsequent recrystallization from acetonitrile provided N- (adamant-1-yl) -5-bromo-1-phenyl-1H-imidazol-4-carboxamide (0.51 grams, 26% yield). Melting point: 229 to 232 ° C.

Similarly, compound 28 was prepared in 17% yield using N-chlorosuccinimide (NCS) as the chlorinating agent for 40 hours at room temperature. Scintillant chromatography (dichloromethane / acetone = 19/1 (v / v)). Melting point: 209 to 213 ° C.

Door 28

Synthesis of compound 29

To a magnetically stirred solution of N- (adamant-1-yl) -5-bromo-1-phenyl-1H-imidazol-4-carboxylate (0.60 grams) in dichloromethane (20 ml) was added a solution of Br2 ( 0.30 ml) in dichloromethane (5 ml) and triethylamine (0.21 ml). The resulting mixture was reacted at room temperature for 50 hours. Dichloromethane and 5% aqueous NaHCO3 solution were added to the reaction mixture. The separated organic layer was dried by MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by scintillation chromatography (dichloromethane). Subsequent stirring in diethyl ether followed by filtration gave N- (adamant-1-yl) -2,5-dibromo-1-phenyl-1H-imidazol-4-carboxamide (0.29 g). Melting point: 228 to 231 ° C.

<formula> formula see original document page 47 </formula>

29

Similarly, compound 30 in 32% yield was prepared from N- (adamant-1-yl) -5-chloro-1-phenyl-1H-imidazole-4-carboxylate using N-chlorosuccinimide (NCS) as the agent of chlorination. Melting point: 193 to 195 ° C. <formula> formula see original document page 48 </formula>

Synthesis of compound 31

To a magnetically stirred suspension of N- (adamant-1-yl) -2-methyl-1-phenyl-1H-imidazol-4-carboxylate (2.01 grams, 0.006 mol) in anhydrous THF (20 ml) under N 2 in At -70 ° C a solution of lithium diisopropylamide (LDA) (9.0 ml of a 2 M solution in heptane / THF, 0.018 mol LDA) under N 2 at -70 ° C was slowly added and the resulting solution was stirred for 1 hour. A solution of para-tolylsulfonyl cyanide (1.63 grams, 0.009 mol) in anhydrous THF (10 mL) was added and the resulting solution was stirred for 1 hour at -70 ° C. The solution was allowed to reach room temperature and stirred for a further 12 hours and subsequently quenched with water. The mixture was extracted with diethyl ether. The organic layer is dried by MgSO 4, filtered and concentrated in vacuo. The resulting residue was purified by scintillation chromatography (dichloromethane / acetone = 19/1 (v / v)) and subsequently recrystallized from acetonitrile to afford compound 31 (0.23 gram, 11% yield). Melting point of compound 30: 246 at 248 ° C.

<formula> formula see original document page 48 </formula>

Similarly, compound 32 in 31% yield was prepared from N- (adamant-1-yl) -2-methyl-1-phenyl-1H-imidazol-4-carboxylate using dimethyldisulfide (CH 3 SSCH 3). Melting point: 172 to 20 173 ° C. <formula> formula see original document page 49 </formula>

32

Similarly, compound 33 in 28% yield was prepared from N- (adamant-1-yl) -2-methyl-1-phenyl-1H-imidazol-4-carboxylate using para-tolylsulfonyl chloride. Melting point: 216 to 218 ° C.

Similarly, compound 33A was prepared from N- (adamant-1-yl) -2-methyl-1-phenyl-1H-imidazol-4-carboxylate using para-tolylsulfonyl bromide. Melting point: 242 to 244 ° C.

Similarly, compound 34 in 7% yield was prepared from N- (adamant-1-yl) -1-phenyl-1H-imidazol-4-carboxylate using para-tolylsulfonyl cyanide. Melting point: 237 to 239 ° C.

<formula> formula see original document page 49 </formula>

34

Similarly, compound 35 in 12% yield was prepared from N- (adamant-1-yl) -1-phenyl-1H-imidazol-4-carboxylate using dimethyldisulfide (CH 3 SSCH 3). Melting point: 166 to 168 ° C. <formula> formula see original document page 50 </formula>

General: Compounds 36 to 114 were all prepared according to the general method outlined in Scheme 3 above. The obtained compounds of formula (IV) were converted (see Scheme 1 above) by the corresponding carboxylic acids of structure (V) into the compounds of formula (I) wherein X represents subgroup (ii).

Synthesis of compound 36

Part A: NaNO2 (13.8 grams) was dissolved in water (48 ml) at 4 ° C. The resulting solution was slowly added to a magnetically stirred solution of 3-oxo-butyric acid methyl ester (17.4 grams, 0.15 mol) while maintaining the temperature <5 ° C. After stirring the mixture for two hours water (120 ml) was added and the resulting mixture was extracted twice with diethyl ether. The combined organic layers were successively washed with water and a 5% aqueous NaHCO3 solution. The organic layer was dried by MgSO4, filtered and completely concentrated to afford crude 2-hydroxyimino-3-oxo-butyric acid methyl ester (24 grams) as a colorless oil which has not yet been purified. 1 H NMR (400 MHz, CDCl 3): [delta] 2.42 (s, 3H), 3.91 (s, 3H), 9.90 (br s, 1H).

Part B: Crude 2-hydroxyimino-3-oxo-butyric acid methyl ester (24 grams, - 0.15 mol) dissolved in a magnetically stirred mixture of acetic acid (293 ml), acetic acid anhydride (110 ml) and Pd / C (4 grams) was hydrogenated for 20 hours at room temperature under 1 atmosphere H2 pressure. After filtration through Hyflo, acetic acid and acetic acid anhydride were removed by concentration in vacuo. The resulting crude mixture was purified by scintillation chromatography (dichloromethane / methanol = 95/5 (v / v)) to afford 2-acetylamino-3-oxo-butyric acid methyl ester (16.7 grams, 60% yield) as a solid White. Rf (dichloromethane / methanol = 95/5 (v / v)) = 0.4. 1 H-NMR (400 MHz, CDCl 3): δ 2.08 (s, 3H), 2.40 (s, 3H), 3.83 (s, 3H), 5.29 (d, J = 7.1H ), 6.71 (br s, 1H).

Part C: To a magnetically stirred solution of 2-acetylamino-3-oxo-butyric acid methyl ester (5 grams, 28.9 mmol) inbredironitrile was added aniline (3.42 mL) and trifluoroacetic acid (2.89 mL) and The resulting mixture was heated at reflux for 45 minutes. Abutyronitrile was removed in vacuo at room temperature and the resulting residues were taken up in dichloromethane and washed twice with an aqueous potassium carbonate solution. The organic layer was dried over MgSO 4, filtered and concentrated in vacuo. The resulting residue was purified by scintillation chromatography (diethyl ether / acetone = 4/1 (v / v)) to provide methyl 2,5-dimethyl-1-phenyl-1H-imidazole-4-carboxylate (3.0 grams, 46% income). 1H-NMR (400 MHz, CDCl3): δ 2.22 (s, 3H), 2.33 (s, 3H), 3.91 (s, 3H), 7.18 - 7.22 (m, 2H ), 7.51 - 7.59 (m, 3H).

Part D: To a magnetically stirred solution of methyl 2,5-dimethyl-1-phenyl-1H-imidazole-4-carboxylate (8.0 grams, 0.035 mol) in THF (100 ml) was added a solution of LiOH ( 1.68 grams) in water (100 ml). The resulting mixture was heated at 70 ° C for 16 hours, allowed to reach room temperature and acidified with 2 molar equivalents of a 1N HCl solution. The precipitate formed was collected to provide crude 2,5-dimethyl-1-phenyl-1H-imidazole-4-carboxylic acid (7.0 g, 93% yield). 1 H NMR (400 MHz, DMSO-d 6): δ 2.31 (s, 3H), 2.43 (s, 3H), 7.56 to 7.61 (m, 2H), 7.66 to 7, 71 (m, 3H).

Part D: To a magnetically stirred solution of 2,5-dimethyl-1-phenyl-1H-imidazole-4-carboxylic acid (0.6 gram, 0.0028 mol) and macetonitrile (35 ml) was successively added diisopropylethylamine (DIPEA, Hünig base) (1.27 grams), hexafluorophosphate O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium (HBTU) (1.27 grams) and (-) - cis-mirtanylamine (1 0.05 mL, 0.0028 mol). The resulting mixture was reacted at 20 ° C for 16 hours and subsequently concentrated in vacuo. The resulting residue was taken up in dichloromethane and washed with 5% aqueous NaHCO3 solution. The organic layer was dried by MgSO 4, filtered and concentrated in vacuo. The resulting residue was purified by scintillation chromatography (dichloromethane / methanol = 95/5 (v / v)) to provide N - [(1R, 2S, 5R) -rel-6,6-dimethylbicyclo [3.1.1] heptan-2 methyl] -2,5-dimethyl-1-phenyl-1H-imidazole carboxamide (compound 36) (0.70 grams, 72% yield). Rf (silica gel / dichloromethane / methanol = 95/5 (v / v)) ~ 0.6.

<formula> formula see original document page 52 </formula>

Similarly compounds 37 to 47 were prepared:

<formula> formula see original document page 52 </formula>

37: 1 H-NMR (400 MHz, CDCl3): δ 1.26 (t, J = 7.3H), 2.41 (s, 3H), 2.56 (q, J = 7.2H), 7.23 - 7.28 (m, 2H), 7.49 - 7.60 (m, 6H), 7.66 (d, J = 8, 1H), 7.88 (d, J = 8, 1H ), 8.11 (d, J = 8.1H), 8.28 (d, J = 8.1H), 9.85 (s, 1H).

<formula> formula see original document page 52 </formula>

Compound 38: Melting point: 177 to 179 ° C. <formula> formula see original document page 53 </formula>

40

Compound 39: from endo- (1S) -1,3,3-trimethylbicyclo [2.2.1] heptan-2-amine. Melting point: 130 to 132 ° C (DSC).

<formula> formula see original document page 53 </formula>

40

Compound 40: from endo- (1S) -1,3,3-trimethylbicyclo [2.2.1] heptan-2-amine. 1 H-NMR (300 MHz, CDCl3): δ 0.89 (s, 3H), 0.96 (t, J = 7.3H), 1.12 (s, 3H), 1.17 - 1.27 ( m, 5H), 1.40 - 1.60 (m, 2H), 1.67-1.81 (m, 3H), 2.15 (s, 3H), 2.70 - 2.95 (m, 2H), 3.78 (dd, J = 10 and 2.1H), 7.18 - 7.23 (m, 2H), 7.34 (br d, J = 10, 1H), 7.48 - 7 , 57 (m, 3H).

<formula> formula see original document page 53 </formula>

Compound 41: Melting point: 117.5 to 120 ° C (DSC).

<formula> formula see original document page 53 </formula>

Compound 42: Melting point: 193 to 196 ° C (DSC).

<formula> formula see original document page 53 </formula>

Compound 43 Compound 43: Melting point: 157 to 159 ° C (DSC).

<formula> formula see original document page 54 </formula>

44: Melting point: 76 to 79 ° C (DSC).

<formula> formula see original document page 54 </ formula

Compound 45: From R - (+) - phenethylamine. 1H-NMR (300MHz, CDCl3): δ 1.58 - 1.61 (m, 3H), 2.17 (s, 3H), 2.33 (s, 3H), 5.25 - 5.35 ( m, 1H), 7.15-7.54 (m, 11H).

<formula> formula see original document page 54 </ formula

Compound 46: Melting point: 139 to 141 ° C (DSC).

<formula> formula see original document page 54 </ formula

47: 1 H-NMR (400 MHz, CDCl 3): δ 1.10 (s, 9H), 1.69 (s, 3H), 2.24 (s, 3H), 7.00 - 7.06 ( m, 2H), 7.46 - 7.55 (m, 3H), the NH peak is invisible and probably interspersed with the H2 O peak at 5.60.

Compound Synthesis 48

To a magnetically stirred solution of 2,5-dimethyl-1-phenyl-1H-imidazole-4-carboxylic acid (0.66 grams, 0.00306 mol) in dichloromethane (35 ml) was successively added diisopropylethylamine (DIPEA) (3, 1 ml), CEP (2-chloro-1,3-dimethylimidazolium hexafluorophosphate) (2.55 grams) and 3-hydroxydiamantane amine (0.612 grams, 0.00366 mol). The resulting mixture was reacted at 20 ° C for 16 hours and subsequently concentrated in vacuo. The resulting residue was taken up in dichloromethane washed with 5% aqueous NaHCO3 solution. The organic layer was dried over MgSO 4, filtered and concentrated in vacuo. The resulting residue was purified by scintillation chromatography (dichloromethane / methanol = 98/2 (v / v)) to provide N- (3-hydroxydiamant-1-yl) -2,5-dimethyl-1-phenyl-1 H -imidazol-2-one. 4-carboxamide (0.75 grams, 67% yield). Rf (silica gel / dichloromethane / methanol = 98/2 (v / v)) = 0.6. Melting point: 215 to 220 ° C.

<formula> formula see original document page 55 </formula>

Similarly compounds 49 to 85 were prepared:

<formula> formula see original document page 55 </formula>

Compound 49: Melting point: 245 to 247 ° C.

<formula> formula see original document page 55 </formula>

Compound 50: Melting point: 251 to 253 ° C.

<formula> formula see original document page 55 </formula>

Compound 51: (from endo-2-amino-bicyclo [2.2.1] heptanoracemic: 1 H-NMR (400 MHz, DMSO-d 6): δ 0.85 - 1.64 (m, 8H), 2, 13 (s, 3H), 2.21 (br s, 1H), 2.24 (s, 3H), 2.40 (br s, 1H), 4.07 - 4.16 (m, 1H), 7 , 34 (brd, J = 8.2H), 7.40 (brd, J = 7H), 7.52 - 7.61 (m, 3H).

<formula> formula see original document page 56 </formula>

Compound 52: (from noradamantylamine): Melting point: 147 at 150 ° C.

<formula> formula see original document page 56 </formula>

Compound 53: Melting point: 111 to 113 ° C.

<formula> formula see original document page 56 </formula>

54: Melting point: 204 to 207 ° C.

<formula> formula see original document page 56 </formula>

Compound 55: Melting point: 115 to 117 ° C.

<formula> formula see original document page 56 </formula>

Compound 56: Melting point: 208 to 210 ° C. <formula> formula see original document page 57 </formula>

57: Melting point: 243 to 245 ° C.

<formula> formula see original document page 57 </formula>

58: Melting point: 178 to 181 ° C.

<formula> formula see original document page 57 </formula>

59: 1 H NMR (300 MHz, CDCl 3): δ 2.28 (s, 3H), 2.43 (s, 3H), 7.23 - 7.27 (m, 2H), 7.55 - 7 , 60 (m, 3H), 7.79 (dd, J = 9 and 2 Hz, 1H), 8.22 (d, J = 9 Hz, 1H), 8.42 (s, 1H), 8.62 (d, J = 5Hz, 1H), 8.94 (d, J = 5Hz, 1H), 10.25 (br s, 1H). Melting point: 198.5 ° C (DSC).

<formula> formula see original document page 57 </formula>

60: 1 H-NMR (300 MHz, CDCl3): δ 2.29 (s, 3H), 2.43 (s, 3H), 7.23 - 7.27 (m, 2H), 7.54 - 7.60 (m, 3H), 7.70 - 7.76 (m, 2H), 7.95 (d, J = 8 Hz, 1H), 8.17 - 8.21 (m, 1H), 8 , 27 - 8.29 (m, 1H), 8.63 (d, J = 8Hz, 1H), 10.20 (br s, 1H). Melting point: 241.5 ° C (DSC).

<formula> formula see original document page 57 </formula>

Compound 61: Melting point: 171 to 172 ° C. <formula> formula see original document page 58 </formula>

Compound 62: Melting point: -113 ° C. Rf (diethyl ether / petroleum ether (benzine) = 1/1 (v / v) -0.15. 1 H-NMR (400 MHz, CDCl3): δ 1.66-1.78 (m, 6H), 2 .08 - 2.18 (m, 9H), 2.19 (s, 3H), 3.22 (s, 3H), 4.59 (s, 3H), 7.06 (br s, 1H), 7 .25 - 7.30 (m, 2H), 7.47 - 7.55 (m, 3H).

<formula> formula see original document page 58 </formula>

Compound 63: Melting point: 221 to 223 ° C.

<formula> formula see original document page 58 </formula>

Compound 64: Melting point: 170 to 172 ° C.

<formula> formula see original document page 58 </formula>

Compound 65: Melting point: 168 to 170 ° C.

<formula> formula see original document page 58 </formula>

Compound 66: (from endo- (1S) -1,3,3-trimethylbicyclo [2.2.1] heptan-2-amine). Melting point: 102 to 107 ° C. <formula> formula see original document page 59 </formula>

Compound 67: Melting point: 166 to 168 ° C.

<formula> formula see original document page 59 </formula>

Compound 68: Melting point: 208 to 210 ° C.

<formula> formula see original document page 59 </formula>

Compound 69: Melting point: 154 to 156 ° C.

<formula> formula see original document page 59 </formula>

Compound 70: (from endo-2-amino-bicyclo [2.2.1] heptanoracemic.

Melting point: 165 to 167 ° C.

<formula> formula see original document page 59 </formula>

Compound 71: Melting point: 69 to 72 ° C.

<formula> formula see original document page 59 </formula>

72: 1 H-NMR (400 MHz, CDCl3): δ 1.66 - 1.78 (m, 6H), 2.08 - 2.17 (m, 9H), 2.32 (s, 3H), 2.51 (s, 3H), 6.95 (br s, 1H), 7.51 (d, J = 4, 1H), 7.83 (d, J = 4, 1H). Melting point: 130 to 133 ° C.

<formula> formula see original document page 60 </formula>

Compound 73: (from endo- (1S) -1,3,3-trimethylbicyclo [2.2.1] heptan-2-amine). Melting point: 146 to 148 ° C.

<formula> formula see original document page 60 </formula>

74: 1 H-NMR (400 MHz, CDCl3): δ 1.65 to 1.78 (m, 6H), 2.08 to 2.19 (m, 12H), 2.27 (s, 3H), 3.78 (s, 3H), 6.97 (br s, 1H), 7.03 to 7.12 (m, 3H), 7.43 to 7.49 (m, 1H).

75: 1 H-NMR (400 MHz, CDCl 3): δ 2.21 (s, 3H), 2.37 (s, 3H), 3.82 (s, 3H), 7.07 - 7.13 ( m, 2H), 7.16 - 7.21 (m, 1H), 7.46-7.59 (m, 4H), 7.66 (d, J = 8, 1H), 7.87 (d, J = 8, 1H), 8.13 (d, J = 8, 1H), 8.28 (d, J = 8, 1H), 9.70 (br s, 1H).

<formula> formula see original document page 60 </formula>

Compound 76: Melting point: 217 to 219 ° C.

<formula> formula see original document page 60 </formula>

Compound 77: Melting point: 217 to 218 ° C. In the synthesis of this particular compound 2-chloro-1,3-dimethylimidazolium chloride was used in the last reaction step as the coupling reagent in place of CIP.

<formula> formula see original document page 61 </formula>

Compound 78: Melting point: 186 to 187 ° C. In the synthesis of this particular compound 2-chloro-1,3-dimethylimidazolium chloride was used in the last reaction step as the coupling reagent in place of CIP.

<formula> formula see original document page 61 </formula>

Compound 79: Melting point: 123 to 125 ° C.

<formula> formula see original document page 61 </formula>

Compound 80: Melting point: 214 to 217 ° C.

<formula> formula see original document page 61 </formula>

Compound 81: Melting point: 149 to 150 ° C.

<formula> formula see original document page 61 </formula>

82: 1 H NMR (400 MHz, CDCl3): δ 0.75 - 0.80 (m, 2H), 0.97 - 1.03 (m, 2H), 1.45 - 1.52 (m, 1H), 1.65 - 1.78 (m, 6H), 2.08 - 2.18 (m, 9H), 2.34 (s, 3H), 6.98 (br s, 1H), 7, 23 - 7.28 (m, 2H), 7.45 - 7.56 (m, 3H). In the synthesis of this particular compound 2-chloro-1,3-dimethylimidazolium chloride was used in the last reaction step as the coupling reagent in place of CEP.

<formula> formula see original document page 62 </formula>

83: 1 H-NMR (400 MHz, CDCl 3): δ 0.75 to 0.80 (m, 2H), 0.97 to 1.02 (m, 2H), 1.45 to 1.52 (m , 1H), 2.38 (s, 3H), 4.80 (br d, J = 7.2H), 7.25 to 7.30 (m, 2H), 7.35 (br t, J = 7 , 1H), 7.47 to 7.68 (m, 7H).

<formula> formula see original document page 62 </formula>

Compound 84: Melting point: 136 to 137 ° C.

<formula> formula see original document page 62 </formula>

Compound 85: Rf (dichloromethane / methanol = 97/3 (v / v)) = 0.2.

<formula> formula see original document page 62 </formula>

Compound 86: Melting point: 242 to 244 ° C. Mrf (free base) = 368. Compound 86 was derived from exo-2-aminobicyclo [2.2.1] heptanoracemic and 2-acetylamino-3-oxo-butyric acid methyl ester analogously to synthesis as described above for compound 36, Part C. Compound 87: Melting point: 181 to 183 ° C. Compound 87 was derived from (-) - cis -mirtanylamine (CAS 38235-68-6) and methyl ester give 2-acetylamino-3-oxo-butyric acid analogously to the synthesis described above for compound 36, part C .

<formula> formula see original document page 63 </formula>

Compound 88: Rf (dichloromethane / methanol = 97/3 (v / v)) = 0.2. In the synthesis of this particular compound 2-chloro-1,3-dimethylimidazolium chloride was used in the last reaction step as the coupling reagent. instead of CIP.

Synthesis of compound 89

Part A: To a magnetically stirred suspension of 2,5-dimethyl-1-phenyl-1H-imidazole-4-carboxylic acid (0.4 grams, 1.85 mmol) in CHCl 3 (4 mL) was added oxalyl chloride (0, 34 grams, 2.685 mmol) and the resulting mixture was reacted at 58 ° C for 2 hours and subsequently concentrated in vacuo. The resulting residue was taken up in dichloromethane and diisopropylethylamine (0.28 grams, 2.148 mmol) was subsequently added. A solution of 2,3-dichloroaniline (0.35 grams, 2.146 mmol) in dichloromethane (5 mL) was slowly added to the resulting mixture and the resulting mixture was reacted for 2 hours at room temperature and subsequently concentrated in vacuo. The resulting residue was purified by scintillation chromatography (dichloromethane) to afford N- (2,3-dichlorophenyl) -2,5-dimethyl-1-phenyl-1H-imidazole-4-carboxamide (compound 89) (0.24 grams, 36 % yield). Melting point: 127 to 129 ° C.

<formula> formula see original document page 63 </formula>

Compound 89 Similarly, compounds 90 to 114 were prepared:

<formula> formula see original document page 64 </ formula

Compound 90: 1 H-NMR (400 MHz, CDCl 3): δ 1.50 - 1.78 (m, 12H), 1.88 - 1.98 (m, 2H), 2.18 (s, 3H), 2 , 34 (s, 3H), 4.12 - 4.23 (m, 1H), 7.10-7.20 (m, 3H), 7.48 - 7.57 (m, 3H). LC / MS: Retention time: 2.88 minutes; MH + = 326.

<formula> formula see original document page 64 </ formula

91: 1 H-NMR (400 MHz, CDCl 3): δ 1.65 - 2.07 (m, 9H), 2.17 (s, 3H), 2.32 (s, 3H), 3.73 ( S, 2H), 7.16 - 7.20 (m, 2H), 7.41 (br s, 1H), 7.49 - 7.57 (m, 3H). LC / MS: Retention time: 2.22 minutes; MH + = 314.

<formula> formula see original document page 64 </ formula

Compound 92: 1 H-NMR (400 MHz, CDCl 3): δ 1.56 - 1.66 (m, 4H), 1.73 - 1.87 (m, 4H), 2.18 (br s, 6H) , 3.65 (t, J = 7.2H), 3.91 (t, J = 7.2H), 7.19 - 7.23 (m, 2H), 7.47 - 7.56 (m, 3H). LC / MS: Retention time: 2.12 minutes; MHT = 297.

<formula> formula see original document page 64 </ formula

Compound 93: Rf (dichloromethane / methanol = 95/5 (v / v)) = 0.65. <formula> formula see original document page 65 </formula>

Compound 94: LC / MS: retention time: 1.88 minutes; MH

<formula> formula see original document page 65 </formula>

Compound 95: Melting point: 134 to 135 ° C.

<formula> formula see original document page 65 </formula>

Compound 96: Melting point: 119 to 121 ° C.

<formula> formula see original document page 65 </formula>

Compound 97: Rf (dichloromethane / methanol = 97/3 (v / v)) = 0.6.

<formula> formula see original document page 65 </formula>

Compound 98: Melting point: 125 to 127 ° C.

<formula> formula see original document page 65 </formula>

Compound 99: 1 H-NMR (400 MHz, CDCl 3): δ 1.60 (d, J = 73H), 2.17 (s, 3H), 2.33 (s, 3H), 5.30 (quintet, J = 7.2H), 7.15 - 7.54 (m11H). LC / MS: Retention time: 2.60 minutes; MH * = 320. <formula> formula see original document page 66 </formula>

100: 1 H-NMR (400 MHz, CDCl3): δ 2.15 (s, 3H), 2.36 (s, 3H), 2.97 (dd, J = 15 and 6.2H), 3, 40 (dd, J = 15 and 8.2H), 4.88 - 4.98 (m, 1H), 7.16 - 7.27 (m, 6H), 7.37 (br d, J = 8, 1H), 7.48 - 7.57 (m, 3H) .LC / MS: retention time: 2.63 minutes; MtT = 332.

<formula> formula see original document page 66 </formula>

Compound 101: 1 H-NMR (400 MHz, CDCl 3): δ 2.18 (s, 3H), 2.34 (s, 3H), 6.44 (d, J = 8, 1H), 7.15 - 7.38 (m, 12H), 7.48 - 7.57 (m, 3H), 7.92 (br d, J = 8, 1H). LC / MS: Retention time: 3.59 minutes; MH * = 382.

<formula> formula see original document page 66 </formula>

Compound 102: LC / MS: retention time: 1.30 minutes; MH + = 338.

<formula> formula see original document page 66 </formula>

Compound 103: LC / MS: retention time: 2.81 minutes;

<formula> formula see original document page 66 </formula>

Compound 104: LC / MS: retention time: 2.98 minutes; MH + = 396. <formula> formula see original document page 67 </formula>

Compound 105: LC / MS: Retention time: 2.17 minutes; MH + = 300.

<formula> formula see original document page 67 </formula>

Compound 106: LC / MS: retention time: 2.08 minutes; MH + = 346.

<formula> formula see original document page 67 </formula>

Compound 107: Melting point: 117 to 118 ° C.

<formula> formula see original document page 67 </formula>

Compound 108: Melting point: 123 to 125 ° C.

<formula> formula see original document page 67 </formula>

Compound 109: Melting point: 130 to 132 ° C.

<formula> formula see original document page 67 </formula>

110: 1 H NMR (400 MHz, CDCl3): δ 2.17 (s, 3H), 2.37 (s, 3H), 3.86 (s, 3H), 3.88 (s, 3H), 4.55 (d, J = 6.2H), 6.82 (d, J = 8.1H), 6.90 - 6.95 (m, 2H), 7.17 - 7.21 (m, 2H ), 7.45 (br s, 1H), 7.50 - 7.57 (m, 3H).

<formula> formula see original document page 68 </formula>

Compound 111: Rf (dichloromethane / methanol = 95/5 (v / v)) = 0.65.

112: 1 H-NMR (400 MHz, CDCl 3): δ 2.16 (s, 3H), 2.35 (s, 3H), 2.93 (t, J = 7.2H), 3.66 ( q, J = 7.2H), 7.16 - 7.34 (m, 8H), 7.48 - 7.56 (m, 3H). LC / MS: Retention time: 3.13 minutes; MJrt = 320.

<formula> formula see original document page 68 </formula>

Compound 113: LC / MS: retention time: 2.67 minutes; MH + = 352.

<formula> formula see original document page 68 </formula>

114: 1 H-NMR (400 MHz, CDCl3): δ 0.94 - 1.05 (m, 2H), 1.11 - 1.31 (m, 3H), 1.52 - 1.87 (m 6.18), 2.18 (s, 3H), 2.35 (s, 3H), 3.25 (t, J = 7.2H), 7.16 - 7.21 (m, 2H), 7, 22 - 7.29 (m, 1H), 7.48 - 7.57 (m, 3H) .LC / MS: retention time: 2.76 minutes; MH1 "= 312.

EXAMPLE 3: FORMULATION OF COMPOUND 1

For oral administration (p.o.): In the desired amount (0.5 to 5mg) of solid compound 1 in a glass tube, a few glass beads were added and the solid was vortexed for 2 minutes. After the addition of 1 ml of a solution of 1% methylcellulose in water and 2% (v / v) Poloxamer 188 (Lutrol F68), the compound was suspended in mediantevortex for 10 minutes. The pH was adjusted to 7 with a few drops of aqueous NaOH (0.1 N). The remaining particles in the suspension were suspended in suspension using an ultrasonic bath.

For intraperitoneal (i.p.) administration: At the desired amount (0.5 to 5 mg) of solid compound 1 in a glass tube, a few glass globules were added and the solid was vortexed for 2 minutes. After adding 1 ml of a solution of 1% methylcellulose and 5% mannitol in water, the compound was suspended by vortexing for 10 minutes. Finally the pH was adjusted to 7.

EXAMPLE 4: PHARMACOLOGICAL TEST RESULTS

Cannabinoid receptor affinity data obtained according to the given protocols are shown in the table below. BMS-1, BMS-II and BMS-III are the three imidazoles exemplified in WO 01/58869 (Examples 64, 65 and 66, respectively). These three specific imidazole derivatives all contain a carboxy-derivative component of L-phenylalanine at position 4 of its (1H) -imidazole component as shown below. Our invention includes novel 1H-imidazole derivatives which require such a carboxyamide component derived from L-phenylalanine, but have approximately two hundred higher CB2 affinities as compared to the prior art compounds exemplified in WO 01/58869 as is clear from the above. from the data described in Table 1.

<formula> formula see original document page 69 </formula> <table> table see original document page 70 </column> </row> <table>

Claims (12)

1. Compounds characterized in that they are of the formula <formula> formula see original document page 71 </formula> wherein: Ri represents a hydrogen or halogen atom or a C1-4 alkyl group, where C1-3 group Alkyl may contain from 1 to 3 fluorine atoms or a hydroxy or amino group, or R 1 represents a C 2-3 alkynyl group, a C 2-3 alkenyl group, wherein the C 2-3 alkynyl group or group of C2-3 alkenyl may contain from 1 to 3 fluorine atoms, or R1 represents a group of acetyl, cyclopropyl, cyano, methylsulfonyl, ethylsulfonyl, methylsulfinyl, ethylsulfmyl trifluoromethylsulfanyl, methylsulfanyl, ethylsulfanyl, formyl group or a group of C2-4 alkenyl. -heteroalkyl, R2 represents a phenyl group which may be substituted with -1, 2, 3, 4 or 5 Y substituents, which may be the same or different, selected from the group consisting of methyl, ethyl, propyl, methoxy, ethoxy, hydroxy, chlorine, iodine, bromine, fluoro, trifluoromethyl, trifluoromethoxy, methylsulfonyl, carbam Oyl, phenyl and cyano, or R2 represents a heteroaryl group wherein the heteroaryl group may be substituted with 1, 2 or 3 Y substituents, wherein Y has the meaning as defined above, provided that R2 is not a group of 6. -methyl-2-pyridyl, or R2 represents a fused monocyclic, fused bicyclic monocyclic or fused to 10-membered monocyclic carbocyclic ring system, or R2 represents a fused monocyclic, fused bicyclic or fused tricyclic monocyclic ring system monounsaturated or fully saturated members wherein the carbocyclic or heterocyclic ring system may be substituted with 1 to 5 substituents selected from methyl, ethyl, amino, hydroxy or fluorine, or R 2 represents a group of formula CH 2 -R 5 wherein R 5 represents a phenyl group which is substituted with 1, 2, 3, 4 or 5 substituents Y as defined above, or R5 represents a heteroaryl group or a 1,2,3,4-tetrahydronaphthyl group or indanyl, wherein the heteroaryl group or group of 1,2,3,4-tetrahydronaphthyl or indanyl may be substituted with 1, 2 or 3 Y substituents as defined above or R 5 represents a monocyclic, fused bicyclic 4- to 10-membered carbocyclic ring system or fully monounsaturated fused tricyclic or R5 represents a fused monocyclic, fused bicyclic monocyclic or fused monocyclic 4- to 10-membered saturated heterocyclic ring system, wherein the carbocyclic or heterocyclic ring systems are optionally substituted with 1 to 5 selected substituents from the group consisting of methyl, ethyl, amino, hydroxy or fluorine, or R 2 represents a methylsulfonylaminoalkyl, methylsulfonylalkyl group or an acetamidoalkyl group, R 3 represents a hydrogen or halogen atom or a formyl group, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfanyl, trifluoromethylsulfanyl, benzylsulfanyl or cyano, or R 3 rep is a C 1-8 alkyl group, wherein the C 1-6 alkyl group may be substituted with 1 to 5 substituents selected from the group consisting of fluoro, hydroxy or amino, or R 3 represents a C 2-6 alkynyl, C 2-6 alkenyl, C 1-6 group. C 1-8 alkanoyl, C 3-8 cycloalkyl, C 5-8 heterocycloalkyl or a C 2-6 heteroalkyl group, wherein the groups are optionally substituted with 1 to 3 methyl groups, an ethyl, amino or hydroxy group or with 1 at 3 fluorine atoms, or R 3 represents a phenyl group which is substituted with 1 to 5 Y substituents, wherein Y has the meaning as defined above, or R 3 represents a heteroaryl group wherein the heteroaryl group may be substituted with 1,2 or -3 substituents Y, wherein Y has the meaning as defined above or R3 represents a benzyl or heteroaryl methyl group wherein the debenzyl or heteroaryl methyl group may be substituted with 1, 2 or 3 substituents YR4 represents one of subgroups (i) or (ii) <formula> formula see gives rise to wherein Ks is a branched or linear C4.8 alkyl group, C3.g cycloalkyl group, C3.8-cycloalkyl-C2-alkyl group, C5-7-heterocycloalkyl-C group .2-alkyl, C5-10-bicycloalkyl group, C5-10-bicycloalkyl-C1-2 alkyl group, C5-10-heterobicycloalkyl-C1-2 alkyl group, C6-10 tricycloalkyl group, C6 group wherein the groups may be substituted with 1 to 5 substituents selected from methyl, hydroxy, ethyl, trifluoromethyl or fluoro, or R 1 represents a. phenyl, benzyl, naphthyl or phenethyl group wherein the groups may be substituted on their ring aromatic system with 1 to 3 Y substituents as defined above, with the proviso that R <5 is not a 2-methylphenyl group, or R $ represents a depyridyl or thienyl group, R7 represents a hydrogen atom or a linear C1-6 alkyl group wherein the linear C1-6 alkyl group may be substituted. substituted with 1 to 3 fluorine atoms or R 7 represents an isopropyl group, R 8 represents a C 2-6 alkyl group wherein the group is substituted with a hydroxy or amino group or 1 to 3 fluorine atoms, or R 6 represents a branched C7-10 alkyl group, C3.8 cycloalkyl group, C5.8 heterocycloalkyl group, C3.8-cycloalkyl-C1.2-alkyl group, C5.7-heterocycloalkyl-C1.2-alkyl group, C5-10bicycloalkyl group, C5-10-bicycloalkyl-C1-4 alkyl group, C5-10-heterobicycloalkyl-C1-4 alkyl group, C6-10 tricycloalkyl group, C1-6-tricycloalkyl-C1-4 group 2-alkyl, C10-10 heterocycloalkyl-C1-4 alkyl group wherein the groups may be substituted with 1 to 5 substituents selected from methyl, hydroxy, ethyl, amino, hydroxymethyl, trifluoromethyl or fluorine, or R3 represents a phenyl group in which the group is substituted with 1 to 5 substituents Y as defined above, or R8 represents a group of naphthyl, -1,2,3,4-tetrahydronaphthyl or indanyl wherein the naphthyl, 1,2,3,4-tetrahydronaphthyl or indanyl groups may be substituted with 1 to 3 Y substituents, or R g represents a phenyl-C 1-3 alkyl group, a diphenyl-C 1 group. -3-alkyl, wherein the groups may be substituted on their phenyl ring with 1 to 5 Y substituents, wherein Y has the above-mentioned meaning, or Rg represents a benzyl group, wherein the benzyl group is substituted with -1 the 5 substituents Y, or R 8 represents a group of heteroaryl, heteroarylmethyl, naphthylmethyl or heteroarylethyl, wherein the group of heteroaryl, heteroarylmethyl, naphthylmethyl or heteroarylethyl may be substituted with 1 to 3 substituents Y, wherein Y has the above-mentioned meaning, or Rg is a group of piperidinyl, azepanyl, morpholinyl, azabicyclo [3.3.0] octanyl, 4-hydroxypiperidinyl or pyrrolidinyl, provided that Rg is neither a group of 6-methoxy-benzothiazol-2-ylan in a group of [3- chloro-5- (trifluoromethyl) pyrid-2-yl] methyl, or R7 and R8 - together with the nitrogen atom to which they are attached - form a saturated or unsaturated monocyclic, bicyclic nonaromatic or partially aromatic heterocyclic group saturated or unsaturated having from 7 to 10 ring atoms, wherein the monocyclic, bicyclic or tricyclic monocyclic heterocyclic group or partially saturated or unsaturated aromatic may be substituted with 1 to 5 substituents selected from the group consisting of Q 3 alkyl, hydroxy, methoxy, cyano, phenyl, trifluoromethyl or halogen, or R 7 and R 8 - together with the nitrogen atom to which they are attached - form a saturated monocyclic heterocyclic group, optionally containing another heteroatom (selected from N, O, S), has from 5 to 6 ring atoms, wherein the heterocyclic group is substituted with 1 to 5 substituents selected from the group consisting of C1-3 alkyl, hydroxy , amino, phenyl, benzyl, or fluoro, with the proviso that R7 and Rg - together with the denitrogen atom a to which they are attached - do not form a trimethyl substituted aza-bicyclo [3.2.1] octanyl group, and tautomers, stereoisomers and N-oxides thereof, as well as pharmaceutically acceptable salts, hydrates and solvates of said compounds of formula (1) and their tautomers, stereoisomers and N-oxides. Compounds according to claim 1, characterized in that they are of the general formula (I) wherein: R1 represents a halogen atom or a group of Q.3- wherein the C1-3 alkyl group may contain from 1 to 3 fluorine atoms or a hydroxy or amino group, or R1 represents a C2-3 alkynyl group, a C2-3 alkenyl group wherein the C2-3 alkynyl group or C2-3 alkenyl group may contain from 1 to 3 fluorine atoms, or R1 represents a group of acetyl, cyclopropyl, cyano, methylsulfonyl, ethylsulfonyl, methylsulfinyl trifluoromethylsulfanyl, methylsulfanyl, ethylsulfanyl, of formyl or a group of C 2-4 heteroalkyl, and R 2, R 3 and R 4 have the meaning as given according to claim 1. Compounds according to claim 2, characterized in that they are of the general formula (I): wherein: R3 represents a hydrogen or halogen atom or a formyl group; methylsulfonyl, ethylsulfonyl, methylsulfinyl, ethylsulfinyl, trifluoromethylsulfanyl, methylsulfanyl, ethylsulfanyl or cyano, or R3 represents a C1-6 alkyl group, wherein the C1-6 alkyl group may contain from 1 to 3 fluorine atoms or a hydroxy or amino group, or R 3 represents a C 2-6 alkynyl, C 2-6 alkenyl, C 1-6 alkanoyl, C 3-8 cycloalkyl, C 5-8 heterocycloalkyl or C 2-6 heteroalkyl group, wherein the groups are optionally substituted with 1 to 3 methyl groups , an ethyl, amino or hydroxy group having 1 to 3 fluorine atoms, or R 3 represents a phenyl group which is substituted with 1 to 5 Y substituents, wherein Y has the meaning as defined above, or R 3 represents a heteroaryl group at that the group of heteroarila may be substituted with 1, 2 or 3 Y substituents, wherein Y has the meaning as defined above or R 3 represents a benzyl or heteroarylmethyl group wherein the benzyl or heteroarylmethyl group may be substituted with 1, 2 or 3 substituents YR 4 represents the subgroup ( (ii) where R 7 represents a hydrogen atom or a linear C 1-6 alkyl group or an isopropyl group, R 6 represents a C 2-6 alkyl group wherein the group is substituted with a hydroxy or amino group or with 1 to 3 fluorine atoms, or R8 represents a branched C7-10 alkyl group, C3.8 cycloalkyl group, C5.8 heterocycloalkyl group, C3.g-cyclo-C1.2-alkyl group C5-10-heterocycloalkyl-C1-4 alkyl group C5-10-bicycloalkyl group, C5-10-bicycloalkyl-C1-4 alkyl group C5-10-heterobicycloalkyl-C1-4 alkyl group C6-10 tricycloalkyl, C6-10-tricycloalkyl-C2-alkyl group, C6-10-heteroalkyl group cycloalkylC 1-2 alkyl wherein the groups may be substituted with 1 to 5 substituents selected from methyl, hydroxy, ethyl, amino, hydroxy methyl, trifluoromethyl, or fluoro, or R 1 represents a phenyl group wherein the group is substituted with 1 to 5. Y is as defined above, or Rg represents a naphthyl or a group of 1,2,3,4-tetrahydronaphthyl or indanyl wherein the groups may be substituted with 1 to 3 Y substituents, or Rg represents a phenyl-C 1-3 group. alkyl, a C 1-3 -phenyl diphenyl group, wherein the groups may be substituted on their phenyl ring with 1 to 5 Y substituents, wherein Y has the aforementioned meaning, or R 6 represents a benzyl group, wherein the group of benzyl is substituted with 1 to 5 Y substituents, or R 8 represents a group of heteroaryl, heteroarylmethyl or heteroarylethyl, wherein the group of heteroaryl, heteroarylmethyl or heteroarylethyl may be substituted with 1 to 3 Y substituents as defined above, or R g represents a piperidinyl rupture, azepanyl, morpholinyl, azabicyclo [3.3.0] octanyl, 4-hydroxypiperidinyl or pyrrolidinyl, with the proviso that R8 is neither a 6-methoxy-benzothiazol-2-yl group nor a group of [3-chloro- 5- (trifluoromethyl) pyrid-2-yl] methyl, or R 7 and R 8 - together with the nitrogen atom to which they are attached - form a non-aromatic or partially aromatic saturated or unsaturated monocyclic, bicyclic or non-aromatic heterocyclic group having from 7 to 10 atoms wherein the heterocyclic group may be substituted with one or two C1-3 alkyl groups, a hydroxy group, a phenyl group, a trimethylfluoromethyl group, a benzyl group, a diphenyl methyl group or a halogen atom, or R7 and Rg - together with the nitrogen atom to which they are attached - form a saturated monocyclic heterocyclic group, optionally containing another heteroatom (selected from N, O, S), having from 5 to 6 ring atoms, wherein the heterocyclic group cyclic is substituted with 1 to 3 groups of C1.3 alkyl, a hydroxy group or 1 to 2 fluorine atoms, provided that R7 and R8 - together with the denitrogen atom to which they are attached - do not form a group of. trimethyl substituted aza-bicyclo [3.2.1] octanyl, and R 1 and R 2 have the meanings as given according to claim 2. Compounds according to claim 3, characterized in that they are of the general formula (I): alkyl, wherein the C 1-3 alkyl group may contain from 1 to 3 fluorine atoms or a hydroxy group, or represents a group of C2-3-alkynyl, a group of C2-3-alkenyl, a group of acetyl, cyclopropyl, cyano, methylsulfonyl, methylsulphinyl, or a group of C2-4-heteroalkyl, -1, 2, 3, 4 or 5 Y substituents, which may be the same or different, selected from the group consisting of methyl, ethyl, propyl, methoxy, ethoxy, hydroxy, chlorine, iodine, bromine, fluoro, trifluoromethyl, trifluoromethoxy, methylsulfonyl, carbamoyl, phenyl and cyano, or R2 represents a group monocyclic deheteroaryl wherein the heteroaryl group may be substituted with 1, 2 or 3 Y substituents, where Y is as defined above, provided that R2 is not a 6-methyl-2-pyridyl group, or > formula see original document page 78 </formula> where: Ri represents a halogen atom nio or a group of Q.3-R2 represents a phenyl group that may be substituted with R2 represents a monocyclic, fused bicyclic or fused tricyclic monocyclic or fused to 10-membered ring carbocyclic ring system, or R2 represents a ring system monocyclic, fused bicyclic or fused tricyclic monocyclic 4- to 10-membered monocyclic or fully saturated heterocyclic heterocyclic ring wherein the carbocyclic or heterocyclic ring system may be substituted with 1 to 5 substituents selected from methyl, ethyl, amino, hydroxy or fluorine, or R 2 represents a group of wherein R5 represents a phenyl group which is substituted with 1, 2, 3, 4 or 5 Y substituents as defined above, or R5 represents a heteroaryl group or a 1,2,3,4-tetrahydronaphthyl group or indanyl, wherein the heteroaryl group or group of 1,2,3,4-tetrahydronaphthyl or indanyl may be substituted with 1, 2 or 3 Y substituents as defined above or R 5 represents a monocyclic, fused bicyclic fused monocyclic, fused bicyclic or monocyclic fused monocyclic ring moiety, or R 5 represents a fused monocyclic, fused bicyclic monocyclic or fused monocyclic ring system, wherein carbocyclic or heterocyclic ring systems are optionally substituted with 1 to 3 groups of methyl, an ethyl, amino or hydroxy group or a fluorine atom, R3 represents a hydrogen or halogen atom or a cyano group, or R3 represents a C1-6 group -alkyl, wherein the C 1-6 alkyl group may contain from 1 to 3 fluorine atoms or a hydroxy or amino group, or R 3 represents a C 2-6 alkynyl or C 2,6-alkenyl group wherein are optionally substituted with 1 to 3 fluorine atoms, R4 represents subgroup (ii) wherein R7 represents a hydrogen atom or a C1.3 alkyl group. 1a, R 8 represents a C 2-6 alkyl group wherein the group is substituted with a hydroxy or amino group or 1 to 3 fluorine atoms, or R 8 represents a branched C 7-10 alkyl group, C 3-8 cycloalkyl group , C 5-8 heterocycloalkyl group, C 3-8 -cycloalkyl-C 1-4 alkyl group, C 5-7 -heterocycloalkyl-C 1-4 alkyl group, C 5-6 -cycloalkyl group, C 5-10 -cycloalkyl-C 1-8 group. 2-alkyl, C5-10-heterobicycloalkyl-C1-6 alkyl group, C6-10 tricycloalkyl group, C6-10-tricycloalkyl C1-4 alkyl group, C6-10-heterotriccyclo-C1-2 alkyl group -alkyl wherein the groups may be substituted with 1 to 5 substituents selected from methyl, hydroxy, ethyl, amino, hydroxymethyl, trifluoromethyl, or fluorine, or R 8 represents a phenyl group wherein the group is substituted with 1 to 5 Y substituents as defined above, or R8 represents a naphthyl or a 1,2,3,4-tetrahydronaphthyl or indanyl group wherein the groups may be substituted with 1 to 3 Y, or R 8 represents a phenyl-C 1-3 alkyl group, a diphenyl-C 1,3-alkyl group, wherein the groups may be substituted on their phenyl ring with 1 to 5 Y substituents, wherein Y has meaning mentioned above, or R 8 represents a benzyl group, wherein the benzyl group is substituted with 1 to 5 Y substituents, or R 8 represents a heteroaryl, heteroarylmethyl or heteroarylethyl group, wherein the heteroaryl, heteroarylmethyl or heteroarylethyl group may be substituted with 1 to 5 3 substituents Y, as defined above, or R8 represents a group of piperidinyl, azepanyl, morpholinyl, azabicyclo [3.3.0] octanyl, 4-hydroxypiperidinyl or pyrrolidinyl, provided that R8 is not a group of 6-methoxy-benzothiazole; 2-yl or a group of [3-chloro-5- (trifluoromethyl) pyrid-2-yl] methyl. Compounds according to claim 4, characterized in that they are of the general formula (I): wherein: R 1 represents a halogen atom or a group of d. wherein the C1-3 alkyl group may contain from 1 to 3 fluorine atoms or a hydroxy group, or R1 represents a cyano or methylsulfanyl group, R2 represents a monocyclic 5- to 7-membered monocyclic carbocyclic ring system unsaturated or fully saturated which may be substituted with 1 to 5 substituents selected from methyl, ethyl, amino, hydroxy or fluorine, or R 2 represents a phenyl group which may be substituted with 1, 2, 3, 4 or 5 Y substituents, which may be same or different, selected from the group consisting of methyl, ethyl, propyl, methoxy, ethoxy, hydroxy, chlorine, iodine, bromine, fluorine, trifluoromethyl, trifluoromethoxy, methylsulfonyl, carbamoyl, phenyl and cyano, R3 represents a hydrogen or halogen atom or a group of methylsulfanyl or cyano, or R3 represents C1-6 alkyl group, wherein C1-6 alkyl group may contain from 1 to 3 fluorine atoms or a hydroxy or amino group, R4 represents subgroup (ii) <formula> formula see wherein R7 represents a hydrogen atom or a methyl group, R8 represents a C2-6 alkyl group wherein the group is substituted with 1 to 3 fluorine atoms, or R8 represents a C7 group branchedioalkyl, C3.8-cycloalkyl group, C5.8-heterocycloalkyl group, C3.8-cycloalkyl-C1-2-alkyl group, C5.7-heterocycloalkyl-C1-2-alkyl group, C5-10-bicycloalkyl group C5-10-bicycloalkyl-C1-6 alkyl group, C5-10heterobicyclo-C1-6 alkyl group, C6-10-tricycloalkyl group, C6-10-tricycloalkyl-C1-4 alkyl group, C6-10 hetero-tricycloalkyl-C1-2 alkyl group wherein the groups may be substituted with 1 to 5 substituents selected from methyl, hydroxy, ethyl, amino, hydroxymethyl, trifluoro methyl, or fluorine, or Rg represents a defenyl group wherein the group is substituted with 1 to 5 Y substituents as defined above, or Rg represents a naphthyl or a 1,2,3,4-tetrahydronaphthyl or indanyl group in which the groups may be substituted. be substituted with 1 to 3 substituents Y, or R 8 represents a phenyl-C 1-3 alkyl group, a diphenyl-C 1-3 alkyl group, wherein the groups may be substituted on their phenyl ring with 1 to 5 substituents. Y, wherein Y has the above-mentioned meaning, or Rg represents a substituted benzyl group, wherein the benzyl group is substituted with 1 to 5 Y substituents, or R8 represents a heteroaryl, heteroarylmethyl or heteroarylethyl group, wherein the group of heteroaryl, heteroarylmethyl or heteroarylethyl may be substituted with 1 to 3 Y substituents as defined above, provided that R 8 is neither a 6-methoxy-benzothiazol-2-yl group nor a [3-chloro-5] group. - (trifluoromethyl) pyrid-2-yl] methyl. Compounds according to claim 5, characterized in that they are of the general formula (I): wherein: Ri represents a halogen atom or a group of C1.3. -alkyl, wherein the C1-3 alkyl group may contain from 1 to 3 fluorine atoms, or R1 represents a cyano or methylsulfanyl group, R2 represents a saturated monocyclic carbocyclic ring or R2 represents a phenyl group which may be substituted with 1, 2 or 3 Y substituents, which may be the same or different, selected from the group consisting of methyl, ethyl, propyl, methoxy, ethoxy, hydroxy, chlorine, iodine, bromine, fluoro, trifluoromethyl, trifluoromethoxy, methylsulfonyl, carbamoyl, phenyl and cyano, R3 represents a hydrogen or halogen atom or a group of methylsulfanyl or cyano, or R3 represents C1-4 alkyl group, wherein the C1-4 alkyl group may contain from 1 to 3 fluorine atoms, R4 represents subgroup (ii) <formula> formula s wherein R 7 represents a hydrogen atom or a methyl group, R 8 represents a C 2-6 alkyl group wherein the group is substituted with 1 to 3 fluorine atoms, or R 8 represents a C 7 group. 10 branched alkyl, C3.8-cycloalkyl group, C5.8-heterocycloalkyl group, C3.8-cycloalkyl-C1-2-alkyl group, C5.7-heterocycloalkyl-C1-2-alkyl group, C5.10-bicycloalkyl group C5-10-bicycloalkyl-C1-6 alkyl group, C5-10heterobicycloalkyl-C1-4 alkyl group, C6-10-tricycloalkyl group, C6-7-tricycloalkyl-C1-6 alkyl group, C6-10-hetero-tricycloalkyl group 2-alkyl, wherein the groups may be substituted with 1 to 5 substituents selected from methyl, hydroxy, ethyl, amino, hydroxymethyl, trifluoromethyl, or fluorine, or R 8 represents a defenyl group wherein the group is substituted with 1 to 3 substituents. Y, where Y has the meaning as defined above, or Rg represents a denaftyl group wherein the group may be substituted with 1 to 3 Y substituents, or R 8 represents a phenyl-C 1-2 alkyl group, wherein the group may be substituted on the phenyl ring with 1 to 3 Y substituents, wherein Y has the above-mentioned meaning, or R 8 represents a substituted benzyl group, wherein the benzyl group is substituted with 1 to 5 Y substituents. A compound characterized in that it is of the formula <formula> formula see original document page 84 </formula> wherein: Ki represents a halogen atom or a C1.3-alkyl group, wherein the group of C1. 3-Alkyl may contain from 1 to 3 fluorine atoms or a hydroxy or amino group, or R1 represents a C2-3-alkynyl group, a C2-3-alkenyl group, wherein C2-3-alkynyl or C2-3-alkenyl group may contain from 1 to 3 fluorine atoms, or R1! represents a group of acetyl, cyclopropyl, cyano, methylsulfonyl, ethylsulfonyl, methylsulfinyl, ethylsulfinyl trifluoromethylsulfanyl, methylsulfanyl, ethylsulfanyl, formyl group or a group of C 2-4 -heteroalkyl, R2 represents a phenyl group which may be substituted with -1, 2, 3, 4 or 5 Y substituents, which may be the same or different, selected from the group consisting of methyl, ethyl, propyl, methoxy, ethoxy, hydroxy, chlorine, iodine, bromine, fluorine, trifluoromethyl, trifluoromethoxy, methylsulfonyl, carbamoyl, phenyl and cyano, or R 2 represents a heteroaryl group wherein the heteroaryl group may be substituted with 1, 2 or 3 Y substituents, wherein Y has the meaning as defined above, provided that R 2 is not a 6-methyl-2-methyl group. 2-pyridyl, or R2 represents a fused monocyclic, fused bicyclic monocyclic or 4- to 10-membered fused tricyclic carbocyclic ring system, or R2 represents a monocyclic monocyclic ring system fused to bicyclic, fused bicyclic or 4 to 10 membered monounsaturated or fully saturated tricyclic ring wherein the carbocyclic or heterocyclic ring system may be substituted with 1 to 5 substituents selected from methyl, ethyl, amino, hydroxy or fluorine, or R2 represents a group of formula CH 2 -R 5 wherein R 5 represents a phenyl group which is substituted with 1, 2, 3, 4 or 5 Y substituents as defined above, or R 5 represents a heteroaryl group or a 1,2,3,4-tetrahydronaphthyl or indanyl group wherein the heteroaryl group or group of 1,2,3,4-tetrahydronaphthyl or indanyl may be substituted with 1, 2 or 3 Y substituents as defined above or R 5 represents a monocyclic, fused bicyclic 4- to 10-membered carbocyclic ring system monounsaturated or fully saturated monocyclic fused tricyclic, or R5 represents a monocyclic fused monocyclic, fused bicyclic or 4- to 10-membered fused monocyclic or fully saturated heterocyclic ring system wherein the carbocyclic or heterocyclic ring systems are optionally substituted with 1 to 5 selected substituents from the group consisting of methyl, ethyl, amino, hydroxy or fluorine, or R2 represents a group of methylsulfomlaminoalkyl, methylsulfonylalkyl or an acetamidoalkyl group, with the proviso that wherein R2 is not a phenyl, 4-methylphenyl or 4-methoxyphenyl group, R3 represents a hydrogen or halogen atom or a group of formyl, C1-6 alkylsulfonyl, C1-6 alkylsulfinyl, C1-6 alkylsulfanyl, trifluoromethylsulfanyl, benzylsulfanyl or cyano, represents C 1-8 alkyl group, wherein the C 1-6 alkyl group may be substituted with 1 to 5 substituents selected from the group consisting of fluorine, hydroxy or amino, or R 3 represents a C 2-6 alkynyl group, C 2 C 1-6 alkenyl, C 1-6 alkanoyl, C 3-8 cycloalkyl, C 5-8 heterocycloalkyl or C 2-6 heteroalkyl, wherein the groups are optionally substituted with 1 to 3 methyl groups, one group of ethyl, amino or hydroxy or with 1 to 3 fluorine atoms, or R3 represents a defenyl group which is substituted with 1 to 5 Y substituents, wherein Y has the meaning as defined above, or R3 represents a heteroaryl group in which the group The heteroaryl group may be substituted with 1, 2 or 3 Y substituents, wherein Y has the meaning as defined above or R 3 represents a benzyl or heteroaryl methyl group wherein the benzyl or heteroarylmethyl group may be substituted with 1, 2 or 3 Y substituents Z represents a chlorine atom or a group of Q3 alkyl, a hydroxy group, or a group of -O-Na, -OK, -O-Li or -O-Cs, or Z represents a group of N- methoxy-N-methylamino, such compounds being useful in the synthesis of compounds of formula (I) wherein R 15 R 2 and R 3 have the meanings as provided according to claim 2. Pharmaceutical composition characterized in that it comprises, in addition to a pharmaceutically acceptable carrier and / or at least a pharmaceutically acceptable auxiliary substance, a pharmacologically active amount of at least one compound of one of claims 1 to 6, or a salt thereof, as an ingredient. active. Method for preparing pharmaceutical compositions according to claim 8, characterized in that a compound of any one of claims 1 to 6 is presented in a form suitable for administration. A compound according to any one of claims 1 to 6, or a salt thereof, for use as a medicament. Use of a compound according to claims 1 to 6, characterized in that it is for the preparation of a pharmaceutical composition for the treatment of disorders involving cannabinoid receptor CB2 aneurotransmission. Use according to claim 11, characterized in that said disorders in which CB2 cannabinoid receptors are involved, or which can be treated by manipulation of these receptors, are immune system disorders, inflammatory disorders, Huntington's disease, multiple sclerosis, allergies, cancer and pain, including dorneuropathic pain.