HK1086552B - Adamantyl acetamides as 11-beta hydroxysteroid dehydrogenase inhibitors - Google Patents

Description

Adamantyl acetamides as 11-beta hydroxysteroid dehydrogenase inhibitors

Metabolic syndrome is a disease that is increasing in incidence, both in the western world, as well as in asia and developing countries. It is characterized by obesity and especially central or visceral obesity, type II Diabetes, hyperlipidemia, hypertension, arteriosclerosis, coronary heart disease and ultimately chronic renal failure (c.t. montague et al (2000), Diabetes, 49, 883-.

Glucocorticoid and 11 β -HSD1 are known to be important factors in the differentiation of adipose stromal cells into mature adipocytes. 11 β -HSD1 mRNA levels were increased in visceral stromal cells in obese patients compared to subcutaneous tissue. Furthermore, overexpression of 11 β -HSD1 in adipose tissue in transgenic mice was associated with increased corticosterone levels in adipose tissue, visceral obesity, insulin sensitivity, type II diabetes, hyperlipidemia, and appetite stimulation (H.Masuzaki et al (2001), Science, 294, 2166-2170). Thus, 11 β -HSD1 is likely to be involved in the pathogenesis of visceral obesity and metabolic syndrome.

Inhibition of 11 β -HSD1 resulted in a decrease in differentiation and an increase in adipose stromal cell proliferation. Also, glucocorticoid deficiency (adrenal ablation) increases the anorexia-and weight-loss-inducing activity of insulin and leptin (leptin), and this effect is reversed by glucocorticoid administration (p.m. stewart et al (2002), trends endocrin. metabanol, 13, 94-96). These data show that: the increased reactivation of 11-dehydro-17-oxycorticosterone by 11 β -HSD1 may exacerbate obesity and it may help to inhibit this enzyme in adipose tissue of obese patients.

Obesity is also associated with cardiovascular disease. There is an important relationship between cortisol excretion rate and HDL cholesterol in both men and women, suggesting that glucocorticoids regulate key components of cardiovascular disease. In the simulation, aortic sclerosis in elderly is also associated with visceral obesity.

Glucocorticoids and glaucoma

Glucocorticoids increase the risk of glaucoma by increasing intraocular pressure when administered externally and under specific conditions that increase products similar to those in cushing's syndrome. The increase in intraocular pressure caused by corticosteroids is due to the increased resistance to fluid flow caused by the glucocorticoid causing changes in the trabecular meshwork and its internal intracellular matrix. Zhou et al (Int J Mol Med (1998)1, 339-: corticosteroids increase the amount of fibronectin and type I and type IV collagen in the trabecular meshwork of the anterior part of the bovine in organ culture.

11 β -HSD1 was expressed in basal cells of corneal epithelium and non-pigmented epithelial cells. Glucocorticoid receptor mRNA was only detected in the trabecular meshwork, whereas mineral corticoid receptor and 11 β -HSD1 were also present in the pigment-free epithelial cell mRNA for glucocorticoids. Administration of gastrin to patients caused a significant decrease in intraocular pressure (s.rauz et al (2001), invest.ophtalmol.vis.science, 42, 2037-.

The basic problem to be solved by the present invention is therefore to identify potent inhibitors of 11 β -HSD1, which are highly selective for 11 β -HSD1 and which have utility in the treatment of diseases associated with excessive cortisol formation, such as obesity, diabetes, obesity-related cardiovascular disease, and glaucoma.

The present invention relates to compounds of formula (I):

the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein

n represents an integer of 0, 1 or 2,

m represents an integer of 0 or 1,

R¹and R²Independently of one another, hydrogen and C_1-4Alkyl, NR⁹R¹⁰、C_1-4Alkoxy, Het³-O-C_1-4An alkyl group; or

R¹And R²With themThe carbon atoms to which they are attached together forming a carbonyl group or C_3-6A cycloalkyl group; and when n is 2, R¹And R²One may be absent to form an unsaturated bond;

R³represents hydrogen, Ar¹、C_1-8Alkyl radical, C_6-12Cycloalkyl or a monovalent group having one of the following formulae:

wherein Ar is¹、C_6-12The cycloalkyl or monovalent group may be optionally substituted with 1, or possibly 2 or 3 substituents selected from the group consisting of: c_1-4Alkyl radical, C_1-4Alkoxy, phenyl, halogen, oxygen (OXO), carbonyl, 1, 3-dioxolyl (1, 3-dioxolyl) or hydroxy; in particular R³Represents a monovalent group having formula a) or b), optionally substituted with 1, or possibly 2 or 3 substituents selected from the group consisting of: c_1-4Alkyl radical, C_1-4Alkoxy, phenyl, halogen, oxygen, carbonyl, 1, 3-dioxolyl or hydroxy;

R⁴represents hydrogen, C_1-4Alkyl or C_2-4An alkenyl group;

q represents C_3-8Cycloalkyl, Het¹Or Ar²Wherein said C is_3-8Cycloalkyl, Het¹Or Ar²Optionally substituted with 1 or possibly more substituents selected from the group consisting of: halogen, C_1-4Alkyl radical, C_1-4Alkoxy, hydroxy, nitro, Het⁴Phenyl, phenoxy, C_1-4Alkoxycarbonyl, hydroxycarbonyl, NR⁵R⁶Is 1 or possibly 2 or 3 independently selected from C_1-4Alkyl, hydroxycarbonyl, Het²、C_1-4Alkyl or NR⁷R⁸C substituted by a substituent of_1-4Alkoxy, selected from phenyl-C_1-4Alkoxycarbonyl group, C_1-4Alkoxycarbonyl, hydroxycarbonyl or Het⁵C substituted by 1 substituent of the carbonyl group_2-4Alkenyl, and substituted with 1 or possibly 2 or 3 substituents independently selected from halogen, dimethylamine, trimethylamine, amine, cyano, Het⁶、Het⁷-carbonyl group, C_1-4C substituted by substituents of alkoxycarbonyl or hydroxycarbonyl groups_1-4An alkyl group;

R⁵and R⁶Independently of one another, selected from: hydrogen, C_1-4Alkyl radical, C_1-4Alkoxy radical C_1-4Alkyl radical, C_1-4Alkoxycarbonyl group, C_1-4Alkylcarbonyl, substituted by 1 or possibly 2 or 3 independently selected from halogen, C_1-4Alkyl and C_1-4C substituted by substituents of alkoxy_1-4Alkylcarbonyl, or R⁵And R⁶Independently of one another, represents C substituted by phenyl_1-4An alkyl group;

R⁷and R⁸Independently of one another, selected from: hydrogen or C_1-4An alkyl group;

R⁹and R¹⁰Independently of one another, selected from: hydrogen, C_1-4Alkyl or C_1-4An alkoxycarbonyl group;

l represents an optionally substituted or optionally substituted number 1 or more selected from C_1-4C substituted by alkyl or phenyl substituents_1-4An alkyl group;

Het¹represents a heterocycle selected from the group consisting of: pyridyl, piperidyl, pyrimidinyl, pyrazinyl, piperazinyl, pyridazinyl, indolyl, isoindolyl, indolinyl, furyl, benzofuryl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, benzothiophenyl, thiophenyl, 1, 8-diazanaphthyl, 1, 6-diazanaphthyl, quinolinyl, 1, 2, 3, 4-tetrahydroquinolinyl, isoquinolinyl, 1, 2, 3, 4-tetrahydroisoquinolinyl, quinoxalinyl, quinazolinyl, 2, 3-diazanaphthyl, 2H-benzopyranyl, 3, 4-dihydro-2H-benzopyranyl, 2H-benzothiopyranyl, 3, 4-dihydro-2H-benzothiopyranyl, or 1, 3-benzodioxolyl (1, 3-benzodioxolyl);

Het²represents a monocyclic heterocycle selected from the group consisting of: piperidinyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 2H-pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl or morpholinyl, said Het²Optionally substituted by 1 or possibly 2 or more independently selected from hydroxy, C_1-4Alkyl or C_1-4Substituent substitution of alkoxy;

Het³represents a monocyclic heterocycle selected from the group consisting of: 2H-pyranyl, 4H-pyranyl, furanyl, tetrahydro-2H-pyranyl, pyridinyl, piperidinyl, or furanyl;

Het⁴represents a monocyclic heterocycle selected from the group consisting of: pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrazinyl, piperazinyl, triazolyl, tetrazolyl or morpholinyl, said Het⁴Optionally substituted by 1 or possibly 2 or more independently selected from hydroxy, carbonyl, C_1-4Alkyl or C_1-4Substituent substitution of alkoxy;

Het⁵represents a monocyclic heterocycle selected from the group consisting of: pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrazinyl, piperazinyl or morpholinyl, said Het⁵Optionally substituted by 1 or possibly 2 or more independently selected from hydroxy, carbonyl, C_1-4Alkyl or C_1-4Substituent substitution of alkoxy; preferably piperazinyl or morpholinyl;

Het⁶represents a monocyclic heterocycle selected from the group consisting of: pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrazinyl, piperazinyl or morpholinyl, said Het⁶Optionally substituted by 1 or possibly 2 or more independently selected from hydroxy, carbonyl, C_1-4Alkyl or C_1-4Substituent substitution of alkoxy;

Het⁷represents a monocyclic heterocycle selected from the group consisting of: pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrazinyl, piperazinyl or morpholinyl, said Het⁷Optionally substituted by 1 or possibly 2 or more independently selected from hydroxy, carbonyl, C_1-4Alkyl or C_1-4Substituent substitution of alkoxy; preferably piperazinyl or morpholinyl;

Ar¹represents a carbocyclic group containing one or more rings selected from the group consisting of: phenyl, biphenyl, indenyl, 2, 3-indanyl, fluorenyl, 5,6, 7, 8-tetrahydronaphthyl or naphthyl;

Ar²represents a carbocyclic group containing one or more rings selected from the group consisting of: phenyl, biphenyl, benzocyclobutene, benzocycloheptyl, benzocycloheptenyl, indenyl, 2, 3-dihydroindenyl, fluorenyl, 1, 2-dihydronaphthyl, 5,6, 7, 8-tetrahydronaphthyl, or naphthyl;

as used above and in the following definitions, halogen is typically fluorine, chlorine, bromine and iodine; c_1-4Alkyl represents a straight or branched chain saturated hydrocarbon group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl, 2-dimethylethyl, and the like; c_1-8Alkyl represents a straight-chain or branched saturated hydrocarbon radical having 1 to 8 carbon atoms, e.g. C_1-4Alkyl-defined groups and pentyl, hexyl, octyl, 2-methylbutyl, 2-methylpentyl, 2-dimethylpentyl, and the like; c_3-6Cycloalkyl generally denotes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; c_6-12Cycloalkyl typically denotes cycloheptyl, cyclooctyl, cyclononane, cyclodecane, cycloundecane, cyclododecane; c_1-4Alkoxy denotes straight-chain or branched saturated hydrocarbon radicals, such as methoxy, ethoxy, propoxy, butoxy, 1-methylethoxy, 2-methylpropoxy and the like.

As used herein before, the term "oxygen" or "carbonyl" denotes (═ O), which together with the carbon atom to which it is attached forms a carbonyl moiety.

The pharmaceutically acceptable addition salts mentioned above include the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are able to form. The latter can be conveniently obtained by treating the base form with a suitable acid. Suitable acids include, for example, inorganic acids, e.g., hydrohalic acids, such as hydrochloric or hydrobromic acid; acids such as sulfuric acid, nitric acid, phosphoric acid, etc.; or organic acids such as acetic, propionic, glycolic, lactic, pyruvic, oxalic, malonic, succinic (i.e., succinic), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.

The pharmaceutically acceptable addition salts mentioned above include the therapeutically active non-toxic base addition salt forms which the compounds of formula (I) are able to form. Examples of such base addition salts are, for example, the sodium, potassium, calcium salts, and pharmaceutically acceptable amine salts, such as ammonia, alkylamines, benzathine (benzathine), N-methyl-D-glucamine, hydrabamine (hydrabamine), amino acids, such as arginine, lysine.

Rather, the salt form may be brought to its free acid or free base form by treatment with a suitable base or acid.

The term "addition salt" as used above also comprises solvates of the compounds of formula (I), as well as the salts which they are able to form. Such solvates are, for example, hydrates, alcoholates and the like.

The term "stereochemically isomeric forms" as used above denotes the various isomeric forms which are possible, as well as the conformational forms which the compounds of formula (I) may possess. Unless otherwise indicated or indicated, the chemical designation of a compound denotes the mixture of all possible stereoisomeric and conformational isomeric forms, said mixtures including all diastereomers, enantiomers and/or conformational isomers of the basic molecular structure. All stereochemically isomeric forms, including the pure form or mixtures of forms, of the compounds of formula (I) are intended to be embraced within the scope of the present invention.

The N-oxide form of the compounds of formula (I) means that one or several nitrogen atoms in the compounds of formula (I) are oxidized to the so-called N-oxide.

A group of compounds comprising compounds of formula (I) subject to one or more of the following limitations:

(i) n represents an integer of 1 or 2, with the proviso that when n ═ 2, Q represents Het¹Or Ar²Wherein said Het is¹Or Ar²Optionally substituted with one or possibly more substituents selected from the group consisting of: halogen, C_1-4Alkyl radical, C_1-4Alkoxy, hydroxy, nitro, Het⁴Phenyl, phenoxy, hydroxycarbonyl, NR⁵R⁶1 or possibly 2 or 3 independently selected from hydroxycarbonyl, Het²And NR⁷R⁸C substituted by a substituent of_1-4Alkoxy, and C substituted by 1 or possibly 2 or 3 halo_1-4An alkyl group;

(ii)R¹and R²Independently of one another, hydrogen, C_1-4Alkyl, NR⁹R¹⁰、C_1-4Alkoxy, Het³-O-C_1-4An alkyl group; or

R¹And R²Form a carbonyl group with the carbon atom to which they are attached, or C_3-6A cycloalkyl group;

(iii)R³represents phenyl, C_6-12Cycloalkyl or a monovalent group having one of the following formulae:

wherein said phenyl, C_6-12Cycloalkyl or a monovalent group may optionally be selected by 1, or possibly 2 or 3 from C_1-4Alkyl radical, C_1-4Alkoxy, halogen, carbonyl, phenyl or hydroxy; in particular R³Represents a monovalent radical of the general formula a) or b), optionally substituted by 1, or possibly 2 or 3, selected from C_1-4Alkyl radical, C_1-4Alkoxy, halogen, carbonyl, phenyl or hydroxy;

(iv)R⁴represents hydrogen or C_1-4An alkyl group;

(v) q represents Het¹Or Ar²Wherein said Het is¹Or Ar²Optionally substituted with 1 or possibly more substituents selected from the group consisting of: halogen, C_1-4Alkyl radical, C_1-4Alkoxy, hydroxy, nitro, Het⁴Phenyl, phenoxy, hydroxycarbonyl, NR⁵R⁶Is 1 or possibly 2 or 3 independently selected from C_1-4Alkyl, hydroxycarbonyl, Het²And NR⁷R⁸C substituted by a substituent of_1-4Alkoxy, and C substituted by 1 or possibly 2 or 3 halo_1-4An alkyl group;

(vi)Het¹represents a heterocycle selected from the group consisting of: piperidinyl, pyrimidinyl, pyrazinyl, piperazinyl, pyridazinyl, indolyl, isoindolyl, indolinyl, benzofuranyl, benzothiophenyl, 1, 8-diazanaphthyl, 1, 6-diazanaphthyl, quinazolinyl, 2, 3-diazanaphthyl, or 1, 3-benzodioxolyl;

(vii)Ar²represents an optional quilt C_1-4Alkyl radical, C_1-4Alkoxy or halogen, preferably phenyl or naphthyl substituted by methyl or methoxy.

Another group of compounds includes compounds of formula (I) subject to one or more of the following limitations:

(i)R¹and R²Independently of one another, hydrogen, C_1-4Alkyl, NR⁹R¹⁰(ii) a Or R¹And R²Form C with the carbon atom to which they are attached_3-6A cycloalkyl group; and when n is 2, R¹Or R²One of which may be absent to form an unsaturated bond;

(ii)R³is represented by C_6-12Cycloalkyl or a monovalent group having one of the following formulae:

wherein said C_6-12The cycloalkyl or monovalent group may optionally be substituted by 1, or possibly 2, 3 or more groups selected from C_1-4Alkyl radical, C_1-4Alkoxy, halogenCarbonyl, hydroxy or 1, 3-dioxolyl; in particular R³Represents a monovalent radical of formula a) or b), optionally substituted by 1, or possibly 2 or 3, selected from C_1-4Alkyl radical, C_1-4Alkoxy, halogen, carbonyl, or hydroxy;

(iii) q represents Het¹Or Ar²Wherein said Het is¹Or Ar²Optionally substituted with 1 or possibly 2 or more substituents selected from the group consisting of: halogen, C_1-4Alkyl radical, C_1-4Alkoxy, hydroxy, C_1-4Alkoxycarbonyl, Het⁴、NR⁵R⁶Is independently selected from hydroxycarbonyl, Het by 1 or possibly 2 or 3²And NR⁷R⁸C substituted by a substituent of_1-4Alkoxy, selected from phenyl-C_1-4Alkoxycarbonyl or Het⁵-C optionally substituted by a carbonyl substituent_2-4Alkenyl, and substituted with 1 or possibly 2 or 3 substituents independently selected from halogen, dimethylamine, amine, cyano, Het⁶、Het⁷-C substituted by a substituent of carbonyl or hydroxycarbonyl_1-4An alkyl group;

(iv)R⁵and R⁶Independently of one another, from hydrogen, C_1-4Alkyl radical, C_1-4Alkylcarbonyl, C substituted by 1 or possibly 2 or 3 halo_1-4An alkylcarbonyl group.

(v)R⁹And R¹⁰Independently of one another, from hydrogen or C_1-4An alkyl group;

(vi) l represents C_1-4Alkyl, preferably methyl;

(vii)Het¹represents a heterocycle selected from the group consisting of: pyridyl, pyrimidinyl, indolyl, thiophenyl, benzothiophenyl, quinolinyl, 1, 2, 3, 4-tetrahydro-quinolinyl, isoquinolinyl, 1, 2, 3, 4-tetrahydro-isoquinolinyl, 2H-benzopyranyl, 3, 4-dihydro-2H-benzopyranyl, 2H-benzothiopyranyl, 3, 4-dihydro-2H-benzothiopyranyl, or 1, 3-benzodioxolyl;

(viii)Het²represents a heterocycle selected from the group consisting of: piperidinyl, piperazinyl, pyridinyl, pyrrolidinyl, or morpholinyl, wherein said Het²Optionally substituted by 1 or possibly 2 or more C_1-4Alkyl substitution;

(ix)Het⁴represents a tetrazolyl group;

(x)Het⁵represents morpholinyl;

(xi)Het⁶represents a monocyclic heterocycle selected from pyrrolidinyl, piperazinyl or morpholinyl, wherein said Het is⁶Optionally substituted with 1 or possibly 2 or more hydroxyl groups, preferably with one hydroxyl group;

(xii)Het⁷represents a monocyclic heterocycle selected from piperazinyl or morpholinyl, preferably morpholinyl;

(xiii)Ar²represents a carbocyclic group containing one or more rings selected from the group consisting of: phenyl, benzocyclobutenyl, benzocyclocycloheptyl, benzocycloheptenyl, indenyl, 2, 3-dihydroindenyl, 5,6, 7, 8-tetrahydronaphthyl, or naphthyl.

Particular compounds of formula (I) are compounds that exhibit high HSD1 specificity. To this end, the compounds of the formula (I) are subject to one or more of the following limitations:

(i) n represents an integer of 0, 1 or 2;

(ii)R¹and R²Independently of one another, hydrogen and C_1-4Alkyl, NR⁹R¹⁰(ii) a Or R¹And R²Together with the carbon atom to which they are attached form C_3-6A cycloalkyl group; and when n is 2, R¹Or R²One of which may be absent to form an unsaturated bond;

(iii)R³is represented by C_6-12Cycloalkyl, preferably cyclooctyl, or a monovalent group having one of the following formulae:

preferably of formula (a) or (b) above, wherein C is_6-12Cycloalkyl or monovalent radicals optionally substituted by 1, or possibly 2, 3 or more radicals selected from C_1-4Alkyl radical, C_1-4Alkoxy, halogen or hydroxy; preferably with an optional coating C_1-4Alkyl radical, C_1-4Alkoxy, halogen or hydroxy substituted of the above formula a);

(iv) q represents Het¹Or Ar²Wherein said Het is¹Or Ar²Optionally substituted with 1 or possibly 2 or more substituents selected from the group consisting of: halogen, C_1-4Alkyl radical, C_1-4Alkoxy, hydroxy, NR⁵R⁶，

Is selected from 1 or possibly 2, 3 or more independently from hydroxycarbonyl, Het²Or NR⁷R⁸C substituted by a substituent of_1-4Alkoxy, selected from phenyl-C_1-4Alkoxycarbonyl or Het⁵C substituted by 1 substituent of the carbonyl group_2-4An alkenyl group, and,

is selected from 1 or possibly 2 or 3 halogen, Het⁶、C_1-4C substituted by substituents of alkoxycarbonyl or hydroxycarbonyl groups_1-4An alkyl group;

(v)R⁵and R⁶Independently of one another, hydrogen or C_1-4An alkyl group;

(vi)R⁹and R¹⁰Independently of one another, hydrogen or C_1-4An alkoxycarbonyl group;

(vii) l represents C_1-4An alkyl group;

(viii)Het¹represents a heterocycle selected from the group consisting of: pyridyl, piperidyl, thiophenyl, 1, 2, 3, 4-tetrahydro-quinolyl, 1, 2, 3, 4-tetrahydro-isoquinolyl, 2H-benzopyranyl, 3, 4-dihydro-2H-benzothiopyranyl, or 1, 3-benzodioxolyl;

(ix)Het²represents pyridyl, pyrrolidinyl or morpholinyl;

(x)Het⁶represents morpholinyl;

(xi)Ar²represents phenyl, benzocyclobutenyl, benzocyclocycloheptyl, benzocycloheptenyl, 2, 3-dihydroindenyl, 5,6, 7, 8-tetrahydronaphthyl, naphthyl or indenyl.

This subgroup of high HSD1 specific inhibitors has been shown to have superior cellular activity and includes compounds of formula (I) subject to one or more of the following limitations:

(i) n represents an integer of 0, 1 or 2;

(ii)R¹and R²Independently of one another, hydrogen and C_1-4An alkyl group; or

R¹And R²Together with the carbon atom to which they are attached form C_3-6A cycloalkyl group; and when n is 2, R¹Or R²One of which may be absent to form an unsaturated bond;

(iii)R³is represented by C_6-12Cycloalkyl, preferably cyclooctyl, or a monovalent group having one of the following formulae:

preferably of formula (a) or (b) above, wherein C is_6-12Cycloalkyl or monovalent radicals optionally substituted by 1, or possibly 2, 3 or more radicals selected from C_1-4Alkyl radical, C_1-4Alkoxy, halogen or hydroxy; preferably with an optional coating C_1-4Alkyl radical, C_1-4Alkoxy, halogen or hydroxy substituted of the above formula a);

(iv) q represents Het¹Or Ar²Wherein said Het is¹Or Ar²Optionally selected by 1 or possibly 2 or moreSubstituent group substitution: halogen, C_1-4Alkyl radical, C_1-4Alkoxy, hydroxy, NR⁵R⁶，

Is selected from 1 or possibly 2, 3 or more independently from hydroxycarbonyl, Het²Or NR⁷R⁸C substituted by a substituent of_1-4An alkoxy group,

quilt Het⁵-carbonyl-substituted C_2-4An alkenyl group, which is a radical of an alkenyl group,

and is selected from halogen, Het by 1 or possibly 2 or 3⁶、C_1-4C substituted by substituents of alkoxycarbonyl or hydroxycarbonyl groups_1-4An alkyl group;

(v)R⁵and R⁶Independently of one another, hydrogen or C_1-4An alkyl group;

(vi) l represents C_1-4An alkyl group;

(vii)Het¹represents a heterocycle selected from the group consisting of: pyridyl, piperidyl, thiophenyl, 2H-benzopyranyl, 3, 4-dihydro-2H-benzothiopyranyl or 1, 3-benzodioxolyl;

(viii)Het²represents pyrrolidinyl or morpholinyl;

(ix)Het⁵represents morpholinyl;

(x)Het⁶represents morpholinyl;

(xi)Het⁷represents morpholinyl;

(xii)Ar²represents phenyl, benzocyclobutenyl, benzocyclocycloheptyl, benzocycloheptenyl, 5,6, 7, 8-tetrahydronaphthyl, naphthyl or indenyl.

Further advantageous compounds according to the invention are compounds of formula (I) subject to one or more of the following limitations:

(i) n represents an integer of 1 or 2;

(ii)R¹and R²Independently of one another, hydrogen and C_1-4Alkyl, NR⁹R¹⁰、C_1-4An alkoxy group; or

R¹And R²Together with the carbon atom to which they are attached form C_3-6A cycloalkyl group; and when n is 2, R¹Or R²One of which may be absent to form an unsaturated bond;

(iii)R³is represented by C_6-12Cycloalkyl, preferably cyclooctyl and cyclohexyl, or R³Represents a monovalent group having one of the following formulae:

wherein said C_6-12The cycloalkyl or monovalent group may optionally be substituted by 1, or possibly 2, 3 or more groups selected from C_1-4Alkyl radical, C_1-4Alkoxy, halogen or hydroxy; in particular R³Represents a monovalent group having formula (a) or (b), wherein C_6-12The cycloalkyl or monovalent group may optionally be substituted by 1, or possibly 2, 3 or more groups selected from C_1-4Alkyl radical, C_1-4Alkoxy, halogen or hydroxy; preferably with an optional coating C_1-4Alkyl radical, C_1-4Alkoxy, halogen or hydroxy substituted of the above formula a);

(iv) q represents C_3-8Cycloalkyl, Het¹Or Ar²Wherein said C is_3-8Cycloalkyl, Het¹Or Ar²Optionally substituted with 1 or possibly 2 or more substituents selected from the group consisting of: halogen, C_1-4Alkyl radical, C_1-4Alkoxy, hydroxy, nitro, NR⁵R⁶Is independently selected from 1 or possibly 2, 3 or more from hydroxycarbonyl, Het²And NR⁷R⁸C substituted by a substituent of_1-4Alkoxy, and, C substituted by 1 or possibly 2 or 3 halogens_1-4Alkyl, preferably trifluoromethyl;

(v)R⁵and R⁶Independently of one another, hydrogen and C_1-4Alkyl or C substituted by phenyl_1-4An alkyl group;

(vi) l represents C_1-4An alkyl group;

(vii)Het¹represents a heterocycle selected from pyridyl, piperidyl or thiophenyl;

(viii)Het²represents piperidinyl, pyrrolidinyl or morpholinyl;

(ix)Ar²represents phenyl, naphthyl or indenyl.

Particularly advantageous compounds of the formula (I) are those having one or more of the following limitations:

(i) n represents an integer of 0, 1 or 2;

(ii)R¹and R²Independently of one another, hydrogen and C_1-4Alkyl, NR⁹R¹⁰、C_1-4An alkoxy group; or

R¹And R²Together with the carbon atom to which they are attached form C_3-6A cycloalkyl group; and when n is 2, R¹Or R²One of which may be absent to form an unsaturated bond;

(iii)R³is represented by C_6-12Cycloalkyl, preferably selected from cyclooctyl and cyclohexyl, or R³Represents a monovalent group having one of the following formulae:

preferably having the general formula (a) above, wherein C is_6-12Cycloalkyl or monovalent radicals optionally substituted by 1, or possibly 2, 3 or more radicals selected from C_1-4Alkyl radical, C_1-4Alkoxy, halogen or hydroxy;

(iv)R⁴represents hydrogen or C_1-4An alkyl group;

(v) q represents Het¹Or Ar²Wherein said C is_3-8Cycloalkyl, Het¹Or Ar²Optionally substituted with 1 or possibly 2 or more substituents selected from the group consisting of: halogen, C_1-4Alkyl radical, C_1-4Alkoxy, hydroxy, nitro, NR⁵R⁶，

Is selected from 1 or possibly 2, 3 or more independently of one another from hydroxycarbonyl, Het²Or NR⁷R⁸C substituted by a substituent of_1-4An alkoxy group,

by phenyl-C_1-4Alkoxycarbonyl substituted C_2-4An alkenyl group, which is a radical of an alkenyl group,

and is selected from halogen, Het by 1 or possibly 2 or 3⁶、Het⁷-carbonyl group, C_1-4C substituted by substituents of alkoxycarbonyl or hydroxycarbonyl groups_1-4An alkyl group;

(vi)R⁵and R⁶Independently of one another, hydrogen and C_1-4Alkyl, or C substituted by phenyl_1-4An alkyl group;

(vii) l represents C_1-4An alkyl group;

(viii)Het¹represents a heterocycle selected from the group consisting of: pyridyl, thiophenyl, 2H-benzopyranyl, 3, 4-dihydro-2H-benzothiopyranyl or 1, 3-benzodioxolyl;

(ix)Het²represents piperidinyl, pyrrolidinyl or morpholinyl;

(x)Het⁶represents a monocyclic heterocycle selected from piperazinyl or morpholinyl, preferably morpholinyl;

(xi)Ar²represents phenyl, benzocyclobutenyl, benzocyclocycloheptyl, benzocycloheptenyl, 2, 3-dihydroindenyl, 1, 2-dihydronaphthyl, 5,6, 7, 8-tetrahydronaphthyl, naphthyl or indenyl.

Preferred compounds include compounds of formula (I) subject to one or more of the following limitations:

(i) q represents phenyl, which phenyl is optionally substituted with 1 or 2 substituents selected from the group consisting of: halogen, preferably chlorine or fluorine, or C_1-4Alkoxy, preferably methoxy;

(ii) n is 1;

(iii) m is 0;

(iv)R¹and R²Is represented by C_1-4Alkyl, preferably methyl; or

R¹And R²Together with the carbon atom to which they are attached form C_3-6Cycloalkyl, preferably cyclopropyl;

(v)R⁴represents hydrogen;

(vi)R³represents a monovalent group having one of the following formulae:

wherein the monovalent group may optionally be substituted by 1, or possibly 2 or 3 groups selected from halogen, carbonyl, hydroxy or C_1-4Alkoxy, preferably methoxy, in particular R³Represents a monovalent group of formula (a) or (b) optionally substituted by 1, or possibly 2, 3 or more selected from halogen, carbonyl, hydroxy or C_1-4Substituent substitution of alkoxy; preferably optionally substituted by hydroxy or C_1-4Alkoxy, preferably methoxy substituted, of the above formula a);

also advantageous are compounds of formula (I) having one or more of the following limitations:

(i)Het¹represents a heterocycle selected from the group consisting of: piperidinyl, pyrimidinyl, pyrazinyl, piperazinyl, pyridazinyl, indolyl, isoindolyl, indolinyl, benzofuranyl, phenylAn acenylthio group, a1, 8-naphthyridine group, a1, 6-naphthyridine group, a quinazolinyl group, a2, 3-naphthyridine group, or a1, 3-benzodioxolyl group;

(ii) q represents Het¹Or Ar²Wherein said Het is¹Or Ar²Optionally substituted with 1 or possibly 2 or more substituents selected from the group consisting of: halogen, C_1-4Alkyl radical, C_1-4Alkoxy, hydroxy, NR⁵R⁶Is selected from the group consisting of hydroxycarbonyl, Het, by 1 or possibly 2, 3 or more independently of one another²And NR⁷R⁸C substituted by a substituent of_1-4Alkoxy, and C substituted by 1 or possibly 2 or 3 halogens_1-4An alkyl group; or Q represents phenyl optionally substituted by 1 or 2 substituents selected from halogen, preferably chlorine or fluorine, or C_1-4Alkoxy, preferably methoxy;

(iii) n represents an integer of 1 or 2; or n is 1;

(iv) m is 0;

(v)R¹and R²Represents hydrogen, C_1-4Alkyl, NR⁹R¹⁰Preferably C_1-4Alkyl, particularly preferably methyl; or

R¹And R²Together with the carbon atom to which they are attached form C_3-6Cycloalkyl, preferably cyclopropyl; and when n is 2, R¹Or R²One of which may be absent to form an unsaturated double bond;

(vi)R⁴represents hydrogen;

(vii)R³represents a monovalent group having one of the following formulae:

wherein the monovalent group may optionally be substituted by 1, or possibly 2 or 3 groups selected from halogen, carbonyl, hydroxyOr C_1-4Alkoxy, preferably methoxy, or

R³Is represented by C_6-12Cycloalkyl, preferably cyclooctyl, or a monovalent group having one of the following formulae:

wherein said C_6-12Cycloalkyl or monovalent radicals optionally substituted by 1 or possibly 2, 3 or more radicals selected from C_1-4Alkyl radical, C_1-4Alkoxy, halogen or hydroxy; or R³Is represented by C_6-12Cycloalkyl, or a monovalent group having one of the following formulae:

wherein said C_6-12Cycloalkyl or monovalent radicals optionally substituted by 1 or possibly 2, 3 or more radicals selected from C_1-4Alkyl radical, C_1-4Alkoxy, halogen or hydroxy; preferably R³Represents a monovalent group having one of the following formulae:

wherein the monovalent radical is optionally substituted by 1 or possibly 2, 3 or more groups selected from halogen, carbonyl, hydroxy or C_1-4Alkoxy, preferably substituted with a substituent selected from bromo, fluoro, chloro, hydroxy or methoxy; particularly preferred compounds are those wherein R is³The substituent is 2-adamantyl, optionally substituted by 1 or possibly 2, 3 or more substituents selected from C_1-4Alkyl radical, C_1-4Alkoxy, halogen, oxygen, carbonyl or hydroxy, preferably substituted with a substituent selected from bromo, fluoro, chloro, hydroxy or methoxy;

(viii)R⁵and R⁶Independently of one another, hydrogen or C_1-4An alkyl group;

(ix)R⁹and R¹⁰Independently of one another, hydrogen or C_1-4An alkoxycarbonyl group;

(x) L represents C_1-4An alkyl group;

(xi)Het¹represents a heterocycle selected from pyridyl, piperidyl, thiophenyl or 1, 3-benzodioxolyl;

(xii)Het²represents pyridyl, pyrrolidinyl or morpholinyl;

(xiii)Ar²represents phenyl, naphthyl or indenyl.

Particularly preferred compounds are those of the formula (I) R³A compound which is an optionally substituted 2-adamantyl group and in which Q represents an optionally substituted phenyl group, hereinafter referred to as a compound of the formula (I'),

the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein:

R¹and R²Independently of one another, hydrogen and C_1-4Alkyl, NR⁹R¹⁰、C_1-4Alkoxy or Het³-O-C_1-4An alkyl group; preferably C_1-4Alkyl, particularly preferably methyl; or

R¹And R²Together with the carbon atom to which they are attached form C_3-6Cycloalkyl, preferably cyclopropyl or cyclobutyl;

R⁴represents hydrogen, C_1-4Alkyl radical, C_2-4An alkenyl group;

u represents hydrogen, C_1-4Alkyl radical, C_1-4Alkoxy, phenyl, halogen, oxygen, carbonyl, or hydroxy;

R⁵and R⁶Independently of one another, hydrogen and C_1-4Alkyl radical, C_1-4Alkoxy radical C_1-4Alkyl radical, C_1-4Alkoxycarbonyl group, C_1-4Alkylcarbonyl, by 1 or possibly 2 or 3 radicals independently of one another selected from halogen, C_1-4Alkyl and C_1-4C substituted by substituents of alkoxy_1-4Alkylcarbonyl, or R⁵And R⁶Independently of one another, represents C substituted by phenyl_1-4An alkyl group;

R⁷and R⁸Independently of one another, from hydrogen or C_1-4An alkyl group;

R⁹and R¹⁰Independently of one another, from hydrogen, C_1-4Alkyl or C_1-4An alkoxycarbonyl group;

R¹¹and R¹²Independently of one another, from hydrogen, halogen, C_1-4Alkyl radical, C_1-4Alkoxy, hydroxy, nitro, Het⁴Phenyl, phenoxy, C_1-4Alkoxycarbonyl, hydroxycarbonyl, NR⁵R⁶1 or possibly 2 or 3 independently of one another from hydroxycarbonyl, Het²、NR⁷R⁸C substituted by a substituent of_1-4Alkoxy, selected from phenyl-C_1-4Alkoxycarbonyl group, C_1-4Alkoxycarbonyl, hydroxycarbonyl, Het⁵C substituted by one substituent of a carbonyl group_2-4Alkenyl, and is selected from the group consisting of halogen, dimethylamine, trimethylamine, amine, cyano, Het independently of one another by 1 or possibly 2 or 3⁶、Het⁷-carbonyl group, C_1-4C substituted by substituents of alkoxycarbonyl or hydroxycarbonyl groups_1-4An alkyl group;

Het¹represents a heterocycle selected from the group consisting of: pyridyl, piperidyl, pyrimidinyl, pyrazinyl, piperazinyl, pyridazinyl, indolyl, isoindolyl, indolinyl, furyl, benzofuryl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, and mixtures thereof,Isothiazolyl, benzothiophenyl, thiophenyl, 1, 8-naphthyridinyl, 1, 6-naphthyridinyl, quinolyl, isoquinolyl, 1, 2, 34-tetrahydroisoquinolinyl, quinoxalinyl, quinazolinyl, 2, 3-naphthyridinyl, 2H-benzopyranyl, 3, 4-dihydro-2H-benzopyranyl, 2H-benzothiopyranyl, 3, 4-dihydro-2H-benzothiopyranyl or 1, 3-benzodioxolyl;

Het²represents a monocyclic heterocycle selected from the group consisting of: piperidinyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 2H-pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl or morpholinyl, said Het²Optionally substituted by 1 or possibly 2 or more independently selected from hydroxy, carbonyl, C_1-4Alkyl or C_1-4Substituent substitution of alkoxy;

Het³represents a monocyclic heterocycle selected from the group consisting of: 2H-pyranyl, 4H-pyranyl, furanyl, tetrahydro-2H-pyranyl, pyridinyl, piperidinyl, or furanyl;

Het⁴represents a monocyclic heterocycle selected from the group consisting of: pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrazinyl, piperazinyl, triazolyl, tetrazolyl or morpholinyl, said Het⁴Optionally substituted by 1 or possibly 2 or more independently selected from hydroxy, carbonyl, C_1-4Alkyl or C_1-4Substituent substitution of alkoxy;

Het⁵represents a monocyclic heterocycle selected from the group consisting of: pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrazinyl, piperazinyl or morpholinyl, said Het⁵Optionally substituted by 1 or possibly 2 or more independently selected from hydroxy, carbonyl, C_1-4Alkyl or C_1-4Substituent substitution of alkoxy; preferably piperazinyl or morpholinyl;

Het⁶represents a monocyclic heterocycle selected from the group consisting of: pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrazinyl, piperazinyl or morpholinyl, said Het⁶Optionally substituted by 1 or possibly 2 or more independently selected from hydroxy, carbonyl, C_1-4Alkyl or C_1-4Taking alkoxy groupsSubstituent groups;

Het⁷represents a monocyclic heterocycle selected from the group consisting of: pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrazinyl, piperazinyl or morpholinyl, said Het⁷Optionally substituted by 1 or possibly 2 or more independently selected from hydroxy, carbonyl, C_1-4Alkyl or C_1-4Substituent substitution of alkoxy; preferably piperazinyl or morpholinyl; especially preferred is morpholinyl.

Further preferred are compounds of formula (I') having one or more of the following limitations:

(i)R¹and R²Independently of one another, hydrogen and C_1-4Alkyl radical, C_1-4An alkoxy group; preferably methyl or methoxy;

(ii)R⁴represents hydrogen;

(iii) u represents hydrogen, hydroxy or halogen, in particular hydrogen, hydroxy, fluorine or chlorine;

(iv)R⁵and R⁶Independently of one another, from hydrogen, C_1-4Alkyl radical, C_1-4Alkoxy radical C_1-4Alkyl radical, C_1-4Alkylcarbonyl, or C substituted by halogen_1-4An alkylcarbonyl group;

(v)R⁷and R⁸Is represented by C_1-4Alkyl, preferably methyl;

(vi)R¹¹and R¹²Independently of one another, from hydrogen, C_1-4Alkyl radicals, e.g. especially methyl or propyl, C_1-4Alkoxy, hydroxy, nitro, Het⁴、NR⁵R⁶Is selected from hydroxycarbonyl, Het independently of one another by one or possibly 2 or 3²、C_1-4Alkyl or NR⁷R⁸C substituted by a substituent of_1-4Alkoxy, selected from phenyl C_1-4Alkoxycarbonyl group, C_1-4Alkoxycarbonyl, hydroxycarbonyl, Het⁵C substituted by one substituent of a carbonyl group_2-4Alkenyl, and 1 or possibly 2 or 3 substituents independently of one another selected from halogen, dimethylamine, trisMethylamine, amine, Het⁶、Het⁷-C substituted by a substituent of carbonyl or hydroxycarbonyl_1-4An alkyl group;

(vii)Het²represents piperidinyl, piperazinyl, pyrrolidinyl or morpholinyl, said Het²Optionally is covered with C_1-4Alkyl, especially methyl;

(viii)Het⁴represents a tetrazolyl group;

(ix)Het⁵represents morpholinyl;

(x)Het⁶represents pyridazinyl, pyrrolidinyl or morpholinyl, said Het⁴Optionally substituted by carbonyl or C_1-4Alkyl substitution;

further advantageous compounds are compounds of the formula (I'),

n-oxide forms, pharmaceutically acceptable addition salts and stereochemically isomeric forms thereof, wherein:

R⁴represents hydrogen, C_1-4Alkyl radical, C_2-4An alkenyl group;

u represents hydrogen, C_1-4Alkyl radical, C_1-4Alkoxy, phenyl, halogen, oxygen, carbonyl, or hydroxy;

q represents Het¹Or Ar²Wherein said Het is¹Or Ar²Optionally substituted with 1 or possibly more substituents selected from the group consisting of: halogen, C_1-4Alkyl radical, C_1-4Alkoxy, hydroxy, nitro, Het⁴Phenyl, phenoxy, C_1-4Alkoxycarbonyl, hydroxycarbonyl, NR⁵R⁶、

Is selected from 1 or possibly 2 or 3 independently from hydroxycarbonyl, Het²And NR⁷R⁸C substituted by a substituent of_1-4Alkoxy radical,

And C substituted with 1 or possibly 2 or 3 substituents independently selected from halogen or hydroxycarbonyl_1-4An alkyl group;

R⁵and R⁶Independently of one another, from hydrogen, C_1-4Alkyl radical, C_1-4Alkoxy radical C_1-4Alkyl radical, C_1-4Alkoxycarbonyl group, C_1-4Alkylcarbonyl, by 1 or possibly 2 or 3 radicals independently of one another selected from halogen, C_1-4Alkyl and C_1-4C substituted by substituents of alkoxy_1-4Alkylcarbonyl, or R⁵And R⁶Independently of one another, represents C substituted by phenyl_1-4An alkyl group;

R⁷and R⁸Independently of one another, from hydrogen or C_1-4An alkyl group;

R⁹and R¹⁰Independently of one another, from hydrogen, C_1-4Alkyl or C_1-4An alkoxycarbonyl group;

Het¹represents a bicyclic heterocycle selected from: indolyl, isoindolyl, indolinyl, benzofuranyl, benzothiophenyl, thiophenyl, 1, 8-naphthyridinyl, 1, 6-naphthyridinyl, quinolinyl, 1, 2, 3, 4-tetrahydroquinolinyl, isoquinolinyl, 1, 2, 3, 4-tetrahydroisoquinolinyl, quinoxalinyl, quinazolinyl, 2, 3-naphthyridinyl, 2H-benzopyranyl, 3, 4-dihydro-2H-benzopyranyl, 2H-benzothiopyranyl, 3, 4-dihydro-2H-benzothiopyranyl, or 1, 3-benzodioxolyl;

Het²represents a monocyclic heterocycle selected from the group consisting of: piperidinyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 2H-pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl or morpholinyl, said Het²Optionally substituted by 1 or possibly 2 or more independently selected from hydroxy, C_1-4Alkyl or C_1-4Substituent substitution of alkoxy;

Het³represents a unit selected from the groupCyclic heterocyclic ring: 2H-pyranyl, 4H-pyranyl, furanyl, tetrahydro-2H-pyranyl, pyridinyl, piperidinyl, or furanyl;

Het⁴represents a monocyclic heterocycle selected from the group consisting of: pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrazinyl, piperazinyl or morpholinyl, said Het⁴Optionally substituted by 1 or possibly 2 or more independently selected from hydroxy, carbonyl, C_1-4Alkyl or C_1-4Substituent substitution of alkoxy;

Ar²represents a carbocyclic group containing two rings selected from the group consisting of: benzocyclobutenyl, benzocycloheptyl, benzocycloheptenyl, indenyl, 2, 3-dihydroindenyl, 5,6, 7, 8-tetrahydronaphthyl, or naphthyl;

another group of compounds are those of formula (I') having one or more of the following limitations:

(i) u represents hydrogen, halogen or hydroxy;

(ii) q represents Het¹Or Ar²Wherein said Het is¹Or Ar²Optionally substituted with 1 or possibly 2 or more substituents selected from the group consisting of: halogen, C_1-4Alkyl radical, C_1-4Alkoxy, hydroxy, C_1-4Alkoxycarbonyl, C substituted by hydroxycarbonyl_1-4Alkoxy and C substituted by hydroxycarbonyl_1-4An alkyl group;

(iii)Het¹represents a bicyclic heterocycle selected from: benzothiophenyl, quinolinyl, 1, 2, 3, 4-tetrahydroquinolinyl, isoquinolinyl, 1, 2, 3, 4-tetrahydroisoquinolinyl, 2H-benzopyranyl, 3, 4-dihydro-2H-benzopyranyl, or 2H-benzothiopyranyl;

(iv)Ar²represents benzocyclobutenyl, benzocycloheptyl, benzocycloheptenyl, indenyl, 2, 3-dihydroindenyl or 5,6, 7, 8-tetrahydronaphthyl.

The amide compounds of the present invention can be prepared by one of several standard synthetic methods known to those skilled in the art of organic chemistry and are disclosed, for example, in "Introduction to organic chemistry" Streittweiser and Heathcock, Macmillan Publishing Co., second edition Inc., New York Section 24.7(part A) p. 753-756. Generally, amides can be prepared by base-catalyzed nucleophilic addition of the appropriate carboxylic acid to the corresponding amine (scheme 1), or by nucleophilic substitution reaction between the appropriate amine and the corresponding acid halide, anhydride or ester (scheme 2), to produce the desired amide.

When coupling acids to amines, standard chemical coupling reagents such as Carbonyldiimidazole (CDI), 1, 3-Dicyclohexylcarbodiimide (DCC) or 1-ethyl-3- (3' -dimethylaminopropyl) carbodiimide hydrochloride (EDCI) can be used with or without hydroxybenzotriazole (HOBt). The addition of a carboxylic acid of formula (III) to an amine of formula (II) typically occurs under base-catalyzed reaction conditions, resulting in the formation of an amine salt in equilibrium with its weak acid and base. To equilibrate the production of the amide of formula (I), a dehydrogenating agent, for example a carbodiimide such as DCC and CDI, is added to the reaction mixture.

Scheme 1

In another embodiment, the carboxylic acid is converted to the corresponding acid halide either by reaction with, for example, thionyl chloride or oxalyl chloride. The acid halide (V) is then added to the amine of formula (II) using known reaction methods, for example the Schotten-Baumann method, to give the amide of formula (I).

Scheme 2

The carboxylic acids of formula (III) and amines of formula (II) are readily available or can be prepared using methods well known in the art. Many of the compounds are available from, for example, Aldrich Chemicals, or, when these compounds are not commercially available, they can be readily prepared from available precursors using direct transformations well known in the art.

For example, carboxylic acids are typically prepared by hydrolysis of nitriles (scheme 3), carbonization of organometallic compounds (carbonation), or oxidation of primary alcohols or aldehydes, see, for example, "Introduction to organic chemistry" Streittweiser and Heathcock, Macmillan publishing Co., second edition, New York Section 19.6(part A), pp.509-. In particular carboxylic acids of the formula (III) can be prepared as follows: the corresponding (hetero) arylacetonitrile (formula VI) is converted to the dialkyl or spiro alkyl derivative (VII) using, for example, sodium hexamethyldisilazane and methyl iodide or dibromobutane (see, for example, Trivedi et al, J.Med.chem.1993, 36, 3300) and subsequently hydrolyzed under acidic or basic conditions to give the corresponding carboxylic acid III. Suitable acids and bases for use in the hydrolysis are, for example, sulfuric acid and potassium hydroxide. The hydrolysis reaction may conveniently be carried out under microwave heating. Many nitriles of formula (VI) are commercially available, and when they are not, they can be readily prepared using the available (hetero) arylmethyl derivatives (X) under known conditions, for example, by bromination of N-bromo-succinamide (NBS), followed by substitution of the bromine with CN, using, for example, KCN.

Scheme 3

In most cases, the carboxylic acid (III-A) in which Q represents a bromoaryl group is further modified according to reaction scheme 4. In the first step, the bromine substituent is modified with an acrylate, amide or acrylonitrile using a Heck reaction to give the compound of formula (XII). Reduction of the double bond and the functional group gives an amine of the formula (XIII).

Scheme 4

For compounds of formula (I) in which Q represents a carbocyclic group containing two rings, suitable bicyclic carboxylic acids of formula (III-B) are synthesized as follows: for example, acidic or basic hydrolysis of the nitrile compound (XVI) is carried out by adding the trimethylsilyl cyanide to the corresponding ketone (XV) and then using standard conditions. This ketone is not commercially available and is synthesized by intramolecular cyclization of the corresponding acid (XVIII) (scheme 5).

Scheme 5

The amines of formula (II) are generally prepared using methods known in the art, see for example "Introduction to organic chemistry" Streittweiser and Heathcock, Macmillan Publishing Co., second edition Inc. New York Section 24.6, page 742-753 ", and include the following syntheses: by direct alkylation of the appropriate (hetero) aryl halide, especially by Gabriel synthesis, by reduction of the corresponding nitro or nitrile compound, by reductive amination using for example the eschewler-crick reaction, and especially by reduction of the oxime (IX), which can be prepared by reaction of an aldehyde or ketone (VIII) with hydroxylamine (scheme 6). In the latter case, the oxime is reduced with lithium aluminium hydride or hydrogenated using a suitable catalyst, for example Raney nickel, said reduction being carried out in an inert anhydrous solvent, for example ether or Tetrahydrofuran (THF).

Scheme 6

Further examples of the synthesis of compounds of formula (I) using the above synthetic methods are provided in the experimental section below.

Any one or more of the following steps may be performed in any order, as necessary or desired:

(i) removing any remaining protecting groups;

(ii) converting a compound of formula (I) or a protected form thereof to another compound of formula (I) or a protected form thereof;

(iii) converting a compound of formula (I) or a protected form thereof to an N-oxide, salt, quaternary amine, or solvate of the compound of formula (I), or a protected form thereof;

(iv) converting an N-oxide, salt, quaternary amine or solvate of a compound of formula (I), or a protected form thereof, to a compound of formula (I), or a protected form thereof;

(v) converting the N-oxide, salt, quaternary amine or solvate, or protected form thereof, of the compound of formula (I) to another N-oxide, pharmaceutically acceptable addition salt, quaternary amine or solvate, or protected form thereof, of the compound of formula (I);

(vi) when the compound of formula (I) is obtained as a mixture of the (R) and (S) enantiomers, separating the mixture to obtain the desired enantiomer;

(vii) when Q in the compound of formula (I) consists of a bromocarbocyclic group containing 1 or 2 rings, a variety of transformations may be performed, for example, see scheme 7, including:

a) alkylation using, for example, alkyl iodides;

b) conversion to amine using Buchwald reaction;

c) arylation using Heck-reaction conditions;

d) alkylation using Heck-reaction conditions;

e) the nitrile is converted using, for example, potassium cyanide, and the resulting nitrile may be further converted to an amine, which may be alkylated or acylated under conditions known in the art.

Scheme 7

One skilled in the art will recognize that the functional groups of the intermediate compounds in the above-described methods may need to be protected by protecting groups.

Functional groups to be protected include hydroxyl, amino and carboxylic acid. Suitable protecting groups for hydroxy include: trialkylsilyl (e.g.tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), benzyl and tetrahydropyranyl. Suitable protecting groups for amino groups include tert-butoxycarbonyl or benzyloxycarbonyl. Suitable protecting groups for carboxylic acids include C_1-6Alkyl or benzyl esters.

The protection and deprotection of the functional groups can be carried out before or after the reaction stage.

The use of protecting Groups has been fully disclosed in "Protective Groups in Organic chemistry", ed.g. by J W F McOmie, Plenum Press (1973), and "Protective Groups in Organic Synthesis", second edition, T W Greene & P G M Wutz, Wiley Interscience (1991).

Alternatively, the nitrogen atom in the compound of formula (I) may be replaced by CH in a suitable solvent such as 2-propanone, tetrahydrofuran or dimethylformamide using methods known in the art₃-I methylation.

The various compounds of formula (I) may also be interconverted according to methods known in the art for functional group transformations, some examples of which are described above.

The compounds of formula (I) may also be converted to their corresponding N-oxide form using methods known in the art to convert the trivalent nitrogen therein to its N-oxide form. The N-oxidation reaction can be generally carried out as follows: the starting material of formula (I) is reacted with 3-phenyl-2- (phenylsulfonyl) oxaaziridine (oxaziridine) or with a suitable organic or inorganic peroxide. Suitable inorganic peroxides include, for example, hydrogen peroxide, alkali or alkaline earth metal peroxides, such as sodium peroxide, potassium peroxide; suitable organic peroxides include peroxy acids, for example, phenylcarbonic peroxyacids (benzzene carbonic peroxyoic aic aicd) or halophenylcarbonic peroxyacids, for example 3-chlorophenyl carbonic peroxyacids, peroxy alkanoic acids, for example peroxyacetic acid, alkyl hydroperoxides, for example t-butyl hydroperoxide. Suitable solvents are, for example, water, lower alkanols, for example ethanol and the like, hydrocarbons, for example toluene, ketones, for example 2-butanone, halogenated hydrocarbons, for example dichloromethane, and also mixtures of these solvents.

Pure stereochemically isomeric forms of the compounds of formula (I) may be obtained by methods known in the art. Diastereomers may be separated by physical means such as selective crystallization and chromatographic techniques such as countercurrent distribution, liquid chromatography and the like.

Some of the compounds of formula (I) and some of their intermediates of the present invention may contain asymmetric carbon atoms. Pure stereochemically isomeric forms of said compounds and of said intermediates may be obtained by methods known in the art. For example, the diastereomers may be separated by physical means, such as selective crystallization and chromatographic techniques, e.g., countercurrent distribution, liquid chromatography, and the like. Enantiomers may be separated from a racemic mixture by first converting the racemic mixture into a mixture of diastereomeric salts or compounds with a suitable resolving agent, such as a chiral acid; the mixture of diastereomeric salts or compounds is then physically separated by methods such as selective crystallization or chromatographic techniques, e.g., liquid chromatography; finally converting said isolated diastereomeric salt or compound into its corresponding enantiomer. Pure stereochemically isomeric forms may also be obtained from the pure stereochemically isomeric forms of the appropriate intermediates and starting materials, provided that the intermediate reaction proceeds stereospecifically.

Other methods of separating the enantiomeric forms of the compounds of formula (I) and intermediates thereof include liquid chromatography, particularly using a chiral stationary phase.

Specific enantiomeric intermediates of the compounds of the invention include the cis and trans isomers of 1-hydroxy-4-aminoadamantane, which are intermediates useful in the synthesis of compounds of formula (I) wherein R is³Represents an optionally substituted 2-adamantyl group.

1-hydroxy-4-aminoadamantanes are generally prepared by hydroxylation of 2-aminoadamantanes, for example using a mixture of nitric and sulfuric acids (Khimiko Farmatsevischeski Zhumnal 1986, 20, 810; Zhumnal Organichsekoi Khimii 1976, 2369).

The reaction yields two isomers of 1-hydroxy-4-aminoadamantane in a ratio of 3: 1 to 1: 1, which reaction favors the production of the cis isomer. Indeed, the trans isomer was found to have better HSD1 inhibitory activity and there is a need for a synthetic method that provides better selectivity for the trans isomer.

Alternatively, following reductive amination, 1-hydroxy-4-aminoadamantane can also be derived from the corresponding ketone, i.e., a cyclic ketone, via imine formation of an oxime and subsequent reduction of the double bond to an amine. The reduction may be carried out using lithium aluminium hydride, raney nickel or a noble metal such as palladium, platinum, ruthenium or rhodium supported on carbon. Reductive amination using borohydride is an alternative to the one-step process (e.g. as disclosed in Advanced of Organic Chemistry from 3 months of 2003). The selectivity of the reduction depends on the structure of the substrate (ketone) and the catalyst used.

If the two isomers of 1-hydroxy-4-aminoadamantane obtained after oxime reduction or reductive amination using aqueous ammonia cannot be detected in LCMC or GCMS, they are difficult to separate. The coupling reaction with the acid of formula (III) gives a mixture of two coupled products of formula (I), which can be separated using chromatography. However, separation from enantiomerically pure intermediates is required to reduce synthesis costs and increase the yield of the trans isomer.

It is an object of the present invention to provide a solution to the above problems, including a process for the preparation of 1-hydroxy-4-aminoadamantane, which comprises reductive amination of 5-hydroxy-adamantan-2-one with L (-) -1-phenylethylamine, using for example ruthenium on carbon catalysis. Provides a selectivity of 3: 1, which is favorable for generating trans-isomer. The resulting isomer is easily separated and subsequent debenzylation of trans-4- (1-phenyl-ethylamino) adamantan-1-ol yields pure trans-1-hydroxy-4-aminoadamantane.

Scheme 8

In particular, 1-hydroxy-4-aminoadamantane was prepared as follows:

a)4- (1-phenyl-ethylamino) -adamantan-1-ol

Preparation of

Commercially available 5-hydroxyadamantan-2-one (0.1mol), L (-) - α -methyl-benzylamine (0.105mol), aluminum isopropoxide (0.1mol) and rhodium supported on carbon (20 mol%) were suspended in 500ml of toluene and 20ml of 4% thiophene solution was added. The reaction mixture was stirred at 50 ℃ for 24 hours. The catalyst was filtered off and the filtrate was concentrated in vacuo. The residue, which comprises the two isomers in a trans: cis ratio of 3: 1, was separated by column chromatography to give 12g of intermediate XVIII-A and 4g of intermediate XVIII-B.

b) 1-hydroxy-4-aminoadamantane

Preparation of

The amine VIII-A (0.05mol) was dissolved in methanol (100ml), and palladium on activated carbon (0.002mol) was added to the mixture and hydrogenated at room temperature for 16 hours. The catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was triturated with methylene chloride to give the title compound (II-A) (7.5 g).

Some of the intermediates and starting materials used in the above reactions are known compounds and are commercially available or can be prepared according to methods known in the art.

The compounds of the present invention are useful due to their pharmacological properties. They are therefore useful as pharmaceuticals, in particular for the treatment of diseases associated with excessive cortisol formation, such as obesity, diabetes, obesity-related cardiovascular diseases and glaucoma.

As described in the experimental section below, the compounds of the present invention showed an inhibitory effect on 11b-HSD 1-reductase activity (11-dehydro-17-hydroxycorticosterone to cortisol conversion) in vitro, as measured by HPLC purification and quantitative analysis methods in an enzyme assay using recombinant 11b-HSD1 enzyme. And also shows 11b-HSD 1-reductase inhibitory effect in an in vitro cell-based assay comprising contacting cells with a test compound and expressing 11b-HSD1, and determining the effect of said compound on cortisol formation in the cell culture medium (cellular medium) of said cells. The cells preferably used in the assay of the invention are selected from the group consisting of mouse fibroblast 3T3-L1 cells, HepG2 cells, porcine kidney cells, especially LCC-PK1 cells and rat liver cells.

The present invention therefore provides compounds of formula (I), (I'), (I ") as well as pharmaceutically acceptable N-oxides, addition salts, quaternary amines and stereochemically isomeric forms thereof, for use in therapy. More particularly for the treatment or prevention of diseases mediated by cell proliferation. The compounds of formulae (I), (I') and the pharmaceutically acceptable N-oxides, addition salts, quaternary amines and stereochemically isomeric forms thereof are hereinafter referred to simply as the compounds of the present invention.

In view of the utility of the compounds of the present invention, there is provided a method of treating an animal, such as a mammal (including a human), suffering from a cellular proliferative disease, including, for example, atherosclerosis, restenosis (restinosis), and cancer, comprising administering an effective amount of a compound of the present invention.

Said method comprising the systemic or topical administration of an effective amount of a compound of the invention to warm-blooded animals, including humans.

It is therefore an object of the present invention to provide a compound of the present invention for use as a medicament. In particular, the use of a compound of the invention for the manufacture of a medicament for the treatment of conditions associated with excessive cortisol formation including, for example, obesity, diabetes, obesity-related cardiovascular disease and glaucoma.

In another aspect of the invention, the invention provides the use of a compound of the invention in the manufacture of a medicament for the treatment of any of the above cell proliferative diseases or disorders.

The amount of the compound of the present invention used herein also refers to the amount of the active ingredient required to achieve a certain therapeutic effect, which will, of course, vary with the particular compound, the route of administration, the age and the health of the recipient, and the particular condition or disease to be treated. Suitable daily dosages are from 0.001mg/kg to 500mg/kg body weight, especially from 0.005mg/kg to 100mg/kg body weight. The treatment method further comprises administering the effective ingredient in a 1-4 times/day administration.

Although the active ingredient may be administered alone, it is preferred that it is present in the form of a pharmaceutical composition. Accordingly, the present invention also provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier or diluent. The carrier or diluent must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.

The Pharmaceutical compositions of the invention may be prepared according to methods well known in the Pharmaceutical art, for example using the methods disclosed by Gennaro et al in Remington's Pharmaceutical Sciences (18 th edition, Mack Press, 1990, see especially section 8: Pharmaceutical preparation and the same Manual). When the active ingredient is intimately admixed with a pharmaceutically acceptable carrier, a therapeutically effective amount of the particular compound, in base form or addition salt form, may take a wide variety of forms depending on the intended form of administration of the formulation. The pharmaceutical compositions are preferably administered in a suitable unit dose, preferably systemically, e.g. orally, transdermally or parenterally; or topically, e.g., by inhalation, nasal spray, eye drops, or by cream, gel, shampoo, or the like. For example, in preparing the compositions in oral dosage form, in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions, any of the usual pharmaceutical media may be employed, such as water, glycols, oils, alcohols and the like; or in the case of powders, pills, capsules and tablets, solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like may be used. Because of their ease of use, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. For compositions for parenteral administration, the carrier will typically comprise sterile water, at least in large part, but may also comprise other components, for example, components to aid solubility. Injectable solutions can be prepared using carriers such as saline, dextrose solution, or a mixture of saline and dextrose solution. Injectable suspensions may also be prepared using suitable liquid carriers, suspending agents and the like. In compositions suitable for transdermal administration, the carrier optionally includes a penetration enhancer and/or a suitable wetting agent, optionally in admixture with suitable natural additives in minor proportions, which additives do not cause any significant deleterious effects on the skin. The additives may aid in administration to the skin and/or aid in the preparation of the desired composition.

These compositions may be administered in a variety of ways, for example as a transdermal patch, patch (spot-on) or ointment. Suitable compositions for topical administration include all compositions normally used for topical administration, such as creams, gelling agents (gels), dressings (dressing), shampoos, tinctures, pastes, ointments, salves (salves), powders, and the like. The composition may also be used by aerosol, e.g. using as propellant e.g. nitrogen, carbon dioxide, freon, or without propellant, e.g. pump nebulization, drops, lotions, or semi-solids, e.g. of concentrated compositions, which may be administered by swab. In particular semi-solid compositions such as ointments, creams, jellies, ointments and the like may be conveniently employed.

For ease of administration or uniform dosage, it is especially advantageous to formulate the above pharmaceutical compositions in dosage unit form. Dosage unit form as used herein the specification and claims refer to physically discrete units suitable as unitary dosages, each unit containing a desired pharmaceutical carrier and a predetermined quantity of active ingredient which produces the desired therapeutic effect. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonful (teaspoonful), tablesponful (tablesponful), and the like, as well as segregated mntriplets thereof.

To improve the solubility and/or stability of the compounds of the formula (I), (I') in the pharmaceutical composition, it is advantageous to use α -, β -or γ -cyclodextrins or derivatives thereof. And co-solvents such as alcohols may also improve the solubility and/or stability of the compounds of formula (I), (I') in the pharmaceutical composition. When preparing an aqueous composition, it is apparent that the addition of a salt of the subject compound is more appropriate because of its higher water solubility.

Experimental part

The followingThe term "RT" denotes room temperature, "THF" denotes tetrahydrofuran, "AcOH" denotes acetic acid, EtOH denotes ethanol, "DME" denotes dimethyl ether, "DIPE" denotes diisopropyl ether, "TFA" denotes trifluoroacetic acid, "EtOAc" ethyl acetate, "iPrOH" denotes isopropanol, "HOBt" denotes 1-hydroxy-1H-benzotriazole, "DMA" denotes N, N-dimethylacetamide, "DMF" denotes N, N-dimethylformamide, "NaHMDS" denotes sodium N-hexamethyldisilazane (N-sodi hexy propyldisilazane), "DPPP" denotes 1, 3-propanediyl-bis [ diphenylphosphine ] s]"EDCI" means N' - (ethylcarbonimidoyl) -N, N-dimethyl-1, 3-propanediamine monohydrochloride, "DAST" means (diethylamino) thiotrifluoride, and Extrelut^TMPurchased from Merck KgaA (Darmstadt, Germany) and is a short column containing diatomaceous earth.

A. Preparation of intermediates

Example A1

Intermediate 1Preparation of

Intermediate 2Preparation of

Bicyclo [3.3.1]Nonane-2-ketoxime [16473-10-2]Dissolved in anhydrous THF (30ml) and a solution of lithium aluminum tetrahydride (15ml, 1M diethyl ether solution) was added. The solution was boiled under reflux for 16 hours. Water (0.6ml), 15% sodium hydroxide (0.6ml) and water (1.8ml) were added, followed by filtration and drying of the filtrate (MgSO₄) And evaporated to give the crude amine. The residue was dissolved in dichloromethane and extracted with 15% citric acid. The aqueous layer was basified with 1M potassium hydroxide and extracted with dichloromethane. The organic layer was washed with brine, dried and evaporated to give a mixed amine (0.5g) of intermediate (1) to intermediate (2) in a ratio of 1: 1; NMR (CDCl)₃)δ1.2-2.1(m，CH)，2.45(t，1H)，2.9(m，1H)。

Example A2

a) Intermediate 3Preparation of

Commercially available spiro [1, 3-dioxolan-2, 2 '-tricyclo [3.3.1.13.7] decan ] -6' -one [50776-11-9] (2.3g, 0.012mol) (containing about 30% of the diketal) was dissolved in ethanol, followed by addition of hydroxylamine hydrochloride (1.7g, 0.025mol) and NaOH (1.0g) in water (30 ml). The mixture was stirred overnight. The volatiles were evaporated in vacuo and the remaining residue was extracted with dichloromethane. The organic layer was washed with brine, dried and evaporated to give oxime intermediate (3) (2.4 g).

NMR(DMSO-d6)δ1.3-2.3(m，CH)，2.5(bs，1H)，3.5(bs，1H)，3.95(s，4H，CH₂CH₂)

b) Intermediate 4Preparation of

6-oximino-adamantan-2-ylethylene ketal (2.4g) in 7M NH₃In MeOH (100ml), Raney nickel (1g) was added and the mixture was hydrogenated at 14 ℃. The mixture was filtered and evaporated to give 2.0g of intermediate (4).

NMR(DMSO-d6)δ1.3-2.3(m，CH)，3.23(bs，2H，NH2)，3.95(s，4H，CH₂CH₂).

Example A3

a) Intermediate 5Preparation of

A solution of 3-methoxy-5-methylbenzonitrile (0.016mol) in THF (20ml) was cooled to-40 ℃ and then NaHMDS (0.0355mol) was added dropwise and the mixture was stirred at-30 ℃ for 1 hour. A mixture of methyl iodide (0.0355mol) in THF (q.s.) was added dropwise at-30 deg.CThe reaction mixture was stirred at-40 ℃ for 1 hour, then the reaction mixture was brought to room temperature and stirred overnight. The resulting mixture was treated with 1N hydrochloric acid and the layers were separated. Extracting the crude product with CH₂Cl₂Hexane (3/2) treatment and isolation of the expected product gave 2.5g (83%) of intermediate (5).

b) Intermediate 6Preparation of

Potassium hydroxide, 6N in water (20ml), was added to a solution of intermediate (5) (0.013mol) in ethanol (40ml), and the reaction mixture was stirred under microwave conditions at 160 ℃ for 4 hours. The resulting mixture was washed with water and extracted with DIPE. The aqueous layer was acidified to pH 1 with concentrated hydrochloric acid and extracted with dichloromethane. The organic extracts were washed with water and brine, dried and the solvent was evaporated. The resulting residue was triturated with hexane and the expected product was collected to yield 1.69g (61.5%) of intermediate (6).

c) Intermediate 7Preparation of

A solution of intermediate (6) (0.005mol) in dichloromethane (20ml) was cooled to-78 ℃ and a solution of tribromoborane (1M) in dichloromethane (10.5ml) was added dropwise. The reaction mixture was returned to room temperature and stirred at room temperature overnight. Water (50ml) and 6N potassium hydroxide (10ml) were added successively, and the resulting mixture was stirred for 30 minutes. The aqueous layer was separated and extracted with dichloromethane, then acidified to pH 1 with concentrated HCl and extracted with dichloromethane (3X 40 ml). The organic extracts were washed with water and brine, dried and the solvent was evaporated to give 0.620g of intermediate (7).

d) Intermediate 8Preparation of

Chloro (1, 1-dimethylethyl) dimethylsilane (0.0048mol), 1H-imidazole (0.0048mol) and N, N-dimethyl-4-pyridylamine (0.020g) were added to a solution of intermediate (7) (0.032mol) in dichloromethane (30ml), and the reaction mixture was stirred at room temperature overnight. The resulting precipitate was filtered off and the filtrate was evaporated. The resulting residue (1.6g) was triturated with DIPE and the expected product was collected to yield 0.85g of intermediate (8).

Example A4

a) Intermediate 9Preparation of

A solution of potassium cyanide (0.09mol) in water (20ml) was added to 1-bromo-3- (bromomethyl) -5-toluene [ 51719-69-8%](0.085mol) in ethanol (100ml) and the resulting reaction mixture was stirred at room temperature overnight, then the mixture (18g) was purified by column chromatography on silica gel (eluent: 2: 1 CH)₂Cl₂And heptane). The product fractions were collected and the solvent was evaporated, yielding 7.5g (90%) of intermediate (9).

b) Intermediate 10Preparation of

A solution of intermediate (9) (0.036mol) in THF (150ml) was cooled to-40 ℃ under a nitrogen atmosphere, a solution of NaHMDS (2M) in THF (0.080mol) was added dropwise at below-25 ℃ and the reaction mixture was stirred for 1 hour at-30 ℃. A mixture of methyl iodide (0.080ml) in THF (20ml) was added dropwise at below-30 ℃ and the resulting mixture was returned to room temperature and then stirred overnight. Hydrochloric acid (1N, 100ml) was added and the layers were separated. The aqueous layer was extracted 2 times with EtOAc, then the organic layers were combined and washed with 5% NaHCO₃The solution, water, brine washed and dried. Finally, the solvent was evaporated to give 8.2g of intermediate (10).

c) Intermediate 11Preparation of

A mixture of potassium hydroxide (10g) in water (60ml) was added to a solution of intermediate (10) (0.034mol) in ethanol (160ml) and the reaction mixture was stirred and refluxed over the weekend. The reaction mixture was diluted with ice water and extracted with dichloromethane to give extract (I) and aqueous layer (I). The aqueous layer (I) was acidified with hydrochloric acid and extracted with dichloromethane. The extract was washed with brine, dried and the solvent was evaporated to give 8g of residue (LCMS: 90% P). The resulting residue was triturated with hexane and two product fractions were collected, giving fraction 1: 2.8g of intermediate (11).

d) Intermediate 12Preparation of

N, N-diethylethylamine (0.005mol), benzyl 2-acrylate (0.002mol), tris (4-methylphenyl) phosphine (0.0006mol) were added to a solution of intermediate (11) (0.001mol) in DMF (6ml) followed by addition of Pd₂(dibenzylidene acetone)₃Complex (0.0002 mol). The reaction mixture was heated to 90 ℃ and shaken at 90 ℃ for 4 hours. The reaction mixture was diluted with EtOAc and DIPE, then the resulting precipitate was filtered off and the filtrate was washed 3 times with water. The aqueous layer was acidified with 1N hydrochloric acid and extracted with EtOAc. The organic layer was washed with brine, dried, filtered and the solvent was evaporated to give 0.340g of intermediate (12).

Example A5

Intermediate 13Preparation of

3-bromo-alpha, alpha-dimethylphenylacetic acid [81606-47-5 ]](0.001mol) in DMF (6ml) was added N, N-diethylethylamine (0.005mol) followed by benzyl 2-acrylate [ 2495-35-4%](0.002 mol). Tris (4-methylphenyl) phosphine (0.0006mol) and Pd were added₂(dibenzylidene acetone)₃Complex (0.0002mol) and the reaction mixture was shaken at 90 ℃ for 4 hours. The reaction mixture was diluted with EtOAc and washed with water. The aqueous layer was collected and acidified to pH 1-2 with 1N hydrochloric acid and extracted with EtOAc. Combining the extracts, water and brineWashing, drying, filtration and evaporation of the solvent (vacuum) gave 0.340g of intermediate (13).

Example A6

Intermediate 14Preparation of

3-bromo-alpha, alpha-dimethylphenylacetic acid [81606-47-5 ]](0.001mol) in N, N-diethylethanamine (q.s.), the solution is degassed and then N, N-diethylethanamine (0.005mol), 4- (1-oxo-2-propyl) morpholine [5117-12-4 ] is added](0.002mol), tris (4-methylphenyl) phosphine (0.0005mol) and Pd₂(dibenzylidene acetone)₃Complex (0.00015 mol). The reaction mixture was shaken at 90 ℃ overnight and diluted with EtOAc. The catalyst was filtered off over celite and washed with EtOAc, then water was added and the organic layer was separated. The aqueous layer was extracted with EtOAc, acidified to pH 1 with hydrochloric acid, and re-extracted with EtOAc. The extract was washed with water and brine, dried, filtered and the solvent was evaporated to give 0.291g of intermediate (14).

Example A7

a) Intermediate 15Preparation of

3-bromo-alpha, alpha-dimethyl phenylacetic acid ethyl ester [81606-46-4 ] at 100 DEG C](0.0018mol), 2-acrylonitrile (1g), palladium acetate (2+) salt (0.0006mol), DPPP [6737-42-4]A mixture of (0.0012mol) and potassium acetate salt (1g) was reacted in ethanol (150ml) for 16 hours, and then the solvent was evaporated. The residue was dissolved in dichloromethane and the resulting solution was washed. The crude product was purified by column chromatography on silica gel (eluent: 3: 2 CH)₂Cl₂And heptane). The product fractions were collected and the solvent was evaporated, yielding 0.750g of intermediate (15).

b) Intermediate 16Preparation of

Intermediate (15) (0.0031mol) was reduced with palladium (catalytic amount) supported on activated carbon, followed by reduction with Raney nickel (catalytic amount). After uptake of hydrogen (3 equivalents), the catalyst was filtered off and the filtrate was evaporated to yield 0.7g of intermediate (16).

c) Intermediate 17Preparation of

1, 1' -O-bis [ 2-chloroethane ] [111-44-4] (0.0025mol) was added to a solution of intermediate (16) (0.0012mol) and potassium carbonate (0.006mol) in DMF (15ml) and the reaction mixture was stirred at 100 ℃ for 22 hours. The reaction mixture was filtered and the filter residue was diluted with EtOAc, then washed with water and dried. Finally, evaporation of the solvent gave 0.6g of intermediate (17).

d) Intermediate 18Preparation of

Potassium hydroxide (6ml) was added to a solution of intermediate (17) (0.0012mol) in ethanol (12ml), and the reaction mixture was stirred and refluxed for 1 hour. The mixture was cooled, diluted with water and extracted with DIPE. The aqueous layer was acidified with concentrated hydrochloric acid and extracted with dichloromethane. The organic layer was washed with water and brine, and then the solvent was evaporated. The aqueous layer was concentrated (vacuum) and the resulting concentrate was washed with methanol. Finally, evaporation of the solvent gave 0.400g of intermediate (18).

Example A8

Intermediate 19Preparation of

Potassium hydroxide (6N) (10ml) was added to a solution of 3, 5-dimethoxy- α, α -dimethylbenzylacetonitrile [22972-63-0] (0.011mol) in ethanol (40ml), and the reaction mixture was stirred under reflux for 5 days, after which the mixture was diluted with water and extracted with dichloromethane. The aqueous layer was acidified with hydrochloric acid and extracted with dichloromethane. The extract was washed with water and brine, then dried and the solvent was evaporated to give 0.190g of intermediate (19).

Example A9

Intermediate 20Preparation of

N, N-diethylethylamine (0.005mol), 4- (1-oxo-2-propenyl) morpholine [ 5117-12-4%](0.002mol), tris (4-methylphenyl) phosphine [1038-95-5](0.0006mol) and Pd₂(dibenzylidene acetone)₃The complex (0.00016mol) was added to a solution of intermediate (11) in DMF (10ml) and the reaction mixture was stirred at 90 ℃ overnight and diluted with EtOAc (20 ml). The resulting mixture was washed with water, then the aqueous layer was acidified to pH 1 with 1N hydrochloric acid and extracted with EtOAc. The extract was dried and the solvent was evaporated to give 0.500g of a residue (LCMS: 69% P). The residue was purified by chromatography on a silica gel column (eluent: 99: 1 CH)₂Cl₂And CH₃OH). The product fractions were collected and the solvent was evaporated, yielding 0.196g (62%) of intermediate (20).

Example A10

a) Intermediate 21Preparation of

2-Phenoxyphenylacetonitrile [25562-98-5] (0.010mol) was dissolved in THF (40ml) under a nitrogen atmosphere and the mixture was cooled to-40 ℃ and then a solution of NaHMDS (2M) in THF (0.025mol) was added dropwise and the resulting mixture was stirred for 30 minutes. A mixture of iodomethane (0.030mol) in THF, p.a. (10ml) was added dropwise and after reaching room temperature the reaction mixture was stirred for 2 hours. The mixture was filtered through celite, then the filter residue was washed with EtOAc, and 0.1M hydrochloric acid (60ml) was added to the filtrate. The aqueous layer was separated and extracted twice with EtOAc. The organic layers were combined, washed with water and brine, dried, filtered and the solvent was evaporated to give 2.7g of intermediate (21).

b) Intermediate 22Preparation of

A solution of intermediate (21) (0002mol) in potassium hydroxide (6M) in water (10ml) and ethanol (20ml) was placed in a teflon vessel of a microwave labstation (Milestone company) and the solution was stirred in a closed vessel at 170 ℃ for 6 hours. The resulting mixture was then cooled and washed with EtOAc. The aqueous layer was separated and acidified with hydrochloric acid. The resulting precipitate was finally filtered to give intermediate (22).

Example A11

a) Intermediate 23Preparation of

3, 5-difluorophenylacetonitrile [122376-76-5] (0.013mol) was dissolved in THF, p.a. (60ml) under nitrogen and the mixture was cooled to-30 ℃ before a solution of NaHMDS (2M) in THF (0.029mol) was added dropwise and the mixture stirred for 1 h. A mixture of iodomethane (0.030mol) in THF, p.a. (10ml) was added dropwise and the reaction mixture stirred for 6 hours after reaching room temperature. The mixture was filtered through celite, then the filter residue was washed with EtOAc, and the filtrate was treated with 1N hydrochloric acid. The organic layer was separated, washed with water and brine, dried, filtered and the solvent was evaporated to give 2.4g of intermediate (23).

b) Intermediate 24Preparation of

A solution of intermediate (23) (0.013mol) in potassium hydroxide (6M) in water (20ml) and ethanol (40ml) was stirred and refluxed for 24 h, then the mixture was cooled and washed with EtOAc. The aqueous layer was acidified with hydrochloric acid and the resulting precipitate was filtered to give 1.5g (60%) of intermediate (24).

Example A12

a) Intermediate 25Preparation of

2, 6-difluorophenylacetonitrile [654-01-3] (0.013mol) was dissolved in THF (25ml) under nitrogen, and the mixture was cooled to-40 ℃ and a solution of NaHMDS (2M) in THF (0.028mol) was added dropwise and the mixture was stirred for 30 minutes. Methyl iodide (0.028mol) was added dropwise and when the temperature reached room temperature, the reaction mixture was stirred for 6 hours. The mixture was filtered through celite, then the filter residue was washed with EtOAc, and the filtrate was treated with 1N hydrochloric acid. The organic layer was separated, washed with water and brine, then dried, filtered and the solvent was evaporated. The residue (2.2g) was purified by column chromatography on silica gel (eluent: dichloromethane). The product fractions were collected and the solvent was evaporated, yielding 1.4g of intermediate (25).

b) Intermediate 26Preparation of

Hydrochloric acid (40ml) was added to a solution of intermediate (25) (0.006mol) in glacial acetic acid (20ml) and the reaction mixture was stirred at reflux for 24 h. The solvent was evaporated, then the residue was dissolved in dichloromethane and washed with sodium carbonate (1M). The aqueous layer was acidified with concentrated hydrochloric acid and extracted with dichloromethane. The organic extracts were collected, dried and the solvent was evaporated, yielding 0.6g (72%) of intermediate (26).

Example A13

Intermediate 27Preparation of

Tin (II) chloride (0.068mol) was added to 3, 4-dihydro-4- [ (trimethylsilyl) oxy under a nitrogen atmosphere]-2H-1-benzopyran-4-carbonitrile [74187-63-6](0.017mol), then acetic acid (20ml) and hydrochloric acid (20ml) were added to the reaction mixtureReflux with stirring overnight under nitrogen. The mixture was cooled, poured into ice and extracted with dichloromethane. The organic layer was washed, dried, filtered and the solvent was evaporated to give 1.4g of a residue (54% P). The residue was purified by chromatography on a silica gel column (eluent: 98: 2 CH)₂Cl₂And CH₃OH). The product fractions were collected and the solvent was evaporated, yielding 1g of intermediate (27).

Example A14

a) Intermediate 28Preparation of

A mixture of 2, 3-dihydro-8-methoxy-4H-1-benzopyran-4-one [20351-79-5] (0.02mol) and zinc iodide (0.125g) in chloroform was stirred in the presence of ice under a nitrogen atmosphere. Trimethylsilanenitrile [7677-24-9] (0.067mol) was added dropwise and the reaction mixture was stirred overnight. Dichloromethane (50ml) was added and the mixture was washed 2 times with sodium carbonate solution. The organic layer was dried, filtered and the solvent was evaporated to give 4g of intermediate (28).

b) Intermediate 29Preparation of

A mixture of intermediate (28) (0.0072mol) in acetic acid (15ml) and hydrochloric acid (15ml) was stirred and refluxed overnight under a nitrogen atmosphere, and then the reaction mixture was cooled. The mixture was poured into water and extracted with dichloromethane. The organic layer was extracted with dilute sodium hydroxide solution, then the aqueous layer was acidified with hydrochloric acid and extracted with dichloromethane. The organic layer was separated and dried (MgSO)₄) Filtration and evaporation of the solvent gave 1g of residue (56% P). The residue was purified by Biotage Flash-40 column chromatography (eluent: 99: 1 CH)₂Cl₂And CH₃OH). The product fractions were collected and the solvent was evaporated, yielding 0.39g (28%) of intermediate (29).

Example A15

Intermediate 30Preparation of

Reacting 3, 4-dihydro-4- [ (trimethylsilyl) oxy]-2H-1-benzothiopyran-4-carbonitrile [74187-62-5]A mixture (0.021mol) in acetic acid (40ml) and hydrochloric acid (40ml) was stirred using a Dean-Starck apparatus and refluxed overnight. The reaction mixture was cooled and extracted with dichloromethane. The organic layer was washed with sodium carbonate solution and then the aqueous layer was acidified to pH 2 with hydrochloric acid and extracted with dichloromethane. The organic layer was separated, washed and dried (MgSO)₄) Filtration and evaporation of the solvent gave 0.7g (28%) of intermediate (30).

Example A16

a) Intermediate 31Preparation of

A mixture of 3, 4-dihydro-5, 7-dimethyl-1 (2H) -naphthalenone [13621-25-5] (0.02mol) and zinc iodide (0.125g) in chloroform (5ml) was stirred in the presence of ice, and trimethylsilanenitrile [7677-24-9] (0.075mol) was added. The reaction mixture was stirred overnight and washed 2 times with sodium bicarbonate solution. The organic layer was dried, filtered and the solvent was evaporated to give 5.7g of intermediate (31).

b) Intermediate 32Preparation of

A mixture of intermediate (31) (0.02mol) in acetic acid (40ml) and hydrochloric acid (40ml) was stirred and refluxed for 3 days under a nitrogen atmosphere. The reaction mixture was then cooled and extracted with dichloromethane. The organic layer was extracted with sodium carbonate solution, then the aqueous layer was acidified with hydrochloric acid and extracted with dichloromethane. The organic layer was separated, washed and dried (MgSO)₄) Filtration and evaporation of the solvent gave 1.2g (29%) of intermediate (32).

Example A17

a) Intermediate 33Preparation of

A mixture of 5-hydroxytricyclo [3.3.1.13, 7] decanone [20098-14-0] (0.01mol) and (. alpha.S) -alpha-methylphenylbenzenemethamine [2627-86-3] (0.01mol) in ethanol (20ml) was refluxed with stirring over the weekend and then the solvent was evaporated (vacuum) to give 2.8g of intermediate (33).

b) Intermediate 34Preparation of

And intermediate 35Preparation of

Intermediate (33) (0.001mol) was placed in THF (anhydrous) (5ml) under a nitrogen atmosphere and the mixture was cooled to 0 ℃, then sodium tetrahydroborate (0.00115mol) and trifluoroacetic acid (0.00344mol) were added and the reaction mixture was stirred at 0 ℃. Dichloromethane (10ml) and saturated sodium bicarbonate solution were added. The organic layer was separated, washed with sodium bicarbonate, dried and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: 95: 5 CH)₂Cl₂EtOAc). The two product fractions were collected and the solvent was evaporated, yielding 0.130g of intermediate (34) and 0.090g of intermediate (35).

Example A18

Intermediate 36Preparation of

1, 2, 3, 4-tetrahydro-1-isoquinoline carboxylate [92932-74-6 ]]A mixture of (0.00117mol) and N, N-diethylethylamine (0.2g) in 2-propanone (10ml) and water (10ml) was stirredThen adding bis (1, 1-dimethylethyl) dicarbonate [24424-99-5 ]](0.0022 mol). The reaction mixture was stirred over the weekend, then poured into dichloromethane and washed with water. The organic layer was separated and dried (MgSO)₄) Filtration and evaporation of the solvent gave 0.38g of intermediate (36).

B. Preparation of the Compounds

Example B1

Compound 1Preparation of

2, 2-dimethyl- (4-chlorophenyl) acetic acid [6258-30-6] (2.0g, 10mmol) and 2-aminoadamantane hydrochloride [13074-39-0] (1.9g, 10mmol) were dissolved in dichloromethane (50ml), HOBt (2.7g, 20mol), N-diethylethylamine (2.1g, 20mmol) and EDCI (2.1g, 11mmol) were added, and the mixture was stirred overnight. The reaction mixture was washed with 15% citric acid, saturated sodium bicarbonate and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from isopropanol to give 2.0g (6mmol, 60%) of compound (1).

NMR：(DMSO-d6)δ1.4-1.8(m，CH)，1.47(s，6H，(CH3)2)，3.79(d，1H，CH)，6.42(d，1H，NH)，7.38(dd，Ar-H).

LC-MS：M+1 332.89，334.89

Example B2

Compound 2Preparation of

Compound 1(1.7g, 5mmol) was dissolved in methanol (100ml), 0.5g palladium (10%) and CaO (1g) on activated carbon were added, and the mixture was hydrogenated at 50 ℃. After absorbing 1 equivalent of hydrogen, the reaction was filtered and evaporated to dryness. The residue was dissolved in dichloromethane, washed with saturated sodium carbonate, dried and evaporated. The residue was crystallized from diisopropyl ether to give 0.65g (60%) of compound (2).

NMR：(DMSO-d6)δ1.4-1.8(m，CH)，1.49(s，6H，(CH3)2)，3.79(d，1H，CH)，6.21(d，1H，NH)，7.25-7.37(m，5H，Ar-H).

LC-MS：M+1 298.44

Example B3

Compound 3Preparation of

2, 2-dimethylphenylacetic acid [826-55-1] was dissolved in anhydrous dichloromethane, and oxalyl chloride and 1 drop of DMF were added. After stirring for 2 hours the solution was evaporated to dryness, redissolved in 10ml of dichloromethane and added to a solution of 2-aminoadamantane [13074-39-0] and triethylamine in dichloromethane. The mixture was stirred overnight, extracted with 15% citric acid, saturated sodium bicarbonate and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from isopropyl ether.

NMR：(CDCl3)δ1.3-1.8(m，CH)，1.55(s，6H，(CH3)2)，2.31(s，6H，2xCH3)，3.96(d，1H，CH)，5.50(d，1H，NH)，6.91(s，1H，Ar-H)，6.99(s，2H，ArH).

Example B4

a) Compound 4Preparation of

2-methyl-2- (3-methoxyphenyl) propionic acid (2.0g, 10mmol) and 2-aminoadamantane hydrochloride [13074-39-0] (1.9g, 10mmol) were dissolved in dichloromethane (50ml), HOBt (2.7g, 20mol), N-diethylethylamine (2.1g, 20mmol) and EDCI (2.1g, 11mmol) were added, and the mixture was stirred overnight. The reaction mixture was washed with 15% citric acid, saturated sodium bicarbonate and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from isopropanol to yield 2.0g (6mmol, 60%) of compound (4).

NMR：(DMSO-d6)δ1.4-1.8(m，CH)，1.48(s，6H，(CH3)2)，3.75(s，3H，OCH3)，3.79(d，1H，CH)，6.23(d，1H，NH)，6.8-7.3(m，3H，Ar-H).

b) Compound 5Preparation of

Compound 4 was dissolved in dichloromethane, cooled to-78 ℃ and boron tribromide was added. The reaction mixture was stirred at room temperature for 1 hour, poured into aqueous ammonia and extracted with dichloromethane. The organic layer was washed with brine, dried and evaporated. The solid residue was crystallized from ethyl acetate to give compound (5).

NMR：(DMSO-d6)δ1.4-1.8(m，CH)，1.44(s，6H，(CH3)2)，3.79(d，1H，CH)，6.18(d，1H，NH)，6.65-7.16(dd，4H，Ar-H)，9.35(s，1H，OH).

c) Compound 6Preparation of

Compound 4 was dissolved in DMF and ethyl bromoacetate and potassium carbonate were added. The mixture was stirred at 60 ℃ overnight, poured onto ice and extracted with dichloromethane. The organic layer was washed with 1M sodium bicarbonate and brine and evaporated. The residue was dissolved in ethanol, 1M potassium hydroxide was added, and the mixture was stirred for 2 hours. The solution was acidified with 1M hydrochloric acid, extracted with EtOAc, the organic layer was dried and evaporated. The solid residue was crystallized from ethyl acetate to give compound (6).

NMR：(DMSO-d6)δ1.4-1.8(m，CH)，1.47(s，6H，(CH3)2)，3.78(d，1H，CH)，4.67(s，2H，CH2COOH)，6.23(d，1H，NH)，6.77-7.3(m，4H，Ar-H).

Example B5

Compound 7Preparation of

Compound 4 was dissolved in DMF and dimethylaminoethyl chloride hydrochloride and potassium carbonate were added sequentially. The mixture was stirred at 60 ℃ overnight, poured onto ice and extracted with dichloromethane. The organic layer was washed with 1M sodium bicarbonate and brine and evaporated. The residue was dissolved in isopropanol under heating, oxalic acid was added, and the crystalline amine was filtered to give compound (7).

NMR：(DMSO-d6)δ1.4-1.8(m，CH)，1.49(s，6H，(CH3)2)，2.78(s，6H，N(CH3)2)，3.43(t，2H，CH2)，3.79(d，1H，CH)，4.27(t，2H，CH2)，6.29(d，1H，NH)，6.85-7.35(m，4H，Ar-H).

Example B6

Compound 8Preparation of

Compound 9Preparation of

α, α -2, 2-dimethylphenylacetic acid [826-55-1] (2.5g, 15mmol) was dissolved in anhydrous dichloromethane (50ml), oxalyl chloride (1.5ml, 0.017mol) and 1 drop of DMF were added. After stirring for 2 hours the solution was evaporated to dryness, redissolved in 50ml dichloromethane and added to a solution of 2-aminoadamantane (CAS 13074-39-0) (2.5g, 15mmol) and N, N-diethylethylamine (3.0g, 30mmol) in dichloromethane (50 ml). The mixture was stirred overnight. The reaction mixture was washed with 15% citric acid, saturated sodium bicarbonate and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (eluent: dichloromethane with 3-5% MeOH) to give 1.8g of compound (8).

NMR：(CDCl₃)δ1.2-1.85(m，CH)，1.59(s，6H，(CH₃)₂)，1.95-2.00(m，2H，CH)，3.91(dt，1H，CH)，5.32(d，1H，NH)，7.25-7.47(m，5H，Ar-H).

And 1.8g of Compound 9

NMR：(CDCl₃)δ1.2-1.7(m，CH)，1.56(s，6H，(CH₃)₂)，2.05-2.10(m，2H，CH)，3.83(dt，1H，CH)，5.32(d，1H，NH)，7.25-7.50(m，5H，Ar-H).

Example B7

Compound 10Preparation of

Under a nitrogen atmosphere, compound 8(80mg) was dissolved in dichloromethane (2ml) and cooled to-78 ℃. DAST (0.1ml) was added, the mixture was stirred and the mixture was warmed to room temperature. Saturated sodium bicarbonate was added and the layers separated. The organic layer was washed with brine and dried (MgSO)₄) And evaporated. The residue was crystallized from diisopropyl ether to yield 40mg (50%) of compound (10).

NMR：(CDCl3)δ1.2-1.85(m，CH)，1.59(s，6H，(CH3)2)，1.95-2.10(m，2H，CH)，3.93(dt，1H，CH)，5.27(d，1H，NH)，7.27-7.43(m，5H，Ar-H).

Example B8

Compound 11Preparation of

Compound 8(100mg, 0.3mmol) was dissolved in dichloromethane (2ml) and cooled to-78 deg.C and boron tribromide (0.15ml, 1.5mmol) was added. The mixture was warmed to room temperature, diluted with dichloromethane and poured onto a mixture of ice and concentrated aqueous ammonia. The layers were separated and the organic layer was washed with brine and dried (MgSO)₄) And evaporated. The residue was crystallized from ethyl acetate to give compound 11. LC-MS: m + 1393.34, 395.34;

NMR；(CDCl3)δ1.25-1.52(m，CH)，1.57(s，6H，(CH3)2)，1.90-2.42(m，CH)，3.97(dt，1H，CH)，5.37(d，1H，NH)，6.28-7.30(m，4H，Ar-H).

example B9

Compound 12Preparation of

2, 2-dimethylphenylacetic acid [826-55-1] (0.5g, 2.7mmol) was dissolved in anhydrous dichloromethane, and oxalyl chloride (0.4g) and 1 drop of DMF were added. After stirring for 2 hours the solution was evaporated to dryness, redissolved in 10ml dichloromethane and added to a solution of 6-oxo-adamantan-2-ylamine ethanediol ketal (0.6g, 2.7mmol) and N, N-diethylethylamine (0.5ml) in dichloromethane. The mixture was stirred overnight, extracted with 15% citric acid, saturated sodium bicarbonate and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified on silica gel (eluent: dichloromethane with 5% MeOH) and recrystallized from isopropyl ether to yield 600mg (50%) of compound (12).

NMR：(CDCl3)δ1.52-2.05(m，CH)，1.60(s，6H，(CH3)2)，3.85(dt，1H，CH)，3.85-3.90(m，4H，CH2CH2)，5.45(d，1H，NH)，7.23-7.42(m，5H，Ar-H).

Example B10

Compound 13Preparation of

The ketal (450mg) from example B9 was dissolved in acetone (10ml), 1M hydrochloric acid (5ml) was added and the mixture was stirred at 45 ℃ for 3 hours. The reaction mixture was concentrated and extracted with dichloromethane. The organic layer was washed with saturated sodium bicarbonate and brine, dried and evaporated. The residue was crystallized from ethanol to give 300mg of compound (13).

NMR：(CDCl3)δ1.52-1.75(m，CH)，1.60(s，6H，(CH3)2)，1.95-2.15(m，2H，CH)，2.30(d，2H，CH)，2.50(s，2H，CH)，4.12(dt，1H，CH)，5.45(d，1H，NH)，7.27-7.47(m，5H，Ar-H).

Example B11

Compound 14Preparation of

Compound 13(50mg) was dissolved in methanol and NaBH added₄(50 mg). The mixture was stirred at room temperature for 6 hours. 1M hydrochloric acid was added, and the mixture was extracted with dichloromethane. The organic phase was washed with brine, dried and evaporated. Chromatography on silica gel (5% MeOH in dichloromethane) afforded 20mg (40%) of compound (14).

NMR：(CDCl3)δ1.52-2.00(m，CH)，1.60(s，6H，(CH3)2)，3.85(dt，1H，CH)，5.45(d，1H，NH)，7.23-7.42(m，5H，Ar-H).

Example B12

Compound 17Preparation of

1-Phenylcyclopropanecarboxylic acid (0.00028mol) was added to a mixture of polymer-supported N-cyclohexylcarbodiimide (0.0004mol) in dichloromethane (5 ml). The mixture was stirred for 15 minutes. 2-methyl-2-propylamine (0.0002mol) was added to the solution, and the reaction mixture was stirred at room temperature overnight. The resin was filtered off and the filtrate was evaporated. The residue was purified by means of a liquid chromatography column (14ml, eluent: dichloromethane) previously packed with silica gel. The product fractions were collected and the solvent was evaporated to give compound (17).

Example B13

Compound 31Preparation of

Suspending the Polymer-Supported carbodiimide (0.0004mol)In dichloromethane (5 ml). 1-phenylcyclopropanecarboxylic acid (0.00028mol) and N, N-dimethyl-4-pyridylamine (0.00001mol) were then added and the mixture was stirred for 20 minutes. Addition of tricyclo [3.3.3.13, 7]]Decane-1-methylamine (0.0002 mol; 6 isomers) and the mixture was stirred at room temperature overnight. The mixture was filtered. The filter residue was washed with dichloromethane and the filtrate solvent was evaporated. The residue was passed through TRIKONEX Flashtube^TMPurification by flash column chromatography (eluent: 9: 2 hexane and EtOAc). The product fractions were collected and then extracted, and the extract was evaporated to give 0.037g of compound (31).

Example B14

a) Compound 89Preparation of

A mixture of m, α -dimethylhydroatropic acid (0.001mol), 1-hydroxy-1H-benzotriazole (0.0011mol) and N' - (ethylcarboximidoyl) -N, N-dimethyl-1, 3-propanediamine monohydrochloride (0.00105mol) in dichloromethane (5ml) was stirred at room temperature until completely dissolved (+ -20 min). A mixture of 2-adamantanamine hydrochloride (0.0013mol) in dichloromethane (2ml), triethylamine (1ml) and DMF (0.5ml) was added and the resulting mixture was stirred at room temperature overnight. Water (2ml) was added and the mixture was stirred for 10 minutes. The mixture was passed through Extrelt^TMThe filtrate was filtered and the solvent was evaporated. The residue was passed through TRIKONEX Flashtube^TMFlash column chromatography (eluent: 95: 5 CH)₂Cl₂And EtOAc) purification. The product fractions were collected and purified by HPLC. The product fractions were collected and the solvent was evaporated to give compound (89).

b) Compound 270Preparation of

A suspension of compound (89) (0.005mol), 1-bromo-2, 5-pyrrolidinedione (0.0055mol) and 2, 2' -azobis (2-methylpropanenitrile [ cas: 78-67-1] (0.030g) in tetrachloromethane (50ml) was stirred and refluxed for 1 hour, then the precipitate was filtered off and the solvent was evaporated, the residue was dissolved in dichloromethane, and the solution was washed with 2% sodium bicarbonate, water and brine, the mixture was dried and the solvent was evaporated to give 2g of a product, a part of the residue (0.100g) was purified by high performance liquid chromatography, the product fractions were collected and the solvent was evaporated to give compound (270).

c) Compound 161Preparation of

A suspension of compound (270) (0.0013mol), potassium cyanide (0.0065mol) and potassium iodide (0.00013mol) in acetonitrile (10ml) was stirred at room temperature overnight, then the solvent was evaporated. The residue was dissolved in dichloromethane and the solution was extracted with water. The mixture was passed through Extrelt^TMFilter and evaporate the solvent. The residue was purified by column chromatography over silica gel (eluent: 2: 1 hexane and EtOAc). The product fractions were collected and the solvent was evaporated, yielding 0.12g (96%) of compound (161).

d) Compound 170Preparation of

A mixture of compound (161) (0.0009mol) in a mixture of ammonia in ethanol (50ml) was hydrogenated at 14 ℃ with Raney nickel (catalytic amount) as a catalyst. After absorption of hydrogen (2 equivalents), the catalyst is filtered off and the solvent is evaporated, yielding 0.270g (88%) of compound (170).

e) Compound 191Preparation of

A suspension of compound (170) (0.0006mol) and potassium carbonate (0.0018mol) in N, N-dimethylformamide (8ml) was stirred for 15 minutes, a mixture of 1-chloro-2- (chloromethoxy) ethane (0.00066mol) in N, N-dimethylformamide (q.s.) was added dropwise, and then the reaction mixture was stirred at room temperature over the weekend. The mixture was heated overnight to 65 ℃ and 1-chloro-2- (chloromethoxy) ethane (0.030g) was additionally added. The resulting mixture was stirred at 65 ℃ for 3 hours, then poured into water and extracted with dichloromethane. The product was purified by high performance liquid chromatography. The product fractions were collected, the solvent was evaporated, and the residue was shaken with activated carbon to give 0.021g (8.5%) of compound (191).

Example B15

Compound 178Preparation of

To a suspension of compound (170) (0.0003mol) and potassium carbonate (0.001mol) in N, N-dimethylformamide (3ml) was added dropwise a mixture of methyl iodide (0.001mol) in N, N-dimethylformamide (1ml), and the reaction mixture was stirred at room temperature overnight, after which the mixture was poured into water and extracted with dichloromethane. The resulting mixture was passed through Extrelt^TMFiltration and evaporation of the solvent gave the product (NMR: CTS, LCMS: 100% MW 382). The residue was triturated with DIPE; the resulting precipitate was filtered off and dried to yield 0.075g (65%) of compound (178).

Example B16

a) Compound 271Preparation of

A mixture of 3-bromo- α, α -dimethylphenylacetic acid (0.0004mol), 2-adamantanamine hydrochloride (0.0006mol) and 1-hydroxy-1H-benzotriazole (0.0008mol) in dichloromethane (5ml), DMF (1ml) and N, N-dimethylformamide (3ml) was stirred, then N' - (ethylcarbonimidoyl) -N, N-dimethyl-1, 3-propanediamine monohydrochloride (0.00045mol) was added and the resulting mixture was stirred overnight. Water (2ml) was added and the mixture stirred for 10 min and passed through an Extrelt^TMAnd (5) filtering. The solvent was evaporated and the residue was passed through TRIKONEXFlashTtube^TMFlash column chromatography (eluent: 98: 2 CH)₂Cl₂And EtOAc) purification. The product fractions were collected and the solvent was evaporated. The residue was purified by high performance liquid chromatography. The product fractions were collected and the solvent was evaporated. The residue was dissolved in dichloromethane and washed with sodium carbonate solution. The mixture was passed through Extrelt^TMFiltration and evaporation of the organic solvent gave 0.0148g of compound (271).

b) Compound 180Preparation of

A mixture of compound (271) (0.00080mol), ethyl 2-acrylate (1g), palladium (II) acetate (0.0002mol), 1, 3-propanediylbis [ diphenylphosphine (0.0004mol) and triethylamine (1ml) in THF (100ml) was reacted at 125 ℃ for 16 hours, followed by evaporation of the solvent. The residue (0.5g) was purified by column chromatography on silica gel (eluent: dichloromethane). The two product fractions were collected and the solvent was evaporated, yielding 0.120g (97%) of compound (180).

c) Compound 193Preparation of

A mixture of compound (180) (0.0003mol) in THF (40ml) was hydrogenated over a catalyst of palladium (10%) on activated carbon (0.03 g). After absorption of hydrogen (1 equivalent), the catalyst is filtered off and the filtrate is evaporated. The residue was dissolved in dichloromethane and the residue was purified by column chromatography on silica gel (eluent: dichloromethane). The two product fractions were collected and the solvent was evaporated, yielding 0.045g of compound (193).

d) Compound 196Preparation of

A mixture of compound (193) (0.00015mol) and 1, 4-dioxane (0.5ml) in hydrochloric acid (2ml) was stirred at 70 ℃ for 1 hour, then the solvent was evaporated. The residue was dissolved in dichloromethane and filtered (dichloromethane) through a silica path (silica-path). The filtrate was evaporated and the resulting residue was dried to yield 0.025g (45%) of compound (196).

Example B17

Compound 159Preparation of

The compound (271) (0.00013mol) and Pd₂(dibenzylidene acetone)₃Complex (0.026g), 1' -bis (diphenylphosphino) ferrocene (0.033g), Zn/Zn (CN)₂A mixture of (0.012g/0.105g), sodium azide (0.100g) and ammonium chloride (0.082g) in DMA (50ml) was reacted at 150 ℃ for 45 minutes in a microwave. The reaction mixture was then poured into water and extracted with EtOAc/DIPE. The extract was washed with water and passed through an Extrelt^TMFiltered and then the solvent is evaporated. The aqueous phase is extracted with dichloromethane and passed through an Extrelt^TMAnd (5) filtering. The solvent was evaporated and the residue was purified by high performance reverse phase liquid chromatography. The product fractions were collected and the solvent was evaporated to give compound (159).

Example B18

Compound 166Preparation of

Butyllithium (0.0011mol) was added dropwise to a solution of compound (271) (0.0005mol) in THF (5ml) at-78 ℃ under a nitrogen atmosphere, and the mixture was stirred for 30 minutes. A mixture of iodopropane (0.0006mol) in THF (5ml) was then added dropwise and the reaction mixture was stirred at-78 deg.C for 1 hour. The mixture was allowed to warm overnight and then saturated ammonium chloride solution (5ml) was added. Separating the organic layer, washing, passing through an Extrelt^TMFilter and evaporate the solvent. The residue (0.170g) was purified by liquid chromatography on silica gel (5g) (eluent: 10: 1 hexane and EtOAc). The product fractions were collected and the solvent was evaporated. The residue was purified by high performance reverse phase liquid chromatography. The product fractions were collected and the solvent was evaporated to give compound (166).

Example B19

a) Compound 272Preparation of

The compound (271) (0.00013mol) and Pd₂(dibenzylidene acetone)₃Complex (0.026g), 1' -bis (diphenylphosphino) ferrocene (0.033g), Zn/Zn (CN)₂(0.012g/0.105g) mixture in DMA (50ml) was reacted at 150 ℃ for 15 minutes in a microwave. The reaction mixture was then poured into water and extracted with EtOAc/DIPE. The extract was washed with water and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH)₂Cl₂) Purified by solid phase extraction. The product fractions were collected and the solvent was evaporated, yielding 0.055g of compound (272).

b) Compound 273Preparation of

A mixture of compound (272) (0.001mol) in ammonia in ethanol (50ml) was hydrogenated at 14 ℃ with Raney nickel (catalytic amount) as a catalyst. After absorption of hydrogen (2 equivalents), the catalyst is filtered off and the filtrate is evaporated. The residue was dissolved in dichloromethane, the resulting solution was filtered and the filtrate was evaporated to give 0.270g of compound (273).

c) Compound 274Preparation of

A solution of compound (273) (0.00015mol) and N, N-diethylethylamine (0.0003mol) in dichloromethane (q.s.) was stirred at room temperature for 15 minutes. Then 4-chlorobutyryl chloride (4635-59-0) is added dropwise](0.000165mol) in dichloromethane (2.5ml) and the resulting reaction mixture was stirred at room temperature overnight. The mixture was washed with hydrochloric acid (1N), 5% sodium bicarbonate solution and water. The resulting mixture was passed through Extrelt^TMFilter and evaporate the solvent. Medicine for removing residuePurification by column chromatography over silica gel (eluent: 99: 1 dichloromethane and methanol). The product fractions were collected and the solvent was evaporated, yielding 0.072g of compound (274) (colorless oil).

d) Compound 160Preparation of

N, N, N-triethylbenemethanaminium chloride (0.00015mol) and sodium hydroxide (50%) (0.5ml) were added to a solution of compound (274) (0.00014mol) in dichloromethane (5ml) and the reaction mixture was stirred at room temperature overnight. The mixture was washed 2 times with hydrochloric acid (1N), 5% sodium bicarbonate solution and water. The resulting mixture was passed through Extrelt^TMFiltration and evaporation of the solvent gave 0.050g of a colorless oil. The residue was purified by solid phase extraction on a liquid chromatography column (eluent: 90: 10 dichloromethane and methanol) previously packed with silica gel. The product fractions were collected and the solvent was evaporated, yielding 0.024g of compound (160).

Example B20

a) Compound 171Preparation of

A mixture of intermediate (29) (0.0019mol) in N, N-diethylethylamine (2ml) and dichloromethane (15ml) was stirred and 1-hydroxy-1H-benzotriazole (0.002mol) was added. N' - (ethylcarbonimidoyl) -N, N-dimethyl-1, 3-propanediamine (0.002mol) was then added and the mixture was stirred for 10 minutes. 2-adamantanamine hydrochloride (0.0022mol) was added and the reaction mixture was stirred overnight. Citric acid solution (2ml) was added and the resulting mixture was passed through an Extrelt^TMAnd (5) filtering. The filtrate was evaporated and the residue was passed through a TRIKONEXFlashTtube^TMPurification by flash column chromatography (eluent: 90: 10 dichloromethane and EtOAc). The product fractions were collected and the solvent was evaporated. The remaining fractions were purified by high performance liquid chromatography, then the product fractions were collected and the solvent was evaporated, yielding 0.155g (25%) of compound (171).

b) Compound 172Preparation of

A mixture of compound (171) (0.00044mol) in methanol (50ml) was hydrogenated over night with palladium on activated carbon (0.1g) as a catalyst. After uptake of hydrogen (1 eq), the catalyst was filtered off and the filtrate was evaporated, then the residue was dried (vacuum) to yield 0.12g of compound (172).

Example B21

Compound 192Preparation of

A mixture of compound (170) (0.0006mol) and formaldehyde (0.2g) in methanol (40ml) was hydrogenated at 50 ℃ in the presence of a thiophene solution (0.1ml) with palladium on activated carbon (0.05g) as a catalyst. After absorption of hydrogen (1 eq), the catalyst is filtered off and the filtrate is evaporated. The residue was dissolved in dichloromethane and washed with hydrochloric acid (1N), 5% sodium bicarbonate solution and brine. The mixture was passed through Extrelt^TMFilter and evaporate the solvent. The residue was purified by column chromatography on silica gel (eluent: 90: 10 dichloromethane/(methanol/ammonia (1%))). The product fractions were collected and the solvent was evaporated to give compound (192).

Example B22

a) Compound 198Preparation of

The compound (271) (0.0005mol), benzyl 2-acrylate (0.002mol), Pd₂(dibenzylidene acetone)₃Complex (0.0001mol), tris (2-methylphenyl) phosphine [6163-58-2 ]]A mixture of (0.00025mol) and N, N-dibutyl-1-butylamine (0.0025mol) in DMF (5ml) was stirred at 90 ℃ overnight before the reaction mixture was cooled. Adding water (3ml), mixingThe mixture was extracted with EtOAc. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue was purified by column chromatography on silica gel (eluent: dichloromethane). The product fractions were collected and the solvent was evaporated, yielding 0.167g of compound (198).

b) Compound 202Preparation of

A mixture of compound (198) (0.0003mol) in acetic acid (4ml) and hydrochloric acid (2ml) was stirred at 60 ℃ overnight, then the reaction mixture was cooled and extracted with dichloromethane. The organic layer was separated, washed, dried, filtered and the solvent was evaporated. The residue was purified by high performance liquid chromatography. The product fractions were collected and the solvent was evaporated, yielding 0.045g of compound (202).

Example B23

a) Compound 204Preparation of

A mixture of intermediate (36) (0.0013mol) in dichloromethane (10ml) and N, N-diethylethylamine (3ml) was stirred and 1-hydroxy-1H-benzotriazole (0.002mol) was added. N' - (ethylcarbonimidoyl) -N, N-dimethyl-1, 3-propanediamine monohydrochloride (0.002mol) was then added and the mixture was stirred for 10 minutes. After addition of DMF (2ml), 2-adamantane hydrochloride (0.0016mol) was added and the reaction mixture was stirred overnight. The mixture was washed with water (2ml), potassium hydroxide solution and again with water. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue was purified by chromatography on a column of silica gel (eluent: 98: 2 dichloromethane and methanol). The product fractions were collected and the solvent was evaporated to yield 0.176g of compound (204).

b) Compound 208Preparation of

A mixture of compound (204) (0.00036mol) in TFA in dichloromethane (28%) (3ml) was stirred for 3 hours, then the solvent was evaporated. The residue was dissolved in dichloromethane and the solution was washed with sodium carbonate solution. Separating organic layer by Extrelt^TMFiltration and evaporation of the solvent gave 0.116g of compound (208).

Example B24

Compound 252Preparation of

Reacting 1- [ (2, 3-dihydro-1H-indol-1-yl) carbonyl]-3-methyl-1H-imidazolium iodide [548763-29-7 ]]A mixture of (0.0028mol) and 2-adamantanamine hydrochloride (0.0028mol) in N, N-diethylethylamine (2ml) and a mixture of dichloromethane, THF and DMF (1/1/0.5) (50ml) were stirred over the weekend and the reaction mixture was poured into water and extracted with dichloromethane. The extract was washed with a citric acid (15%) solution, and the organic layer was dried and then filtered. Evaporating the solvent and passing the residue through a TRIKONEX Flashtube^TMPurification by flash column chromatography (eluent: 90: 10 dichloromethane and EtOAc). The product fractions were collected and the solvent was evaporated, yielding 0.18g of compound (252).

Example B25

Compound 200Preparation of

2-isocyanato-tricyclo [3.3.1.13, 7] decane [71189-14-5] (0.0053mol) was added to a solution of 1, 2, 3, 4-tetrahydroquinoline (0.00586mol) in EtOAc (10ml) and the reaction mixture was stirred overnight. The solvent was evaporated and the residue crystallized from 2-propanol. Finally, the final product was collected to yield 0.500g of compound (200); melting point: 163 ℃ and 165 ℃.

Example B26

Compound 219Preparation of

And compound 218Preparation of

To a solution of 4-amino-tricyclo [3.3.1.13, 7] decan-1-ol [75375-89-2] (0.01mol) and N, N-diethylethylamine (0.01mol) in a mixture of dichloromethane, THF and DMF (1/1/0.2) (100ml) was added 1- [ (3, 4-dihydro-1 (2H) -quinolinyl) carbonyl ] -3-methyl-1H-imidazolium iodide [213134-25-7] (0.01mol) and the reaction mixture was stirred overnight. The mixture was washed with hydrochloric acid (1N), potassium hydroxide (2N) and sodium chloride, then dried and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: 3/1- >1/1 hexane/EtOAc). The two product fractions were collected and the solvent was evaporated, yielding 1.5g (46%) of compound (219), melting point: 185 ℃ and 188 ℃; and 1.4g (44%) of compound (218), melting point: 170 ℃ and 172 ℃.

Example B27

Compound 231Preparation of

1-Methylpiperazine (0.0015mol) was added to a portion of a dichloromethane (5ml) solution of compound (270) (0.0003mol), and the mixture was stirred at room temperature overnight. Sodium hydroxide (1N) (1ml) was added and the reaction mixture was stirred vigorously for 30 minutes. The layers were separated and the aqueous layer was extracted. The organic layer was dried, filtered and the solvent was evaporated to give compound (231).

Example B28

Compound 232Preparation of

To a solution of compound (270) (0.00044mol) in dichloromethane (10ml) was added morpholine (0.0012mol), and the mixture was stirred at room temperature overnight. Sodium hydroxide (1N) (1ml) was added and the reaction mixture was stirred vigorously for 15 minutes. The aqueous layer was separated, then the organic layer was washed with water and passed through an Extrelt^TMAnd (5) filtering. The filtrate was evaporated and the residue was purified by column chromatography on silica gel (eluent: 99/1 dichloromethane/methanol). The product fractions were collected and the solvent was evaporated to give compound (232).

Example B29

a) Compound 265Preparation of

A mixture of 1-isoquinolinecarboxylic acid (0.0056mol) in DMF (50ml) was stirred and 1-hydroxy-1H-benzotriazole (0.0067mol) was added. N' - (ethylcarbonimidoyl) -N, N-dimethyl-1, 3-propanediamine monohydrochloride (0.00067mol) was then added and the mixture was stirred for 20 minutes. Adding 1-amantadine [768-94-5 ]](0.0067mol) and the reaction mixture is stirred for 3 hours. The resulting mixture was poured into water and extracted with EtOAc. The separated organic layer was washed and dried (MgSO)₄) Filtered and the solvent evaporated. The residue was purified by column chromatography on silica gel (eluent: dichloromethane). The product fractions were collected and the solvent was evaporated to yield 1.5g of compound (265).

b) Compound 267Preparation of

A mixture of compound (265) (0.004mol) and hydrochloric acid (12N) (1ml) in methanol (50ml) was hydrogenated over night with platinum (1g) supported on activated carbon as a catalyst. After absorption of hydrogen (2 equivalents), the catalyst is filtered off and the filtrate is evaporated. The residue was dissolved in dichloromethane and washed with sodium carbonate solution. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue was purified by column chromatography on silica gel (eluent: 99/1->95/5 twoMethyl chloride/methanol). The product fractions were collected and the solvent was evaporated, yielding 0.8g of compound (267).

Example B30

a) Compound 278Preparation of

Compound 238(0.0036mol) was dissolved in dichloromethane (50ml) and the solution was cooled to-70 ℃ before DAST (0.0015mol) was added dropwise and the reaction mixture was stirred at-70 ℃ for 30 min. After removal of the cold bath, the mixture was brought to room temperature over 1 hour, and then a saturated sodium bicarbonate solution was added in portions. The separated organic layer was washed with water and brine, then dried, filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: 98/2 dichloromethane/methanol). The product fractions were collected and the solvent was evaporated, yielding 1g of compound (278) (LCMS: 94% P).

b) Compound 279Preparation of

A mixture of compound (278) (0.002mol) in THF (50ml) was hydrogenated over Pd/C (10%) (0.2g) as a catalyst. After absorption of hydrogen (2 equivalents), the catalyst is filtered off and the filtrate is evaporated (vacuum). The residue was triturated with DIPE and the crude product was collected and purified by column chromatography on silica gel (eluent: 99/1 dichloromethane/methanol). The product fractions were collected and the solvent was evaporated to give compound (279).

Example B31

a) Compound 280Preparation of

A suspension of intermediate 12(0.0192mol), N' - (ethylcarbonimidoyl) -N, N-dimethyl-1, 3-propanediamine (0.021mol) and HOBt (0.021mol) in DMF (10ml) was stirred at room temperature for 30 minutes, then a solution of 2-amino-adamantane hydrochloride [62058-03-1] (0.0231mol) in DMF (q.s.) was added and the reaction mixture was stirred overnight. The crude product was triturated with DIPE and the expected product was collected, yielding 7.8g of compound (280) (83%).

b) Compound 281Preparation of

A mixture of compound (280) (0.0065mol) in THF (150ml) was hydrogenated over B (1g) as catalyst. After uptake of hydrogen (2 eq), the catalyst is filtered off and the filtrate is evaporated (vacuum) yielding 2.6g of compound (281) (100%).

c) Compound 277Preparation of

A solution of compound (281) (0.00024mol), N' - (ethylcarbonimidoyl) -N, N-dimethyl-1, 3-propanediamine (0.000275mol) and HOBt (0.000275mol) in DMF (10ml) was stirred at room temperature for 30 minutes, then B (0.000325mol) was added. The reaction mixture was stirred at room temperature overnight, washed with water and 5% sodium bicarbonate solution and passed through an Extrelut^TMAnd (5) filtering. The solvent was evaporated and the residue (0.200g) was purified by column chromatography on silica gel (2g) (eluent: 95/5 dichloromethane/methanol). The pure product fractions were collected and the solvent was evaporated. The expected product is finally dried (vacuum) to yield 0.106g of compound (277).

The compounds of the invention prepared according to one of the above examples are listed in tables 1, 2 and 3.

TABLE 1

TABLE 2

TABLE 3

Table 4 lists compounds prepared according to one of the above examples. The following abbreviations are used in table 4: HCl represents the hydrochloride salt.

TABLE 4

Compound (I)	NMR data	Melting Point (. degree.C.)
			155		165-167
156	(CDCl)1.25-1.45(m, adamantane-H); 1.54(s, 3H, 2 xMe); 1.56-1.72(m, adamantane-H); 2.10(m, adamantane-H); 2.38(s, 3H, Me); 3.82(m, 1H, CH); 5.38(bd, NH); 7.10(d, 1H, H-aromatic); 7.18(m, 2H-aromatic); 7.27(t, 1H-aromatic)
			157	(CDCl)1.15-1.35(m, adamantane-H); 1.55(s, 3H, 2 xMe); 1.65-2.05(m, adamantane-H); 2.35(s, 3H, Me); 3.92(m, 1H, CH-NH); 5.32(bd, 1H, NH)7.10(d, 1H, Ar-H), 7.20(m, 2H, Ar-H), 7.27(t, 1H, Ar-H)
158		155-160
			162	CDCl(ii) a δ 1.64-2.05(m, 14H-adamantane); 4.23(d, CH); 5.30(d, CH 2); 6,14(d, NH); 6.22(t, CH); 6.86-7.48(m, 4H-aromatic)
162	CDCl(ii) a δ 1.59-2.30(m, 13H-adamantane); 4.12(d, CH); 6,18(d, NH); 7.31-7.43(m, 2H-aromatic); 7.81(d, 2H-aromatic); 8.26(d, 1H-aromatic)
			164	CDCl(ii) a δ 1.50-2.24(m, 13H-adamantane); 4.22(d, CH); 6,15(d, NH); 7.31-7.42(m, 2H-aromatic); 7.81(d, 2H-aromatic); 8.25 (d) of the total of,

	1H-aromatic)
			165	CDCl(ii) a Delta 1.10-1.83(m, 14H-adamantane + 2xCH))；2.38(m，CH)；2.83(t，CH) (ii) a 3.95(d, CH); 5.55(d, NH); 7.15-7.38(m, 4H-aromatic)
166	CDCl；δ0.92(t，CH) (ii) a 1.22 and 1.47(2xd, 4H-adamantane); 1.58(s, 2xCH)) (ii) a 1.60-1.82(m, 10H-adamantane); 2.59(t, CH)) (ii) a 3.94(d, CH); 5,47(d, NH); 7.11-7.31(m, 4H-aromatic)
			167	CDCl(ii) a δ 1.22-1.91(m, 14H-adamantane); 2.15(m, H)-CH)；2.50(m，H-CH)；3.63(m，CH)；4.05(m，CH) (ii) a 4.08(d, CH); 5.96(d, NH); 6.88-7.25(m, 4H-aromatic)
168	CDCl(ii) a Delta 1.5-2.0(m, 16H, H-adamantane and CH))；2.25(quint.，CH)；2.59(t，CH) (ii) a 4.15(d, CH); 6,02(d, NH); 7.28-7.32(m, 4H-aromatic, CH)

169	CDCl(ii) a Delta 1.22-1.95(m, 18H, H-adamantane and 2xCH))；2.43(m，CH)；2.78(t，CH) (ii) a 3.72(dd, CH); 4.08(d, CH); 5.72(d, NH); 7.12-7.22(m, 4H-aromatic)
			171	CDCl(ii) a δ 1.65-2.03(m, 14H-adamantane); 3.88(s, CH))；4.22(d，CH)；4.86(d，CH) (ii) a 6.12(d, NH); 6.26(t, CH); 6.86-7.11(m, 3H-aromatic)
172	CDCl(ii) a δ 1.23-1.91(m, 14H-adamantane); 2.15 and 2.53(2xm, CH))；3.64(m，CH)；3.91(s，CH)；4.08(m，CH) (ii) a 4.42(m, CH); 6.03(d, NH); 6.74-6.94(m, 3H-aromatic)
			173	CDCl(ii) a Delta 1.21-1.91(m, 14H-adamantane + CH)) (ii) a 2.36 and 2.56 and 2.81(3xm, 2xCH))；3.67(t，CH)；3.85(s，CH) (ii) a 4.01(d, CH); 5.72(d, NH); 6.77(d, 2H-aromatic); 7.18(t, 1H-aromatic)
174	CDCl(ii) a δ 1.24 and 1.40(2xd, 4H-adamantane); 1.56(s, 2xCH)) (ii) a 1.68-2.00(m, 9H-adamantane); 3.92(d, CH); 5,45(d, NH); 7.25-7.55(m, 4H-aromatic)
			175	CDCl(ii) a δ 1.30-1.74(m, 13H-adamantane); 1.54(s, 2xCH)) (ii) a 3.75(dt, CH); 5,35(d, NH); 7.28-7.52(m, 4H-aromatic)
176	CDCl: 1.51-1.88(m, 15H-adamantane); 2.16(s, CH)) (ii) a 3.87(dt, CH); 5.12(d, NH); 6.11(d, NH); 7.27-7.36(m, 3H-aromatic).
			177	CDCl(ii) a δ 1.44-1.96(m, 14H-adamantane); 3.30(dd, H)-CH)；3.61(dd，H-CH) (ii) a 4.05(d, CH); 4.23(dd, CH); 6.09(m, NH); 7.14-7.31(m, 4H-aromatic)
178	Aceton d-6; δ 1.38-1.74(m, 14H-adamantane); 1.62(s, 2xCH))；3.15(m，CH)；3.48(s，3xCH) (ii) a 3.94(m, CH and CH)) (ii) a5, 68(d, NH); 7.28-7.39(m, 4H-aromatic)
			179	CDCl(ii) a δ 1.61-2.4(m, 14H-adamantane); 3.39(d, CH)) (ii) a 4.22(dt, CH); 6.03(m, NH); 6.51(t, CH); 7.16(m, 2H-aromatic); 7.34 and 7.50(2xm, 2H-aromatic)
180	CDCl(ii) a δ 1.27-1.72(m, 14H-adamantane); 1.59(s, 2xCH)) (ii) a 3.97(d, CH); 5,46(d, NH); 6.35(d, CH); 7.40-7.55(m, 4H-aromatic); 7.59(d, CH)
			181	CDCl(ii) a δ 1.64-2.30(m, 14H-adamantane); 2.27(s, 2xCH))；

Compound (I)	NMR data	Melting Point (. degree.C.)
				2.34(m，CH)；2.69(t，CH) (ii) a 4.23(d, CH); 6.12(d, NH); 6.49(t, CH); 6.91 and 7.12(2xs, 2H-aromatics)
182	CDCl(ii) a δ 1.17-1.85(m, 14H-adamantane); 1.99(m, H)-CH)；2.88(m，H-CHAnd H-CH)；3.08(m，H-CH) (ii) a 3.75(t, CH); 4.00(d, CH); 6.72(d, NH); 7.03-7.21(m, 4H-aromatic)
			183	CDCl(ii) a Delta 1.22-2.15(m, 14H-adamantane)+CH)；2.32(m，H-CH)；2.55(m，H-CHAnd H-CH)；2.70(m，H-CH)；3.65(t，CH)；3.83(s，CH) (ii) a 3.89(dt, CH); 5.62(d, NH); 6.75(t, 2H-aromatic); 7.17(t, H-aromatics)
184	CDCl(ii) a Delta 1.15-2.05(m, 14H-adamantane + CH))；2.36(m，H-CH)；2.56(m，H-CH)；2.70(m，CH)；3.66t，CH)；3.84(s，CH) (ii) a 3.98(d, CH); 5.59(d, NH); 6.75(t, 2H-aromatic); 7.18(t, H-aromatics)
			185	CDCl: delta 1.20-1.92(m, 14H-adamantane + CH)) (ii) a 2.21 and 2.27(2xs, 2xCH))；2.34(m，H-CH)；2.54(m，H-CHAnd H-CH)；2.69(m，H-CH) (ii) a 4.02(dt, CH); 5.72(d, NH); 6.81 and 6.93(2xs, 2H-aromatics)
186	CDCl(ii) a δ 1.35-1.45(m, adamantane-H); 1.57(s, 3H, 2 xMe); 1.60-1.82(m, adamantane-H); 2.15(m, adamantane-H); 2.38(s, 3H, Me); 3.82(m, 1H, CH-NH); 5.32(bd, 1H, NH); 7.10(d, 1H, Ar-H); 7.18(m, 2H, Ar-H); 7.27(t, 1H, Ar-H)
			187		115-117
188		110-112
			189		105-107
190	CDCl(ii) a δ 1.19-2.13(m, 13H-adamantane); 1.54(s, 2xCH)) (ii) a 3.95(d, CH); 5.37(d, NH); 7.22-7.54(m, 4H-aromatic)
			194	CDCl(ii) a δ 1.60-2.29(m, 14H-adamantane); 3.41(dd, H)-CH)；3.55(dd，H-CH)；4.23(s，CH)；4.26(m，H-CH)；4.41(m，H-CH) (ii) a 4.48(dd, CH); 5.19(brd, ═ CH 2); 5.93(m, ═ CH); 7.06-7.26(m, 4H-aromatic)
195	CDCl(ii) a δ 1.65-2.06(m, 14H-adamantane); 2.35(m, CH))；2.72(t，CH)；3.77(s，CH) (ii) a 4.24(d, CH); 6.15(d, NH); 6.54(t, CH); 6.75(dd, H-aromatic); 7.18(m, 2H-aromatic)

196	CDCl(ii) a δ 1.20-1.72(m, 14H-adamantane); 1.58(s, 2xCH)) (ii) a 2.67 and 2.97(2xt, 2xCH)) (ii) a 3.95(d, CH); 5,48(d, NH); 7.14-7.34(m, 4H-aromatic);
			197	CDCl(ii) a δ 1.40-1.94(m, 14H-adamantane); 2.30-2.53(m, CH))；2.87-3.09(m，CH) (ii) a 3.94(dd, CH); 4.05(d, CH); 5.71(d, NH); 7.20-7.32(m, 4H-aromatic)
198	CDCl(ii) a δ 1.28 and 1.49(2xd, 4H-adamantane); 1.58(s, 2xCH)) (ii) a 1.62-1.82(m, 10H-adamantane); 3.96(d, CH); 5.26(s, CH)) (ii) a5, 44(d, NH); 6.50(d, CH); 7.33-7.54(m, 9H-aromatic); 7.72(d, CH)
			199		165-170
200		163-165
			201		145-147

202	CDCl(ii) a δ 1.29 and 1.51(2xd, 4H-adamantane); 1.61(s, 2xCH)) (ii) a 1.65-1.84(m, 10H-adamantane); 3.98(d, CH); 5,49(d, NH); 6.48(d, CH); 7.40-7.58(m, 9H-aromatic); 7.80(d, CH)
			203	CDCl(ii) a Delta 1.26-1.88(m, 14H-adamantane + CH))；1.88-1.98(m，CH) (ii) a 2.32 and 2.75(2xm, 2xCH))；3.69(t，CH)；3.77(s，CH) (ii) a 4.03(d, CH); 5.68(d, NH); 6.66(d, H-aromatics); 6.80(dd, H-aromatic); 7.09(d, 1H-aromatic)
204	CDCl(ii) a Delta 1.50-1.95(m, 14H-adamantane, 3 xCH))；2.88(t，CH) (ii) a 3.58 and 3.81(m, CH)) (ii) a 4.00(d, CH); 5.49(s, CH); 7.10-7.28(m, 4H-aromatic)
			205	CDCl(ii) a δ 1.19 and 1.37(2xd, 4H-adamantane); 1.50(s, 2xCH)) (ii) a 1.80-2.1(m, 9H-adamantane); 3.94(d, CH); 5,25(d, NH); 5.26(s, CH)) (ii) a 6.51(d, CH); 7.35-7.54(m, 9H-aromatic); 7.72(d, CH)
206	CDCl(ii) a δ 1.63-2.05(m, 14H-adamantane); 2.34(m, CH))；2.78(t，CH)；3.81(s，CH) (ii) a 4.23(d, CH); 6.14(d, NH); 6.38(t, CH); 6.73(m, 2H-aromatic); 7.39(m, 1H-aromatic)
			207	CDCl(ii) a δ 1.63-2.28(m, 14H-adamantane); 4.30(dd, CH))；4.34(s，CH)；5.21(m，CH) (ii) a 5.95(m, ═ CH); 6.85(d, CH); 7.30-7.52(m, 5H-aromatic); 7.68(d, CH)

208	CDCl(ii) a δ 1.50-1.92(m, 14H-adamantane); 2.75-2.92(m, CH))；3.09-3.21(m，CH) (ii) a 4.00(d, CH); 4.63(s, CH); 7.05-7.22(m, 3H-aromatic); 7.53(m, 1H-aromatic); 7.59(d, NH)
			209	CDCl(ii) a δ 1.28 and 1.51(2xd, 4H-adamantane); 1.57(s, 2xCH)) (ii) a 1.66 and 1.78(2xm, 9H-adamantane); 2.36(s, CH))；3.96(d，CH)；5.25(s，CH) (ii) a5, 46(d, NH); 6.48(d, CH); 7.20-7.42(m, 9H-aromatic); 7.70(d, CH)
210	CDCl(ii) a δ 1.31 and 1.50(2xd, 4H-adamantane); 1.55(s, 2xCH)) (ii) a 1.67 and 1.78(2xm, 10H-adamantane); 2.33(s, CH))；3.79(s，CH) (ii) a 3.95(d, CH); 5,55(d, NH); 6.62; 6.73 and 6.79(3xs, 3H-aromatics)
			211	CDCl(ii) a δ 1.24 and 1.36(2xd, 4H-adamantane); 1.56(s, 2xCH)) (ii) a 1.60 and 1.82(2xm, 10H-adamantane); 2.28(s, CH)) (ii) a 4.01(d, CH); 5,49(d, NH); 7.15-7.26(m, 3H-aromatic); 7.39-7.48(s, 1H-aromatic)
212	CDCl(ii) a δ 1.32-1.85(m, 14H-adamantane); 1.50(d, CH))；3.88(s，CH) (ii) a 3.96(d, CH); 4.05(q, CH); 6.12(d, NH); 6.88-7.10 and 7.22-7.34(2xm, 4H-aromatic)
			213	CDCl(ii) a δ 1.26 and 1.43(2xd, 4H-adamantane); 1.60(s, 2xCH)) (ii) a 1.65 and 1.79(2xm, 10H-adamantane); 3.65-3.78(m, 4 xCH)) (ii) a 3.96(d, CH); 5,47(d, NH); 6.83(d, CH); 7.38-7.52(m, 3H-aromatic); 7.70(d, CH)
214	CDCl(ii) a δ 1.28-2.18(m, 13H-adamantane); 1.58(s, 2xCH))；3.36(dt，CH)；5.27(s，CH) (ii) a 5.36(d, NH); 6.50(d, CH); 7.34-7.52(m, 9H-aromatic); 7.70(d, CH)
			215	CDCl(ii) a δ 1.18-2.10(m, 13H-adamantane); 1.58(s, 2xCH))；

	3.93(dt，CH)；5.25(s，CH) (ii) a 5.31(d, NH); 6.50(d, CH); 7.34-7.54(m, 9H-aromatic); 7.73(d, CH)
			216	CDCl：δ1.28(d，CH) (ii) a 1.63-2.06(m, 14H-adamantane); 2.19(m, H)-CH)；2.50(m，H-CH) (ii) a 2.93 (mCH); 4.24(d, CH); 6.13(d, NH); 6.46(t, CH); 7.18-7.47(m, 4H-aromatic)
217	CDCl(ii) a δ 1.15 and1.36(2xd, 4H-adamantane); 1.59(s, 2xCH)) (ii) a 1.80-2.10(m, 10H-adamantane); 2.67(t, CH))；2.97(t，CH) (ii) a 3.94(d, CH); 5.39(d, NH); 7.12-7.40(m, 4H-aromatic)
			218		170-172

219		185-188
			220	CDCl(ii) a Delta 1.21-1.86(m, 14H-adamantane, CH))；1.92(m，H-CH)；2.34(m，H-CH)；2.80(m，CH) (ii) a 3.63(d, CH); 5.68(d, NH); 6.70-6.78(m, 2H-aryl)Aromatic); 7.06(d, H-aromatic)
221	CDCl(ii) a δ 1.18 and 1.40(2xd, 4H-adamantane); 1.50(s, 2xCH)) (ii) a 1.58 and 1.72(2xm, 10H-adamantane); 2.28(t, 2xCH))；2.35(m，2xCH)；2.58(t，CH)；3.65(t，2xCH) (ii) a 3.88(dt, CH); 5.38(d, NH); 7.05-7.25(m, 4H-aromatic)
			222	CDCl(ii) a δ 1.66-2.06(m, 14H-adamantane); 2.38(m, CH))；2.74(t，CH) (ii) a 4.22(d, CH); 6.11(d, NH); 6.52(t, CH); 7.04(d, H-aromatic); 7.30(d, H-aromatics); 7.65(S, H-aromatic)
223	CDCl(ii) a δ 1.64-2.05(m, 14H-adamantane); 2.40(m, CH))；2.94(t，CH) (ii) a 4.22(d, CH); 6.11(d, NH); 6.49(t, CH); 7.07(t, H-aromatics); 7.42(m, 2H-aromatic)
			224	CDCl(ii) a δ 1.59-1.95(m, 14H-adamantane); 1.98 and 2.10(2xm, CH))；2.55(m CH)；2.86-3.08(m，2xCH) (ii) a 4.08(dt, CH); 5.78(d, NH); 7.08-7.15(m, 4H-aromatic)
225	CDCl(ii) a Delta 1.29-2.00(m, 14H-adamantane, CH))；2.30(m，CH)；2.76(m，CH) (ii) a 3.63(t, CH); 4.02(d, CH); 5.60(d, NH); 7.04(d, H-aromatic); 7.33(m, 2H-aromatic)
			226		182-184
227		210-215
			228		208-210
229	CDCl(ii) a δ 1.60-2.08(m, 14H-adamantane); 2.39(m, CH))；2.81(t，CH)；4.24(d，CH)；5.22(d，CH) (ii) a 6.14(d, NH); 6.44(d, CH); 6.53(t, CH); 7.16-7.43(m, 9H-aromatic)
			230	CDCl(ii) a δ 1.28 and 1.50(2xd, 4H-adamantane); 1.55(s, 2xCH)) (ii) a 1.66 and 1.78(2xm, 10H-adamantane); 2.32(s, CH))；2.63(t，CH)；2.93(t，CH) (ii) a 3.94(dt, CH); 5.53(d, NH); 6.90-7.10(m, 3H-aromatic)
231	CDCl(ii) a δ 1.22 and 1.46(2xd, 4H-adamantane); 1.58(s，2xCH) (ii) a 1.64 and 1.76(2xm, 10H-adamantane); 2.30(s, CH)；2.40-2.54(m，4xCH)；3.51(s，CH) (ii) a 3.94(d, CH); 5.44(d, NH); 7.23-7.36(m, 4H-aromatic)

232

CDCl(ii) a δ 1.22 and 1.48(2xd, 4H-adamantane); 1.60(s, 2xCH)) (ii) a 1.64-1.76(m, 10H-adamantane); 2.42(m, 2xCH))；3.51(s，CH)；3.70(m，2xCH)；3.94(d，CH)；5.45(d，NH)；7.22-

	7.38(m, 4H-aromatic)
			234	CDCl(ii) a Delta 1.62-1.99(m, 14H-adamantane, CH))；2.91(dd，H-CH)；3.30(dd，H-CH) (ii) a 4.05-4.13(m, 2 xCH); 6.06(d, NH); 7.44-7.80(m, 4H-aromatic)
235	CDCl(ii) a δ 1.64-2.07(m, 14H-adamantane); 2.39(m, CH))；2.91(t，CH)；4.23(d，CH)；5.27(s，CH) (ii) a 6.12(d, NH); 6.39(d, CH); 6.52(t, CH); 7.19-7.50(m, 9H-aromatic); 8.08(d, CH)
			238	CDCl(ii) a δ 1.18-2.02(m, 13H-adamantane); 1.56(s, 2xCH))；2.38(s，CH)；3.93(dt，CH)；5.25(s，CH) (ii) a 5.32(d, NH); 6.49(d, CH); 7.20-7.42(m, 8H-aromatic); 7.69(d, CH)
239	CDCl(ii) a Delta 1.23-1.93(m, 14H-adamantane, CH))；2.34(m，CH)；2.61-2.95(m，CH) (ii) a 3.68(t, CH); 4.03(d, CH); 5.60(d, NH); 7.10(m, 2H-aromatic); 7.51(m, 1H-aromatic)
			240	CDCl(ii) a Delta 1.19-1.97(m, 14H-adamantane, CH))；2.38(m，CH)；2.58-3.00(m，4xCH) (ii) a 3.70(t, CH); 4.01(d, CH); 5.17(d, NH); 7.01-7.18(m, 3H-aromatic)
241	CDCl(ii) a δ 1.20-2.03(m, 13H-adamantane); 1.58(s, 2xCH))；2.39(s，CH)；3.67-3.76(m，4xCH) (ii) a 3.93(dt, CH); 5.33(d, NH); 6.82(d, CH); 7.19; 7.26 and 7.32(3xs, 3H-aromatic); 7.66(d, CH)
			243	CDCl(ii) a Delta 1.45-2.15(m, 13H-adamantane, CH))；2.58(m，CH)；2.79-3.17(m，2xCH) (ii) a 4.03(d, CH); 5.75(d, NH); 6.82(d, CH); 7.05-7.15(m, 4H-aromatic)
245	CDCl(ii) a Delta 1.36-1.93(m, 14H-adamantane, CH))；2.26(m，CH2)；2.59-2.86(m，CH) (ii) a 3.62(t, CH); 4.04(d, CH); 5.61(d, NH); 7.38 and 7.67(2xd, 2H-aromatic)
			246	CDCl(ii) a δ 1.18 and 1.36(2xd, 4H-adamantane); 1.53(s, 2xCH)) (ii) a 1.69 and 1.72 and 1.99(3xm, 9H-adamantane); 2.33(s, CH))；2.64(t，CH)；2.92(t，CH) (ii) a 3.91(d, CH); 5.36(d, NH); 6.95-7.05(m, 3H-aromatic)
248	CDCl；δ1.21-2.02(m, 13H-adamantane); 1.54(s, 2xCH))；2.32(s，CH)；2.59(t，CH)；2.93(t，CH)；3.39(t，CH)；3.58(t，CH)；3.65(m，2xCH) (ii) a 3.92(d, CH); 5.36(d, NH); 6.95-7.05(m, 3H-aromatic)

249	CDCl(ii) a δ 1.18 and 1.38(2xd, 4H-adamantane); 1.56(s, 2xCH)) (ii) a 1.58-2.10(m, 9H-adamantane); 2.37(s, CH))；3.94(dt，CH)；5.25(s，CH) (ii) a 5.28(d, NH); 6.48(d, CH); 7.20-7.44(m, 8H-aromatic); 7.70(d, CH)
			252	CDCl(ii) a δ 1.65-2.01(m, 14H-adamantane); 3.19(t, CH))；3.96(t，CH) (ii) a 4.08(d, CH); 4.93(d, NH); 6.90(t, 1H-aromatic); 7.15(m, 2H-aromatic); 7.85(d, 1H-aromatic)
253	CDCl(ii) a δ 1.45-1.90(m, 14H-adamantane); 1.95(m, H)-CH)；2.31(m，H-CH)；2.60(m，H-CH)；2.75(m，H-CH) (ii) a 3.90(q, CH); 4.05(dt, CH); 4.16(d, NH); 6.70(m, 2H-aromatic); 7.02(m, 2H-aromatic); 7.22(d, NH)
			254	CDCl(ii) a δ 1.18 and 1.38(2xd, 4H-adamantane); 1.55(s, 2X)

	CH) (ii) a 1.85-2.18(m, 9H-adamantane); 2.32(s, CH))；2.65(t，CH)；2.93(t，CH) (ii) a 3.92(dt, CH); 5.32(d, NH); 6.95-7.15(m, 3H-aromatic)
			255	CDCl(ii) a δ 1.59-1.95(m, 14H-adamantane); 2.83(dd, H)-CH)；3.26(dd，H-CH)；3.57(m，H-CH)；3.97-4.08(m，3H，2xCH，H-CH) (ii) a m, 2H-aromatic); 7.05-7.18(m, 4H-aromatic); 7.68(d, NH)
256	CDCl(ii) a δ 1.59-1.95(m, 14H-adamantane); 2.83(dd, H)-CH)；3.26(dd，H-CH)；3.58(m，H-CH)；3.97-4.08(m，3H，2xCH，H-CH) (ii) a m, 2H-aromatic); 7.05-7.18(m, 4H-aromatic); 7.68(d, NH)
			257		215-220
258	LCMS M417 retention time, 97% P
			259	CDCl(ii) a δ 1.20 and 1.36(2xd, 4H-adamantane); 1.55(s, 2xCH)) (ii) a 1.69; 1.83 and 1.98(3xd, 9H-adamantane); 2.34(s, CH))；3.30(d，CH) (ii) a 3.93(dt, CH); 5.38(d, NH); 6.28(d, CH); 6.48(d, CH); 7.07, 7.12 and 7.18(3xs, 3H-aromatics)
260	CDCl(ii) a Delta 1.14-2.02(m, 13H-adamantane, CH))；1.56(s，2xCH)；2.33(s，CH)；2.35(t，CH)；2.63(t，CH) (ii) a 3.92(d, CH); 5.38(d, NH); 6.92, 6.98 and 7.04(3xs, 3H-aromatic)
			262	CDCl(ii) a Delta 1.22-2.02(m, 13H-adamantane, CH))；1.53(s，2xCH)；2.33(s，CH)；3.79(s，CH) (ii) a 3.92(d, CH); 5.42(d, NH); 6.63, 6.74 and 6.78(3xs, 3H-aromatics)

263	CDCl(ii) a δ 1.22 and 1.39(2xd, 4H-adamantane); 1.54(s, 2xCH)) (ii) a 1.83-2.19(m, 9H-adamantane); 2.32(s, CH))；3.78(s，CH) (ii) a 3.92(d, CH); 5.36(d, NH); 6.64, 6.74 and 6.78(3xs, 3H-aromatics)
			264	CDCl(ii) a δ 1.14-1.38(m, 4H-adamantane); 1.55(s, 2xCH)) (ii) a 1.62-1.99(m, 9H-adamantane, 2xCH))；2.32(s，CH)；2.36(t，CH)；2.60(t，CH) (ii) a 3.90(d, CH); 5.40(d, NH); 6.85-7.10(m, 3H-aromatic)
265	CDCl(ii) a δ 1.61-2.22(m, 14H-adamantane); 7.60-8.00(m, 5H-aromatic); 8.42(d, H-arom.)
			266	CDCl(ii) a δ 1.58-2.04(m, 14H-adamantane); 3.21(d, CH)) (ii) a 5.39(d, NH); 7.63-7.87(m, 5H-aromatic); 8.46(d, H-arom.)
267	CDCl(ii) a δ 1.64 and 1.97 and 2.05(2xbrs, 14H-adamantane); 2.70-2.89(m, CH))；3.09(t，CH) (ii) a 4.40(s, CH); 6.93-7.19(m, 4H-aromatic); 7.50(m, NH)
			268	CDCl(ii) a δ 1.39-1.97(m, 14H-adamantane); 2.73-2.97(m, 2xCH))；3.11(m，CH) (ii) a 4.59(s, CH); 7.07-7.54(m, 4H-aromatic)
269	LCMS retention time: 6.27min., M＝411；100％
			275	CDCl: 1.23-1.46(m, 5H-adamantane), 1.60(s, 2xCH)) 1.72(m, 4H-adamantane), 1.85(d, 2H-adamantane); 2.03(brs, 3H-adamantane); 2.35(s, CH)) (ii) a 3.96(d, CH); 5.48(d, NH); 7.50, 8.38 and 3.48(3xd, 3H-aromatic)

276	CDCl: 1.43(d, 3H-adamantane); 1.62(s, 2xCH)) (ii) a 1.60-2.05(m, 10H-adamantane); 2.55(s, CH 3); 3.92(d, CH); 7.04 and 7.22(2xd, 2H-aromatic); 7.56(t, H-aromatic); 8.33(d, NH)
			277	CDCl(ii) a 1.25-1.49(m, 4H-adamantane); 1.45(s, 3 xCH))；1.54(s，2xCH) (ii) a 1.64-2.04(m, 10H-aromatic, CH)) (ii) a 2.43(s, CH 3); 2.60 and 2.91(2xt, 2xCH)) (ii) a 3.22-3.57(m, 8 h-homopiperidine); 3.92(d, CH); 5.47(d, NH); 6.95 and 7.04(2xs, 3H-aromatics).

C. Pharmacological test

Example c.1: test Compounds for Activity on type 1 and type 2 11 b-hydroxysteroid dehydrogenase Sexual enzyme assay

Effect of Compounds on 11-dehydro-17-hydroxycorticosterone-to-cortisol 11b-HSD 1-dependent conversion (reductase activity) Studies were performed in a reaction mixture (final volume 100. mu.L) containing 30mM Tris-HCl buffer, pH 7.2, 180. mu.M NADPH, 1mM DTA, 2. mu.M 11-dehydro-17-hydroxycorticosterone, 1. mu.L of drug and/or solvent, and 11. mu.g of recombinant protein.

Study of the Effect of 11b-HSD 1-deoxyenzyme activity (conversion of Cortisol to 11-dehydro-17-Hydrocotrione) was performed in a reaction mixture (final volume 100. mu.L) containing 0.1M sodium phosphate buffer, pH 9.0, 300. mu. MNADP, 25. mu.M Cortisol, 1. mu.L of drug and/or solvent and 3.5. mu.g recombinant protein.

Study of the Effect of Compounds on 11b-HSD 2-dependent dehydrogenase activity, was performed in a reaction mixture (final volume 100. mu.L) containing 0.1M sodium phosphate buffer, pH7.5, 300. mu.M NAD, 100nM cortisol (2 nM of which is radiolabeled with 3H), 1. mu.L of drug and/or solvent, and 2.5. mu.g recombinant protein.

All incubations were carried out in a 37 ℃ water bath for 45 minutes. The reaction was stopped by adding 100 μ L acetonitrile containing 20 μ g corticosterone as an internal standard. After centrifugation, the product formed was analyzed by HPLC in the supernatant using 0.05mM ammonium acetate/methanol (50/50) as solvent on a Hypersyl BDS-C18 column. In all of the above experiments, all test drugs were taken from stock solutions and tested at 10^-5M-3.10^-9Final concentration of M was tested. From the resulting dose response curve, pIC50 values were calculated and evaluated as follows: score 1 ═ pIC50 values < 5, score 2 ═ pIC50 values between 5 and 6, and score 3 ═ pIC50 values > 6. Part of the data thus obtained are listed in the following table (NT in the table indicates no test).

Example c.2: test Compounds for Activity on type 1 and type 2 11 b-hydroxysteroid dehydrogenase Sexual cell assay

The effect on 11b-HSD1 activity was tested in different 3T3-L1 cells and rat hepatocytes.

Mouse fibroblast 3T3-L1 cells (ATCC-CL-173) were seeded at a density of 16500 cells/ml in 12-well plates and at 37 ℃ in 5% CO₂In DMEM medium (supplemented with 10% heat-inactivated fetal bovine serum, 2mM glutamine and 25mg gentamicin) for 7 days. The medium was refreshed twice weekly. Fibroblasts at 37 ℃ in growth medium containing 2. mu.g/mL insulin, 55. mu.g/mL IBMX, and 39.2. mu.g/mL dexamethasone₂The humidified air is divided into fat cells.

Primary hepatocytes from male rats were seeded at a density of 250000 cells/well on BD-Biocoat Matrigel matrix multi-well plates and incubated at 37 ℃ in 5% CO₂Incubation was carried out in humidified air for 10 days in DMEM-HAM' F12 medium containing 5% Nu serum, 100U/ml penicillin, 100. mu.g/ml streptomycin, 0.25. mu.g/ml amphotericin B, 50. mu.g/ml gentamicin sulfate, 5. mu.g/ml insulin and 392ng/ml dexamethasone. The medium was refreshed 3 times per week.

After 4 hours of pre-incubation of the test compounds, 0.5. mu. Ci was added to the cultures³H-11-dehydro-17-hydroxy-corticosterone or dehydrocorticosterone. After 1 hour, the medium is in Extrelt³The column was extracted with 15ml of diethyl ether and the extract was analyzed by HPLC as described above.

Effect of Compounds on 11b-HSD2 Activity Studies were performed in HepG2 and LCC-PK 1-cells. HepG2 cells (ATCC HB-8065) were seeded at a density of 100,000 cells/ml in 12-well plates and at 37 ℃ in 5% CO₂The cells were cultured in MEM-Rega-3 medium (supplemented with 10% heat-inactivated fetal bovine serum, 2mM L-glutamine and sodium bicarbonate) in a humidified atmosphere. The medium was refreshed 2 times per week.

Porcine kidney cells (LCC-PK1, ATCC CRL-1392) were seeded at a density of 150,000 cells/ml in 12-well plates and at 37 ℃ in 5% CO₂Cultures were grown in Medium 199 (supplemented with Earls modified saline, 100U/ml penicillin, 100 μ g/ml streptomycin and 10% fetal bovine serum) in humidified air. The medium was refreshed 2 times per week.

24 hours before the start of the experiment, the medium was replaced with a medium containing 10% charcoal-adsorbed fetal calf serum.

After 4 hours of pre-incubation of the test compounds, 0.5. mu. Ci was added to the cultures³H-cortisol or corticosterone. After 1 hour, the medium is in Extrelt³The column was extracted with 15ml of diethyl ether and the extract was analyzed by HPLC as described above.

For the enzyme assay, test compounds were taken from stock solutions and tested at 10^-5M-3.10^-9Final concentration of M was tested. From the resulting dose response curve, pIC50 values were calculated and evaluated as follows: score 1 ═ pIC50 values < 5, score 2 ═ pIC50 values between 5 and 6, and score 3 ═ pIC50 values > 6. Part of the data thus obtained are listed in the following table (NT in the table indicates no test).

D. Composition examples

The following formulations are given as examples of typical pharmaceutical compositions of the invention suitable for systemic or local administration to a test animal or human.

The "active ingredient" (a.i.) used in these examples represents a compound of formula (I) or a pharmaceutically acceptable addition salt thereof.

Example d.1: film coated tablet

Preparation of the tablet core

A mixture of a.i. (100g), lactose (570g) and starch (200g) was mixed thoroughly and then moistened with a solution of sodium lauryl sulfate (5g) and polyvinylpyrrolidone (10g) in about 200ml of water. The wet meal mixture was sieved, dried and sieved again. Then microcrystalline cellulose (100g) and hydrogenated vegetable oil (15g) were added thereto. All components were mixed thoroughly and compressed to give 10,000 tablets containing 10mg of active ingredient per tablet.

Coating film

To a solution of methylcellulose (10g) in denatured ethanol (75ml) was added a solution of ethylcellulose (5g) in methylene chloride (150 ml). Methylene chloride (75ml) and 1, 2, 3-propanetriol (2.5ml) were then added thereto. Polyethylene glycol (10g) was melted and dissolved in dichloromethane (75 ml). The latter solution was added to the former solution and magnesium octadecanoate (2.5g), polyvinylpyrrolidone (5g) were added, the coloured suspension was concentrated (30ml) and homogenized. The tablet cores are coated with the mixture thus obtained in a coating device.

Claims (16)

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

pharmaceutically acceptable addition salts thereof and stereoisomers thereof, wherein

n represents an integer of 1, and n represents an integer of 1,

m represents an integer of 0, and m represents,

R¹and R²Independently of one another represent C_1-4Alkyl radical(ii) a Or

R¹And R²Together with the carbon atom to which they are attached form C_3-6A cycloalkyl group;

R³is represented by C_6-12Cycloalkyl or a monovalent group having one of the following formulae:

wherein said C_6-12The cycloalkyl or monovalent group may be optionally substituted with 1 or more substituents selected from the group consisting of: c_1-4Alkyl radical, C_1-4Alkoxy, halogen, hydroxy or 1, 3-dioxolyl;

R⁴represents hydrogen;

q represents Ar²Wherein Ar is²Optionally substituted with 1 or more substituents selected from the group consisting of: halogen, C_1-4Alkyl radical, C_1-4Alkoxy, hydroxy, C_1-4Alkoxycarbonyl, NR⁵R⁶Is selected from 1 or 2 or 3 independently from hydroxycarbonyl, Het²And NR⁷R⁸C substituted by a substituent of_1-4An alkoxy group,

is substituted by 1 member selected from phenyl-C_1-4Alkoxycarbonyl or Het⁵C substituted by a substituent of a carbonyl group_2-4An alkenyl group, which is a radical of an alkenyl group,

and is selected from 1 or 2 or 3 independently from halo, dimethylamino, amino, cyano, Het⁶、Het⁷-C substituted by a substituent of carbonyl or hydroxycarbonyl_1-4An alkyl group;

R⁵and R⁶Independently of one another, selected from: hydrogen, C_1-4Alkyl radical, C_1-4Alkylcarbonyl, C substituted by 1 or 2 or 3 halogen substituents_1-4An alkylcarbonyl group;

R⁷and R⁸Independently of one another, selected from: hydrogen or C_1-4An alkyl group;

Het²represents a monocyclic heterocycle selected from the group consisting of: piperazinyl or morpholinyl radical, the Het²Optionally substituted by 1 or more C_1-4Alkyl substituent group substitution;

Het⁵represents morpholinyl;

Het⁶represents a monocyclic heterocycle selected from the group consisting of: piperazinyl or morpholinyl radical, the Het⁶Optionally substituted with 1 or more hydroxyl groups;

Het⁷represents a monocyclic heterocycle selected from the group consisting of: pyridazinyl or morpholinyl radicals, the compounds mentioned⁷Optionally substituted by 1 or more groups independently selected from hydroxy, C_1-4Alkyl or C_1-4Substituent substitution of alkoxy;

Ar²represents a phenyl group.

2. A compound according to claim 1, wherein said Het⁶Substituted by 1 hydroxyl group.

3. A compound according to claim 1, wherein said Het⁷Represents a morpholino group.

4. A compound according to claim 1 or 3, wherein:

R³is represented by C_6-12Cycloalkyl or a monovalent group having one of the following formulae:

wherein said C_6-12The cycloalkyl or monovalent group may be optionally substituted with 1 or more substituents selected from the group consisting of: c_1-4Alkyl radical, C_1-4Alkoxy, halogen, hydroxy or 1, 3-dioxolyl;

q represents Ar²Wherein Ar is²Optionally substituted with 1 or more substituents selected from the group consisting of: halogen, C_1-4Alkyl radical, C_1-4Alkoxy, hydroxy, C_1-4Alkoxycarbonyl, NR⁵R⁶Is selected from 1 or 2 or 3 independently from hydroxycarbonyl, Het²And NR⁷R⁸C substituted by a substituent of_1-4Alkoxy, and is substituted by 1 or 2 or3 are independently selected from halo, dimethylamino, amino, cyano, Het⁶、Het⁷-C substituted by a substituent of carbonyl or hydroxycarbonyl_1-4An alkyl group;

R⁵and R⁶Independently of one another, selected from: hydrogen, C_1-4Alkyl radical, C_1-4Alkylcarbonyl, C substituted by 1 or 2 or 3 halogen substituents_1-4An alkylcarbonyl group;

R⁷and R⁸Independently of one another, selected from: hydrogen or C_1-4An alkyl group;

Het²represents a monocyclic heterocycle selected from the group consisting of: piperazinyl or morpholinyl radical, the Het²Optionally substituted by 1 or more C_1-4Alkyl substitution;

Het⁵represents morpholinyl;

Het⁶represents a monocyclic heterocycle selected from piperazinyl or morpholinyl, said Het⁶Optionally substituted with 1 or more hydroxyl groups;

Ar²represents a phenyl group.

5. A compound according to claim 4, wherein Het⁶Optionally substituted with 1 hydroxy group.

6. A compound according to any one of claims 1-3, wherein:

R³is represented by C_6-12Cycloalkyl, or a monovalent group having one of the following formulae:

wherein said C_6-12The cycloalkyl or monovalent group may be optionally substituted with 1 or more substituents selected from the group consisting of: c_1-4Alkyl radical, C_1-4Alkoxy, halogen or hydroxy;

q represents Ar²Wherein Ar is²Optionally substituted with 1 or more substituents selected from the group consisting of:

halogen, C_1-4Alkyl radical, C_1-4Alkoxy, hydroxy, NR⁵R⁶，

Is selected from 1 or 2 or 3 independently from hydroxycarbonyl, Het²Or NR⁷R⁸C substituted by a substituent of_1-4An alkoxy group,

is selected from phenyl-C_1-4Alkoxycarbonyl or Het⁵C substituted by one substituent of a carbonyl group_2-4An alkenyl group, which is a radical of an alkenyl group,

and is substituted by 1 or 2 or 3 substituents selected from halogen, Het⁶Or C substituted by a substituent of hydroxycarbonyl_1-4An alkyl group;

R⁵and R⁶Independently of one another, hydrogen or C_1-4An alkyl group;

R⁷and R⁸Independently of one another, hydrogen or C_1-4An alkyl group;

Het²represents morpholinyl;

Het⁶represents morpholinyl;

Ar²represents a phenyl group.

7. The compound of claim 6, wherein R³Represents a cyclooctyl group.

8. A compound according to any one of claims 1-3, wherein

R³Is represented by C_6-12Cycloalkyl, or R³Represents a monovalent group having one of the following formulae:

wherein said C_6-12The cycloalkyl or monovalent group may be optionally substituted with 1 or more substituents selected from the group consisting of: c_1-4Alkyl radical, C_1-4Alkoxy, halogen or hydroxy;

R⁴represents hydrogen;

q represents Ar²Wherein Ar is²Optionally substituted by 1 or more groups selected fromAnd (3) substituent: halogen, C_1-4Alkyl radical, C_1-4Alkoxy, hydroxy, NR⁵R⁶，

Is selected from 1 or 2 or 3 independently from hydroxycarbonyl, Het²Or NR⁷R⁸C substituted by a substituent of_1-4An alkoxy group,

by 1 phenyl-C_1-4Alkoxycarbonyl substituted C_2-4An alkenyl group, which is a radical of an alkenyl group,

and is substituted by 1 or 2 or 3 substituents selected from halogen, Het⁶、Het⁷-C substituted by a substituent of carbonyl or hydroxycarbonyl_1-4An alkyl group;

R⁵and R⁶Independently of one another, hydrogen or C_1-4An alkyl group;

Het²represents morpholinyl;

Het⁶represents a monocyclic heterocycle selected from piperazinyl or morpholinyl;

Ar²represents a phenyl group.

9. The compound of claim 8, wherein R³Represents a group selected from cyclooctyl or cyclohexyl.

10. The compound of claim 8, wherein Het⁶Represents a morpholino group.

11. The compound of any one of claims 1-3, wherein the compound is:

(1 α,2 β,3 β,5 β, 7 β) -N- (5-hydroxytricyclo [3.3.1.13, 7] decan-2-yl) - α, α -dimethyl-3- [2- (4-morpholinyl) ethoxy ] -phenylacetamide;

n- (tricyclo [3.3.1.13, 7] decan-2-yl) - α, α -dimethyl-3- (carboxymethoxy) -phenylacetamide;

n- (tricyclo [3.3.1.13, 7] decan-2-yl) - α, α -dimethyl-3-hydroxy-phenylacetamide;

n- (tricyclo [3.3.1.13, 7] decan-2-yl) - α, α -dimethyl-3, 5-dimethyl-phenylacetamide;

3- (3- {2- [ (5-fluoro-2-adamantyl) amino ] -1, 1-dimethyl-2-oxoethyl } -5-methylphenyl) propionic acid; or

A pharmaceutically acceptable addition salt thereof or a stereoisomer thereof.

12. A compound according to any one of claims 1 to 3, which is a compound of formula (I'),

pharmaceutically acceptable addition salts thereof and stereoisomers thereof, wherein:

R¹and R²Independently of one another represent C_1-4An alkyl group; or

R¹And R²Together with the carbon atom to which they are attached form C_3-6A cycloalkyl group;

R⁴represents hydrogen;

u represents hydrogen, C_1-4Alkyl radical, C_1-4Alkoxy, halogen or hydroxy;

R⁵and R⁶Independently of one another, hydrogen and C_1-4Alkyl radical, C_1-4Alkylcarbonyl, C substituted with 1 or 2 or 3 substituents independently selected from halogen_1-4An alkylcarbonyl group;

R¹¹and R¹²Independently of one another, from hydrogen, halogen, C_1-4Alkyl radical, C_1-4Alkoxy, hydroxy, NR⁵R⁶Is selected from 1 or 2 or 3 independently of one another from hydroxycarbonyl, Het²And NR⁷R⁸C substituted by a substituent of_1-4Alkoxy, selected from phenyl-C_1-4Alkoxycarbonyl, Het⁵C substituted by one substituent of a carbonyl group_2-4Alkenyl, and substituted by 1 or 2 or 3 substituents independently of one another from the group consisting of halogen, dimethylamino, amino, cyano, Het⁶、Het⁷-C substituted by a substituent of carbonyl or hydroxycarbonyl_1-4An alkyl group;

Het²represents a monocyclic heterocycle selected from the group consisting of: piperazinyl or morpholinyl radical, the Het²Optionally with 1 or moreIndependently selected from C_1-4Alkyl substituent substitution;

Het⁵represents morpholinyl;

Het⁶represents a monocyclic heterocycle selected from morpholinyl;

Het⁷represents a monocyclic heterocycle selected from morpholinyl, said Het⁷Optionally substituted by 1 or more groups independently selected from hydroxy, C_1-4Alkyl or C_1-4Substituent of alkoxy.

13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, 11 β -HSD1 inhibiting effective amount of a compound as claimed in any one of claims 1 to 12.

14. A process for preparing a pharmaceutical composition according to claim 13, wherein: a pharmaceutically acceptable carrier in intimate admixture with 11 β -HSD1 in an inhibitory effective amount of a compound as claimed in any one of claims 1 to 12.

15. The use of a compound according to any one of claims 1 to 12 in the manufacture of a medicament for the treatment of a disease associated with excess cortisol formation.

16. The use as claimed in claim 15, wherein the disease is selected from obesity, diabetes, cardiovascular diseases associated with obesity, dementia, cognitive assessment, osteoporosis and glaucoma.