# Patent

## Title
Inhibitor compounds of 11-beta-hydroxysteroid dehydrogenase type 1

## Abstract

The compounds of formula (I) are derived from perhydroquinoline and perhydroisoquinoline and are useful as active pharmaceutical ingredients for the prophylaxis or treatment of diseases caused by 11-beta-hydroxysteroid dehydrogenase type 1 (11-beta-HSD1) enzyme-associated disorders, such as glaucoma, elevated ocular pressure, metabolic disorders, obesity, metabolic syndrome, dyslipidemia, hypertension, diabetes, atherosclerosis, Cushing's syndrome, psoriasis, rheumatoid arthritis, cognitive disorders, Alzheimer's disease or neurodegeneration.

## Background
This application is a §371 national stage application of PCT International Application No. PCT International Application No. PCT/ES2010/000,258, filed Jun. 4, 2010, claiming priority of Spanish Patent Application No. P200901402, filed Jun. 4, 2009, the contents of all of which are hereby incorporated by reference into this application.
The present invention relates to perhydroquinoline and perhydroisoquinoline derivatives and methods of treating certain diseases using such compounds.
STATE OF THE ART
Glucocorticoids (cortisol in humans, corticosterone in mice and rats) are an important adrenocorticosteroid group regulating many metabolic and homeostatic processes and form a key element of stress response. Glucocorticoids act through the intracellular glucocorticoid receptors and, in some tissues, through mineralocorticoid receptors, both being nuclear transcription factors. The action of glucocorticoids on the target tissues depends not only on circulating steroid concentrations and the cellular expression of the receptors, but also on the intracellular enzymes which critically determine up to what point the glucocorticoids will have active access to the receptors. The 11-beta-hydroxysteroid dehydrogenases (11-beta-HSD) catalyze the interconversion between the main active 11-hydroxy-glucocorticoid (cortisol in man) and its inactive 11-keto metabolites (cortisone in man).
The 11-beta-hydroxysteroid dehydrogenase type 1 (11-beta-HSD1) enzyme reconverts inactive glucocorticoids into active ones, thus playing an important role in modulating cellular agonist concentration and, therefore, in activating corticosteroid receptors in the target tissues. It has been described that the overexpression of 11-beta-HSD1 in mice adipocytes leads to visceral obesity and to the phenotype similar to that of the metabolic syndrome. Collectively, these data significantly confirm the important role of 11-beta-HSD1 in inducing obesity and the disequilibrium of glucose homeostasis and lipid parameters. Therefore, the selective inhibition of this enzyme could reduce the levels of blood glucose in type 2 diabetes patients, normalize the elevated lipid parameters and/or reduce the weight of obese subjects.
The first pharmacological indication that the inhibition of 11-beta-HSD1 in man could have beneficial effects has been achieved by using carbenoxolone, an anti-ulcer drug which inhibits both 11-beta-HSD1 and the similar 11-beta-HSD2 enzyme. Treatment with carbenoxolone increases the sensitivity to insulin, which indicates that the inhibition of 11-beta-HSD1 can reduce the levels of cortisol in the cells and therefore minimize some of its damaging effects.
Studies conducted with the non-specific carbenoxolone inhibitor clearly show the importance of developing 11-beta-HSD1 specific inhibitors. Inhibition of the 11-beta-HSD2 enzyme is poorly tolerated and increases blood pressure. In contrast, inhibition of 11-beta-HSD1 would be well tolerated because it has been observed that the 11-beta-HSD1 knockout mice are healthy and resist hyperglycemia caused by obesity or stress (cf. Kotelevtsev et al., Proc. Natl. Acad. Sci. USA 1997, vol. 94, pp. 14924-14929). Other studies indicate that 11-beta-HSD1 inhibitors can also be beneficial for reducing high blood pressure (cf. Masuzaki et al., J. Clin. Invest. 2003, vol. 112, pp. 83-90), for reducing intraocular pressure (cf. Rauz et al., Q J Med 2003, vol. 96, pp. 481-490), for improving cognitive capacity (cf. Sandeep et al., Proc Natl Acad Sci. USA 2004, vol. 101, pp. 6734-6739) or for improving deficiencies associated with Alzheimer's disease. Overall, inhibition of 11-beta-HSD1 can be a safe and effective strategy for treating symptoms of glaucoma, diabetes, obesity and other diseases.
Glucocorticoids increase the risk of glaucoma by increasing intraocular pressure when they are exogenously administered and in certain conditions of increased production such as Cushing's syndrome. The increase of intraocular pressure induced by corticosteroids is caused by an increased resistance to the aqueous efflux due to changes induced by glucocorticoids.
11-beta-HSD1 is expressed in corneal epithelium basal cells and non-pigmented epithelial cells. The mRNA of the glucocorticoid receptor has been detected in the trabecular reticulum, whereas mRNA for the glucocorticoid receptor, the mineralocorticoid receptor and 1-beta-HSD1 was present in non-pigmented epithelial cells. The administration of carbenoxolone to patients resulted in a significant reduction in intraocular pressure (cf. Rauz et al., Invest. Ophtalmol. Vis. Sci. 2001, vol. 42, pp. 2037-2042), which suggests a role for HSD1 inhibitors in the treatment of glaucoma.
The expression of 11-beta-HSD isoenzymes in human and rodent eyes has been described (cf. Stokes et al., Invest Ophthalmol Vis Sci. 2000, vol. 41, pp. 1629-1638), particularly 11-beta-HSD1 in ciliary epithelial cells, which suggests the possibility of a role in producing aqueous humor and in regulating intraocular pressure. In aqueous humor, cortisol concentrations are approximately 14 times greater than those of cortisone. This suggests to a large extent predominant 11-beta-reductase HSD1 activity. In a double blinded controlled study with glaucoma patients it was observed that treatment with carbenoxolone significantly reduces intraocular pressure therefore 11-beta-HSD1 inhibitors can represent a therapeutic strategy suitable for treating glaucoma.
Document WO2007026920 describes N-arylamide compounds and related compounds as Rho kinase (ROCK) inhibitors, as well as pharmaceutical compositions and the use thereof in treating diseases related to ROCK.




Document WO2006106423 describes N-pyridyl heterocyclylsulfonamide compounds and the use thereof as 11-beta-HSD1 modulators.




Document WO2006048330 describes N-benzylsulfonamide compounds and related derivatives as 11-beta-HSD1 inhibitors, pharmaceutical compositions and the use thereof in therapy.




Document WO2003045367 describes compounds derived from pyridylalkylurea, some of which are structurally similar to those of the present invention but with a different use.




Nevertheless, providing new 11-beta-HSD1 inhibitor compounds is desirable.


DESCRIPTION OF THE INVENTION
The present invention provides new compounds derived from perhydroquinoline and perhydroisoquinoline of formula (I) which are effective as 11-beta-HSD1 inhibitors and have selectivity for 11-beta-HSD1 with respect to 11-beta-HSD2.
Thus, a first aspect of the invention refers to compounds of formula (I)




and pharmaceutically acceptable salts thereof, wherein:
s and p are an integer selected in an opposite manner between 0 and 1, such that when s is 1, p is 0 (to form a perhydroquinoline) and when s is 0, p is 1 (to form a perhydroisoquinoline).
Y is a biradical selected from CO, CS and SO2,
W1 and W2 can be independently a bond or a biradical selected from O, S and NR1, wherein R1 is optionally H, C1-4 alkyl or C3-10 cycloalkyl,
n is an integer selected from 0, 1, 2, 3 and 4,
V is a radical selected from —CO-T, —CS-T and —SO2-T or a radical selected from:




T is a group selected from NR2R3, R2, OR2 and SR2; or a group selected from




wherein R2 and R3 are independently selected from H, COR4, SO2R4, C1-4 alkyl, aryl, benzyl, phenethyl, C2-4 alkenyl, C2-4 alkynyl, C3-10 cycloalkyl or heterocycle
wherein when R2 or R3 is an alkyl or an alkenyl these can be optionally substituted with one or several substituents independently selected from F, OR4, NR4R5, COOR4, CONR4R5, C3-10 cycloalkyl, aryl and heterocycle;
wherein when R2 or R3 is an aryl, a benzyl, a phenethyl, a cycloalkyl or a heterocycle, these can be optionally substituted with one or several substituents independently selected from NH2, F, Cl, CN, NO2, COOH, R4, COOR4, OR4, OCF3, SH, SR4, CONR4R5, SO2NR4R5, COR4, NR1COR4, OCOR4, SOR4, SO2R4 and heterocycle,
wherein when R2 or R3 is a cycloalkyl this can be optionally substituted with one or several benzene rings fused with the cycloalkyl, the benzene could be optionally substituted with one or several substituents independently selected from alkyl, alkoxide or halogen,
wherein R4 and R5 are independently selected from H, C1-4 alkyl, aryl, benzyl, phenethyl, C2-4 alkenyl, C2-4 alkynyl, C3-10 cycloalkyl and heterocycle
wherein optionally R4 and R5 can be bound to one another forming a 3 to 8 membered cycle.
R6, R7, R8 and R9 are independently selected from H, OR4, F and Cl,
R10 is independently selected from H, OH, F, C1-4 alkyl, COOR11, COR11, phenyl, benzyl, benzhydryl, C2-4 alkenyl, C2-4 alkynyl, C3-10 cycloalkyl and heterocycle, and wherein the alkyl, phenyl, benzyl, benzhydryl, cycloalkyl or heterocycle can be optionally substituted with one or several substituents independently selected from NH2, F, Cl, NO2, COOH, COOR4, OR4, CF3, SH, SR4, CONR4R5, SO2NR4R5, COR4, NR1COR4, OCOR4, SOR4, SO2R4 and C1-4 alkyl;
and R11 is selected from H, C1-4 alkyl, aryl and C3-10 cycloalkyl.
In a particular embodiment of the invention, s is 0 and p is 1. In another particular embodiment of the invention, s is 1 and p is 0.
In another particular embodiment of the invention, Y is selected from CO and SO2.
In another particular embodiment of the invention, W1 and W2 are independently selected from a bond, S and NR1. In another particular embodiment of the invention, R1 is H.
In another particular embodiment of the invention, V is selected from —CO-T, —CS-T and —SO2-T.
In another particular embodiment of the invention, V is selected from




In another particular embodiment of the invention, R2 and R3 are independently selected from H, COR4, SO2R4, C1-4 alkyl, phenyl, naphthyl, benzyl, phenethyl, C2-4 alkenyl, C3-10 cycloalkyl, and heterocycle, particularly, 2-furanyl, 2-thiophenyl, 2-(1-methylindole), quinoline, isoquinoline, 2-benzofuranyl.
In another particular embodiment of the invention, when R2 or R3 are independently C1-4 alkyl or C2-4 alkenyl, R2 or R3 can be optionally substituted with one or several substituents independently selected from F, OR4, NR4R5, COOR4, CONR4R5, phenyl, C3-10 cycloalkyl, hexenyl, naphthyl and heterocycle, particularly pyridine, 3-(1-methylindole), 3-thiophenyl and 2-furanyl.
In another particular embodiment of the invention, when R2 or R3 are independently phenyl, benzyl, phenethyl or C3-10 cycloalkyl, R2 or R3 can be optionally substituted with one or several substituents independently selected from F, Cl and OR4.
In another particular embodiment of the invention, when R2 or R3 is a cycloalkyl this can be optionally substituted with one or several benzene rings fused with the cycloalkyl, the benzene could be optionally substituted with one or several substituents independently selected from alkyl, alkoxide or halogen.
In another particular embodiment of the invention, R4 and R5 are independently selected from C1-4 alkyl, benzyl, phenethyl and phenyl.
In another particular embodiment of the invention, R4 and R5 can be optionally bound to one another forming a 3 to 8 membered cycle.
In another particular embodiment of the invention, R6, R7, R8 and R9 are independently selected from H, OR4, F and Cl.
In another particular embodiment of the invention, R10 is selected from H, OH, F, C1-4 alkyl, COOR11, COR11, phenyl, benzyl and benzhydryl.
In another particular embodiment of the invention, R10 is selected from phenyl, benzyl and benzhydryl, all of them optionally substituted with one or several substituents, independently selected from F, OR4, CF3, COR4 and C1-4 alkyl.
In another particular embodiment of the invention, R11 is selected from H and C3-10 cycloalkyl.
In another particular embodiment, T is selected from NR2R3, R2, OR2 and SR2.
In another particular embodiment, T is selected from




A second aspect of the present invention refers to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament, particularly for the prophylaxis or treatment of diseases caused by 11-beta-HSD1-associated disorders, particularly glaucoma, elevated ocular pressure, metabolic disorders, obesity, metabolic syndrome, dyslipidemia, hypertension, diabetes, particularly type II diabetes, atherosclerosis, Cushing's syndrome, psoriasis, rheumatoid arthritis, cognitive disorders, Alzheimer's disease or neurodegeneration, preferably for the prophylaxis or treatment of glaucoma or metabolic syndrome.
Another aspect of the present invention refers to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicaments intended for the prophylaxis or treatment of diseases caused by 11-beta-HSD1-associated disorders, particularly one of the disorders mentioned above.
Another aspect of the present invention refers to a method of prophylaxis or treatment of an individual who is suffering or is susceptible to suffering a disease caused by 11-beta-HSD1-associated disorders, particularly one of the disorders mentioned above, which comprises administrating to said individual a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable excipients.
The compounds of formula (I) and the pharmaceutically acceptable salts thereof, particularly the compounds of formula (I) described as examples or as intermediates are preferred.
The compounds of the present invention can be used alone or in combination with one or more compounds which are useful for the prophylaxis or treatment of diseases such as glaucoma, elevated ocular pressure, metabolic disorders, such as obesity, metabolic syndrome, dyslipidemia, hypertension and/or diabetes, particularly type II diabetes, atherosclerosis, Cushing's syndrome, psoriasis, rheumatoid arthritis, cognitive disorders, Alzheimer's disease and/or neurodegeneration.
The term “C1-4 alkyl”, alone or in combination, means a linear- or branched-chain alkyl group having 1 to 4 carbon atoms.
The terms “C2-4 alkenyl”, and “C2-4 alkynyl”, alone or in combination, mean a linear- or branched chain radical having 2 to 4 carbon atoms and having one or more unsaturated bonds.
The term “C3-10 cycloalkyl”, alone or in combination, refers to a stable monocyclic, bicyclic or tricyclic radical of 3 to 10 members, which is saturated or partially saturated, and which only consists of carbon and hydrogen atoms. Examples of C3-10 cycloalkyl are the following: cyclopropyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, cycloheptyl, cyclooctyl, 1-tricyclo[3.3.1.13,7]decanyl, 2-tricyclo[3.3.1.13,7]decanyl and 2-bicyclo[2.2.1]heptanyl. Unless otherwise specifically established in the specification, the term “cycloalkyl” refers to that including cycloalkyl radicals which are optionally substituted with one or more substituents such as alkyl, halogen, hydroxyl, amino, cyano, nitro, alkoxyl, carboxyl, alkoxycarbonyl, phenyl, etc.
The term “aryl”, alone or in combination refers to radicals of a single ring and multiple rings, including radicals of multiple rings containing separated and/or condensed aryl groups. The typical aryl groups contain 1 to 3 separated or condensed rings and from 6 to 18 carbon ring atoms, such as phenyl or naphthyl radicals, preferably a phenyl group optionally having one or several substituents, preferably from one to three, chosen independently from one another from halogen, trifluoromethyl, trifluoromethoxy, amino, alkyl, alkoxy, alkylcarbonyl, cyano, carbamoyl, alkoxycarbamoyl, methylenedioxy, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxy, nitro, alkyl-SO2—, amino-SO2—, cycloalkyl and the like. Phenyl or naphthyl is preferred, particularly phenyl optionally substituted from one to three times, preferably one or two times by substituents chosen independently from one another from alkyl, halogen, alkoxy, trifluoromethoxy, nitro and trifluoromethyl. Phenyl is particularly preferred.
The terms “benzyl” and “phenethyl”, can optionally have one or several substituents, chosen independently from one another from halogen, trifluoromethyl, trifluoromethoxy, amino, alkyl, alkoxy, alkylcarbonyl, cyano, carbamoyl, alkoxycarbamoyl, methylenedioxy, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxy, nitro, alkyl-SO2—, amino-SO2—, cycloalkyl and the like.
The term “heterocycle”, alone or in combination, means a saturated, partially unsaturated or aromatic, 5 to 10 membered heterocycle, containing one or several heteroatoms chosen between nitrogen, oxygen and sulfur. For the purposes of this invention, the heterocycle can be a monocyclic, bicyclic or tricyclic ring system which can include condensed ring systems. The heterocycle can be substituted on one or several carbon atoms e.g. by halogen, alkyl, phenyl, alkoxy, oxo, etc. and/or on a secondary nitrogen atom (i.e., —NH—) by alkyl, cycloalkyl, aralkoxycarbonyl, alcanoyl, phenyl or phenylalkyl or on a tertiary nitrogen atom (i.e., ═N—) by oxide, being especially preferred halogen, alkyl, cycloalkyl and alkoxy. Examples of heterocycle groups are pyrrolidinyl, piperidinyl, piperazinyl, azepine, morpholinyl, thiomorpholinyl, imidazolyl (e.g. imidazol-4-yl and 1-benzyloxycarbonylimidazol-4-yl), pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, hexahydropyrimidinyl, furyl, thienyl, thiazolyl, oxazolyl, indolyl (e.g. 2-indolyl), quinolyl (e.g. 2-quinolyl, 3-quinolyl and 1-oxide-2-quinolyl), isoquinolyl (e.g. 1-isoquinolyl and 3-isoquinolyl), tetrahydroquinolyl (e.g. 1,2,3,4-tetrahydro-2-quinolyl), 1,2,3,4-tetrahydroisoquinolyl (e.g. 1,2,3,4-tetrahydro-1-oxoisoquinolyl)benzimidazoyl, benzothiazoyl and quinoxalinyl. Preferred examples are thiophenyl, quinolyl, piperidyl, morpholyl, thiomorpholyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl and thiazolyl.
The term “pharmaceutically acceptable salts” means those salts which conserve the efficiency and the biological properties of the free bases or of the free acids and which are not disturbing in a biological sense or in any other sense.
According to the invention, the compounds of formula I and their pharmaceutically acceptable salts are useful for the prophylaxis or treatment of diseases caused by 11-beta-HSD1 enzyme-associated disorders.
Unless defined otherwise, all the technical and scientific terms used herein have the same meaning as those commonly understood by a person skilled in the field of the invention. Methods and materials which are similar or equivalent to those described herein can be used in practicing the present invention. Throughout the description and claims the word “comprises” and its variants do not aim to exclude other technical features, additives, components, steps or stereoisomers of the compounds involved. For the persons skilled in the art, other objects, advantages and features of the invention will be inferred partially from the description and partially from practicing the invention.
The compounds of formula (I) can be prepared following different methods known by any person skilled in the field of organic synthesis, particularly through the general processes shown in the following schemes. The starting materials for the preparative methods are commercially available or they can be prepared by means of methods of the literature. All of them started with perhydroquinoline but they are analogous for perhydroisoquinoline.




According to this method an acid-ester (IIa) is treated with decahydroquinoline in the presence of a suitable coupling agent, such as for example the combination of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) and 1-hydroxybenzotriazole (HOST), or by means of converting the acid to the corresponding acyl halide with a large variety of reagents such as thionyl chloride, sulfuryl chloride, oxalyl chloride, etc. In the presence of a tertiary base such as Et3N (Elmore, Amino Acids Pep. Proteins 2001, vol. 32, pp. 107-162) for obtaining the amide-ester intermediate (IIIa). The diamide (Ia) is obtained by means of a prior saponification of the compound (IIIa) in aqueous medium with bases of the LiOH type, NaOH type, etc. and subsequent formation of the diamide with any of the methods previously described for the intermediate (IIIa).




Scheme 2 shows the reaction of the decahydroquinoline with diphosgene or triphosgene and subsequent addition of amino-ester, hydroxy-ester or mercapto-ester type derivatives respectively providing the urea-ester, carbamate-ester or thiocarbamate-ester type intermediates. Subsequently a deprotection and coupling treatment similar to that described in scheme 1 for obtaining the amide derivatives is performed.




Scheme 3 shows a method for preparing the compounds amido-succinimide (Ic and Ik), amido-amide (Id), amido-sulfonamide (It) and amido-urea or amido-thiourea (Ie) of the present invention. The intermediate amine (Vc) can be prepared by means of two alternative methods: on one hand Gabriel synthesis with potassium phthalimide from the intermediate (IIIc) providing the compound (Ic) and subsequent treatment of this compound with hydrazine under EtOH reflux yielding the mentioned amine (Vc), optionally the intermediate (IIIc) is reacted with sodium azide generating alkyl azide (IVc) which provides the amine (Vc) by reduction.
The intermediate amine (Vc) can be converted both into amide (Id) and into sulfamide (It) by any of the methods previously described or into urea or thiourea (Ie) by means of reaction with an isocyanate or thioisocyanate, respectively. The compound of formula (Ik) can easily be prepared by condensing an anhydride of a 1,2-dicarboxylic acid of general formula (IIc) and the intermediate amine (Vc) previously described.




Scheme 4 shows a method for preparing the compounds of the present invention applying a combination of methods previously described in the schemes above to provide ureas and thioureas from decahydroquinoline with different terminal functionalities already described previously in scheme 3.




Scheme 5 shows a method for preparing the compounds of the present invention of amido-carbamate and amido-O-thiocarbamate type. The reduction of the intermediate ester (IIIa) to alcohol (IVj) by means of saponification of the ester, formation of a mixed anhydride and subsequent reduction thereof with sodium borohydride. The reaction of the alcohol (IVj) with isocyanate, thiocyanate, carbamoyl chloride or thiocarbamoyl chloride provides the carbamate or O-thiocarbamate (Ij).




Scheme 6 shows a method for preparing the compounds of the present invention of amido-S-thiocarbamate and amido-dithiocarbamate type. After the formation of the intermediate amide (IVp) by methods previously described and its subsequent reaction with isocyanate, thiocyanate, carbamoyl chloride or thiocarbamoyl chloride provides S-thiocarbamate or dithiocarbamate (Ip).




Scheme 7 shows a method for preparing the sulfonamide (Im) in which decahydroquinoline is reacted with the sulfonyl ester chloride (IIm). The deprotection and coupling treatment previously described in scheme 1 provides the sulfonamides (Im),
EXAMPLES
The following examples serve to better illustrate the invention but they must not be considered as limiting the same.
The nomenclature used in the present document is based on the Beilstein-Institut computer program known as AUTONOM (Automatic Nomenclature), which uses the systematic nomenclature of the IUPAC
Abbreviations:


    AcOEt ethyl acetate
    Brine saturated NaCl solution
    DCM dichloromethane
    DMF dimethylformamide
    DMSO dimethylsulfoxide
    EDC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
    Et3N triethylamine
    EtOH ethanol
    HOBT 1-hydroxybenzotriazole
    HPLC High performance liquid chromatography
    MeOH methanol
    MS Mass spectrometry
    m/z Mass/charge ratio
    rt Room temperature
    THF tetrahydrofuran
    TLC Thin layer chromatography
    tr Retention time
    UV Ultraviolet

General Data:



The products were analyzed using Agilent HPLC-UV-MS equipment provided with a UV detector of variable wavelength and a mass spectrometer model 1100 VL. The wavelength used for detecting UV was 210 nm, whereas the MS detector has been operated in a positive electrospray ionization mode and a 100 to 700 m/z scan has been performed. Concerning chromatographic separation, the column used was a Kromasil 100 C18, 40×4.0 mm, 3.5 μm, and 2-5 μl have been injected. For the elution one of the two solvent gradients described below was followed:
Method A: 5-90% B, 0-8 min; 90% B, 8-11 min; 5% B, 9-11 min. The flow rate of the mobile phase is 0.7 ml/min.
Method B: 5-90% B, 0-4.5 min; 90% B, 45-6 min; 5% B, 6-7 min. The flow rate of the mobile phase is 1.4 ml/min.
In both cases, the solvent A consists of 0.2% formic acid in water, whereas B is 0.2% formic acid in acetonitrile.
Alternatively, the analysis was conducted by means of Waters HPLC-UV-MS equipment provided with a detector having diodes in series and a mass spectrometer model EMDI000. The wavelength used for detecting UV was 210 nm, whereas the MS detector has been operated in a positive electrospray ionization mode and a 100 to 700 m/z scan has been performed. Concerning chromatographic separation, the column used was a Kromasil C18 2.1×50 mm, 3.5 μm and 2 μl have been injected. For the elution, the following gradient was followed:
The flow rate of the mobile phase is 0.5 ml/min.
Intermediate IIIa.1
ethyl 3-(octahydroquinolin-1-yl)-3-oxopropionate




3.38 mL of Et3N and 1.44 mL (11 mmol) of ethyl 3-chloro-3-oxopropionate are added to a solution of 1.5 mL (10 mmol) of decahydroquinoline in 100 mL of AcOEt. The resulting solution is kept under stirring at reflux for 10 h. Then water is added and the organic phase is separated, the aqueous phase is extracted once again with AcOEt. The organic phases are pooled and they are first washed with 5% solution of NaHCO3 and subsequently with brine, they are dried over anhydrous
Na2SO4, they are filtered and the solvent is evaporated under reduced pressure. 2.0 g of a yellow oil are obtained. It is identified as intermediate IIIa.1. Method A: tr: 6.76 min; m/z: 268.
Intermediate IIIa.2
6-(octahydroisoquinolin-2-yl)-6-oxohexanoic acid methyl ester




80 mL of AcOEt and, then, 3 mL (22 mmol) of Et3N are added to a mixture formed by 1.1 mL (8.32 mmol) of decahydroisoquinoline, 1.5 mL (10 mmol) of monomethyl adipate, 2 g (15 mmol) of HOBT and 2.9 g (15 mmol) of EDC. The solution formed is kept under stirring for 18 h. Then, it is treated with water and AcOEt, the organic phase is separated and the aqueous phase is extracted once more with AcOEt. The organic phases are pooled and they are washed successively with saturated NaHCO3 solution, 1N HCl and brine. It is then dried over anhydrous Na2SO4, it is filtered and the solvent is evaporated under reduced pressure. 1.5 g of an oil identified as intermediate IIIa.2 are obtained.
Method B: tr: 3.66 min/3.78 min; m/z: 282/282
The following intermediates were prepared in a manner similar to intermediates IIIa.1 or IIIa.2:















Int.
structure
name
method
tr (min) 
m/z







IIIa.3




(Octahydroquinolin-1-yl)oxoacetic acid ethyl ester
A
6.83
240


 


IIIa.4




3-(octahydroquinolin-1-yl)-3- oxopropionic acid ethyl ester
A
6.37
254


 


IIIa.5




5-(octahydroquinolin-1-yl)-5- oxopentanoic acid ethyl ester
A
6.96
282


 


IIIa.6




(Octahydroisoquinolin-2-yl)oxoacetic  acid ethyl ester
A
6.83 7.05
240 240


 


IIIa.7




3-(octahydroisoquinolin-2-yl)-3- oxopropionic acid methyl ester
A
5.86 6.09
240 240


 


IIIa.8




4-(octahydroisoquinolin-2-yl)-4- oxobutyric acid ethyl ester
A
6.72 6.92
268 268


 


IIIa.9




5-(octahydroisoquinolin-2-yl)-5- oxopentanoic acid ethyl ester
A
7.13 7.55
282 282


 


IIIa.10




6-(octahydroquinolin-1-yl)-6- oxohexanoic acid methyl ester
B
3.67
282









Intermediate IIIb.1
3-[(octahydroquinoline-1-carbonyl)amino]propionic acid methyl ester




Step 1:





2.5 g (18 mmol) of decahydroquinoline are dissolved in 150 mL of DCM and 2.7 g (9 mmol) of triphosgene are slowly added to the solution formed, preventing the temperature from exceeding 25° C. The resulting mixture is then refluxed for 18 h. It is then evaporated to dryness and the residue obtained is purified by means of silica gel filtration using AcOEt as eluent, obtaining 2 g of a yellowish oil identified as 1-chlorocarbonyloctahydroquinoline.
IR: 1729.
Step 2:
0.5 g (3.5 mmol) of the 3-aminopropionic acid methyl ester hydrochloride are dissolved in 5 mL of anhydrous THF and 0.9 mL of Et3N. Once dissolved, 650 mg of 1-chlorocarbonyloctahydroquinoline are slowly added and it is refluxed for 18 h. AcOEt is then added and the resulting solution is sequentially washed with water, 1N HCl and brine. The organic phase is dried over anhydrous Na2SO4, it is filtered and the solvent is evaporated under reduced pressure yielding 580 mg of intermediate IIIb.1.
Method B: tr: 3.17 min; m/z: 269.
The following intermediates were prepared in a manner similar to intermediate IIIb.1:















Int.
structure
name
method
tr (min)
m/z







IIIb.2




4-[(octahydroquinoline-1- carbonyl)amino]butyric acid methyl ester
B
3.29
283


 


IIIb.3




3-(octahydroisoquinoline-2-  carbonyl)amino]propionic acid methyl ester
B
3.29
269


 


IIIb.4




4-[(octahydroisoquinoline-2- carbonyl)amino]butyric acid methyl ester
B
3.40
283









Intermediate IIIb.5
3-(octahydroisoquinoline-2-carbonylsulfenyl)propionic acid methyl ester




Step 1:





2-chlorocarbonyloctahydroisoquinoline: it was prepared in a manner similar to that described for step 1 of intermediate IIIb.1. IR: 1737.
Step 2:
1 g (5 mmol) of 2-chlorocarbonyloctahydroisoquinoline is added to a 0° C. solution of 0.55 mL (5 mmol) of 3-mercaptopropionic acid methyl ester in 10 mL of pyridine. Once added, it is left under stirring at rt for 18 h. AcOEt is then added to the reaction mixture and it is sequentially washed with a 5% solution of NaHCO3, 1N HCl and brine. The organic phase is dried over anhydrous Na2SO4, it is filtered and the solvent is evaporated under reduced pressure being purified by means of silica gel column chromatography, using a (1:1) mixture of hexane:AcOEt as eluent, yielding 1.17 g of a residue identified as intermediate IIIb.5. and 210 mg of a solid identified as his-(octahydroisoquinolin-2-yl)methanone (Vb.1)




Method B: for IIIb.5 tr: 4.35 min; m/z: 286.

    
    
        for Vb.1: tr: 5.34 min; m/z: 305,
    
    


The following intermediates were prepared in a manner similar to intermediate IIIb.5:















Int.
structure
name
method
tr (min)
m/z







IIIb.6




3-(octahydroquinoline-1- carbonylsulfenyl)propionic  acid methyl ester
B
4.23
286


 


IIIb.7




4-(octahydroquinoline-1- carbonylsulfenyl)butyric acid benzyl ester
B
5.04
376


 


IIIb.8




4-(octahydroisoquinoline-2- carbonylsulfenyl)butyric acid benzyl ester
B
5.14
377









Intermediate IIIm.1
3-(octahydroquinoline-1-sulfonyl)propionic acid methyl ester




Step 1

4.48 mL (55.9 mmol) of sulfuryl chloride are added dropwise to a mixture formed by 2.47 mL (22.4 mmol) of methyl 3-mercaptopropionate and 5.64 g (55.9 mmol) of potassium nitrate cooled to 0° C. Once added it is left to reach rt keeping the stirring for 10 h. Saturated NaHCO3 solution is added and the organic phase is separated, which is subsequently washed again with NaHCO3 and then with brine. The organic phase is dried over anhydrous Na2SO4, it is filtered and the solvent is evaporated under reduced pressure yielding 2.6 g of an oil identified as the 3-chlorosulfonylpropionic acid methyl ester.
Method B: tr: 2.05 min; m/z: non ionizable.
Step 2
2.1 mL of Et3N (15.3 mmol) and subsequently, dropwise, 1.3 g (7 mmol) of the 3-chlorosulfonylpropionic acid methyl ester are added to a solution formed by 1.1 mL (7.6 mmol) of decahydroquinoline in 70 mL of AcOEt. The mixture is heated to 70° C. and that temperature is maintained for 12 h. It is then left to cool and water is added, the organic phase is separated and it is sequentially washed with 5% solution of sodium bicarbonate, 2N HCl and brine. The organic phase is dried over anhydrous Na2SO4, it is filtered and the solvent is evaporated under reduced pressure yielding 1.32 g of a reddish oil identified as intermediate IIIm.1.
Method B: tr: 3.36 min: m/z: 290
The following intermediates were prepared in a manner similar to intermediate IIIm.1:















Int.
structure
name
method
tr (min)
m/z







IIIm.2




4-(octahydroquinoline-1- sulfonyl)butyric acid methyl  ester
B
3.73
304


 


IIIm.3




3-(octahydroisoquinoline-2-  sulfonyl)propionic acid  methyl ester
B
3.79
290


 


IIIm.4




4-(octahydroisoquinoline-2- sulfonyl)butyric acid methyl  ester
B
3.83  3.91
304 304









Intermediate IVb.1
4-[(octahydroisoquinoline-2-carbonyl)amino]butyric acid




1.2 g (4.21 mmol) of intermediate IIIb.4 are dissolved in a mixture formed by 37.5 mL of THF and 12.5 mL of MeOH, and 5.1 mL of a 1M LiOH solution in water are added to the solution formed. The resulting mixture is kept under stirring at rt for 18 h. Then it is diluted in AcOEt and washed with water, the aqueous phase is acidified with a 1N solution of HCl until pH=3 and it is extracted with AcOEt. Finally, the organic phases are pooled, they are dried over anhydrous Na2SO4, they are filtered and the solvent is evaporated under reduced pressure. 570 mg of a white solid are obtained.
Method B: tr: 2.85 min/2.96 min; m/z: 269/269
The following intermediates were prepared in a manner similar to intermediate IVb.1:















Int.
structure
name
method
tr (min)
m/z







IVa.1




3-(octahydroquinolin-1-yl)-3- oxopropionic acid
A
5.18
226


 


IVa.2




4-(octahydroquinolin-1-yl)-4- oxobutyric acid
A
5.32
240


 


IVa.3




5-(octahydroquinolin-1-yl)-5- oxopentanoic acid
A
5.42
254


 


IVa.4




6-(octahydroisoquinolin-2-yl)-6- oxobutyric acid
B
3.08
268


 


IVa.5




(octahydroisoquinolin-2- yl)oxoacetic acid
A
4.25  4.40
212 212


 


IVa.6




3-(octahydroisoquinolin-2-yl)-3- oxopropionic acid
A
5.19 5.40
226 226


 


IVa.7




4-(octahydroisoquinolin-2-yl)-4- oxobutyric acid
A
5.30 5.51
240 240


 


IVa.8




5-(octahydroisoquinolin-2-yl)-5- oxopentanoic acid
A
5.44 5.64
254 254


 


IVa.9




6-(octahydroisoquinolin-2-yl)-6- oxohexanoic acid
B
3.09 3.20 
268 268


 


IVb.2




3-[(octahydroquinoline-1- carbonyl)amino]propionic acid
B
2.75
255


 


IVb.3




4-[(octahydroquinoline-1- arbonyl)amino]butyric acid
B
2.85
269


 


IVb.4




3-[(octahydroisoquinoline-2- carbonyl)amino]propionic acid
B
2.87
255


 


IVb.5




3-(octahydroquinoline-1- carbonylsulfenyl)propionic acid
B
3.53
272


 


IVb.6




3-(octahydroisoquinoline-2- carbonylsulfenyl)propionic acid
B
3.66
272


 


IVb.7




4-(octahydroisoquinoline-2- carbonylsulfenyl)butyric acid
B
3.81
286


 


IVm.1




3-(octahydroquinoline-1- sulfonyl)propionic acid
B
3.10
276


 


IVm.2




4-(octahydroquinoline-1- sulfonyl)butyric acid
B
3.18
290


 


IVm.3




3-(octahydroisoquinoline-2- sulfonyl)propionic acid
B
3.18 3.27
276 276


 


IVm.4




4-(octahydroisoquinoline-2- sulfonyl)butyric acid 
B
3.25 3.34
290 290









Intermediate IIIc.1
4-bromo-1-(octahydroquinolin-1-yl)butan-1-one




1.37 mL (9.9 mmol) of Et3N and 0.5 mL (4.5 mmol) of 5-bromovaleric acid chloride are added to a solution of 1 mL (4.0 mmol) of the decahydroquinoline in AcOEt. The resulting solution is kept under stirring for 18 h at rt. The solution is then washed with water, and the water re-extracted twice with AcOEt. The pooled organic phases are sequentially washed with 5% solution of NaHCO3, 1N HCl and saturated ammonium chloride solution. Finally the organic phase is dried over anhydrous Na2SO4, it is filtered and the solvent is evaporated under reduced pressure. 1.2 g of a yellow oil, which was used without subsequent purification, are obtained.
The following intermediates were prepared in a manner similar to intermediate IIIc.1:















Int.
structure
name
method
tr (min)
m/z







IIIc.2




2-chloro-1-(octahydroquinolin- 1-yl)ethanone 
A
6.45
216, 218 


 


IIIc.3




3-chloro-1-(octahydroquinolin- 1-yl)propan-1-one
A
7.02
230, 232 


 


IIIc.4




5-bromo-1- (octahydroisoquinolin-2- yl)-pentan-1-one
A
7.60 7.78
(302, 304) (302, 304)


 


IIIc.5




2-chloro-1- (octahydroisoquinolin-2- yl)ethanone
A
6.44 6.68
(216, 218) (216, 218) 


 


IIIc.6




3-bromo-1- (octahydroisoquinolin-2- yl)propan-1-one
A
7.00 7.21
(274, 276) (274, 276)


 


IIIc.7




5-bromo-1-(octahydroquinolin- 1-yl)-pentan-1-one
A
—
—









Intermediate IIIf.1
Octahydroquinoline-1-carboxylic acid 3-chloropropylamide




2.5 g (21 mmol) of 3-chloropropylisocyanate are dissolved in 150 mL of anhydrous THF and 6.4 mL (46 mmol) of Et3N. Once dissolved 3.4 mL (23 mmol) of decahydroquinoline are slowly added and it is refluxed for 18 h. AcOEt is then added and the resulting solution is sequentially washed with water, 1N HCl and brine. The organic phase is dried over anhydrous Na2SO4, it is filtered and the solvent is evaporated under reduced pressure yielding 4.6 g of intermediate IIIf.1. Method B: tr: 3.58 min; m/z: 259
Intermediate IIIf.2
Octahydroisoquinoline-2-carboxylic acid 3-(chloropropyl)amide




It was prepared in a manner similar to that described for intermediate IIIf.1. Method B: tr: 357 min/3.68 min; m/z: 259, 259
Intermediate IVc.1
4-azido-1-(octahydroquinolin-1-yl)butan-1-one




710 mg (10.8 mmol) of sodium azide are added to a solution of 1.1 g (3.6 mmol) of intermediate IIIc.1 in 35 mL of anhydrous DMF. The resulting solution is kept under stirring for 18 h at a temperature of 90° C. The solution is then cooled and water is added, extracting three times with AcOEt. The pooled organic phases are washed with brine. Finally the organic phase is dried over anhydrous Na2SO4, it is filtered and the solvent is evaporated under reduced pressure. 830 mg of a yellow oil, which was used without subsequent purification, are obtained. Method A: tr: 7.07 min; m/z: 251.
The following intermediates were prepared in a manner similar to intermediate IVc.1:















Int.
structure
name
method
tr (min)
m/z







IVc.2




2-azido-1-(octahydroquinolin- 1-yl)ethanone
A
6.48
223


 


IVc.3




3-azido-1-(octahydroquinon- 1-yl)propan-1-one
A
6.79
237


 


IVc.4




5-azido-1-(octahydroquinolin- 1-yl)pentan-1-one
A
7.33
265


 


IVc.5




2-azido-1- (octahydroisoquinolin-2- yl)ethanone
A
6.46 6.70
223 223


 


IVc.6




3-azido-1- (octahydroisoquinolin-2- yl)propan-1-one
A
6.77 6.99
237 237


 


IVc.7




4-azido-1- (octahydroisoquinolin-2- yl)butan-1-one
A
7.07 7.27
251 251


 


IVc.8




5-azido-1- (octahydroisoquinolin-2- yl)pentan-1-one
A
7.33 7.51
265 265


 


IVf.1




Octahydroquinoline-1- carboxylic acid (3- azidopropyl)amide
B
3.56
266


 


IVf.2




Octahydroisoquinoline-2- carboxylic acid (3- azidopropyl)amide
B
3.55 3.66
266 266









Intermediate Ic.1
2-[4-(octahydroquinolin-1-yl)-4-oxobutyl]isoindole-1,3-dione




200 mg (1.1 mmol) of potassium phthalimide are added to a solution of 307 mg (1.1 mmol) of intermediate IIIc.1 in 10 mL of anhydrous DMF. The resulting solution is kept under stirring for 18 h at a temperature of 90° C. The solution is then cooled and water is added, extracting it with AcOEt. The pooled organic phases are washed with brine. Finally the organic phase is dried over anhydrous Na2SO4, it is filtered and the solvent is evaporated under reduced pressure. 360 mg of a paste, which was purified by means of silica gel column chromatography using a (1:1) mixture of hexane:AcOEt as eluent, yielding 180 mg of an oil identified as intermediate Ic.1, are obtained. Method A: tr: 7.17 min; m/z: 355.
The following intermediates were prepared in a manner similar to intermediate Ic.1:















Ex.
structure
name
method
tr (min)
m/z







Ic.2




2-[2-(octahydroquinolin-1-yl)- 2-oxoethyl]isoindole-1,3-dione
A
6.93
327


 


Ic.3




2-[3-(octahydroquinolin-1-yl)- 3-oxopropyl]isoindole-1,3-dione
A
7.00
341


 


Ic.4




2-[4-(octahydroquinolin-1-yl)- 4-oxobutyl]isoindole-1,3-dione
A
7.17
355


 


Ic.5




2-[2-(octahydroisoquinolin-2- yl)-2-oxoethyl]isoindole-1,3- dione
A
6.92 7.10
327 327


 


Ic.6




2-[3-(octahydroisoquinolin-2- yl)-3-oxopropyl]isoindole-1,3- dione
A
6.96 7.12
341 341


 


Ic.7




2-[4-(octahydroisoquinolin-2- yl)-4-oxobutyl]isoindole-1,3- dione
A
7.16 7.33
355 355


 


Ic.8




2-[5-(octahydroisoquinolin-2- yl)-5-oxopentyl]isoindole-1,3- dione
A
7.39 7.55
369 369









Intermediate Vc.1
4-amino-1-(octahydroquinolin-1-yl)butan-1-one




    
    
        Option A: 0.1 mL of hydrazine (2.5 mmol) is added to a solution formed by 172 mg (0.48 mmol) of intermediate Ic.1 in 5 mL of EtOH and it is heated to reflux temperature for 2 h. The solution is then cooled and concentrated HCl is added until acidic pH is reached, stirring it for 2 h or more. The resulting suspension is filtered and the water is basified with 1N NaOH, extracting it with DCM. The pooled organic phases are washed with brine and are dried over anhydrous Na2SO4, it is filtered and the solvent is evaporated under reduced pressure. The resulting residue is purified by means of silica gel column chromatography, using a (10:1) mixture of DCM:MeOH as eluent, yielding 90 mg of an oil identified as intermediate Vc.1.
        Option B: A suspension formed by 830 mg (3.32 mmol) of intermediate IVc.1 and 83 mg of 5% Pd/C in 35 mL of MeOH is stirred under hydrogen atmosphere until the disappearance of the starting product by monitoring by TLC. It is filtered through Celite and it is evaporated to dryness yielding 700 mg of an oil identified as intermediate Vc.1.
    
    


Method A: tr: 3.94 min; m/z: 225
The following intermediates were prepared in a manner similar to intermediate Vc.1:















Int.
structure
name
method
tr (min)
m/z







Vc.2




2-amino-1-(octahydroquinolin- 1-yl)ethanone
A
3.41
197


 


Vc.3




3-amino-1-(octahydroquinolin- 1-yl)propan-1-one
A
3.64
211


 


Vc.4




5-amino-1-(octahydroquinolin- 1-yl)pentan-1-one
A
4.01
239


 


Vc.5




2-amino-1- (octahydroisoquinolin-2- yl)ethanone
A
3.69
197


 


Vc.6




3-amino-1- (octahydroisoquinolin-2- yl)propan-1-one
A
4.00
211


 


Vc.7




4-amino-1- (octahydroisoquinolin-2- yl)butan-1-one
A
4.03
225


 


Vc.8




5-amino-1- (octahydroisoquinolin-2- yl)pentan-1-one
A
4.27
239


 


Vc.9




Octahydroquinoline-1- carboxylic acid (3- aminopropyl)amide
B
2.11
240


 


Vc.10




Octahydroisoquinoline-2- carboxylic acid (3- aminopropyl)amide
B
2.22
240









Intermediate IVj.1
5-hydroxyl-1-(octahydroisoquinolin-2-yl)pentan-1-one




0.63 mL (4.93 mmol) of isobutyl chloroformate are added dropwise to a solution of 1.25 g (4.93 mmol) of intermediate IVa.8 and 0.6 mL of N-methylmorpholine (5.4 mmol) in 50 mL of anhydrous THF and cooled to 0° C. The resulting solution is left to stir for 30 minutes at that temperature and 370 mg (9.86 mmol) of sodium borohydride are then added. Once added it is left to reach rt and it is stirred for 2 h. It is then partitioned between AcOEt and water. The aqueous phase is extracted twice with AcOEt, the organic phases are pooled, dried over anhydrous Na2SO4, filtered and evaporated to dryness, 1 g of a yellow oil, which was used without subsequent purification, being obtained.
Method B: tr: 2.94 min/3.06 min; m/z: 240/240.
Intermediate IVj.2
5-hydroxyl-1-(octahydroquinolin-1-yl)pentan-1-one




It is prepared in a manner similar to that described for intermediate IVj.1. Method B: tr: 2.94 min; mfz: 240
Intermediate IVp.1
3-mercapto-1-(octahydroquinolin-1-yl)propan-1-one




8.5 mL of Et3N, 6.5 g of EDC (mmol) and 5.7 g of HOBT (mmol) are added to a solution formed by 3 g (28.2 mmol) of 3-mercaptopropionic acid in 45 mL of DMF and cooled to 0° C. and it is left for 15 minutes under stirring at that temperature. 4.2 g (28.3 mmol) of decahydroquinoline are then added and it is stirred at rt for 18 h. Then, it is treated with water and AcOEt, the organic phase is separated and the aqueous phase is extracted once more with AcOEt. The organic phases are pooled and successively washed with saturated NaHCO3 solution, 1N HCl and brine. It is then dried over anhydrous Na2SO4, it is filtered and the solvent is evaporated under reduced pressure. The resulting residue is purified by means of silica gel column chromatography, using a (50:1) mixture of DCM:MeOH as eluent, yielding 600 mg of the thiol intermediate
Intermediate IVp.2
3-mercapto-1-(octahydroisoquinolin-2-yl)propan-1-one




It is prepared in a manner similar to that described for intermediate IVp.1, Method B: tr: 3.59 min/3.72 min; m/z: 228/228
Intermediate IVp.3
4-mercapto-1-(octahydroquinolin-1-yl)butan-1-one




1.5 mL of decahydroquinoline (10 mmol) and 10 mg of camphorsulfonic acid are added to a solution formed by 0.9 mL (10 mmol) of γ-thiolactone in 80 mL of toluene. The resulting mixture is left to stir at 100° C. for 6 h. The solvent is then evaporated under reduced pressure and the resulting residue is purified by means of silica gel column chromatography, using a (50:1) mixture of DCM:MeOH as eluent, yielding 1.5 g of the thiol intermediate IVp.3. Method B: tr: 3.75 min; m/z: 242
Intermediate IVp.4
4-mercapto-1-(octahydroisoquinolin-2-yl)butan-1-one




It is prepared in a manner similar to that described for intermediate IVp.3. Method B: tr: 3.75 min/3.87 min; m/z: 242/242
Example Ia.1
N-bicyclo[2.2.1]hept-2-yl-3-(octahydroisoquinolin-2-yl)-3-oxopropionamide




43 μL (0.31 mmol) of Et3N, 29 mg (0.21 mmol) of HOBT, 41 mg (0.21 mmol) of EDC and 18.6 μL (0.16 mmol) of 2-aminonorbornan are added to a solution of 32 mg (0.14 mmol) of the acid intermediate IVa.6 in 2 mL of AcOEt. The solution formed is kept under stirring for 18 h. It is then treated with water and more AcOEt is added, the organic phase is separated and the aqueous phase is extracted once more with more AcOEt. The organic phases are pooled and successively washed with saturated NaHCO3 solution, 1N HCl and brine. It is then dried over anhydrous Na2SO4, it is filtered and the solvent is evaporated under reduced pressure. 27 mg of the compound identified as example Ia.1 are obtained. Method A: tr: 6.76 min/6.84 min; m/z: 319/319
The following examples were prepared in a manner similar to example Ia.1:















Ex.
structure
name
method
tr (min)
m/z




















Ia.2




1-(3,5-dimethylpiperidin-1 yl)-2-(octahydroquinolin-1- yl)ethane-1,2-dione
A
7.22 7.35
307 307


 


Ia.3




1-(6,7-dimethoxy-3,4- dihydro-1-H-isoquinolin-2- yl)-2-(octahydroquinolin-1- yl)ethane-1,2-dione
A
6.54
387


 


Ia.4




1,2-bis-(octahydroquinolin- 1-yl)ethane-1,2-dione
A
7.66 7.76
333 333


 


Ia.5




1-(octahydroquinolin-1-yl)- 2-(piperidin-1-yl)ethane- 1,2-dione
A
6.19
279


 


Ia.6




1-((2S,6R)-2,6- dimethylmorpholin-4-yl)- 2-(octahydroquinolin-1- yl)ethane-1,2-dione
A
6.19
309


 


Ia.7




1-(octahydroquinolin-1-yl)- 2-(4-oxopiperidin-1- yl)ethane-1,2-dione
A
5.10
293


 


Ia.8




1-(4-methylpiperazin-1-yl)- 2-(octahydroquinolin-1- yl)ethane-1,2-dione
A
3.82
294


 


Ia.9




1-[4-(2- methoxyphenyl)piperazin- 1-yl]-2-(octahydroquinolin- 1-yl)ethane-1,2-dione
A
7.00
386


 


Ia.10




1-(octahydroquinolin-1-yl)- 2-[4-(3- trifluoromethylphenyl) piperazin-1-yl]-ethane-1,2- dione
A
7.90
424


 


Ia.11




1-(octahydroquinolin-1-yl)- 2-(4-o-tolylpiperazin-1- yl)ethane-1,2-dione
A
7.82
370


 


Ia.12




2-(octahydroquinolin-1-yl)- 2-oxo-N- tricyclo[3.3.1.13.7]decan-2- ylacetamide
A
7.99 8.18
345 345


 


Ia.13




1-(octahydroisoquinolin-2- yl)-2-(octahydroquinolin-1- yl)ethane-1,2-dione
A
7.69 7.84
333 333


 


Ia.14




N-(bicyclo[2.2.1]hept-2- yl)-2-(octahydroquinolin-1- yl)-2-oxoacetamide
A
6.98 7.13
305 305 


 


Ia.15




2-(octahydroquinolin-1-yl)- 2-oxo-N- tricyclo[3.3.1.13,7]decan-1- ylacetamide
A
8.15 8.33
345 345


 


Ia.16




1-(octahydroquinolin-1-yl)- 3-(piperidin-1-yl)propane- 1,3-dione
A
6.09
293


 


Ia.17




1-[4-(2- methoxyphenyl)piperazin- 1-yl]-3-(octahydroquinolin- 1-yl)propane-1,3-dione
A
6.46
400


 


Ia.18




1-(3,5-dimethylpiperidin-1- yl)-3-(octahydroquinolin-1- yl)propane-1,3-dione
A
7.03 7.17
321 321


 


Ia.19




1-(4-methylpiperidin-1-yl)- 3-(octahydroquinolin-1- yl)propane-1,3-dione
A
6.62
307


 


Ia.20




1-(3-methylpiperidin-1-yl)- 3-(octahydroquinolin-1- yl)propane-1,3-dione
A
6.62
307


 


Ia.21




1-((2S,6R)-2,6- dimethylmorpholin-4-yl)- 3-(octahydroquinolin-1- yl)propane-1,3-dione 
A
5.90
323


 


Ia.22




1,3-bis-(octahydroquinolin- 1-yl)propane-1,3-dione
A
7.53
347


 


Ia.23




1-(octahydroquinolin-1-yl)- 3-(4-o-tolylpiperazin-1- yl)propane-1,3-dione
A
7.56
384


 


Ia.24




1-(4-benzylpiperidin-1-yl)- 3-(octahydroquinolin-1- yl)propane-1,3-dione
A
6.31
460


 


Ia.25




1-(4-benzhydrylpiperazin- 1-yl)-3-(octahydroquinolin- 1-yl)propane-1,3-dione
A
7.72
383


 


Ia.26




N-bicyclo[2.2.1]hept-2-yl- 3-(octahydroquinolin-1-yl)- 3-oxopropionamide
A
6.76 6.84
319 319


 


Ia.27




1-(octahydroisoquinolin-2- yl)-3-(octahydroquinolin-1- yl)propane-1,3-dione
A
7.54 7.68
347 347


 


Ia.28




1-(4-methylpiperazin-1-yl)- 3-(octahydroquinolin-1- yl)propane-1,3-dione
A
3.90
308


 


Ia.29




1-(octahydroisoquinolin-2- yl)-4-(octahydroquinolin-1- yl)butane-1,4-dione
A
7.75 7.90
361 361


 


Ia.30




1,4-bis-(octahydroquinolin- 1-yl)butane-1,4-dione
A
7.84
361


 


Ia.31




1-(octahydroquinolin-1-yl)- 4-(4-o-tolylpiperazin-1- yl)butane-1,4-dione
A
7.78
398


 


Ia.32




1-(4-benzylpiperidin-1-yl)- 4-(octahydroquinolin-1- yl)butane-1,4-dione
A
7.99 8.11
397 397


 


Ia.33




1-[4-(2- methoxyphenyl)piperazin- 1-yl]-4-(octahydroquinolin- 1-yl)butane-1,4-dione
A
6.53
414


 


Ia.34




1-(3,5-dimethylpiperidin-1- yl)-4-(octahydroquinolin-1- yl)butane-1,4-dione
A
7.32 7.48
335 335


 


Ia.35




1-(4-methylpiperidin-1-yl)- 4-(octahydroquinolin-1- yl)butane-1,4-dione
A
6.93
321


 


Ia.36




1-(3-methylpiperidin-1-yl)- 4-(octahydroquinolin-1- yl)butane-1,4-dione
A
6.92
321


 


Ia.37




1-(octahydroquinolin-1-yl)- 4-piperidin-1-ylbutane-1,4- dione
A
6.36
307


 


Ia.38




1-(octahydroquinolin-1-yl)- 4-(6-oxooctahydroindol-1- yl)butane-1,4-dione
A
4.25
361


 


Ia.39




1-(4-methylpiperazin-1-yl)- 4-(octahydroquinolin-1- yl)butane-1,4-dione
A
4.19
322


 


Ia.40




N-bicyclo[2.2.1]hept-2-yl- 4-(octahydroquinolin-1-yl)- 4-oxobutyramide
A
6.84
333


 


Ia.41




1-(3-methylpiperidin-1-yl)- 5-(octahydroquinolin-1- yl)pentane-1,5-dione
A
7.01
335


 


Ia.42




1-((2S,6R)-2,6- dimethylmorpholin-4-yl)- 5-(octahydroquinolin-1- yl)pentane-1,5-dione
A
6.28
351


 


Ia.43




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid bicyclo[2.2.1]hept-2-ylamide
A
6.88
347


 


Ia.44




1-[4-(2- methoxyphenyl)piperazin- 1-yl]-5-(octahydroquinolin- 1-yl)pentane-1,5-dione
A
6.75
428


 


Ia.45




1-(3,5-dimethylpiperidin-1- yl)-5-(octahydroquinolin-1- yl)pentane-1,5-dione
A
7.41 7.57
349 349


 


Ia.46




1,5-bis-(octahydroquinolin- 1-yl)pentane-1,5-dione
A
7.92
375


 


Ia.47




1-(octahydroisoquinolin-2- yl)-5-(octahydroquinolin-1- yl)pentane-1,5-dione
A
7.91 8.08
375 375


 


Ia.48




1-(octahydroquinolin-1-yl)- 5-(4-o-tolylpiperazin-1- yl)pentane-1,5-dione
A
7.89
412


 


Ia.49




1-(4-benzylpiperidin-1-yl)- 5-(octahydroquinolin-1- yl)pentane-1,5-dione
A
8.05
411


 


Ia.50




1-(4-benzhydrylpiperazin- 1-yl)-5-(octahydroquinolin- 1-yl)pentane-1,5-dione
A
6.54
488


 


Ia.51




1-(3,4-dihydro-2-H- quinolin-1-yl)-5- (octahydroquinolin-1- yl)pentane-1,5-dione
A
7.49
369


 


Ia.52




1-(octahydroquinolin-1-yl)- 5-(1-oxo-3,4-dihydro-1-H- isoquinolin-2-yl)pentane- 1,5-dione
A
7.75
383


 


Ia.53




1-(6,7-dimethoxy-3,4- dihydro-1-H-isoquinolin-2- yl)-5-(octahydroquinolin-1- yl)pentane-1,5-dione
A
6.58
429


 


Ia.54




1-(octahydroquinolin-1-yl)- 5-(6-oxooctahydroindol-1- yl)pentane-1,5-dione
A
4.30
375


 


Ia.55




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid cyclohexylamide
B
3.68
335


 


Ia.56




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid (3- phenylpropyl)amide
B
3.84
371


 


Ia.57




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid (pyridin-3-ylmethyl)amide
B
2.29
344


 


Ia.58




1-(4-benzylpiperazin-1-yl)- 5-(octahydroquinolin-1- yl)pentane-1,5-dione
B
2.63
412


 


Ia.59




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid phenethylamide
B
3.66
357


 


Ia.60




1-(4-hydroxypiperidin-1- yl)-5-(octahydroquinolin-1- yl)pentane-1,5-dione
B
2.75
337


 


Ia.61




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid  benzylamide
B
3.54
343


 


Ia.62




1-(3-hydroxypiperidin-1- yl)-5-(octahydroquinolin-1- yl)pentane-1,5-dione
B
2.87
337


 


Ia.63




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid  ethylmethylamide
B
3.24
295


 


Ia.64




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid methylpropylamide
B
3.51
309


 


Ia.65




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid butylmethylamide
B
3.79
323


 


Ia.66




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid methylnaphthalen-1- ylmethylamide
B
4.24
407


 


Ia.67




5-(octahydroquinolin-1-yl)- 1-perhydroazepin-1- ylpentane-1,5-dione
B
3.72
335


 


Ia.68




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid benzylmethylamide
B
3.84
357


 


Ia.69




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid methyl-(2-pyridin-2- ylethyl)amide
B
2.47
372


 


Ia.70




5-(octahydroquinolin-1-yl)- 1-perhydroazocin-1- ylpentane-1,5-dione
B
3.84
349


 


Ia.71




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid  cyclooctylamide
B
4.10
363


 


Ia.72




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid dimethylamide
B
3.01
281


 


Ia.73




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid tricyclo[3.3.1.13,7]decan-1- ylamide
B
4.35
387


 


Ia.74




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid tricyclo[3.3.1.13,7]decan-2- ylamide
B
4.28
387


 


Ia.75




1-(4-benzoylpiperazin-1- yl)-5-(octahydroquinolin-1- yl)pentane-1,5-dione
B
3.34
426


 


Ia.76




1-(octahydroquinolin-1-yl)- 5-piperidin-1-ylpentane- 1,5-dione
A
6.52
321


 


Ia.77




1-(4-methylpiperazin-1-yl)- 5-(octahydroquinolin-1- yl)pentane-1,5-dione
A
4.20
336


 


Ia.78




1-(4-methylpiperidin-1-yl)- 5-(octahydroquinolin-1- yl)pentane-1,5-dione
A
7.02
335


 


Ia.79




1-(octahydroquinolin-1-yl)- 6-(4-oxopiperidin-1- yl)hexane-1,6-dione
B
3.04
349


 


Ia.80




1-(octahydroquinolin-1-yl)- 6-piperidin-1-ylhexane- 1,6-dione
B
3.65
335


 


Ia.81




6-(octahydroquinolin-1-yl)- 6-oxohexanoic acid (3- phenylpropyl)amide
B
3.94
385


 


Ia.82




1-(4-benzylpiperazin-1-yl)- 6-(octahydroquinolin-1- yl)hexane-1,6-dione
B
2.74
426


 


Ia.83




6-(octahydroquinolin-1-yl)- 6-oxohexanoic acid phenethylamide
B
3.76
371


 


Ia.84




6-(octahydroquinolin-1-yl)- 6-oxohexanoic acid benzylamide
B
3.64
357


 


Ia.85




6-(octahydroquinolin-1-yl)- 6-oxohexanoic acid ethylmethylamide
B
3.36
309


 


Ia.86




6-(octahydroquinolin-1-yl)- 6-oxohexanoic acid methylpropylamide
B
3.62
323


 


Ia.87




6-(octahydroquinolin-1-yl)- 6-oxohexanoic acid butylmethylamide
B
3.89
337


 


Ia.88




6-(octahydroquinolin-1-yl)- 6-oxohexanoic acid methylnaphthalen-1- ylmethylamide
B
4.24 4.31
421 421


 


Ia.89




1,6-bis-(octahydroquinolin- 1-yl)hexane-1,6-dione
B
4.39
389


 


Ia.90




6-(octahydroquinolin-1-yl)- 1-perhydroazepin-1- ylhexane-1,6-dione
B
3.83
349


 


Ia.91




1-(3,5-dimethylpiperidin-1- yl)-6-(octahydroquinolin-1- yl)hexane-1,6-dione
B
4.11 4.20
363 363


 


Ia.92




6-(octahydroquinolin-1-yl)- 6-oxohexanoic acid benzylmethylamide
B
3.93
371


 


Ia.93




1-(octahydroquinolin-1-yl)- 6-(4-o-tolylpiperazin-1- yl)hexane-1,6-dione
B
4.37
426


 


Ia.94




6-(octahydroquinolin-1-yl)- 1-perhydroazocin-1- ylhexane-1,6-dione
B
4.04
363


 


Ia.95




6-(octahydroquinolin-1-yl)- 6-oxohexanoic acid tricyclo[3.3.1.13,7]decan-1- ylamide
B
4.42
401


 


Ia.96




6-(octahydroquinolin-1-yl)- 6-oxohexanoic acid tricyclo[3.3.1.13,7]decan-2- ylamide
B
4.34
401


 


Ia.97




1-(4-methylpiperidin-1-yl)- 6-(octahydroquinolin-1- yl)hexane-1,6-dione
B
3.92
349


 


Ia.98




1-(3-methylpiperidin-1-yl)- 6-(octahydroquinolin-1- yl)hexane-1,6-dione
B
3.92
349


 


Ia.99




6-(octahydroquinolin-1-yl)- 6-oxohexanoic acid cyclohexylmethylamide
B
4.13
363


 


Ia.100




1-(octahydroisoquinolin-2- yl)-6-(octahydroquinolin-1- yl)hexane-1,6-dione
B
4.38 4.47
389 389


 


Ib.1 




Octahydroquinoline-1- carboxylic acid (4-oxo-4- piperidin-1-ylbutyl)amide
B
3.42
336


 


Ib.2




Octahydroquinoline-1- carboxylic acid [3-(3- phenylpropylcarbamoyl) propyl]amide
B
3.81
386


 


Ib.3




Octahydroquinoline-1- carboxylic acid [4-(4- benzylpiperazin-1-yl)-4- oxobutyl]amide
B
2.61
427


 


Ib.4




Octahydroquinoline-1- carboxylic acid (3- phenethylcarbamoylpropyl) amide
B
3.61
372


 


Ib.5




Octahydroquinoline-1- carboxylic acid (3- benzylcarbamoylpropyl) amide 
B
3.50
358


 


Ib.6




Octahydroquinoline-1- carboxylic acid [3- (methylpropylcarbamoyl) propyl]amide
B
3.39
324


 


Ib.7




Octahydroquinoline-1- carboxylic acid [3- (butylmethylcarbamoyl) propyl]amide
B
3.65
338


 


Ib.8




Octahydroquinoline-1- carboxylic acid [3- (methylnaphthalen-1- ylmethylcarbamoyl) propyl]amide
B
4.08
422


 


Ib.9




Octahydroquinoline-1- carboxylic acid (4-oxo-4- perhydroazepin-1- ylbutyl)amide
B
3.59
350


 


Ib.10




Octahydroquinoline-1- carboxylic acid [4-(3,5- dimethylpiperidin-1-yl)-4- oxobutyl]amide
B
3.87 3.96
364 364


 


Ib.11




Octahydroquinoline-1- carboxylic acid [3- (benzylmethylcarbamoyl) propyl]amide
B
3.71
372


 


Ib.12




Octahydroquinoline-1- carboxylic acid [4-oxo-4- (4-o-tolylpiperazin-1- yl)butyl]amide
B
4.14
427


 


Ib.13




Octahydroquinoline-1- carboxylic acid (4-oxo-4- perhydroazocin-1- ylbutyl)amide
B
3.80
364


 


Ib.14




Octahydroquinoline-1- carboxylic acid [3- (tricyclo[3.3.1.13,7]decan-1- ylcarbamoyl)propyl]amide
B
4.31
402


 


Ib.15




Octahydroquinoline-1- carboxylic acid [3- (tricyclo[3.3.1.13,7]decan-2- ylcarbamoyl)propyl]amide
B
4.23
402


 


Ib.16




Octahydroquinoline-1- carboxylic acid [4-(4- methylpiperidin-1-yl)-4- oxobutyl]amide
B
3.69
350


 


Ib.17




Octahydroquinoline-1- carboxylic acid [4-(3- methylpiperidin-1-yl)-4- oxobutyl]amide
B
3.68
350


 


Ib.18




Octahydroquinoline-1- carboxylic acid [4- (octahydroisoquinolin-2- yl)-4-oxobutyl]amide
B
4.14 4.24
390 390


 


Ib.19




Octahydroquinoline-1- carboxylic acid [3- (cyclohexylmethylcarba- moyl)propyl]amide
B
3.89
364


 


Ib.20




Octahydroquinoline-1- carboxylic acid [3-oxo-3- (4-oxopiperidin-1- yl)propyl]amide
B
2.78
336


 


Ib.21




Octahydroquinoline-1- carboxylic acid (3-oxo-3- piperidin-1-yl propyl)amide
B
3.35
322


 


Ib.22




Octahydroquinoline-1- carboxylic acid [2-(3- phenylpropylcarbamoyl) ethyl]amide
B
3.72
372


 


Ib.23




Octahydroquinoline-1- carboxylic acid [3-(4- benzylpiperazin-1-yl)-3- oxopropyl]amide
B
2.56
413


 


Ib.24




Octahydroquinoline-1- carboxylic acid (2- phenethylcarbamoylethyl) amide
B
3.56
358


 


Ib.25




Octahydroquinoline-1- carboxylic acid (2- benzylcarbamoylethyl) amide
B
3.42
344


 


Ib.26




Octahydroquinoline-1- carboxylic acid [2- (ethylmethylcarbamoyl) ethyl]amide
B
3.07
296


 


Ib.27




Octahydroquinoline-1- carboxylic acid [2- (methylpropylcarbamoyl) ethyl]amide
B
3.33
310


 


Ib.28




Octahydroquinoline-1- carboxylic acid [2- (butylmethylcarbamoyl) ethyl]amide
B
3.60
324


 


Ib.29




Octahydroquinoline-1- carboxylic acid [2- (methylnaphthalen-1- ylmethylcarbamoyl) ethyl]amide
B
4.08
408


 


Ib.30




Octahydroquinoline-1- carboxylic acid (3-oxo-3- perhydroazepin-1- ylpropyl)amide
B
3.52
336


 


Ib.31




Octahydroquinoline-1- carboxylic acid [3-(3,5- dimethylpiperidin-1-yl)-3- oxopropyl]amide
B
3.82 3.90
350 350


 


Ib.32




Octahydroquinoline-1- carboxylic acid [2- (benzylmethylcarbamoyl) ethyl]amide
B
3.67
358


 


Ib.33




Octahydroquinoline-1- carboxylic acid {3-[4-(2- fluorophenyl)piperazin-1- yl]-3-oxopropyl}amide
B
3.81
417


 


Ib.34




Octahydroquinoline-1- carboxylic acid [3-oxo-3- (4-o-tolylpiperazin-1- yl)propyl]amide
B
4.09
413


 


Ib.35




Octahydroquinoline-1- carboxylic acid (3-oxo-3- perhydroazocin-1- ylpropyl)amide
B
3.74
350


 


Ib.36




Octahydroquinoline-1- carboxylic acid [2- (tricyclo[3.3.1.13,7]decan-2- ylcarbamoyl)ethyl]amide
B
4.11
388


 


Ib.37




Octahydroquinoline-1- carboxylic acid [3-(4- methylpiperidin-1-yl)-3- oxopropyl]amide
B
3.62
336


 


Ib.38




Octahydroquinoline-1- carboxylic acid [3- (octahydroisoquinolin-2- yl)-3-oxopropyl]amide
B
4.08 4.17
376 376


 


Ib.39




Octahydroquinoline-1- carboxylic acid [2- (cyclohexylmethylcarbamoyl) ethyl]amide
B
3.83
350


 


Ib.40




Octahydroquinoline-1- carboxylic acid [3-oxo-3- (4-oxooctahydroquinolin- 1-yl)propyl]amide
B
3.44
390


 


Ib.41




Octahydroquinoline-1- carboxylic acid [3-(3- methylpiperidin-1-yl)-3- oxopropyl]amide
B
3.61
336


 


Ib.42




Octahydroquinoline-1- carbothioic acid S-[3-(3- methylpiperidin-1-yl)-3- oxopropyl] ester
B
4.55
353


 


Ib.43




Octahydroquinoline-1- carbothioic acid S-[3-(4- methylpiperidin-1-yl)-3- oxopropyl] ester
B
3.57
353


 


Ib.44




Octahydroquinoline-1- carbothioic acid S-[2- (tricyclo[3.3.1.13,7]decan-2- ylcarbamoyl)ethyl] ester
B
4.79
405


 


Ib.45




Octahydroquinoline-1- carbothioic acid S-[2- (tricyclo[3.3.1.13,7]decan-1- ylcarbamoyl)ethyl] ester
B
4.88
405


 


Ib.46




Octahydroquinoline-1- carbothioic acid S-[3-(3,5- dimethylpiperidin-1-yl)-3- oxopropyl] ester
B
4.75
367


 


Ib.47




Octahydroquinoline-1- carbothioic acid S-(3-oxo- 3-perhydroazepin-1- ylpropyl) ester
B
4.56
353


 


Ib.48




Octahydroquinoline-1- carbothioic acid S-[2- (methylpropylcarbamoyl) ethyl] ester
B
4.14
327


 


Ib.49




Octahydroquinoline-1- carbothioic acid S-[2- (ethylmethylcarbamoyl) ethyl] ester
B
3.88
313


 


Ib.50




Octahydroquinoline-1- carbothioic acid S-(3-oxo- 3-piperidin-1-ylpropyl) ester
B
4.20
339


 


Ib.51




Octahydroquinoline-1- carbothioic acid S-[3-oxo- 3-(4-oxopiperidin-1- yl)propyl] ester
B
3.49
353


 


Ib.52




Octahydroquinoline-1- carbothioic acid S-[2- (cyclohexylmethyl- carbamoyl)ethyl] ester
B
4.67
364


 


Ib.53




Octahydroquinoline-1- carbothioic acid S-[3-oxo- 3-(4-o-tolylpiperazin-1- yl)propyl] ester
B
4.86
430


 


Ib.54




Octahydroquinoline-1- carbothioic acid S-[2- (benzylmethylcarbamoyl) ethyl] ester
B
4.42
375


 


Ib.55




Octahydroquinoline-1- carbothioic acid S-[2- (methylnaphthalen-1- ylmethylcarbamoyl) ethyl]ester
B
4.78
425


 


Ib.56




Octahydroquinoline-1- carbothioic acid S-[2- (butylmethylcarbamoyl) ethyl]ester
B
4.41
341


 


Ib.57




Octahydroquinoline-1- carbothioic acid S-(2- benzylcarbamoylethyl) ester 
B
4.06
361


 


Ib.58




Octahydroquinoline-1- carbothioic acid S-[3-(4- benzylpiperazin-1-yl)-3- ozopropyl] ester
B
2.98
430


 


Ib.59




Octahydroquinoline-1- carbothioic acid S-(3-oxo- 3-perhydroazocin-1- ylpropyl) ester
B
4.58
367


 


Ib.60




Octahydroquinoline-1- carbothioic acid S-{3-[4- (2-fluorophenyl)piperazin- 1-yl]-3-oxopropyl} ester
B
4.59
434


 


Ib.61




Octahydroquinoline-1- carbothioic acid S-(2- phenethylcarbamoylethyl) ester
B
4.20
375


 


Ib.62




Octahydroquinoline-1- carbothioic acid S-[2-(3- phenylpropylcarbamoyl) ethyl] ester
B
4.34
389


 


Im.1




1-[4-(octahydroquinoline-1- sulfonyl)butyryl]piperidin- 4-one
B
3.16
371


 


Im.2




4-(octahydroquinoline-1- sulfonyl)-1-piperidin-1- ylbutan-1-one
B
3.79
357


 


Im.3




1-(4-hydroxypiperidin-1- yl)-4-(octahydroquinoline- 1-sulfonyl)butan-1-one
B
2.96
373


 


Im.4




4-(octahydroquinoline-1- sulfonyl)-1- perhydroazepin-1-ylbutan- 1-one
B
3.96
371


 


Im.5




1-[4-(2- methoxyphenyl)piperazin- 1-yl]-4- (octahydroquinoline-1- sulfonyl)butan-1-one
B
3.92
464


 


Im.6




1-(3.5-dimethylpiperidin-1- yl)-4-(octahydroquinoline- 1-sulfonyl)butan-1-one
B
4.34
385


 


Im.7




4-(octahydroquinoline-1- sulfonyl)-1-(4-o- tolylpiperazin-1-yl)butan- 1-one
B
4.49
448


 


Im.8




4-(octahydroquinoline-1- sulfonyl)-1- perhydroazocin-1-ylbutan- 1-one
B
4.17
385


 


Im.9




1-((R)-3-hydroxypiperidin- 1-yl)-4- (octahydroquinoline-1- sulfonyl)butan-1-one
B
3.07
373


 


Im.10




1-(4-benzhydrylpiperazin- 1-yl)-4- (octahydroquinoline-1- sulfonyl)butan-1-one
B
3.82
524


 


Im.11




1-(4-methylpiperidin-1-yl)- 4-(octahydroquinoline-1- sulfonyl)butan-1-one
B
4.06
371


 


Im.12




1-(3-methylpiperidin-1-yl)- 4-(octahydroquinoline-1- sulfonyl)butan-1-one
B
4.05
371


 


Im.13




1-(octahydroisoquinolin-2- yl)-4-(octahydroquinoline- 1-sulfonyl)butan-1-one
B
4.50 4.59
411 411


 


Im.14




N-cyclohexyl-N-methyl-4- (octahydroquinoline-1- sulfonyl)butyramide
B
4.26
385


 


Im.15




1-(3,3-difluoropiperidin-1- yl)-4-(octahydroquinoline- 1-sulfonyl)butan-1-one
B
3.80
393


 


Im.16




1-(4,4-difluoropiperidin-1- yl)-4-(octahydroquinoline- 1-sulfonyl)butan-1-one
B
3.81
393


 


Ia.101




1-(octahydroisoquinolin-2- yl)-2-piperidin-1-ylethane- 1,2-dione
A
6.28 6.45
279 279


 


Ia.102




1-(4-methylpiperazin-1-yl)- 2-(octahydroisoquinolin-2- yl)ethane-1,2-dione
A
4.04
294


 


Ia.103




1-[4-(2- methoxyphenyl)piperazin- 1-yl]-2- (octahydroisoquinolin-2- yl)ethane-1,2-dione
A
7.03 7.17
386 386


 


Ia.104




1-(3,5-dimethylpiperidin- 1-yl)-2- (octahydroisoquinolin-2- yl)ethane-1,2-dione  
A
7.41 7.53
307 307


 


Ia.105




1-(4-methylpiperidin-1-yl)- 2-(octahydroisoquinolin-2- yl)ethane-1,2-dione
A
6.86 7.01
293 293


 


Ia.106




1-(3-methylpiperidin-1-yl)- 2-(octahydroisoquinolin-2- yl)ethane-1,2-dione
A
6.83 6.99
293 293


 


Ia.107




1-((2S,6R)-2,6- dimethylmorpholin-4-yl)- 2-(octahydroisoquinolin-2- yl)ethane-1,2-dione
A
6.20 6.38
309 309


 


Ia.108




1-(octahydroisoquinolin-2- yl)-2-(4-o-tolylpiperazin-1- yl)ethane-1,2-dione
A
7.98
370


 


Ia.109




1-(4-benzylpiperidin-1-yl)- 2-(octahydroisoquinolin-2- yl)ethane-1,2-dione
A
8.04
369


 


Ia.110




1-(4-benzhydrylpiperazin- 1-yl)-2- (octahydroisoquinolin-2- yl)ethane-1,2-dione
A
7.63 7.80
446 446


 


Ia.111




1,2-bis- (octahydroisoquinolin-2- yl)ethane-1,2-dione
A
8.06
333


 


Ia.112




1-(octahydroisoquinolin-2- yl)-3-piperidin-1- ylpropane-1,3-dione
A
6.11 6.28
293 293


 


Ia.113




1-[4-(2- methoxyphenyl)piperazin- 1-yl]-3- (octahydroisoquinolin-2- yl)propane-1,3-dione
A
6.47 6.64
400 400


 


Ia.114




1-(3,5-dimethylpiperidin-1- yl)-3- (octahydroisoquinolin-2- yl)propane-1,3-dione
A
7.20 7.33
321 321


 


Ia.115




1-(4-methylpiperidin-1-yl)- 3-(octahydroisoquinolin-2- yl)propane-1,3-dione
A
6.66 6.81
307 307


 


Ia.116




1-(3-methylpiperidin-1-yl)- 3-(octahydroisoquinolin-2- yl)propane-1,3-dione  
A
6.63  6.79
307 307


 


Ia.117




1-((2S,6R)-2,6- dimethylmorpholin-4-yl)- 3-(octahydroisoquinolin-2- yl)propane-1,3-dione
A
5.91 6.09
323 323


 


Ia.118




1-(octahydroisoquinolin-2- yl)-3-(4-o-tolylpiperazin-1- yl)propane-1,3-dione
A
7.57 7.70
384 384


 


Ia.119




1-(4-benzylpiperidin-1-yl)- 3-(octahydroisoquinolin-2- yl)propane-1,3-dione
A
7.73 7.85
383 383


 


Ia.120




1-(4-benzhydrylpiperazin- 1-yl)-3- (octahydroisoquinolin-2- yl)propane-1,3-dione
A
6.34 6.48
460 460


 


Ia.121




1-(4-methylpiperazin-1-yl)- 3-(octahydroisoquinolin-2- yl)propane-1,3-dione
A
4.06
308


 


Ia.122




1-(6,7-dimethoxy-3,4- dihydro-1-H-isoquinolin-2- yl)-2- (octahydroisoquinolin-2- yl)ethane-1,2-dione
A
6.65
387


 


Ia.123




1-(octahydroisoquinolin-2- yl)-4-piperidin-1-ylbutane- 1,4-dione
A
6.37 6.56
307 307


 


Ia.124




1-(4-methylpiperazin-1-yl)- 4-(octahydroisoquinolin-2- yl)butane-1,4-dione
A
4.32
322


 


Ia.125




1-[4-(2- methoxyphenyl)piperazin- 1-yl]-4- (octahydroisoquinolin-2- yl)butane-1,4-dione
A
6.52 6.71
414 414


 


Ia.126




1-((2S,6R)-2,6- dimethylmorpholin-4-yl)- 4-(octahydroisoquinolin-2- yl)butane-1,4-dione
A
6.15 6.34
337 337


 


Ia.127




1-(octahydroisoquinolin-2- yl)-4-(4-o-tolylpiperazin-1- yl)butane-1,4-dione
A
7.66 7.81
398 398


 


Ia.128




1-(4-benzylpiperidin-1-yl)- 4-(octahydroisoquinolin-2- yl)butane-1,4-dione
A
7.90 8.03
397 397


 


Ia.129




1,4-bis- (octahydroisoquinolin-2- yl)butane-1,4-dione
A
7.94 8.09
361 361


 


Ia.130




1-(3,5-dimethylpiperidin-1- yl)-4- (octahydroisoquinolin-2- yl)butane-1,4-dione
A
7.44 7.59
335 335


 


Ia.131




1-(4-methylpiperidin-1-yl)- 4-(octahydroisoquinolin-2- yl)butane-1,4-dione
A
6.91 7.08
321 321


 


Ia.132




1-(3-methylpiperidin-1-yl)- 4-(octahydroisoquinolin-2- yl)butane-1,4-dione
A
6.89 7.06
321 321


 


Ia.133




1-(4-benzhydrylpiperazin- 1-yl)-4- (octahydroisoquinolin-2- yl)butane-1,4-dione
A
6.24 6.34
474 474


 


Ia.134




1-(octahydroisoquinolin-2- yl)-5-piperidin-1- ylpentane-1,5-dione
A
6.51 6.70
321 321


 


Ia.135




1-(4-methylpiperazin-1-yl)- 5-(octahydroisoquinolin-2- yl)pentane-1,5-dione
A
4.27
336


 


Ia.136




1-[4-(2- methoxyphenyl)piperazin- 1-yl]-5- (octahydroisoquinolin-2- yl)pentane-1,5-dione
A
6.74 6.93
428 428


 


Ia.137




1-(3,5-dimethylpiperidin-1- yl)-5- (octahydroisoquinolin-2- yl)pentane-1,5-dione
A
7.52  7.68
349 349


 


Ia.138




1-(3-methylpiperidin-1-yl)- 5-(octahydroisoquinolin-2- yl)pentane-1,5-dione
A
7.01 7.19
335 335


 


Ia.139




1-((2S,6R)-2,6- dimethylmorpholin-4-yl)- 5-(octahydroisoquinolin-2- yl)pentane-1,5-dione
A
6.26 6.45
351 351


 


Ia.140




1-(octahydroisoquinolin-2- yl)-5-(4-o-tolylpiperazin-1- yl)pentane-1,5-dione
A
7.85 8.01
412 412


 


Ia.141




1-(4-benzylpiperidin-1-yl)- 5-(octahydroisoquinolin-2- yl)pentane-1,5-dione
A
8.01 8.16
411 411


 


Ia.142




1,5-bis- (octahydroisoquinolin-2- yl)pentane-1,5-dione
A
8.04 8.21
375 375


 


Ia.143




1-(4-methylpiperidin-1-yl)- 5-(octahydroisoquinolin-2- yl)pentane-1,5-dione
A
7.03 7.22
335 335


 


Ia.144




1-(4-benzhydrylpiperazin- 1-yl)-5- (octahydroisoquinolin-2- yl)pentane-1,5-dione
A
6.53 6.67
488 448


 


Ia.145




1-(3,4-dihydro-2-H- quinolin-1-yl)-5- (octahydroisoquinolin-2- yl)pentane-1,5-dione
A
7.49 7.66
369 370


 


Ia.146




1-(octahydroisoquinolin-2- yl)-5-(1-oxo-3,4-dihydro- 1-H-isoquinolin-2- yl)pentane-1,5-dione
A
7.73 7.90
383 383


 


Ia.147




1-(octahydroisoquinolin-2- yl)-6-(4-oxopiperidin-1- yl)hexane-1,6-dione
B
3.04 3.14
349 349 


 


Ia.148




1-(octahydroisoquinolin-2- yl)-6-piperidin-1-ylhexane- 1,6-dione
B
3.64 3.75
335 335


 


Ia.149




6-(octahydroisoquinolin-2- yl)-6-oxohexanoic acid (3- phenylpropyl)amide
B
3.93 4.02
385 385


 


Ia.150




1-(4-benzylpiperazin-1-yl)- 6-(octahydroisoquinolin-2- yl)hexane-1,6-dione
B
2.77 2.83
426 426


 


Ia.151




6-(octahydroisoquinolin-2- yl)-6-oxohexanoic acid phenethylamide
B
3.75 3.84
371 371


 


Ia.152




6-(octahydroisoquinolin-2- yl)-6-oxohexanoic acid benzylamide
B
3.63 3.73
357 357


 


Ia.153




6-(octahydroisoquinolin-2- yl)-6-oxohexanoic acid ethylmethylamide
B
3.36 3.46
309 309


 


Ia.154




6-(octahydroisoquinolin-2- yl)-6-oxohexanoic acid methylpropylamide
B
3.61 3.72
323 323


 


Ia.155




6-(octahydroisoquinolin-2- yl)-6-oxohexanoic acid butylmethylamide
B
3.88 3.98
337 337


 


Ia.156




6-(octahydroisoquinolin-2- yl)-1-perhydroazepin-1- ylhexane-1,6-dione
B
3.82 3.92
349 349


 


Ia.157




1-(3,5-dimethylpiperidin-1- yl)-6- (octahydroisoquinolin-2- yl)hexane-1,6-dione
B
4.20 4.29
363 363


 


Ia.158




6-(octahydroisoquinolin-2- yl)-6-oxohexanoic acid benzylmethylamide
B
3.92 4.02
371 371


 


Ia.159




1-[4-(2- fluorophenyl)piperazin-1- yl]-6- (octahydroisoquinolin-2- yl)hexane-1,6-dione
B
4.08 4.17
430 430


 


Ia.160




1-(octahydroisoquinolin-2- yl)-6-(4-o-tolylpiperazin-1- yl)hexane-1,6-dione
B
4.35 4.44
426 426


 


Ia.161




6-(octahydroisoquinolin-2- yl)-1-perhydroazocin-1- ylhexane-1,6-dione
B
4.03 4.13
363 363


 


Ia.162




6-(octahydroisoquinolin-2- yl)-6-oxohexanoic acid tricyclo[3.3.1.13,7]ldecan-1- ylamide
B
4.41 4.50
401 401


 


Ia.163




6-(octahydroisoquinolin-2- yl)-6-oxohexanoic acid tricyclo[3.3.1.13,7]decan- 2-ylamide
B
4.32 4.41
401 401


 


Ia.164




1-(4-methylpiperidin-1-yl)- 6-(octahydroisoquinolin-2- yl)hexane-1,6-dione
B
3.92 4.02
349 349


 


Ia.165




1-(3-methylpiperidin-1-yl)- 6-(octahydroisoquinolin-2- yl)hexane-1,6-dione
B
3.91 4.02
349 349


 


Ia.166




1,6-bis- (octahydroisoquinolin-2- yl)hexane-1,6-dione
B
4.47 4.56
389 389


 


Ia.167




6-(octahydroisoquinolin-2- yl)-6-oxohexanoic acid cyclohexylmethylamide
B
4.12 4.21
363 363


 


Ib.63




Octahydroisoquinoline-2- carboxylic acid [2-(3- phenylpropylcarbamoyl) ethyl]amide
B
3.72 3.80
372 372


 


Ib.64




Octahydroisoquinoline-2- carboxylic acid (2- benzylcarbamoylethyl) amide
B
3.42 3.50
344 344


 


Ib.65




Octahydroisoquinoline-2- carboxylic acid [2- (ethylmethylcarbamoyl) ethyl]amide
B
3.06 3.17
296 296


 


Ib.66




Octahydroisoquinoline-2- carboxylic acid [2- (methylpropylcarbamoyl) ethyl]amide
B
3.32 3.42
310 310


 


Ib.67




Octahydroisoquinoline-2- carboxylic acid [3-(3,5- dimethylpiperidin-1-yl)-3- oxopropyl]amide
B
3.91 3.98
350 350


 


Ib.68




Octahydroisoquinoline-2- carboxylic acid [2- (benzylmethylcarbamoyl) ethyl]amide
B
3.66 3.75
358 358


 


Ib.69




Octahydroisoquinoline-2- carboxylic acid [3-(4- methylpiperidin-1-yl)-3- oxopropyl]amide
B
3.62 3.71
336 336


 


Ib.70




Octahydroisoquinoline-2- carboxylic acid [3-(3- methylpiperidin-1-yl)-3- oxopropyl]amide
B
3.61 3.70
336 336


 


Ib.71




Octahydroisoquinoline-2- carboxylic acid [2- (cyclohexylmethylcarba- moyl)ethyl]amide
B
3.83 3.91
350 350


 


Ib.72




Octahydroisoquinoline-2- carboxylic acid (4-oxo-4- piperidin-1-ylbutyl)amide
B
3.41 3.51
336 336


 


Ib.73




Octahydroisoquinoline-2- carboxylic acid [3-(3- phenylpropylcarbamoyl) propyl]amide
B
3.88
386


 


Ib.74




Octahydroisoquinoline-2- carboxylic acid [4-(4- benzylpiperazin-1-yl)-4- oxobutyl]amide
B
2.67
427


 


Ib.75




Octahydroisoquinoline-2- carboxylic acid (3- phenethylcarbamoylpropyl) amide
B
3.70
372


 


Ib.76




Octahydroisoquinoline-2- carboxylic acid (3- benzylcarbamoylpropyl) amide
B
3.58
358


 


Ib.77




Octahydroisoquinoline-2- carboxylic acid [3- (ethylmethylcarbamoyl) propyl]amide
B
3.24
310


 


Ib.78




Octahydroisoquinoline-2- carboxylic acid [3- (methylpropylcarbamoyl) propyl]amide
B
3.37 3.47
324 324


 


Ib.79




Octahydroisoquinoline-2- carboxylic acid [3- (butylmethylcarbamoyl) propyl]amide
B
3.74
338


 


Ib.80




Octahydroisoquinoline-2- carboxylic acid [3- (methylnaphthalen-1- ylmethylcarbamoyl) propyl]amide
B
4.15
422


 


Ib.81




Octahydroisoquinoline-2- carboxylic acid (4-oxo-4- perhydroazepin-1- ylbutyl)amide
B
3.57  3.67
350 350


 


Ib.82




Octahydroisoquinoline-2- carboxylic acid [4-(3,5- dimethylpiperidin-1-yl)-4- oxobutyl]amide
B
3.95 4.04
364 364


 


Ib.83




Octahydroisoquinoline-2- carboxylic acid [3- (benzylmethylcarbamoyl) propyl]amide
B
3.69 3.78
372 372


 


Ib.84




Octahydroisoquinoline-2- carboxylic acid {4-[4-(2- fluorophenyl)piperazin-1- yl]-4-oxobutyl}amide
B
3.85 3.94
431 431


 


Ib.85




Octahydroisoquinoline-2- carboxylic acid [4-oxo-4- (4-o-tolylpiperazin-1- yl)butyl]amide
B
4.12 4.20
427 427


 


Ib.86




Octahydroisoquinoline-2- carboxylic acid (4-oxo-4- perhydroazocin-1- ylbutyl)amide
B
3.78 3.87
364 364


 


Ib.87




Octahydroisoquinoline-2- carboxylic acid [3- (tricyclo[3.3.1.13,7]decan-1- ylcarbamoyl)propyl]amide
B
4.38
402


 


Ib.88




Octahydroisoquinoline-2- carboxylic acid [4-(4- methylpiperidin-1-yl)-4- oxobutyl]amide
B
3.67 3.77
350 350


 


Ib.89




Octahydroisoquinoline-2- carboxylic acid [4-(3- methylpiperidin-1-yl)-4- oxobutyl]amide
B
3.66 3.76
350 350


 


Ib.90




Octahydroisoquinoline-2- carboxylic acid [3- (cyclohexylmethylcarba- moyl)propyl]amide
B
3.87  3.96
364 364


 


Ib.91




Octahydroisoquinoline-2- carbothioic acid S-[3- (cyclohexylmethylcarba- moyl)propyl] ester
B
4.49
381


 


Ib.92




Octahydroisoquinoline-2- carboxylic acid [3- (octahydroquinolin-1-yl)-3- oxopropyl]amide
B
4.10 4.17
376 376


 


Ib.93




Octahydroisoquinoline-2- carboxylic acid [3-oxo-3- (4-oxooctahydroquinolin- 1-yl)propyl]amide
B
3.46 3.53
390 390


 


Ib.94




Octahydroquinoline-1- carboxylic acid [4- (octahydroquinolin-1-yl)-4- oxobutyl]amide
B
4.15
390


 


Ib.95




Octahydroisoquinoline-2- carboxylic acid [4- (octahydroquinolin-1-yl)-4- oxobutyl]amide
B
4.22
390


 


Ib.96




Octahydroisoquinoline-2- carboxylic acid [3- (octahydroisoquinolin-2- yl)-3-oxopropyl]amide
B
4.17 4.25
376 376


 


Ib.97




Octahydroquinoline-1- carboxylic acid N-[3- [(3s,5s,7s)-adamantan-1- ylamino-3-oxopropyl] amide
B
4.18
388


 


Im.17




1-[4- (octahydroisoquinoline-2- sulfonyl)butyryl]piperidin- 4-one
B
3.25 3.31
371 371


 


Im.18




4-(octahydroisoquinoline- 2-sulfonyl)-1-piperidin-1- ylbutan-1-one
B
3.93
357


 


Im.19




1-(4-hydroxypiperidin-1- yl)-4- (octahydroisoquinoline-2- sulfonyl)butan-1-one
B
3.04 3.11
373 373


 


Im.20




4-(octahydroisoquinoline- 2-sulfonyl)-1- perhydroazepin-1- ylbutan-1-one
B
4.02 4.09
371 371


 


Im.21




1-(3,5-dimethylpiperidin-1- yl)-4- (octahydroisoquinoline-2- sulfonyl)butan-1-one
B
4.37 4.45
385 385


 


Im.22




4-(octahydroisoquinoline- 2-sulfonyl)-1- perhydroazocin-1-ylbutan- 1-one
B
4.23 4.30
385 385


 


Im.23




1-((R)-3-hydroxypiperidin- 1-yl)-4- (octahydroisoquinolin-2- sulfonyl)butan-1-one
B
3.15 3.22
373 373


 


Im.24




1-(4-methylpiperidin-1-yl)- 4-(octahydroisoquinoline- 2-sulfonyl)butan-1-one
B
4.12 4.19
371 371


 


Im.25




1-(3-methylpiperidin-1-yl)- 4-(octahydroisoquinoline- 2-sulfonyl)butan-1-one
B
4.11 4.18
371 371


 


Im.26




N-cyclohexyl-N-methyl-4- (octahydroisoquinoline-2- sulfonyl)butyramide
B
4.31 4.37
385 385


 


Im.27




1-(3,3-difluoropiperidin-1- yl)-4- (octahydroisoquinoline-2- sulfonyl)butan-1-one
B
3.87 3.93
393 393


 


Im.28




1-(4,4-difluoropiperidin-1- yl)-4- (octahydroisoquinoline-2- sulfonyl)butan-1-one
B
3.87 3.94
393 393


 


Im.29




4-(octahydroquinoline-1- sulfonyl)-1- (octahydroquinolin-1- yl)butan-1-one
B
4.51
411


 


Im.30




4-(octahydroisoquinoline- 2-sulfonyl)-1- (octahydroisoquinolin-2- yl)butan-1-one
B
4.63 4.70
411 411


 


Ia.168




1-(octahydroisoquinolin-2- yl)-4-(6- oxooctahydroindol-1- yl)butane-1,4-dione
B
4.33 4.41
361 361


 


Ia.169




1-(octahydroisoquinolin-2- yl)-5-(6- oxooctahydroindol-1- yl)pentane-1,5-dione
B
4.38 4.48
375 375


 


Ia.170




1-[4-(2- fluorophenyl)piperazin-1- yl]-6-(octahydroquinolin-1- yl)hexane-1,6-dione
B
4.09
430


 


Ia.171




1-(octahydroquinolin-1-yl)- 6-(4- oxooctahydroquinolin-1- yl)hexane-1,6-dione
B
3.72
403


 


Ia.172




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N-[3- (1H-imidazol-1- yl)propyl]amide
B
2.29
361


 


Ia.173




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N- (2,4- dichlorophenethyl)amide
B
4.20
 425, 427


 


Ia.174




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N-[2- (5-methoxy-1H-indol-3- yl)ethyl]amide
B
3.47
426


 


Ia.175




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N- (3,4- dimethoxyphenethyl]amide
B
3.41
417


 


Ia.176




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N-[2- (pyridin-2-yl)ethyl]amide
B
2.34
358


 


Ia.177




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N-(4- aminophenethyl)amide
B
2.44
372


 


Ia.178




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N- (3,3-diphenylpropyl)amide
B
4.28
447


 


Ia.179




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N-(2- methoxyphenethyl)amide
B
3.74
387


 


Ia.180




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N-(2- chlorophenethyl)amide
B
3.88
391


 


Ia.181




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N-(4- sulfamoylphenethyl)amide
B
2.97
436


 


Ia.182




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N-(2- phenoxyethyl)amide
B
3.67
373


 


Ia.183




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N-(3- methoxyphenethyl)amide
B
3.65
387


 


Ia.184




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N-(3- chlorophenethyl)amide
B
3.92
391


 


Ia.185




5-(octahydroquinolin-1)- yl)-5-oxopentanoic acid N- [2-(benzo[d][1,3]dioxol-5- yl)ethyl]amide
B
3.56
401


 


Ia.186




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N-[(1- phenylcyclopropyl)methyl] amide
B
3.92
383


 


Ia.187




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N-[2- (naphthalen-2- yl)ethyl]amide
B
4.05
407


 


Ia.188




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N- [(R)-2-phenyl-2- hydroxyethyl]amide
B
3.19
373


 


Ia.189




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N- [(1R,2S)-1-phenyl-1- hydroxypropan-2-yl]amide
B
3.37
387


 


Ia.190




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N- (2,3-dihydro-1H-inden-2- yl)amide
B
3.77
369


 


Ia.191




(2S)-3-(4-hydroxyphenyl)- 2-[5-(octahydroquinolin-1- yl)-5- oxopentanamide]propanoic acid methyl ester
B
3.21
431


 


Ia.192




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N-[2- (thiophen-2-yl)ethyl]amide
B
3.58
363


 


Ia.193




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N-(4- chlorophenethyl)amide
B
3.93
391


 


Ia.194




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N- (2,2-diphenylpropyl)amide
B
4.39
447


 


Ia.195




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N- (2,2-diphenylethyl)amide
B
4.16
433


 


Ia.196




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N-(4- methylphenethyl)amide
B
3.88
371


 


Ia.197




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N-(4- methoxyphenethyl)amide
B
3.61
387


 


Ia.198




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N-(3- fluorophenethyl)amide
B
3.72
375


 


Ia.199




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N-(4- hydroxyphenethyl)amide
B
3.10
373


 


Ia.200




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N-(1- hydroxyl-1-(4- hydroxyphenyl)propan-2- yl)amide
B
2.88
403


 


Ia.201




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N-(1- hydroxyl-1-(3- hydroxyphenyl)propan-2- yl)amide
B
3.00
403


 


Ia.202




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N-[2- (5-hydroxyl-1H-indol-3- yl)ethyl]amide
B
3.04
412


 


Ia.203




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N- [(R)-1-amino-3-phenyl-1- oxopropan-2-yl]amide
B
3.19
400


 


Ia.204




N-methyl-5- (octahydroquinolin-1-yl)-5- oxopentanoic acid N-((4- phenyltetrahydro-2H- pyran-4-yl)methyl)amide
B
3.89
441


 


Ia.205




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N-(2- phenylpropyl)amide
B
4.02
385


 


Ia.206




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N-[2- (naphthalen-1- yl)ethyl]amide
B
4.06
407


 


Ia.207




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N-[(4- phenyltetrahydro-2H- pyran-4-yl)methyl]amide
B
3.06
427


 


Ia.208




5-(octahydroquinolin-1-yl)- 5-oxopropanoic acid N- [(S)-3-phenyl-1-oxo-1- (pyrrolidin-1-yl)propan-2- yl]amide
B
3.65
454


 


Ia.209




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N- [(S)-1-(cyclohexylamino)- 3-phenylpropane-1-oxo-2- yl]amide
B
4.06
482


 


Ia.210




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N- [(S)-1-amino-3-phenyl-1- oxopropan-2-yl]amide
B
3.19
400


 


Ia.211




N-(2-amino-2-oxoethyl)-5- (octahydroquinolin-1-yl)-5- oxopentanoic acid N- phenethylamide
B
3.41
414


 


Ia.212




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N- [(S)-1-amino-3-(1H-indol- 3-yl)-1-oxopropan-2- yl]amide
B
3.15
439


 


Ia.213




1-(2-phenyl-4- methylpiperazin-1-yl)-5- (octahydroquinolin-1- yl)pentane-1,5-dione
B
2.58
412


 


Ia.214




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N- benzyl-N-ethylamide
B
4.06
371


 


Ia.215




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N-(4- methoxybenzyl)amide
B
3.50
373


 


Ia.216




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N-(4- (trifluoromethyl)benzyl) amide
B
3.97
411


 


Ia.217




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N- [(R)-1-phenylethyl]amide
B
3.70
357


 


Ia.218




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N,N- dibenzylamide
B
4.53
433


 


Ia.219




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N- (9H-fluoren-9-yl)amide
B
4.18
417


 


Ia.220




2-(N-benzyl-5- (octahydroquinolin-1-yl)-5- oxopentanamide)acetic acid ethyl ester
B
4.12
429


 


Ia.221




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N- [cyano(phenyl)methyl] amide
B
3.68
368


 


Ia.222




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N- benzhydrylamide
B
4.15
419


 


Ia.223




(2R)-2-(5- (octahydroquinolin-1-yl)- 5-oxopentanamido)-2- phenylacetic acid methyl  ester
B
3.67
401


 


Ia.224




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N- (1,2,3,4- tetrahydronaphthalen-1- yl)amide
B
3.96
383


 


Ia.225




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N- (benzo[d][1,3]dioxol-5-yl methyl)amide
B
3.46
387


 


Ia.226




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N- benzyl-N-butylamide
B
4.51
399


 


Ia.227




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N- benzyl-N-[2- (dimethylamino)ethyl] amide
B
2.83
414


 


Ia.228




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N- benzyl-N-isopropylamide
B
4.22
385


 


Ia.229




2-[N-[3-(1H-imidazol-1- yl)propyl]-5- (octahydroquinolin-1-yl)-5- oxopentanamido]acetic acid ethyl ester
B
2.67
447


 


Ia.230




2-[5-(octahydroquinolin-1- yl)-5-oxo-N-(4- sulfamoylphenethyl)pentan- amido]acetic acid ethyl ester
B
3.43
522


 


Ia.231




2-[N-[2-(5-methoxy-1H- indol-3-yl)ethyl]-5- (octahydroquinolin-1-yl)-5- oxopentanamido]acetic acid ethyl ester
B
3.92
512


 


Ia.232




2-[5-(octahydroquinolin-1- yl)-5-oxo-N-[2-(pyridin-2- yl)ethyl]pentanamido] acetic acid ethyl ester
B
2.79
444


 


Ia.233




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N-(2- amino-2-oxoethyl)-N- benzylamide
B
3.28
400


 


Ia.234




3-[N-benzyl-5- (octahydroquinolin-1-yl)-5- oxopentanamido]propanoic acid ethyl ester
B
4.15
443


 


Ia.235




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N- benzyl-N-(2- hydroxyethyl)amide
B
3.47
387


 


Ia.236




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N- (1,2-diphenylethyl)amide
B
4.21
433


 


Ia.237




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N-  benzhydryl-N-methylamide
B
4.53
433


 


Ia.238




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N-(4- chlorobenzyl)amide
B
3.82
377


 


Ia.239




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N-[4- (trifluoromethoxy)benzyl] amide
B
4.06
427


 


Ia.240




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N-[3- (trifluoromethoxy)benzyl] amide
B
4.06
427


 


Ia.241




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N-[3- (trifluoromethyl)benzyl] amide
B
3.97
411


 


Ia.242




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N- phenethyl-N-[2- (phenethylamino)-2- oxoethyl]amide
B
4.25
518


 


Ia.243




5-(octahydroquinolin-1-yl) 5-oxopentanoic acid N-[2- oxo-2-{[2-(thiophen-2- yl)ethyl]amino}ethyl]-N- [2-(thiophen-2- yl)ethyl]amide
B
4.11
530


 


Ia.244




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N- [(S)-3-phenyl-1- hydroxypropan-2-yl]amide
B
3.31
387


 


Ia.245




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N- [(S)-1-phenylethyl]amide
B
3.70
357


 


Ia.246




2-[N-(4- hydroxyphenethyl)-5- (octahydroquinolin-1-yl)-5- oxopentanamido]acetic acid ethyl ester
B
3.59
459


 


Ia.247




2-(N-(3,4- dimethoxyphenethyl)-5- (octahydroquinolin-1-yl)-5- oxopentanamido]acetic acid ethyl ester
B
3.91
503


 


Ia.248




2-[N-[2-(1H-indol-3- yl)ethyl]-5- (octahydroquinolin-1-yl)-5- oxopentanamido]acetic acid ethyl ester
B
4.04
482


 


Ia.249




2-[N-[2-(5-hydroxy-1H- indol-3-yl)ethyl]-5- (octahydroquinolin-1-yl)-5- oxopentanamido]acetic acid ethyl ester
B
3.47
498


 


Ia.250




2-[N-(4-nitrophenethyl)-5- (octahydroquinolin-1-yl)-5- oxopentanamido]acetic acid ethyl ester
B
4.10
488


 


Ia.251




2-(N-(2,4- dichlorophenethyl)-5- (octahydroquinolin-1-yl)-5- oxopentanamido]acetic acid ethyl ester
B
4.73
511


 


Ia.252




2-[N-(4-chlorophenethyl)- 5-(octahydroquinolin-1-yl)- 5-oxopentanamido]acetic acid ethyl ester
B
4.45
477


 


Ia.253




2-[N-(4- methoxyphenethyl)-5- (octahydroquinolin-1-yl)-5- oxopentanamido]acetic acid ethyl ester
B
4.14
473


 


Ia.254




2-[5-(octahydroquinolin-1- yl)-5-oxo-N-[2- (trifluoromethyl)benzyl] pentanamido]acetic acid methyl ester
B
4.27
483


 


Ia.255




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N-(2- amino-2-oxoethyl)-N-[2- (1H-indol-3-yl)ethyl]amide
B
3.34
453


 


Ia.256




5-(octahydroquinolin-1-yl)- 5-oxopentanoic acid N- (2,4-dichlorophenethyl)-N- [2-[(2,4- dichlorophenethyl)amino]- 2-oxoethyl]amide
B
5.13
 654, 656


 


Ia.257




2-[N-[4- (benzyloxy)benzyl]-5- (octahydroquinolin-1-yl)-5- oxopentanamido]acetic acid methyl ester
B
4.46
521


 


Ia.258




2-[5-(octahydroquinolin-1- yl)-5-oxo-N-(3- phenoxybenzyl)pentan- amido]acetic acid ethyl ester
B
4.65
521


 


Ia.259




2-[5-(octahydroquinolin-1- yl)-5-oxo-N-(4- phenylbutyl)pentanamido] acetic acid ethyl ester
B
4.54
471


 


Ia.260




3-[N-[4- (benzyloxy)benzyl]-5- (octahydroquinolin-1-yl)-5- oxopentanamido]propanoic acid methyl ester
B
4.48
535


 


Ia.261




6-(octahydroisoquinolin-2- yl)-6-oxohexanoic acid N- methyl-N-(naphthalen-1- ylmethyl)amide
B
4.31 4.40
421 421


 


Ia.262




1-(octahydroisoquinolin-2- yl)-6-(4- oxooctahydroquinolin-1- yl)hexane-1,6-dione
B
3.72 3.81
403 403


 


Ia.263




5-(octahydro-quinolin-1- yl)-5-oxo-pentanoic acid (3-methyl-10,11-dihydro- 5H- dibenzo[a,d]cyclohepten-5- yl)amide
C
5.01
459


 


Ia.264




5-(octahydro-quinolin-1- yl)-5-oxo-pentanoic acid (3-ethyl-10,11-dihydro-5H- dibenzo[a,d]cyclohepten-5- yl)amide
C
5.20
473


 


Ia.265




5-[(R)-1-phenyl-3,4- dihydro-1H-isoquinolin-2- yl]-1-(octahydro-quinolin- 1-yl)-pentane-1,5-dione
C
5.02
445


 


Ia.266




5-(octahydro-quinolin-1- yl)-5-oxo-pentanoic acid (1-phenyl- cyclobutylmethyl)amide
C
4.64
397


 


Ia.267




5-(octahydro-quinolin-1- yl)-5-oxo-pentanoic acid (2-cyclohexyl-2-phenyl- ethyl)amide
C
5.19
439









Ex. Ie.1
1-[5-(octahydroquinolin-1-yl)-5-oxopentyl]-3-tricyclo[3.3.1.13,7]decan-1-ylurea




35 mg (0.15 mmol) of intermediate Vc.4 are dissolved in 2 mL of anhydrous THF and 23 μL (0.25 mmol) of Et3N. Once dissolved 17.3 mg (0.1 mmol) of 1-adamantyl isocyanate are slowly added and it is refluxed for 2 days. AcOEt is then added and the resulting solution is sequentially washed with water, 1N HCl and brine. The organic phase is dried over anhydrous Na2SO4, it is filtered and the solvent is evaporated under reduced pressure yielding 47.5 mg of a yellowish oil identified as example Ie.1. Method B: tr: 4.27 min; m/z: 416.
The following examples were prepared in a manner similar to example Ie.1.















Ex.
structure
name
method
tr (min) 
m/z







Ie.2




1-[3-(octahydroquinolin- 1-yl)-3-oxopropyl]-3- phenylurea
B
3.49
330


 


Ie.3




1-s-butyl-3-[3- (octahydroquinolin-1-yl)- 3-oxopropyl]urea
B
3.28 3.56
310 310


 


Ie.4




1-[3-(octahydroquinolin- 1-yl)-3-oxopropyl]-3- tricyclo[3.3.1.13.7]decan- 1-ylurea
B
4.18
388


 


Ie.5




1-[3-(octahydroquinolin- 1-yl)-3-oxopropyl]-3-(4- thiophen-2- yltetrahydropyran-4- yl)urea
B
3.40
420


 


Ie.6




1-cyclohexyl-3-[3- (octahydroquinolin-1-yl)- 3-oxopropyl]urea
A
6.55
336


 


Ie.7




1-benzyl-3-[3- (octahydroquinolin-1-yl)- 3-oxopropyl]urea
A
6.28
344


 


Ie.8




1-(4-fluorophenyl)-3-[3- (octahydroquinolin-1-yl)- 3-oxopropyl]urea
A
6.56
348


 


Ie.9




1-t-butyl-3-[3- (octahydroquinolin-1-yl)- 3-oxopropyl]urea
A
6.25
310


 


Ie.10




1-isopropyl-3-[3- (octahydroquinolin-1-yl)- 3-oxopropyl]urea
A
5.65
296


 


Ie.11




1-furan-2-ylmethyl-3-[3- (octahydroquinolin-1-yl)- 3-oxopropyl]urea
A
5.85
334


 


Ie.12




1-(6-fluoro-4-H-1,3- benzodioxin-8-yl)-3-[3- (octahydroquinolin-1-yl)- 3-oxopropyl]urea
A
6.75
406


 


Ie.13




1-cycloheptyl-3-[3- (octahydroquinolin-1-yl)- 3-oxopropyl]urea
A
6.93
350


 


Ie.18




1-benzyl-3-[4- (octahydroquinolin-1-yl)- 4-oxobutyl]urea
B
3.44
358


 


Ie.19




1-[4-(octahydroquinolin- 1-yl)-4-oxobutyl]-3- thiophen-2-ylurea
B
3.41
350


 


Ie.20




1-[4-(octahydroquinolin- 1-yl)-4-ozobutyl]-3- tricyclo[3.3.1.13.7]decan- 1-ylurea
B
4.18
402


 


Ie.21




1-cyclohexyl-3-[4- (octahydroquinolin-1-yl)- 4-oxobutyl]urea
B
3.59
350


 


Ie.22




1-cycloheptyl-3-[4- (octahydroquinolin-1-yl)- 4-oxobutyl]urea
B
3.80
364


 


Ie.23




1-cyclohexyl-3-[5- (octahydroquinolin-1-yl)- 5-oxopentyl]urea
B
3.69
364


 


Ie.24




1-[5-(octahydroquinolin- 1-yl)-5-oxopentyl]-3- phenylurea
B
3.61
358


 


Ie.25




1-benzyl-3-[5- (octahydroquinolin-1-yl)- 5-oxopentyl]urea
B
3.55
372


 


Ie.26




1-(4-fluorophenyl)-3-[5- (octahydroquinolin-1-yl)- 5-oxopentyl]urea
B
3.67
376


 


Ie.27




1-s-butyl-3-[5- (octahydroquinolin-1-yl)- 5-oxopentyl]urea
B
3.44
338


 


Ie.28




1-t-butyl-3-[5- (octahydroquinolin-1-yl)- 5-oxopentyl]urea
B
3.55
338


 


Ie.29




1-isopropyl-3-[5- (octahydroquinolin-1-yl)- 5-oxopentyl]urea
B
3.24
324


 


Ie.30




1-furan-2-ylmethyl-3-[5- (octahydroquinolin-1-yl)- 5-oxopentyl]urea
B
3.33
362


 


Ie.31




1-cycloheptyl-3-[5- (octahydroquinolin-1-yl)- 5-oxopentyl]urea
B
3.88
378


 


Ig.1




Octahydroquinoline-1- carboxylic acid [3-(3- cyclohexylureido)propyl] amide
B
3.60
365


 


Ig.2




Octahydroquinoline-1- carboxylic acid [3-(3- phenylureido)propyl]amide 
B
3.52
359


 


Ig.3




Octahydroquinoline-1- carboxylic acid [3-(3- benzylureido)propyl]amide
B
3.45
373


 


Ig.4




Octahydroquinoline-1- carboxylic acid {3-[3-(4- fluorophenyl)ureido] propyl}amide
B
3.58
377


 


Ig.5




Octahydroquinoline-1- carboxylic acid [3-(3-s- butylureido)propyl]amide
B
3.33
339


 


Ig.6




Octahydroquinoline-1- carboxylic acid [3-(3-t- butylureido)propyl]amide
B
3.48
339


 


Ig.7




Octahydroquinoline-1- carboxylic acid [3-(3- furan-2-ylmethylureido) propyl]amide
B
3.22
363


 


Ig.8




Octahydroquinoline-1- carboxylic acid [3-(3- tricyclo[3.3.1.13.7]decan- 1-ylureido)propyl]amide
B
4.26
417


 


Ig.9




Octahydroquinoline-1- carboxylic acid [3-(3- cycloheptylureido)propyl] amide
B
3.80
379


 


Ig.10




Octahydroquinoline-1- carboxylic acid {3-[3-(4- thiophen-2- yltetrahydropyran-4- yl)ureido]propyl}amide
B
3.47
449


 


Ie.32




l-cyclohexyl-3-[2- (octahydroisoquinolin-2- yl)-2-oxoethyl]urea
B
3.52 3.62
322 322


 


Ie.33




1-s-butyl-3-[2- (octahydroisoquinolin-2- yl)-2-oxoethyl]urea
B
3.35
296


 


Ie.34




1-ethyl-3-[2- (octahydroisoquinolin-2- yl)-2-oxoethyl]urea
B
2.78 2.90
268 268


 


Ie.35




1-isopropyl-3-[2- (octahydroisoquinolin-2- yl)-2-oxoethyl]urea
B
3.01 3.12
282 282


 


Ie.36




1-furan-2-ylmethyl-3-[2- (octahydroisoquinolin-2- yl)-2-oxoethyl]urea
B
3.15 3.26
320 320


 


Ie.37




1-[2- (octahydroisoquinolin-2- yl)-2-oxoethyl]-3- tricyclo[3.3.1.13.7]decan- 1-ylurea
B
4.25
374


 


Ie.38




1-cycloheptyl-3-[2- (octahydroisoquinolin-2- yl)-2-oxoethyl]urea
B
3.83
336


 


Ie.39




1-[2- (octahydroisoquinolin-2- yl)-2-oxoethyl]-3- phenylurea
B
3.60
316


 


Ie.40




1-benzyl-3-[2- (octahydroisoquinolin-2- yl)-2-oxoethyl]urea
B
3.41 3.50
330 330


 


Ie.41




1-(4-fluorophenyl)-3-[2- (octahydroisoquinolin-2- yl)-2-oxoethyl]urea
B
3.57 3.67
334 334


 


Ig.11




octahydroisoquinoline-2- carboxylic acid [3-(3- cyclohexylureido)propyl] amide
B
3.59 3.68
365 365


 


Ig.12




Octahydroisoquinoline- 2-carboxylic acid [3-(3- phenylureido)propyl]amide
B
3.51 3.60
359 359


 


Ig.13




Octahydroisoquinoline- 2-carboxylic acid [3-(3- benzylureido)propyl]amide
B
3.45 3.54
373 373


 


Ig.14




Octahydroisoquinoline- 2-caxboxylic acid {3-[3- (4-fluorophenyl)ureido] propyl}amide
B
3.57 3.66
377 377


 


Ig.15




Octahydroisoquinoline- 2-carboxylic acid [3-(3-s- butylureido)propyl]amide
B
3.33 3.42
339 339


 


Ig.16




Octahydroisoquinoline- 2-carboxylic acid [3-(3-t- butylureido)propyl]amide
B
3.46 3.56
339 339


 


Ig.17




Octahydroisoquinoline- 2-carboxylic acid [3-(3- furan-2- ylmethylureido)propyl] amide
B
3.22 3.32
363 363


 


Ig.18




Octahydroisoquinoline- 2-carboxylic acid {3-[3- (6-fluoro-4H-1,3- benzodioxin-8- yl)ureido]propyl}amide
B
3.67 3.75
435 435


 


Ig.19




Octahydroisoquinoline- 2-carboxylic acid [3-(3- tricyclo[3.3.1.13.7]decan- 1-ylureido)propyl]amide
B
4.23 4.31
417 417


 


Ig.20




Octahydroisoquinoline- 2-carboxylic acid [3-(3- cycloheptylureido)propyl] amide
B
3.79 3.88
379 379


 


Ie.43




1-[3-(octahydroquinolin- 1-yl)-3-oxopropyl]-3- tricyclo[3.3.1.13.7]decan- 1-ylthiourea
B
4.68
404


 


Ie.44




1-benzyl-3-[3- (octahydroquinolin-1-yl)- 3-oxopropyl]thiourea
B
3.88
360


 


Ie.45




1-cyclopentyl-3-[3- (octahydroquinolin-1-yl)- 3-oxopropyl]thiourea
B
3.84
338


 


Ie.46




1-(2-cyclohex-1- enylethyl)-3-[3- (octahydroquinolin-1-yl)- 3-oxopropyl]thiourea
B
4.40
378


 


Ie.47




1-cyclohexylmethyl-3- [3-(octahydroquinolin-1- yl)-3-oxopropyl]thiourea
A
7.92
366


 


Ie.48




1-t-butyl-3-[3- (octahydroquinolin-1-yl)- 3-oxopropyl]thiourea
A
7.11 
326


 


Ie.49




1-cyclohexyl-3-[3- (octahydroquinolin-1-yl)- 3-oxopropyl]thiourea
A
7.47
352


 


Ie.50




1-[3-(octahydroquinolin- 1-yl)-3-oxopropyl]-3- phenylthiourea
A
6.94
346


 


Ie.51




1-benzhydryl-3-{3- (octahydroquinolin-1-yl)- 3-oxopropyl]thiourea
A
8.22
436


 


Ie.52




1-cyclohexylmethyl-3- [4-(octahydroquinolin-1- yl)-4-oxobutyl]thiourea
B
4.33
380


 


Ie.53




l-cyclohexyl-3-[4- (octahydroquinolin-1-yl) 4-oxobutyl]thiourea
B
4.10
366


 


Ig.21




Octahydroquinoline-1- carboxylic acid [3-(3- cyclohexylmethyl- thioureido)propyl]amide
B
4.23
395


 


Ig.22




Octahydroquinoline-1- carboxylic acid [3-(3-t- butylthioureido)propyl] amide
B
3.79
355


 


Ig.23




Octahydroquinoline-1- carboxylic acid [3-(3- benzylthioureido)propyl] amide
B
3.82
389


 


Ig.24




Octahydroquinoline-1- carboxylic acid [3-(3- cyclopentylthioureido) propyl]amide
B
3.79
367


 


Ig.25




Octahydroquinoline-1- carboxylic acid {3-[3-(2- cyclohex-1- enylethyl)thioureido] propyl}amide
B
4.32
407


 


Ig.26




Octahydroquinoline-1- carboxylic acid [3-(3- phenylthioureido)propyl] amide
B
3.66
375


 


Ig.27




Octahydroquinoline-1- carboxylic acid [3-(3- cyclohexylthioureido) propyl]amide
B
4.00
381


 


Ig.28




Octahydroquinoline-1- carboxylic acid [3-(3- benzhydrylthioureido) propyl]amide
B
4.41
465


 


Ie.54




1-cyclohexylmethyl-3- [5-(octahydroquinolin-1- yl)-5-oxopentyl]thiourea
B
4.32
394


 


Ie.55




1-[5-(octahydroquinolin- 1-yl)-5-oxopentyl]-3- tricyclo[3.3.1.13.7]decan- 1-ylthiourea
B
4.67
432


 


Ie.56




1-t-butyl-3-[5- (octahydroquinolin-1-yl)- 5-oxopentyl]thiourea
B
3.90
354


 


Ie.57




1-cyclohexyl-3-[5- (octahydroquinolin-1-yl)- 5-oxopentyl]thiourea
B
4.10
380


 


Ie.58




1-benzhydryl-3-[5- (octahydroquinolin-1-yl)- 5-oxopentyl]thiourea
B
4.49
464


 


Ie.59




1-benzyl-3-[5- (octahydroquinolin-1-yl)- 5-oxopentyl]thiourea
B
3.93
388


 


Ie.60




1-cyclopentyl-3-[5- (octahydroquinolin-1-yl)- 5-oxopentyl]thiourea 
B
3.89
366


 


Ie.61




1-(2-cyclohex-1- enylethyl)-3-[5- (octahydroquinolin-1-yl)- 5-oxopentyl]thiourea
B
4.42
406


 


Ie.62




1-[5-(octahydroquinolin- 1-yl)-5-oxopentyl]-3- phenylthiourea
B
3.81
374


 


Ie.63




1-cyclohexylmethyl-3-[2- (octahydroisoquinolin-2- yl)-2-oxoethyl]thiourea
B
4.35 4.44
352 352


 


Ie.64




1-[2- (octahydroisoquinolin-2- yl)-2-oxoethyl]-3- tricyclo[3.3.1.13.7]decan- 1-yl thiourea
B
4.77 4.81
390 390


 


Ie.65




1-t-butyl-3-[2- (octahydroisoquinolin-2- yl)-2-oxoethyl]thiourea
B
3.90 4.01
312 312


 


Ie.66




1-cyclohexyl-3-[2- (octahydroisoquinolin-2- yl)-2-oxoethyl]thiourea
B
4.10 4.19
338 338


 


Ie.67




1-benzhydryl-3-[2- (octahydroisoquinolin-2- yl)-2-oxoethyl]thiourea
B
4.52 4.59
nd nd


 


Ie.68




1-cyclopentyl-3-[2- (octahydroisoquinolin-2- yl)-2-oxoethyl]thiourea
B
3.89 3.99
324 324


 


Ie.69




1-(2-cyclohex-1- enylethyl)-3-[2- (octahydroisoquinolin-2- yl)-2-oxoethyl]thiourea
B
4.45 4.53
364 364


 


Ig.29




Octahydroisoquinoline- 2-carboxylic acid [3-(3- cyclohexylmethyl- thioureido)propyl]amide
B
4.22 4.30
395 395


 


Ig.30




Octahydroisoquinoline- 2-carboxylic acid [3-(3- tricyclo[3.3.1.13.7]decan- 1-ylthioureido)propyl] amide
B
4.65 4.71
433 433


 


Ig.31




Octahydroisoquinoline- 2-carboxylic acid [3-(3-t- butylthioureido)propyl] amide
B
3.78 3.87
355 355


 


Ig.32




Octahydroisoquinoline- 2-carboxylic acid [3-(3- benzylthioureido)propyl] amide
B
3.81 3.89
389 389


 


Ig.33




Octahydroisoquinoline- 2-carboxylic acid [3-(3- cyclopentylthioureido) propyl]amide
B
3.78 3.87
367 367


 


Ig.34




Octahydroisoquinoline- 2-carboxylic acid {3-[3- (2-cyclohex-1- enylethyl)thioureido] propyl}amide
B
4.31 4.39
407 407


 


Ig.35




Octahydroisoquinoline- 2-carboxylic acid{3-[3- (4-thiophen-2- yltetrahydropyran-4- yl)ureido]propyl}amide
B
3.45 3.54
449 449


 


Ie.70




1-[4-(octahydroquinolin- 1-yl)-4-oxobutyl]-3-[4- (thiophen-2- yl)tetrahydropyran-4- yl]urea
B
3.43
434


 


Ie.71




Octahydroquinoline-1- carboxylic acid N-[3- (octahydroquinolin-1-yl)- 3-oxopropyl]amide
B
4.09
376


 


Ie.72




1-[(3s,5s,7s)-adamantan- 1-yl]-3-[3- (octahydroisoquinolin-2- yl)-3-oxopropyl]urea
B
4.17 4.26
388 388


 


Ie.73




1-isopropyl-3-[5- (octahydroisoquinolin-2- yl)-5-oxopentyl]urea
B
4.60 4.68
324 324


 


Ie.74




1-[(3s,5s,7s)-adamantan- 1-yl]-3-[5- (octahydroisoquinolin-2- yl)-5-oxopentyl]urea
B
4.27 4.35
416 416


 


Ie.75




1-t-butyl-3-[2- (octahydroisoquinolin-2- yl)-2-oxoethyl]urea
B
3.47
296


 


Ie.76




1-[2- (octahydroisoquinolin-2- yl)-2-oxoethyl]-3- (thiophen-2-yl)urea
B
3.50
322


 


Ie.77




1-[(3s,5s,7s)-adamantan- 1-yl]-3-[4- (octahydroquinolin-1-yl)- 4-oxobutyl]thiourea
B
4.68
418


 


Ie.78




1-[2-(cyclohex-1-en-1- yl)ethyl]-3-[4- (octahydroquinolin-1-yl)- 4-oxobutyl]thiourea
B
4.44
392


 


Ie.79




1-[(3s.,5s.7s)-adamantan- 1-yl]-3-[5- (octahydroisoquinolin-2- yl)-5-oxopentyl]thiourea
B
4.67 4.74
432 432


 


Ie.80




1-cyclopentyl-3-[5- (octahydroisoquinolin-2- yl)-5-oxopentyl]thiourea
B
3.88 3.98
366 366


 


Ie.81




3-phenyl-1-[5- (octahydroisoquinolin-2- yl)-5-oxopentyl]-thiourea
B
3.81 3.87
374 374


 


Ie.82




1-(cyclohexylmethyl)-3-[5- (octahydroisoquinolin-2- yl)-5-oxopentyl]thiourea
B
4.32 4.40
394 394


 


Ie.83




1-t-butyl-3-[5- (octahydroisoquinolin-2- yl)-5-oxopenty]thiourea
B
3.89 3.99
354 354


 


Ie.84




1-cyclohexyl-3-[5- (octahydroisoquinolin-2- yl)-5-oxopentyl]thiourea
B
4.09 4.18
380 380


 


Ie.85




1-benzhydryl-3-[5- (octahydroisoquinolin-2- yl)-5-oxopentyl]thiourea
B
4.49 4.56
464 464


 


Ie.86




1-[2-(cyclohex-1-en-1 yl)ethyl]-3-[5- (octahydroisoquinolin-2- yl)-5-oxopentyl]thiourea
B
4.41 4.49
406 406


 


Ig.36




Octahydroquinoline-1- carboxylic acid N-[3-(3- ethylureido)propyl]amide
B
2.91
311


 


Ie.37




Octahydroquinoline-1- carboxylic acid N-[3-(3- isopropylureido)propyl] amide
B
3.13
325


 


Ig.38




Octahydroquinoline-1- carboxylic acid N-[3-[3- (6-fluoro-4H- benzo[d][1,3]dioxin-8- yl)ureido]propyl]amide
B
3.69
435


 


Ig .39




Octahydroquinoline-1- carboxylic acid N-[3-[3- thiophen-2- yl)ureido]propyl]amide
B
3.34
365


 


Ig.40




Octahydroisoquinoline- 2-carboxylic acid N-[3- (3-ethylureido)propyl] amide
B
3.02
311


 


Ig.41




Octahydroisoquinoline- 2-carboxylic acid N-[3- (3-isopropylureido)propyl] amide
B
3.23
325


 


Ig.42




Octahydroisoquinoline- 2-carboxylic acid N-[3- [3-(thiophen-2- yl)ureido]propyl]amide
B
3.51
365


 


Ig.43




Octahydroquinoline-1- carboxylic acid N-[3-[3- [(3s,5s,7s)-adamantan-1-  yl]thioureido]propyl] amide
B
4.67
433









Example Id.1
N-[3-(octahydroquinolin-1-yl)-3-oxopropyl]-2-thiophen-2-ylacetamide




46 μL of Et3N, 30.4 mg (0.22 mmol) of HOBT and 43.1 mg (0.22 mmol) of EDC are added to a solution of 21.3 mg (0.15 mmol) of 2-thienylacetic acid in 2 mL of AcOEt; 35 mg (0.17 mmol) of the intermediate amine Vc.3 are added to it. The suspension formed is kept under stirring for 18 h. It is then treated with water and more AcOEt is added, the organic phase is separated and the aqueous phase is extracted once more with more AcOEt. The organic phases are pooled and successively washed with saturated NaHCO3 solution, 1N HCl and brine. It is then dried over anhydrous Na2SO4, it is filtered and the solvent is evaporated under reduced pressure. The residue is purified by means of silica gel column chromatography, using a (30:1) mixture of DCM-MeOH as eluent, yielding 5 mg of an oil identified as example Id.1. Method A: tr: 6.30 min; m/z: 335.
Example Id.2
N-[3-(octahydroquinolin-1-yl)-3-oxopropyl]propionamide




35 mg (0.17 mmol) of the intermediate amine Vc.3 and 46 μL of Et3N are added to a solution of 13 μL (0.15 mmol) of propionyl chloride in 2 mL of AcOEt. The solution formed is kept under stirring for 18 h. It is then treated with water and more AcOEt is added, the organic phase is separated and the aqueous phase is extracted once more with more AcOEt. The organic phases are pooled and successively washed with saturated NaHCO3 solution, 1N HCl and brine. It is then dried over anhydrous Na2SO4, it is filtered and the solvent is evaporated under reduced pressure, 11 mg of example Id.2 being obtained. Method A: tr: 5.35 min; m/z: 267.
The following examples were prepared in a manner similar to examples 1d.1 or Id.2:















Ex.
structure
name
method
tr (min)
m/z







Id.3 




1-methyl-1H-indole-2- carboxylic acid [3- (octahydroquinolin-1-yl)-3- oxopropyl]amide
A
7.41
368


 


Id.4 




3-cyclohexyl-N-[3- (octahydroquinolin-1-yl)-3- oxopropyl]propionamide
A
7.70
349


 


Id.5 




N-[3-(octahydroquinolin-1-yl)- 3-oxopropyl]-3- phenylpropionamide
A
6.71
343


 


Id.6 




Isoquinoline-3-carboxylic acid [3-(octahydroquinolin-1-yl)-3- oxopropyl]amide
A
7.05
366


 


Id.7 




2-naphthalen-2-yl-N-[3- (octahydroquinolin-1-yl)-3- oxopropyl]acetamide
A
7.16
379


 


Id.8 




Benzofuran-2-carboxylic acid [3-(octahydroquinolin-1-yl)-3- oxopropyl]amide
A
7.03
355


 


Id.9 




Isoquinoline-1-carboxylic acid [3-(octahydroquinolin-1-yl)-3- oxopropyl]amide
A
7.11
366


 


Id.10




Quinoline-4-carboxylic acid [3- (octahydroquinolin-1-yl)-3- oxopropyl]amide
A
5.65
366


 


Id.11




Quinoline-3-carboxylic acid [3- (octahydroquinolin-1-yl)-3- oxopropyl]amide
A
6.00
366


 


Id.12




Quinoline-2-carboxylic acid [3- (octahydroquinolin-1-yl)-3- oxopropyl]amide
A
7.29
366


 


Id.13




Isoquinoline-5-carboxylic acid [3-(octahydroquinolin-1-yl)-3- oxopropyl]amide
A
4.68
366


 


Id.14




1-phenylcyclopentanecarboxylic acid [3-(octahydroquinolin-1- yl)-3-oxopropyl]amide
A
7.87
383


 


Id.15




1-phenylcyclohexanecarboxylic acid [3-(octahydroquinolin-1- yl)-3-oxopropyl]amide
A
8.21
397


 


Id.16




4,4- difluorocyclohexanecarboxylic acid [3-(octahydroquinolin-1- yl)-3-oxopropyl]amide
A
6.49
357


 


Id.17




N-[3-(octahydroquinolin-1-yl)- 3-oxopropyl]-2- phenylacetamide
A
6.42
329


 


Id.18




Cyclopentanecarboxylic acid [3-(octahydroquinolin-1-yl)-3- oxopropyl]amide
A
6.39
307


 


Id.19




Cyclohexanecarboxylic acid [3- (octahydroquinolin-1-yl)-3- oxopropyl]amide
A
6.76
321


 


Id.20




Furan-2-carboxylic acid [3- (octahydroquinolin-1-yl)-3- oxopropyl]amide
A
5.89
305


 


Id.21




3-cyclopentyl-N-[3- (octahydroquinolin-1-yl)-3- oxopropyl]propionamide
A
7.28
335


 


Id.22




N-[3-(octahydroquinolin-1-yl)- 3-oxopropyl]benzamide
A
6.39
315


 


Id.23




(E)-N-[3-(octahydroquinolin-1- yl)-3-oxopropyl]-3- phenylacrylamide
A
6.77
341


 


Id.24




N-[3-(octahydroquinolin-1-yl)- 3-oxopropyl]-4- phenylbutyramide
A
7.05
357


 


Id.25




2-(1-methyl-1H-indol-3-yl)-N- [3-(octahydroquinolin-1-yl)-3- oxopropyl]acetamide
A
6.83
382


 


Id.26




N-[3-(octahydroquinolin-1-yl)- 3-oxopropyl]-2-thiophen-3- ylacetamide
A
6.27
335


 


Id.27




Thiophene-2-carboxylic acid [3-(octahydroquinolin-1-yl)-3- oxopropyl]amide
A
6.26
321


 


Id.28




Naphthalene-1-carboxylic acid [3-(octahydroquinolin-1-yl)-3- oxopropyl]amide
A
7.09
365


 


Id.29




N-[3-(octahydroquinolin-1-yl)- 3-oxopropyl]butyramide
A
5.79
281


 


Id.30




N-[4-(octahydroquinolin-1-yl)- 4-oxobutyl]benzamide
A
6.43
329


 


Id.31




(E)-N-[4-(octahydroquinolin-1- yl)-4-oxobutyl]-3- phenylacrylamide
A
6.75
355


 


Id.32




N-[4-(octahydroquinolin-1-yl)- 4-oxobutyl]-4- phenylbutyramide
A
7.03
371


 


Id.33




N-[4-(octahydroquinolin-1-yl)- 4-oxobutyl]-2-phenylacetamide
A
6.44
343


 


Id.34




Thiophene-2-carboxylic acid [4-(octahydroquinolin-1-yl)-4- oxobutyl]amide
A
6.32
335


 


Id.35




Naphthalene-1-carboxylic acid [4-(octahydroquinolin-1-yl)-4- oxobutyl]amide
A
7.04
379


 


Id.36




Cyclohexanecarboxylic acid [4- (octahydroquinolin-1-yl)-4- oxobutyl]amide
A
6.77
335


 


Id.37




Furan-2-carboxylic acid [4- (octahydroquinolin-1-yl)-4- oxobutyl]amide
A
5.87
319


 


Id.38




3-cyclopentyl-N-[4- (octahydroquinolin-1-yl)-4- oxobutyl]propionamide
A
7.27
349


 


Id.39




2-cyclohexyl-N-[4- (octahydroquinolin-1-yl)-4- oxobutyl]acetamide
A
7.14
349


 


Id.40




1-(3-fluorophenyl) cyclopentanecarboxylic acid [4- (octahydroquinolin-1-yl)-4- oxobutyl]amide
A
7.95
415


 


Id.41




1-phenylcyclopentanecarboxylic acid [4-(octahydroquinolin-1- yl)-4-oxobutyl]amide
A
7.83
397


 


Id.42




1-phenylcyclopropanecarboxylic acid [4-(octahydroquinolin-1- yl)-4-oxobutyl]amide
A
7.23
369


 


Id.43




1-phenylcyclohexanecarboxylic acid [4-(octahydroquinolin-1- yl)-4-oxobutyl]amide
A
8.16
411


 


Id.44




1-(4-chlorophenyl) cyclobutanecarboxylic acid [4- (octahydroquinolin-1-yl)-4- oxobutyl]amide
A
7.94
417


 


Id.45




2-cyclopentyl-N-[4- (octahydroquinolin-1-yl)-4- oxobutyl]acetamide
A
6.77
335


 


Id.46




Cyclohexanecarboxylic acid [3- (octahydroisoquinolin-2-yl)-3- oxopropyl]amide
A
6.74 6.93
321 321


 


Id.47




3-cyclopentyl-N-[3- (octahydroisoquinolin-2-yl)-3- oxopropyl]propionamide
A
7.27 7.44
335 335


 


Id.48




1-(4-chlorophenyl) cyclobutanecarboxylic acid [3- (octahydroisoquinolin-2-yl)-3- oxopropyl]amide
A
7.95 8.09
 403, 405  403, 405


 


Id.49




N-[3-(octahydroisoquinolin-2- yl)-3-oxopropyl]benzamide
A
6.34 6.53
315 315


 


Id.50




(E)-N-[3- (octahydroisoquinolin-2-yl)-3- oxopropyl]-3-phenylacrylamide
A
6.71 6.88
341 341


 


Id.51




N-[3-(octahydroisoquinolin-2- yl)-3-oxopropyl]-4- phenylbutyramide
A
7.02 7.19
357 357


 


Id.52




N-[3-(octahydroisoquinolin-2- yl)-3-oxopropyl]-2- phenylacetamide
A
6.41 6.59
329 329


 


Id.53




Cyclopentanecarboxylic acid [3-(octahydroisoquinolin-2-yl)- 3-oxopropyl]amide
A
6.38 6.57
307 307


 


Id.54




Naphthalene-1-carboxylic acid [3-(octahydroisoquinolin-2-yl)- 3-oxopropyl]amide
A
7.04 7.21
365 365


 


Id.55




Furan-2-carboxylic acid [3- (octahydroisoquinolin-2-yl)-3- oxopropyl]amide
A
5.84 6.05
305 305


 


Id.56




2-cyclohexyl-N-[3- (octahydroisoquinolin-2-yl)-3- oxopropyl]acetamide
A
7.14 7.30
335 335


 


Id.57




3-cyclohexyl-N-[3- (octahydroisoquinolin-2-yl)-3- oxopropyl]propionamide
A
7.67 7.83
349 349


 


Id.58




1-(3-fluorophenyl) cyclopentanecarboxylic acid [3- (octahydroisoquinolin-2-yl)-3- oxopropyl]amide
A
7.95 8.09
401 401


 


Id.59




1-phenylcyclopentanecarboxylic acid [3-(octahydroisoquinolin- 2-yl)-3-oxopropyl]amide
A
7.84 7.99
383 383


 


Id.60




1-phenylcyclopropanecarboxylic acid [3-(octahydroisoquinolin- 2-yl)-3-oxopropyl]amide
A
7.25 7.41
355 355


 


Id.61




1-phenylcyclohexanecarboxylic acid [3-(octahydroisoquinolin- 2-yl)-3-oxopropyl]amide
A
8.17 8.31
397 397


 


Id.62




Thiophene-2-carboxylic acid [3-(octahydroisoquinolin-2-yl)- 3-oxopropyl]amide
A
6.21 6.39
321 321









Example It.1
N-[3-(octahydroquinolin-1-yl)-3-oxopropyl]propionamide




23.4 mg (0.11 mmol) of the intermediate amine Vc.6 and 29 μL of Et3N are added to a solution of 18.1 mg (0.10 mmol) of benzenesulfonyl chloride in 2 mL of AcOEt. The solution formed is kept under stirring at rt for 18 h. It is then treated with water and more AcOEt is added, the organic phase is separated and the aqueous phase is extracted once more with more AcOEt. The organic phases are pooled and successively washed with saturated NaHCO3 solution, 1N HCl and brine. It is then dried over anhydrous Na2SO4, it is filtered and the solvent is evaporated under reduced pressure. The residue is purified by means of silica gel column chromatography, using a (1:1) mixture of hexane-AcOEt as eluent, yielding 23 mg of a yellowish paste identified as example It.1. Method A: tr: 6.76 min/6.97 min; m/z: 351/351
The following examples were prepared in a manner similar to example 1t.1:















Ex.
structure
name
method
tr (min) 
m/z







It.2




N-[4-(octahydroquinolin-1-yl)- 4-oxobutyl]-C- phenylmethanesulfonamide
A
6.84
379


 


It.3




N-[4-(octahydroquinolin-1-yl)- 4-oxobutyl]benzosulfonamide
A
6.79
365


 


It.4




Propane-1-sulfonic acid [3- (octahydroquinolin-1-yl)-3- oxopropyl]amide
A
6.26
317


 


It.5




N-[3-(octahydroquinolin-1-yl)- 3-oxopropyl]benzesulfonamide
A
6.82
351


 


It.6




N-[3-(octahydroquinolin-1-yl)- 3-oxopropyl]-C- phenylmethanesulfonamide
A
6.85
365


 


It.7




N-[3-(octahydroisoquinolin-2- yl)-3-oxopropyl]-C- phenylmethanesulfonamide
A
6.84 7.01
365 365









Example Ip.1
Cycloheptylthiocarbamic acid S-[4-(octahydroisoquinolin-2-yl)-4-oxobutyl]ester




12.8 μL of cycloheptylisocyanate (0.1 mmol) are added to a solution of 35 mg (0.15 mmol) of intermediate IVp.4 and 23 μL of Et3N in 2 mL of THF at 0° C. Once added it is left to stir at reflux for 24 h. AcOEt is then added to the reaction mixture and it is sequentially washed with water and brine. The organic phase is dried over anhydrous Na2SO4, it is filtered and the solvent is evaporated under reduced pressure. The residue is purified by means of silica gel column chromatography, using a (200:3) mixture of DCM-MeOH as eluent, yielding 23 mg of a colorless paste identified as example Ip.1. Method B: tr: 4.63 min; m/z: 381
The following compounds were prepared in a manner similar to example Ip.1:















Ex.
structure
name
method
tr (min)
m/z







Ip.2 




Cyclohexylthiocarbamic acid S-[4- (octahydroquinolin-1-yl)-4- oxobutyl] ester
B
4.34
367


 


Ip.3 




Phenylthiocarbamic acid S-[4- (octahydroquinolin-1-yl)-4- oxobutyl] ester
B
4.14
361


 


Ip.4 




(4-fluorophenyl)thiocarbamic acid S-[4-(octahydroquinolin-1-yl)-4- oxobutyl] ester
B
4.19
379


 


Ip.5 




Benzylthiocarbamic acid S-[4- (octahydroquinolin-1-yl)-4- oxobutyl] ester
B
4.08
375


 


Ip.6 




(2-cyclohex-1- enylethyl)dithiocarbamic acid 4- (octahydroisoquinolin-2-yl)-4- oxobutyl ester
B
5.19
409


 


Ip.7 




(Furan-2-ylmethyl)carbamic acid S-[4-(octahydroquinolin-1-yl)-4- oxobutyl] ester
B
3.82
365


 


Ip.8 




Cycloheptylthiocarbamic acid S- [4-(octahydroquinolin-1-yl)-4- oxobutyl] ester
B
4.54
381


 


Ip.9 




Octahydroquinoline-1- thiocarbamic acid S-[3- (octahydroquinolin-1-yl)-3- oxopropyl] ester
B
4.94
393


 


Ip.10




Benzyldithiocarbamic acid 4- (octahydroquinolin-1-yl)-4- oxobutyl ester
B
4.54
391


 


Ip.11




[2-(cyclohex-1-en-1- yl)ethyl]dithiocarbamic acid 4- (octahydroquinolin-1-yl)-4- oxobutyl ester
B
5.13
409


 


Ip.12




Cyclohexyldithiocarbamic acid 4- (octahydroquinolin-1-yl)-4- oxobutyl ester
B
4.82
383


 


Ip.13




Benzhydryldithiocarbamic acid 4- (octahydroquinolin-1-yl)-4- oxobutyl ester
B
4.98
467


 


Ip.14




Octahydroquinoline-1- thiocarbamic acid S-[3- (octahydroisoquinolin-2-yl)-3- oxopropyl] ester
B
4.93 5.02
393 393


 


Ip.15




Cyclohexyldithiocarbamic acid 4- (octahydroisoquinolin-2-yl)-4- oxobutyl ester
B
4.83 4.89
383 383









Example Ik.1
1-[2-(octahydroquinolin-1-yl)-2-oxoethyl]-3,4-diphenylpyrrole-2,5-dione




22 mg of the intermediate amine Vc.2 (0.11 mmol) are added to a solution of 34 mg (0.13 mmol) of 3,4-diphenylfuran-2,5-dione in 2 mL of DMF. Once added it is left to stir at 100° C. for 48 h. AcOEt is then added to the reaction mixture and it is sequentially washed with water, 5% NaHCO3 solution and brine. The organic phase is dried over anhydrous Na2SO4, it is filtered and the solvent is evaporated under reduced pressure. The residue is purified by means of silica gel column chromatography, using a (3:2) mixture of hexane-AcOEt as eluent, yielding 7.5 mg of a paste identified as example Ik.1. Method A: tr: 8.55 min; m/z; 429
The following compounds were prepared in a manner similar to example Ik.1:















Ex.
structure
name
method
tr (min)
m/z







Ik.2 




5,6-dichloro-2-[2- (octahydroquinolin-1-yl)-2- oxoethyl]isoindole-1,3-dione
A
8.12
 395,  397, 399


 


Ik.3 




(2R,6S)-4-[2- (octahydroquinolin-1-yl)-2- oxoethyl]-4- azatricyclo[5.2.2.0(2,6)]undec-8- ene-3,5-dione
A
6.85
357


 


Ik.4 




5-fluoro-2-[2- (octahydroquinolin-1-yl)-2- oxoethyl]isoindole-1,3-dione
A
7.16
345


 


Ik.5 




4-fluoro-2-[2- (octahydroquinolin-1-yl)-2-  oxoethyl]isoindole-1,3-dione
A
7.03
345


 


Ik.6 




(3aR,7aS)-2-[2- (octahydroquinolin-1-yl)-2- oxoethyl]hexahydroisoindole- 1,3-dione
A
6.76
333


 


Ik.7 




(3aS,7aR)-2-[3- (octahydroquinolin-1-yl)-3- oxopropyl]hexahydroisoindole- 1,3-dione
A
6.89
347


 


Ik.8 




(2R,6S)-4-[3- (octahydroquinolin-1-yl)-3- oxopropyl]-4- azatricyclo[5.2.2.0(2,6)]undec-8- ene-3,5-dione
A
7.07
371


 


Ik.9 




(3aS,7aS)-2-[3- (octahydroquinolin-1-yl)-3- oxopropyl]hexahydroisoindole- 1,3-dione
A
6.89
347


 


Ik.10




4-hydroxy-2-[3- (octahydroquinolin-1-yl)-3- oxopropyl]isoindole-1,3-dione
A
6.28
357


 


Ik.11




5-fluoro-2-[3- (octahydroquinolin-1-yl)-3- oxopropyl]isoindole-1,3-dione
A
7.25
359


 


Ik.12




5,6-dichloro-2-[3- (octahydroquinolin-1-yl)-3- oxopropyl]isoindole-1,3-dione
A
8.27
 409,  411, 413


 


Ik.13




1-[3-(octahydroquinolin-1-yl)- 3-oxopropyl]-3,4- diphenylpyrrole-2,5-dione
A
8.62
443


 


Ik.14




5,6-dichloro-2-[4- (octahydroquinolin-1-yl)-4- oxobutyl]isoindole-1,3-dione
A
8.43
 423,  425, 427


 


Ik.15




1-[4-(octahydroquinolin-1-yl)- 4-oxobutyl]-3,4- diphenylpyrrole-2,5-dione
A
8.75
457


 


Ik.16




(3aR,7aR)-2-[4- (octahydroquinolin-1-yl)-4- oxobutyl]hexahydroisoindole- 1,3-dione
A
7.04
361


 


Ik.17




(2R,6S)-4-[4- (octahydroquinolin-1-yl)-4- oxobutyl]-4- azatricyclo[5.2.2.0(2,6)]undec-8- ene-3,5-dione
A
7.14
385


 


Ik.18




5-fluoro-2-[4- octahydroquinolin-1-yl)-4- oxobutyl]isoindole-1,3-dione
A
7.38
373


 


Ik.19




4-fluoro-2-[4- (octahydroquinolin-1-yl)-4- oxobutyl]isoindole-1,3-dione
A
7.19
373


 


Ik.20




(3aR,7aS)-2-[4- (octahydroquinolin-1-yl)-4- oxobutyl]hexahydroisoindole- 1,3-dione
A
7.13
361


 


Ik.21




4-hydroxy-2-[5- (octahydroquinolin-1-yl)-5- oxopentyl]isoindole-1,3-dione
A
6.64 6.69
385 385


 


Ik.22




(2R,65)-4-[5- (octahydroquinolin-1-yl)-5- oxopentyl]-4- azatricyclo[5.2.2.0(2,6)]undec-8- ene-3,5-dione
A
7.32
399


 


Ik.23




5,6-dichloro-2-[5- (octahydroquinolin-1-yl)-5- oxopentyl]isoindole-1,3-dione
A
8.62
 437,  439, 441


 


Ik.24




(3aS,7aR)-2-[5- (octahydroquinolin-1-yl)-5- oxopentyl]hexahydroisoindole- 1,3-dione
A
7.22
375


 


Ik.25




5-fluoro-2-[5- (octahydroquinolin-1-yl)-5- oxopentyl]isoindole-1,3-dione
A
7.61
387


 


Ik.26




1-[5-(octahydroquinolin-yl)-1- yl)-5-oxopentyl]-3,4- diphenylpyrrole-2,5-dione
A
8.90
471


 


Ik.27




5,6-dichloro-2-[2- (octahydroisoquinolin-2-yl)-2- oxoethyl]isoindole-1,3-dione
A
8.24
 395,  397, 399


 


Ik.28




4-hydroxy-2-[2- (octahydroisoquinolin-2-yl)-2- oxoethyl]isoindole-1,3-dione
A
6.45
343


 


Ik.29




(2R,6S)-4-[2- (octahydroisoquinolin-2-yl)-2- oxoethyl]-4- azatricyclo[5.2.2.0(2,6)]undec-8- ene-3,5-dione
A
7.02
357


 


Ik.30




5-fluoro-2-[2- (octahydroisoquinolin-2-yl)-2- oxoethyl]isoindole-1,3-dione
A
7.14 7.31
345 345


 


Ik.31




4-fluoro-2-[2- (octahydroisoquinolin-2-yl)-2- oxoethyl]isoindole-1,3-dione
A
7.19
345


 


Ik.32




(3aR,7aS)-2-[2- (octahydroisoquinolin-2-yl)-2- oxoethyl]hexahydroisoindole- 1,3-dione
A
6.76 6.94
333 333


 


Ik.33




1-[3-(octahydroisoquinolin-2- yl)-3-oxopropyl]-3,4- diphenylpyrrole-2,5-dione
A
8.61 8.73
443 443


 


Ik.34




(3aR,7aR)-2-[3- (octahydroisoquinolin-2-yl)-3- oxopropyl]hexahydroisoindole- 1,3-dione
A
6.89 7.07
347 347


 


Ik.35




5-fluoro-2-[3- (octahydroisoquinolin-2-yl)-3- oxopropyl]isoindole-1,3-dione
A
7.36
359


 


Ik.36




4-fluoro-2-[3- (octahydroisoquinolin-2-yl)-3- oxopropyl]isoindole-1,3-dione
A
7.01 7.18
359 359


 


Ik.37




4-hydroxy-2-[4- (octahydroisoquinolin-2-yl)-4- oxobutyl]isoindole-1,3-dione
A
6.45 6.61
371 371


 


Ik.38




(2R,6S)-4-[4- (octahydroisoquinolin-2-yl)-4- oxobutyl]-4- azatricyclo[5.2.2.0(2,6)]undec-8- ene-3,5-dione
A
7.14 7.32
385 385


 


Ik.39




5,6-dichloro-2-[4- (octahydroisoquinolin-2-yl)-4- oxobutyl]isoindole-1,3-dione
A
8.43 8.56
 423,  425, 427  423,  425, 427


 


Ik.40




1-[4-(octahydroisoquinolin-2- yl)-4-oxobutyl]-3,4- diphenylpyrrole-2,5-dione
A
8.77 8.89
457 457


 


Ik.41




(3aS,7aR)-2-[4- (octahydroisoquinolin-2-yl)-4- oxobutyl]hexahydroisoindole- 1,3-dione
A
7.04 7.22
361 361


 


Ik.42




5-fluoro-2-[4- (octahydroisoquinolin-2-yl)-4- oxobutyl]isoindole-1,3-dione
A
7.39 7.55
373 373


 


Ik.43




4-fluoro-2-[4- (octahydroisoquinolin-2-yl)-4- oxobutyl]isoindole-1,3-dione
A
7.20 7.36
373 373


 


Ik.44




4-hydroxy-2-[5- (octahydroisoquinolin-2-yl)-5- oxopentyl]isoindole-1,3-dione
A
6.64 6.80
385 385


 


Ik.45




(2R,6S)-4-[5- (octahydroisoquinolin-2-yl)-5- oxopentyl]-4- azatricyclo[5.2.2.0(2,6)]undec-8- ene-3,5-dione
A
7.50
399


 


Ik.46




5-fluoro-2-[5- (octahydroisoquinolin-2-yl)-5- oxopentyl]isoindole-1,3-dione
A
7.59 7.75
387 387


 


Ik.47




5,6-dichloro-2-[5- (octahydroisoquinolin-2-yl)-5- oxopentyl]isoindole-1,3-dione
A
8.60 8.72
 437,  439, 441  437,  439, 441









Example Ij.1
[3-(octahydroquinolin-1-yl)-3-oxopropyl]carbamic acid t-butylester




0.12 mg (1 μmol) of 4-dimethylaminopyridine and 43 mg (0.2 mmol) of di-tertbutyl dicarbonate are added to a solution of 21 mg (0.1 mmol) of intermediate Vc.3 in 2 mL of DCM. The mixture is stirred for 18 h at rt. The solvent is evaporated and water and AcOEt are then added, the aqueous phase is separated and extracted again with AcOEt, the pooled organic phases are sequentially washed with 1N HCl and brine. The organic phase is dried over anhydrous Na2SO4, it is filtered and the solvent is evaporated under reduced pressure. The residue is purified by means of silica gel column chromatography, using a (20:1) mixture of DCM-MeOH as eluent, yielding 6.5 mg of a colorless paste identified as example Ij.1. Method A: tr: 7.15 min; m/z: 311
Pharmacological Examples
Determination of the Inhibitory Activity of 11-Beta-HSD1 in the Microsomal Fraction of Transfected HEK293 Cells
99 μL of a reaction mixture which contained 80 nM [3H]-cortisone, 1 mM NADPH and 40 μg/mL of the microsome preparations of HEK-293 cells stably transfected with the 11-beta-HSD1 clone, dissolved in assay buffer (50 mM HEPES, 100 mM KCl, 5 mM NaCl, 2 mM MgCl2/100 mL H2O) were added to a 96-well plate. The inhibitors to be analyzed were dissolved in 100% DMSO, and the final concentration in the reaction was 1%.
The reaction mixture was incubated for 2 hours at 37° C. under stirring. The total reaction volume per well was 100 μL. The stop solution (5 mg/mL ProteinA Spa bead, Superblock Blocking Buffer, 30 μM glycyrrhetinic acid, 1 μg/mL anticortisol monoclonal antibody) was simultaneously prepared, being incubated under stirring for two hours at rt and protected from light. Once the two hours lapsed, 50 μL of the stop solution were dispensed to each well in the reaction plate and was left to incubate for two hours at rt under stirring and protected from light. Once the second incubation ended, the plate was read in a 1450 Microbeta Tritalux (Wallac®) scintillation counter for 30 seconds per well.
Determination of the Inhibitory Activity of 11-Beta-HSD2 in the Microsomal Fraction of Transfected HEK293 Cells
59 μL of the reaction mixture were added to a 96-well plate. This contained 1 mM NAD+ and 80 μg/mL of the microsome preparations of HEK-293 cells stably transfected with the 11-beta-HSD2 clone, dissolved in assay buffer (50 mM HEPES, 100 mM KCl, 5 mM NaCl, 2 mM MgCl2/100 mL H2O). The inhibitors to be analyzed were dissolved in 100% DMSO, and the final concentration in the reaction was 1%. The reaction mixture was pre-incubated for 30 minutes at 37° C. under stirring. 40 μL of the reaction substrate, 3.2 nM [3H]-cortisol dissolved in assay buffer were added. It was incubated at 37° C. for two hours under stirring. The stop solution was simultaneously prepared, being incubated for two hours at rt and protected from light. After this time 50 μL of the stop solution were added to end the reaction, and it was incubated for two hours at rt under stirring and protected from light. The signal emitted by SPA heads-cortisol complex was measured in the 1450 Microbeta Tritalux (Wallac®) scintillation counter for 30 seconds per well. This case measures the binding to the substrate, and not to the product as in the assay for the type 1 isoenzyme.
The following table indicates the activity values of some compounds described in the examples expressed as percentage of inhibition at a 10 μM concentration.














% Inhibition (10 μM)












Example
11-beta-HSD1
11-beta-HSD2















Ia.59
100
0



Ia.61
93
0



Ia.66
100
6



Ib.8
100
5



Ib.18
100
10



Ib.80
100
13



Ie.16
100
5



Ib.8
100
0



Id.6
100
0



Id.12
100
0



If.1
100
0



Ik.25
100
6



If.8
100
4

## Claims

1. A compound of formula (I)



and pharmaceutically acceptable salts thereof, wherein:
s and p are an integer selected in an opposite manner between 0 and 1, such that when s is 1, p is 0 (to form a perhydroquinoline) and when s is 0, p is 1 (to form a perhydroisoquinoline),
Y is a biradical selected from CO, CS and SO2,
W1 and W2 is each independently a bond or a biradical selected from O, S and NR1, wherein R1 is selected from H, C1-4 alkyl and C3-10 cycloalkyl,
n is an integer selected from 0, 1, 2, 3 and 4,
V is a radical selected from the group consisting of —CO-T, —CS-T and —SO2-T, or a radical selected from the group consisting of:




where T is a group selected from the group consisting of NR2R3, R2, OR2 and SR2; or a group selected from the group





consisting of:
wherein R2 and R3 is each independently H, COR4, SO2R4, C1-4 alkyl, aryl, benzyl, phenethyl, C2-4 alkenyl, C2-4 alkynyl, C3-10 cycloalkyl or a saturated, partially unsaturated or aromatic, 5 to 10 membered heterocycle, containing one or several heteratoms elected from the group consisting of nitrogen, oxygen and sulfur,
wherein when R2 or R3 is an alkyl, or an alkenyl these can be optionally substituted with one or several substituents independently selected from the group consisting of F, OR4, NR4R5, COOR4, CONR4R5, C3-10 cycloalkyl, aryl and heterocycle; and
wherein when R2 or R3 is an aryl, a benzyl, a phenethyl, a cycloalkyl or a heterocycle, these can be optionally substituted with one or several substituents independently selected from the group consisting of NH2, F, Cl, CN, NO2, COOH, R4, COOR4, OR4, OCF3, SH, SR4, CONR4R5, SO2NR4R5, COR4, NR1COR4, OCOR4, SOR4, SO2R4 and heterocycle; and
wherein when R2 or R3 is a cycloalkyl, this can be optionally substituted with one or several fused benzene rings, the benzene could be optionally substituted with one or several substituents independently selected from the group consisting of alkyl, alkoxide and halogen,
wherein R4 and R5 is each independently selected from the group consisting of H, C1-4 alkyl, aryl, benzyl, phenethyl, C2-4 alkenyl, C2-4 alkynyl, C3-10 cycloalkyl and heterocycle, or optionally R4 and R5 can be bound to one another forming a 3 to 8 membered cycle,
wherein R6, R7, R8 and R9 is each independently selected from the group consisting of H, OR4, F and Cl, and
wherein R10 is independently selected from the group consisting of H, OH, F, C1-4 alkyl, COOR11, COR11, phenyl, benzyl, benzhydryl, C2-4 alkenyl, C2-4 alkynyl, C3-10 cycloalkyl and heterocycle, and wherein the alkyl, phenyl, benzyl, benzhydryl, cycloalkyl or heterocycle can be optionally substituted with one or several substituents independently selected from the group consisting of NH2, F, Cl, NO2, COOH, COOR4, OR4, CF3, SH, SR4, CONR4R5, SO2NR4R5, COR4, NR1COR4, OCOR4, SOR4, SO2R4 and C1-4 alkyl; and where R11 is selected from H, C1-4 alkyl and C3-10 cycloalkyl.

2. The compound according to claim 1, wherein Y is CO or SO2.

3. The compound according to claim 1, wherein W1 and W2 is each independently selected from the group consisting of a bond, S and NR1.

4. The compound according to claim 3, wherein R1 is H.

5. The compound according to claim 1, wherein V is —CO-T, —CS-T or -SO2-T.

6. The compound according to claim 1, wherein V is selected from the group consisting of:

7. The compound according to claim 1, wherein T is NR2R3, R2, OR2 or SR2.

8. The compound according to claim 1, wherein R2 and R3 is each independently selected from the group consisting of H, COR4, SO2R4, C1-4 alkyl, phenyl, naphthyl, benzyl, phenethyl, C2-4 alkenyl, C3-10 cycloalkyl, and heterocycle, particularly, 2-furanyl, 2-thiophenyl, 2-(1-methylindole), quinoline, isoquinoline and 2-benzofuranyl.

9. The compound according to claim 8, wherein R2 and R3 is each independently selected from the group consisting of C1-4 alkyl and C2-4 alkenyl.

10. The compound according to claim 9, wherein R2 or R3 are optionally substituted with one or several substituents independently selected from the group consisting of F, OR4, NR4R5, COOR4, CONR4R5, phenyl, C3-10 cycloalkyl, hexenyl, naphthyl and heterocycle, particularly pyridine, 3-(1-methylindole), 3-thiophenyl and 2-furanyl.

11. The compound according to claim 8, wherein R2 and R3 is each independently selected from the group consisting of phenyl, benzyl, phenethyl and C3-10 cycloalkyl.

12. The compound according to claim 11, wherein R2 or R3 are optionally substituted with one or several substituents independently selected from the group consisting of F, Cl and OR4.

13. The compound according to claim 1, wherein R4 and R5 is each independently selected from the group consisting of C1--4 alkyl, benzyl, phenethyl and phenyl.

14. The compound according to claim 1, wherein T is selected from the group consisting of:

15. The compound according to claim 1, wherein R6, R7, R8 and R9 is each independently selected from H, OR4, F and Cl, and wherein R10 is independently selected from the group consisting of H, OH, F, C1-4 alkyl, COOR11, COR11, phenyl, benzyl and benzhydryl.

16. The compound according to claim 15, wherein R10 is phenyl, benzyl or benzhydryl.

17. The compound according to claim 16, wherein R10 is optionally substituted with one or several substituents, independently selected from the group consisting of F, OR4, CF3, COR4 and C1-4 alkyl.

18. The compound according to claim 1, wherein R11 is H or C3-10 cycloalkyl.

19. The compound according to claim 1, wherein s is 0 and p is 1.

20. The compound according to claim 1, wherein s is 1 and p is 0.