MXPA06011540A - Pgd2 receptor antagonists for the treatment of inflammatory diseases. - Google Patents

Pgd2 receptor antagonists for the treatment of inflammatory diseases.

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Publication number
MXPA06011540A
MXPA06011540A MXPA06011540A MXPA06011540A MXPA06011540A MX PA06011540 A MXPA06011540 A MX PA06011540A MX PA06011540 A MXPA06011540 A MX PA06011540A MX PA06011540 A MXPA06011540 A MX PA06011540A MX PA06011540 A MXPA06011540 A MX PA06011540A
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Mexico
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methyl
substituted
phenyl
haloalkyl
group
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MXPA06011540A
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Spanish (es)
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Shomir Ghosh
Amy M Elder
Kenneth G Carson
Kevin T Sprott
Sean J Harrison
Frederick A Hicks
Christelle C Renou
Dominic Reynolds
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Millennium Pharm Inc
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Publication of MXPA06011540A publication Critical patent/MXPA06011540A/en

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Abstract

Disclosed herein are compounds represented by Structural Formula: (I) and (I-A). Also disclosed is the use of such compounds for inhibiting the G-protein coupled receptor referred to as chemoattractant receptor-homologous molecule expressed on Th2, or simply "CRTH2" for the treatment of inflammatory disorders. The variables in Structural Formula (I) and (I-A) are defined herein.

Description

ANTAGONISTS OF THE RECEIVER OF PGD2 FOR THE TREATMENT OF INFLAMMATORY DISEASES BACKGROUND OF THE INVENTION CRTH2 is a chemoattractant receptor coupled to the G protein expressed in Th2 cells (Nagat et al., J. Immunol., 1999, 162, 1278-1286), eosinophils and basophils (Hirai et al., J. Exp. Med. , 2001, 193, 255-261). Prostaglandin D2 (PGD2) is a natural ligand for CRTH2, and is the major inflammatory mediator produced by mast cells. It has been shown that activation of CRTH2 by PGD2 induces the migration and activation of Th2 cells (Hirai et al., J. Exp. Med. 2001, 193, 255-261; Gervais et al., J. Allergy Clin. Immunol. 2001, 108, 982-988) that in turn are involved in the organization of an allergic inflammatory response directly or indirectly inducing the migration, activation, preparation and prolonged survival of effector cells, such as eosinophils and basophils (Sanz et al. , J. Immunol, 1998, 160, 5637-5645, Pope et al., J. Allergy Clin. Immunol. 2001, 108, 594-601; Teran L. M., Clin. Exp. Allergy 1999, 29, 287-290). The role of PGD2 in the initiation and maintenance of allergic inflammation has also been demonstrated in mouse models of asthma showing overproduction of PGD2 in vivo by airway inflammation exacerbated by PGD2 synthase (Fujitani et al., J. Immunol 2002, 168, 443-449). Accordingly, compounds that are modulators, preferably inhibitors, of the interaction between CRTH2 and PGD2 should be useful for the treatment of diseases and disorders mediated by CRTH2, PGD2, Th2 cells, eosinophils and / or basophils. These diseases include, but are not limited to, allergic disorders, asthmatic disorders and inflammatory disorders such as allergic rhinitis, allergic asthma, bronchoconstriction, atopic dermatitis and systemic inflammatory disorders. DETAILED DESCRIPTION OF THE INVENTION The compounds of this invention, and the pharmaceutically acceptable compositions thereof, are effective as inhibitors of the interaction between CRTH2 and its natural ligand PGD2. In this manner, the compounds of the invention and the pharmaceutical compositions thereof are therefore useful for treating inflammatory disorders and / or disorders with an inflammatory component. 1. Description of Compounds of General Formula I (and subsets thereof): In one embodiment, the present invention relates to a compound of formula I: I or a pharmaceutically acceptable salt thereof, wherein: Ring A is an optionally substituted monocyclic aromatic ring; R is -X1-R1, where: X1 is a bond, S (O), S (O) 2, C (O) or C (O) NH, with the proviso that when X1 is a bond, SO or SO2 , then R1 is not H; and R1 is H or a cycloaliphatic group, aromatic group or optionally substituted non-aromatic heterocyclic group; X is -C (O) - or -C (R2) 2-, where: each R2 is independently -H, -X / R8 or an aliphatic group, cycloaliphatic group, aromatic group or an optionally substituted non-aromatic heterocyclic group; Rx is -X2-R4, where: X2 is a bond, S (O), S (O) 2, C (O) or C (O) NH; and R 4 is -H, -X 6 -R 10 or an aliphatic group, cycloaliphatic group, aromatic group or optionally substituted non-aromatic heterocyclic group; with the proviso that when X2 is a bond, SO or SO2, then R4 is not H; R3 is a cycloaliphatic group, aromatic group or optionally substituted non-aromatic heterocyclic group; or -NRXR3, taken together, is a non-aromatic heterocyclic group containing nitrogen; X4 and XQ are each independently a linear or branched hydrocarbyl group optionally substituted with one or more groups selected from the group consisting of halo, -OH, = O, C-1-C3 alkoxy, nitro and cyano; R5 and R6 are each independently H or C1-C3 alkyl; R8 and R10 are each independently H, -C (O) OR "or a cycloaliphatic group, aromatic group or optionally substituted non-aromatic heterocyclic group; R" is H or R13; and R 13 is C 1 -C 6 alkyl or C 3 -C 8 cycloalkyo.
In another embodiment, the present invention relates to a compound of formula I: or a pharmaceutically acceptable salt thereof, wherein: Ring A is an optionally substituted monocyclic aromatic ring; R is -X1-R1; Rx is -X2-R4, and R3 is an optionally substituted aromatic group; or -NRXR3, taken together, is a non-aromatic heterocyclic group containing optionally substituted nitrogen; X is -C (O) - or -C (R2) 2-; X1 and X2 are each independently a bond, S (O), S (O) 2, C (O) or C (O) NH; R1 is H or a cycloaliphatic group, aromatic group or optionally substituted non-aromatic heterocyclic group; with the proviso that when X1 is a bond, SO or SO2, then R1 is not H; each R2 is independently H, -X4-R8 or an aliphatic group, cycloaliphatic group, aromatic group or optionally substituted non-aromatic heterocyclic group; R 4 is H, -Xß-R 10 or an aliphatic group, cycloaliphatic group, aromatic group or optionally substituted non-aromatic heterocyclic group; with the proviso that when X2 is a bond, SO or SO2, then R4 is not H; X4 and Xß are each independently a linear or branched hydrocarbyl group optionally substituted with one or more groups selected from the group consisting of halo, -OH, = O, C1-C3 alkoxy, nitro and cyano; R5 and R6 are each independently H or C1-C3 alkyl; and R8 and R10 are each independently H, -C (O) OR "or a cycloaliphatic group, aromatic group or optionally substituted non-aromatic heterocyclic group, R" is H or R13; and R13 is C1-C6 alkyl or C3-C8 cycloalkyl.
In one embodiment, the compounds of formula I include compounds other than: 2-Methyl-N-phenyl-N- [1, 2,3,4-tetrahydro-2-methyl-1- (2-methyl-1-oxobutyl) -4-quinolinylj-butamide; N- (1-Acetyl-1, 2,3,4-tetrahydro-2-methyl-4-quinolinyl) -N-phenyl-heptamide; N-phenyl-N- [1, 2,3,4-tetrahydro-2-methyl-1- (1-oxo-3-phenylpropyl) -4-quinolinyl] -benzenepropanamide; N-phenyl-N- [1, 2,3,4-tetrahydro-2-methyl-1- (3-nitrobenzoyl) -4-quinolinyl] -hexanamide; N- [1,1-biphenyl] -3-yl-N- [1, 2,3,4-tetrahydro-1- (4-methoxybenzoyl) -2-methyl-4-quinolinyl] -acetamide; N- (1-benzoyl-1, 2,3,4-tetrahydro-2-methyl-4-quinolinyl) -N- (4-nitrophenyl) -heptanamide; N- (1-benzoyl-1, 2,3,4-tetrahydro-2-methyl-4-quinolinyl) -N- (4-methoxyphenyl) -2-methyl-propanamide; N- [1- (4-fluorobenzoyl) -1, 2,3,4-tetrahydro-2-methyl-4-quinolinyl] -N-phenyIbutanamide; N-phenyl-N- [1, 2,3,4-tetrahydro-1- (3-methoxybenzoyl) -2-methyl-4-quinolinyl] -pentanamide; 2-Ethyl-N- [1- (2-ethyl-1-oxobutyl) -1,2,3,4-tetrahydro-2,8-dimethyl-4-quinolinyl] -N- (2-methylphenyl) - butanamide; N- [1 - [(4-fluorophenyl) acetyl] -1,2,3,4-tetrahydro-2-methyl-4-quinolinyl] -N-phenylpropanamide; N-phenyl-N- [1, 2,3,4-tetrahydro-2-methyl-1- (4-nitrobenzoyl) -4-quinoIinyl] -octanamide; N-cyclohexyl-4 - [(cyclohexylamino) carbonyl] phenylaminoj-3,4-dihydro-2-methyl-1 (2H) -quinolinecarboxamide; N- [1 - (4-ethylbenzoyl) -1, 2,3,4-tetrahydro-2,8-dimethyl-4-quinolinyl] -N- (2-methylphenyl) -3- (4-nitrophenyl) -2- propenamide; 3- (4-methoxyphenyl) -N-phenyl-N- [1, 2,3,4-tetrahydro-1 - [3- (4-methoxyphenyl) -1 -oxo-2-propenyl] -2-methyl-4 -quinolinyl] -2-propenamide; 4 - [(ethoxyoxoacetyl) phenylamino] -3,4-dihydro-2-methyl-V-oxo-ethyl ester-1 (2H) -quinoline acetic acid; N- [1- (3-cyclohexyl-1-oxo-propyl) -1,2,3,4-tetrahydro-2-methyl-4-quinolin-1] -N-phenyl-cyclohexanopropanamide; 4- (Acetylphenylamino) -3,4-dihydro-2-methyl-gamma-oxo-1 (2H) -quinoline-pentanoic acid; N- (1-benzoyl-1, 2,3,4-tetrahydro-2-methyl-4-quinoiinyl) -2,2-d.methyl-N-phenyl-propanamide; N- (1-benzoyl-6-bromo-1, 2,3,4-tetrahydro-2-methyl-4-quinolinyl) -N-phenyl-pentanamide; N- [1 - (2-furanylcarbonyl) -1,2,3,4-tetrahydro-2-methyl-4-quinolinyl] -N-phenyl-acetamide; 2-methy1-N-phenyl-N- [1, 2,3,4-tetrahydro-1- (3-methoxybenzoyl) -2-methyl-4-quinolinyl] -propanamide; N- [1 - [(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) acetyl] -1,2,3,4-tetrahydro-2-methyl-4-quinoIinyl] -N phenyl acetamide; 2,2,2-trifluoro-N-phenyI-N- [1, 2,3,4-tetrahydro-1- (3-methoxybenzoyl) -2-methyl-4-quinolinyl] -acetamide; 2-Ethyl-N- [1 - (2-ethyl-1-oxobutyl) -1, 2,3,4-tetrahydro-2-methyl-4-quinolinyl] -N-phenyl-butanamide; N- (1-benzoyl-1, 2,3,4-tetrahydro-2-methyl-4-quinolinyl) -N- (3-methoxyphenyl) -acetamide; N-phenyl-N- [1, 2,3,4-tetrahydro-2-methyl-1- (1-oxohexyl) -4-quinoIinyl] -acetamide; N- (1-acetyl-1, 2,3,4-tetrahydro-2-methyl-4-quinolinyl) -N-phenyl-2-thiophenecarboxamide; N- [1 - (2-fluorobenzoyl) -1, 2,3,4-tetrahydro-2-methyl-4-quinolyl] -N-phenyl-hexanamide; N-phenyl-N- [1, 2,3,4-tetrahydro-1- (4-methoxybenzoyl) -2-methyl-4-quinolin-1] -hexanamide; N-phenyl-N- [1, 2,3,4-tetrahydro-1- (4-methoxybenzoyl) -2-methyl-4-quinolinyl] -hexanamide; N- [1 - (cyclopropylcarbonyl) -1, 2,3,4-tetrahydro-2-methyl-4-quinolinyl] -N-phenyl-cyclopropanecarboxamide; N- (1-benzoyl-1, 2,3,4-tetrahydro-2-methyl-4-quinolinyl) -N- (4-methylphenyl) -acetamide; 2-methyl-N-phenyl-N- [1, 2,3,4-tetrahydro-2-methyl-1- (2-methyl-1-oxopropyl) -4-quinolinyl] -propanamide; N-phenyl-N- [1, 2,3,4-tetrahydro-1- (4-methoxybenzoyl) -2-methyl-4-quinolinyl] -2-thiophenecarboxamide; 1- (3,5-dinitrobenzoyl) -N-formyl-1, 2,3,4-tetrahydro-2-methyl-N-phenyl-4-quinolinamine; N- [1 - (4-chloro-3-nitrobenzoyl) -1, 2,3,4-tetrahydro-2-methyl-4-quinoliniI] -N-phenyl-acetamide; N-phenyl-N- [1, 2,3,4-tetrahydro-2-methyl-1- (3-nitrobenzoyl) -4-quinolinyl] -acetamide; N-phenyl-N- [1, 2,3,4-tetrahydro-1- (3-methoxybenzoyl) -2-methyl-4-quinolinyl] -hexanamide; N- [1 - (2-furanylcarbonyl) -1,2,3,4-tetrahydro-2-methyl-4-quinoyl] nyl-N-phenyl-2-furancarboxamide; N-phenyl-N- [1, 2,3,4-tetrahydro-2-methyl-1- (1-oxopropyl) -4-quinolinyl] -acetamide; N-phenyl-N- [1, 2,3,4-tetrahydro-1- [3- (4-methoxyphenyl) -1-oxo-2-propenyl] -2-methyl-4-quinoliniI] -acetamide; 3- (2-furanyl) -N- [1 - [3- (2-furanyl) -1 -oxo-2-propenyl] -1, 2,3,4-tetrahydro-2-methyl-4-quinolinyl] - N-phenyl-2-propenamide; N- [1- [2- (1,3-dihydro-1,3-dioxo-2H-isindol-2-yl) -1-oxo-3-phenylpropyl] -1,2,3,4-tetrahydro- 2-methyl-4-quinolinyl] -N-phenyl-octanamide; N- [1 - (3-chlorobenzoyl) -1, 2,3,4-tetrahydro-2-methyl-4-quinoiinyl] -N-phenyl-acetamide; N-phenyl-N - [(2R, 4S) -1,2,3,4-tetrahydro-2-methyl-1- (1-oxopropyl) -4-quinolinylj-acetamide of relative stereochemistry; N - [(2R, 4S) -1-benzoyl-1, 2,3,4-tetrahydro-2-methyl-4-quinolinyl] -2-methyl-N-phenyl-propanamide of relative stereochemistry; N - [(2R, 4S) -1-acetyl-1, 2,3,4-tetrahydro-2-methyl-4-quinolyl] -N-phenyl-hexanamide of relative stereochemistry; N - [(2R, 4S) -1-acetyl-1, 2,3,4-tetrahydro-2-methyl-4-quinolin-1] -N-phenyI-propanamide of relative stereochemistry; N - [(2R, 4S) -1-acetyl-1, 2,3,4-tetrahydro-2-methyl-4-quinolinyl] -N-phenyl-heptanamide of relative stereochemistry; N - [(2R, 4S) -1-benzoyl-1, 2,3,4-tetrahydro-2-methyl-4-quinolinyl] -2,2-dimethyl-N-phenylpropanamide of relative stereochemistry; N- [1- (3-fluorobenzoyl) -1, 2,3,4-tetrahydro-2-methyl-4-quinolinyl] -N-phenyl-acetamide; N- [1 - [4- (1, 1-dimethylethyl) benzoyl] -1, 2,3,4-tetrahydro-2-methyl-4-quinolinyl] -N-phenyl-acetamide; N- (1-acetyl-1, 2,3,4-tetrahydro-2-methyl-4-quinolinyl) -2-methyl-N-phenyl-propanamide; 2,2,2-Trifluoro-N-phenyl-N- [1, 2,3,4-tetrahydro-2-methyl-1- (trifluoroacetyl) -4-quinolinyl] -acetamide; N - [(2R, 4S) -1-acetyl-1, 2,3,4-tetrahydro-2-methyl-4-quinolinyl] -2,2-dimethyl-N-phenyl-propanamide of relative stereochemistry; N - [(2R, 4S) -1-acetyl-1, 2,3,4-tetrahydro-2-methyl-4-quinolinyl] -N-phenyl-butanamide of relative stereochemistry; N - [(2R, 4S) -1-benzoyl-1, 2,3,4-tetrahydro-2-methyl-4-quinolinyl] -N-phenyl-acetamide of relative stereochemistry; N-phenyl-N - [(2R, 4, S) -1,2,3,4-tetrahydro-2-methyl-1- (1-oxoheptyl) -4-quinolinyl] -acetamide of relative stereochemistry; N-phenyl-N - [(2R, 4S) -1,2,3,4-tetrahydro-2-methyl-1- (1-oxohexyl) -4-quinolyl] -acetamide of relative stereochemistry; N - [(2R, 4S) -1-acetyl-1, 2,3,4-tetrahydro-2-methyl-4-quinolinyl] -N-phenyl-pentanamide of relative stereochemistry; N-phenyl-N- [1, 2,3,4-tetrahydro-2-methyl-1- (1-oxo-3-phenyl-2-propenyl) -4-quinolinyl] -acetamide; N - [(2R, 4S) -1-benzoyl-1, 2,3,4-tetrahydro-2-methyl-4-quinolinyl] -N-phenyl-heptanamide of relative stereochemistry; N - [(2R, 4S) -1-acetyl-1, 2,3,4-tetrahydro-2-methyl-4-quinolinyl] -N-phenyl-acetamide of relative stereochemistry; N - [(2R, 4S) -1-benzoyl-1, 2,3,4-tetrahydro-2-methyl-4-quinolinyl] -N-phenyl-pentanamide of relative stereochemistry; N-Phenyl-N- [1, 2,3,4-tetrahydro-2-methyl-1- (tricyclo [3.3.1, 13,7] dec-1-ylcarbonyl) -4-quinolinyl] - acetamide; N-phenyl-N- [1, 2,3,4-tetrahydro-2-methyl-1- (1-oxopropyl) -4-quinolyl] -propanamide; N-phenyl-N- [1, 2,3,4-tetrahydro-2-methyl-1- (2-thienylcarbonyl) -4-quinolinyl] -acetamide; N-phenyl-N- [1, 2,3,4-tetrahydro-1- (4-methoxybenzoyl) -2-methyl-4-quinolinyl] -2-furancarboxamide; N-phenyl-N- [1, 2,3,4-tetrahydro-1- (4-methoxybenzoyl) -2-methyl-4-quinolinyl] -acetamide; N- [1 - (3,5-dinitrobenzoyl) -1, 2,3,4-tetrahydro-2-methyl-4-quinolinyl] -N-phenyl-acetamide; N-phenyl-N- [1, 2,3,4-tetrahydro-2-methyl-1- (4-nitrobenzoyl) -4-quinolinyl] -acetamide; N-phenyl-N- [1, 2,3,4-tetrahydro-1- (2-iodobenzoyl) -2-methyl-4-quinoliniI] -acetamide; N-phenyl-N- [1, 2,3,4-tetrahydro-2-methyl-1- (2-methyl-1-oxopropyl) -4-quinolyl] -acetamide; N-phenyl-N- [1, 2,3,4-tetrahydro-2-methyl-1 - [(4-methylphenyl) sulfonyl] -4-quinolinyl] -acetamide; N-phenyl-N- [1, 2,3,4-tetrahydro-2-methyl-1 - [(4-nitrophenyl) methyl] -4-quinolin-1] -acetamide; N-phenyl-N- [1, 2,3,4-tetrahydro-1- (3-methoxybenzoyl) -2-methyl-4-quinolinyl] -acetamide; N- (1-acetyl-1, 2,3,4-tetrahydro-2-methyl-4-quinolinyl) -N-phenyl-butanamide; N-phenyl-N- [1, 2,3,4-tetrahydro-2-methyl-1- (1-oxobutyl) -4-quinolinyl] -acetamide; N- (1-benzoyl-1, 2,3,4-tetrahydro-2-methyl-4-quinolinyl) -N-phenyl-hexanamide; N- (1-benzoyl-1, 2,3,4-tetrahydro-2-methyl-4-quinolinyl) -N-phenyl-pentanamide; N- (1-benzoyl-1, 2,3,4-tetrahydro-2-methyl-4-quinolinyl) -N-phenyl-propanamide; 1-benzoyl-1, 2,3,4-tetrahydro-4- (N-phenylacetamido) quinaldine; N- (1-acetyl-6-bromo-1, 2,3,4-tetrahydro-2-methyl-4-quinolinyl) -N-phenyl-acetamide; N- (1-acetyl-1, 2,3,4-tetrahydro-2-methyl-6-nitro-4-quinolyl) -acetanilide; N- (1-acetyl-6-chloro-1, 2,3,4-tetrahydro-2-methyl-4-quinolyl) -acetanilide; N- (1-acetyl-1, 2,3,4-tetrahydro-2-methyl-4-quinolinyl) -N-phenyl-acetamide; N- (1-benzoyl-6-bromo-1, 2,3,4-tetrahydro-2-methyl-4-quinoxy) -N-phenyl-acetamide; N- (1-benzoyl-6-chloro-1, 2,3,4-tetrahydro-2-methyl-4-quinolinyl) -N-phenyl-acetamide; N- (1-benzoyl-1, 2,3,4-tetrahydro-2-methyl-4-quinolinii) -N-phenyl-butanamide; N-Phenyl-N- [1, 2,3,4-tetrahydro-1- (3-fluorobenzoyl) -2-methyl-4-quolinyl] -hexanamide. N- [1- (3-Chloro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide; N- [1 - (4-Fluoro-benzoyl) -2-methyl-6-nitro-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide; pentanoic acid (1-benzoyl-6-bromo-2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl) -phenyl-amide; N- (1-Benzoyl-6-chloro-2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl) -N-phenyl-acetamide; N- [6-Chloro-1- (4-fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide; N- [6-Bromo-1- (4-fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide; N- (1-Benzoyl-6-nitro-2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl) -N-phenyl-acetamide; N- (1-Benzoyl-2-methyl-1, 2,3,4-tetrahydro-quinoIin-4-yl) -N-phenyl-butyramide; or N- [1- (3-Methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -2,2-dimethyl-N-phenyl-propionamide.In a preferred embodiment of the present invention, X is -CHR2-, R2 is -H, methyl or ethyl; R3 is a substituted or unsubstituted aromatic group; R5 and R6 are -H; and the rest of the variables in the Structural Formula (I) are as defined above. More preferably, the compound is represented by a structural formula selected from Structural Formulas (ll) - (VIII): (") (III) (IV) (V) (VI) (VII) (VIII) The variables in the Structural Formulas (ll) - (VIII) are as described above for the Structural Formula (I). Below are preferred values for these variables. The phenyl ring A is a substituted or unsubstituted phenyl group. Unless otherwise indicated, suitable substituents for the phenyl ring A are provided in the section below which describes suitable aryl ring substituents. R1 in Structural Formulas (II) - (IV) and (VI) - (VIII) is -H, cycloaliphatic group, aromatic group or optionally substituted non-aromatic heterocyclic group, with the proviso that R1 in Structural Formulas (III) It's not -H. R2 in Structural Formulas (ll) - (VIII) is -H, methyl or ethyl. R3 in the Structural Formulas (ll) - (VIII) is an optionally substituted phenyl group.
R4 in the Structural Formulas (ll) - (VI) and (VIII) is -H, -CH2C (O) R14, -CH2R15, -CH2OR14 or an optionally substituted C1-C3 alkyl group or a cycloalkyl group, aromatic group or group optionally substituted non-aromatic heterocyclic, with the proviso that R 4 in Structural Formula (VI) is not -H; and R4 in the Structural Formulas (VII) is - (CH2) n -R13a. R13a is -H, -CH2C (O) R14, -CH2R15, -CH2OR14 or an optionally substituted C1-C3 alkyl group or a cycloalkyl group, aromatic group or optionally substituted non-aromatic heterocyclic group. Each R 14 is independently a -H or an alkyl group, aromatic group, cycloalkyl group or optionally substituted non-aromatic heterocyclic group. Each R15 is independently an optionally aromatic group, cycloalkyl group or non-aromatic heterocyclic group, n is 0, 1, 2 or 3, The most preferred values for R1, R4 and R13a in Structural Formulas (ll) - (VIII) are R1 and R13a are a group, phenyl, pyridyl, furanyl, thiophenyl, isoxazolyl, imidazolyl, pyrazolyl, pyrrolyl, benzofuranyl, tetrazolyl, thiazolyl, benzyl, benzothiazolyl, benzoimidazolyl, benzotriazolyl, benzomorpholinyl, benzopyrazolyl, indolyl, -CH2 - (/ V-pyridyl) ), -CH2-furanyl, -CH2-thiophienyl, -CH2-isoxazolyl, -CH2-imidazolyl, -CH2-pyrazolyl, -CH2-pyrolyl, -CH2-benzofuranyl, -CH2-tetrazolyl, -CH2-thiazolyl, -CH2- tetrazolyl, -CH2-benzothiazolyl, -CH2-benzimidazoyl, -CH2-O-phenyl, -CH2C (O) -phenyl, naphthalimidyl, tetrahydrofuranyl, cyclohexyl, cyclopentyl or optionally substituted cyclopropyl; and R 4 is C 4 alkyl, -CH 2 OH, -CH 2 OCH 3, -CH 2 OCH 2 CH 3, -CH 2 CH 2 OCH 3, -CH 2 CH 2 OCH 2 CH 3 or a group, phenyl, pyridyl, furanyl, thiophenyl, isoxazolyl, imidazolyl, pyrazolyl, pyrrolyl, benzofuranyl, tetrazolyl, benzyl, benzothiazolyl, benzoimidazolyl. , benzotriazolyl, benzomorpholinyl, benzopyrazolyl, indolyl, -CH2 - (/ V-pyridyl), -CH2-furanyl, -CH2-thiophenyl, -CH2-isoxazolyl, -CH2-imidazolyl, -CH2-pyrazolyl, -CH2-pyrollyl , -CH2-benzofuranyl, -CH2-tetrazolyl, -CH2-thiazolyl, -CH2-tetrazolyl, -CH2-benzothiazolyl, -CH2-benzimidazolyl, -CH2-O-phenyl, -CH2C (O) -phenyl, naphthalimidyl, tetrahydrofuranyl, cyclohexyl, cyclopentyl or optionally substituted cyclopropyl, wherein R1, R4 and R13 are independently selected; and Ring A is optionally substituted in position five, six, seven and / or eight.
Even more preferably, the compounds in the Structural Formulas (ll) - (VIII) have one of the following characteristics and preferably all of the following characteristics: The phenyl ring A is optionally substituted at position five, six, seven and / or eight with R11, wherein R11 is selected from substituents provided in the section below which describes suitable aryl ring substituents unless otherwise indicated herein. R1 is phenyl, thiophenyl, furanyl, pyridyl, oxazolyl, benzotriazole, pyrimidinyl, isoxazolyl or benzomorpholinyl, each group optionally being substituted with R11; R3 is [R11] -phenyl; and R 4 is methyl, ethyl, propyl, / so-propyl, n-butyl, sec-butyl, urea-butyl, -CH 2 OCH 3 or -CH 2 OCH 2 CH 3? Especially preferred are compounds represented by Structural Formulas (11) - (VIII) where Phenyl ring A is optionally substituted in the six and / or seven position with R 11; R1 is thiophenyl, [R11] -thiophenyl, oxazolyl, [R11] -oxazolyl, pyridinyl, [R11] -pyridinyl, benzotriazolyl, [R11] -benzotriazolyl, benzomorpholinyl, [R11] -benzomorpholinyl, phenyl or phenyl substituted with one to four groups selected from the group consisting of halo, -OR ° and -N (R11) 2, [R11] - R3 is phenyl substituted with one to four atoms or groups selected from the group consisting of Br, Cl, -CH3, -N (R16) 2, -NHC (O) OR ", -S (O) 2CH3, -S ( O) 2N (R16) 2 and -R13C (O) N (R16) 2, where R16 is C? -C6 alkyl In a third preferred embodiment, Ring A in the formulas Structural (I) is a monocyclic heteroaryl group such as thiophene, furan, pyridine, pyrazole, pyrrole, [2,3] pyrimidine, [3,4] pyrimidine, [4,5] pyrimidine, [5,6] pyrimidine, oxazole , isoxazole or 1,2,3-triazole, each group being optionally substituted with R11, When Ring A has these values, then the compound preferably has at least one and preferably all of the following characteristics: X is -CHR2-, R2 are -H, methyl or ethyl; R5 and R6 are -H; and R3 is a substituted or unsubstituted phenyl group. When the compound has at least one or all of these characteristics, then preferably R1 and R4 are independently -H, -CH2C (O) R14, -CH2R15 or -CH2OR14 or an alkyl group, cycloalkyl group, aromatic group or non-aromatic heterocyclic group optionally replaced; and R14 and R15 are as described above for Structural Formula (II). When Ring A in Structural Formula (I) is a monocyclic heteroaryl, as described in the previous paragraph, the values commonly selected for Xi and X2 are as follows: Xi and X2 are the two C (O); X1 is S (O) 2 and X2 is C (O); X - is C (O) NH and X2 is C (O); X-, is a bond and X2 is C (O); and X2 is C (O); X1 is C (O) and X2 is S (O) 2; X! is C (O) y; X! is C (O) and X2 is a link; or X-i is C (O) and X2 is C (O) NH. Alternatively, the phenyl ring A in the Structural Formulas (ll) - (VIII) is substituted with one of the monocyclic aromatic groups described in the previous paragraph and the rest of the variables are as described above. In a fourth preferred embodiment, R 2 in Structural Formulas (I) - (VIII) is -H, C 1 -C 4 alkyl, C 1 -C 6 halogenated alkyl, C 3 -C 8 cycloalkyl, substituted C 3 -C 8 cycloalkyl, phenyl, substituted phenyl, -C (O) OR16, benzyl, substituted benzyl or - (CH2) nO (CH2) m; R16 is C 1 -C 2 alkyl; n and m are positive integers such that n + m = 6; and the rest of the variables are as described above. Therefore, a compound represented by Structural Formula (II) and methods of using same to inhibit CRTH2 in a subject in need of treatment and pharmaceutical compositions comprising the same, wherein R1 has the corresponding value of any one of the compounds in Tables 1-6 and R3 and R4 are as described above for Structural Formula (II). Therefore, a compound represented by Structural Formula (II) and methods of using same to inhibit CRTH2 in a subject in need of treatment and pharmaceutical compositions comprising the same, wherein R3 has the corresponding value of any one of the compounds in Tables 1-6 and R1 and R4 are as described above for Structural Formula (II). Therefore, a compound represented by Structural Formula (II) and methods of using same to inhibit CRTH2 in a subject in need of treatment and pharmaceutical compositions comprising the same, wherein R4 has the corresponding value of any one of the compounds in Tables 1-6 and R1 and R3 are as described above for Structural Formula (II). Therefore, a compound represented by Structural Formula (III) and methods of using same to inhibit CRTH2 in a subject in need of treatment and pharmaceutical compositions comprising the same, wherein R3 has the corresponding value of any one of the compounds in Tables 1-6 and R1 and R4 are as described above for Structural Formula (III). Therefore, a compound represented by Structural Formula (III) and methods of using same to inhibit CRTH2 in a subject in need of treatment and pharmaceutical compositions comprising the same are also described herein., where R4 has the value corresponding to any one of the compounds in Tables 1-6 and R1 and R3 are as described above for Structural Formula (III). Therefore, a compound represented by Structural Formula (III) and methods of using same to inhibit CRTH2 in a subject in need of treatment and pharmaceutical compositions comprising the same, wherein R1 has the corresponding value of any one of the compounds in Tables 1-6 and R3 and R4 are as described above for Structural Formula (III). Therefore, a compound represented by the Structural Formula (IV) and methods of using same to inhibit CRTH2 in a subject in need of treatment and pharmaceutical compositions comprising the same, wherein R3 has the corresponding value is also described herein. any one of the compounds in Tables 1-6 and R1 and R4 are as described above for Structural Formula (IV). Therefore, a compound represented by Structural Formula (IV) and methods of using same to inhibit CRTH2 are also described herein, where R4 has the value corresponding to any one of the compounds in Tables 1-6 and R1 and R3 are as described above for Structural Formula (IV). Also described herein is a compound represented by Structural Formula (IV) and methods of using same to inhibit CRTH2, where R has the value corresponding to any one of the compounds in Tables 1-6 and R3 and R4 are as it has been described above for the Structural Formula (IV). Therefore, a compound represented by Structural Formula (V) and methods of using same to inhibit CRTH2 in a subject in need of treatment and pharmaceutical compositions comprising the same, wherein R3 has the corresponding value of any one of the compounds in Tables 1-6 and R1 and R4 are as described above for the Structural Formula (V). Therefore, a compound represented by Structural Formula (V) and methods of using same to inhibit CRTH2 in a subject in need of treatment and pharmaceutical compositions comprising the same, wherein R4 has the value corresponding to any one of the compounds in Tables 1-6 and R1 and R3 are as described above for the Structural Formula (V). Therefore, a compound represented by Structural Formula (V) and methods of using same to inhibit CRTH2 in a subject in need of treatment and pharmaceutical compositions comprising the same, wherein R1 has the corresponding value of any one of the compounds in Tables 1-6 and R3 and R4 are as described above for Structural Formula (V). Therefore, a compound represented by the Structural Formula (vi.) And methods of using same to inhibit CRTH2 in a subject in need of treatment and pharmaceutical compositions comprising the same, wherein R3 has the corresponding value are also described herein. any one of the compounds in Tables 1-6 and R1 and R4 are as described above for the Structural Formula (vi.). Therefore, a compound represented by Structural Formula (VI) and methods of using same to inhibit CRTH2 in a subject in need of treatment and pharmaceutical compositions comprising the same, wherein R4 has the value corresponding to any one of the compounds in Tables 1-6 and R1 and R3 are as described above for Structural Formula (VI). Therefore, a compound represented by Structural Formula (VI) and methods of using same to inhibit CRTH2 in a subject in need of treatment and pharmaceutical compositions comprising the same are also described herein., wherein R1 has the value corresponding to any one of the compounds in Tables 1-6 and R3 and R4 are as described above for Structural Formula (VI). Therefore, a compound represented by Structural Formula (VII) and methods of using same to inhibit CRTH2 in a subject in need of treatment and pharmaceutical compositions comprising the same, wherein R3 has the corresponding value of any one of the compounds in Tables 1-6 and R1 and R4 are as described above for the Structural Formula (VII). Therefore, a compound represented by Structural Formula (VII) and methods of using same to inhibit CRTH2 in a subject in need of treatment and pharmaceutical compositions comprising the same, wherein R4 has the corresponding value of any one of the compounds in Tables 1-6 and R1 and R3 are as described above for Structural Formula (VII). Therefore, a compound represented by Structural Formula (VII) and methods of using same to inhibit CRTH2 in a subject in need of treatment and pharmaceutical compositions comprising the same, wherein R1 has the corresponding value of any one of the compounds in Tables 1-6 and R3 and R4 are as described above for the Structural Formula (VII). Therefore, a compound represented by Structural Formula (VIII) and methods of using same to inhibit CRTH2 in a subject in need of treatment and pharmaceutical compositions comprising the same, wherein R3 has the corresponding value of any one of the compounds in Tables 1-6 and R1 and R4 are as described above for Structural Formula (VIII). Therefore, a compound represented by Structural Formula (VIII) and methods of using same to inhibit CRTH2 in a subject in need of treatment and pharmaceutical compositions comprising the same, wherein R4 has the corresponding value of any one of the compounds in Tables 1-6 and R1 and R3 are as described above for Structural Formula (VIII). Therefore, a compound represented by Structural Formula (VIII) and methods of using same to inhibit CRTH2 in a subject in need of treatment and pharmaceutical compositions comprising the same, wherein R1 has the corresponding value of any one of the compounds in Tables 1-6 and R3 and R4 are as described above for Structural Formula (VIII). Specific examples of compounds of general formula I are shown in the exemplification section herein.
It will be understood that the definitions and description that follow immediately apply to compounds of general formula I (and subsets thereof described above in this section 1 entitled "Description of Compounds of General Formula I (and subsets thereof)" As used In this document, the following definitions will apply unless otherwise indicated: For purposes of this invention, the chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. In addition, the general principles of organic chemistry are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito: 1999, and March's Advanced Organic Chemistry, 5th Ed., Ed .: Smith, MB and March, J. , John Wiley &Sons, New York: 2001, Many of the CRTH2 inhibitors described contain one or more chiral centers.The presence of chiral centers in a molecule gives rise to stereo isomers For example, there is a pair of optical isomers, called "enantiomers", for each chiral center in a molecule; and there are a pair of diastereomers for each chiral center in a compound having two or more chiral centers. Even though Structural Formulas (l) - (VIII) do not explicitly represent stereochemistry, it will be understood that these formulas encompass enantiomers without the corresponding optical isomer, racemic mixtures, mixtures enriched in one enantiomer in relation to their corresponding optical isomer, a diastereomer without other diastereomers, a pair of diastereomers without other diastereomeric pairs, mixtures of diastereomers, mixtures of diastereomeric pairs, mixtures of diastereomers in which one diastereomer is enriched in relation to the other diastereomer (s) and mixtures of diastereomeric pairs in which a diastereomeric pair is enriched in relation to the other diastereomeric pair (s). A preferred diastereomeric pair is when R2 and NRXR3 in Structural Formulas (1) - (VIII) are cis in relation to one another. By way of example, the diastereomeric cis pair for the compound represented by Structural Formula (II) is shown below in Structural Formulas (IX) and (X): (IX) (X). The preferred configuration for R2 and NRXR3 (represented by N (R3) (COR4) in the Structural Formulas (IX) and (X) is (2R, 4S), as shown in Structural Formula (IX). Structural Formula (IX) represents a preferred optical isomer for the compound represented by Structural Formula (II) Likewise, the corresponding optical isomer (2, 4S) for the compounds represented by Structural Formulas (I) and (III) ) - (HIV) and Tables 1-6 are also specifically described The most preferred configuration for R2 and NRXR3 (represented by N (R3) (COR4)) in the Structural Formulas (IX) and (X) is (2S, 4R ), as shown in Structural Formula (X) In this manner, Structural Formula (X) represents a more preferred optical isomer for the compound represented by Structural Formulas (I) and (III) - (VIII) and in Tables 1-6, As used in this document, a structure representing an isomer or optical or a reference to an optical isomer is intended to include enantiomeric mixtures that are enriched with the enantiomer represented or mentioned in relation to its optical isomer, for example, an enantiomeric excess of at least 50%, 75%, 90%, 95% 99% or 99.5%. As used herein, a structure representing a diastereomeric pair or a reference to a diastereomeric pair is intended to include mixtures that are enriched with the diastereomeric pair represented or mentioned in relation to other diastereomers or diastereomeric pairs (s) for the compound, example, a molar excess of at least 50%, 75%, 90%, 95% 99% or 99.5%.
The enantiomers of the present invention can be resolved by methods known to those skilled in the art, for example by formation of diastereomeric salts which can be separated, for example, by crystallization; formation of diastereomeric derivatives or complexes that can be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of an enantiomer with a specific enantiomer reagent, for example enzymatic esterification; or gas-liquid chromatography or liquids in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent. When the desired enantiomer is converted to another chemical entity by one of the separation methods mentioned above, an additional step is required to release the desired enantiomeric form. Alternatively, specific enantiomers can be synthesized by asymmetric synthesis using reagents, substrates, catalysts or optically active solvents, or by converting one enantiomer into the other by asymmetric transformation. The diastereoisomeric pairs can be separated by methods known to those skilled in the art, for example chromatography or crystallization and the individual enantiomers within each pair can be separated as described above. In Schemes 1 and 2 specific procedures are provided for separating diastereomeric pairs of precursors used in the preparation of compounds described herein. In certain cases the compounds of the present invention may be associated in isolation with solvent or water, as in a "solvate" or "hydrate". References to the disclosed compounds or structural formulas representing the disclosed compounds are intended to include said solvates and hydrates.
The term "aliphatic" as used herein means straight chain or branched hydrocarbons that are completely saturated or that contain one or more units of unsaturation, but are not aromatic.
An aliphatic group is typically C-i-s, more typically C-i-β, For example, suitable aliphatic groups include linear or branched substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof. The terms "alkyl", "alkoxy", "hydroxyalkyl", "alkoxyalkylene", and "alkoxycarbonyl", used alone or as part of a larger moiety include linear and branched saturated chains containing from one to eight carbon atoms. The terms "alkenyl" and alkynyl "used alone or as part of a larger moiety will include linear and branched chains containing from two to eight carbon atoms and one or more double and / or triple bonds, respectively." The term "cycloaliphatic" used alone or as part of a larger moiety will include cyclic C3-C10 hydrocarbons that are completely saturated or that contain one or more unsaturation units, but are not aromatic.The cycloaliphatic groups are typically C3-10, more typically C3-? A "cycloalkium" is a cyclic aliphatic group that is fully saturated "Alkoxy" means (alkyl) -O-; "alkoxyalkylene" means (alkyl) -O- (alkylene) such as methoxymethylene (CHsOCH2); "hydroxyalkyl" means group substituted hydroxy alkyl; "alkoxycarbonyl means a carbonyl substituted with a carbonyl as in (alkyl) -OC (O) -; and "aralkyl" means alkyl substituted with an aromatic group. A "C 1 -C 4 aralkyl group", for example, has a C 1 -C 4 alkyl group substituted with an aromatic group. The term "heteroatom" means nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen and sulfur, and the quatemized form of any basic nitrogen. In addition, the term "nitrogen" includes a substitutable nitrogen of a heterocyclic ring. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2 / -pyrrolyl), NH (as in pyrrolidinyl) ) or NR + (as in N-substituted pyrrolidinyl). The term "aromatic group" used alone or as part of a larger moiety such as "aralkyl," "aralkoxy," or "aryloxyalkyl," includes carbocyclic aromatic ring groups and heteroaryl ring groups. The term "aromatic group" can be used interchangeably with the terms "aryl", "aryl ring" or "aromatic ring". Carbocyclic aromatic ring groups only have carbon atoms in the ring and include monocyclic aromatic rings such as phenyl and condensed polycyclic aromatic ring systems in which two or more carbocyclic aromatic rings condense with one another. Examples include 1-naphthyl, 2-naphthyl, 1-anthracyl and 2-anthracyl. Also included within the scope of the term "carbocyclic aromatic ring", as used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings (aliphatic or heterocyclic), such as in an indanyl , phthalimidyl, naphthymidyl, phenanthridinyl, or tetrahydronaphthyl, where the radical or point of attachment is in the aromatic ring. The term "heteroaryl" or "heteroaromatic", used alone or as part of a larger moiety such as "heteroaralkyl" or "heteroarylalkoxy", refers to heteroaromatic ring groups having five to fourteen members, including monocyclic heteroaromatic rings and polycyclic aromatic rings in which a monocyclic aromatic ring is fused with one or more different carbocyclic or heteroaromatic aromatic rings. Examples of heteroaryl rings include 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl., 4-isoxazoliol, 5-isoxazolyl, 2-oxadiazolyl, 5-oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, pyrazolyl, 2-pyridyl, 3-pyridyl , 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidiio, 3-pyridazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolium, 2-triazoyl, 5-triazoly, tetrazolyl, 2-thienyl, 3-thienyl , carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzooxazolyl, benzimidazolyl, isoquinolinyl, indolyl, isoindolyl, acridinyl, or benzoisazolyl. Also included within the scope of the term "heteroaryl", as used herein, is a group in which a heteroaryl ring is fused to one or more non-aromatic cycloaliphatic or heterocyclic groups where the radical or point of attachment is in the ring heteroaromatic. Examples include tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido [3,4-d] pyrimidinyl. The term "heteroaryl" may be interchangeable with the term "heteroaryl ring" or the term "heteroaromatic". The term "non-aromatic heterocyclic ring", used alone or as part of a larger moiety as in "heterocyclylalkyl", refers to non-aromatic ring systems that typically have from five to fourteen members, preferably five to ten, in which one or more carbons of the ring, preferably one to four, is each substituted by a heteroatom such as N, O, or S. Examples of non-aromatic heterocyclic rings include 3-1 H-benzimidazol-2-one, 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, [1,3] -dioxalanyl, [1,3] -dithiolanyl, [1, 3] -dioxanil, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2-morpholinyl, 3- morpholinyl, 4-morpholinyl, 2-thiomorpholinyl, 3-thiomorpholinyl, 4-thiomorpholinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinium, 4-piperidinyl, 4-thiazolidinyl, diazolonyl, N-substituted diazolonyl, 1-phthalimidinyl, be nzoxanil, benzopyrrolidinyl, benzopiperidinyl, benzoxolanyl, benzothiolanyl, and benzothianyl. A "hydrocarbyl group" is a polymethylene group, i.e., - (CH2) n-, where n is a positive integer. Preferably, n is an integer from 1 to 6, more preferably from 2 to 4 and more preferably from 2 to 3. A "substituted hydrocarbyl" is a hydrocarbyl group in which one or more methylene hydrogen atoms are substituted with a substituent . Suitable substituents are as described below for a substituted aliphatic group. Preferred substituents for the hydrocarbyl groups represented by X3-X6 are halo, -OH, = O, C1-C3 alkyl, C1-C3 alkoxy, nitro and cyano. A hydrocarbyl group may be optionally interrupted by one or more functional groups. A hydrocarbyl is interrupted by a functional group when one of the internal methylenes is replaced with the functional group. Examples of suitable "interruption functional groups" include -O-, -S-, -N (Ra) -, -S (O) -, -SO2-, -C (O) -, -OC (O) - , -N (Ra) C (O) -, -C (O) N (Ra) -, -SO2N (Ra) -, and -N (Ra) SO2-. Ra is -H or a CrC3 alkyl group. An aromatic group (including Ring A, carbocyclic aromatic, heteroaryl, aralkyl, aralkoxy, aryloxyalkyl and heteroaralkyl and the like) may contain one or more substituents. Examples of suitable substituents on an unsaturated carbon atom of an aromatic group include a halogen -R °, -OR °, -SR °, 1,2-methylene-dioxy, 1,2-ethylenedioxy, protected OH (such as acyloxy), phenyl (Ph), substituted Ph, -O (Ph), -O (Ph) substituted, -CH2 (Ph), -CH2 (Ph) substituted, -CH2CH2 (Ph), -CH2CH2 (Ph) substituted, -NO2, -CN, -N (R ') 2, -NR'CO2R °, -NRO (O) R °, -NR'NR'C (O) R °, -N (R') C (O) N (R ') 2, -NR'NR'C (O) N (R') 2, -NR'NR'COzR0, -C (O) C (O) R °, -C (O) CH2C (O ) R °, -CO2R °, -C (O) R °, -C (O) N (R °) 2, -OC (O) N (R °) 2, -S (O) 2R °, -SO2N (R ') 2, -S (O) R °, -NR'SOzNÍR' ^, -NR'SO2R °, -C (= S) N (R ') 2, - (CH2) and N (R') 2, -C (= NH) -N (R ') 2, - (CH2) and NHC (O) R °, - (CH2) andNHC (O) CH (V-R °) (R0). R 'is R °, -CO2R °, -SO2R ° or -C (O) R ° and preferably hydrogen, aliphatic C-.6, CO2R °, SO2R ° or C (O) R °. R ° is hydrogen or substituted or unsubstituted aliphatic, cycloaliphatic, aromatic, aralkyl or non-aromatic heterocyclic group, and preferably hydrogen, C? _6 alkyl, phenyl (Ph), -CH 2 (Ph), aralkyl, non-aromatic heterocyclic or heteroaryl group; and is 0-6; and V is alkylene group C -? - C6. examples of substituents on the aliphatic group or the phenyl ring of R ° include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, aminoalkyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl , hydroxy, haloalkoxy, or haloalkyl. An aliphatic group or a non-aromatic heterocycle may contain one or more substituents. Examples of suitable substituents on the saturated carbon of an aliphatic group of a non-aromatic heterocycle include those listed above for the unsaturated carbon of an aromatic group and the following: = O, = S, = NNHR *, = NN (R *) 2, = NNHC (O) R *, = NNHCO2 (alkyl), = NNHSO2 (alkyl), or = NR *. Each R * is independently selected from hydrogen, an unsubstituted aliphatic group or a substituted aliphatic group. Examples of substituents in the aliphatic group represented by R * include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, or haloalkyl. Suitable substituents on the substitutable nitrogen of a heteroaryl or non-aromatic heterocyclic group include -R +, -N (R +) 2, -C (O) R +, -CO 2 R +, -C (O) C (O) R +, -C (O) CH2 C (O) R +, -SO2 R +, -SO2 N (R +) 2, -C (= S) N (R +) 2, -C (= NH) -N (R +) 2, and -NR + SO2 R +; where R + is hydrogen, an aliphatic group, a substituted aliphatic group, phenyl (Ph), substituted Ph, -O (Ph), -O (Ph) substituted, CH2 (Ph), or an unsubstituted heteroaryl or non-aromatic heterocyclic ring . Examples of substituents on the aliphatic group or the phenyl ring represented by R + include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, or haloalkyl. 2. Description of Compounds of General Formula l-A (and subsets thereof): Another embodiment of the present invention is a compound represented by Structural Formula (l-A): l-A or a pharmaceutically acceptable salt thereof, wherein: Ring A is an optionally substituted monocyclic aromatic; R is -XrR1; Rx is -X2-R4; each of Xi and X2 are independently -S (O) 2-, -C (O) - or -C (O) NH-; R1 is: A) an aromatic group or heteroaromatic group having 5-6 ring atoms, fused to a monocyclic non-aromatic heterocyclic ring or monocyclic aromatic or heteroaromatic ring where the non-aromatic heterocyclic ring, the aromatic ring or the heteroaromatic ring are optionally substituted; or B) an aromatic group or heteroaromatic group having 5-6 ring atoms, substituted with: i) T1-V-T-R ?; ii) T -V-T-M-R ?; or iii) V-R9, wherein R9 is an optionally substituted non-aromatic carbocyclic or heterocyclic group; and wherein the aromatic or heteroaromatic group having 5-6 ring atoms is optionally substituted with 1-2 selected groups independently represented by Rz; each Rz is independently selected from halogen, haloalkyl, R °, -OR °, -O (haloalkyl), -SR °, -NO2, -CN, -N (R ') 2, -NR'CO2R °, -NR' C (O) R °, -NR'NR'C (O) R °, -N (R ') C (O) N (R') 2, -NR'NR'C (O) N (R ') 2, -NR'NR'CO2R0, -C (O) C (O) R °, -C (O) CH2C (O) R °, -CO2R °, -C (O) R °, -C (O) N (R °) 2, -OC (O) R °, -OC (O) N (R °) 2, -S (O) 2R °, -SO2N (R ') 2, -S (O) R ° , -NR'SO2N (R ') 2, -NR'SO2R °, -C (= S) N (R') 2 and -C (= NH) -N (R ') 2; each R is independently hydrogen, alkyl, -C (O) OR °, S (O) 2R ° or -C (O) R °; each R ° is independently hydrogen or an alkyl group, non-aromatic heterocyclic group or aromatic group and the alkyl, the non-aromatic heterocyclic group and the aromatic group represented by R ° are optionally substituted with one or more groups selected independently represented by R #; R # is R +, -OR +, -O (haloalkyl), -SR +, -NO2, -CN, -N (R +) 2, -NHCO2R +, -NHC (O) R +, -NHNHC (O) R +, -NHC ( O) N (R +) 2, -NHNHC (O) N (R +) 2, -NHNHCO2R +, -C (O) C (O) R +, -C (O) CH2C (O) R +, -CO2R +, -C ( O) R +, -C (O) N (R +) 2, -OC (O) R +, -OC (O) N (R +) 2, -S (O) 2R +, -SO 2 N (R +) 2, -S ( O) R +, -NHSO 2 N (R +) 2, -NHSO 2 R +, -C (= S) N (R +) 2 or -C (= NH) -N (R +) 2; R + is -H, a C1-C3 alkyl group, a monocyclic heteroaryl group, a non-aromatic heterocyclic group or a phenyl group optionally substituted with alkyl, haloalkyl, alkoxy, haloalkoxy, halo, -CN, -NO2, amine, alkylamine or dialkylamine; or -N (R +) 2 is a non-aromatic heterocyclic group, with the proviso that the non-aromatic heterocyclic groups represented by R + and -N (R +) 2 comprising a secondary ring amine are optionally acylated or alkylated; V is a covalent bond, -O-, -C (O) -, -N (R>, -S-, -S (O) -, -C (O) NR5-, -NR5C (O) -, -S (O) 2NR5-, -NR5S (O) 2- or -S (O) 2-; T is straight chain C-MO alkylene, T1 is a covalent bond or a straight chain C1-10 alkylene, where T and T1 together contain no more than 10 carbon atoms and where T and T1 are optionally and independently substituted on any one or more of the carbon atoms substitutable with halide, alkyl, gem dialkyl, gem dihalo, haloalkyl, alkoxy, haloalkoxy , spiro cycloalkyl, optionally? / - substituted nitrogen containing a spiro, amine, alkylamine, dialkylamine, alkoxy or hydroxyl non-aromatic heterocyclic group; M is an optionally substituted group selected from monocyclic aromatic, heteroaromatic, non-aromatic monocyclic or heterocyclic carbocyclic group; R is -C (O) OR 5, -C (O) R 5, -OC (O) R 5, -C (O) N (R 5) 2, -NR 5 C (O) R 5, -NR 5 C (O) OR 5, - S (O) 2R5, -S (O) 2COR5, -S (O) 2N (R5) 2, -NR5S (O) 2R5, -NR5S (O) 2R5, S (O) 2OR5, -S (O) OR5 , -S ( O) R5, -SR5, -C (O) NR5S (O) 2R5, -CN, -NR5C (O) N (R5) 2, -OC (O) N (R5) 2, -N (R5) 2, -OR5, an optionally substituted non-aromatic heterocyclic group or an optionally substituted heteroaryl group; with the proviso that T is C2-? or when V is a covalent bond and T is C2-? or when V is -O-, -S- or -N (R> and R? is -CN, -OH , -SH, -N (R5) 2 each R5 is independently -H, alkyl, haloalkyl, hydroxyalkyl, carboxyalkyl, -C (O) OCH2C6H5, S (O) 2CH3, -C (O) OH, -C (O) OMe, -C (O) OEt, C (O) NH2, benzyl, pyrrolidinyl, morpholinyl or -N (R5) 2 is a non-aromatic heterocyclic group containing nitrogen, R2 is C-1,3 alkyl, R3 is a group optionally substituted monocyclic or bicyclic selected from an aromatic, heteroaromatic, non-aromatic carbocyclic and non-aromatic heterocyclic group, and R 4 is optionally substituted C 1-6 alkyl, C 1-4 hydroxyalkyl, or optionally substituted C 3-6 cycloalkyl. Compounds of formula IA or a pharmaceutically acceptable salt thereof are provided, wherein: Ring A is an optionally substituted monocyclic aromatic; each of X1 and X2 are independently -S (O) 2-, -C (O) - or -C (O) NH-; R1 is: A) an aromatic group or heteroaromatic group having 5-6 ring atoms, substituted with: i) T1-V-T-R ?; ü) t1-V-T-M-R ?; or iii) V-R9 wherein R9 is an optionally substituted non-aromatic carbocyclic or heterocyclic group; and wherein the aromatic or heteroaromatic group represented by R1 is optionally substituted with 1-2 selected groups independently represented by Rz; or B) an aromatic group or heteroaromatic group having 5-6 ring atoms, fused to a monocyclic non-aromatic monocyclic or aromatic monocyclic heterocyclic ring wherein the non-aromatic heterocyclic ring or the aromatic ring are optionally substituted; each Rz is independently selected from halogen, haloalkyl, R °, -OR °, -O (haloalkyl), -SR °, -NO2, -CN, -N (R ') 2, -NROO2R °, -NR'C (O) R °, -NR'NR'C (O) R0, - N (R ') C (O) N (R') 2, -NR'NR'C (O) N (R ') 2, -NR'NROO2R °, -C (O) C (O) R °, - C (O) CH 2 C (O) R °, -CO 2 R °, -C (O) R °, -C (O) N (R °) 2, -OC (O) R °, -OC (O) N (R °) 2, -S (O) 2R °, -SO2N (R ') 2, -S (O) R °, -NR'SO2N (R') 2, -NR'SO2R °, -C (= S) N (R ') 2 and -C (= NH) -N (R') 2; each R is independently hydrogen, alkyl, -C (O) OR °, S (O) 2R ° or -C (O) R °; each R ° is independently hydrogen or an alkyl group, non-aromatic heterocyclic group or aromatic group and the alkyl, the non-aromatic heterocyclic group and the aromatic group represented by R ° is optionally substituted with one or more groups selected independently represented by R #; R # is R +, -OR +, -O (haloalkyl), -SR \ -NO2, -CN, -N (R +) 2, -NHCO2R +, -NHC (O) R +, -NHNHC (O) R +, -NHC ( O) N (R +) 2, -NHNHC (O) N (R +) 2, -NHNHCO2R +, -C (O) C (O) R +, -C (O) CH2C (O) R +, -CO2R +, -C ( O) R +, -C (O) N (R +) 2, -OC (O) R +, -OC (O) N (R +) 2, -S (O) 2R +, -SO 2 N (R +) 2, -S ( O) R +, -NHSO 2 N (R +) 2, -NHSO 2 R +, -C (= S) N (R +) 2 or -C (= NH) -N (R +) 2; R + is -H, a C1-C3 alkyl group, a monocyclic heteroaryl group, a non-aromatic heterocyclic group or a phenyl group optionally substituted with alkyl, haloalkyl, alkoxy, haloalkoxy, halo, -CN, -NO2, amine, alkylamine or dialkylamine; or -N (R +) 2 is a non-aromatic heterocyclic group, with the proviso that the non-aromatic heterocyclic groups represented by R + and -N (R +) 2 comprising a secondary ring amine are optionally attached or alkylated; R? is -C (O) OR 5, -C (O) R 5, -OC (O) R 5, -C (O) NR 52, -NR 5 C (O) R 5, -NR 5 C (O) OR 5, -S (O) 2 R 5, -S (O) 2COR5, -S (O) 2NR52, -NR5S (O) 2R5, -NR5S (O) 2R5, S (O) 2OR5, -S (O) OR5, -S (O) R5, -SR5 , -C (O) NR5S (O) 2R5, -CN, -NR5C (O) NR52, -OC (O) NR52, -NR52, -OR5, an optionally substituted non-aromatic heterocyclic group or an optionally substituted heteroaryl group; V is a covalent bond, -O-, -C (O) -, -N (R>, -S-, -S (O) -, -C (O) NR5-, -NR5C (O) -, -S (O) 2NR5-, -NR5S (O) 2- or -S (O) 2-; T is straight chain C1-C-10 alkylene, with the proviso that T is C2-? 0 when V is a covalent bond and T is C2-? Or when V is -O-, -S- or -N (R ') - and R? is -CN, -OH, -SH, -N (R5) 2; T1 is a covalent bond or a straight chain C-O alkylene, where T and T1 together do not contain more than 10 carbon atoms and where T and T1 are optionally and independently substituted on any one or more of the substitutable carbon atoms with halide, alkyl, gem dialkyl, gem dihalo, haloalkyl, alkoxy, haloalkoxy, spiro cycloalkyl, optionally N-substituted nitrogen containing a non-aromatic heterocyclic group spiro, amine, alkylamine, dialkylamine or hydroxyl; each R5 is independently -H, alkyl, haloalkyl, hydroxyalkyl, carboxyalkyl, -C (O) OCH2C6H5, S (O) 2CH3, -C (O) OH, -C (O) OMe, -C (O) OEt, C (O) NH2, benzyl, pyrrolidinyl, morpholinyl or -N (R5) 2 is a non-aromatic heterocyclic group containing nitrogen; M is an optionally substituted monocyclic aromatic, heteroaromatic or an optionally substituted monocyclic monocyclic carbocyclic or heterocyclic group; R2 is C -? - 3 alkyl; R3 is an optionally substituted aromatic group having 5-6 ring atoms; and R 4 is C 1 -C 3 alkyl or C 1 -C 3 hydroxyalkyl. The sections shown below that define the terms "aromatic group", "heteroaromatic group", "non-aromatic carbocycle" and "non-aromatic heterocyclic group" provide specific examples of values suitable for M. Suitable substituents for aromatic rings represented by M are as defined for R11; Suitable substituents for the carbocycles and non-aromatics are as described in the sections shown below which define suitable substituents for these two groups. In certain aspects, the compounds of the invention are compounds other than the following compounds: When R1 is phenyl substituted in para position with VTR ?, R2 is methyl, R3 is for chlorophenyl, Rx is C (O) CH3, X1 is -C (O) and V is -O-, TR? is -CH2-CH2- C (CH3) 2-CONH2, -CH2-CH2-C (CH3) 2-OH, -CH2-CH2-CH2-C (CH3) 2-OH, -CH2-CH2-C (CH3) ) 2-COOH, -CH2-C (spiro cyclopropyl) -CH2-COOH or -CH2-C (CH3) -COOH. When R1 is phenyl substituted in para position with V-T-R? R2 is methyl, R3 is for chlorophenyl, Rx is C (O) CH3, Xi is -C (O) and V is a covalent bond, then T-R? is -CH2-CH2-COOH. When R2 is methyl, R3 is for chlorophenyl, RX is C (O) CH3, Xi is C (O) and R1 is phenyl substituted in para position with V-R9 where R9 is an optionally substituted non-aromatic heterocyclic group, V is a covalent bond, R1 is? -morpholinyl,? / - ethoxycarbonyl-4-piperdinyl, / V-acetyl-4-piperdine, N-ethoxycarbonyl-4-piperid-3-enyl,? / - pyrrolidinyl , N-ethyl-N-piperazinyl, N-acet \\ - N-piperazinyl, A / - (2'-hydroxyacetyl) -A / '- piperazinyl,? / - (CH2C (O) OH -? / - piperazinyl or N- (CH2C (O) NH2) -? / - piperazinyl When R2 is methyl, R3 is for chlorophenyl, Rx is C (O) CH3, Xi is C (O) and R1 is phenyl substituted in para position with V- R9 where R9 is an optionally substituted non-aromatic heterocyclic group, V is -O-, R1 is N-ethoxycarbonyl-4-piperdinyl or? / - acetyl-4-piperdinyl When R2 is methyl, R3 is phenyl, Rx is C ( O) CH2CH3, X ^ is C (O) and R1 is phenyl substituted in the para position with a non-aromatic heterocyclic group, R1 is? / - acetyl-4-piperdiniIo or? / - morpholinyl. is methyl, R3 is for chlorophenyl, Rx is C (O) CH3, Xi is C (O) and R1 is phenyl fused to an optionally substituted non-aromatic heterocyclic group, R1 tetrahydrofuranyl or N'-methylmorpholinyl. When R2 is methyl, R3 is for chlorophenyl, Rx is C (O) CH3, Xi is C (O) and R1 is para-substituted pyridinyl with a non-aromatic heterocyclic group, R1 is? / -morpholinyl. When R2 is methyl, R3 is for chlorophenyl, Rx is C (O) CH3, Xi is C (O) and R1 is phenyl fused to an optionally substituted aromatic group, R1 is N-isopropyltriazolyl,? -methyltriazolyl,? / - isopropylimidazolyl, 2-methyl- / V-hydroxyethylimidazolyl, 2-methyl-? / - carboxymethylimidazoyl, / V-carboxyethyltriazolyl, N -isopropylpyrazolyl.
When R j e "s" | R D3 is for chlorophenyl ?, R n is C (O) CH 3, X-i is C (O) and R is imidazolyl fused to an optionally substituted aromatic group, R 1 is phenyl. When R2 is methyl, R3 is for chlorophenyl, Rx is C (O) CH3, X-i is C (O) and R1 is thiazolyl fused to an optionally substituted aromatic group, R1 is phenyl. In some embodiments, the compounds of the invention are compounds other than the compounds described in our United States Patent Application 10 / 678,872 filed October 4, 2003 (the entire contents of which are incorporated herein by reference). In other embodiments, the compounds of the invention are compounds other than: (±) -C / s -? / - [1 - (1 H -indole-2-carbonii) -2-methyl-1, 2,3,4 -tetrahydro-quinoIin-4-yl] - / V-phenyl-propionamide; (±) -C / s -? / - [1 - (benzofuran-2-carbonyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -? / - phenyl-propionamide; ethyl ester of the acid (±) -C / s-. { 4- [2-methyl-4- (phenyl-propionyl-amine) -3,4-dihydro-2H-quinoline] -1-carbonyl] -phenoxy} -acetic; Acid (±) -Cs--. { 4- [2-methyl-4- (phenyI-propionyl-amino) -3,4-dihydro-2H-quinoline-1-carbonyl] -phenoxy} -acetic; (±) -C / s -? / -. { 2-methyl-1 - [4- (2-morpholin-4-yl-ethoxy) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -? / - phenyl-propionamide; (±) -C / s- / V- [1- (4-carbamoylmethoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -? / - phenyl-propionamide; (±) -C / s -? / -. { 1- [4- (2-hydroxy-2-methyl-propoxy) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -? / - phenyl-propionamide; (±) -C / s -? / - [1 - (4-dimethylcarbamoylmethoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide; (±) -C / s -? / - [1- (benzo [b] thiophene-3-carbonyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl -? / - phenyl acetamide; (±) -C / s -? / - [1 - (benzo [b] thiophene-2-carbonyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -? / - phenyl-propionamide; Acid (±) -C / s-. { 4- [4- (Acetyl-phenyl-amino) -2-methyl-3,4-dihydro-2H-quinoline-1 -carbonyl] -phenylamino} -acetic; (±) -Cis-N - [\ - (1-isopropyl-1 H-benzotriazole-5-carbonyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -? / -phenyl-propionamide; Acid ethyl ester (±) -C / s-4-. { 4- [2-methyl-4- (phenyl-propionyl-amino) -3,4-dihydro-2H-quinoline-1 -carbonyl] -phenyl} -peridine-1-carboxylic acid; (±) -C / s- / V- [2-methyl-1- (4-piperidin-4-yl-benzoyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] - V-phenol-propionamide; (±) -C / s -? / -. { 1 - [4- (1-Acetyl-piperidin-4-yl) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -? / - phenyl-propionamide; (±) -C / s -? / -. { 1- [4- (1-ethyl-piperidin-4-yl) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -? / - phenyl-propionamide; (±) -C / s -? / -. { 2-methyl-1- [4- (4-methyl-piperazin-1-yl) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -? / - phenyl-propionamide; (±) -C / s -? / - [2-methyl-1- (4-methyl-3,4-dihydro-2H-benzo [1,4] oxazine-7-carbonyl) -1, 2,3, 4-tetrahydro-quinolin-4-yl] -? / - phenyl-propionamide; (±) -C / s -? / - [2-Methyl-1- (4-morpholin-4-yl-benzoyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] -? / - phenyl-propionamide; (±) -C / s -? / - [2-methyl-1- (4-pyrrolidin-1-yl-benzoyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] -? / - phenyl-propionamide; Acid methyl ester (±) -C / s-2-. { 4- [4- (acetyl-phenyl-amino) -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl] -phenylamino} -propionic; (±) -C / s-2-. { 4- [4- (Acetyl-phenyl-amino) -2-methyl-3,4-dihydro-2H-quinoline-1 -carbonyl] -phenylamino} -propionamide; (±) -C / s -? / - [1 - (2,3-dihydro-benzo [1,4] -oxin-6-carbonyl) -2-methylene-1, 2,3, 4-tetrahydro-quinolin-4-yl] -? / - phenyl-propionamide; (±) -C / s -? / - [1 - (benzo [c] isoxazole-3-carbonyl) -2-methyI-1, 2,3,4-tetrahydro-quinolin-4-yl] -? phenyl propionamide; Ethyl ester of the acid (±) -C / s-4- (4- { 4 - [(4-cyoro-phenyl) -propionyl-amino] -2-methyl-3,4-dihydro-2H- quinoline-1-carbonyl.}. -phenoxy) -butyric; Acid (±) -C / s-4- (4- { 4 - [(4-Chloro-phenyl) -propionyl-amino] -2-methyl-3,4-d -hydro-2H-quinoline -1-carbonyl.}. -phenoxy) -butyric; (±) -C / s -? / - (4-chloro-phenyl) -? / -. { 2-methyl-1 - [4- (1 H -tetrazol-5-ylmethoxy) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -propionamide; (±) -C / s -? / - (4-chloro-phenyl) - / -. { 1- [4- (3-hydroxy-2,2-dimethyl-propoxy) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -acetamide; Acid methyl ester (±) -C / s-3- (4-. {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H- quinoline-1-carbonyl.}. -phenoxy) -2,2-dimethyl-propionic; (±) -C / s- / V- (4-chloro-phenyl) - / V- [1- (4-cyclopentyloxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4 -yl] -acetamide; (±) -C / s- / V-. { 1 - [4- (4-Acetyl-piperazin-1-yl) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinoline-4-yl} -? / - (4-chloro-phenyl) -acetamida; (2S, 4R) -A / - (4-Chloro-phenyl) -? / - [2-methyl-1- (4-morpholin-4-yl-benzoyl) -1, 2,3,4-tetrahydro-quinolin -4-yl] -acetamide; Acid (2S, 4R) -4- (4-. {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl .}. -phenoxy) -butyric; (2S, 4R) - / V- (4-Chloro-phenyl) -? / - [2-methyl-1- (6-morpholin-4-yl-pyridine-3-carbonyl) -1, 2 , 3,4-tetrahydro-quinolin-4-yl] -acetamide; Ethyl ester of (2S, 4R) -4- (4-. {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl] -2,4-dihydro-2H-quinol na-1 -carbonyl.}. -phenoxy) -piperidin-1-carboxylic acid; (2S, 4R) -? / - (4-Chloro-phenyl) -N-. { 2-methyl-1- [4- (2-morpholin-4-yl-ethoxy) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -acetamide; (2S, 4R) - (4-. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl} - phenoxy) -acetic; (2S, 4R) -? / - (4-Chloro-phenyl) - -. { 2-methyl-1- [4- (1 H -tetrazol-5-ylmethoxy) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -acetamide; (2S, 4R) -? -. { 1 - [4- (1-Acetyl-piperidin-4-yloxy) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} - / V- (4-chloro-phenyl) -acetamide; (2S, 4R) -? / - (4-Chloro-phenyl) -A / -. { 2-methy1- [4- (pyridin-4-ylmethoxy) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -acetamida; (2S, 4R) -4- (3- {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl} .-phenoxy) -butyric; (2S, 4R) -4- (4-. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-ethyl ester carbonyl, phenyl) -piperidine-1-carboxylic acid; (2S, 4R) - / V- (4-Chloro-phenyl) -? / - [2-methyl-1- (4-pyrrolidin-1-yl-benzoyl) -1, 2,3,4-tetrahydro-quinoline -4-il] -acetamida; (2S, 4R) -? / - (4-Chloro-phenyl) - / V- [1 - (1-isopropyl-1 H-benzotriazole-5-carbon I) -2-methyl-1, 2,3, 4-tetrahydro-quinolin-4-yl] -acetamide; Acid (2S, 4R) -3- (4-. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1 -carbonyl.}. -phenyl) -propionic; (2S, 4R) -3- (4-. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl) .}. -phenyl) -acrylic; ? / -. { (2S, 4R) -1 - [4- (1-Acetyl-piperidin-4-yl) -benzoyl] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} - V-phenylpropanamide; ? / -. { (2R, 4S) -1 - [4- (1-Acetylpiperidin-4-yl) benzoyl] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} - / V-phenolpropanamide; ? / - [(2S, 4R) -2-methyl-1 - (4-morpholin-4-ylbenzoyl) -1, 2,3,4-tetrahydroquinolin-4-yl] -? / - phenylpropanamide; ? / - [(2R, 4S) -2-methyl-1- (4-morpholin-4-ylbenzoyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] -? / - phenylpropanamide; N-. { (2S, 4R) -1 - [4- (1-Acetylpiperidin-4-yl) benzoyl] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} -? / - phenylpropanamide; ? / -. { (2R, 4S) -1 - [4- (1-Acetylpiperidn-4-yl) benzoyl] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} -A / -phenylpropanamide; ? / -. { (2S, 4R) -1- [4- (1-Acetylpiperidin-4-yl) benzoyI] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} -? / - (4-chlorophenyl) acetamide; Acid (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dithyquinoline-1 (2H) -yl] carbonyl .}. phenoxy) butanoic; ? / -. { (2S, 4R) -1- [4- (2-amino-2-oxoethoxy) benzoyl] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} -? / - (4-chlorophenyl) acetamide; 4- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methylene-3,4-dihydroquinolin-1 (2H) -yl] carbonyl}. phen.l) -3,6-dihydroxypyridine-1 (2H) -carboxylic acid ethyl ester; ? / - [(2S, 4R) -1- (1,3-benzodioxol-5-ylcarbonyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] -A- -phenylacetamide; TO/-. { (2S, 4R) -2-methyl-1 - [(3-methyl-1-benzofuran-2-yl) carbonyl] -1,2,3,4-tetrahydroquinolin-4-yl} -? / - phenylacetamide; 4- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl, phenoxy) -? / - ethylbutanamide; ? / - (4-Chlorophenyl) -? / - [(2S, 4R) -1- (3-ethyl-4-fluorobenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] acetamide; 4- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolyl-1 (2H) -yl] carbonyl) phenoxy) -2,2-dimethylbutanamide; ? / - (4-chlorophenyl) - / V-. { (2S, 4R) -2-methyI-1- [4- (4-oxo-4-pyrrolidin-1-ylbutoxy) benzoyl] -1, 2,3,4-tetrahydroquinolin-4-yl} acetamide; 4- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolyl-1 (2H) -yl] carbonyl. phenoxy) butanamide; 4- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl. phenoxy) -? / - (methylsulfonyl) butanamide; 4- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl} phenoxy) ethyl butanoate; 4- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl, phenoxy) - / V-hydroxybutanamide; ? / - (4-chlorophenyl) -? / -. { (2S, 4R) -1- [4- (3-Cyanopropoxy) benzoyl] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} acetamida; ? / - (4-chlorophenyl) -? / - ((2S, 4R) -2-metii-1 - { 4- [3- (1, 2,4-oxadiazol-5-yl) propoxy] benzoyl ., -1, 2,3,4-tetrahydroquinolin-4-yl) acetamide; 3- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl} phenoxy) propanamide; ? / -. { (2S, 4R) -1 - [4- (3-aminopropoxy) benzoyl] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} -A / - (4-chlorophenyl) acetamide; ? / -. { (2S, 4R) -1 - [4- (2-amino-2-oxoethoxy) benzoyl] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} -? / - (4-chlorophenyl) acetamide; ? - (4-chlorophenyl) -? - ((2S, 4R) -2-methyl-1-. {4- [2- (methylamino) -2-oxoethoxy] benzoyl} -1, 2,3, 4-tetrahydroquinolin-4-yl) acetamide; 2- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methylene-3,4-d-hydroquinolin-1 (2H) -l] carbonyl .}. phenoxy) -N, N-dimethylacetamide; ? / - (4-chlorophenyl) -N-. { (2S, 4R) -2-methyl-1- [4- (2-morpholin-4-yl-2-oxoethoxy) benzoyl] -1, 2,3,4-tetrahydroquinolin-4-yl} acetamide; ? / - (4-chlorophenyl) - / V- ((2S, 4R) -2-methyl-1 -. {4- [2- (2-oxopyrrolidin-1-yl) ethoxy] benzoyl] -1 2,3,4-tetrahydroquinolyl-4-yl) acetamide; ? / - (4-chlorophenyl) - / V - ((2S, 4R) -1 -. {4- [2- (1 H -imidazol-1-yl) ethoxy] benzoyl} -2-methyl- 1, 2,3,4-tetrahydroquinolin-4-yl) acetamide; ? / - (4-chiorophenyl) - N-. { (2S, 4R) -2-methyl-1 - [4- (2-pyrroidin-1-ylethoxy) benzoyl] -1, 2,3,4-tetrahydroquinin-4-yl} acetamide; / V- (4-chlorophenyl) - / V - [(2S, 4R) -1 - (2,3-dihydro-1-benzofuran-5-ylcarbonyl) -2-methyl-1, 2,3,4-tetrahydroquinolin -4-il] acetamida; N- (4-Chlorophenyl) -? / -. { (2S, 4R) -2-methyl-1 - [4- (3-pyrrolidin-1-ylpropoxy) benzoyl] -1, 2,3,4-tetrahydroquinolin-4-yl} acetamide; ? / - (4-chlorophenyl) -? / -. { (2S, 4R) -2-methyl-1 - [4- (3-morpholin-4-ylpropoxy) benzoyl] -1,2,3,4-tetrahydroquinolin-4-yl} acetamide; ? - (4-chlorophenyl) -? / - ((2S, 4R) -2-methyl-1- { 4 - [(4-oxopentyl) oxy] benzoyl.] -1, 2,3,4- tetrahydroquinolyl-4-yl) acetamide; / V- (4-Chlorophenyl) - / V- ^ S ^ RJ-1 - ^ - IS-hydroxy-S-methylbutoxy-benzoxy-methyl-1 ^. S ^ -tetrahydroquinoline ^ -yljacetamide; A / - (4-Chlorophenyl) -? / - ((2S, 4R) -1- { 4 - [(4-hydroxy-4-methylpentyl) oxy] benzoyl} -2-methyl-1 , 2,3,4-tetrahydroquinolin-4-yl) acetamide; ? / - (4-chlorophenyl) -? / - ((2S, 4R) -1-. {4 - [(1-ethylpiperidin-4-yl) methoxy] benzoyl} -2-methyl-1, 2 , 3,4-tetrahydroquinolin-4-yl) acetamide; ? - (4-chloropheni) -? - ((2S, 4R) -1 -. {4- [3- (1 H -imidazol-1-yl) propoxy] benzoyl} -2-methyl-1, 2 , 3,4-tetrahydroquinolin-4-yl) acetamide; (2S, 4R) -? / - (4-Chloro-phenyl) -? / - [2-methyl-1- (4-methyl-3,4-dihydro-2H-benzo [1,4] oxazine-7-) carbonyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide; ? / - (4-chlorophenyl) - / V-. { (2S, 4R) -2-metiI-1 - [(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl) carbonyl] -1,2,3,4-tetrahydroquinoline-4 -il} acetamide; ? / - (4-chlorophenyl) -? / -. { (2S, 4R) -1 - [4- (4-ethylpiperazin-1 -yl) benzoyl] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} acetamide; ? / -. { (2S, 4R) -1 - [4- (4-Acetyl-piperazin-1-yl) benzoyl] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} -? / - (4-chlorophenol) acetamide; ? / - (4-chlorophenyl) -? / -. { (2S, 4R) -1 - [4- (4-glycolylpiperazin-1-yl) benzoyl] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} acetamide; ? / - (4-chlorophenyl) -N-. { (2S, 4R) -2-methyl-1 - [4- (3-morfoin-4-ylprop-1-yn-1-yl) benzoyl] -1,2,3,4-tetrahydroquinolin-4-yl} acetamide; 4- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl}. ) but-3-inoic; W - [(2S, 4R) -1 - (1 H-benzimidazol-2-ylcarbonyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] - / V- (4-chlorophenyl) acetamide; ? / - [(2S, 4R) -1- (1,3-benzothiazol-2-ylcarbonyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] -? / - (4-chlorophenyl) acetamide; ? / - (4-chlorophenyl) -? / -. { (2S, 4R) -2-methyl-1 - [(1-methyl-1 H-1, 2,3-benzotriazol-5-yl) carbonyl] -1, 2,3,4-tetrahydroquinolin-4-yl} acetamide; ? / - (4-chlorophenyl) -? / -. { (2S, 4R) -1 - [(1-isopropyl-1 H -benzimidazol-5-yl) carbonyl] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} acetamide; Acid [4- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinoline-1 (2H) - il] carbonyl, phenyl) piperazin-1-yl-acetic acid; ? / - ((2S, 4R) -1 - { 4- [4- (2-amino-2-oxoethyl) piperazin-1-yl] benzoyl.} -2-methyl-1, 2,3, 4-tetrahydroquinoline-4-yl) -? / - (4-chlorophenyl) acetamide; 3- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl} phenoxy acid propanoic; 4- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl} phenoxy ) -2,2-dimethylbutanoic; Acid { 1 - [(4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl} phenoxy) methylocyclopropyl} acetic; Acid (2E) -4- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl .}. phenoxy) but-2-enoic; 3- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -l] carbonyl} phenoxy) -2,2-dimethylpropanoic acid; Acid (2E) -4- (4- { [(2S, 4R) -4- [acetyl (4-cyranophenol) amino] -2-methylene-3,4-dihydroquinoline-1 ( 2H) -yl] carbonyl, phenoxy) -2-methylbut-2-enoic; ? / - (4-chlorophenyl) - / V-. { (2S, 4R) -2-methyl-1- [4- (3- {[[(trifluoromethyl) sulfonyl] amino} propoxy) benzoyl] -1, 2,3,4-tetrahy droquinolin-4-il} acetamide; ? / - (4-chlorophenyl) -? / - ((2S, 4R) -1 - { [1 - (2-hydroxyethyl) -2-methyl-1 H-benzimidazol-5-yl] carbonyl}. -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl) acetamide; Acid 5-. { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl} -2-methyl-1 H-benzimidazol-1-yl) acetic acid; 3- (5- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolyl-1 (2H) -yl] carbonyl acid .} -1 H-1, 2,3-benzotriazol-1-yl) propanoic acid; (2S, 4R) - / V- (4-Chloro-phenyl) -? / - [1 - (1-isopropyl-1 H -indazol-5-carbonyl) -2-methyl-1, 2,3, 4-tetrahydro-quinolin-4-yl] -acetamide; and (2S, 4R) - / V- (4-Chloro-phenyl) -? / - (2-methyl-1 - { 4- [3- (1 H-tetrazol-5-yl) -propoxy] - benzoyl) -1, 2,3,4-tetrahydro-quinolin-4-yl) -acetamide. The classes and subclasses described in more detail below and in the specification of this document apply to each of the emments for compound l-A as described above. In one emment, the present invention is a compound represented by the Structural Formulas (II-A), (III-A) or (IV-A).
Ar in the Structural Formula (III-A) is a monocyclic aromatic ring. Cy in the Structural Formula (IV-A) is a carbocyclic or non-aromatic heterocyclic group. The rest of the variables in the Structural Formulas (ll-A) - (IV-A) are as described for the Structural Formula (l-A). Preferably, V in the Structural Formulas (11-A) - (IV-A) is a covalent bond, -O- or -N (R ') -, and T in the Structural Formulas (II-A) - (IV-) A) is a straight chain C -? - 6 alkylene optionally substituted on any one or more of the carbon atoms substitutable with halide, alkyl, gem dialkyl, gem dihalo, haloalkyl, spiro cycloalkyl, non-aromatic heterocyclic group spiro optionally? / -substituted which contains nitrogen, amine, alkylamine, dialkyamymine or hydroxyl.
Alternatively, in the Structural Formulas (ll-A) - (IV-A) V is a covalent bond, -NR'- or -O-; and T is a straight chain (preferably C1-5, more preferably C1.3) alkylene, optionally mono-substituted at any halogen, alkyl, haloalkyl, amine, dialkylamine or hydroxyl substitutable carbon atom. Preferably, R? in the Structural Formulas (lA) and (ll-A) is -C (O) OR5, -C (O) NR52, -NR5C (O) R5, -NR5C (O) OR5, -S (O) 2N (R5 ) 2, -NR5S (O) 2R5, -OR5, -CN, -NR5C (O) N (R5) 2, -N (R5) 2, an optionally substituted non-aromatic heterocyclic group represented by R7 or an optionally substituted heteroaryl group represented by R8. R7 is an optionally substituted piperidinonyl, oxazolidinyl, oxazolidinonyl, thiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, tetrahydrothiophene, morpholinyl, thiomorpholinyl, imidazolidinyl, imidazolidinonyl, dioxanyl, dioxolanyl, dithiolanyl, pyrrolidinyl, pyrrolidinonyl, piperazinyl or piperidinyl. R8 is an optionally substituted furanyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrimidyl, thiazolyl, thienyl or imidazolyl and the rest of the variables are as described in the previous paragraph. More preferably, R? in Structural Formulas (lA) and (ll-A) is -C (O) OR5, -C (O) N (R5) 2, -NR5C (O) R5, -NR5C (O) OR5, -S (O ) 2N (R5) 2, -NR5S (O) 2R5, -NR5C (O) N (R5) 2, -OH, an optionally substituted non-aromatic heterocyclic group represented by R7 or an optionally substituted heteroaryl group represented by R8. R7 is piperidinonyl, morpholinyl, imidazolidinonyl, pyrrolidinyl, pyrrolidinonyl, piperazinyl or piperidinyl. R8 is tetrazolyl, oxazolyl, oxadiazolyl, pyrrolyl, pyrazolyl, pyridinyl or imidazolyl. R5 is independently H or alkyl or N (R5) 2 is a non-aromatic heterocyclic group containing nitrogen. V is a covalent bond or -O-; and T is an optionally substituted straight chain C1.5 alkylene at the carbon atom adjacent to R? with halide, alkyl, gem dialkyl, gem dihalo, haloalkyl, spiro cycloalkyl, optionally spiro non-aromatic heterocyclic group / V-substituted nitrogen, amine, dialkyamylamine or hydroxyl.
More preferably, R1 in the Structural Formulas (1- A) - (III-A) is a phenyl ring optionally substituted at the meta and para positions (more preferably for) with V-T-R? or V-T-M-R ?. Even more preferably R? is -C (O) OR 5, -C (O) N (R 5) 2, -OH,? / - morpholinyl, 2-morpholinyl, 3-morpholinyl,? / - substituted 2-morpholinyl,? / - substituted 3-morpholinyl , N-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl,? / - substituted 2-imidazolidinyl,? / - N-substituted imidazolidinyl, 4-imidazolidinyl? / - substituted, 5-imidazolidinyl A / -substituted , N-Midazolidinonyl, 4-imidazolidinonyl, 5-imidazolidinonyl, 4-imidazolidinonyl N-substituted, 5-imidazolidinonyl? / - substituted,? - pyrrolid? Nile, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolidinyl? / - substituted, 3-pyrrolidinyl? / - substituted,? -pyrrolidin-2-onyl, 3-pyrrolidin-2-ynyl, 4-pyrrolidin-2-ynyl, 5-pyrrolidin-2-ynyl, 3-pyrrolidin-2-ynyl? / -substituted, 4-pyrrolidin-2-onyl? / - substituted, 5-pyrrolidin-2-onyl? / - substituted, N-pyrrolidin-3-onyl, 2-pyrrolidin-3-onyl, 4-pyrroidin-3-onyl, 5-pyrrolidin-3-onyl, 2-pyrrolidin-3-onyl? / - substituted, -pyrrolidin-3-onyl? / - substituted, N-substituted 5-pyrrolidin-3-onyl,? / - piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-piperidinyl / V-substituted, 3-piperidinyl / V-substituted, 4-piperidinyl / V-substituted, N-piperidin-2-onyl, 3-piperidin-2-onyl, 4-piperidin-2-onyl, 5-piperidin-2-onyl, 6-piperidin-2 -onyl, 3-piperidin-2-onyl? / - substituted, 4-pipéridin-2-onyl? / - substituted, 5-piperidn-2-onyl? / - substituted, 6-piperidin -2-onyl? / - substituted,? / - piperidin-3-onyl, 2-piperidin-3-onyl, 4-piperidin-3-onyl, 5-piperidin-3-onyl, 6-piperidin- 3-oniOo, N-substituted 2-piperidin-3-onyl, 4-piperidin-3-onyl? / - substituted, 5-piperidin-3-oniyl? / - substituted, 6-piperidin-3 -onyl? / - substituted, / V-piperidin-4-onyl, 2-piperidin-4-onyl, 3-piperidin-4-onyl, d-piperidin-4-onyl, 6-piperidin-4-onyl, 2- piperidin-4-oniyl? / - substituted, 3-pi N-substituted peridin-4-onyl, 5-piperidin-4-onyl? / -substituted, N-substituted 6-piperidin-4-onyl, / V-piperazinyl, 2-piperazinyl,? / - piperazinyl? / '- substituted , 2-piperazinyl A / -substituted, furanyl,? / - tetrazolyl, 5-tetrazolyl, 5-tetrazolyo /? -substituted, 4- (1, 2,3) oxadiazolyl, 5- (1, 2,3) oxadiazolyl, 3- (1, 2,4) oxadiazolyl, 5- (1, 2,4) oxadiazolyl, 3- (1, 2,5) oxadiazolium, 4- (1, 2,5) oxadiazolyl, 2- (1, 3 , 4) oxadiazolyl, 5- (1, 3,4) oxadiazolyl,? / - pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyrrolyl? / - substituted, 3-pyrrolium? / - substituted,? / - pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 3-pyrazolyl-substituted, 4-pyrazolyl / V-substituted, 5-pyrazolyl N-substituted, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, / V- imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl; 2-imidazolyl / V-substituted, 4-imidazolyl? / - substituted or 5-imidazolyl / V-substituted. V is -O- and T is a substituted straight-chain C? -3 alkylene at the carbon atom adjacent to R? with fluorine, methyl, gem dimethyl, gem difluorofluoromethyl, spiro cyclopropyl, spiro cyclobutyl, spiro azetidinyl optionally / V-substituted, spiro aziridinyl optionally / V-substituted, spiro pyrrolidinyl optionally / V-substituted, spiro piperidinyl optionally N-substituted, amine, methylamine, dimethylamine or hydroxyl. Even more preferably R? is -C (O) OR 5, -C (O) N (R 5) 2, -OH,? / - tetrazole, 5-tetrazolyl, 5-tetrazolyl? / - substituted, / V-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl; 2-Midazolyl / V-substituted, 4-midazoyl / V-substituted or 5-imidazolyl N-substituted. R5 is -H, methyl or ethyl. R1 in Structural Formulas (l-A) - (III-A) is a phenyl ring optionally substituted in the para position with V-T-R? or V-T-M-R ?. In another preferred embodiment, the present invention is a compound represented by the Structural Formula (V-A): (V-A) All the variables of the Structural Formula (V-A) are as described for the Structural Formula (l-A). Preferably, R9 in the Formula Structural (VA) is an optionally substituted cyclohexanyl, oxazolidinyl, oxazolidinonyl, thiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, tetrahydrothienyl, morpholinyl, thiomorpholinyl, imidazolidinyl, imidazolidinonyl, dioxanyl, dioxolanyl, dithiolanyl, pyrrolidinyl, pyrrolidinonyl, piperazinyl,, piperidinyl, or 1, 2,5-S, isothiazolidinyl S-dioxide. In other embodiments, R9 in Structural Formula (VA) is an optionally substituted cyclohexanyl, oxazolidinyl, oxazolidinonyl, thiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, tetrahydrothienyl, morpholinyl, thiomorpholinyl, imidazolidinyl, imidazolidinonyl, dioxanyl, dioxolanyl, dithiolanyl, pyrrolidinyl, pyrrolidinonyl, piperazinyl, S, S-isothiazolidinyl dioxide or piperidinyl. R9 is preferably meta or para to the carbon atom attached to the carbonyl, more preferably para. V is preferably a covalent bond or -O-, more preferably a covalent bond. More preferably, R9 in the Structural Formula (VA) is oxazolidinyl, thiazolidinyl, tetrahydrofuranyl, morpholinyl, imidazolidinyl, imidazolidinonyl, pyrrolidinyl, pyrrolidinonyl, piperazinyl or piperidinyl, each optionally substituted with alkyl, halide, haloalkyl, hydroxyalkyl, -C (O) OR12, -C (O) R12, -OC (O) R12, -R2C (O) OR12, -C (O) N (R12) 2, -NR12C (O) R12, -NR12C (O) OR12, - S (O) 2 R 12, -S (O) 2 COR 12, -S (O) 2 N (R 12) 2, -S (O) 2OR 12, -S (O) OR 12, -OR 12, -SR 12, -CN, -NR 12 C ( O) N (R12) 2, -OC (O) N (R12) 2, - (CH2) nCO2H, - (CH2) nC (O) NR, (CH2) nC (CH3) 2CO2H, - (CH2) nC (CH3) 2C (O) NR0 or -N (R12) 2, n is an integer from 1 to 4 and each R12 is independently -H, alkyl, haloalkyl or hydroxyalkyl; and the rest of the variables are as described in the previous paragraph. Alternatively, for those groups represented by R9 having a substitutable ring nitrogen, the group is / V-substituted with T2-RY1, which is defined below or optionally substituted on one or more ring carbon atoms replaceable with one or more groups listed earlier in this paragraph. More preferably, R9 in Structural Formula (VA) is / V-morpholinyl, 2-morpholinyl, 3-morpholinyl, 2-morpholinyl / V-substituted, 3-morphoylinyl / substituted, N-pyrrolidinyl, 2-pyrrolidinyl, -pyrrolidinyl, 2-pyrrolidinyl / V-substituted, 3-pyrrolidinyl N-substituted, / V-piperazinyl, 2-piperazinyl, / V-piperazinyl / V-substituted, 2-piperazinyl / V-substituted, / V-piperidinyl , 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-piperidinyl / V-substituted, 3-piperidinyl / V-substituted, 4-piperidinyl / V-substituted, each optionally substituted at any alkyl atom substitutable with alkyl, halide, haloalkyl, hydroxyalkyl, -C (O) OR 12, -C (O) R 12, -OC (O) R 12 or -C (O) N (R 2) 2 and where the N substituents are alkyl, haloalkyl, hydroxyalkyl, -C (O) OR12, -C (O) R12, - (CH2) nCO2H, - (CH2) nC (O) NR °, - (CH2) nC (CH3) 2CO2H, (CH2) nC (CH3) 2C ( O) NR ° or -C (O) N (R12) 2. For these groups represented by R9 having an N of the substitutable ring, a preferred N substituent is T2-RY1, which is as defined below. Still more preferably, R9 in the Structural Formula (VA) is / V-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-piperidinyl? / -substituted, 3-piperidinyl N-substituted, 4-piperidinyl / V-substituted, / V-piperazinyl, 2-piperazinyl, / V-piperazinyl / V-substituted or 2-piperazinyl? / - substituted and is optionally substituted at any carbon atom substitutable with chloride, fluoride, bromide, methyl, ethyl, -C (O) OR12, -OC (O) R12, -C (O) R12 or C (O) NH2 and where the N substituents are methyl, ethyl, -C (O) OR12, -C (O) R12, - (CH2) nCO2H, - (CH2) nC (O) NR0, - (CH2) nC (CH3) 2CO2H, - (CH2) nC (CH3) 2C (O) NR0 or - C (O) NH2 and each R12 is independently -H, methyl or ethyl. For these groups represented by R9 having an N of the substitutable ring, a preferred N substituent is T2-RY1, which is as defined below. In another preferred embodiment, the present invention is a compound represented by Structural Formula (VI-A): (VI-A) B is an optionally substituted non-aromatic monocyclic heterocyclic ring represented by R 10 or a monocyclic aromatic ring (preferably heteroaromatic) represented by R 13; the rest of the variables of the Structural Formula (VI-A) are as described for the Structural Formula (l-A). Preferably, R 10 in Structural Formula (VI-A) is oxazolidinyl, oxazolidinonyl, dioxolanyl, thiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothienyl, morpholinyl, thiomorpholinyl, imidazolidinyl, imidazolidinonyl, dioxanyl, dithiolanyl, pyrrolidinyl, piperazinyl, piperidinyl, piperidinyl, S , S-tetrahydrothienyl dioxide, S, S-thiomorpholinyl dioxide, S, S-tetrahydrothiopyranyl dioxide, each of which is optionally substituted. R 13 is pyrazolyl, triazolyl, imidazolyl, furanyl, pyrrolyl, thienyl, cyclopentadienyl and S, S-thienyl dioxide, each of which is optionally substituted. The rest of the variables of the Structural Formula (VI-A) are as described in the previous paragraph. Other examples of suitable values for R 10 include tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, imidazolidinyl, imidazolidinonyl, pyrrolidinyl, piperazinyl or piperidinyl each of which optionally substituted on any carbon atom of the alkyl-substituted ring, halide, haloalkyl, hydroxyalkyl, -C ( O) OR12, -C (O) R12, -OC (O) R12, -R12C (O) OR12-, -C (O) N (R12) 2, -NR12C (O) R12, -NR12C (O) OR12 , -S (O) 2R 12, -S (O) 2COR 12, -S (O) 2 N (R 12) 2, -S (O) 2OR 12, -S (O) OR 12, -OR 12, -SR 12, -CN, - NR12C (O) N (R12) 2, -OC (O) N (R12) 2, -N (R12) 2, - (CH2) 1-4CO2R12, -O (CH2) 1-4CO2R12, - (CH2) 1 -4CON (R12) 2, -O (CH2)? - 4CON (R12) 2, - (CH2) or -3 (C (CH3) 2) CO2R12, -O (CH2) or -3 (C (CH3) 2 ) CO2R12, (CH2) or -3 (C (CH3) 2) CO2 (R12) 2, or -O (CH2) 0-3 (C (CH3) 2) CO2 (R12) 2 and each of which optionally substituted at any ring nitrogen atom substitutable with alkylhaloalkyl, hydroxyalkyl, -C (O) OR12, -C (O) R12, -R12C (O) OR12-, -C (O) N (R12) 2; and other examples of suitable values for R 13 include triazolyl, imidazolyl, furanyl, pyrrolyl, thienyl, each of which optionally substituted on any carbon atom of the alkyl-substituted ring, halide, haloalkyl, hydroxyalkyl, -C (O) OR 12, -C (O) R12, -OC (O) R12, -C (O) OR12-, -C (O) N (R12) 2, -NR12C (O) R12, -NR12C (O) OR12, -S ( O) 2R12, -S (O) 2COR 12, -S (O) 2N (R 12) 2, -S (O) 2OR 12, -S (O) OR 12, -OR 12, -SR 12, -CN, -NR 12 C (O) N (R12) 2, -OC (O) N (R12) 2, -N (R12) 2, - (CH ^ i ^ COsR12, -O (CH2) 1-4CO2R12, - (CH2) 1-4CON (R12) ) 2, -O (CH2) 1-4CON (R12) 2, - (CH2) or -3 (C (CH3) 2) CO2R12, -O (CH2) 0-3 (C (CH3) 2) CO2R12, ( CH2) 0-3 (C (CH3) 2) CO2 (R12) 2, or -O (CH2) 0-3 (C (CH3) 2) CO2 (R12) 2 and each of which optionally substituted on any atom of nitrogen of the ring substitutable with alkylhaloalkyl, hydroxyalkyl, -C (O) OR12, -C (O) R12, -R12C (O) OR12, -S (O) 2R12, S (O) 2N (R12) 2, -C (O) N (R12) 2. Each R12 is independently H, alkyl, haloalkyl or hydroxyalkyl, etc. Further examples of values suitable for R 10 include tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, imidazolidinyl, imidazolidinonyl, pyrrolidinyl, piperazinyl or piperidinyl each of which optionally substituted on any carbon atom of the ring substitutable with alkyl, halide, haloalkyl, hydroxyalkyl, -C (O) OR 12, -C (O) R12, -OC (O) R12, -R12C (O) OR12-, -C (O) N (R12) 2, -NR12C (O) R12, -NR12C (O) OR12, -S (O) 2R12, -S (O) 2COR 12, -S (O) 2N (R 12) 2, -S (O) 2OR 12, -S (O) OR 12, -OR 12, -SR 12, -CN, -NR 12 C (O) N ( R12) 2, -OC (O) N (R12) 2, or -N (R12) 2, and each of which optionally substituted on any nitrogen atom of the ring substitutable with alkylhaloalkyl, hydroxyalkyl, -C (O) OR12 , -C (O) R12, -R12C (O) OR12-, -C (O) N (R12) 2; and other examples of suitable values for R 13 include triazolyl, imidazolyl, furanyl, pyrrolyl, thienyl, each of which optionally substituted on any carbon atom of the alkyl-substituted ring, halide, haloalkyl, hydroxyalkyl, -C (O) OR 12, -C (O) R12, -OC (O) R12, -C (O) OR12-, -C (O) N (R12) 2, -NR12C (O) R12, -NR12C (O) OR12, -S (O) 2R 12, -S (O) 2COR 12, -S (O) 2 N (R 12) 2, -S (O) 2OR 12, -S (O) OR 12, -OR 12, -SR 12, -CN, -NR 12 C (O ) N (R12) 2, -OC (O) N (R12) 2, or -N (R12) 2, and each of which optionally substituted on any nitrogen atom of the ring substitutable with alkylhaloalkyl, hydroxyalkyl, -C ( O) OR12, -C (O) R12, -R12C (O) OR12, -S (O) 2R12, S (O) 2N (R12) 2, -C (O) N (R12) 2. Each R12 is independently H, alkyl, haloalkyl or hydroxyalkyl.
Even more preferably, in Structural Formula (VI-A) R 10 is dioxolanyl, tetrahydrofuranyl, morpholinyl, each optionally substituted at any carbon atom substitutable with alkyl, halide, haloalkyl, hydroxyalkyl, -C (O) OR 12, -C (O ) R12, -OC (O) R12 or -C (O) N (R12) 2 or each optionally substituted at any nitrogen atom substitutable with alkyl, haloalkyl, hydroxyalkyl, -C (O) OR12, -C (O) R12 or -C (O) N (R12) 2. R13 is triazolyl, imidazolyl or pyrrolyl each optionally substituted on any carbon atom substitutable with alkyl, halide, haloalkyl, hydroxyalkyl, -C (O) OR12, -C (O) R12, -OC (O) R12 or -C (O ) N (R12) 2 and each optionally substituted at any nitrogen atom substitutable with alkyl, haloalkyl, hydroxyalkyl, C (O) OR12, -C (O) R12, -R12C (O) OR12, -S (O) 2R12, S (O) 2 N (R 12) 2, -C (O) N (R 12) 2. Still more preferably, in Structural Formula (VI-A) R10 is morpholinyl and is optionally? / - substituted with methyl, ethyl, -C (O) OR12, C (O) NH2 or -C (O) R12, R13 is triazolyl and is optionally / V-substituted with methyl, ethyl, -C (O) OR12, C (O) NH2 or -C (O) R12 and each R12 is independently -H, methyl or ethyl. In another preferred embodiment, in Structural Formula (VI-A), Ring B is a non-aromatic monocyclic heterocycle or a monocyclic heteroaryl group comprising a ring nitrogen atom that is substituted with T2-RY1. These monocyclic non-aromatic and heteroaryl groups are optionally substituted. Preferably, the non-aromatic monocyclic heterocyclic ring is represented by R 10, Preferably, the monocyclic heteroaromatic ring is represented by R 13. Examples of suitable values for R10 include oxazolidinyl, oxazolidinonyl, thiazolidinyl, morpholinyl, thiomorpholinyl, imidazolidinyl, imidazolidinonyl, pyrrolidinyl, piperazinyl or piperidinyl, each of which N-substituted with T2-RY1 and optionally further substituted in any of one or more ring carbon atoms with alkyl, halide, haloalkyl, hydroxyalkyl, -C (O) OR12, -C (O) R12, -OC (O) R12, -R12C (O) OR12-, -C (O) N ( R12) 2, -NR 2 C (O) R 12, -NR 12 C (O) OR 12, -S (O) 2 R 12, -S (O) 2 COR 12, -S (O) 2 N (R 12) 2, -S (O) 2 OR 12 , -S (O) OR12, -OR12, -SR12, -CN, -NR12C (O) N (R12) 2, -OC (O) N (R12) 2, -N (R12) 2, - (CH2) 1-4CO2R12, - O CHsy ^ COzR12, - (CH2)? - 4CON (R12) 2, -O (CH2)? - 4CON (R12) 2, - (CH2) or- 3 (C (CH3) 2) CO2R12 , -O (CH2) or -3 (C (CH3) 2) CO2R12, (CH2) or -3 (C (CH3) 2) CO2 (R12) 2, or -O (CH2) 0-3 (C (CH3 ) 2) CO2 (R12) 2. Other examples of suitable values for R10 include oxazolidinyl, oxazolidinonyl, thiazolidinyl, morpholinyl, thiomorpholinyl, imidazolidinyl, imidazolidinonyl, pyrrolidinyl, piperazinyl or piperidinyl, each of which N-substituted with T2-RY1 and optionally further substituted in any of one or more carbon atom of the ring with alkyl, halide, haloalkyl, hydroxyalkyl, -C (O) OR12, -C (O) R12, -OC (O) R12, -R12C (O) OR12-, -C (O) N ( R12) 2, -NR12C (O) R12, -NR12C (O) OR12, -S (O) 2R12, -S (O) 2COR12, -S (O) 2N (R12) 2, -S (O) 2OR12, -S (O) OR 12, -OR 12, -SR 12, -CN, -NR 12 C (O) N (R 12) 2, -OC (O) N (R 12) 2 or -N (R 12) 2. Examples of suitable values for R13 include pyrazolyl, triazolyl, imidazolyl or pyrrolyl, each of which / V-substituted with T2-RY1 and optionally further substituted on any one or more carbon atom of the ring with alkyl, halide, haloalkyl, hydroxyalkyl, -C (O) OR12, -C (O) R12, -OC (O) R12, -R12C (O) OR12-, -C (O) N (R12) 2, -NR12C (O) R12, - NR12C (O) OR12, -S (O) 2R12, -S (O) 2COR12, -S (O) 2N (R12) 2, -S (O) 2OR12, -S (O) OR12, -OR12, -SR12 , -CN, -NR12C (O) N (R12) 2, -OC (O) N (R12) 2, -N (R12) 2, - (CH2)? - 4CO2R12, -O (CH2)? - 4CO2R12, - (CH2 ) 1-4CON (R12) 2, -O (CH2) 1-4CON (R12) 2, - (CH2) or -3 (C (CH3) 2) CO2R12, -O (CH2) or -3 (C (CH3 ) 2) CO2R12, (CH2) 0-3 (C (CH3) 2) CO2 (R12) 2, or -O (CH2) 0-3 (C (CH3) 2) CO2 (R12) 2. Other examples of suitable values for R13 include pyrazolyl, triazolyl, imidazolyl or pyrrolyl, each of which / V-substituted with T2-RY1 and optionally further substituted at any one or more carbon atom of the ring with alkyl, halide, haloalkyl , hydroxyalkyl, -C (O) OR12, -C (O) R12, -OC (O) R12, -R12C (O) OR12-, -C (O) N (R12) 2, -NR12C (O) R12, -NR 12 C (O) OR 12, -S (O) 2 R 12, -S (O) 2 COR 12, -S (O) 2 N (R 12) 2, -S (O) 2 OR 12, -S (O) OR 12, -OR 12, - SR12, -CN, -NR12C (O) N (R12) 2, -OC (O) N (R12) 2 or -N (R12) 2. Each R12 is independently H, alkyl, haloalkyl or hydroxyalkyl. The rest of the variables are as described above for the Structural Formula (VI-A).
Preferably, T2 in the Structural Formula (VI-A) is a straight chain C6-C6 alkylene optionally substituted on any one or more carbon atoms substitutable with halide, alkyl, gem dialkyl, gem dihalo, haloalkyl, spiro cycloalkyl, optionally N-substituted non-aromatic spiro heterocyclic group containing nitrogen, amine, alkylamine, dialkyamymine or hydroxyl. RY1 is -C (O) OR5, -C (O) N (R5) 2, -NR5C (O) R5, -NR5C (O) OR5, -S (O) 2N (R5) 2, -NR5S (O) 2R5, -OR5, -CN, -NR5C (O) N (R5) 2, -N (R5) 2, an optionally substituted non-aromatic heterocyclic group represented by R7 or an optionally substituted heteroaryl group represented by R8. R7 is an optionally substituted piperidinonyl, oxazolidinyl, oxazolidinonyl, thiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, tetrahydrothiophene, morpholinyl, thiomorpholinyl, imidazolidinyl, imidazolidinonyl, dioxanyl, dioxolanyl, dithiolanyl, pyrrolidinyl, pyrrolidinonyl, piperazinyl or piperidinyl. R8 is an optionally substituted furanyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrimidyl, thiazolyl, thienyl or imidazolyl. Other examples of suitable values for R10 include morpholinyl, thiomorpholinyl, imidazolidinyl, imidazolidinonyl, pyrrolidinyl, piperazinyl or piperidinyl each of which / V-substituted with T2-RY1 and optionally further substituted at any carbon atom of the alkyl-substituted ring, halide , haloalkyl, hydroxyalkyl, -C (O) OR12, -C (O) R12, -OC (O) R12, -R12C (O) OR12-, -C (O) N (R12) 2, -NR12C (O) R12, -NR12C (O) OR12, -S (O) 2R12, -S (O) 2COR12, -S (O) 2N (R12) 2, -S (O) 2OR12, -S (O) OR12, -OR12 , -SR 12, -CN, -NR 12 C (O) N (R 12) 2, -OC (O) N (R 12) 2 or -N (R 12) 2. Other examples of suitable values for R 13 include triazolyl, imidazolyl or pyrrolyl, each of which / V-substituted with T 2 -RY 1 and optionally further substituted at any carbon atom of the ring substitutable with alkyl, halide, haloalkyl, hydroxyalkyl, -C (O) OR12, -C (O) R12, -OC (O) R12, -R12C (O) OR12-, -C (O) N (R12) 2, -NR12C (O) R12, -NR12C (O) OR12, -S (O) 2R12, -S (O) 2COR12, -S (O) 2N (R12) 2, -S (O) 2OR12, -S (O) OR12, -OR12, -SR12, -CN, -NR 12 C (O) N (R 12) 2, -OC (O) N (R 2) 2 or -N (R 12) 2. RY1 is -C (O) OR5, -C (O) N (R5) 2, -NR5C (O) R5, -NR5C (O) OR5, -S (O) 2N (R5) 2, -NR5S (O) 2R5, -NR5C (O) N (R5) 2, -OH, an optionally substituted non-aromatic heterocyclic group represented by R7 or an optionally substituted heteroaryl group represented by R8. Each R5 is independently H or alkyl or N (R5) 2 is a non-aromatic heterocyclic group containing nitrogen. R7 is piperidinonyl, morpholinyl, imidazolidinonyl, pyrrolidinyl, pyrrolidinonyl, piperazinyl or piperidinyl. R8 is tetrazolyl, oxazolyl, oxadiazolyl, pyrrolyl, pyrazolyl, pyridinyl or imidazolium. T2 is a straight chain C? -5 alkylene optionally substituted on the carbon atom adjacent to R? with halide, alkyl, gem dialkyl, gem dihalo, haloalkyl, spiro cycloalkyl, optionally spiro non-aromatic heterocyclic group / V-substituted containing nitrogen, amine, dialkylamine or hydroxyl. Preferably, other examples of suitable values for R 10 include morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl each of which N-substituted with T 2 -RY 1 and optionally further substituted at any carbon atom substitutable with alkyl, halide, haloalkyl, hydroxyalkyl, -C (O) OR 12, -C (O) R 12, -OC (O) R 12. Other examples of suitable values for R13 include imidazolyl or pyrrolyl each of which / V-substituted with T2-RY1 and optionally further substituted at any carbon atom substitutable with alkyl, halide, haloalkyl, hydroxyalkyl, -C (O) OR12, -C (O) R12, -OC (O) R12 or -C (O) N (R12) 2 and each optionally substituted at any nitrogen atom substitutable with alkyl, haloalkyl, hydroxyalkyl, C (O) OR12, -C ( O) R12, -R12C (O) OR12, -S (O) 2R12, S (O) 2N (R12) 2, -C (O) N (R12) 2. RY1 is -C (O) OR5, -C (O) N (R5) 2, -OH, / V-morpholinyl, 2-morpholinyl, 3-morpholinyl, 2-morpholinyl N-substituted, 3-morpholinyl / V-substituted, / V-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl, 2-imidazolidinyl / V-substituted, / V-imidazolidinyl N Substituted, 4-imidazolidinyl? / - substituted, 5-imidazolidinyl / V-substituted, N-imidazolidinonyl, 4-imidazolidinonyl, 5-imidazolidinonyl, 4-imidazolidinonyl / V-substituted, 5-imidazolidinonyl / V-substituted ,? / - pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolidinyl V-substituted, 3-pyrrolidinyl / V-substituted,? / - pyrrolidin-2-onyl, 3-pyrrolidin-2-onyl, 4-pyrrolidin- 2-onyl, 5-pyrrolidin-2-onyl, 3-pyrrolidin-2-onyl / V-substituted, 4-pyrrolidin-2-onyl / V-substituted, 5-pyrrolidin-2-onyl V-substituted, V - pyrrolidin-3-onyl, 2-pyrrolidin-3-onyl, 4-pyrrolidin-3-onyl, 5-pyrrolidin-3-onyl, V-substituted 2-pyrrolidin-3-onyl, 4-pyrrolidin- 3-onyl / V-substituted, N-substituted 5-pyrrolidin-3-onyl, / V-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-piperid substituted-butyl, 3-piperidinyl / V-substituted, V-substituted 4-piperidinyl,? / - piperdin-2-onyl, 3-piperidin-2-onyl, 4-piperidin-2-onyl, 5- piperdin-2-onyl, 6-piperidin-2-one, 3-piperidin-2-oneyl / V-substituted, 4-piperidin-2-oneyl / V-substituted, 5-piperidin-2-oneyl / V-substituted, 6-piperidin-2-onyl / V-substituted,? / - piperidin-3-onyl, 2-piperidin-3-onyl, 4-piperidin-3-onyl, 5-piperidin-3-onyl, -piperidin-3-onyl, 2-piperidin-3-onyl / V-substituted, 4-piperidin-3-onyl / V-substituted, 5-piperidin-3-onyl / V-substituted, 6-piperidin-3-onyl / V-substituted, V-piperidin-4-onyl, 2-piperidin-4-onyl, 3-piperidin-4-onyl, 5-piperidin-4-onyl, 6-piperidin-4-onyl, 2-piperidin-4 -onyl? / - substituted, 3-piperidin-4-onyl / V-substituted, 5-piperidin-4-onyl / V-substituted, 6-piperidin-4-onyl N-substituted, / V-piperazinyl, 2-piperazinyl , / V-substituted / V-piperazinyl, 2-piperazinyl / V-substituted, furanyl, / V-tetrazolyl, 5-tetrazolyl, 5-tetrazolyl / V-substituted, 4- (1, 2,3) oxadiazo lyl, 5- (1, 2,3) oxadiazolyl, 3- (1, 2,4) oxadiazolyl, 5- (1, 2,4) oxadiazolyl, 3- (1, 2,5) oxadiazoyl, 4- (1 , 2,5) oxadiazolyl, 2- (1, 3,4) oxadiazolyl, 5- (1, 3,4) oxadiazolyl, / V-pyrrolyl, 2-pyrrolyl, 3-pyrroyl, 2-pyrrolyl / V-substituted, 3-pyrrolyl? / - substituted,? / - pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 3-pyrazolyl / V-substituted, 4-pyrazolyl / V-substituted, 5-pyrazolyl N-substituted, 2- pyridinyl, 3-pyridinyl, 4-pyridinyl, / V-imidazolyl, 2-imidazoyl, 4-imidazolyl, 5-imidazolyl; 2-Imidazole / V-substituted, 4-methoZyloxy / V-substituted or 5-imidazolyl / V-substituted. T2 is a straight chain C? -3 alkylene substituted with fluorine, methyl, gem dimethyl, gem difluoro fluoromethyl, spiro cyclopropyl, spiro cyclobutyl, spiro azetidinyl optionally? / - substituted, optionally spiro aziridinyl / V-substituted, spiro pyrrolidinyl optionally? / -substituted, optionally / V-substituted spiro piperidinyl, amine, methylamine, dimethylamine or hydroxyl. More preferably, other examples of suitable values for R 10 include morpholinyl, V-substituted with T 2 -RY 1 and optionally further substituted on the alpha carbon of the nitrogen atom with methyl or gem dimethyl. Other examples of suitable values for R 13 include imidazolyl / V-substituted with T 2 -RY 1 and optionally further substituted on the alpha carbon of the nitrogen atom with methyl or gem dimethyl. RY1 is -C (O) OR5, -C (O) N (R5) 2, -OH,? / - tetrazolyl, 5-tetrazolyl, 5-tetrazolyl / V-substituted, / V-imidazolyl, 2-methyldazoyl, 4-imidazolyl, 5-imidazolyl; 2-imidazolyl / V-substituted, 4-imidazolyl / V-substituted or 5-imidazolyl N-substituted. In one embodiment, in Structural Formula (VI-A) R1 is an optionally substituted phenyl ring fused to the group represented by R10 as represented by the following Structural Formulas: In one embodiment of the Structural Formula (VI-A), R1 is an optionally substituted phenyl ring fused to the group represented by R13 as represented by the following Structural Formulas: The Structural Formulas shown above for the fused bicyclic rings may also be optionally substituted on any one or more carbon atoms or nitrogen atoms. Examples of suitable substituents are those described above for the groups represented by R10 and R13. In a more specific embodiment, any bicyclic fused ring system shown above having asymmetric nitrogen atoms is? / - substituted with T2-RY1. T2-RY1 is as described above. As described above, Ring A (preferably phenyl ring A) in Structural Formulas (1- A) - (VI-A) is optionally substituted (preferably in positions six and seven) with one or more groups represented by R 14; In Structural Formulas (1-A) - (V-A), R 1 is an aromatic group (preferably a phenyl ring) optionally substituted with 1-2 selected groups independently represented by Rz; and in Structural Formulas (1- A) - (VI-A), R 3 is an aromatic group (preferably, for example, a phenyl group) optionally substituted with one or more groups represented by R 11. Suitable values for R14, Rz and R11 are those that do not substantially decrease the ability of the compound of the invention to inhibit CRTH2. Examples of suitable substituents are halogen, haloalkyl, R °, -OR °, -O (haloalkyl), -SR °, -NO 2, -CN, -N (R ') 2, -NR'CO 2 R °, -NR' C (O) R °, -NR'NRO (O) R °, -N (R ') C (O) N (R') 2, -NR'NRO (O) N (R ') 2, NR' NROO2R °, -C (O) C (O) R °, -C (O) CH2C (O) R °, -CO2R °, -C (O) R °, -C (O) N (R °) 2 , -OC (O) R °, -OC (O) N (R °) 2, -S (O) 2R °, -SO2N (R ') 2, -S (O) R °, -NR'SO2N ( R ') 2, -NR'SO 2 R °, -C (= S) N (R') 2 and -C (= NH) -N (R ') 2. Other R11 values include 3,4-methylene-dioxy and 3,4-ethylene-dioxy. In other embodiments, suitable substituents for R 11 also include halogen, haloalkyl, R °, -OR °, -O (haloalkyl), -SR °, 3,4-methylene-dioxy, 3,4-ethylene-dioxy-NO 2? -CN, -N (R ') 2, -NR'CO2R °, -NR'C (O) R °, -NR'NR'C (O) R °, -N (R') C (O) N (R ') 2, -NR'NR'C (O) N (R') 2, -NR'NR'CO2R0, -C (O) C (O) R °, -C (O) CH2C (O) R °, -CO2R °, -C (O) R °, -C (O) N (R °) 2, -OC (O) R °, -OC (O) N (R °) 2, -S ( O) 2R °, -SO 2 N (R ') 2, -S (O) R °, -NR, SO 2 N (R') 2, -NR'SO 2 R °, -C (= S) N (R ') 2 - (CH2) 1-4COR °, -O (CH2) 1- COR °, - (CH2) 1-4CON (R °) 2, -O (CH2) 1-4CON (R °) 2, - (CH2) or -3 (C (CH3) 2) CO2R0, -O (CH2) or -3 (C (CH3) 2) CO2R0, - (CH2) 0-3 (C (CH3) 2) CON (R0) 2, -O (CH2) 0-3 (C (CH3) 2) CON (Ro) 2, or -C (= NH) -N (R ') Each R is independently hydrogen, alkyl, -C (O) OR °, S ( O) 2R ° or -C (O) R °. Each R ° is independently hydrogen or an alkyl group, non-aromatic heterocyclic group or aromatic group and the alkyl, the non-aromatic heterocyclic group and the aromatic group represented by R ° is optionally substituted with one or more groups independently selected represented by R R # is R +, -OR +, -O (haloalkyl), -SR +, -NO2, -CN, -N (R +) 2, -NHCO2R +, -NHC (O) R +, -NHNHC (O) R +, -NHC ( O) N (R +) 2, -NHNHC (O) N (R +) 2, -NHNHCO2R +, -C (O) C (O) R +, -C (O) CH2C (O) R +, -CO2R +, -C ( O) R +, -C (O) N (R +) 2, -OC (O) R +, -OC (O) N (R +) 2, -S (O) 2 R \ -SO 2 N (R +) 2, -S ( O) R +, -NHSO2N (R +) 2, -NHSO2R +, -C (= S) N (R +) 2 or -C (= NH) -N (R +) 2. R + is -H, a C1-C3 alkyl group, a monocyclic heteroaryl group, a non-aromatic heterocyclic group or a phenyl group optionally substituted with alkyl, haloalkyl, alkoxy, haloalkoxy, halo, -CN, -NO2, amine, alkylamine or dialkylamine; or -N (R +) 2 is a non-aromatic heterocyclic group, with the proviso that the non-aromatic heterocyclic groups represented by R + and -N (R +) 2 comprising a secondary ring amine are optionally attached or alkylated. Preferred values for Rz and R11 are halogen, haloalkyl, -R °, -OR °, -O (haloalkyl), -CO2R °, -C (O) R °, -NR'SO2R °, -C (O) N (R °) 2, -OC (O) R ° and -OC (O) N (R °) 2. 3,4-methylene-dioxy and 3,4-ethylene-dioxy and -N (R ') 2 are also preferred values for R 11. Each R ° is independently hydrogen, haloalkyl or an alkyl group, each R 'is independently H or alkyl. Preferably, R3 is a phenyl ring optionally substituted at the meta or para positions with one or more groups represented by R11. The most preferred values for R11 and Rz are halogen, haloalkyl, -R °, -OR ° and -O (haloalkyl). -NR'SO2R ° and -N (R ') 2 are also preferred values for R11. More preferably, R3 is a phenyl ring optionally substituted in the para position with R11. R1 is a phenyl ring optionally substituted at the meta position with Rz. The most preferred values for Rz and R11 are chloride, fluoride, bromide, -OR ° or R °. -NR'SO2R ° and -N (R ') 2 are also preferred values for R11.
Each R ° is independently hydrogen, haloalkyl or a C1-C3 alkyl group. Each R 'is independently hydrogen or a C1-C3 alkyl group. R14 is an optional substituent, preferably at positions six and seven of the phenyl ring A; the preferred values are halogen R °, -OR °, -CO2R °, -C (O) R °, -C (O) N (R °) 2, -CN, -OC (O) R °, (CH2) nCO2R °, O (CH2) nC2R0, NHSO2R °, NHC (O) N (R °) 2, (CH2) nOH, O (CH2) nOH, (CH2) pC (O) N (R0) 2 or O (CH2) nC (O) N (R0) 2. R ° is hydrogen, haloalkyl or a C1-C3 alkyl group. Another embodiment of the present invention is a compound represented by the Structural Formula (X-A): V is a covalent bond or -O-. T is an unsubstituted straight chain C-MO alkylene. R? is -C (O) OR 5, -C (O) R 5, -OC (O) R 5, -C (O) N (R 5) 2, -NR 5 C (O) R 5, - NR 5 C (O) OR 5, -S ( O) 2R5, -S (O) 2COR5, -S (O) 2N (R5) 2, -NR5S (O) 2, -NR5S (O) 2R5, S (O) 2OR5, -S (O) OR5, - SR5, -C (O) NR5S (O) 2R5, -CN, -NR5C (O) N (R5) 2, -OC (O) N (R5) 2, -N (R5) 2, -OR5, a group optionally substituted non-aromatic heterocyclic or an optionally substituted heteroaryl group. In some embodiments, the compound of Structural Formula (X-A) excludes compounds in which T-R? is -CH2R20, -CH2CH2R21 or - (CH2) 3R22. R20 is -COOH, -C (O) NH2, -C (O) NHCH3, C (O) N (CH3) 2, 5-tetrazolyl, 4-pyridinyl, N-ethyl-4-piperidinyl or C (O)? / -morpholinyl. R21 is -COOH, / V-morpholinyl, C (O) NH2, N-pyrrolidin-2-onyl, / V-imidazolyl or / V-pyrrolidinyl. R22 is -COOH, C (O) N (CH2CH3) 2, C (O) NH (CH2CH3), C (O) NH2, C (O) NHS (O) 2CH3, C (O) NHOH, C (O) OCH2CH3, NH2, C (O) CH3, CN, NHS (O) 2CF3, C (O) V-pyrrolidinyl, / V-pyrrolidinyl, 5-tetrazolyl, 5- (1, 2,4) oxadiazolyl, / V-morpholinyl or / V-imidazolyl. In other embodiments, compounds of Structural Formula (X-A) (or a pharmaceutically acceptable salt thereof) are provided: (X-A) or a pharmaceutically acceptable salt thereof, wherein: V is a covalent bond or -O-; T is a straight chain C-O alkylene substituted with alkyl, gem dimethyl, spiro cycloalkyl, or an optionally N-substituted nitrogen containing a non-aromatic heterocyclic spiro group; R? is R? is -C (O) OR 5, -C (O) R 5, -OC (O) R 5, -C (O) N (R 5) 2, -NR 5 C (O) R 5, - NR 5 C (O) OR 5, -S ( O) 2R5, -S (O) 2COR5, -S (O) 2N (R5) 2, -NR5S (O) 2, -NR5S (O) 2R5, S (O) 2OR5, -S (O) OR5, - SR5, -C (O) NR5S (O) 2R5, -CN, -NR5C (O) N (R5) 2, -OC (O) N (R5) 2, -N (R5) 2, -OR5, a group optionally substituted non-aromatic heterocyclic or an optionally substituted heteroaryl group; and each R5 is independently -H, alkyl, haloalkyl, hydroxyalkyl, carboxyalkyl, -C (O) OCH2C6H5, S (O) 2CH3, -C (0) OH, -C (O) OMe, -C (O) OEt, C (O) NH2, benzyl, pyrrolidinyl, morpholinyl or -N (R5) 2 is an optionally substituted non-aromatic heterocyclic group containing nitrogen.
In still other embodiments, compounds of Structural Formula (X-A) (or a pharmaceutically acceptable salt thereof) are provided: where: V is -O-; T is a straight chain C? -10 alkylene optionally substituted on any one or more carbon atoms substitutable with halide, alkyl, gem dialkyl, gem dihalo, haloalkyl, alkoxy, haloalkoxy, spiro cycloalkyl, non-aromatic heterocyclic group spiro optionally / V-substituted containing nitrogen, amine, alkylamine, dialkyamymine or hydroxyl; R? is R? is -C (O) OR 5, -C (O) R 5, -OC (O) R 5, -C (O) N (R 5) 2, -NR 5 C (O) R 5, - NR 5 C (O) OR 5, -S ( O) 2R5, -S (O) 2COR5, -S (O) 2N (R5) 2, -NR5S (O) 2, -NR5S (O) 2R5, S (O) 2OR5, -S (O) OR5, - SR5, -C (O) NR5S (O) 2R5, -CN, -NR5C (O) N (R5) 2, - OC (O) N (R5) 2, -N (R5) 2, -OR5, a group optionally substituted non-aromatic heterocyclic or an optionally substituted heteroaryl group; and each R5 is independently -H, alkyl, haloalkyl, hydroxyalkyl, carboxyalkyl, -C (O) OCH2C6H5, S (O) 2CH3, -C (O) OH, -C (O) OMe, -C (O) OEt, C (O) NH2, benzyl, pyrrolidinyl, morpholinyl or -N (R5) 2 is an optionally substituted non-aromatic heterocyclic group containing nitrogen. The compounds of general formula I-A (and subsets thereof as described just before in section 2) include those described generally above and are illustrated in more detail by the classes, subclasses and species described before and in this document. As used in this document, the following definitions will apply unless otherwise indicated. For the purposes of this invention, the chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. In addition, the general principles of organic chemistry are described in Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito: 1999 and "March's Advanced Organic Chemistry", 5th Ed., Ed .: Smith, MB and March, J., John Wiley & amp;; Sons, New York: 2001. The term "alkylene" as used herein refers to a straight chain hydrocarbon that is completely saturated. An alkylene group is typically C-O, more typically C1-6, more preferably C? -5 and even more preferably C-? -3. A "substituted alkylene" is an alkylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents are as described below for a substituted alkyl group. Preferred substituents for the alkylene group represented by T are fluorine, methyl, gem dimethyl, gem difluorofluoromethyl, spiro cyclopropyl, spiro cyclobutyl, spiro azetidinyl optionally / V-substituted, spiro aziridinyl optionally / V-substituted, spiro pyrrolidinyl optionally / V-substituted , optionally N-substituted spiro piperidinyl, amine, methylamine, dimethylamine or hydroxyl. A "substitutable alkylene carbon atom" is a carbon atom of the alkylene that binds to one or more hydrogen atoms. Therefore, the hydrogen atoms can optionally be replaced with the substituent. The terms "alkyl", "hydroxyalkyl", "carboxyalkyl", "haloalkyl","alkylamine", "dialkyamymine", used alone or as part of a larger moiety include linear and branched saturated chains containing from one to ten carbon atoms, preferably from one to six, more preferably from one to five and even more preferably from one to three.
The term "allyl" as used herein has the formula -CH2CH = CH2 and may be optionally substituted at any substitutable carbon atom. A "substitutable carbon atom of allyl" is a carbon atom of allyl that binds to one or more hydrogen atoms. Therefore, the hydrogen atom can be optionally replaced with the substituent. Suitable substituents are as described for the alkyl group. The terms "gem dialkyl" and "gem dihalo" include compounds in which two alkyl substituents or two halo substituents, respectively, bind to the same carbon atom, for example, -C (CH3) 2- or C (F) 2 -. A "spiro cycloalkyl" or "non-aromatic heterocyclic spiro" group is a cycloalkyl or non-aromatic heterocyclic group that shares a carbon atom of the ring with a carbon atom of an alkylene group or alkyl group. The terms "carbocyclic non-aromatic" or "cycloaliphatic" will include cyclic C3.-10 hydrocarbons that are completely saturated or that contain one or more units of unsaturation, but are not aromatic. The cycloaliphatic groups are typically 03.-10, more typically C3-. "Alkoxy" means (alkyl) -O; "haloalkoxy" means (halide) -O-; "alkoxyalkylene" means (alkyl) -O- (alkylene) such as methoxymethylene (CHsOCH2); "hydroxyalkyl" means an alkyl group substituted with hydroxy, adited means "-C (O) - (alkyl"). The term "heteroatom" refers to nitrogen, oxygen or sulfur and includes any oxidized form of nitrogen or sulfur, and the quatemized form of any basic nitrogen. The term "nitrogen" also includes a substitutable nitrogen of a heterocyclic ring. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in pyrrolidinyl / V-substituted). The term "aromatic group" includes carbocyclic aromatic ring groups and heteroaryl ring groups. The term "aromatic group" can be used interchangeably with the terms "aryl", "aryl ring" or "aromatic ring".
The aromatic carbocyclic ring groups have only carbon atoms in the ring and include monocyclic aromatic rings such as phenyl and fused polycyclic aromatic ring systems in which two or more carbocyclic aromatic rings condense to each other. Examples include 1-naphthyl, 2-naphthyl, 1-anthracyl and 2-anthracyl. Also included within the scope of the term "carbocyclic aromatic ring", as used herein, is a group in which an aromatic ring is condensed to one or more non-aromatic rings (aliphatic or heterocyclic), such as in an indanyl, phthalimidyl, naphthymidyl, phenanthridinyl or tetrahydronaphthyl, where the radical or point of attachment is in the aromatic ring. The term "heteroaryl" or "heteroaromatic" refers to heteroaromatic ring groups having from five to fourteen members, including monocyclic heteroaromatic rings and polycyclic aromatic rings in which a monocyclic aromatic ring is condensed to one or more other carbocyclic aromatic rings or heteroaromatics. Examples of heteroaryl rings include 2-furanyl, 3-furanyl, / V-imidazolyl, 2-imidazolyl, 4-imidazoyl, 5-methyldazole, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, oxadiazolyl, 2- oxadiazolyl, 5-oxadiazolyl, 2-oxazoyl, 4-oxazolyl, 5-oxazolyl, / V-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, pyrazolyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-pyrimidyl, -pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 2-thiazolyl4-thiazolyl, 5-thiazolyl, 2-triazolyl, 5-triazolyl, tetrazolyl, 2-thienyl, 3-thienyl, carbazolyl benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolium, benzooxazolyl, benzimidazolyl, isoquinolinyl, indolyl, isoindolyl, acridinyl or benzoisazolyl. Also included within the scope of the term "heteroaryl", as used herein, is a group in which a heteroaryl ring is condensed to one or more heterocyclic cycloaliphatic or non-aromatic groups where the radical or point of attachment is in the ring heteroaromatic. Examples include tetrahydroquinolinyl, tetrahydroisoquinolinyl and pyrido [3,4-d] pyrimidinyl. The term "heteroaryl" can be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic".
The term "non-aromatic heterocyclic group" or "non-aromatic heterocyclic ring" refers to non-aromatic ring systems typically having three to fourteen members, preferably three to six, wherein one or more ring carbons, preferably one to four, each is replaced with a heteroatom such as N, O or S. Examples of non-aromatic heterocyclic rings include 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, [1, 3] -dioxalanyl, [ 1,3] -dithiolanyl, [1, 3] -dioxanil, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2-morpholinyl, 3-morpholinyl, / V-morpholinyl, 2-thiomorpholinyl, 3-thiomorpholinyl, 4-thiomorpholinyl, / V -pyrrolidinyl, 2-pyrroidinyl, 3-pyrrolidinyl, / V-piperazinyl, 2-piperazinyl, / V-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, piperidinonyl, 4-thiazolidinyl, diazolonyl, N-substituted diazolonyl, oxazolidinyl, oxazolidinyl, tetrahydrothienyl, imidazolidinyl, imi dazolidinonyl, pyrrolidinonyl, S-siazolidinyl S, S-piperidinyl, 1-phthalimidinyl, 3-1 / -benzimidazol-2-one, benzoxanil, benzopyrrolidinyl, benzopiperidinyl, benzoxolanyl, benzothiolanyl and benzothianyl. A "substituted aromatic" group is an aromatic group with a substituent on one or more ring carbon atoms or substitutable ring nitrogen atoms. Each substituent is independently selected. Examples of suitable substituents on an unsaturated carbon atom or substitutable carbon atom of an aromatic group are as described above for Rz, R11 and R14. A "substitutable ring carbon atom" in an aromatic ring (including the aromatic groups represented by Ring A, phenyl ring A, R 1 and R 3) is a ring carbon atom that binds to a hydrogen atom. Therefore, the hydrogen atom can be optionally replaced with the substituent. Thus, the term "substitutable ring carbon atom" in an aromatic ring excludes ring carbon atoms that condense with other rings or that are represented as already attached to a substituent. An alkyl group or a non-aromatic heterocycle or carbocycle may contain one or more substituents on any substitutable carbon atom. A "substitutable alkyl carbon atom" is an alkyl carbon atom that binds to one or more hydrogen atoms. Therefore, the hydrogen atoms can optionally be replaced with the substituent. Examples of suitable substituents on the saturated carbon of an alkyl group or a non-aromatic heterocycle include those listed above for the unsaturated carbon of an aromatic group and, on the internal carbon atoms of an alkyl group or on the carbon atoms of the ring of a non-aromatic heterocyclic group, the following: = O, = S, = NNHR *, = NN (R *) 2, = NNHC (O) R *, = NNHCO2 (aIquilo), = NNHSO2 (alkyl) or = NR *. Each R * is independently selected from hydrogen, an unsubstituted alkyl group or a substituted alkyl group. Examples of substituents on the alkyl group represented by R * include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy or haloalkyl . Suitable substituents on the substitutable nitrogen of a heteroaryl or aromatic heterocyclic group include -R12, -N (R12) 2, -C (O) R12, -CO2R12, -C (O) C (O) R12, -C (O CH2 C (O) R12, -SO2R12, -SO2N (R12) 2, -C (= S) N (R12) 2, -C (= NH) -N (R12) 2 and -NR12SO2R12; where R12 is hydrogen, an alkyl group, a substituted alkyl group, phenyl (Ph), substituted Ph, -O (Ph), -O (Ph) substituted, CH2 (Ph) or an unsubstituted non-aromatic heteroaryl or heterocyclic ring. Examples of substituents on the alkyl group or the phenyl ring represented by R12 include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy or haloalkyl. A "substitutable ring nitrogen atom" in a non-aromatic heteroaryl or heterocyclic group containing nitrogen is a ring nitrogen atom that binds to a hydrogen atom. Therefore, the hydrogen atom can be optionally replaced with the substituent. Therefore, the term "nitrogen atom of the substitutable ring" excludes ring nitrogen atoms which are represented as already attached to a substituent, and ring nitrogen atoms which are ring atoms in two fused rings (as in , for example, indolizine) and ring nitrogen atoms having three covalent bonds to other ring atoms (such as pyridine, for example). In certain cases, the compounds of the present invention may be associated in isolation with solvent or water, as in a "solvate" or "hydrate". References to the structural compounds or formulas described which represent the disclosed compounds are intended to include such solvates and hydrates. 3. Uses, Formulation and Administration As discussed above, the present invention provides compounds which are useful as inhibitors of CRTH2, and thus the present compounds are useful for treating (therapeutically or prophylactically) disorders with an inflammatory component and allergic conditions. They can also be used to inhibit inflammatory disorders and allergic conditions mediated by Th2, eosinophil and basophil cells. Accordingly, in another aspect of the present invention, pharmaceutically acceptable compositions are provided, wherein said compositions comprise the compounds described herein and optionally comprise a pharmaceutically acceptable excipient, adjuvant or vehicle. In certain embodiments, these compositions optionally comprise one or more additional therapeutic agents. It will also be appreciated that certain of the compounds of the present invention may exist in free form for treatment, or when appropriate, in the form of a pharmaceutically acceptable derivative thereof. According to the present invention, pharmaceutically acceptable derivatives include, but not limited to, prodrugs, salts, esters, salts of such esters, or any other adduct or pharmaceutically acceptable derivative which upon administration to a patient in need thereof is capable of provide, directly or indirectly, a compound of those described herein, or a metabolite or residue thereof. As used herein, the term "pharmaceutically acceptable salt" refers to those salts that are, within the scope of medical judgment, suitable for use in contact with the tissues of humans and lower animals without inducing toxicity, irritation, allergic response and the like, and are restrained with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are known in the art. For example, S.M. Berge et al., Discloses pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. The pharmaceutically acceptable salts of the compounds of this invention include those derived from inorganic and organic acids and bases. Examples of addition salts of pharmaceutically acceptable non-toxic acids are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid and / or by the use of other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3- phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C? -4) alkyl salts. This invention also relates to the quaternization of any basic nitrogen-containing group of the compounds described herein. By means of such quaternization, soluble or dispersible products can be obtained in water or oil. Representative alkaline or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include, when appropriate, non-toxic ammonium, quaternary ammonium and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkylsulfonate and arylsulfonate. As described above, the pharmaceutically acceptable compositions of the present invention further comprise a pharmaceutically acceptable excipient, adjuvant or vehicle which, as used herein, includes any and all solvents, diluents or other liquid carriers, dispersion aids or excipients. suspension, surfactants, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, which are suitable for the particular dosage form desired. Remington's Pharmaceutical Sciences, 16th Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) describes several vehicles used in the formulation of pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as the conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a noxious manner with any other component or components of the pharmaceutically acceptable composition, its use is contemplated within the scope of the invention. Some examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, whey proteins, such as human serum albumin, buffering substances such as phosphates, glycine, acid. sorbic or potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates , waxes, polyethylene-polyoxypropylene block polymers, wool fats, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; jelly; talcum powder; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; saffron oil; Sesame oil; olive oil; corn oil and soybean oil; glycols; such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; water without pyrogens; isotonic saline solution; Ringer's solution; Ethyl alcohol and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweeteners, flavoring and perfuming agents, preservatives and antioxidants may also be present. present in the composition, according to the formulator's judgment.
In another aspect, there is provided a method for the treatment of an inflammatory disease or a disease with an inflammatory component comprising administering an effective amount of a compound, or a pharmaceutical composition thereof to a subject in need thereof. The compounds and compositions of the invention are inhibitors of CRTH2, and thus, without wishing to be bound by any particular theory, the compounds and compositions are particularly useful for treating or decreasing the severity of a disease, condition or disorder where the activation of one or more of CRTH2, PGD2 (including DP activity), Th2 cells, eosinophils and / or basophils is involved in the disease, condition or disorder. When the activation of one or more of CRTH2, PGD2 (including DP activity), Th2 cells, eosinophils and / or basophils is involved in a particular disease, condition or disorder, the disease, condition or disorder may also be referred to as a "disease mediated by CRTH2"or symptom of disease. Accordingly, in another aspect, the present invention provides a method for treating or decreasing the severity of a disease, condition or disorder where activation of one or more of CRTH2, PGD2 (including DP activity), Th2 cells, eosinophils is involved. and / or basophils in the disease state. In certain embodiments of the present invention, an "effective amount" of the pharmaceutically acceptable compound or composition is that amount effective to treat an inflammatory disease or disease with an inflammatory component. In other embodiments, an "effective amount" of a compound is an amount that inhibits the binding of PGD2 to its CRTH2 receptor and therefore inhibits one or more processes mediated by binding in a subject, for example, the release of proinflammatory mediators. . An "effective amount" of a compound can achieve a desired therapeutic and / or prophylactic effect, such as an amount that results in the prevention of or a decrease in symptoms associated with an inflammatory disease or a disease mediated by one or more of CRTH2, PGD2 (including DP activity), Th2 cells, eosinophils and basophils. In one embodiment, the inflammatory disease is an allergic condition. Examples of allergic conditions for which the compounds, pharmaceutical compositions and methods described are believed to be particularly effective include atopic dermatitis, allergic rhinitis, rheumatoid arthritis, chronic obstructive pulmonary disorder or allergic asthma. Other allergic conditions include systemic anaphylaxis or hypersensitivity responses, drug allergies (e.g., to penicillin, cephalosporins), allergies to insect bites and dermatoses such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis and urticaria. Examples of diseases with an inflammatory component for which the compounds, pharmaceutical compositions and methods described are believed to be particularly effective include osteoarthritis, inflammatory bowel disease [eg, such as ulcerative colitis, Crohn's disease, ileitis, celiac disease, non-tropical sprue, enteritis, enteropathy associated with seronegative arthropathies, microscopic or collagenous colitis, eosinophilic gastroenteritis or pouchitis as a result of proctocolectomy, and ileoanal anastomosis] and skin disorders [eg, psoriasis, erythema, pruritis and acne]. Many autoimmune diseases also have an inflammatory component. Examples include multiple sclerosis, systemic lupus erythematosus, myasthenia gravis, juvenile onset diabetes, glomeruionephritis and other nephritis, autoimmune thyroiditis, Behcet's disease, and graft rejection (including rejection of allograft or nonograft-versus-host disease). It is believed that the inflammatory component of these disorders is mediated, at least in part, by CRTH2. Diseases characterized by reperfusion have an inflammatory component that is thought to be mediated, at least in part, by CRTH2. Examples include stroke, cardiac ischemia and the like. The compounds and compositions described can also be used to treat these disorders. Other diseases and conditions with an inflammatory component believed to be mediated by CRTH2 include mastitis (mammary gland), vaginitis, cholecystitis, cholangitis or pericolangitis (bile duct and surrounding liver tissue), chronic bronchitis, chronic sinusitis, chronic inflammatory diseases of the lung that results in interstitial fibrosis, such as interstitial lung diseases (ILD) (eg, idiopathic pulmonary fibrosis, or ILD associated with rheumatoid arthritis, or other autoimmune conditions), hypersensitivity pneumonitis, collagen diseases, and sarcoidosis. Other diseases or conditions more with inflammatory components that can be treated according to the methods described herein include vasculitis (e.g., necrotising, cutaneous and hypersensitivity vasculitis), spondyloarthropathies, scleroderma, atherosclerosis, restenosis, and myositis (including polymyositis, dermatomyositis) , pancreatitis and diabetes mellitus dependent on insulin.
In a preferred embodiment, the invention provides a method for treating asthma which comprises administering an effective amount of a compound of general formula I (and subsets thereof as described herein) to a subject in need thereof. The compounds and compositions, according to the method of the present invention, can be administered using any amount and route of administration effective to treat an inflammatory disease or allergic condition. The exact amount required will vary from subject to subject, depending on the species, age and general condition of the subject, the severity of the infection, the particular agent, its mode of administration and the like. The compounds of the invention are preferably formulated in a unit dosage form to facilitate administration and uniformity of dosage. The term "unit dosage form" as used herein refers to a physically discrete unit of agent appropriate for the patient being treated. It will be understood, however, that the total daily dose of the compounds and compositions of the present invention will be decided by attending to the physician within the scope of the medical judgment. The specific effective dosage level for any particular patient or organism will depend on a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or at the same time as the specific compound employed, and similar factors well known in the medical arts. The term "patient", as used herein, means an animal, preferably a mammal, and more preferably a human. The pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (in the form of powders, ointments or drops), buccally, in the form of an oral or nasal spray , or similar, depending on the severity of the infection that is being treated. In certain embodiments, the compounds of the invention may be administered orally or parenterally at dosage levels of from about 0.01 mg / kg to about 50 mg / kg and preferably from about 1 mg / kg to about 25 mg / kg of weight body of the subject a day, one or more times a day, to obtain the desired therapeutic effect. Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents usually used in the art such as, for example, water or other solvents, solubilizing and emulsifying agents such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate. , benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, peanut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan esters of fatty acids, and mixtures thereof. In addition to inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifiers and suspending agents, sweetening, flavoring and perfuming agents. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, can be formulated according to the known art using suitable dispersing agents or humectants and suspending agents. The sterile injectable preparation can also be a solutionsterile injectable suspension or emulsion in a non-toxic parenterally-acceptable diluent or solvent, for example, in the form of a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile fixed oils are commonly employed as solvent or suspension medium. For this purpose, any soft fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectable solutions. The injectable formulations can be sterilized, for example, by filtration through a bacteria retention filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium before use. In order to prolong the effect of a compound of the present invention, it is often desired to slow the absorption of the compound in the subcutaneous or intramuscular injection. This can be achieved by the use of a liquid suspension of crystalline or amorphous material with poor solubility in water. The rate of absorption of the compound therefore depends on its rate of dissolution which, in turn, may depend on the size of the crystal and the crystalline form. Alternatively, the delayed absorption of a compound administered parenterally is achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are manufactured by forming microencapsulated matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of the compound to the polymer and the nature of the particular polymer employed, the rate of release of the compound can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues. Compositions for rectal or vaginal administration are preferably suppositories that can be repaired by mixing the compounds of this invention with non-irritating excipients or vehicles such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore both melt in the rectal or vaginal cavity and release the active compound.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert and pharmaceutically acceptable excipient or vehicle such as sodium citrate or dicalcium phosphate and / or) fillers or binders such as starches, lactose, sucrose, glucose, mannitol and acid. silicic, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose and gum arabic, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato starch or tapioca , alginic acid, certain silicates and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbers such as kaolin clay and bentonite, and i) lubricants such as talc, calcium stearate, magnesium stearate, polyethylene solid ilen glycols, sodium lauryl sulphate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type can also be used as fillers in hard and soft filled gelatin capsules using excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition that they release the active ingredient or ingredients alone or, preferably, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of introduced compositions that may be used include polymeric substances and waxes. Solid compositions of a similar type can also be used as fillings in hard and soft filled gelatin capsules using excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The active compounds may also be in micro-encapsulated form with one or more excipients as indicated above. The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings, release control coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms, the active compound can be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as in conventional practice, additional substances other than inert diluents, e.g., tabletting lubricants and other tabletting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and may also be of a composition that they release the active ingredient (s) alone, or preferably, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of introduced compositions that may be used include polymeric substances and waxes. Dosage forms for topical and transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, nebulizations, inhalants or patches. The active component is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers that may be required. The ophthalmic formulation, eardrops and eye drops are contemplated within the scope of this invention. In addition, the present invention contemplates the use of transdermal patches, which have the added advantage that they provide a controlled release of a compound in the body. Such dosage forms can be made by dissolving or dispersing the compound in the appropriate medium.
Absorption enhancers can also be used to increase the flow of the compound through the skin. The speed can be controlled by providing a speed control membrane or by dispersing the compound in a polymer matrix or gel. It will also be appreciated that the compounds and pharmaceutically acceptable compositions of the present invention can be used in combination therapies, that is, the compounds and pharmaceutically acceptable compositions can be administered simultaneously with, before, or after, one or more other therapeutic or therapeutic procedures. desired doctors. The particular combination of therapies (therapeutic compounds or procedures) for use in a combination regimen will take into account the compatibility of the therapeutic compounds and / or desired procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed can achieve a desired effect for the same disorder (for example, a compound of the invention can be administered simultaneously with another agent used to treat the same disorder) or can achieve different effects (for example, control of any adverse effect). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition, are known as "appropriate for the disease, or condition, that is being treated." For example, the compounds of the invention may also be administered in combination with one or more additional therapeutic agents, such as theophylline, β-adrenergic bronchodilators, corticosteroids, antihistamines, anti-allergic agents, immunosuppressive agents (eg, cyclosporin A, FK-506, prednisone, methylprednisolone), hormones (e.g., adrenocorticotropic hormone (ACTH)), cytokines (e.g., interferons (e.g., IFNβ-1a, IFNd-1b)) and the like. The amount of additional therapeutic agent present in the compositions of this invention will not be greater than the amount that would normally be administered in a composition comprising that therapeutic agent as the sole active agent. Preferably, the amount of additional therapeutic agent in the described compositions will vary from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent. The pharmaceutically acceptable compounds or compositions of this invention can also be incorporated into compositions for implantable medical coating devices, such as prostheses, artificial valves, vascular grafts, cannulas and catheters. Accordingly, the present invention, in another aspect, includes a composition for coating an implantable device comprising a compound of the present invention as described above in broad lines, and in classes and subclasses herein, and a suitable vehicle for coating said implantable device. In still another aspect, the present invention includes an implantable device coated with a composition comprising a compound of the present invention as described above in broad outline, and in classes and subclasses of this document, and a suitable vehicle for coating said device. Implantable. Another aspect of the invention relates to inhibiting the activity of CRTH2 in a biological sample or in a patient, wherein the method comprises administering to the patient, or contacting said biological sample with a compound of formula I or a composition comprising said compound . The term "biological sample", as used herein, includes, without limitation, cell cultures or extracts thereof; the material subjected to biopsy obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears or other bodily fluids or extracts thereof. The inhibition of CRTH2 activity in a biological sample is useful for a variety of purposes that are known to those skilled in the art. Examples of such purposes include, but without limitation, blood transfusion, organ transplantation, storage of biological samples and biological tests. 4. General Synthetic Methods Another embodiment of the present invention is a method for preparing an amino acid compound represented by the Structural Formula (Xl-A): (Xl-A) The method comprises the step of reacting Ar-NH2 with a lactone represented by the Structural Formula (XXII-A): (Xll-A). Ar is an optionally substituted monocyclic aromatic group and R 2 is C 1 -C 3 alkyl. Preferably, Ar is an optionally substituted phenyl group and R 2 is methyl or ethyl. Suitable substituents for Ar are as described above for Ring A or Ring Phenyl A, provided, however, that the functional groups which may interfere with the reaction are protected. Functional groups that require protection will be obvious to one skilled in the art and include amines, alcohols, carboxylic acids and the like. Examples of preferred substituents include halo, cyano, R °, -OR30, -CO2R31, -C (O) R °, -C (O) N (Rx) 2, -OC (O) R °, (CH2) nCO2R31 , O (CH2) nCO2R31, NHSO2R °, NHC (O) NRx2, (CH2) nOR30, O (CH2) nOR30, (CH2) nC (O) N (Rx) 2, O (CH2) nC (O) N ( Rx) 2; n is an integer of 1-4; R ° is independently hydrogen, C1.3 haloalkyl or a C1-C3 alkyl group; one Rx is -H or C1-C3 alkyl and the other is an amine protecting group; R30 is an alcohol protecting group; and R31 is a carboxylic acid protecting group. Suitable protecting groups are well known in the art and are described, for example, in Greene and Wuts, "Protective Groups in Organic Synthesis", John Wiley & Sons (1991). The complete teachings of Greene and Wits are incorporated herein by reference. Ar is a phenyl group. Also included within the present invention is the corresponding reaction with the enantiomer of the amino acid compound represented by the Structural Formula (Xll-A), thereby forming the enantiomer of the compound represented by the Structural Formula (Xl-A). The reaction of arylamine and the above cyclic lactone can be carried out in solvents in which both reagents are soluble. Examples include protic solvents (such as water and methanol) and polar aprotic solvents (dimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide and the like). An excess of one reactant can be used in relation to the other (for example, an excess of up to ten times), however, equimolar amounts are more typical. The reaction is typically carried out at the boiling point of the solvent that is used, but it can also be carried out normally at temperatures ranging from room temperature to temperatures up to 200 ° C. Temperatures of 70 ° C to 90 ° C are the most commonly used. Another embodiment is a method for preparing an intermediate compound represented by the Structural Formula (Xlll-A) from the amino acid compound represented by the Structural Formula (Xl-A): (Xlll-A) The method comprises the step of amidating the carboxylic acid group of the amino acid compound with NH2C (O) ORz. The group -C (O) ORz is an amine protecting group that taken together with -NH2 forms a carbamate. In this manner, Rz is an unsubstituted or substituted alkyl, allyl or aryl group. The substituents which may be present in the alkyl, allyl or aryl group represented by Rz are those which do not interfere with the reactions carried out and are easily recognized by the specialist. Examples include alkyl, halogen and alkoxy. Thus, the values suitable for Rz are well known to those skilled in the art and are described, for example, in Green and Wuts, "Protective Groups in Organic Synthesis", John Wiley & Sons (1991). Specific examples include, but are not limited to, benzyl, methyl, ethyl, allyl, 2,2,2, -trichloromethyl, 2,2,2-trichloro-t-butyl, fer-butyl or fluorenylmethyl. The term "amidation with a carboxylic acid with NH2C (O) ORz" refers to converting a carboxylic acid (-COOH) to the amide -C (O) NHC (O) ORz in one or more reaction steps. Many methods for converting a carboxylic acid to an amide are known in the art. Typically, the carboxylic acid is first converted to a group that can be more easily displaced with an amine or amide than -OH. In this way, -OH becomes a better outgoing group. A "leaving group" is a group that can be easily moved by a nucleophile. In the present invention, the amino acid compound can be converted directly into the intermediate compound by activating the carboxylic acid of the amino acid compound and then being reacted with NH2C (O) ORz. Alternatively, the carboxylic acid can first be converted to the carboxamide (-C (O) NH2) by activating the carboxylic acid group of the amino acid compound and then reacting it with NH3 or an equivalent functional group thereof (eg, NH4CI) and then protecting the resulting carboxamide. When NH2C (O) ORz is used as the nucleophile, the amidation is preferably carried out in the presence of at least one equivalent of a non-nucleophilic base such as an alkoxide (lithium ferc-butoxide, potassium urea-butoxide, lithium isopropoxide and sopropoxide). of potassium) or amide base (For example, lithium or potassium isopropylamide or hexamethylpiperidide). In one example, -OH of the carboxylic acid is converted to a leaving group by replacing it with a halogen, typically with chloride. The carboxylic acid is thus converted to an acid halide, for example, an acid chloride. Suitable reagents for preparing acid chlorides from carboxylic acids are well known in the art and include thionyl chloride, oxalyl chloride, phosphorus trichloride and phosphorus pentachloride. Typically, each carboxylic acid group is reacted with about one equivalent or a slight excess of thionyl chloride, oxalyl chloride, phosphorus trichloride and phosphorus pentachloride in an inert solvent such as an ethereal solvent (eg, diethyl ether, tetrahydrofuran) or 1,4-dioxane), a halogenated solvent (e.g., methylene chloride or 1,2-dichloroethane) or aromatic solvent (e.g., benzene or toluene). When oxalyl chloride is used, a tertiary amine is usually added to accelerate the reaction in amounts ranging from a catalytic amount to approximately one equivalent relative to oxalyl chloride. Alternatively, the carboxylic acid is first converted to an "activated ester". An ester -COOR is said to be "activated" when -OR is easily displaced by an amine or amide which -OH. -OR is more easily displaced as R becomes more removable of electrons. Some activated esters are stable enough to be isolated, for example, esters in which R is phenyl or substituted phenyl. For example, diphenyl malonate can be prepared from malonyl chloride and phenol, both commercially available from Aldrich Chemical Co., Milwaukee, Wl., By the above procedures. Other activated esters are more reactive and are generally prepared and used in situ. The formation of an activated ester in situ requires a "coupling agent", also referred to as a "carboxylic acid activating agent", which is a reagent that replaces the hydroxyl group of a carboxylic acid with a group that is susceptible to nucleophilic displacement. Examples of coupling agents include 1, -carbonyldiimidazole (CDI), isobutyl chloroformate, dimethylaminopropylethylcarbodiimide (EDC), dicyclohexylcarbodiimide (DCC). When amidated by in situ generation of an activated ester, an excess of the carboxylic acid or amine (typically an excess of 50%, more typically an excess of about 10-15%) can be used. However, it is more common when carrying out the present invention to use equimolar amounts of both reagents. Generally, from about 1.0 equivalents to about 10 equivalents of coupling agent are used in relation to each carboxylic acid group, preferably from about 1.0 equivalents to 1.5 equivalents. When DCC is used, a weak acid such as 1-hydroxybenzotriazole (HOBt) is usually added to accelerate the reaction. Typically, between one and about 1.5 equivalents of HOBt are used in relation to DCC; preferably between one and about 1.2 equivalents. The reaction is generally carried out in inert aprotic solvents, for example, halogenated solvents such as methylene chloride, dichloroethane and chloroform, ethereal solvents such as tetrahydrofuran, 1,4-dioxane and diethyl ether and dimethylformamide. The suitable reaction temperature generally ranges from about 0 ° C to about 100 ° C, but the reaction is preferably carried out at room temperature. Yet another embodiment of the present invention is a method for preparing a product compound represented by the Structural Formula (XIV-A): (XIV-A) The method comprises the step of reducing the amide carbonyl of the intermediate compound to form a second intermediate and then cyclizing the second intermediate to form the product compound. The variables of the Structural Formula (XIV-A) are as described above for the Structural Formulas (XI-A) - (XIII-A). The "carbonyl of the amide" is understood as the carbonyl that is between the methylene carbon and the nitrogen atom and not the carbonyl that binds to a nitrogen atom and another oxygen atom. To carry out the reduction step, a reducing agent is used which can reduce the carbonyl of the amide but not the carbamate group. A common example is sodium borohydride together with a Lewis acid such as magnesium chloride or calcium chloride. The reduction step is typically performed in an alcohol solvent such as methanol or ethanol. An excess of sodium borohydride and Lewis acid of up to 50% may be used, but typically 0.5 to 1.0 equivalent of sodium borohydride and 0.5 to 2.0 equivalents of Lewis acid are used. The deletion step is carried out in dilute aqueous or alcoholic acid, using, for example, HCl of 0.1 N to 10 N, H 2 S 4, H 3 PO 4 or a sulfonic acid such as methanesulfonic acid, toluenesulfonic acid or phenylsulfonic acid. More typically, acid between 0.8 N and 1.2 N is used. Commonly, an organic acid, such as acetic acid, benzoic acid, citric acid and the like, for example between 0.5 equivalents and 10 equivalents, is also present. Typically, a co-solvent immiscible in water or alcohol is used. Common co-solvents include halogenated solvents such as dichloromethane or chloroform and ether solvents such as tetrahydrofuran and diethyl ether. Another embodiment of the present invention is a method for preparing the product compound represented by the Structural Formula (XIV-A) from the cyclic lactone represented by the Structural Formula (Xll-A). The method comprises combining the three reaction steps described previously. Alternatively, the enantiomer of the compound represented by the Structural Formula (XIV-A) is prepared using the same three reaction steps, provided, however, that the enantiomer of the starting lactone represented by the Structural Formula is used. (Xll-A). Yet another embodiment of the present invention is a compound represented by any of the Structural Formulas (XI-A) - (XIV-A). The invention is illustrated by the following examples which are not intended to be limiting in any way. EXEMPLIFICATION General. All the reactions involving air sensitive reagents were carried out in a nitrogen atmosphere. Reagents were used as received from commercial suppliers unless otherwise indicated. 1 H NMR data were recorded using the Bruker UltraShield 300 MHz 54 mm instrument equipped with a Bruker B-ACS60 Auto Sampler or the 300 MHz Varian instrument. Intermediates and final compounds were purified by flash chromatography using one of the following instruments: 1. Ultra-fast Biotage 4-channel Quad UV collector equipped with a Quad 1 Pump Module and Quad 12/25 Cartridge module. 2. Biotage Ultra-Fast 12-channel Quad UV collector equipped with a Quad 3 Pump Module and a Quad 3 Cartridge module. 3. ISCO flash-flash chromatography instrument. The LC / ES spectra were obtained using a MicroMass Platform LC (Phenomenex C18 column, 5 microns, 50 x 4.6 mm) equipped with a Gilson 215 Liquid Handler. The conventional LC / MS conditions are as follows: Formic Acid - Conventional conditions% C (Water) 95.0 Pump Gradient times table HP1100 % D (Acetonitrile) 5.0% Formic Acid 0.1 The Gradient Time Table contains 5 entries Flow rate (ml / min) 3,500 which are: Stop time (min) 4.4 TimeA% B% C% D% FlowPressure Pressure Min (bar) 0 0.00 0.0 0.0 95.0 5.0 3.500 400 Pressure Max (bar) 400 3.50 0.0 0.0 0.0 100.0 3.500 400 Temp. left of oven (° C) 25,0 4,30 0,0 0,0 0,0 100,0 3,500 400 Temp. right of oven (° C) 25.0 4.40 0.0 0.0 95.0 5.0 4,000 400 5.00 0.0 0.0 95.0 5.0 4,000 400 Scheme 1 1 = trans 2 = cis (±) -Cis- and (±) -frans- (2-ethyl-1,2,3,4-tetrahydro-quinolin-4-yl) -phenyl-amine (1) and (2) ): A 250 ml flask under a nitrogen atmosphere was charged with aniline (1.0 g, 10.7 mmol, 1.0 equiv.), Acetaldehyde (0.599 ml, 10.7 mmol), benzotriazole (0.255 g, 2.1 mmol, 0.2 equiv.) And dry toluene (100 ml) (Caution: an exotherm was observed). The benzotriazole / precipitated aldehyde adduct was observed immediately. The solution was allowed to stir at room temperature for 12 h. The precipitate that formed after stirring overnight was filtered and washed with a minimum amount of diethyl ether, yielding exclusively the cis isomer. The trans isomer can be obtained by concentration of the filtrate. The residue was purified by the ultra-rapid Biotage system (95% hexanol / 5% diethyl ether) to produce the cis and trans isomers in the form of a mixture. Then, the resulting oily residue was triturated with hexane to remove the cis isomer as a white solid and the filtrate was concentrated to give the trans isomer. Isomer (±) -cis - 1 H NMR (CDCl 3) d: 1, 24 (d, 3 H), 1, 52 (c, 1 H), 2.38 (dddd, 1 H), 3.63 (m, 1 H) , 3.75 (sa, 2H, -NH), 4.83 (dd, 1 H), 6.51 (d, 1 H), 6.68 (m, 4H), 7.05 (m, 1 H ), 7.19-7.26 (m, 2H), 7.39 (d, 1 H). Isomer (±) -trans - 1 H NMR (CDCl 3) d: 1, 22 (d, 3 H), 1, 56 (m, 1 H), 2,20 (dt, 1 H), 3,4 (m, 1 H), 3.89 (sa, 2H, -NH), 4.55 (dt, 1H), 6.56 (dd, 1H), 6.66-6.75 (m, 4H), 7.08 (m, 1 H), 7.19-7.26 (m, 3H). Scheme 2 C / s- (±) -1 - (2-methyl-4-phenylamino-3,4-dihydro-2H-quinolin-1-yl) -ethanone (3) A 30 ml flask in a nitrogen atmosphere was charged with (±) -c / s- (2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl) -phenyl-amine (0.520 g, 2.2 mmol, 1.0 eq.), Acetic anhydride (0.209 ml, 2.2 mmol, 1.0 equiv.) And dry toluene (31 ml). The solution was heated at 50 ° C for 15 h. The reaction mixture was evaporated in vacuo. The residue was purified by the ultra-rapid Biotage system (hexane 70% / 30% ethyl acetate) to produce the cis isomers of 2-acetyl, yield 67%. 1 H NMR (CDCl 3) d: 1, 17 (d, 3 H), 1, 25 (c, 1 H), 2.19 (s, 3 H), 2.22 (sa, 1 H), 2.65 (m, 1 H), 4.21 (dd, 1H), 4.96 (m, 1H), 6.65 (d, 2H), 6.75 (t, 1H), 7.12-7.33 (m, 6H). (1-Acetyl-2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl) -phenyl-amide of c / s- (±) -furan-2-carboxylic acid (4) A flask of Round bottom in a nitrogen atmosphere was charged with c / s-1- (2-methyl-4-phenylamino-3,4-dihydro-2H-quinoIin-1-yl) -ethanone (0.163 g, 0.58 mmol, 1.0 equiv.), 2-furoyl chloride (0.285 ml, 2.9 mmol, 5.0 equiv.), pyridine (1.0 equiv.) and dry toluene (3 ml). The solution was heated at 90 ° C for 15 h. The reaction mixture was evaporated in vacuo. The residue was purified by the ultra-rapid Biotage system (50% hexane / 50% ethyl acetate) to produce the cis isomer, 40% yield. 1 H NMR (CDCl 3) d: 1, 08 (d, 3 H), 1, 63 (m, 1 H), 2.14 (s, 3 H), 2.2 (s a, 1 H), 4.77 (m, 1H), 5.75 (br s, 1H), 6.23 (dd, 1H), 7.12-7.45 (m, 10H). Scheme 3 (±) -rrans-1- (2-Methyl-4-phenylamino-3,4-dihydro-2H-quinolin-1-yl) -ethanone (5) A 30 ml flask under a nitrogen atmosphere was charged with ( ± ytrans- (2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl) -phenyl-amine (0.260 g, 1.1 mmol, 1.0 equiv.) And acetyl chloride (0.075 mL) , 1.0 mmol, 0.95 equiv.) In pyridine (5 ml) The solution was allowed to stir at room temperature for 6 h.The reaction mixture was evaporated in vacuo.The residue was purified by the ultrafast Biotage system. (from 70% hexane / 30% ethyl acetate to 60% hexane / 40% ethyl acetate to 50% hexane / 50% ethyl acetate) to produce the trans isomers of 2-acetyl, 35% .1H NMR (CDCl3) d: 1.19 (d, 3H), 1.76 (m, 1H), 2.17 (s, 3H), 2.52 (dd, 1H), 4.60 ( t, 1 H), 4.93 (m, 1 H), 6.67 (d, 2H), 6.71 (t, 1 H), 7.13-7.36 (m, 6H), 7, 41 (d, 1 H). (1) -tra /? S-furan- (1-Acetyl-2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl) -phenyl-amide 2-carboxylic acid (6) A bottom flask red The mixture was charged with (±) -ira / 7S-1- (2-methyl-4-phenylamino-3) under a nitrogen atmosphere., 4-dihydro-2H-quinolin-1-yl) -ethanone (0.110 g, 0.39 mmol, 1.0 equiv.), 2-fluroyl chloride (0.193 mL, 1.9 mmol, 5.0 equiv. ), pyridine (1.0 equiv.) and dry toluene (5 ml). The solution was heated at 50 ° C for 5 h. The reaction mixture was evaporated in vacuo. The residue was purified by the ultra-rapid Biotage system (from 30% hexane / 70% ethyl acetate to 50% hexane / 50% ethyl acetate) to produce the trans isomer, 34% yield. 1 H NMR (CDCl 3) d: 1, 11 (d, 3 H), 1, 76 (s, 3 H), 2.07 (dd, 1 H), 2.37 (m, 1 H), 5.00 (m , 1 H), 5.48 (d, 1 H), 6.14 (dd, 1 H), 6.29 (t, 1 H), 6.90 (m, 1H), 6.99 (m, 1 H), 7.22-7.32 (m, 6H), 7.34 (d, 1 H), 7.54 (dd, 1 H). (±) -C / sN- (1-Acetyl-2-methyl-1,253,4-tetrahydro-quinolin-4-yl) -4-fluoro-N-phenyl-benzamide (7) A 30 ml flask in an atmosphere of nitrogen was charged with (±) -cis- (2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl) -phenyl-amine (0.520 g, 2.2 mmol , 1.0 eq.), Acetic anhydride (0.209 ml, 2.2 mmol, 1.0 equiv.) And dry toluene (31 ml). The solution was heated at 50 ° C for 15 h. The reaction mixture was evaporated in vacuo. The residue was purified by the ultra-rapid Biotage system (70% hexane / 30% ethyl acetate) to produce the cis 2-acetyl isomers, 67% yield. 1 H NMR (CDCl 3) d: 1, 17 (d, 3 H), 1.25 (c, 1 H), 2.19 (s, 3 H), 2.22 (sa, 1 H), 2.65 (, 1 H) ), 4.21 (dd, 1H), 4.96 (m, 1 H), 6.65 (d, 2H), 6.75 (t, 1H), 7.12-7.33 (m, 6H) ). A round bottom flask in a nitrogen atmosphere was charged with (±) -c / s-1- (2-methyl-4-phenylamino-3,4-dihydro-2H-quinolin-1-yl) -ethanone (1 , 0 equiv.), 2-fluorobenzoyl chloride (5.0 equiv.), Pyridine (1.0 equiv.) And dry toluene (3 ml). The solution was heated at 90 ° C for 15 h. The reaction mixture was evaporated in vacuo. The residue was purified by the ultra-rapid Biotage system (50% hexane / 50% ethyl acetate) to produce the cis isomer, 40% yield. 1 H NMR (CDCl 3) d: 1.1 (3 H, d), 1.2 (1 H, m), 2.1 (3 H, s), 2.1 (1 H, m), 4.8 (1 H, m), 5.4 (1H, m), 6.8 (2H, m), 6.9-7.4 (9H, m), 7.5 (1H, m). MS m / z: 403 (M + 1). (±) -rraps-N- (1-Acetyl-2-methyl-152,3,4-tetrahydro-quinolin-4-yl) -4-fluoro-N-phenyl-benzamide (8) A 30 ml flask in a nitrogen atmosphere was charged with (± and trans- (2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl) -phenyl-amine (0.260 g, 1.1 mmol, 1.0 equiv. .) and acetyl chloride (0.075 ml, 1.0 mmol, 0.95 equiv.) in pyridine (5 ml) The solution was allowed to stir at room temperature for 6 h.The reaction mixture was evaporated in vacuo. The residue was purified by the ultra-rapid Biotage system (from 70% hexane / 30% ethyl acetate to 60% hexane / 40% ethyl acetate to 50% hexane / 50% ethyl acetate) to afford the trans isomers of 2-acetyl, 35% yield: 1 H NMR (CDCl 3) d: 1, 19 (d, 3 H), 1, 76 (m, 1 H), 2.17 (s, 3 H), 2.52 ( dd, 1 H), 4.60 (t, 1 H), 4.93 (m, 1 H), 6.67 (d, 2 H), 6.71 (t, 1 H), 7.13-7 , 36 (m, 6H), 7.41 (d, 1 H) A round-bottomed flask in a nitrogen atmosphere was charged with (±) -frans-1- (2-methyI-4-phenylamino-314-dihydro-2H-quinolin-1-yl) -ethanone (1.0 equiv.), 4-fluorobenzoyl chloride (5.0 equiv.), pyridine (1.0 equiv.) and dry toluene (5 ml). The solution was heated at 50 ° C for 5 h. The reaction mixture was evaporated in vacuo. The residue was purified by the ultra-rapid Biotage system (from 30% hexane / 70% ethyl acetate to 50% hexane / 50% ethyl acetate) to produce the trans isomers, 34% yield. 1 H NMR (CDCl 3) d: 1, 2 (3 H, d), 1, 9 (3 H, s), 2.0 (1 H, m), 2.3 (1 H, m), 5.0 (1 H, m), 6.2 (1 H, m), 6.6-6.8 (4H, m), 7.1 (3H, m), 7.3 (4H, m), 7.6 ( 1 H, m). MS m / z: 403 (M + 1). General Procedure A Scheme 4 A-1 (±) -C / sN- [1- (furan-2-carbonyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide (A -1) To a solution of (±) -c / s- (2-methyl-1, 2,3,4-tetrahydro-quinoIin-4-yl) -phenyl-amine (430 mg, 1.83 mmol) in dichloromethane (18 ml) at room temperature was added diisopropylethylamine (318 μl, 1.83 mmol) followed by 2-furoyl chloride. It was left stirring at room temperature for 12 h. The mixture was poured into water and extracted with dichloromethane. The extracts were washed with 1 M NaOH (aq.) And brine, dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by chromatography on silica gel (80% hexanes / 20% ethyl acetate) to yield the amide (500 mg, 83%). To a solution of (±) -c / s-furan-2-yl- (2-methyl-4-phenylamino-3,4-dihydro-2H-quinolin-1-yl) -methanone (360 mg, 1 , 0 mmol) in methylene chloride (5 mL) was added diisopropylethylamine (1.9 mL, 10 mmol) followed by acetyl chloride (388 μL, 5 mmol). The mixture was stirred at room temperature overnight. The mixture was poured into water and extracted with dichloromethane. The extracts were washed with 1 M NaOH (aq.) And brine, dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by chromatography on silica gel (50% hexanes / 50% ethyl acetate) to yield the amide (230 mg, 57%). 1 H NMR (CDCl 3) d: 1, 12 (d, 3 H), 1, 25 (t, 1 H), 2.01 (s, 3 H), 2.32 (m, 1 H), 4.12 (sextuplet, 1H), 5.49 (sa, 1H), 6.22 (m, 2H), 6.84 (d, 1H), 7.10 (t, 1H), 7.28-7.31 (m, 4H) ), 7, 38 (m, 4H).
MS m / z: 375 (M + 1). (±) -C / s-2-methoxy-N- [1- (3-methoxy-benzoyl) -2-methyl-152,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide ( A-2) (±) -c / s-2-methoxy-N- [1- (3-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl was prepared ] -N-phenol-acetamide following general procedure A, substituting 2-furoyl chloride for 3-methoxybenzoyl chloride and acetyl chloride for methoxyacetyl chloride. 1 H NMR (CDCl 3) d: 1, 14 (d, 3 H), 1, 25 (t, 1 H), 2.33 (m, 1 H), 3.39 (s, 3 H), 3.60 (s, 3H), 3.85 (d, 1 H), 3.98 (d, 1 H), 4.79 (sextuplet, 1 H), 5.62 (sa, 1H), 6.53 (d, 1 H) ), 6.72 (s, 1 H), 6.81 (d, 1H), 6.92 (t, 1H), 7.08 (t, 1H), 7.16 (t, 1 H), 7 , 29 (m, 2H), 7, 35-7.42 (m, 3H). MS m / z: 445 (M + 1). (±) -C / s-4-chloro-N- [1- (3-methoxy-benzoyl) -2-metiM52 ^ 4-tetrahydro-quinolin-4-yl] -N-phenyl-benzamide (A-3) Prepared (±) -c / s-4-chloro-N- [1- (3-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N- phenyl-benzamide following general procedure A, substituting 2-furoyl chloride for 3-methoxybenzoyl chloride and acetyl chloride for 4-chlorobenzoyl chloride. 1 H NMR (CDCl 3) d: 1, 24 (d, 3 H), 1, 26 (m, 1 H), 2.29 (m, 1 H), 3.60 (s, 3 H), 4.84 (sextuplete , 1 H), 5.92 (sa, 1H), 6.58 (d, 1H), 6.78 (d, 2H), 6.82 (s, 1 H), 6.95 (t, 1 H), 7.08 (t, 2H), 7.16-7.25 (m, 7H), 7.34 (d, 2H), 7.53 (d, 1H). MS m / z: 511, 0 (M + 1). (±) -C / sN- [1- (3-Methoxy-benzoyl) -2-methyl-1,2,3J4-tetrahydro-quinolin-4-yl] -N-phenyl-isobutyramide (A-4) was prepared (±) -c / sN- [1- (3-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-isobutyramide following the general procedure A, substituting 2-furoyl chloride for 3-methoxybenzoyl chloride and acetyl chloride for isobutyryl chloride. 1 H NMR (CDCl 3) d: 1, 14 (d, 9 H), 1.23 (t, 1 H), 2.28 (m, 1 H), 2.65 (sextuplet, 1 H), 3.65 (s, 3H), 4.77 (sextuplet, 1H), 5.63 (s, 1H), 6.51 (d, 1H), 6.67 (d, 1H), 6.78 (d, 1 H), 6.86 (m, 2H), 7.01 (t, 1 H), 7.14 (t, 1 H), 7.24-7.37 (m, 6H). MS m / z: 443.0 (M + 1). (±) -C / sN- [2-Methyl-1 - (thiophene-2-carbonyl) -1, 253,4-tetrahydro-quinolin-4-yl] - N -phenyl-acetamide (A-5) Prepared (±) -c / sN- [2-methyl-1- (thiophene-2-carbonyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide following the general procedure A , substituting 2-furoyl chloride for 2-thiophenecarbonyl chloride. (±) -c / sN- [2-Methyl-1- (thiophene-2-carbonyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide chiral HPLC was separated using a chiral OD cel column and eluting with a 90% hexane isocratic system / 10% ethanol to give (2 4S) - and (2S, 4R) -N- [2-meti-1- (thiophene-2-carbonyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] - N- phenyl acetamide (A-11 and A-10, respectively). 1 H NMR (CDCl 3) d: 1, 15 (d, 3 H), 1, 25 (m, 1 H), 2.02 (s, 3 H), 2.31 (m, 1 H), 4.73 (sextuplet, 1 H), 5.53 (sa, 1H), 6.68 (dd, 1 H), 6.77 (t, 1 H), 6.88 (d, 1 H), 7.06 ( t, 1 H), 7.25-7.32 (m, 4H), 7.39 (m, 4H). MS m / z: 391, 0 (M + 1). (±) -C / sN- [1- (4-tert-butyl-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide (A- 6) Prepared (±) -c / sN- [1- (4-tert-butyl-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl- acetamide following general procedure A, substituting 2-furoyl chloride for 4-tert-butylbenzoyl chloride. Separated (+) - c / sN- [1- (4-tert-butyl-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide by Chiral HPLC using a chiral OD cel column and eluting with a 90% hexane isocratic system / 10% ethanol to give (2R, 4S) - and (2S, 4R) -c / sN- [1- (4-tert-butyl-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinoline- 4-l ] -N-phenol-acetamida (A-8 and A-9, respectively). 1 H NMR (CDCl 3) d: 1, 14 (d, 3 H), 1, 16 (m, 1 H), 1, 23 (s, 9 H), 2.04 (s, 3 H), 2.33 (m, 1 H), 4.78 (sextuple, 1 H), 5.62 (sa, 1 H), 6.53 (d, 1 H), 6.91 (t, 1 H), 7.15-7, 40 (m, 11 H). MS m / z: 441 (M + 1). (±) -C / sN- [1 - (4-Fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide (A-7) (±) -c / sN- [1- (4-Fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide was prepared following the procedure A, substituting 2-furoyl chloride for 4-fluorobenzoyl chloride. Separated (±) -c / sN- [1- (4-fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide by HPLC chiral using a chiral OD cel column and eluting with a 90% hexane isocratic system / 10% ethanol to give (2R, 4S) - and (2S, 4R) -c / sN- [1- (4-fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N phenyl acetamide (A-52 and A-44, respectively). 1 H NMR (CDCl 3) d: 1, 13 (d, 3 H), 1, 25 (m, 1 H), 2.03 (s, 3 H), 2.32 (m, 1 H), 4.78 (sextuplet, 1 H), 5.62 (sa, 1 H), 6.47 (d, 1 H), 6.83-6.95 (m, 3H), 7.16-7.40 (m, 9H).
MS m / z: 403 (M + 1). (±) -C / sN- [2-methyl-1- (5-methyl-thiophene-2-carbonyl) -1,2,3,4-tetrahydro-quinolin-4-irj-N-phenyl-acetamide (A -12) Prepared (±) -c / sN- [2-methyl-1- (5-methyl-thiophene-2-carbonyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] -N phenyl acetamide following general procedure A, substituting 2-furoyl chloride for 5-methyl-2-thiophenecarbonyl chloride. Separated (±) -c / sN- [2-methyl-1- (5-methyl-thiophene-2-carbonyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl- acetamide by chiral HPLC using a chiral OD cell column and eluting with a 90% hexane isocratic system / 10% ethanol to give (2R, 4S) - and (2S, 4R) -c / sN- [2-methyl-1- (5-methyl-thiophene-2-carbonyl) -1, 2,3,4-tetrahydro-quinolin-4- il] -N-phenyl-acetamide (A-59 and A-60, respectively). 1 H NMR (CDCl 3) d: 1, 07 (m, 1 H), 1, 12 (d, 3 H), 2.01 (s, 3 H), 2.31 (m, 1 H), 2.39 (s) , 3H), 4.69 (sextuplet, 1 H), 5.50 (sa, 1 H), 6.44 (s, 1 H), 6.51 (d, 1 H), 6.94 (d, 1 H), 7.09 (t, 1 H), 7.21-7.30 (m, 3H), 7.39-7.41 (m, 4H).
MS m / z: 405 (M + 1) (± JC / sNp-methyl-l ^ -methyl ^ -pyrazin ^ -yl-thiazole-S-carbonyl) -! ^^^ - tetrahydro-quinolin-4-yl] -N-phenyl-acetamide (A-13) was prepared (±) -c / sN- [2-ethyl-1- (4-methyI-2-pyrazin-2-yl-thiazole-5-carbonyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide following general procedure A, substituting 2-furoyl chloride for 4-methyl-2- (2-pyrazinyl) -1-chloride, 3-thiazole-5-carbonyl. 1 H NMR (CDCl 3) d: 1, 18 (d, 3 H), 1.77 (sa, 1 H), 2.03 (s, 3 H), 2.10 (s, 3 H), 2.32 (m, 1 H), 4.79 (sextuplet, 1 H), 5.50 (sa, 1 H), 6.74 (d, 1 H), 7.03 (t, 1 H), 7.26-7, 41 (m, 7H), 8.55 (d, 1 H), 9.32 (s, 1 H). MS m / z: 484 (M + 1). (± JC / sNp-methyl-l-IS-methyl-thiophene ^ -carboni-l ^^^ - tetrahydro-quinolin-4-yl] -N-phenyl-acetamide (A-14) Prepared (±) -c / sN- [2-methyl-1- (3-methyl-thiophene-2-carbonyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide following the general procedure A, substituting 2-furoyl chloride for 3-methyl-2-thiophenecarbonyl chloride. 1 H NMR (CDCl 3) d: 1, 13 (d, 3 H), 1, 16 (m, 1 H), 1.80 (s, 3 H), 2.00 (s, 3H), 2.29 (m, 1H), 4.73 (sextuplet, 1H), 5.49 (sa, 1H), 6.56 (d, 1H), 6.66 (d) , 1H), 6.97 (t, 1H), 7.16 (d, 2H), 7.25 (d, 2H), 7.32 (d, 1 H), 7.38 (sa, 3H). MS m / z: 405 (M + 1). (±) -C / sN- [2-methyl-1- (5-phenyl-thiophene-2-carbonyl) -1,2,3,4-tetrahydro-quinoline -4-yl] -N-phenyl-acetamide (A-15) was prepared (+) - c / sN- [2-methyl-1- (5-phenyl-thiophene-2-carbonyl) -1, 2,3 , 4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide following general procedure A, substituting 2-furoyl chloride for 5-phenyl-2-thiophenecarbonyl chloride: 1 H NMR (CDCl 3) d: 1, 15 (d, 3H), 1, 17 (m, 1 H), 2.03 (s, 3H), 2.3 1 (m, 1H), 4.73 (sextuplet, 1H), 5.55 (sa, 1H), 6.59 (s, 1H), 6.95 (d, 2H), 6.99 (s, 1 H), 7.10 (t, 1 H), 7.26-7.44 (m, 9H), 7.53 (d, 2H). MS m / z: 467 (M + 1).
(± J-Cis-Np-methyl-l ^ -methyl ^ -phenyl-thiazole-S-carboni-l ^^^ - tetrahydro-quinolin-4-yl] -N-phenyl-acetamide (A-16) was prepared (±) -c / sN- [2-methyl-1- (4-methyl-2-phenyl-thiazole-5-carbonyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] - N-phenyl acetamide following general procedure A, substituting 2-furoyl chloride for 4-methyl-2-phenyl-1,3-thiazole-5-carbonyl chloride H NMR (CDCl 3) d: 1, 16 (d , 3H), 1, 18 (m, 1H), 2.03 (s, 3H), 2.14 (s, 3H), 2.32 (m, 1 H), 4.74 (sextuplet, 1 H) , 5.53 (sa, 1H), 6.77 (d, 2H), 7.04 (t, 1H), 7.24-7.28 (m, 3H), 7.38-7.40 (m , 7H), 7.83 (d, 2H) MS m / z: 482 (M + 1). (±) -C / sN- [2-methyl-1 - (4-methyl- [1, 2, 3] thiadiazole-5-carbonyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide (A-17) was prepared (±) -c / sN- [2-methyl] -1- (4-methyl- [1, 2,3] thiadiazole-5-carbonyl) -1, 2,3,4-tetrahydro-quinoxy-4-yl] -N-phenyl-acetamide following the procedure General A, substituting 2-furoyl chloride for 4-methyl- [1, 2,3] thiadiazole-5-carbonyl chloride. 1 H NMR (CDCl 3) d: 1.17 (d, 3H), 1, 21 (m, 1H), 2.01 (s, 3H), 2.36 (s, 3H), 2.24 (m, 1 H), 4.81 (sextuplet, 1 H), 5.48 (br s, 1H), 6.52 (d, 1 H), 6.98 (t, 1 H), 7.22-7.26 (m, 3H), 7.37-7.42 ( m, 4H). MS m / z: 407 (M + 1). (±) -C / sN- [1 - (5-isopropyl-thiophene-2-carbonyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide ( A-19) Prepared (±) -c / sN- [1- (5-isopropyl-thiophene-2-carbonyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] - N-phenyl-acetamide following general procedure A, substituting 2-furoyl chloride for 5-isopropylthiophene carbonyl chloride. 1 H NMR (CDCl 3) d: 1, 11 (d, 3 H), 1, 15 (m, 1 H), 1, 19-1, 25 (m, 6 H), 2.01 (s, 3 H), 2, 30 (m, 1 H), 2.70 (m, 1 H), 4.69 (sextuplet, 1 H), 5.51 (sa, 1 H), 6.45 (s, 1 H), 6, 55 (s, 1 H), 6.87-6.95 (m, 1 H), 7.04-7.08 (m, 1 H), 7.27 (s, 3H), 7.38 (s) , 4H). MS m / z: 433 (M + 1). (±) -C / sN- [2-methyl-1- (3,4,5-trifluoro-benzoyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide ( A-20) Prepared (±) -c / sN- [2-methy1- (3,4,5-trifluoro-benzoyl) -1, 2,3,4-tetrahydro-quinolin-4-yl ] -N-phenyl-acetamide following general procedure A, substituting 2-furoyl chloride for 3,4,5-trifluorobenzoyl chloride. 1 H NMR (CDCl 3) d: 1, 12 (d, 3 H), 1, 21 (m, 1 H), 2.03 (s, 3 H), 2.31 (m, 1 H), 4.71 (sextuplet, 1 H), 5.55 (sa, 1 H), 6.50 (d, 1 H), 6.82 (t, 1 H), 6.99 (t, 1 H), 7.06 (t, 1 HOUR), 7.24-7.27 (m, 3H), 7.39 (m, 3H), 7.46 (d, 1 H). MS m / z: 439 (M + 1). (±) -C / sN- [1- (4-fluoro-3-methyl-bTzozoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl- acetamide (A-21) was prepared (±) -c / sN- [1- (4-fluoro-3-methyl-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinoIin-4-yl ] -N-phenol-acetamide following general procedure A, substituting 2-furoyl chloride for 4-fluoro-3-methylbenzoyl chloride. 1 H NMR (CDCl 3) d: 1, 12 (d, 3 H), 1, 22 (m, 1 H), 2.04 (s, 3 H), 2.15 (s, 3 H), 2.29 (m, 1H), 4.75 (sextuplet, 1 H), 5.60 (sa, 1 H), 6.50 (d, 1 H), 6.73 (t, 1 H), 6.86 (s, 1 H), 6.93 (t, 1 H), 7.15-7.39 (m, 8H). MS m / z: 417 (M + 1). (+) - C / sN- [1- (4-Fluoro-3-trifluoromethyl-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide ( A-22) (±) -c / sN- [1- (4-fluoro-3-trifluoromethyl-benzoyl) -2-methyI-1, 2,3,4-tetrahydroquinoline-4-yl was prepared ] -N-phenyl-acetamide following general procedure A, substituting 2-furoyl chloride for 4-fluoro-3- (trifluoromethyl) -benzoyl chloride. 1 H NMR (CDCl 3) d: 1, 15 (d, 3 H), 1, 24 (m, 1 H), 2.04 (s, 3 H), 2.33 (m, 1 H), 4.75 (sextuplet, 1 H), 5.58 (sa, 1H), 6.46 (d, 1 H), 6.87-6.96 (m, 3H), 7.10-7.41 (m, 6H) ), 7.49 (d, 1H), 7.74 (d, 1H). MS m / z: 471 (M + 1). (± JC / sN-fl-ÍS-chloro ^ -fluoro-benzoylJ ^ -methyl-I ^. S ^ -tetrahydro-quinolin-4-yl] -N-phenyl-acetamide (A-23) Prepared (±) -c / sN- [1- (3-chloro-4-fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-ylj-N-phenyl-acetamide following the general procedure A , substituting 2-furoyl chloride for 3-chloro-4-fluorobenzoyl chloride. 1 H NMR (CDCl 3) d: 1, 13 (d, 3 H), 1.24 (m, 1 H), 2.04 (s, 3 H), 2.31 (m, 1 H), 4.76 (sextuplet, 1 H) ), 5.59 (sa, 1H), 6.50 (d, 1H), 6, 85 (d, 2H), 6.96 (t, 1H), 7.21 (t, 1H), 7.27 (m, 2H), 7.39 (m, 4H), 7.50 (d, 1 HOUR). MS m / z: 437 (M + 1). (±) -C / sN- [2-methyl-1 - (2,4,6-trifluoro-benzoyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide ( A-24) Prepared (±) -c / sN- [2-methyl-1- (2,4,6-trifluoro-benzoyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] - N-phenyl acetamide following general procedure A, substituting 2-furoyl chloride for 2,4,6-trifluorobenzoyl chloride. 1 H NMR (CDCl 3) d: 1, 13 (d, 3 H), 1, 21 (m, 1 H), 2.05 (s, 3 H), 2.29 (m, 1 H), 4.86 (sextuplet, 1 H), 5.45 (sa, 1 H), 6.35 (t, 1 H), 6.70 (d, 2 H), 6.95 (t, 1 H), 7.2 -7.5 (m, 7H). MS m / z: 439 (M + 1). (±) -C / sN- [1- (4-chloro-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide (A-25) (±) -c / sN- [1- (4-Chloro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide was prepared following the procedure A, substituting 2-furoyl chloride for 4-chlorobenzoyl chloride and acetyl chloride for propionyl chloride. 1 H NMR (CDCl 3) d: 1, 09 (t, 3 H), 1.12 (d, 3 H), 1, 22 (m, 1 H), 2.23 (m, 3 H), 4.73 (sextuplet, 1 H), 5.58 (sa, 1H), 6.46 (d, 1 H), 6.78 (d, 1H), 6.88 (t, 1H), 6.98 (t, 1 H) , 7.15 (t, 1 H), 7.18-7.44 (m, 8H). MS m / z: 433 (M + 1). (±) -C / sN- [2-methyl-1- (4-trifluoromethoxy-benzoyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide (A-26) (±) -c / sN- [2-methyl-1- (4-trifluoromethoxy-benzoyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide was prepared following the procedure General A, substituting 2-furoyl chloride for 4- (trifluoromethoxy) benzoyl chloride. 1 H NMR (CDCl 3) d: 1, 16 (d, 3 H), 1, 24 (m, 1 H), 2.28 (m, 3 H), 4.78 (sextuplet, 1 H), 5.61 (sa, 1H), 6.46 (d, 1 H), 6.91 (t, 1H), 6.92 (t, 1 H), 7.02 (d, 2H), 7.18 (t, 1 H) , 7.23-7.27 (m, 4H), 7.33 (d, 1 H), 7.39 (s, 3H). MS m / z: 469 (M + 1). (±) -C / sN- [2-methyl-1- (3-trifluoromethoxy-benzoyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide (A-27) (±) -c / sN- [2-Methyl-1- (3-trifluoromethoxy-benzoyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide was prepared following the procedure A, substituting 2-furoyl chloride for 3- (trifluoromethoxy) benzoyl chloride. 1 H NMR (CDCl 3) d: 1, 14 (t, 3 H), 1, 15 (d, 3 H), 1, 25 (m, 1 H), 2.25 (m, 3 H), 4.78 (sextuplet, 1 H), 5.59 (sa, 1 H), 6.46 (d, 1H), 6.91 (t, 1H), 6.95 (d, 1H), 7.12 -7.27 (m , 6H), 7.34 (d, 1 H), 7.39 (s, 3H). MS m / z: 469 (M + 1). (±) -C / sN- [2-methyl-1- (3-phenyl-isoxazole-5-carbonyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide ( A-28) It < prepared (±) -c / sN- [2-methyl-1- (3-phenyl-isoxazole-5-carbonyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide following general procedure A, substituting 2-furoyl chloride for 3-phenyl-5-isoxazole carbonyl chloride and acetyl chloride for propionyl chloride. 1 H NMR (CDCl 3) d: 1, 14 (t, 3 H), 1, 19 (d, 3 H), 1, 61 (m, 1 H), 2.24 (m, 3 H), 4.78 (sextuplet, 1 H), 5.49 (sa, 1 H), 6.34 (sa, 1 H), 6.85 (d, 1H), 7.10 (t, 1H), 7.26 (s, 3H), 7.32 (t, 1 H), 7.40 (m, 6H), 7.67 (s, 2H). MS m / z: 466 (M + 1). (±) -C / s-N-. { 2-methyl-1 - [4- (5-methyl-tetrazol-1-yl) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -N-phenyl-propionamide (A-29) was prepared (±) -c / s-N-. { 2-methyl-1- [4- (5-methyl-tetrazol-1-yl) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -N-phenyl-propionamide following general procedure A, substituting 2-furoyl chloride for 4- (5-methyl-1 H-tetrazol-1-yl) -benzoyl chloride and acetyl chloride for propionyl chloride. 1 H NMR (CDCl 3) d: 1, 16 (t, 3 H), 1, 17 (d, 3 H), 1, 24 (m, 1 H), 2.26 (m, 3 H), 2.55 (s, 3H), 4.82 (sextuplet, 1 H), 5.64 (sa, 1 H), 6.50 (d, 1H), 6.94 (t, 1 H), 7.21-7.41 ( m, 11H). MS m / z: 481 (M + 1). (±) -C / s-N-. { 1 - [3- (4-Chloro-phenyl) -isoxazole-5-carbonyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -N-phenyl-propionamide (A-30) was prepared (±) -c / s-N-. { 1- [3- (4-Chloro-phenyl) -isoxazole-5-carbonyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -N-phenol-propionamide following general procedure A substituting 2-furoyl chloride for 3- (4-chlorophenyl) -5-isoxazole-carbonyl chloride and acetyl chloride for propionyl chloride. 1 H NMR (CDCl 3) d: 1, 21 (m, 6 H), 1, 24 (m, 1 H), 2.23 (m, 3 H), 4.76 (sextuplet, 1 H), 5.48 (br s, 1H), 6.28 (s, 1H), 6.84 (d, 1 H), 7.07 (m, 2H), 7.26-7.67 (m, 7H), 7.78 (d, 1 H), 8.03 (t, 2H). MS m / z: 500 (M + 1). (±) -C / sN- [1 - (4-Fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -2-hydroxy-N-phenyl-acetamide ( A-31) (±) - N - [1- (4-fluoro-benzoyl) -2-methylene-1, 2,3,4-tetrahydro-quinolin-4-yl] -2-hydroxy- N-phenyl acetamide following general procedure A substituting 2-furoyl chloride for 4-fluorobenzoyl chloride and acetyl chloride for acetoxyacetyl chloride. 1 H NMR (CDCl 3) d: 1, 13 (d, 3 H), 1, 22 (m, 1 H), 2.39 (m, 1 H), 3.42 (s, 1 H), 3.85 (d, 1H), 4.04 (d, 1H), 4.77 (sextuplet, 1H), 5.54 (s a, 1H), 6.49 (d, 1H), 6.85 (t, 2H), 6.94 (t, 1 H), 7.18-7.27 (m, 5H), 7.33 (d, 1H), 7.43 (s, 3H). MS m / z: 419 (M + 1). (±) -C / sN- [1 - (1 H -indole-2-carbonyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide (A -32) Prepared (±) -c / sN- [1- (1 H -indole-2-carbonyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N- phenyl-propionamide following general procedure A substituting 2-furoyl chloride for indole-2-carbonyl chloride and acetyl chloride for propionyl chloride. 1 H NMR (CDCl 3) d: 1.25 (t, 3 H), 1.26 (d, 3 H), 1.27 (m, 1 H), 2.36 (m, 3 H), 4.86 (sextuplet, 1 H), 5.62 (sa, 1 H), 5.95 (s, 1 H), 7.11 (t, 1 H), 7.18 (t, 2H), 7.29 ( t, 1H), 7.37 (m, 4H), 7.44-7.55 (m, 5H). MS m / z: 438 (M + 1). (±) -C / sN- [2-methyl-1- (4-pyrazol-1-yl-benzoyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide ( A-33) Prepared (±) -c / sN- [2-methyl-1- (4-pyrazol-1-yl-benzoyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] - N-phenyl-propionamide following general procedure A substituting 2-furoyl chloride for 4- (1 H-pyrazol-1-yl) -benzoyl chloride and acetyl chloride for propionyl chloride. 1 H NMR (CDCl 3) d: 1, 03 (t, 3 H), 1, 11 (d, 3 H), 1, 20 (m, 1 H), 2.19 (m, 3 H), 4.73(sextuplet, 1H), 5.62 (s a, 1H), 6.39 (s, 1H), 6.48 (d, 1H), 6.86 (t, 1H), 7.10-7.34 (m, 9H), 7.48 (d, 2H), 7.65 (s, 1 H), 7.81 (s, 1 H). MS m / z: 465 (M + 1). (±) -C / sN- [1 - (benzofuran-2-carbonyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide (A-34) (±) -c / sN- [1- (benzofuran-2-carbonyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-ylj-N-phenyl-propionamide was prepared following the general procedure A by substituting 2-furoyl chloride for 2-benzofuranecarbonyl chloride and acetyl chloride for propionyl chloride. 1 H NMR (CDCl 3) d: 1, 04 (t, 3 H), 1.07 (d, 3 H), 1, 18 (m, 1 H), 2.19 (m, 3 H), 4.69 (sextuplet, 1 H), 5.54 (s a, 1 H), 6.41 (d, 1 H), 6.70-7.39 (m, 12H), 7.43 (d, 1 H).
MS m / z: 439 (M + 1). (± JC / sN-ll-ÍS-chloro-benzoyl ^ -methyl-I ^ ^ tetrahydro-quinolin ^ -ilJ-N-phenyl-propionamide (A-35) Prepared (±) -c / sN- [1- (3-chloro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide following the general procedure A substituting 2-furoyl chloride for 3-chloride chlorobenzoyl and acetyl chloride for propionyl chloride. 1 H NMR (CDCl 3) d: 1, 09 (t, 3 H), 1.12 (d, 3 H), 1, 22 (m, 1 H), 2.23 (m, 3 H), 4.73 (sextuplet, 1 H), 5.58 (sa, 1H), 6.46 (d, 1 H), 6.78 (d, 1 H), 6.88 (t, 1 H), 6.98 (t, 1H) ), 7.15 (t, 1H), 7.18-7.44 (m, 8H). MS m / z: 433 (M + 1). Ethyl ester of the acid (±) -c / s-. { 4- [2-methyl-4- (phenyl-propionyl-amino) -3,4-dihydro-2H-quinoline-1 -carbonyl] -phenoxy} -acetic (A-36) Ethyl ester of (±) -c / s- was prepared. { 4- [2-methyl-4- (phenyl-proponyl-amino) -3,4-dihydro-2H-quinoline-1-carbonyl] -phenoxy} -acetic from (±) -N- [1- (4-hydroxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide. (±) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyI-propionamide (0.147 g) was dissolved in DMF (5 ml) at room temperature. Sodium hydride (60% in oil, 0.021 g) was added and the mixture was allowed to stir for 30 min. Ethyl 4-bromoacetate (0.065 g) was added and the reaction was allowed to stir overnight. Ethanol was added and the reaction was concentrated in vacuo. The crude residue was purified by chromatography on silica gel (gradient of 80/20 hexanes / ethyl acetate - 50/50 hexanes ethyl acetate) to yield the product (130 mg, 73%). 1 H NMR (CDCl 3) d: 1, 08-1, 16 (m, 9H), 1, 21 (t, 1 H), 2.24 (m, 3H), 4.09 (c, 2H), 4, 53 (s, 2H), 4.74 (sextuplet, 1 H), 5.59 (sa, 1 H), 6.48 (d, 1 H), 6.67 (d, 2H), 6.89 ( t, 1 H), 7.11-7.37 (m, 9H). MS m / z: 500 (M + 1). (+) - C / sN- [1- (4-hydroxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide (A-37) (±) -c / sN- [1- (4-hydroxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-ylj-N-phenyl-propionamide was prepared from ( ±) -c / sN- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide substituting 3-chlorobenzoyl chloride . It was dissolved (±) -c / sN- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide (0.548 g , 0.001 mol) in dichloromethane and a solution of BBr3 (1.0 M in dichloromethane, 10 ml) was added; the reaction was allowed to stir at room temperature for 4 h or until no starting material remained. The reaction was carefully washed with sat. NaHCO3. and brine. The organic extracts were dried over MgSO 4, filtered and concentrated under reduced pressure. The phenol was concentrated and the residue was purified by flash chromatography Biotage using 100% EtOAc to give a white solid, 68% yield. 1 H NMR (CDCl 3) d: 1, 09 (d, 3 H), 1, 11 (t, 3 H), 1, 19 (m, 1 H), 2.26 (m, 3 H), 4.74 (sextuplet, 1 H), 5.54 (sa, 1 H), 6.46 (d, 1 H), 6.53 (d, 1H), 6.96 (t, 1H), 7.14-7.40 (m) , 9H). MS m / z: 415 (M + 1) (±) - C / sN- [1 - (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] - N-Phenyl-propionamide (A-38) (±) -c / sN- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4- was prepared il] -N-phenyl-propionamide following general procedure A substituting 2-furoyl chloride for 4-methoxybenzoyl chloride and acetyl chloride for propionyl chloride. 1 H NMR (CDCl 3) d: 1, 12 (d, 3H), 1, 15 (t, 3H), 1, 17 (m, 1H), 2.23 (m, 3H), 3.74 (s, 3H), 4.74 (sextuplete, 1 H), 5.61 (sa, 1 H), 6.52 (d, 1 H), 6.67 (d, 2H), 6.92 (d, 1H), 7.17 (d, 2H) , 7.25-7.34 (m, 4H), 7.39 (sa, 3H). MS m / z: 429 (M + 1). Acid (±) -c / s-. { 4- [2-methyl-4- (phenyl-propionyl-amino) -3,4-dihydro-2H-quinoline-1 -carbonyl] -phenoxy} -acétíco (A-39) r Acid (±) -c / s- was prepared. { 4- [2-methyl-4- (phenyl-propionyl-amino) -3,4-dihydro-2H-quinoline-1-carbonyl-phenoxy} -acetic from ethyl ester of acid (±) -c / s-. { 4- [2-methyl-4- (phenyl-propionyl-amino) -3,4-dihydro-2H-quinoline-1-carbonyl] -phenoxy} -acetic. Ethyl ester of (±) -c / s- acid was dissolved. { 4- [2-methyl-4- (phenyl-propionyl-arnino) -3,4-dihydro-2H-quinoline-1-carbonyl] -phenoxy} -acetic in ethanol (5 ml) and 0.5 ml of 1 N NaOH was added at room temperature. The reaction was allowed to stir for 4 h. The ethanol was removed in vacuo and the aqueous solution was acidified with 1 N HCl to give a white precipitate which was filtered to give the desired product in 88% yield. 1 H NMR (CDCl 3) d: 1, 12 (d, 3 H), 1, 16 (t, 3 H), 1, 15 (m, 1 H), 2.28 (m, 3 H), 4.52 (s, 2H), 4.74 (sextuplet, 1 H), 5.63 (sa, 1 H), 6.50 (d, 1H), 6.68 (d, 2H), 6.91 (t, 1 H) , 7.16 (t, 1 H), 7.18 (d, 2H), 7.26-7.32 (m, 4H), 7.40 (br s, 2H). MS m / z: 473.0 (M + 1). (±) -C / s-N-. { 2-methyl-1 - [4- (2-morpholin-4-yl-ethoxy) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -N-phenyl-propionamide (A-40) was prepared (±) -c / s-N-. { 2-methyl-1- [4- (2-morpholin-4-yl-ethoxy) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -N-phenyl-propionamide from (±) -c / sN- [1- (4-hydroxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N -phenyl-propionamide. (±) -c / sN- [1- (4-methoxy-benzoyl) -2-methi-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide was dissolved in DMF (5 ml) at room temperature. Sodium hydride (60% in oil, 0.061 g) was added and the mixture was allowed to stir for 30 min. 4- (2-Chloroethyl) morpholine hydrochloride (0.143 g) was added and the reaction was allowed to stir overnight. Ethanol was added and the reaction was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted 3 times with ethyl acetate, dried over MgSO 4, filtered and concentrated. The crude residue was purified by chromatography on silica gel (gradient 2/98 methanol / dichloromethane-5/95 methanol / dichloromethane) to yield the product (200 mg). 1 H NMR (CDCl 3) d: 1, 09 (d, 3 H), 1, 12 (m, 4 H), 1, 22 (s, 4 H), 2.23 (m, 3 H), 2.50 (s, 4 H) ), 2.70 (m, 2H), 4.01 (t, 2H), 4.70 (sextuplet, 1 H), 5.59 (sa, 1 H), 6.49 (d, 1H), 6 , 64 (d, 2H), 6.89 (t, 1H), 7.13 (d, 2H), 7.23-7.36 (m, 7H). MS m / z: 528.1 (M + 1). (±) -C / sN- [1- (4-carbamoylmethoxy-benzoyl) -2-methyl-1,2J3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide (A-41) was prepared (±) -c / sN- [1- (4-carbamoylmethoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinoxy-4-yl] -N-phenyl-propionamide from (±) -c / sN- [1- (4-hydroxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide. (±) -c / sN- [1- (4-hydroxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide was dissolved ( 0.120 g) in DMF (5 ml) at room temperature. Sodium hydride (60% in oil, 0.70 g) was added and the mixture was allowed to stir for 30 min. 2-Bromoacetamide (0.320 g) was added and the reaction was allowed to stir overnight. Ethanol was added and the reaction was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted 3 times with ethyl acetate, dried over MgSO 4, filtered and concentrated. The crude residue was purified by chromatography on silica gel (gradient 2/98 methanol / dichloromethane-10/90 methanol / dichloromethane) to produce the product (20 mg, 15%). 1 H NMR (CDCl 3) d: 1, 12 (d, 3 H), 1, 14 (t, 3 H), 1, 24 (t, 1 H), 2.25 (m, 3 H), 4.42 (s, 2 H) ), 4.73 (sextuplet, 1H), 5.61 (sa, 1 H), 5.79 (s, 1H), 6.49 (d, 2H), 6.70 (d, 2H), 6, 92 (t, 1 H), 7.14-7.39 (m, 8H). MS m / z: 472.0 (M + 1). (±) -C / s-N-. { 1- [4- (2-hydroxy-2-methyl-propoxy) -benzoyl] -2-methyl-152,3,4-tetrahydro-quinolin-4-yl} -N-phenyl-propionamide (A-42) (±) -c / s-N- was prepared. { 1 - [4- (2-Hydroxy-2-methyl-propoxy) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -N-phenyl-propionamide from ethyl ester of c / s- acid. { 4- [2-methyl-4- (phenyl-propionyl-amino) -3,4-dihydro-2H-quinol-1-carbonyl] -phenoxy} -acetic. Ethyl ester of (+) - c / s- acid was dissolved. { 4- [2-methyl-4- (phenyl-propionyl-amino) -3,4-dihydro-2H-quinoline-1-carbonyl] -phenoxy} -acetic (0.170 g) in THF and cooled to 0 ° C. Methylmagnesium bromide (sol, 3.0 M in diethyl ether, 0.5 ml) was added and the reaction was allowed to stir at 0 ° C for 30 min. The reaction was quenched with a saturated solution of ammonium chloride and diluted with ethyl acetate. The organic extracts were separated and washed with brine, dried over MgSO, filtered and concentrated. The crude residue was purified by chromatography on silica gel (gradient 50/50 hexanes / ethyl acetate - 75/25 hexanes / ethyl acetate) to yield the product (132 mg, 80%). 1 H NMR (CDCl 3) d: 1, 10 (d, 3 H), 1, 14 (t, 3 H), 1, 23 (t, 1 H), 1.29 (s, 6 H), 2.24 (m, 3H), 3.70 (s, 2H), 4.74 (sextuplet, 1H), 5.61 (sa, 1H), 6.50 (d, 1H), 6.66 (d, 2H), 6 , 91 (t, 1 H), 7.13 (t, 1 H), 7.14 (d, 2H), 7.25 (d, 1 H), 7.32 (d, 1H), 7.37 (sa, 4H). MS m / z: 487.1 (M + 1).
(±) -C / sN- [1- (4-dimethylcarbamoylmethoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide (A-43) (±) -c / sN- [1- (4-dimethylcarbamoylmethoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propyl was prepared onamide from acid (±) -c / s-. { 4- [2-methyl-4- (phenyl-propionyl-amino) -3,4-dihydro-2H-quinoline-1 -carbonyl-phenoxy-acetic acid. Acid (±) -c / s- was dissolved. { -4- [2-methyl-4- (phenyl-propionyl-amino) -3,4-dihydro-2H-quinoline-1-carbonyl] -phenoxy} -acetic (0.146 g) in THF (2 ml) at room temperature. HOBt (0.063 g), EDCI (0.071 g), and dimethylamine (2.0 M solution in THF, 0.162 ml) were added together with 2 drops of DMF and stirred at room temperature for 11 h. The reaction was diluted with ethyl acetate and washed with 1 N NaOH, 1 N HCl and brine. The organic extracts were dried over MgSO 4, filtered and concentrated. The crude residue was purified by chromatography on silica gel (100% ethyl acetate) to yield the product (84 mg, 54%). 1 H NMR (CDCl 3) d: 1, 10 (d, 3 H), 1, 13 (t, 3 H), 1, 22 (t, 1 H), 2.23 (m, 3 H), 2.94 (s, 3 H), 3.00 (s, 3 H), 4.60 (s, 2 H), 4.71 (sextuplete, 1 H), 5.58 (sa, 1 H), 6.49 (d, 1 H), 6.70 (d, 2 H), 6.89 (t, 1 H), 7.13 (d, 1 H), 7.24 (d, 2 H), 7.30 (d, 1 H), 7.37 (sa, 7 H). MS m / z: 500.1 (M + 1). (±) -C / sN- [1- (3-dimethylamino-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide (A-45) (±) -c / sN- [1- (3-dimethylamino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide was prepared following the procedure A, substituting 2-furoyl chloride for 3-dimethylaminobenzoyl chloride and acetyl chloride for propionyl chloride. 1 H NMR (300 MHz, CDCl 3) d: 1, 11-1, 24 (m, 7 H), 2.12-2.40 (m, 3 H), 2.83 (s, 6 H), 4, 80 (ddd, 1 H), 5.59 (sa, 1 H), 6.49 (d, 1 H), 6.55 - 6.69 (m, 3 H), 6.92 (dd, 1 H) ), 7.00 (ddd, 1 H), 7.15 (ddd, 1 H), 7.23-7.34 (m, 3 H), 7.35-7.44 (m, 3 H). MS m / z: 442 (M + 1). (±) -C / sN- [1- (4-dimethylamino-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide (A-46) (±) -c / sN- [1- (4-dimethylamino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide was prepared following the procedure General A substituting 2-furoyl chloride for 4-dimethylaminobenzoyl chloride and acetyl chloride for propionyl chloride. 1 H NMR (300 MHz, CDCl 3) d: 1, 09-1, 28 (m, 7 H), 2.12-2.39 (m, 3 H), 2.93 (s, 6 H), 4.73 (ddd, 1 H), 5.61 (sa, 1 H), 6.47 (d, 2 H), 6.62 (d, 1 H), 6.96 (dd, 1 H), 7.12 - 7.20 (m, 3 H), 7.26-7.36 (m, 3 H), 7.38-7.46 (m, 3 H). MS m / z: 442 (M + 1). (iJ-C / sNP-methyl-l-Ípyridine-S-carbonyl J-l ^ jS ^ -tetrahydro-quinolin ^ -yl] -N-phenyl-propionamide (A-47) Prepared (±) -c / s- [2-ethyl-1- (pyridine-3-carbonyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide following the general procedure A substituting 2-chloride furoyl chloride by 3-pyridinyl chloride and acetyl chloride by propionyl chloride. 1 H NMR (300 MHz, CDCl 3) d: 1, 08-1, 32 (m, 7 H), 2.16-2.44 (m, 3 H), 4.84 (ddd, 1 H), 5, 62 (sa, 1 H), 6.53 (d, 1 H), 6.97 (dd, 1 H), 7.11 (dd, 1 H), 7.20-7.51 (m, 8H), 8.55 (dd, 1 H), 8.68 (s a, 1 H). MS m / z: 400 (M + 1). (±) -C / sN- [1- (4-Fluoro-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -4-methoxy-N-phenyl-butyramide ( A-48) Prepared (±) -c / sN- [1- (4-fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -4- methoxy-N-phenyl-butyramide following general procedure A substituting 2-furoyl chloride for 4-fluorobenzoyl chloride and acetyl chloride for 4-methoxy-butyryl chloride. 1 H NMR (300 MHz, CDCl 3) d: 1, 08-1, 20 (m, 4 H), 1.86-2.02 (m, 2 H), 2.21-2.41 (m, 3 H) ), 3.26 (m, 3 H), 3.28 - 3.44 (m, 2 H), 4.76 (ddd, 1 H), 5.64 (sa, 1 H), 6.43 (d, 1 H), 6.83-6.96 (m, 3 H), 7.17-7.34 (m, 5 H), 7.36-7.51 (m, 4 H) ). MS m / z: 461 (M + 1). (±) -C / s-2- (acetyl-methyl-amino) -N- [1- (4-fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl ] -N-phenyl-acetamide (A-49) (±) -c / s-2- (acetyl-methyl-amino) -N- [1- (4-fluoro-benzoyl) -2-methyl- 1 was prepared , 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide following general procedure A substituting 2-furoyl chloride for 4-fluorobenzoyl chloride and acetyl chloride for (acetyl-methyl) chloride. amino) -acetyl. 1 H NMR (300 MHz, CDCl 3) d: 1, 10-1, 18 (m, 4 H), 2.13 (s, 3 H), 2.27-2.43 (m, 1 H), 3.14 (m, 3 H), 3.77 (d, 1 H), 4.03 (d, 1 H), 4.76 (ddd, 1 H), 5.55 (sa, 1 H), 6.45 (d, 1 H), 6.81-6.95 (m, 3 H), 7.15-7.26 (m, 3 H), 7.31-7.49 (m, 5 H), 7 , 54 (d, 1 H). MS m / z = 474 (M + 1). [1 - (3-Methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -phenylamide of (±) -c / s-cyclohexanecarboxylic acid (A-54) prepared [1- (3-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -phenylamide of (±) -c / s-cyclohexanecarboxylic acid following the general procedure A substituting 2-furoyl chloride for 3-methoxybenzoyl chloride and acetyl chloride for cyclohexane carbonyl chloride. 1 H NMR (CDCl 3) d: 0.8 (8 H, m), 1, 5-1, 8 (5 H, m), 2.0-2.4 (3 H, m), 3.7 (3 H, d), 4.8 (1 H, m), 5.6 (1 H, d), 6.2-6.6 (2 H, m), 6.6-7.5 (11 H, m). MS m / z: 483 (M + 1). [1- (3-Methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -phenyl-amide acid (±) -c / s- / soxazole-5- carboxyl (A-55) [1- (3-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -phenyl-amide of (±) -c acid was prepared / s- / soxazole-5-carboxylic following the general procedure A substituting 2-furoyl chloride for 3-methoxybenzoyl chloride and acetyl chloride for isoxazole-5-carbonyl chloride. 1 H NMR (CDCl 3) d: 1, 2 (3 H, d), 1, 2 (1 H, m), 2.4 (1 H,), 3.6 (3 H, s), 4.9 ( 1 H, m), 5.8 (1 H, m), 6.4 (1 H, d), 6.7-7.7 (12 H, m), 8.2 (1 H, s), 8.4 (1 H , m). MS m / z: 468 (M + 1). (±) -C / sN- [1- (furan-3-carbonyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide (A-56) (±) -c / sN- [1- (furan-3-carbonyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide was prepared following the procedure General A substituting 2-furoyl chloride for 3-furoyl chloride. 1 H NMR (CDCl 3) d: 1.1 (3 H, d), 1.2 (1 H, m), 2.0 (3 H, s), 2.2 (1 H, m), 4.7 (1 H, m), 5.5 (1 H, m), 5.9 (1 H, s), 6.9 (1 H, d), 7.1 (2 H, m) 7.2- 7.4 (7 H, m). MS m / z: 375 (M + 1). (±) -C / sN- [1- (3-Fluoro-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide (A- 61) (±) -c / sN- [1- (3-Fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide was prepared following General procedure A substituting 2-furoïium chloride for 3-fluorobenzoyl chloride. 1 H NMR (CDCl 3) d: 1.1 (3 H, d), 1.1 (1 H, m), 2.0 (3 H, s), 2.3 (1 H,), 4.7 ( 1 H, m), 5.6 (1 H, m), 6.4 (1 H, d), 6.8 (1 H, d), 6.9-7.4 (11 H, m). MS m / z: 403 (M + 1). (±) -C / sN- [1 - (3,4-difluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide (A- 62) (±) -c / sN- [1- (3,4-difluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N- was prepared phenyl acetamide following general procedure A substituting 2-furoyl chloride for 3,4-difluorobenzoyl chloride. 1 H NMR (CDCl 3) d: 1.1 (3 H, d), 1.1 (1 H, m), 2.0 (3 H, s), 2.3 (1 H, m), 4.7 (1 H, m), 5.6 (1 H, m), 6.5 (1 H, d), 6.8-7.0 (4 H, d), 7.3-7.5 (7 H, m). MS m / z: 421 (M + 1). (±) -C / sN- [1- (benzo [b] thiophene-3-carbonyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide ( A-63) Prepared (±) -c / sN- [1- (benzo [b] thiophene-3-carbonyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl ] -N-phenyl-acetamide following general procedure A substituting 2-furoyl chloride for benzo [b] thiophene-3-carbonyl chloride. 1 H NMR (CDCl 3) d: 1, 2 (3 H, d), 1, 3 (1 H, m), 2.0 (3 H, s), 2.3 (1 H, m), 4.9 (1 H, m), 5.7 (1 H, m), 6.5 (1 H, d), 6.8 (1 H, m), 7.1-7.5 (10 H, m) , 7.8 (1 H, d), 8.0 (1 H, d).
MS m / z: 442 (M + 2). (±) -Cis-N- [1- (3,5-dimethyl-thiophene-2-carbonyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl- acetamide (A-64) (±) -c / sN- [1- (3,5-dimethyl-thiophene-2-carbonyl) -2-methyl-1, 2,3,4-tetrahydro-quinoline-4 was prepared -yl] -N-phenyl-acetamide following the general procedure A substituting 2-furoyl chloride for 3,5-dimethyl-thiophene-2-carbonyl chloride. 1 H NMR (CDCl 3) d: 1.1 (3 H, d), 1.1 (1 H, m), 1.7 (3 H, s), 2.0 (3 H, d), 2.0 (1 H, m), 2.3 (3 H, s), 4.7 (1 H, m), 5.5 (1 H, m), 6.2 (1 H, s), 6.7 (1 H, d), 7.0 (1 H, t), 7.1-7.4 (7 H, m). MS m / z: 419 (M + 1). (±) -Cis-N- [1- (3-fluoro-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-isobutyramide (A-65) (±) -c / sN- [1- (3-Fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-isobutyramide was prepared following the procedure General A substituting 2-furoyl chloride for 3-fluorobenzoyl chloride and acetyl chloride for isopropyl chloride. 1 H NMR (CDCl 3) d: 1, 0-1, 2 (10 H, m), 2.3 (1 H, m), 2.7 (1 H, m), 4.8 (1 H, m) , 5,6 (1 H, m), 6.5 (1 H, m), 6.8-7.6 (12 H, m). MS m / z: 431 (M + 1). (±) -Cis-N- [1 - (4-f luoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-isobutyramide (A-66) ) (±) -c / sN- [1- (4-Fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-isobutyramide was prepared following the General procedure A substituting 2-furoyl chloride for 4-fluorobenzoyl chloride and acetyl chloride for isopropyl chloride. 1 H NMR (CDCl 3) d: 1, 0-1, 2 (10 H, m), 2.3 (1 H, m), 2.6 (1 H, m), 4.8 (1 H, m) , 5,6 (1 H, m), 6.5 (1 H, d), 6.8-7.0 (3 H, m), 7.1-7.4 (9 H, m). MS m / z: 431 (M + 1). (± JC / sN-ll ^^ - dimethyl-thiazole-S-carboni ^ -methyl-l ^^^ - tetrahydro-quinolin-4-yl] -N-phenyl-acetamide (A-67) Prepared ( ±) -c / sN- [1- (2,4-dimethyl-thiazole-5-carbonyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenol -acetamide following general procedure A substituting 2-furoyl chloride for 2,4-dimethyl-thiazole-5-carbonyl chloride H-NMR (CDCl 3) d: 1,2 (3 H, d), 1, 2 (1 H, m), 2.0 (3 H, s), 2.2 (3 H, s), 2.3 (1 H, m), 2.6 (3 H, s), 4.7 (1 H, m), 5.4 (1 H, m), 6.8 (1 H, d), 7.1 (2 H, m), 7.2-7.5 (6 H, m). m / z: 420 (M + 1). (±) -C / sN- [1- (furan-2-carbonyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4- il] -N-phenyl-propionamide (A-68) was prepared (±) -c / sN- [1- (furan-2-carbonyl) -2-methyl-1, 2,3,4-tetrahydro-quinoline- 4-yl] -N-phenyl-propionamide following general procedure A substituting acetyl chloride for propionyl chloride: 1 H NMR (CDCl 3) d: 1.0-1.2 (7 H, m), 2.2-2 , 4 (3 H, m), 4.7 (1 H, m), 5.4 (1 H, m), 6.2 (2 H, m), 6.8 (1 H, d), 7.0-7.4 (9 H, m). MS m / z: 389 (M + 1). (±) -C / sN- [1- (4-Fluoro-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-butyramide (A-69) (±) -c / sN- [1- (4-Fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-butyramide was prepared following the General procedure A substituting 2-furoyl chloride for 4-fluorobenzoyl chloride and acetyl chloride for butyryl chloride. 1 H NMR (CDCl 3) d: 0.8 (3 H, t), 1, 2 (3 H, d), 1, 2 (1 H, m), 1.5 (2 H, m), 2.0 (3 H, m), 4.7 (1 H, m), 5.4 (1 H, m), 6.5 (1 H, d), 6.6-6.8 (4 H, m), 6.9-7, 3 (8 H, m). MS m / z: 432 (M + 2). (±) -C / sN- [1 - (4-fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -2-phenoxy-N-phenyl-acetamide ( A-72) Prepared (±) -c / sN- [1- (4-fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -2-phenoxy- N-phenyl acetamide following general procedure A substituting 2-furoyl chloride for 4-fluorobenzoyl chloride and acetyl chloride for 1-chloro-3-phenoxy-propan-2-one chloride. 1 H NMR (CDCl 3) d: 1.1 (3 H, d), 1.1 (1 H, m), 2.3 (1 H, m), 4.5 (2 H, s), 4.7 (1 H, m), 5.7 (1 H, m), 6.4 (1 H, d), 6.7-6.9 (7 H, m), 7.1-7.4 (9 H, m), 10.0 (1 H, m). MS m / z: 496 (M + 2). (±) -C / sN- [1- (4-fluoro-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -3, N-diphenyl-propionamide (A- 73) (±) -c / sN- [1- (4-Fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -3, N was prepared -diphenyl propionamide following general procedure A substituting 2-furoyl chloride for 4-fluorobenzoyl chloride and acetyl chloride for 3-phenylpropionyl chloride. 1 H NMR (CDCl 3) d: 1, 2 (3 H, d), 1, 2 (1 H, m), 2.2 (1 H, m), 2.7 (2 H, t), 3.1 (2 H, t), 4.7 (1 H, m), 5.7 (1 H, m), 6.6 (1 H, d), 6.8-7.6 (17 H, m) . MS m / z: 494 (M + 2). (±) -C / sN- [1- (benzo [b] thiophene-2-carbonyl) -2-methyl-1,2,3,4-tetrahydro-quino! In-4-yl] -N-phenyl- propionamide (A-75) was prepared (±) -c / sN- [1- (benzo [b] thiophene-2-carbonyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl ] -N-phenyl-propionamide following general procedure A substituting 2-furoyl chloride for benzo [b] thiophene-2-carbonyl chloride and acetyl chloride for propionyl chloride. H NMR (CDCl 3) d: 1, 1-1, 2 (7 H, m), 2.1-2.3 (3 H, m), 4.8 (1 H, m), 5.6 (1 H, m), 6.9 (1 H, d), 7.0 (2 H, m), 7.2-7.5 (9 H, m), 7.6 (1 H, d), 7 , 8 (1 H, d). MS m / z: 456 (M + 2). (±) -C / sN- [1- (4-cyano-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide (A- 76) (±) -c / sN- [1- (4-cyano-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide following the procedure General A substituting 2-furoyl chloride for 4-cyanobenzoyl chloride and acetyl chloride for propionyl chloride. 1 H NMR (CDCl 3) d: 1, 1-1, 3 (7 H, m), 2.2-2.4 (3 H, m), 4.8 (1 H, m), 5.6 (1 H, m), 6.4 (1 H, d), 6.9 (1 H, t), 7.2-7.6 (11 H, m). MS m / z: 424 (M + 1).
(+) - C / sN- [1- (3-fluoro-4-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl- propionamide (A-77) was prepared (±) -c / sN- [1- (3-fluoro-4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl ] -N-phenyl-propionate following general procedure A substituting 2-furoyl chloride for 3-fluoro-4-methoxybenzoyl chloride and acetyl chloride for propionyl chloride. 1 H NMR (CDCl 3) d: 1, 1-1, 2 (7 H, m), 2.1-2.3 (3 H, m), 3.8 (3 H, s), 4.8 (1 H, m), 5.6 (1 H, m), 6.5 (1 H, d), 6.7 (1 H, t), 6.8 (1 H, d), 6.9 (1 H, t), 7.2-7.5 (8 H, m). MS m / z: 447 (M + 1). (±) -C / sN- [1 - (4-methoxy-3-methyl-benzoyJ) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide ( A-78) Prepared (±) -c / sN- [1- (4-methoxy-3-methyl-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] - N-phenyl-proponamide following general procedure A substituting 2-furoyl chloride for 3-methyl-4-methoxybenzoyl chloride and acetyl chloride for propionyl chloride. 1 H NMR (CDCl 3) d: 0.9-1, 1 (7 H, m), 1.8-2.2 (6 H, m), 3.8 (3 H, s), 4.8 (1 H, m), 5.6 (1 H, m), 6.5 (2 H, m), 6.7-7.8 (10 H, m). MS m / z: 443 (M + 1). (±) -C / sN- [1- (4-ethoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide (A-79) (±) -c / sN- [1- (4-ethoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide was prepared following the procedure General A substituting 2-furoyl chloride for 4-ethoxybenzoyl chloride and acetyl chloride for propionyl chloride. 1 H NMR (CDCl 3) d: 1, 1-1, 3 (7 H, m), 1, 4 (3 H, t), 2.2-2.4 (3 H, m), 4.0 (2 H, c), 4.8 (1 H, m), 5.6 (1 H, m), 6.5 (1 H, d), 6.9 (2 H, d), 6.9 (1 H, t), 7.2-7.6 (9 H, m). MS m / z: 443 (M + 1). (+) - C / sN- [2-methyl-1- (4-trifluoromethyl-benzoyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide (A-80) Prepared (±) -c / sN- [2-methyl-1- (4-trifluoromethyl-benzoyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenol-propyl followed by general procedure A substituting 2-furoyl chloride for 4-trifluoromethylbenzoyl chloride and acetyl chloride for propionyl chloride. 1 H NMR (CDCl 3) d: 1, 1-1, 3 (7 H, m), 2.2-2.4 (3 H, m), 4.8 (1 H, m), 5.6 (1 H, m), 6.4 (1 H, d), 6.9 (1 H, t), 7.2-7.6 (11 H, m). MS m / z: 319 (M-147). (±) -C / sN- [1- (4-benzyl-morpholine-2-carbonyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide ( A-81) Prepared (±) -c / sN- [1- (4-benzyl-morpholine-2-carbonyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] - N-phenyl-propionamide following general procedure A substituting 2-furoyl chloride for 4-benzyl-morpholine-2-carbonyl chloride and acetyl chloride for propionyl chloride. 1 H NMR (CDCl 3) d: 1, 1-1, 2 (7 H, m), 2.1-2.3 (4 H, m), 2.6 (3 H, m), 3.5 (2 H, m), 3.9 (1 H, m), 4.2 (1 H, m), 4.7 (1 H, m), 5.2 (1 H, m), 7.1-7 , 5 (14 H, m). MS m / z: 498 (M + 1). (±) -C / sN- [1- (4-ethyl-morpholine-2-carbonyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide ( A-82) Prepared (±) -c / sN- [1- (4-ethyl-morpholine-2-carbonyl) -2-methyl-1, 2,3,4-tetrahydro-quinoIin-4-ylj-N phenyl propionamide following general procedure A substituting 2-furoyl chloride for 4-ethylmorpholine-2-carbonyl chloride and acetyl chloride for propionyl chloride. 1 H NMR (CDCl 3) d: 1, 1-1, 2 (10 H, m), 2.1-2.4 (6 H, m), 2.6 (2 H, m), 3.6 (1 H, t), 3.9 (1 H, m), 4.2 (1 H, m), 4.7 (1 H, m), 5.2 (1 H, m), 7.2-7 , 5 (14 H, m). MS m / z: 436 (M + 1). (±) -C / sN- [2-methyl-1- (4-phenoxy-benzoyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide (A-83) (±) -c / sN- [2-methyl-1- (4-phenoxy-benzoyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide was prepared following the General procedure A substituting 2-furoyl chloride for 4-phenoxy-benzoyl chloride and acetyl chloride for propionyl chloride. 1 H NMR (CDCl 3) d: 1, 0-1, 2 (7 H, m), 2.2-2.4 (3 H, m), 4.7 (1 H, m), 5.6 (1 H, m), 6.5 (1 H, d), 6.5 (1 H, d), 6.8 (2 H, d), 7.0-7.4 (15 H, m). MS m / z: 491 (M + 1). (±) -C / sN- [1- (4-fluoro-3-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide ( A-84) was prepared (±) -c / sN- [1- (4-fluoro-3-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] - N-phenyl-propionamide following general procedure A substituting 2-furoyl chloride for 4-fluoro-3-methoxy-benzoyl chloride and acetyl chloride for propionyl chloride. 1 H NMR (CDCl 3) d: 1, 0-1, 2 (7 H, m), 2.2-2.4 (3 H, m), 3.6 (3 H, s), 4.7 (1 H, m), 5.6 (1 H, m), 6.4 (1 H, d), 6.7-6.9 (4 H, m), 7.1-7.4 (7 H, m). MS m / z: 447 (M + 1). (±) -C / sN- [1- (4-methoxy-3-trifluoromethyl-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide ( A-85) Prepared (±) -c / sN- [1- (4-methoxy-3-trifluoromethyl-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] - N-phenyl-propionamide following general procedure A substituting 2-furoyl chloride for 4-methoxy-3-trifluoromethylbenzoyl chloride and acetyl chloride for propionyl chloride. 1 H NMR (CDCl 3) d: 1, 0-1, 2 (7 H, m), 2.2-2.4 (3 H, m), 3.8 (3 H, s), 4.7 (1 H, m), 5.6 (1 H, m), 6.5 (1 H, d), 6.7 (1 H, d), 7.0 (2 H, m), 7.2-7.4 (7 H, m) , 7.8 (1 H, s). MS m / z: 497 (M + 1). (±) -C / sN- [1- (2,3-dihydro-benzofuran-5-carbonyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl- propionamide (A-86) (±) -c / sN- [1- (2,3-dihydro-benzofuran-5-carbonyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4 was prepared -yl] -N-phenyl-propionamide following general procedure A substituting 2-furoyl chloride for 2,3-dihydro-benzofuran-5-carbonyl chloride and acetyl chloride for propionyl chloride. 1 H NMR (CDCl 3) d: 1, 1-1, 2 (7 H, m), 2.1-2.3 (3 H, m), 4.5 (2 H, t), 4.8 (1 H, m), 5.6 (1 H, m), 6.5 (2 H, m), 6.9 (2 H, m), 7.1-7.4 (7 H, m).
MS m / z: 441 (M + 1). (± JC / sN ^ -methyl-l- ^ - IS-methyl-ureido-J-benzoyl-J ^^^ -tetrahydro-quinolin-4-yl}. -N-phenyl-acetamide (A-87) was prepared ( ±) -c / sN- {2-methyl-1- [4- (3-methyl-ureido) -benzoyl] -1, 2,3,4-tetrahydro-quinolin-4-yl}. -N phenyl acetamide from (±) -c / sN- [1- (4-amino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinoIin-4-yl] -N-phenyl -acetamide was prepared (±) -c / sN- [1- (4-amino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinoIin-4-yl] -N-phenyl-propionamide following general procedure A, substituting 2-furoyl chloride for 4-nitrobenzoyl chloride and acetyl chloride for propionyl chloride The resulting nitro analogue was reduced with Pd / C (10%) in ethanol in a Parr shaker. 241, 316 kPa (35 psi). (+) - c / sN- [1- (4-Amino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4- was dissolved. il] -N-phenyl-acetamide (150 mg, 0.376 mmol) in 10 ml of toluene and 64 mg of methyl isocyanate (1.13 mmol) was added.The resulting reaction mixture was stirred at room temperature for 2 hours. hours and then heated at 50 ° C overnight. The mixture was concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with methanol-dichloromethane (1:19) to give the title compound (87 mg, 51%). 1 H NMR (CDCl 3) d: 1.1 (3 H, d), 1.1 (1 H, m), 2.0 (3 H, s), 2.3 (1 H, m), 2.7 (3 H, s), 4.7 (1 H, m), 5.1 (2 H, m), 5.6 (1 H, m), 6.5 (1 H, d), 6.9 -7.0 (6 H, m), 7.2 (1 H, t), 7.2-7.4 (5 H, m). MS m / z: 457 (M + 1). (±) -C / sN- [1- (4-dimethylamino-benzoyl) -2-methyl-1,2,3,4-tetra idro-quinolin-4-yl] -N-phenyl-acetamide (A-88) ) (±) -c / sN- [1- (4-diethylamino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide was prepared from of (±) -c / sN- [1- (4-amino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide. It was dissolved (±) -c / sN- [1- (4-amino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide in methylene chloride and ethyl iodide (1.5 equiv.) followed by K2C? 3 was added. The reaction was allowed to stir at room temperature for 12 h. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with methanol-dichloromethane (1:19) to give the title compound. 1 H NMR (CDCl 3) d: 1, 0-1, 2 (10 H, m), 2.0 (3 H, s), 2.4 (1 H, m), 3.3 (4 H, c) , 4.7 (1 H, m), 5.6 (1 H, m), 6.4 (2 H, d), 6.6 (1 H, d), 6.9 (1 H, t) , 7.0-7.4 (9 H, m). MS m / z: 456 (M + 1). Acid (±) -c / s-. { 4- [4- (acetyl-phenyl-amino) -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl] -phenylamino} -acetic (A-89) Acid (±) -c / s- was prepared. { 4- [4- (acetyl-phenyl-amino) -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl-phenylamino} -acetic from (±) -c / sN- [1 - (4-amino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide . It was dissolved (±) -c / s-N- [1 - (4-amino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide in dimethylformamide and bromoacetic acid ethyl ester was added followed by K2CO3. The reaction was allowed to warm to 90 ° C for 12 h. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with methanol-dichloromethane (2:18) to give the ester. The ester was hydrolyzed using NaOH (aq) in methanol and water to give the title compound. 1 H NMR (CDCl 3) d: 1.1 (3 H, d), 1.1 (1 H, m), 2.0 (3 H, s), 2.3 (1 H, m), 3.6 (1 H, s), 4.7 (3 H, a), 5.6 (1 H, m), 6.3 (1 H, m), 6.6 (1 H, d), 6.8 -7.4 (11 H, m). MS m / z: 458 (M + 1). (±) -C / s-. { N- [1- (4-methanesulfonylamino-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide (A-90) was prepared (±) - c / s-. { N- [1- (4-methanesulfonyl-amino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide from (±) -c / sN- [1- (4-amino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide. It was dissolved (±) -c / sN- [1- (4-amino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide (50 mg , 0.12 mmol) in 5 ml of DMF and methanesulfonic anhydride (21 mg, 0.12 mmol) was added. The resulting reaction mixture was heated to 45 ° C and stirred for 1 hour. The mixture was concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with methanol-dichloromethane (1: 9) to give the title compound (15 mg, 25%). 1 H NMR (CDCl 3) d: 1, 1-1, 2 (7 H, m), 2.1-2.3 (3 H, m), 3.0 (3 H, s), 4.7 (1 H, m), 5.6 (1 H, m), 6.5 (1 H, d), 6.7 (2 H, d), 6.9 (1 H, t), 7.1 (2 H, m), 7.2-7.4 (7 H, m). MS m / z: 491 (M). (+) - C / sN- [6-fluoro-1- (4-fluoro-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N- (4 -fluoro-phenyl) -propionamide (A-91) was prepared (±) -c / sN- [6-fluoro-1- (4-fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro -quinolin-4-yl] -N- (4-fluoro-phenyl) -propionamide following general procedure A, substituting 2-furoyl chloride for 4-fluorobenzoyl chloride, (±) -c / s- (2-methyl) -1, 2,3,4-tetrahydro-quinolin-4-yl) -phenyl-amine by (±) -c / s- (6-fluoro-2-methyl-, 2,3,4-tetrahydro-quinoline- 4-yl) - (4-fluoro-phenyl) -amine and acetyl chloride by propionyl chloride. It was synthesized (±) -c / s- (6-fluoro-2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl) - (4-fluoro-phenyl) -amine following the reactions indicated in Scheme 1, substituting aniline for 4-fluoroaniline. 1 H NMR (CDCl 3) d: 1, 1-1, 2 (6H, m), 2.2-2.4 (4H, m), 4.8 (1 H, dd), 5.4-5.6 (1 H, a), 6.4 (1H, dd), 6.6 (1 H, td), 6.8-7.0 (2H, m), 7.0-7.4 (6H, m ). MS m / z: 453 (M + 1). (±) -C / sN- [6-bromo-1- (4-fluoro-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N- (4-bromo) phenyl) -propionamide (A-92) was prepared (±) -c / sN- [6-bromo-1- (4-fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin -4-yl] -N- (4-bromo-phenyl) -propionamide following general procedure A, substituting 2-furoyl chloride for 4-fluorobenzoyl chloride, (±) -c / s- (2-methyl-1 , 2,3,4-tetrahydro-quinolin-4-yl) -phenyl-amine by (±) -c / s- (6-bromo-2-methyl-1, 2,3,4-tetrahydro-quinolin-4 -yl) - (4-bromo-phenyl) -amine and acetyl chloride by propionyl chloride. (±) -c / s- (6-bromo-2-methyl-1, 2,3,4-tetrahydro-quinoIin-4-yl) - (4-bromo-phenyl) -amine was synthesized following the reactions indicated in Scheme 1, substituting aniline for 4-bromoaniline. 1 H NMR (CDCl 3) d: 1, 1-1, 2 (6H, m), 1.6 (1 H, m), 2.2-2.4 (3H, m), 4.8 (1 H, m), 5.4-5.6 (1H, a), 6.4 (1H, d), 6.8 (2H, m), 7.0-7.4 (6H, m), 7 , 8-7.9 (2H, m).
MS m / z: 573 (M + 1). (+) - C / sN- [1- (3-ethoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide (A-93) (±) -c / sN- [1- (3-ethoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide was prepared following the General procedure A, substituting 2-furoyl chloride for 3-ethoxybenzoyl chloride. 1 H NMR (CDCl 3) d: 1, 2 (3 H, m), 1, 4 (4 H, m), 2.1 (3 H, s), 2.4 (1 H, m), 4.0 (2 H, m), 4.9 (1 H, m), 5.6 (1H, a), 6.6 (1H, d), 6.9 (2H, m), 7.0 (1H, m), 7 , 2 (1H, m), 7.3 (1H, m), 7.4 -7.5 (7H, m). MS m / z: 429 (M + 1). (±) -C / sN- [1- (4-isopropoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide (A-94) (±) -c / sN- [1- (4-isopropoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide was prepared following General procedure A, substituting 2-furoyl chloride for 4-isopropoxybenzoyl chloride and acetyl chloride for propionyl chloride. 1 H NMR (CDCl 3) d: 0.9-1.2 (12H, m), 1.4 (1 H, m), 2.0 (3H, m), 4.3 (1 H, m), 4 , 5 (1H, m), 5.4 (1H, a), 6.3 (1H, d), 6.4 (2H, d), 6.7 (1H, m), 6.9 -7.2 (9H, m). MS m / z: 457 (M + 1). (±) -C / sN- [1 - (1-isopropyl-1 H-benzotriazole-5-carbonyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl -propionamide (A-95) was prepared (±) -c / sN- [1- (1-isopropyl-1 H-benzotriazole-5-carbonyl) -2-methyl-1, 2,3,4-tetrahydro-quinol N-4-yl] -N-phenyl-propionamide following general procedure A, substituting 2-furoyl chloride for 1-isopropyl-1 H-benzotriazole-5-carbonyl chloride and acetyl chloride for propionyl chloride . 1 H NMR (CDCl 3) d: 1.3 (7H, m), 1.8 (6H, m), 2.4 (3H, m), 5.0 (1 H, m), 5.1 (1 H , m), 5.7 (1 H, a), 6.6 (1 H, d), 7.0 (1 H, m), 7.2-7.5 (9H, m), 8.3 (1 H, s). MS m / z: 482 (M + 1). (±) -C / sN- [1- (3-ethoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide (A-96) (±) -c / sN- [1- (3-ethoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-ylj-N-phenyl-propionamide was prepared following the general procedure A, substituting 2-furoyl chloride for 3-ethoxybenzoyl and acetyl chloride for propionyl chloride. 1 H NMR (CDCl 3) d: 1, 2 (6H, m), 1.5 (4H, m), 2.4 (3H, m), 4.0 (2H, m), 4.9 (1 H, m), 5.7 (1H, a), 6.6 (1H, d), 6.8 (1H, d), 6.9 (1H, m), 7.1 (2H, m), 7 , 2 (1 H, m), 7.3-7.6 (7H, m). MS m / z: 443 (M + 1). Acid ethyl ester (±) -c / s-4-. { 4- [2-methyl-4- (phenyl-propionyl-amino) -3,4-dihydro-2H-quinoline-1-carbonyl] -phenyl} -piperidine-1-carboxylic acid (A-97) Ethyl ester of (±) -c / s-4- was prepared. { 4- [2-methyl-4- (phenyl-propionyl-amino) -3,4-dihydro-2H-quinoline-1-carbonyl] -phenyl} -piperidine-1-carboxylic following the general procedure A, substituting 2-furoyl chloride for 4- (4-chlorocarbonyl-phenyl) -piperidine-1-carboxylic acid ethyl ester and acetyl chloride for propionyl chloride. 1 H NMR (CDCl 3) d: 1, 1-1, 3 (10H, m), 1.5 (2H, m), 1.7 (2H, m), 2.3 (3H, m), 2.6 (1 H, m), 2.8 (2 H, t), 4.1 (2 H, m), 4.2 (2 H, m), 4.8 (1 H, m), 5.6 (1 H , a), 6.5 (1H, d), 6.9 (1H, m), 7.2 (2H, m), 7.3-7.4 (9H, m). MS m / z: 554 (M + 1). (±) -C / sN- [2-methyl-1- (4-piperidin-4-yl-benzoyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide ( A-98) Prepared (±) -c / sN- [2-methy1- (4-piperidin-4-yl-benzoyl) -1, 2,3,4-tetrahydro-quinolin-4-yl ] -N-phenyl-propionamide from the ethyl ester of the acid (±) -c / s-4-. { 4- [2-methyl-4- (phenyl-propionyl-amino) -3,4-dihydro-2H-quinoline-1-carbonyl] -phenyl} -piperidine-1-carboxylic acid. Ethyl ester of (±) -c / s-4 was dissolved. { 4- [2-methyl-4- (phenyl-propionl-amino) -3,4-dihydro-2H-quinoline-1-carbonyl] -phenyl} -piperidine-1-carboxylic acid (96 mg, 0.17 mmol) in acetonitrile (2 ml). Iodotrimethylsilane (74 μl, 0.51 mmol) was added and the reaction was allowed to stir at room temperature overnight. The excess reagent was quenched by the addition of methanol (1 ml) and the mixture was concentrated under reduced pressure. The crude residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The extracts were washed with 1 M sodium hydroxide, saturated aqueous sodium thiosulfate and brine.were dried over sodium sulfate, filtered, concentrated and purified by chromatography on silica gel (3: 1 methylene chloride / methanol) (77 mg, 94%). 1 H NMR (CDCl 3) d: 1.1 (6H, m), 1.3 (1 H, t), 1.6 (2H, m), 1.7 (2H, d), 2.3 (3H, m), 2.6 (1 H, m), 2.7 (2H, t), 3.2 (2H, d), 4.8 (1H, m), 5.6 (1H, a), 6 , 5 (1H, d), 6.9 (1H, m), 7.0 (2H, d), 7.2 (3H, m), 7.3-7.4 (6H, m). MS m / z: 482 (M + 1). (±) -C / sN- [1 - (4-bromo-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide (A-99) (±) -c / sN- [1- (4-bromo-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide was prepared following the General procedure A, substituting 2-furoyl chloride for 4-bromobenzoyl chloride and acetyl chloride for propionyl chloride. 1 H NMR (CDCl 3) d: 1.2 (6H, m), 1.25 (1 H, m), 2.3 (3H, m), 4.8 (1 H, m), 5.6 (1H , a), 6.4 (1 H, d), 6.9 (1 H, m), 7.1 (2 H, d), 7.2 (1 H, m), 7.3-7.4 (8H, m). MS m / z: 477 (M + 1). (±) -C / s-N-. { 1 - [4- (1-Acetyl-piperidin-4-yl) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -N-phenyl-propionamide (A-100) To a solution of (±) -c / s- (2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl) -phenyl-amine (636) mg, 2.70 mmol) in dichloromethane (10 ml) at room temperature was added diisopropylethylamine (1.04 g, 1.44 ml, 2.98 mmol) followed by tert-butyl 4- (4-chlorocarbonyl) ester phenyl) -piperidine-1-carboxylic acid prepared recently (2.98 mmol). The mixture was stirred at room temperature overnight, poured into water and extracted with dichloromethane. The extracts were washed with 1 M NaOH (aq.) And brine, dried over magnesium sulfate, filtered, dried and concentrated. The crude residue was purified by chromatography on silica gel (gradient of 100% hexanes to 70/30 hexanes / ethyl acetate) to yield the pure amide (827 mg, 58%).
The tert-butyl ester of (±) -c / s-4- [4- (2-methyl-4-phenylamino-3,4-dihydro-2H-quinoline-1-carbonyl) -phenyl] -piperidine-1 acid carboxylic acid (827 mg, 1.57 mmol) formed in this manner was dissolved in methylene chloride (50 ml). Trifluoroacetic acid (3 ml) was added and the mixture was stirred at rt for 70 min. The solvent and excess acid were removed under reduced pressure. The crude residue was dissolved in ethyl acetate and neutralized with 1 M sodium hydroxide (to pH = 10.5). The aqueous phase was extracted twice with more ethyl acetate. The extracts were combined and washed with brine, dried over sodium sulfate, filtered and concentrated to yield the crude diamine (676 mg, 100%) as an oil. To a solution of the above-obtained piperidine amine (676 mg, 1.59 mmol) in methylene chloride (25 ml) was added diisopropylethylamine (616 mg, 849 μl, 4.77 mmol) followed by acetyl chloride (162 mg). , 156 μl, 2.06 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted with more methylene chloride. The extracts were combined, washed with brine, dried over sodium sulfate, filtered, dried and concentrated to yield the piperidine acetamide (844 mg,> 100%). The crude piperidine acetamide obtained above (844 mg) was dissolved in methylene chloride (25 ml), to which was then added diisopropylethylamine (205 mg, 283 μl, 1.59 mmol) followed by propionyl chloride (4.42). g, 4.2 ml, 47.7 mmol). The resulting reaction mixture was stirred at room temperature for 96 h and concentrated. The resulting residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The extracts were washed with brine and dried over sodium sulfate, filtered, dried and concentrated. The crude residue was purified by chromatography on silica gel (gradient 50/50 ethyl acetate / hexanes to 100% ethyl acetate) to yield the product (437 mg, 52%). It separated (±) -cs-N-. { 1- [4- (1-Acetyl-piperidin-4-yl) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -N-phenyl-propionamide by chiral HPLC using a chiral OD cell column and eluting with a 90% isocratic hexane / 10% ethanol system to give (2f?, 4S) - y (2S, 4fi) -c / sN -. { 1- [4- (1-Acetyl-piperidin-4-yl) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -N-phenol-propionamide (A-51 and A-50, respectively). 1 H NMR (CDCl 3) d: 1.2 (7H, m), 1.6 (2H, m), 1.8 (2H, d), 2.1 (3H, s), 2.3 (3H, m ), 2.6 (2H, m), 3.1 (1H, t), 3.9 (1H, m), 4.8 (2H, m), 5.6 (1H, a), 6.5 (1H, d), 6.9 (1H, m), 7.0 (2H, d), 7.1 (2H, d), 7.2-7.4 (7H, m). MS m / z: 524 (M + 1) (±) -C / s-N-. { 1 - [4- (1-ethyl-piperidin-4-yl) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -N-phenyl-propionamide (A-101) was prepared (±) -c / s-N-. { 1 - [4- (1-ethyl-piperidin-4-yl) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -N-phenyl-propionamide from (±) -c / sN- [2-methyl-1- (4-piperidin-4-yl-benzoyl) -1, 2,3,4-tetrahydro-quinolin-4- il] -N-phenyI-propionamide. It was dissolved (±) -c / sN- [2-methyl-1- (4-p¡perdin-4-yl-benzoyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide in dichloromethane (3 ml). Acetaldehyde (18 μl, 0.33 mmol) was added in one portion. The mixture was stirred at room temperature for 30 minutes and then a solution of sodium triacetoxyborohydride (35 mg, 0.165 mmol) in dichloromethane (1 ml) was slowly added, followed by 1 drop of acetic acid. The mixture was allowed to stir at room temperature overnight and was quenched with aqueous sodium bicarbonate. The biphasic mixture was extracted three times with methylene chloride (20 ml); and the combined extracts were washed with brine, dried over magnesium sulfate, filtered, concentrated and purified by HPLC to yield the product (35 mg, 62%). 1 H NMR (CDCl 3) d: 1.0-1.2 (9H, m), 1.3 (1H, m), 1.8 (4H, a), 2.0 (2H, m), 2.3 (3H, m), 2.5 (2H, m), 3.1 (3H, m), 4.8 (1 H, m), 5.6 (1 H, a), 6.5 (1 H, d), 6.9 (1 H, m), 7.0 (2 H, d), 7.1-7.4 (9H, m). MS m / z: 511 (M + 2). (±) -C / sN- [2-Methyl-1- (4-nitro-benzoyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide (A-102) (±) -c / sN- [2-methyl-1- (4-nitro-benzoyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide was prepared following the procedure General A, substituting 2-furoyl chloride for 4-nitrobenzoyl chloride and acetyl chloride for propionyl chloride. 1 H NMR (CDCl 3) d: 1, 2 (7H, m), 2.3 (3H, m), 4.8 (1H, m), 5.6 (1H, a), 6.4 (1H, d ), 6.9 (1 H, m), 7.2-7.4 (9H, m), 8.0 (2H, d). MS m / z: 444 (M + 1). (±) -C / sN- [1- (4-amino-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide (A-103) (±) -c / sN- [1- (4-Amino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-proponamide was prepared from (±) -c / sN- [2-methylmethyl-1- (4-nitro-benzoyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide. It was dissolved (±) -c / sN- [2-methyl-1- (4-nitro-benzoyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide (200 mg , 0.45 mmol) in ethanol (20 ml). Palladium on carbon (10%) was carefully added and the resulting suspension was stirred under an atmosphere of hydrogen gas at 40 psi (275,790 kPa) overnight. The suspension was filtered through Celite® to remove the solids and the filter cake was washed three times with ethanol. The concentration of the solution gave the pure product (160 mg, 86%). 1 H NMR (CDCl 3) d: 1.2 (7 H, m), 2.3 (3 H, m), 3.9 (2 H, a), 4.7 (1 H, m), 5.6 (1 H, a), 6.4 (2 H, d), 6.6 (1 H, d), 6.9 (1 H, m), 7.0 (2 H, d), 7.1 (1 H, m), 7.2-7.4 (6 H, m). MS m / z: 414 (M + 1). (±) -C / sN- [2-methyl-1- (4-pyrrol-1-yl-benzoyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide ( A-104) was prepared (±) -c / sN- [2-methyl-1- (4-pyrrol-1-yl-benzoyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] - N-phenyl-propionamide following general procedure A, substituting 2-furoyl chloride for 4-pyrrol-1-ii-benzoyl chloride and acetyl chloride for propionyl chloride. 1 H NMR (CDCl 3) d: 1.2 (6 H, m), 1.3 (1 H, m), 2.3 (3 H, m), 4.8 (1 H, m), 5.6 (1 H, a), 6.3 (2 H, s), 6.6 (1 H, d), 6.9 (1 H, m), 7.1 (2 H, s), 7.2 -7.4 (11 H, m).
MS m / z: 464 (M + 1). (±) -C / sN- [1- (4-acetylamino-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide (A-105) (+) - c / sN- [1- (4-acetylamino-benzoyl) -2-methyI-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide was prepared from (±) -c / sN- [1- (4-amino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide. To a solution of (±) -c / sN- [1- (4-amino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide ( 100 mg, 0.24 mmol) in 2.5 ml tetrahydrofuran was added acetyl chloride (44 μl, 0.63 mmol) followed by triethylamine (88 μl, 0.63 mmol). The reaction was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with hexane-ethyl acetate (3: 1) to give the title compound (51 mg, 46%). 1 H NMR (CDCl 3) d: 1.1 (7 H, m), 2.2 (3 H, s), 2.3 (3 H, m), 4.8 (1 H, m), 5.6 (1 H, a), 6.5 (1 H, d), 6.9 (1 H, m), 7.1 (2 H, d), 7.2 (1 H, d), 7.3 -7.4 (8 H, m), 8.4 (1 H, a). MS m / z: 456 (M + 1) Ethyl ester of the acid (±) -c / s-. { 4- [2-methyl-4- (phenyl-propionyl-amino) -3,4-dihydro-2H-quinoline-1-carbonyl] -phenyl} -carbamic (A-106) ethyl ester of (±) -c s- acid was prepared. { 4- [2-methyl-4- (phenyl-propionyl-amino) -3,4-dihydro-2H-quinoline-1-carbonyl] -phenyl} -carbamic from (±) -c / sN- [1- (4-aminoamino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide , following the method described above in the synthesis of (±) -c / sN- [1- (4-acetylamino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl ] -N-phenyl-propionamide, substituting acetyl chloride for ethyl chloroformate. 1 H NMR (CDCl 3) d: 1.1 (6 H, m), 1.3 (4 H, m), 2.3 (3 H, m), 4.2 (2 H, m), 4.8 (1 H, m), 5.6 (1 H, a), 6.5 (1 H, d), 6.7 (1 H, a), 6.9 (1 H, m), 7.1 -7.4 (10 H, m). MS m / z: 486 (M + 1). (±) -C / s-N-. { 2-methyl-1 - [4- (4-methyl-piperazin-1-yl) -benzoyl] -1, 2,3,4-tetrahydro-quinolin-4-yl} -N-phenyl-propionamide (A-107) was prepared (±) -c / s-N-. { 2-methyl-1- [4- (4-methyl-piperazin-1-yl) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -N-phenyl-proponamide from (±) -c / sN- [1- (4-bromo-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide. Combine (±) -c / sN- [1- (4-bromo-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide ( 100 mg, 0.22 mmol) with cesium carbonate (355 mg, 1.09 mmol), racemic BINAP (25 mg, 0.04 mmol), Pd2dba3 (36 mmol, 0.04 mmol) and 1-methyl-piperazine. and the mixture was dissolved in toluene (10 ml). The reaction mixture was heated to 100 ° C in an argon atmosphere overnight. The reaction was cooled to room temperature, filtered and the solids washed with ether. The filtrate was washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by HPLC. 1 H NMR (CDCl 3) d: 1.2 (6 H, m), 1.3 (1 H, m), 2.2 (3 H, m), 2.3 (3 H, s), 2.5 (4 H, m), 3.2 (4 H, m), 4.7 (1 H, m), 5.6 (1 H, sa), 6.6 (1 H, d), 6.7 (2 H, d), 7.0 (1 H, m), 7.2-7.4 (9 H, m). MS m / z: 498 (M + 2) (±) -C / sN- [2-methyl-1- (4-pyrimidin-2-yl-benzoyl) -1,2,3,4-tetrahydro-quinoline- 4-yl] -N-phenyl-propionamide (A-108) was prepared (±) -c / sN- [2-methyl-1- (4-pyrimidin-2-yl-benzoyl) -1, 2, 3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide following general procedure A, substituting furoyl chloride for 4-pyrimidin-2-yl-benzoyl chloride and acetyl chloride for propionyl chloride. 1 H NMR (CDCl 3) d: 1, 2 (7 H, m), 2.3 (3 H, m), 4.8 (1 H, m), 5.6 (1 H, a), 6.5 (1 H, d), 6.9 (1 H, m), 7.2-7.4 (10 H, m), 8.3 (2 H, d), 8.8 (2 H, d) . MS m / z: 478 (M + 2). (±) -C / sN- [2-methyl-1 - (4-methyl-3,4-dihydro-2H-benzo [1,4] oxazine-7-carbonyl) -1, 2,3,4-tetrahydro -quinolin-4-yl] -N-phenyl-propionamide (A-109) was prepared (±) -c / sN- [2-methyl-1- (4-methyl-3,4-dihydro-2H-benzo [ 1, 4] oxazine-7-carbonyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide following general procedure A, substituting 2-furoyl chloride for 4-chloride methyl-3,4-dihydro-2H-benzo [1,4] oxazine-7-carbonyl and acetyl chloride by propionyl chloride. 1 H NMR (CDCl 3) d: 1.1 (6H, m), 1.3 (1H, t), 2.3 (3H, m), 2.8 (3H, s), 3.3 (2H, t ), 4.2 (2H, t), 4.7 (1 H, m), 5.6 (1 H, a), 6.3 (1 H, d), 6.5 (1 H, d), 6.6 ( 1 H, d), 6.9 (1 H, s), 7.0 (1 H m), 7.1 (1 H, m), 7.3-7.4 (7 H, m). MS m / z: 471 (M + 2). (±) -C / sN- [2-methyl-1- (4-morpholin-4-yl-benzoyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide ( A-110) Prepared (±) -c / sN- [2-methyl-1- (4-morpholin-4-yl-benzoyl) -1, 2,3,4-tetrahydro-quinolin-4-ylj-N -phenyl-propionamide from (±) -c / sN- [1- (4-bromo-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl -propionamide, following the procedure used to prepare (±) -c / sN-. { 2-methyl-1- [4- (4-methyl-piperazin-1-yl) -benzoyl] -1,2,3,4-tetrahydro-quinoIin-4-yl} -N-phenyl-propionamide substituting 1-methyl-piperazine for morpholine. Separated (±) -c / sN- [2-methyl-1- (4-morpholin-4-yl-benzoyl) -1, 2,3,4-tetrahydro-quinolin-4-ylj-N-phenyl-propionamide by chiral HPLC using a chiral OD cell column and eluting with a 90% isocratic hexane / 10% ethanoI system to give (2R, 4S) - and (2S, 4R) - c / sN- [2-methyl-1 - (4-morpholin-4-yl-benzoii) -1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide (A-120 and A-119, respectively). 1 H NMR (CDCl 3) d: 1.1 (7H, m), 2.3 (3H, m), 3.1 (4H, t), 3.8 (4H, t), 4.7 (1H, m), 5.6 (1H, a), 6.6 (1H, d), 6.7 (2H, d), 6.9 (1H, m), 7.2-7.4 (9H , m). MS m / z: 485 (M + 2). (±) -C / s-N-. { 1 - [4- (2,5-Dimethyl-pyrrol-1-yl) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -N-phenyl-propionamide (A-111) was prepared (±) -c / s-N-. { 1- [4- (2,5-dimethyl-pyrrol-1-yl) -benzoyl] -2-methyl-, 2,3,4-tetrahydro-quinolin-4-yl} -N-phenol-propionamide from (±) -c / sN- [1- (4-amino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4- il] -N-phenyl-propionamide. A solution of (±) -c / sN- [1- (4-amino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide (150 mg, 0.36 mmol) and propionic acid (0.5 ml) in dry benzene (20 ml) was heated to reflux in an argon atmosphere in a flask equipped with a Dean-Stark trap while stirring to the exclusion of light . The resulting solution was cooled to room temperature and concentrated in vacuo. The recovered oil was purified by chromatography on silica gel, eluting with hexane-ethyl acetate (3: 1) to give the title compound (140 mg, 80%). 1 H NMR (CDCl 3) d: 1, 2 (7H, m), 2.0 (6H, s), 2.3 (3H, m), 4.8 (1 H, m), 5.6 (1H, a), 5.9 (2H, s), 6.5 (1H, d), 6.9 (1H, m), 7.0 (1H, d), 7.2 (2H, m) , 7.3-7.4 (8H, m). MS m / z: 493 (M + 2). (±) -C / s-N-. { 1- [4- (2-ethyl-butylamino) -benzoyl] -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl} -N-phenyl-propionamide (A-112) was prepared (±) -c / s-N-. { 1- [4- (2-eti) butylamino) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -N-phenyl-propionamide from (+) - c / sN- [1 - (4-amino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N -pheni-propionamide. To a solution of (±) -c / sN- [1- (4-amino-benzoyl) -2-methyI-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide ( 75 mg, 0.145 mmol) in dichloromethane (3 ml) was added in one portion 2-ethylbutyraldehyde (26 μl, 0.2 mmol). The mixture was stirred at room temperature for 0.5 h before a solution of sodium triacetoxyborohydride (74 mg, 0.348 mmol) and 1 ml of DCM was added slowly. A single drop of acetic acid was added and the reaction was allowed to stir at room temperature overnight. The excess reagent is quenched by the addition of saturated aqueous sodium bicarbonate. The resulting mixture was extracted three times with 20 ml of dichloromethane. The combined extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by HPLC to yield the title compound (60 mg, 83%). 1 H NMR (CDCl 3) d: 0.9 (6H, m), 1.2 (7H, m), 1.4 (5H, m), 2.3 (3H, m), 3.0 (2H, d ), 4.7 (1H, m), 5.6 (1H, a), 6.3 (2H, d), 6.6 (1H, d), 7.0 (1H, m), 7 , 1 (2H, d), 7.2 (1 H,), 7.3-7.4 (6H, m). MS m / z: 499 (M + 2). (±) -C sN- [2-Methyl-1- (4-propylamino-benzoyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide (A-113) prepared (±) -c / sN- [2-methyl-1- (4-propylamino-benzoyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide from (±) -c / sN- [1- (4-amino-benzoyl) -2-methyl-1, 2 , 3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide using the reductive amination conditions described for the synthesis of (±) -c / sN-. { 1 - [4- (2-Ethyl-butylamino) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -N-phenyl-propionamide. 2-Ethylbutyraldehyde was replaced by propionaldehyde. The reaction was poorly selective and produced approximately equivalent amounts of mono- and di-alkylated products (i.e., (±) -c / sN- [1- (4-dipropylamino-benzoyl) -2-methyl-1, 2,3 , 4-tetrahydro-quinolin-4-yl] -N-phenol-propionamide I, see below). 1 H NMR (CDCl 3) d: 1.0 (3H, m), 1.1 (7H, m), 1.6 (2H, m), 2.3 (3H, m), 3.0 (2H, d) ), 4.0 (1 H, a), 4.7 (1 H, m), 5.6 (1 H, a), 6.3 (2 H, d), 6.6 (1 H, d), 6 , 9 (1H, m), 7.06 (2H, d), 7.14 (1H, m), 7.3-7.4 (6H, m). MS m / z: 457 (M + 2). (±) -C / sN- [1- (4-dipropylamino-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide (A-114) (±) -c / sN- [1- (4-dipropylamino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-ylj-N-phenyl-propionamide was prepared as a sub- product in the synthesis of (±) -c / sN- [2-methyl-1- (4-propylamino-benzoyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phen 1-propionamide described above. 1 H NMR (CDCl 3) d: 1.0 (6H, t), 1.1 (6H, m), 1.4 (1H, m), 1.5 (4H, m), 2.3 (3H, m ), 3.2 (4H, t), 4.7 (1 H, m), 5.6 (1 H, a), 6.4 (2H, d), 6.7 (1 H, d), 7.0 (1 H, m), 7.1-7.2 (3H, m), 7.3-7.4 (6H, m). MS m / z: 499 (M + 2). (±) -C / sN- [2-methyl-1- (4-pyrrolidin-1-yl-benzoyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide ( A-115) Prepared (±) -c / sN- [2-methyl-1- (4-pyrrolidin-1-yl-benzoyl) -1, 2,3,4-tetrahydro-quinolin-4- il] -N-phenyl-propionamide from (±) -c / sN- [1- (4-bromo-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl- N-Phenyl-propionamide following the procedure used to prepare (±) -c / sN-. { 2-methyl-1- [4- (4-methyl-piperazin-1-yl) -benzoyl] -1,2,3,4-tetrahydro-quinoxy-4-yl} -N-phenyl-propionamide substituting 1-methylpiperazine for pyrrolidine. 1 H NMR (CDCl 3) d: 1.1 (7H, m), 2.0 (4H, m), 2.3 (3H, m), 3.2 (4H, m), 4.7 (1H, m), 5.6 (1H, a), 6.3 (2H, d), 6.6 (1H, d), 6.9 (1H, m), 7.1-7.4 (9H, m ). MS m / z: 468 (M + 1). (±) -C / sN- [2-methyl-1- (4-ureido-benzoyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide (A-116) (±) -c / sN- [2-methyl-1- (4-ureido-benzoyl!) -1,2,4,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide was prepared from of (±) -c / sN- [1- (4-amino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyI-propionamide. A mixture of (±) -c / sN- [1 - (4-amino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenol-propionam NaH (100 mg, 0.24 mmol) and trimethylsilyl isocyanate (120 μL, 30.72 mmol) in dry DMF (0.5 mL) was stirred at room temperature for 3 days and then concentrated under reduced pressure and at room temperature. ° C to dryness. The residual syrup was stirred with ethyl acetate to which an additional 10 ml of ethyl acetate was added with 10 ml of water. The pH was adjusted to 3.0 with 3 N HCl and the separated aqueous layer was extracted with ethyl acetate. The combined ethyl acetate extracts were washed with water and brine, dried over magnesium sulfate and concentrated in vacuo to yield the product (10 mg, yield 9%). 1 H NMR (CDCl 3) d: 1.2 (7H, m), 2.3 (3H, m), 4.7 (1 H, m), 5.1 (2H, a), 5.6 (1 H , a), 6.5 (1H, d), 6.9 (5H, m), 7.2 (7H, m), 7.9 (1H, a). MS m / z: 457 (M + 1). Acid methyl ester (±) -c / s-2-. { 4- [4- (Acetyl-phenyl-amino) -2-methyl-3,4-dihydro-2H-quinoline-1 -carbonyl] -phenylamino} -propionic (A-117) Methyl ester of (±) -c / s-2- acid was prepared. { 4- [4- (acetyl-phenyl-amino) -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl-phenylamino} -propionic acid from (±) -c / sN- [1- (4-amino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide. A mixture of (±) -c / sN- [1- (4-amino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyI-propionamide (210 mg, 0.53 mmol), potassium carbonate (123 mg, 0.89 mmol) and methyl 2-bromopropionate (70 μl., 0.63 mmol) in dry dimethylformamide (2 ml) was heated at 100 ° C for 6 h, then cooled to room temperature and stirred with 20 ml of water until all the salts were dissolved. The aqueous layer was separated and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting oil was purified by chromatography on silica gel, eluting with (97: 3 methylene chloride / methanol) to yield the title compound (220 mg, 87%). 1 H NMR (CDCl 3) d: 1, 2 (4 H, m), 1, 4 (3 H, d), 2.0 (3 H, s), 2.3 (1 H, a), 3.7 (3 H, s), 4.1 (1H, m), 4.7 (1H, m), 5.6 (1H, a), 6.3 (2H, d), 6.6 (1H, d), 6, 9 (1H, m), 7.0 (2H, d), 7.3-7.4 (7H, m). MS m / z: 487 (M + 2). (±) -C / s-2-. { 4- [4- (Acetyl-phenyl-amino) -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl] -phenylamino} -propionamide (A-118) was prepared (±) -c / s-2-. { 4- [4- (acetyl-phenyl-amino) -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl] -phenylamino} -propionamide from methyl ester of acid (±) -c / s-2-. { 4- [4- (acetyl-phenyl-amino) -2-methyl-3,4-dihydro-2H-quinolyl-1-carbonyl-phenylaminoj-propionic acid. Concentrated ammonium hydroxide (2 ml, 2.0 M) was added methyl ester of (±) -c / s-2- acid. { 4- [4- (acetyl-phenylamino) -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl] -phenylamino} -propionic crude (180 mg, 0.37 mmol) and a minimum amount of ammonium chloride; the mixture was heated at 100 ° C for 6 h in a pressure reactor with good mixing. After cooling to 0 ° C, the resulting precipitate was filtered, washed with ice-cold water and extracted with ether. The combined extracts were washed with water and brine, dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by HPLC to give the title compound (10 mg, 6%). 1 H NMR (CDCl 3) d: 1, 2 (4 H, m), 1, 5 (3 H, d), 2.1 (3 H, s), 2.3 (1 H, a), 3.8 (1 H , s), 4.4 (2H, a), 4.7 (1H, m), 5.6 (2H, m), 6.3 (2H, m), 6.6 (2H, d), 7 , 0 (1H, m), 7.1 (2H, d), 7.2 (1 H, m), 7.3-7.4 (5H, m). MS m / z: 471 (M + 1) (±) - C / sN- [1- (3-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide (A-123) was prepared (±) -c / sN- [1- (3-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4- il] -N-phenyl-acetamide following general procedure A, substituting 2-furoyl chloride for 3-methoxybenzoyl chloride. Separated (±) -c / sN- [1- (3-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide by chiral HPLC using a chiral OD cel column and eluting with 90% hexane / 10% ethanol Socratic system to give (2R, 4S) - and (2S, 4R) - c / sN- [1- (3-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinoIin-4-yl] -N-phenyl-acetamide (A-126 and A-127, respectively). 1 H NMR (CDCl 3) d: 1.15 (3 H, d; overlap of 1 H, t), 2.05 (3 H, s), 2.33 (1 H, m), 3.60 (3 H , s), 4.80 (1 H, m), 5.65 (1 H, m), 6.55 (1 H, d), 6.75-6.85 (3 H, complex), 6, 95 (1 H, t), 7.15 (1 H, t), 7.25 (1 H, t), 7.25-7.55 (6 H, m). MS m / z: 415 (M + 1). (±) -7ra / 7s-N- [1 - (3-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide (A- 124) (±) -frans-N- [1- (3-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl- was prepared acetamide following general procedure A, substituting 2-furoyl chloride for 3-methoxybenzoyl chloride and c / s- (2-etiI-1, 2,3,4-tetrahydro-quinoIin-4-yl) -phenyl-amine for fraA? s- (2-ethyl-1, 2,3,4-tetrahydro-quinolin-4-yl) -phenyl-amine. (±) -C / sN- [1- (3-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide (A-128) (±) -c / sN- [1- (3-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide was prepared following the procedure A, substituting 2-furoyl chloride for 3-methoxybenzoyl chloride and acetyl chloride for propionyl chloride. 1 H NMR (CDCl 3) d: 1, 15 (3 H, d; overlap of 3 H, t, 1 H, t), 2.20 (2 H, c), 2.33 (1 H, m), 3.65 ( 3H, s), 4.80 (1 H, m), 5.60 (1 H, m), 6.55 (1H, d), 6.75-6.85 (3H, complex), 6.95 (1 H, t), 7.15 (1 H, t), 7.20 (1 H, t), 7.25-7.55 (6H, m).
MS m / z: 429 (M + 1). (±) -C / sN- [6-chloro-1- (3-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N- (4-chloro phenyl) -acetamide (A-129) was prepared (±) -c / sN- [6-chloro-1- (3-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin -4-yl] -N- (4-chloro-phenyl) -acetamide following general procedure A, substituting 2-furoyl chloride for 3-methoxybenzoyl chloride and (±) -c / s- (2-methyl-1 , 2,3,4-tetrahydro-quinolin-4-yl) -phenyl-amine by (±) -c / s- (6-chloro-2-methyl-1, 2,3,4-tetrahydro-quinolin -4-yl) - (4-chloro-phenyl) -amine. It was synthesized (±) -c / s- (6-chloro-2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl) - (4-chloro-phenyl) -amine following the reactions indicated in Scheme 1, substituting aniline for 4-chloroaniline. 1 H NMR (CDCl 3) d: 1, 15 (3 H, d; overlap of 1 H, t), 2.02 (3 H, s), 2.35 (1 H, m), 3.65 (3 H, s), 4.80 (1 H, m), 5.60 (1 H, m), 6.42 (1 H, d), 6.65-6.95 (overlap of 1 H, d; 1 H, dd; 1H, dd), 7.15 (1H, t), 7.20-7.30 (6H, m), 7.40 (1H, d). MS m / z: 484 (M + 1). (±) -C / sN- [2-methyl-1- (1-methyl-1H-pyrrole-2-carbonyl) -1,2,3,4-tetrahydroquinoline-4-yl] -N- phenyl-acetamide (A-130) (±) -c / sN- [2-methyl-1- (1-methyl-1 H-pyrrole-2-carbonyl) -1,2,3,4-tetrahydro- quinolin-4-yl] -N-phenyI-acetamide following the general procedure A, substituting 2-furoyl chloride for 1-methyl-1H-pyrrole-2-carbonyl chloride. 1 H NMR (CDCl 3) d: 1, 12 (3 H, d; overlap of 1 H, t), 2.00 (3 H, s), 2.35 (1 H, m), 3.80 (3 H, s) , 4.70 (1H, m), 5.50 (1H, m), 5.80 (1H, d), 6.55 (1H, d), 6.80 (1H, d), 7, 00 (1 H, t), 7.20-7.50 (6H, m). MS m / z: 388 (M + 1). (±) -C / sN- [2-methyl-1- (2-methyl-pyridine-4-carbonyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide ( A-131) Prepared (±) -c / sN- [2-methyl-1- (2-methyl-pyridine-4-carbonyl) -1, 2,3,4-tetrahydro-quinolin-4-yl ] -N-phenyl-proponamide following general procedure A, substituting 2-furoyl chloride for 2-methyl-isonicotinoyl chloride and acetyl chloride for propionyl chloride. 1 H NMR (CDCl 3) d: 1, 11-1, 16 (3H, d; overlap of 3H, t, and 1H, t), 2.20-2.35 (overlap of 2H, c; and 1 H, m ), 2.47 (3H, s), 4.80 (1 H, m), 5.60 (1 H, m), 6.48 (1 H, d), 6.65 (1 H, d) , 6.85 (1 H, t), 7.10-7.40 (8H, m), 8.30 (1 H, d). MS m / z: 414 (M + 1). (±) -C / sN- [1 - (4-Fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -3-methyl-N-phenyl-butyramide ( A-132) Prepared (±) -c / sN- [1- (4-fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -3-methyl- N-phenyl-butyramide following general procedure A, substituting 2-furoyl chloride for 4-fluorobenzoyl chloride and acetyl chloride for 3-methyl-butyryl chloride. 1 H NMR (CDCl 3) d: 0.90 (2 x 3H, d), 1, 15 (3H, d; overlap of 1H, t), 2.15 (1H, m), 2.20-2.35 (overlap of 2H, m; 1H, m), 4.80 (1H, m), 5.65 (1H, m), 6.50 (1H, d), 6.90 (4H, complex), 7.20-7.60 (8H, m). MS m / z: 445 (M + 1). (±) -C / sN- [2-methyl-1- (6-methyl-pyridine-3-carbonyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide ( A-133) Prepared (±) -c / sN- [2-methyl-1- (6-methyl-pyridine-3-carbonyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] - N-Pheni-propionamide following general procedure A, substituting 2-furoyl chloride for 6-methyl-nicotinoyl chloride and acetyl chloride for propionyl chloride. 1 H NMR (CDCl 3) d: 1, 11-1, 16 (3 H, d; overlap of 3 H, t, and 1 H, t), 2.20-2.40 (overlap of 2 H, c, and 1 H, m), 2.49 (3H, s), 4.80 (1H, m), 5.60 (1H, m), 6.48 (1H, d), 6.80-7.00 (1 H, d; 1 H, t), 7.10-7.50 (9H, m), 8.60 (1 H, d). MS m / z: 414 (M + 1). (±) -C / sN- [1 - (4-f luoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -2-morpholin-4-yl-N phenyl acetamide (A-134) was prepared (±) -c / sN- [1- (4-fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -2-morpholin-4-yl-N-phenyl-acetamide following general procedure A, substituting 2-furoyl chloride for 4-fluorobenzoyl chloride and acetyl chloride for morpholinoacetyl chloride.
(±) -C / sN- [1 - (2,3-dihydro-benzo [1,4] dioxin-6-carbonyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl ] -N-phenyl-propionamide (A-135) was prepared (±) -c / sN- [1- (2,3-dihydro-benzo [1,4] dioxin-6-carbonyl) -2-methyl-1 , 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide following general procedure A, substituting 2-furoyl chloride for (±) -c / s-2,3-dihydrochloride benzo [1,4] dioxin-6-carbonyl and acetyl chloride per propionyl chloride. 1 H NMR (CDCl 3) d: 1, 10 (3 H, d; overlap of 3 H, t; 1 H, t), 2,10 (2 H, c, 1 H, m), 4.10 (2 x 2 H, m) , 4.70 (1H, m), 5.65 (1H, m), 6.50-6.60 (2 x 1H, d), 7.20-7.40 (7H, m). MS m / z: 457 (M + 1). (±) -C / sN- [2-methyl-1- (5-trifluoromethyl-thiophene-2-carbonyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide ( A-136) Prepared (±) -c / sN- [2-methyl-1- (5-trifluoromethyl-thiophene-2-carbonyl) -1, 2,3,4-tetrahydro-quinoxy-4 -yl] -N-phenyl-propionate following general procedure A, substituting 2-furoyl chloride for 5-trifluoromethyl-thiophene-2-carbonyl chloride and acetyl chloride for propionyl chloride. 1 H NMR (CDCl 3) d: 1, 10-1, 15 (3 H, d; overlap of 3 H, t; 1 H, t), 2.15-2.35 (2 H, c, 1 H, m), 4, 70 (1 H, m), 5.55 (1H, m), 6.45 (1 H, d), 6.85 (1H, d), 7.00-7.20 (overlap of 1H, d; 1 H, t), 7.20-7.60 (7H, m). MS m / z: 473 (M + 1). (±) -C / sN- [2-methyl-1- (6-trifluoromethyl-pyridine-3-carbonyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide ( A-137) Prepared (±) -c / sN- [2-methyl-1- (6-trifluoromethyl-pyridine-3-carbonyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] - N-phenyl-propionamide following general procedure A, substituting 2-furoyl chloride for 6-trifluoromethyl-nicotinoyl chloride and acetyl chloride for propionyl chloride. 1 H NMR (CDCl 3) d: 1, 10 (3 H, d; overlap of 3 H, t; 1 H, t), 2.00-2.40 (2 H, c, 1 H, m), 4.80 (1 H, m), 5.65 (1 H, m), 6.40 (1 H, d), 7.00 (1 H, d), 7.20-7.50 (9H, m), 8.70 ( 1 HOUR). MS m / z: 468 (M + 1).
(±) -C / sN- [2-methyl-1- (3-methyl-isoxazole-5-carbonyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide ( A-138) Prepared (±) -c / sN- [2-methyl-1- (3-methyl-isoxazole-5-carbonyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] - N-phenyl-propionamide following general procedure A, substituting 2-furoyl chloride for 3-methyl-isoxazole-5-carbonyl chloride and acetyl chloride for propionyl chloride. 1 H NMR (CDCl 3) d: 1.10 (overlap of 3 H, d; 3 H, t; 1 H, t), 2.10- 2.40 (overlap of 3H, s; 2H, c; 1H, m), 4.80 (1H, m), 5.50 (1H, m), 6.80 (1H, d), 7.10 (1 H, t), 7.20-7.50 (9H, m). MS m / z: 404 (M + 1). (±) -C / sN- [2-methyl-1 - (4-oxazol-5-yl-benzoyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide ( A-139) was prepared (±) -c / sN- [2-methyl-1- (4-oxazol-5-yl-benzoyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] - N-phenyl-propionamide following general procedure A, substituting 2-furoyl chloride for 4-oxazol-5-yl-benzoyl chloride and acetyl chloride for propionyl chloride. 1 H NMR (CDCl 3) d: 1, 00-1, 20 (overlap of 3 H, t; 3 H, d; 1 H, t), 2.20-2.40 (2 H, c; 1 H, m), 4 , 80 (1 H, m), 5.65 (1 H, m), 6.55 (1 H, d), 6.90 (1 H, t), 7.20-7.60 (12H, m ), 7.90 (1 H, s). MS m / z: 466 (M + 1). (±) -C / sN- [1- (benzo [c] isoxazole-3-carbonyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide ( A-140) Prepared (±) -c / sN- [1- (benzo [c] isoxazole-3-carbonyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] - N-phenyl-propionamide following general procedure A, substituting 2-furoyl chloride for benzo [c] isoxazole-3-carbonyl chloride and acetyl chloride for propionyl chloride. 1 H NMR (CDCl 3) d: 1, 14 (3H, t); 1, 23 (3H, d), 2.20 (2H, c), 2.40 (1H, m), 4.80 (1H, m), 5.60 (1H, m), 6.60 (1H , d), 7.00 (3H, complex), 7.00-7.40 (8H, m), 7.55 (1H, d). MS m / z: 440 (M + 1).
Acid (±) -c sN- [1 - (4-Fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-succinamic acid ester (A) -141) Methyl ester of (±) -c / sN- [1- (4-fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N was prepared phenyl-succinic following the general procedure A, substituting 2-furoyl chloride for 4-fluorobenzoyl chloride and acetyl chloride for 3-chlorocarbonyl-propionic acid methyl ester. (±) -C s-N-. { 1- [5- (4-chloro-phenyl) -furan-2-carbonyl] -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl} -N-phenyl-propionamide (A-142) (±) -c / s-N- was prepared. { 1- [5- (4-chloro-phenyl) -furan-2-carbonyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -N-phenyl-propionamide following general procedure A, substituting 2-furoyl chloride for 5- (4-chloro-phenyl) -furan-2-carbonyl chloride and acetyl chloride for propionyl chloride. H NMR (CDCl 3) d: 1, 08-1, 36 (7H, m), 2.15-2.35 (3H, m), 4.72 (1H, c), 5.40-5.60 ( 1H, a), 6.53 (2H, d), 6.89 (1H, d), 7.04-7.09 (1H, m), 7.17-7.40 (10H, m) . MS m / z: 499 (M + 1). (±) -C / s-N-. { 1- [5- (2-Chloro-4-trifluoromethyl-phenyl) -furan-2-carbonyl] -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl} -N-phenyl-propionamide (A-143) was prepared (±) -c / s-N-. { 1 - [5- (2-Chloro-4-trifluoromethyl-phenyl) -furan-2-carbonyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -N-phenyl-propionamide following general procedure A, substituting 2-furoyl chloride for 5- (2-chloro-4-trifluoromethyl-phenyl) -furan-2-carbonyl chloride and acetyl chloride for propionyl chloride . 1 H NMR (CDCl 3) d: 1, 08-1, 36 (7H, m), 2.15-2.35 (3H, m), 4.72 (1H, c), 5.40-5.60 ( 1H, a), 6.78-6.87 (2H, m), 7.05-7.49 (11H, m). MS m / z: 567 (M + 1). (±) -C / s-N-. { 2-methyl-1- [5- (4-nitro-phenyl) -furan-2-carbonyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -N-phenyl-propionamide (A-144) was prepared (±) -c / s-N-. { 2-methyl-1- [5- (4-nitro-phenyl) -furan-2-carbonyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -N-phenyl-propionamide propionamide following general procedure A, substituting 2-furoyl chloride for 5- (4-nitro-phenyl) -furan-2-carbonyl chloride and acetyl chloride for propionyl chloride. 1 H NMR (CDCl 3) d: 1.13-1.22 (7H, m), 2.20-2.36 (3H, m), 4.70 (1H, c), 5.40-5.60 ( 1H, a), 6.70 (2H, d), 6.87 (1H, d), 7.03 (1H, t), 7.25-7.47 (8H, m), 8.15 (2H, d). MS m / z: 510 (+1). (±) -C / sN- [2-methyl-1- (5-methyl-isoxazole-3-carbonyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide ( A-145) Prepared (±) -c / sN- [2-methyl-1- (5-methyl-isoxazole-3-carbonyl) -1, 2,3,4-tetrahydro-quinolin-4-yl ] -N-phenyl-propionamide following general procedure A, substituting 2-furoyl chloride for 5-methyl-isoxazole-3-carbonyl chloride and acetyl chloride for propionyl chloride. 1 H NMR (CDCl 3) d: 1, 10-1, 27 (7H, m), 2.13-2.35 (6H, m), 4.78 (1H, c), 5.40-5.60 (1 H, a), 6.84-6.86 (1 H, d), 7.05 (1 H, t), 7.22-7.38 (7H, m). MS m / z: 404 (M + 1). (±) -C / sN- [2-methyl-1 - (2-methyl-thiophene-3-carbonyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide ( A-146) Prepared (±) -c / sN- [2-methyl-1- (2-methyl-thiophene-3-carbonyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] - N-phenyl-propionamide following general procedure A, substituting 2-furoyl chloride for 2-methyl-thiophene-3-carbonyl chloride and acetyl chloride for propionyl chloride. 1 H NMR (CDCl 3) d: 1, 01-1, 27 (7H, m), 2.13-2.39 (6H, m), 4.62-4.78 (1 H, m), 5.40 -5.60 (1 H, a), 6.31-6.45 (2H, m), 6.60-6.83 (2H, m), 7.02-7.38 (6H, m). MS m / z: 420 (M + 1). [1- (4-Fluoro-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -phenyl-amide of (±) -c / s-but-3-enoic acid (A-147) [1- (4-Fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -phenyl-amide of (±) -c / acid was prepared s-¿>ut-3-enoic following general procedure A, substituting 2-furoyl chloride for 4-fluorobenzoyl chloride and acetyl chloride for but-3-enoyl chloride. 1 H NMR (CDCl 3) d: 0.98-1, 17 (4H, m), 2.13-2.29 (1 H, m), 2.98-3.15 (2H, m), 4.60 -4.78 (1 H, m), 4.98-5.20 (2H, m), 5.40-5.60 (1 H, m), 5.70-5.91 (1H, m) , 6.40 (1 H, d), 6.75-7.46 (11 H, m). MS m / z: 429 (M + 1). (±) -C / s-N-. { 1 - [3- (4-Fluoro-phenyl) - [1,4] oxadiazole-5-carbonyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -N-phenyl-propionamide (A-148) (+) - c / s-N- was prepared. { 1- [3- (4-fluoro-phenyl) - [1,4] oxadiazole-5-carbonyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -N-phenyl-propionamide following general procedure A, substituting 2-furoyl chloride for 3- (4-fluoro-phenyl) - [1, 2,4] oxadiazole-5-carbonyl chloride and acetyl chloride for propionyl. 1 H NMR (CDCl 3) d: 1, 14 (3H, t), 1, 23-1, 25 (4H, m), 2.17-2.39 (3H, m), 4.78-4.80 ( 1 H, m), 5.40-5.60 (1 H, a), 7.03-7.09 (3H, m), 7.10-7.22 (4H, m), 7.24- 7.40 (4H, m), 7.97-8.02 (2H, m). MS m / z: 485 (M + 1). (±) -C / sN- (1-benzoyl-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl) -N-phenyl-acetamide (A-150) was prepared (±) - c / sN- (1-benzoyl-2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl) -N-phenyl-acetamide following the general procedure A, substituting 2-furoyl chloride for chloride of benzoyl 1 H NMR (CDCl 3) d: 1, 14 (3 H, d), 1, 58-1, 69 (1 H, m), 2.03 (3 H, s), 2.22-2.37 (1 H, m), 4.72-4.86 (1 H, m), 5.62 (1 H, s), 6.49 (1 H, d), 6.88 (1 H, t), 7.13 -7.46 (12H, m). MS m / z: 385 (M + 1). (±) -C / sN- [1- (4-chloro-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide (A-151) (±) -c / sN- [1- (4-chloro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide was prepared following the procedure General A, substituting 2-furoyl chloride for 4-chlorobenzoyl chloride. 1 H NMR (CDCl 3) d: 1, 14 (3 H, d), 1, 61 (1 H, s a), 2.03 (3 H, s), 2.24-2.36 (1 H, m), 4.71-4.83 (1 H, m), 5.51-5.69 (1 H, m), 6.48 (1 H, d), 6.93 (1 H, t), 7, 12-7.28 (7H, m), 7.35-7.40 (4H, m). MS m / z: 419 (M) (±) -C / sN- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] - N phenyl acetamide (A-152) was prepared (±) -c / sN- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinoIin-4-yl] -N-phenyl-acetamide following general procedure A, substituting 2-furoyl chloride for 4-methoxybenzoyl chloride. 1 H NMR (CDCl 3) d: 1, 12 (3 H, d), 1, 65 (1 H, s a), 2.03 (3 H, s), 2.24-2.37 (1 H, m), 3.74 (3H, s), 4.66-4.84 (1H, m), 5.53-5.70 (1H, m), 6.50-6.54 (1H, d), 6, 68 (2H, d), 6.89-6.96 (1 H, m), 7.05-7.55 (9H, m). MS m / z: 415 (M + 1). (±) -C / sN- [2-methyl-1- (2-methyl-benzoyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide (A-153) (±) -c / sN- [2-methyl-1- (2-methyl-benzoyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide was prepared following the procedure General A, substituting 2-furoyl chloride for 2-toluoyl chloride. 1 H NMR (CDCl 3) d: 1, 11 (3H, d), 1, 60-1, 64 (1H, m), 1.97 (3H, s), 2.03-2.3 (4H, m) , 4.77-4.89 (1 H, m), 5.41-5.58 (1 H, m), 6.38-6.44 (1 H, m), 6.79 (1H, t ), 6.91-7.14 (4H, m), 7.16-7.28 (4H, m), 7.28-7.41 (3H, m). MS m / z: 399 (M + 1). (±) -C / sN- [1- (3,5-dimethyl-isoxazole-4-carbonyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl- acetamide (A-154) (±) -c / sN- [1- (3,5-dimethyl-isoxazole-4-carbonyl) -2-methyl-1, 2,3,4-tetrahydro-quinoline-4 was prepared -yl] -N-phenyl-acetamide following general procedure A, substituting 2-furoyl chloride for 3,5-dimethyl-isoxazole-4-carbonyl chloride. 1 H NMR (CDCl 3) d: 1, 13 (3 H, d), 1, 57-181 (3 H, m), 1, 96-2.03 (5 H, m), 2.15-2.63 (3H, m), 4.66-4.81 (1H, m), 5.41-5.50 (1H, m), 6.12 (1H, d), 7.03-7.15 ( 1 H, m), 7.24-7.48 (7H, m).
MS m / z: 404 (M + 1). (±) -C / sN- [1- (isoxazole-5-carbonyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide (A-155) (±) -c / sN- [1- (isoxazole-5-carbonyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide was prepared following the procedure A, substituting 2-furoyl chloride for isoxazole-5-carbonyl chloride. (+) - c / sN- [1- (isoxazole-5-carbonyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenylaltamide was separated by Chiral HPLC using a chiral OD cel column and eluting with a 90% hexane isocratic system / 10% ethanol to give (2R, 4S) - and (2S, 4R) - c / sN- [1- (isoxazole-5-carbonyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl -acetamide (A-70 and A-71, respectively). H NMR (CDCl 3) d: 1.12 (3H, d), 1.64 (1H, s), 1.96 (3H, s), 2.21-2.31 (1H, m), 4.63. -4.75 (1 H, m), 5.34-5.44 (1 H, s), 5.98 (1 H, s), 6.70 (1 H, d), 7.04 (1 H) , t), 7.21-7.35 (7H, m), 8.04-8.08 (1 H, m). MS m / z: 376 (M + 1). (±) -C / sN- (1-cyclohexanecarbonyl-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl) -N-phenyl-acetamide (A-157) Prepared (± ) -c / sN- (1-cyclohexanecarbonyl-2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl) -N-phenyl-acetamide following general procedure A, substituting 2-furoyl chloride for Cidohexanecarbonyl chloride. 1 H NMR (CDCl 3) d: 0.97 (3H, d), 1, 13-1, 27 (3H, m), 1, 31-1, 47 (2H, m), 1, 58-1, 89 ( 7H, m), 1, 99 (3H, s), 2.14-2.24 (1H, m), 2.62-2.71 (1H, m), 4.70-4.78 (1H, m), 5.24-5.29 (1 H, m), 7.07-7.10 (1H, m), 7.21-7.24 (2H, m), 7.28-7.33 (2H, m), 7.34-7.42 (4H, m). MS m / z: 391 (M + 1). (±) -C / sN- [2-methyl-1 - (pyridine-4-carbonyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide (A-158) (±) -c / sN- [2-methyl-1- (pyridine-4-carbonyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide was prepared following the procedure A, substituting 2-furoyl chloride for isonicotinoyl chloride. 1 H NMR (CDCl 3) d: 1, 16 (3 H, d), 2.04 (3 H, s), 2.25-2.35 (1 H, m), 4.75-4.83 (1 H, m), 5.56-5.67 (1 H, m), 6.45-6.48 (1 H, m), 6.92 (1 H, t), 7.08 (2H, d), 7.19 -7.27 (3H, m), 7.34-7.42 (4H, m), 8.49 (2H, d). MS m / z: 386 (M + 1). (±) -C / sN- [1 - (2,5-dimethyl-2H-pyrazole-3-carbonyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N- phenyl-acetamide (A-159) was prepared (±) -c / sN- [1- (2,5-dimethyl-2H-pyrazole-3-carbonyl) -2-methyl-1, 2,3,4-tetrahydro -quinolin-4-yl] -N-phenyl-acetamide following general procedure A, substituting 2-furoyl chloride for 2,5-dimethyl-2H-pyrazole-3-carbonyl chloride. 1 H NMR (CDCl 3) d: 1, 14 (3 H, d), 2.02 (3 H, m), 2.07 (3 H, m), 2.23-2.32 (2 H, m), 4.68-4.76 (1 H, m), 5.50 (1 H, s), 6.66 (1H, d), 7.04 (1 H, t), 7.21-7.28 (4H, m), 7.34-7.48 (4H, m). MS m / z: 404 (M + 1). (±) -C / sN- [2-methyl-1 - (pyridine-2-carbonyl) -1,2,3,4-tetrahydro-quinolin-4-yl N-phenyl-acetamide (A -160) Prepared (±) -c / sN- [2-methyl-1- (pyridine-2-carbonyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenol -acetamide following general procedure A, substituting 2-furoyl chloride for pyridine-2-carbonyl chloride. 1 H NMR (CDCl 3) d: 1, 17 (3 H, d), 1, 93-2.03 (1 H, m), 2.02 (3 H, s), 2.32 (1 H, s), 4, 78-4.86 (1 H, m), 5.60-5.61 (1H, m), 6.51 (1H, d), 6.86 (1H, t), 6.99 (1 H, d), 7.14-7.50 (9H, m), 8.53 (1H, d). MS m / z: 385 (M + 1). (±) -C / sN- [1- (isoxazole-5-carbonyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide (A- 161) (±) -c / sN- [1 - (isoxazole-5-carbonyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide following the general procedure A, substituting chloride 2-furoyl chloride by isoxazole-5-carbonyl. 1 H NMR (CDCl 3) d: 0.95-1, 20 (5H, m), 2.10-2.30 (4H, m), 4.69-4.74 (1 H, m), 5.30 - 5.43 (1 H, m), 5.96 (1 H, s), 6.75 (1H, d), 7.75 (1H, t), 7.25-7.38 (8H, m ), 8.06 (1H, s).
MS m / z: 390 (M + 1). Scheme 5 (+) - C / sN- [1- (3-Methoxy-benzenesulfonyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide (A-162) It was synthesized (±) -c / sN- [1- (3-methoxy-benzenesulfonyl) -2-methyl-1, 2,3,4-tetrahydro-quinoIin-4-yl] -N-phenyl-acetamida using general procedure A, substituting 2-furoyl chloride for 3-methoxy-benzenesulfonyl chloride. 1 H NMR (CDCl 3) d: 1, 4 (3 H, d), 1.4 (1 H, m), 1.9 (3 H, s), 2.0 (1 H, m), 3.6 (3 H, s ), 4.1 (1 H, m), 6.4 (1 H, m), 6.9-7.4 (12H, m), 7.7 (1 H, d). MS m / z: 451 (M + 1). Scheme 6 (+) - C / sN- [1- (3-Methoxy-benzyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide (A-164) It was synthesized (±) -c / sN ~ [1- (3-methoxy-benzyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenol-acetam Dissolve (±) -c / s- (2-methyl-1, 2,3,4-tetrahydroquinol-4-yl) -aniline in dimethylformamide and add potassium carbonate (1.0-10.0 equiv.), 1 - bromomethyl-3-methoxy-benzene (1-1.3.0 equiv.) and catalytic potassium iodide and the mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered to remove the inorganic salts and concentrated. The crude mixture was purified by flash chromatography on silica gel using an elution gradient of hexane-ethyl acetate (5-20%). Then, the corresponding aniline was added as previously described in general procedure A to give (±) -c / sN- [1- (3-methoxy-benzyl) -2-methyl-1, 2,3,4- tetrahydro-quinolin-4-yl] -N-phenyl-acetamide. 1 H NMR (CDCl 3) d: 1, 15 (3 H, d; overlap of 1 H, t), 1, 90 (1 H, m; 2 H, m), 2.00 (3 H, s), 3.33 (1 H , m), 3.60 (3H, s), 4.30 (1H, m), 6.30 (1H, complex), 6.90 (1H, t), 6.90-7.40 (1 OH , m). MS m / z: 443 (M + 1). (±) -C / sN- (1-Benzyl-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl) -N-phenyl-acetamide (A-165) was prepared (±) - c / sN- (1-benzyl-2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl) -N-phenyl-acetamide following the procedure describing the synthesis of A-164, substituting 1 - bromomethyl-3-methoxy-benzene by benzyl bromide. 1 H NMR (CDCl 3) d: 1, 15 (3 H, d; overlap of 1 H, t), 1, 90 (1 H, m; 2 H, m), 2.00 (3 H, s), 3.33 ( 1 H, m), 4.30 (1 H, m), 6.30 (1 H, m), 6.70 (1 H, t), 6.90-7.40 (11 H, m). MS m / z: 413 (M + 1). (±) -C / sN- (1-Ethyl-2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl) -N-phenyl-acetamide (A-166) was prepared (±) - c / sN- (1-ethyl-2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl) -N-phenyl-acetamide following the procedure describing the synthesis of A-164, substituting 1 - bromomethyl-3-methoxy-benzene by ethyl bromide. 1 H NMR (CDCl 3) d: 1, 01 (3H, t), 1, 15 (3H, d; overlap of 1 H, t), 1, 40 (1 H, m), 1, 90-2.00 (overlap of 3 H, s; 1 H, m), 3.20 (1 H, m), 3, 40 (1 H, c), 3.60 (1 H, m), 4.60 (1 H, s), 6.20 (1 H, a, m), 6.60-6.80 (2H, m), 7.00-7.50 (7H, m). MS m / z: 309 (M + 1). Methyl ester of (±) -c / s- [4- (acetyl-phenyl-amino) -2-methyl-3,4-dihydro-2H-quinolin-1-yl] -acetic acid (A-167) was prepared (±) -c / s- [4- (Acetyl-phenyl-amino) -2-methyl-3,4-dihydro-2H-quinolin-1-yl] -acetic acid methyl ester following the procedure described in the synthesis of A-164, substituting 1-bromomethyl-3-methoxy-benzene for bromo-acetic acid methyl ester. 1 H NMR (CDCl 3) d: 1, 20 (3 H, d; overlap of 1 H, t), 1.80 (1 H, m, 2.00 (3 H, s), 3.40 (1 H, m) , 3.70 (3H, s), 3.90 (2H, s), 4.50 (1H, m), 6.10 (1H, t), 6.20 (1H, d), 6.75 ( 1 H, m), 6.90-7.10 (3H, complex), 7.20-7.50 (3H, m) MS m / z: 353 (M + 1) .Acid (±) -c / s- [4- (Acetyl-phenyl-amino) -2-methyl-3,4-dihydro-2H-quinolin-1-yl] -acetic (A-168) Acid (±) -c / s- was prepared [4- (Acetyl-phenyl-amino) -2-methyl-3,4-dihydro-2H-quinolin-1-yl] -acetic acid from methyl ester of (±) -c / s- [4- ( acetyl-phenyl-amino) -2-methyl-3,4-dihydro-2H-quinolin-1-acetic acid To a solution of methyl ester of (±) -c / s- [4- ( acetyl-phenyl-amino) -2-methyl-3,4-dihydro-2H-quinolin-1-yl] -acetic acid was added 1.0N aqueous sodium hydroxide and heated at 80 ° C for 1 h. The reaction mixture was concentrated and the aqueous mixture was acidified to pH 6.0 using hydrochloric acid (1 N) followed by extraction twice with ethyl acetate.The organic extracts were dried over sodium sulfate. physician, filtered and concentrated to yield the desired product. 1 H NMR (CDCl 3) d: 1, 20 (3 H, d; overlap of 1 H, t), 1.80 (1 H, m, 2.00 (3 H, s), 3.40 (1 H, m) , 3.90 (2H, s), 4.50 (1 H, m), 6.10 (1H, t), 6.20 (1 H, d), 6.75 (1H, m), 6, 90-7.10 (3H, m), 7.20-7.50 (3H, m) MS m / z: 339 (M + 1) Scheme 7 (±) -c / s- (Acetyl-phenyl-amino) -2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid (3-methoxy-phenyl) -amide (A-169) synthesized (±) -c; s- (acetyl-phenyl-amino) -2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid (3-methoxy-phenyl) -amide using general procedure A , substituting 2-furoyl chloride for 3-methoxyphenylisocyanate using the following procedure. To a solution of (±) -c / s- (3-methoxy-phenyI) - (2-methyl-4-anilino-3,4-dihydro-2H-quinolin-1-yl) -methanone (0.1 g , 0.42 mmol) in toluene was added 3-methoxyphenylisocyanate (0.056 ml, 0.4255 mmol) and the reaction mixture was heated at 90 ° C for 18 hours. The reaction was cooled to room temperature and concentrated. The crude mixture was purified by flash chromatography on silica gel using an elution gradient of hexane-ethyl acetate (80% / 20%) to give 38% of the desired product. 1 H NMR (CDCl 3) d: 1, 1 (3 H, d), 1, 2 (1 H, m), 2.0 (3 H, s), 2.3 (1 H, m), 3.8 (3 H, s ), 4.5 (1 H, m), 5.4 (1 H, m), 6.6 (1 H, d), 6.8 (2 H, m) 7.1-7.5 (11 H , m). MS m / z: 430 (M + 1). Scheme 8 (±) -C / sN- (1-alkyl / aroyl-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl) -N-phenyl-alkyl / aryl-sulfonamide They can be prepared (±) -c / s-1- (2-methyl-4-phenylamino-3,4-dihydro-2H-quinolin-1-yl) -alkanone or (±) -c / s- (2-methyl-4-phenylamino- 3,4-dihydro-2H-quinolin-1-yl) -aryl-methanone from compound 1 using general procedure A, substituting acetyl chloride for the corresponding sulfonyl chloride. Scheme 9 (±) -C / s-1- [4- (alkyl-phenyl-amino) -2-methyl-3,4-dihydro-2H-quinolin-1-yl] -alkanone or (±) -c / s- 1- [4- (alkyl-phenyl-amino) -2-methyl-3,4-dihydro-2H-quinolin-1-yl] -aryl-methanone They can be prepared (±) -c / s-1 - [4- (alkyl-phenyl-amino) -2-methyl-3,4-dihydro-2H-quinolin-1-yl] -alkanone or (±) -c / s-1 - [4- (alkyl-phenyl-amino) - 2-methyl-3,4-dithy-2H-quinolin-1-yl] -aryl-methanone from compound 1 using general procedure A, substituting acetyl chloride for the corresponding alkyl chloride and using the Alkylation procedure in the synthesis of A-164. Representative examples of compound 35 are shown in the following table. Scheme 10 (±) -C / s-3-ethyl-1 - [1 - (3-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -1-phenyl- urea (A-170) It was synthesized (±) -c / s-3-ethyl-1- [1- (3-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin -4-yl] -1-phenyl-urea using general procedure A, substituting acetyl chloride for ethyl isocyanate using the following procedure. To a solution of (±) -c / s- (3-methoxy-phenyl) - (2-methyl-4-anilino-3,4-dihydro-2H-quinolin-1-yl) -methanone in DMF was added ethyl isocyanate and the reaction mixture was heated at 90 ° C for 18 hours. The reaction was cooled to room temperature and concentrated. The crude mixture was purified by flash chromatography on silica gel using an elution gradient of hexane-ethyl acetate (5-20%). 1 H NMR (CDCl 3) d: 1, 05-1, 20 (3H, t; overlap of 3H, d; and 1 H, t), 2.35 (1 H, m), 3.30 (2H, c) , 3.67 (3H, s), 4.36 (1 H, t), 4.80 (1 H, m), 5.65 (1 H, m), 6.50 (1 H, d), 6.65 (1H, d), 6.80 (1H, d), 6.85 (2H, complex), 7.00 (1H, t), 7.18 (1H, t), 7, 35-7.50 (6H, m). MS m / z: 444 (M + 1). The compounds A-163, A-171-A-232 can be prepared by the schemes indicated in Schemes 1-10 and by the general procedures A and others described herein. Those skilled in the art will be able to recognize, or determine, using only conventional experimentation, many equivalents of the specific embodiments of the invention described herein. Table 1: Compounds Obtained from General Procedure A Scheme 11 BF3OEt 11 (Exclusively cis) Benzyl ester of (±) -c / 's- (2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl) -carbamic acid (11) Aniline (3) was dissolved , 64 ml, 39.97 mmol, 1.0 eq.) In methylene chloride (100 ml), Na2SO4 (2 g) was added and cooled to -25 ° C. To the solution was added acetaldehyde (2.23 ml, 39.97 mmol, 1.0 equiv.) And stirred for 1 h at -25 ° C. The sodium sulfate was removed by filtration and benzyl ester of N-vinyl carbamic acid (7) was added., 07 g, 39.97 mmol, 1.0 equiv.) Was added to the filtrate at -25 ° C, followed by boron trifluoride diethyl etherate (0.50 ml, 3.9 mmol, 0.1 equiv.). The reaction was allowed to stir at -25 ° C for 1 h, then it was warmed to room temperature and stirred for 10 h. The reaction was evaporated in vacuo and the residue was purified by the ultra-rapid Biotage system (20% ethyl acetate / 80% hexane) to yield 4.0 g of (±) -c / s- (2) benzyl ester 33% methyl, 1,3,4-tetrahydro-quinolin-4-yl) -carbamic acid in the form of a white solid. 1 H NMR (300 MHz, CDCl 3) d: 7.38 (m, 5H), 7.17 (d, 1 H), 7.02 (t, 1H, C7-H), 6.68 (t, 1 H ), 6.47 (d, 1 H), 5.17 (sa, 2H), 5.07 (m, 1 H), 4.92 (d, 1 H), 3.57 (m, 1 H) , 2.30 (m, 1 H), 1.47 (c, 1H), 1, 21 (d, 3H). General Procedure B Scheme 12 ( Benzyl ester of (±) -c / s- [1- (4-dimethylamino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinol-4-yl] -carbamic acid ester (12) To a solution of (±) -c / s- (2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl) -carbamic acid benzyl ester (500 mg, 1.68 mmol) in chloride of methylene (20 ml) at room temperature was added diisopropylethylamine (542 mg, 749 μl, 4.2 mmol), followed by 4-dimethylaminobenzoyl chloride and the mixture was stirred at room temperature until no starting material remained. The mixture was poured into water and extracted with ethyl acetate. The extracts were washed with 1 M NaOH (aq) and brine, dried over sodium sulfate, filtered, dried and concentrated. The crude residue was purified by chromatography on silica gel (gradient of 100% hexanes to 70% hexanes / 30% ethyl acetate) to yield the amide (665 mg, 89%). 1 H NMR (300 MHz, CDCl 3) d: 1, 24 (d, 3 H), 1, 36 (m, 1 H), 2.75 (ddd, 1 H), 2.91 (s, 6 H), 4.79 - 4.92 (m, 3 H), 5.22 (s, 2 H), 6.43 (d, 2 H), 6.65 (d, 1 H), 6.90 (dd, 1 H), 7.07-7.18 (m, 5 H), 7.2-7.48 (m, 4 H). MS m / z: 444 (M + 1). (±) -C / s-1- (4-d-methylamino-benzoyl) -2-methyl-1,2,3,4-tetrahydro-4-aminoquinoline (13) Benzyl ester of (±) - acid was dissolved c / s- [1- (4-dimethylamino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -carbamic acid (665 mg, 1.49 mmol) in ethanol (30 ml). The resulting solution was evacuated and charged again with argon. A catalytic amount of palladium on carbon (10%) was added. The vessel was evacuated once more and this time it was again charged with hydrogen from a balloon. Then, the reaction was allowed to react at room temperature overnight under a hydrogen atmosphere. The reaction was completed after 18 h. The mixture was carefully filtered and concentrated to a volume of 10%. The resulting concentrated solution was filtered through an Acrodisc® and concentrated to yield the crude amine (423 mg, 92%). 1 H NMR (300 MHz, CDCl 3) d: 1, 19-1, 40 (m, 4 H), 2.76 (ddd, 1 H), 2.95 (s, 6 H), 4.08 (dd, 1 H), 4.81 (m, 1 H), 6.42 (d, 2 H), 6.64 (d, 1 H), 6.99 (dd, 1 H), 7.08 -7, 23 (m, 5 H), 7.52 (d, 1 H). MS m / z: 310 (M + 1). (±) -C / s-1 - (4-dimethylamino-benzoyl) -2-metiM, 2,3,4-tetrahydro-4 - (/ V-4-chlorophenyl) aminoquinoline (14) To a solution of (± ) -c / s-1- (4-dimethylamino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-4-aminoquinoline (423 mg, 1.36 mmol) in DMF (15 ml, dry) 4-chlorophenylboronic acid (425 mg, 2.72 mmol), pyridine (322 mg, 330 μL, 4.08 mmol) and copper (II) acetate (494 mg, 2.72 mmol) were added. The heterogeneous green mixture was stirred open in the air for 1 h and then heated to 60 ° C and stirred overnight (14 h). After the mixture was cooled to room temperature, stirred ethyl acetate was poured rapidly (150 ml); the solids were removed by filtration. The extracts were washed several times with water and then once with brine. Then, the extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel (gradient of 100% hexanes to 50/50 hexanes / ethyl acetate) to yield the aniline product (120 mg, 22% >) as a yellow oil . 1 H NMR (300 MHz, CDCl 3) d: 1, 22 (d, 3 H), 1, 36 (ddd, 1 H), 2.82 (ddd, 1 H), 2.95 (s, 6 H), 4.90 (sa, 1 H), 4.41 (day, 1 H), 4.87 (ddd, 1 H), 6.65 (d, 2 H), 6.62 - 6.76 (m, 3 H), 6.97 - 7.11 (m, 2 H), 7.17 - 7.29 (m, 5 H). MS m / z: 420 (M + 1) (±) -C / sN- (4-chloro-phenyl) -N- [1- (4-dimethylamino-benzoyl) -2-methyl-1, 2,3, 4-tetrahydro-quinolin-4-yl] -acetamide (15) To a solution of (±) -c / s-1- (4-dimethylamino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro -4- (? / - 4-chlorophenyl) aminoquinoline (120 mg, 0.29 mmol) in methylene chloride (2 ml) was added diisopropylethylamine (37 mg, 0.051 ml, 0.29 mmol) followed by acetyl chloride ( 2 ml). The mixture was stirred at room temperature for 4 h. The mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with sat. sodium bicarbonate. and brine and dried over sodium sulfate. The drying agent was removed by filtration under reduced pressure, concentrated and purified by chromatography on silica gel (gradient of 100% hexanes -25/75 hexanes / ethyl acetate) to produce (±) -c / sN- Pure (4-chloro-phenyl) -N- [1- (4-dimethylamino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide. mg, 34%). 1 H NMR (300 MHz, CDCl 3) d: 1, 14-1, 33 (m, 4 H), 2.13 (s, 3 H), 2.24-2.39 (m, 1 H), 2, 94 (s, 6 H), 4.75 (ddd, 1 H), 5.61 (sa, 1 H), 6.44 (d, 2 H), 6.63 (d, 1 H), 6, 96 (dd, 1 H), 7.07-7.36 (m, 6 H), 7.40 (d, 2 H). MS m / z: 420 (M + 1) (±) -C / sN- [1- (3-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] Non-tolyl-acetamide (B-1) was prepared (±) -c / sN- [1- (3-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinoline- 4-yl] -N-tolyl-acetamide following general procedure B, substituting 4-dimethylaminobenzoyl chloride for 3-methoxybenzoyl chloride and 4-chlorophenylboronic acid for 2-tolylboronic acid. 1 H NMR (CDCl 3) d: 1, 14 (d, 3 H), 1, 26 (s, 1 H), 1.58 (s, 3 H), 1, 97 (s, 3 H), 2.08 (m, 1 H), 3.63 (s, 3 H), 4.80 (sextuplet, 1 H), 5.55 (s, 1 H), 6.53 (d, 1 H), 6.76 (s, 1 H) ), 6.83 (t, 2H), 6.93 (t, 1 H), 7.10 (t, 1 H), 7.15-7.37 (m, 6H).
MS m / z: 429 (M + 1) N- (4-Chloro-phenyl) -N- [1- (3-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinoline- 4-yl] -acetamide (B-2) was prepared (±) -c / sN- (4-chloro-phenyl) -N- [1- (3-methoxy-benzoyl) -2-methyl-1, 2, 3,4-tetrahydroquinoline-4-yl] -acetamide following the general procedure B, substituting 4-dimethylaminobenzoyl chloride for 3-methoxybenzoyl chloride. Separated (±) -c / sN- (4-chloro-phenyl) -N- [1- (3-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl ] -acetamide by chiral HPLC using a chiral OD cell column and eluting with a 90% hexane socratic system / 10% ethanol to give (2R, 4S) - and (2S, 4R) -c / sN- (4 -chloro-phenyl) -N- [1- (3-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide (B-9 and B-8, respectively) 1 H NMR (CDCl 3) d: 1, 17 (d, 3 H), 1, 25 (t, 1 H), 2.03 (s, 3 H), 2.29 (m, 1 H), 3.62 (s) , 3H), 4.80 (sextuplet, 1 H), 5.60 (s, 1 H), 6.54 (d, 1 H), 6.74 (s, 1 H), 6.80 (t, 1 H), 6.93 (t, 1 H), 7.08 (t, H), 7.14-7.30 (m, 5H), 7.38 (d, 2H). MS m / z: 449 (M + 1) (±) -C / sN- (4-chloro-phenyl) -N- [2-methyl-1- (thiophene-2-carbonyl) -1,2,3, 4-tetrahydro-quinolin-4-yl] -acetamide (B-3) was prepared (±) -c / sN- (4-chloro-phenyl) -N- [2-methyl-1- (thiophene-2-carbonyl ) -1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide following general procedure B, substituting 4-dimethylaminobenzoyl chloride for 2-thiophenecarbonyl chloride.
Separated (±) -c / sN- (4-chloro-phenyl) -N- [2-methyl-1- (thiophene-2-carbonyl) -1, 2,3,4-tetrahydro-quinolin-4-yl ] -acetamide was by chiral HPLC using a chiral OD cell column and eluting with a 90% isocratic hexane / 10% ethanol system to give (2R, 4S) - and (2S, 4f?) - c / sN- ( 4-chloro-phenyl) -N- [2-methyl-1- (thiophene-2-carbonii) -1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide (B-7 and B-6 , respectively). 1 H NMR (300 MHz, CDCl 3) d: 1, 11-1, 24 (m, 4 H), 2.03 (s, 3 H), 2.22-2.35 (m, 1 H), 4, 73 (ddd, 1 H), 5.52 (sa, 1 H), 6.69 (dd, 1 H), 6.67 (dd, 1 H), 6.89 (d, 1 H), 7, 08 (dd, 1 H), 7.21 (d, 2 H), 7.27-7.43 (m, 5 H). MS m / z: 425 (M + 1). (±) -C / sN- (4-chloro-phenyl) -N- [2-methyl-1 - (5-methyl-thiophene-2-carbonyl) -1, 2,3,4-tetrahydro-quinolin-4 -yl] -isobutyramide (B-4) was prepared (±) -c / sN- (4-chloro-phenyl) -N- [2-methyl-1- (5-methyl-thiophene-2-carbonyl) -1 , 2,3,4-tetrahydro-quinolin-4-yl] -isobutyramide following general procedure B, substituting 4-dimethylaminobenzoyl chloride for 5-methyl-2-thiophenecarbonyl chloride and acetyl chloride for isobutyryl chloride. Separated (±) -c / sN- (4-chloro-phenyl) -N- [2-methyl-1 - (5-methyl-thiophene-2-carbon-1) -1, 2,3,4-tetrahydro -quinolin-4-yl] -isobutyramide by chiral HPLC using a chiral OD cell column and eluting with a 90% isocratic hexane / 10% ethanol system to give (2R, 4S) - and (2S, 4R) -c / sN- (4-chloro-phenyl) -N- [2-metii-1- (5-methyl-thiophene-2-carbonyl) -1, 2,3,4-tetrahydro-quinolin-4-yl ] -isobutyramide (B-11 and B-10, respectively). 1 H NMR (CDCl 3) d: 1, 13 (d, 6 H), 1, 16 (d, 3 H), 1, 25 (m, 1 H), 2.23 (m, 3 H), 2.39 (s, 1 H), 2.60 (septuplet, 1 H), 4.66 (sextuplet, 1 H), 5.50 (sa, 1 H), 6.42 (s, 1 H), 6.51 (s, 1 H), 6.93 (d, 1 H), 7.08 (t, 1 H), 7.21 (d, 2H), 7.27 (d, 2H), 7.37 (sa, 2H). MS m / z: 468 (M + 1) (±) -C / sN- [1- (4-fluoro-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N- (4-fluoro-phenyl) -prnamide (B-5) was prepared (±) -c / sN- [1- (4-fluoro-benzoyl) -2-methyl-1, 2,3, 4-tetrahydro-quinoIin-4-yl] -N- (4-fluoro-phenyl) -prnamide following general procedure B, substituting 4-dimethylaminobenzoyl chloride for 4-fluorobenzoyl chloride, 4-chlorophenylboronic acid for 4-fluorophenylboronic acid and acetyl chloride by prnyl chloride. 1 H NMR (CDCl 3) d: 1, 14 (t, 3 H), 1.15 (d, 3 H), 1, 24 (m, 1 H), 2.26 (m, 3 H), 4.75 (sextuplet, 1H), 5.61 (br s, 1H), 6.46 (d, 1H), 6.87 (m, 3H), 7.10-7.26 (m, 8H). MS m / z: 435 (M + 1) (±) -C / sN- (4-chloro-3-methyl-phenyl) -N- [1- (4-fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -prnamide (B-12) was prepared (±) -c / sN- (4-chloro-3-methyl-phenyl) -N- [1 - (4 -fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -prnamide following general procedure B, substituting 4-dimethylaminobenzoyl chloride for 4-fluorobenzoyl chloride, acetyl chloride for prnyl chloride and 4-chlorophenic acid boric acid for 4-chloro-3-tolylboric acid. 1 H NMR (CDCl 3) d: 1, 08 (t, 3 H), 1, 09 (d, 3 H), 1, 18 (m, 1 H), 2.18 (m, 3 H), 2.31 (s, 3H), 4.69 (sextuplet, 1H), 5.49 (sa, 1H), 6.42 (d, 1H), 6.79 (t, 2H), 6.86 (t, 1H), 6, 96 (dd, 1 H), 7.05-7.22 (m, 6H). MS m / z: 465 (M + 1). (±) -C / sN- [1- (4-Fluoro-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N- (4-trifluoromethyl-phenyl) - propionamide (B-13) was prepared (±) -c / sN- [1- (4-fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N- (4-trifluoromethyl-phenyl) -propionamide following general procedure B, substituting 4-dimethylaminobenzoyl chloride for 4-fluorobenzoyl chloride, acetyl chloride for propionyl chloride and 4-chlorophenylboronic acid for 4-trifluoromethylphenylboronic acid. 1 H NMR (CDCl 3) d: 1, 15 (t, 3 H), 1, 17 (d, 3 H), 1, 20 (m, 1 H), 2.29 (m, 3 H), 4.79 (sextuplet, 1 H), 5.62 (sa, 1 H), 6.49 (d, 1 H), 6.87 (m, 3H), 7.19-7.28 (m, 6H), 7.41 (d, 1 H), 7.69 (d, 1 H). MS m / z: 485 (M + 1). (±) -C / sN- (4-chloro-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] - propionamide (B-14) was prepared (±) -c / sN- (4-chloro-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro -quinolin-4-yl] -propionamide following general procedure B, substituting 4-dimethylaminobenzoyl chloride for 4-methoxybenzoyl chloride and acetyl chloride for propionyl chloride. Separated (±) -c / sN- (4-chloro-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4 -yl] -propionamide by chiral HPLC using a chiral OD cell column and eluting with a 90% isocratic hexane / 10% ethanol system to give (2R, 4S) - and (2S, 4R) -c / sN- ( 4-chloro-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -propionamide (B-18 and B-17 , respectively). 1 H NMR (CDCl 3) d: 1, 14 (t, 3 H), 1, 15 (d, 3 H), 1, 25 (t, 1 H), 2.29 (m, 3 H), 3.74 (s, 3 H) ), 4.74 (sextuplet, 1 H), 5.61 (sa, 1 H), 6.53 (d, 1 H), 6.68 (d, 2H), 6.93 (t, 1 H) , 7.14-7.28 (m, 6H), 7.38 (d, 2H). MS m / z: 463 (M + 1). (±) -Cfs-N- (4-chloro-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] - Acetamide (B-15) (±) -c / sN- (4-Chloro-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4 was prepared -tetrahydro-quinolin-4-yl] -acetamide following the general procedure B, substituting 4-dimethylaminobenzoyl chloride for 4-methoxybenzoyl chloride. Separated (±) -c / sN- (4-chloro-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl ] -acetamide by chiral HPLC using a chiral OD cell column and eluting with a 90% hexane socratic system / 10% ethanol to give (2R, 4S) - and (2S, 4R) -c / sN- (4 -chloro-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide (B-34 and B- 35, respectively). 1 H NMR (CDCl 3) d: 1, 14 (d, 3 H), 1, 25 (t, 1 H), 2.04 (s, 3 H), 2.29 (m, 1 H), 3.74 (s) , 3H), 4.74 (sextuplet, 1 H), 5.61 (sa, 1 H), 6.53 (d, 1H), 6.68 (d, 2H), 6.93 (t, 1 H) ), 7.14-7.28 (m, 6H), 7.38 (d, 2H). MS m / z: 449 (M + 1). (±) -C / sN- (4-chloro-phenyl) -N- [1- (4-hydroxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] - propionamide (B-16) was prepared (±) -c / sN- (4-chloro-phenyl) -N- [1- (4-hydroxy-benzoyl) -2-methyl-1, 2,3,4 -tetrahydro-quinolin-4-yl] -propionamide from (±) -c / sN- (4-chloro-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2 , 3,4-tetrahydro-quinoIin-4-yl] -proponamide. It was dissolved (±) -c / sN- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide (0.548 g , 0.001 mol) in dichloromethane and a solution of BBr3 (1.0 M in dichloromethane, 10 ml) was added; the reaction was allowed to stir at room temperature for 4 h or until no starting material remained. The reaction was carefully washed with sat. NaHCOs. and brine. The organic extracts were dried over MgSO, filtered and concentrated. The phenol was concentrated and the residue was purified by flash chromatography Biotage using 100% EtOAc to give a white solid, yield 74%. 1 H NMR (CDCl 3) d: 1, 09 (d, 3 H), 1, 11 (t, 3 H), 1, 19 (m, 1 H), 2.26 (m, 3 H), 4.74 (sextuplet, 1H), 5.54 (sa, 1H), 6.46 (d, 1H), 6.53 (d, 1H), 6.96 (t, 1H), 7.14-7.40 (m, 9H). MS m / z: 415 (M + 1). (±) -C / s-N- [1- (4-fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -Np-tolyl-propionamide (B-21) was prepared (±) -c / sN- [1- (4-fluoro-benzoyl) -2-methyl -1, 2,3,4-tetrahydro-quinolin-4-yl] -Np-tolyl-proponamide following general procedure B, substituting 4-dimethylaminobenzoyl chloride for 4-fluorobenzoyl chloride, acetyl chloride for propionyl chloride and 4-chlorophenylboronic acid for 4-tolyloric acid. 1 H NMR (300 MHz, CDCl 3) d: 1, 05-1, 21 (m, 7 H), 2.11-2.54 (m, 6 H), 4.73 (ddd, 1 H), 5, 56 (br s, 1 H), 6.37 d, 1 H), 6.8-7.0 (m, 3 H), 7.1-7.4 (m, 8 H). MS m / z: 431 (M + 1). (±) -C / sN- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] - acetamide (B-22) was prepared (±) -c / sN- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrah Figure imgf000018_0001 Figure imgf000018_0001 Figure imgf000018_0001 Figure imgf000018_0001 Figure imgf000018_0001 Figure imgf000018_0001 Figure imgf000018_0001 Figure imgf000018_0001 Figure imgf000018_0001 Figure imgf000018_0001 Figure imgf000018_0001 Figure imgf000018_0001 Figure imgf000018_0001 Separated (±) -c / sN- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl ] -acetamide by chiral HPLC using a chiral OD cell column and eluting with a 95% hexane socratic system / 5% ethanol to give (2R, 4S) - and (2S, 4R) -c / sN- (4 -chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide (B-26 and B-27, respectively). 1 H NMR (CDCl 3) d: 1.1 (d, 3 H), 1.1 (m, 1 H), 2.0 (d, 3 H), 2.3 (m, 1 H), 4.7 ( m, 1 H), 5.6 (m, 1 H), 6.5 (d, 1 H), 6.7-7.0 (m, 3H), 7.1-7.4 (m, 8 H). MS m / z: 436 (M + 1). (±) -C / sN- (4-chloro-phenyl) -N- [2-methyl-1- (5-methyl-thiophene-2-carbonyl) -1,2,354-tetrahydro-quinolin-4-yl] - acetamide (B-24) (±) -c / sN- (4-chloro-phenyl) -N- [2-methyl-1- (5-methyl-thiophene-2-carbonyl) -1, 2,3 was prepared , 4-tetrahydro-quinolin-4-yl] -acetamide following general procedure B, substituting 4-dimethylaminobenzoyl chloride for 5-methyl-2-thiophenecarbonyl chloride. Separated (±) -c / sN- (4-chloro-phenyl) -N- [2-methyl-1 - (5-methyl-thiophene-2-carbonyl) -1,2,3,4-tetrahydro-quinoline -4-yl] -acetamide by chiral HPLC using a cel column Chiral OD and eluting with an isocratic system of 90% hexane / 10% ethanol to give (2R, 4S) - and (2S, 4R) -c / sN- (4-chloro-phenyl) -N- [2- methyl-1- (5-methyl-thiophene-2-carbonyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide (B-28 and B-25, respectively). 1 H NMR (CDCl 3) d: 1.1 (3 H, d), 1.1 (1 H, m), 2.0 (3 H, d), 2.3 (1 H, m), 2.4 (3 H, s), 4.7 (1 H, m), 5.6 (1 H, m), 6.4 (1 H, m), 6.6 (1 H, m), 7.0 (1 H, m), 7.1 (1 H, m), 7.2-7.4 (6H, m). MS m / z: 439 (M + 1). (±) -C / sN- (4-chloro-phenyl) -N- [2-methyl-1- (5-methyl-thiophene-2-carbonyl) -1,2,3,4-tetrahydro-quinolin-4 -yl] -propionamide (B-29) was prepared (±) -c / sN- (4-chloro-phenyl) -N- [2-methyl-1- (5-methyl-thiophene-2-carbonyl) -1 , 2,3,4-tetrahydro-quinolin-4-yl] -propionamide following general procedure B, substituting 4-dimethylaminobenzoyl chloride for 5-methyl-2-thiophenecarbonyl chloride and acetyl chloride for propionyl chloride. 1 H NMR (CDCl 3) d: 1, 1-1, 2 (7H, m), 2.1-2.3 (3H, m), 2.3 (3H, s), 4.8 (1 H, m ), 5,6 (1 H, m), 6, .2-6.4 (2H, m), 6.8-7.4 (8H, m). MS m / z: 452 (M + 2). Ethyl ester of (±) -c / s-4- (4- { 4 - [(4-chloro-phenyl) -propionyl-amino] -2-methyl-3,4-dihydro-2H-quinoline- 1-carbonyl.}. -phenoxy) -butyric acid (B-30). (±) -c / s-4- (4-. {4 - [(4-chloro-phenyl) -propionyl) ethyl ester was prepared. -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl.]. -phenoxy) -butyric from (±) -c / sN- (4-chloro-phenyl) -N- [1- (4-hydroxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -propionamide. It was dissolved (±) -c / sN- (4-chloro-phenyl) -N- [1- (4-hydroxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] - propionamide (140 mg, 0.31 mmol) in DMF (5 ml) at room temperature. Sodium hydride (60% in oil, 32 mg, 0.81 mmol) was added and the mixture was allowed to stir for 30 min. Ethyl 4-bromobutyrate (207 mg, 1.06 mmol) was added and the reaction was allowed to stir overnight.
Ethanol was added and the reaction was concentrated in vacuo. The crude residue was purified by chromatography on silica gel (gradient of 80/20 hexanes / ethyl acetate - 50/50 hexanes / ethyl acetate) to yield the product (171 mg, 0.304 mmol, 98% >) . ? NMR (CDCl 3) d: 1, 1-1, 2 (7H, m), 1.3 (3H, t), 2.1 (2H, m), 2.3 (3H, m), 2.5 ( 2H, t), 3.9 (2H, t), 4.2 (2H, c), 4.8 (1H, m), 5.6 (1H, m), 6.5 (1H, d), 6.7 (2H, d), 6.9 (1H, t), 7.1-7.3 (6H, m), 7.4 (2H, m). MS m / z: 563 (M + 1). Acid (±) -c / s-4- (4- { 4 - [(4-Chloro-phenyl) -propion-I-amino] -2-methyl-3,4-dihydro-2H-quinoline-1 -carbonyl.}. -phenoxy) -butyric acid (B-31) Acid (±) -c / s-4- (4-. {4 - [(4-chloro-phenyl) -propionyl-amino] - 2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl.] - phenoxy) -butyric acid from (±) -c / s-4- (4-. {4- [(4-chloro-phenyl) -propionyl-amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl] -phenoxy) -butyric acid. Potassium carbonate (300 mg) water (5 ml) was dissolved and (+) - c / s-4- (4-. {4 - [(4-cyoro-phenyl) -propionyl) ethyl ester was added. -amino] -2-methylene-3,4-dihydro-2H-quinoline-1-carbonyl-] - phenoxy) -butyric acid (171 mg, 0.303 mmol) dissolved in methanol (5 ml). The reaction was allowed to stir overnight at room temperature. The methanol was removed in vacuo and hydrochloric acid (1 N) was added until the reaction became acidic. Dichloromethane was added, extracted 2 times; and the organic blends were dried over magnesium sulfate, filtered and concentrated to yield the carboxylic acid (50 mg, 31%). 1 H NMR (CDCl 3) d: 1, 1-1.2 (7H, m), 2.0 (2H, m), 2.3 (2H, m), 2.4 (3H, m), 3.3 (1H, s), 4.0 (2H, t), 4.8 (1H, m), 5.6 (1H, m), 6.5 (1H, d), 6.7 (2H, d), 6.9 (1 H, t), 7.1-7.3 (3H, m), 7.4-7.6 (5H, m). MS m / z: 535 (M + 1). (±) -C / s-N- (4-chloro-phenyl) -N-. { 2-methyl-1- [4- (1 H -tetrazol-5-ylmethoxy) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -propionamide (B-32) (±) -c / s-N- (4-chloro-phenyl) -N- was prepared. { 2-methyl-1- [4- (1 H-tetrazol-5-ylmethoxy) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -propionamide from (±) -c / sN- (4-chloro-phenyl) -N- [1- (4-hydroxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinoIin- 4-yl] -proponamide.
It was dissolved (±) -c / s-N- (4-chloro-phenyl) -N- [1- (4-hydroxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -propionamide (700 mg, 1.42 mmol) in DMF (10 mL) at room temperature. Sodium hydride (60%) in oil, 227 mg, 5.68 mmol) was added and the mixture was allowed to stir for 30 min. Bromoacetonitrile (850 mg, 7.11 mmol) was added and the reaction was allowed to stir overnight. Ethanol was added and the reaction was concentrated in vacuo. The crude residue was purified by chromatography on silica gel (30/70 ethyl acetate / dichloromethane) to yield the product (320 mg, 42%). The nitrile (140 mg, 0.25 mmol) was dissolved in toluene, sodium azide (160 mg, 2.5 mmol) and triethylammonium hydrochloride (345 mg, 2.5 mmol) were added and the mixture was heated to 80 °. C for one night. The reaction was cooled to room temperature and water was added followed by hydrochloric acid (1 N) until it became acidic. The aqueous solution was extracted three times with dichloromethane. The combined extracts were dried over magnesium sulfate, filtered, dried and concentrated. The crude product was triturated with ethyl ether / hexanes to give a white solid (82 mg, 63%). ? NMR (CDCl 3) d: 1.0-1.2 (7H, m), 2.2-2.4 (3H, m), 4.8 (1H, m), 5.2 (2H, dd) , 5.6 (1 H, m), 6.7 (2H, m), 6.9 (1 H, t), 7.1 (2H, d), 7.2-7.6 (7H, m ). MS m / z: 531 (M + 1). (±) -C / sN- (4-chloro-phenyl) -N- [1 - (4-isobutoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] - acetamide (B-33) was prepared (±) -c / sN- (4-chloro-phenyl) -N- [1- (4-isobutoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro -quinolin-4-yl] -acetamide following general procedure B, substituting 4-dimethylaminobenzoyl chloride for 4-isobutyloxybenzoyl chloride. ? NMR (CDCl 3) d: 0.9-1.0 (8H, m), 1.2 (3H, d), 2.0 (3H, s), 2.3 (1H, m), 3.6 ( 2H, d), 4.7 (1H, m), 5.6 (1H, m), 6.5 (1H, d), 6.6 (2H, d), 6.9 (1H, m), 7.1-7.4 (8H, m). MS m / z: 491 (M + 1). (±) -C / s-N- (4-chloro-phenyl) -N-. { 1- [4- (3-hydroxy-2,2-dimethyl-propoxy) -benzoyl] -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl} -acetamide (B-37) was prepared (±) -c / s-N- (4-chloro-phenyl) -N-. { 1 - [4- (3-hydroxy-2,2-dimethyl-propoxy) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -acetamide from (±) -c / sN- (4-chloro-phenyl) -N- [1- (4-hydroxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinoline- 4-yl] -propionamide. It was dissolved (±) -c / sN- (4-chloro-phenyl) -N- [1- (4-hydroxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl ] -propionamide (210 mg, 0.484 mmol) in DMF (10 ml) at room temperature. Potassium carbonate (1 g, 7.1 mmol) was added followed by 3-bromo-2,2-dimethyl-propan-1-oI (813 mg, 4.84 mmol), the reaction was heated to 95 ° C and He stirred for one night. The reaction mixture was cooled to room temperature, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (95/5 dichloromethane / ethyl acetate - 70/30 dichloromethane / ethyl acetate) to yield the pure ester (0 mg, 44%). 1 H NMR (CDCl 3) d: 1.0 (6H, s), 1.1 (3H, d), 1.1 (1 H, m), 1.7 (1 H, a), 2.0 (3H , s), 2.3 (1 H, m), 3.5 (2 H, s), 3.7 (2 H, s), 4.8 (1 H, m), 5.6 (1 H, m) , 6.5 (1 H, d), 6.7 (2H, d), 6.9 (1 H, t), 7.1-7.3 (7H, m), 7.4 (1 H, d). MS m / z: 521 (M + 1). Acid methyl ester (±) -c / s-3- (4-. {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline- 1-carbonyl.}. -phenoxy) -2,2-dimethyl-propionic acid (B-38). (-) -c / s-3- (4- {4- [acetyl-) methyl ester was prepared. 4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl.] - phenoxy) -2,2-dimethyl-propionic from (±) -c / S N- (4-chloro-phenyl) -N- [1- (4-hydroxy-benzoyl) -2-methylene-1, 2,3,4-tetrahydro-quinolin-4-yl] -proponamide. It was dissolved (±) -c / sN- (4-chloro-phenyl) -N- [1- (4-hydroxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4- iI] -propionamide (400 mg, 0.92 mmol) in DMF (25 ml) at room temperature. Potassium carbonate (1 g, 7.1 mmol) was added followed by 3-bromo-2,2-dimethyI-propionic acid methyl ester (400 mg, 0.92 mmol), the reaction was heated to 95 ° C and He stirred for one night. The reaction mixture was cooled to room temperature, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (95/5 dichloromethane / ethyl acetate - 70/30 dichloromethane / ethyl acetate) to produce the pure ester (40 mg, 8%). ? NMR (CDCl 3) d: 1.1 (3H, d), 1.1 (1H, m), 1.3 (6H, s), 2.0 (3H, s), 2.3 (1H, m) , 3. 7 (3H, s), 3.9 (2H, dd), 4.8 (1H, m), 5.6 (1H, m), 6.5 (1H, d), 6.7 (2H , d), 6.9 (1 H, t), 7.1-7.3 (7H, m), 7.4 (1 H, d). MS m / z: 549 (M + 1). Acid (±) -c / s- (4- { Acetyl- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -amino .}.-phenyl) -acetic acid (B-39) Acid (±) -c / s- (4- { acetyl- [1- (4-methoxy-benzoyl) -2-methyl-1, 2 was prepared , 3,4-tetrahydro-quinolin-4-yl] -amino.}.-Phenyl) -acetic acid from (±) -c / sN- (4-cyanomethyl-phenyl) -N- [1- ( 4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide. Prepared (±) -c / sN- (4-cyanomethyl-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl ] -acetamide following general procedure B, substituting 4-dimethylaminobenzoyl chloride for 4-methoxybenzoyl chloride and 4-chlorophenylboronic acid for 4- (phenylboronic acid) -acetonitrile. It was dissolved (±) -c / sN- (4-cyanomethyl-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl ] -acetamide in ethanol (4 ml), potassium hydroxide (120 mg in 0.3 ml of water) was added and the reaction was heated at 80 ° C overnight. The ethanol was removed in vacuo and hydrochloric acid (1 N) was added until acid was made. Dichloromethane was added, extracted 2 times; and the combined organic extracts were dried over magnesium sulfate, filtered and concentrated to yield the carboxylic acid (30 mg) after purification by HPLC. ? NMR (CDCl 3) d: 1.1 (3H, d), 1.1 (1 H, m), 2.0 (3H, s), 2.3 (1 H, m), 3.6 (2H, s), 3. 8 (3H, s), 4.8 (1 H, m), 5.7 (1 H, m), 6.5 (1 H, m), 6.6 (2H, m), 6.9 ( 1H, m), 7.1-7.3 (8H, m). MS m / z: 495 (M + 23). Acid (±) -c / s-3-. { acetyl- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -amino} -benzoic acid (B-40) Acid (±) -c / s-3 was prepared. { acetyl- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -amino} -benzoic following the procedure for acid (±) -c / s- (4- { acetyl- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinoline- 4-yl] -amino.} - phenyl) -acetic, substituting 4- (phenyl boronic acid) -acetonitrile for 3-cyanophenylboronic acid. Basic hydrolysis of the nitrile using 1 N NaOH in methanol and water yielded both the carboxylic acid and the primary amide, (±) -c / 's-3. { acetyl- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinoIin-4-yl] -amino} -benzamida. 1 H NMR (CDCl 3) d: 1.1 (3 H, d), 1.1 (1 H, m), 2.0 (3 H, s), 2.3 (1 H, m), 3.8 (3 H, s), 4.8 (1 H, m), 5.6 (1 H, m), 6.5 (1 H, d), 6.6 (2 H, d), 6.9 (2 H, m), 7, 1-7.5 (5H, m), 7.9-8.2 (2H, m). MS m / z: 481 (M + 23). (±) -C / s-3-. { Acetyl- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -amino} -benzamide (B-41)? NMR (CDCl 3) d: 1.1 (3H, d), 1.1 (1H, m), 2.0 (3H, s), 2.3 (1H, m), 3.8 (3H, s) , 4.8 (1 H, m), 5.7 (1 H, m), 6.5 (1 H, m), 6.6 (2 H, m), 6.9 (1 H, m), 7 , 1-7.3 (4H, m), 7.4-7.6 (2H, m), 7.7-7.8 (2H, m). MS m / z: 480 (M + 23). (±) -C / sN- (4-Chloro-phenyl) -N- [1- (isoxazole-5-carbonyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] - propionamide (B-44) was prepared (±) -c / sN- (4-chloro-phenyl) -N- [1 - (isoxazole-5-carbonyl) -2-methyl- 1, 2,3,4-tetrahydro -quinolin-4-yl] -propionamide following general procedure B, substituting 4-dimethylaminobenzoyl chloride for 5-isoxazolecarbonyl chloride and acetyl chloride for propionyl chloride. 1 H NMR (CDCl 3) d: 1, 14 (3 H, d; overlap of 3 H, t, and 1 H, t), 2.30 (overlap of 2 H, c; and 1 H,), 4.75 (1 H, m ), 5.45 (1H, m), 6.00 (1H, d), 6.80 (1H, d), 7.10-7.40 (7H, m), 8.05 (1 H, s). MS m / z: 424 (M + 1). (±) -C / sN- (4-chloro-phenyl) -N- [1- (4-cyclopentyloxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] - Acetamide (B-45) was prepared (±) -c / sN- (4-chloro-phenyl) -N- [1- (4-cyclopentyloxy-benzoyl) -2-methyl-1, 2,3,4 -tetrahydro-quinolin-4-yl] -acetamide from (±) -c / sN- (4-chloro-phenyl) -N- [1- (4-hydroxy-benzoyl) -2-methyl-1, 2 , 3,4-tetrahydro-quinoIin-4-yl] -propionamide. To a solution of (+) - c / sN- (4-chloro-phenyl) -N- [1- (4-hydroxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4 -yl] -acetamide in dimethylformamide was added cyclopentyl bromide, potassium carbonate (3.0 equiv.) and potassium iodide (catalytic) and the mixture was heated at 65 ° C overnight. The reaction mixture was filtered to remove the inorganic salts and concentrated. The crude mixture was purified by flash chromatography on silica gel using an elution gradient of ethyl acetate-methanol (2-20% methanol) 1 H NMR (CDCl 3) d: 1.15 (3H, d; overlap of 1H, t), 1.57 (2H, m), 1.79 (3 x 2H, m), 2.04 (3H, s), 2.30 (1 H, m), 4.60- 4.80 (1H, c, 1 H, m), 5.60 (1 H, m), 6.50 (1 H, d), 6.62 (1 H, d), 6.90 (1 H , t), 7.10-7.30 (9H, m), 7.40 (1H, d). MS m / z: 504 (M + 1). (±) -C / s-N-. { 1 - [4- (4-Acetyl-piperazin-1-yl) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -N- (4-chloro-phenyl) -acetamide (B-46) was prepared (±) -c / s-N-. { 1- [4- (4-acetyl-piperazin-1-yl) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -N- (4-Chloro-phenyl) -acetamide from (±) -c / sN- (4-chloro-phenyl) -N- [1- (4-hydroxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -propionamide. It was dissolved (±) -c / sN- (4-chloro-phenyl) -N- [1- (4-hydroxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl ] -propionamide (1. 07 g, 2.39 mmol) in pyridine (5 ml) and trifluoromethanesulfonic anhydride (703 μl, 2.5 mmol) was added. The reaction was stirred at room temperature for 3 h. The reaction was partitioned between ether and water and the aqueous phase was extracted three times with ether. The combined extracts were dried over sodium sulfate, filtered and concentrated. The crude triflate was purified by chromatography on silica gel (gradient of 70/30 hexanes / ethyl acetate -40/60 hexanes / ethyl acetate) to yield (1.0 g, 74%) pure material. To the triflate, Pd2 (dba) 3, BINAP, cesium carbonate and 18-crown-6 ether in toluene was added N-acetyl-piperazine and the reaction mixture was heated to reflux for 18 hours. The reaction mixture was cooled to room temperature, filtered through Celite® and concentrated. The crude mixture was purified by flash chromatography on silica gel using an elution gradient of ethyl acetate-methanol (2-20%). 1 H NMR (CDCl 3) d: 1, 13 (3 H, d; overlap of 1 H, t), 2.02 (3 H, s), 2.10 (3 H, s), 2.35 (1 H, m), 3.20 (2 x 2H, m), 3.60 (2H, t), 3.70 (2H, t), 4.80 (1H, m), 5, 65 (1H, m), 6.55 (1H, d), 6.70 (1H, d), 6.95 (1H, t), 7.10-7.40 (9H, m). MS m / z: 546 (M + 1). (±) -C / sN- (3-chloro-phenyl) -N- [1 - (4-fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] - acetamide (B-50) was prepared (±) -c / sN- (3-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro -quinolin-4-yl] -acetamide following the general procedure B, substituting 4-dimethylaminobenzoyl chloride for 4-fluorobenzoyl chloride and 4-chlorophenylboronic acid for 3-chlorophenylboronic acid. H NMR (CDCl 3) d: 1, 16-1, 26 (4H, m), 2.05 (3H, s), 2.25-2.39 (1 H, m), 4.69 - 4.88 (1 H, m), 5.47 - 5.68 (1 H, broad), 6.49 (1 H, d), 6.84-6.97 (4 H, m), 7.18 - 7 , 42 (7 H, m). MS m / z 437 (M +), 439 (M + 2). (±) -C / sN- [1 - (4-Fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N- (4-phenoxy-phenyl) - acetamide (B-51) (±) -c / sN- [1- (4-Fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N was prepared - (4-phenoxy-phenyl) -acetamide following the general procedure B, substituting 4-dimethylaminobenzoyl chloride for 4-fluorobenzoyl chloride and 4-chlorophenylboronic acid for 4-phenoxyphenylboronic acid. 1 H NMR (CDCl 3) d: 1, 16-1, 18 (4H, m), 2.06 (3H, s), 2.34-2.38 (1H, m), 4.74-4.82 (1 H, m), 5.29 (1H, a), 6.47 (1H, d), 6.83-7.40 (16H, m). MS m / z: 496 (M + 1). (±) -C / sN- [1- (3-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-pyridin-2-yl-acetamide ( B-52) (±) -c / sN- [1- (3-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-pyridine was prepared 2-yl-acetamide following general procedure B, substituting 4-dimethylaminobenzoyl chloride for 3-methoxybenzoyl chloride and synthesis of N-pyridinyl instead of 4-chlorophenyl was performed using the following procedure.
Pd2 (dba) 3 (0.05 equiv.) And rac-BINAP (0.1 equiv.) Were added to a flask with degassed toluene and the mixture was stirred for 1 h. To the previous solution, 2-bromopyridine (1.1 equiv.) And NaO.sub.4 (1.1 equiv.) Were added and stirred for 30 min. (±) -c / s- (4-Amino-2-methyl-3,4-dihydro-2H-quinolin-1-yl) - (3-methoxy-phenyl) -methanone was dissolved in degassed toluene, added to The solution was heated to 100 ° C for 17 h. The reaction was diluted with ether and filtered through celite and concentrated. The compound was purified by Biotage with 20% EtOAc / 80% hexane to 30% EtOAc / 70% hexane to 50% EtOAc / 50% hexane to give 43% of the product. Acetyl (±) -c / s- (3-methoxy-phenyl) - [2-methyl-4- (pyridin-2-ylamino) -3,4-dihydro-2H-quinolin-1-yl] -methanone was acetylated with acetyl chloride as described above to give (±) -c / sN- [1- (3-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl ] -N-pyridin-2-yl-acetamide. 1 H NMR (CDCl 3) d: 1, 16 (d, 3 H), 1, 24 (t, 1 H), 2.02 (s, 3 H), 2.43 (m, 1 H), 3.61 (s) , 3H), 4.81 (sextuplet, 1 H), 5.65 (s, 1 H), 6.52 (d, 1 H), 6.75 (s, 1H), 6.79 (d, 2H) ), 6.90 (t, 1 H), 7.07 (t, 1H), 7.14 (t, 1H), 7.25-7.33 (m, 2H), 7.49 (d, 1H) ), 7.77 (t, 1 H), 8.56 (s, 1 H). MS m / z: 416.0 (M + 1). (±) -C / sN-cyclohexyl-N- [1- (3-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -acetamide (B-53) (±) -c / sN-Cyclohexyl-N- [1- (3-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide was prepared following the procedure General B, substituting 4-dimethylaminobenzoyl chloride for 3-methoxy benzoyl chloride, and synthesis of N-cyclohexyl was carried out in place of 4-phenophenyl using the following procedure. (±) -c / s- (4-amino-2-methyl-3,4-dihydro-2H-quinolin-1-yl) - (3-methoxy-phenyl) -methanone (1.0 eq. ) and cyclohexanone (1.0 equiv.) in ethanol and a catalytic amount of acetic acid was added. The reaction was stirred for ~ 30 minutes, NaBH4 (1.0 equiv.) Was added and stirred at room temperature for a further 2 h. More NaBH 4 (1.0 equiv.) Was added and stirred for a further 12 h. The reaction was concentrated and partitioned between CH2Cl2 and 1 N NaOH. The organic extracts were separated and dried over Na2SO4., filtered and concentrated. The compound was purified by Biotage with 30% EtOAc / 70% hexane to 50% EtOAc / 50% hexane to give 96% of the product. Cis- (±) -N- (4-cyclohexylamino-2-methyl-3,4-dihydro-2H-quinolin-1-yl) - (3-methoxy-phenyl) -methanone was acetylated with acetyl chloride as described above to give cis- (±) -N-cyclohexyl-N- [1- (3-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] - acetamide. 1 H NMR (CDCl 3) d: 1, 1-1, 45 (m, 6H), 1, 5-1, 75 (m, 3H), 1.85-2.2 (m, 3H), 2.3 ( s, 3H), 2.4 (m, 1H), 2.7 (m, 1H), 3.5 (c, 1H), 3.63 (s, 3H), 3.7 (m, 1H), 4.3 (dd, 1H), 4.90 (sextuplet, 1 H), 6.6 (t, 1 H), 6.7 (d, 1 H), 6.8 (s, 1 H), 6 85 (m, 2H), 7.0 (m, 3H). MS m / z: 421 (M + 1). (±) -C / sN- (5-chloro-pyridin-2-yl) -N- [1- (3-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4 -i (-) acetamide (B-54) was prepared (±) -c / sN- (5-cyoro-pyridin-2-yl) -N- [1- (3-methoxy-benzoyl) -2-methyl- 1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide following the general procedure B, substituting 4-dimethylaminobenzoyl chloride for 3-methoxy benzoyl chloride and adding the N-4-chloropyridinyl instead of 4-phenophenyl using the following procedure To a flask was added Pd2 (dba) 3 (0.05 equiv.molar) and rac-BINAP (0.1 equiv.) in degassed toluene and stirred for 1 h. the previous solution was added with 2,5-dichloropyridinepyridine (1.1 equiv.) and NaO.sub.2 (1.1 equiv.) and stirred for 30 min.The corresponding amine, (±) -c / s- (4) -amino-2-methyI-3,4-dihydro-2H-quinolin-1-yl) - (3-methoxy-phenyl) -methanone was dissolved in degassed toluene, added to the solution and heated at 60 ° C for 40 h The reaction was diluted with ether, filtered through celite and concentrated. The compound was purified by Biotage with 20% EtOAc / 80% hexane to give 45% of the product. It was acetylated (±) -c / s- [4- (5-chloro-pyridin-2-ylamino) -2-methyl-3,4-dihydro-2H-quinolin-1-yl] - (3-methoxy-phenyl) ) -metanone with propionyl chloride as described above to give (±) -c / sN- (5-chloro-pyridin-2-yl) -N- [1- (3-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide. 1 H NMR (CDCl 3) d: 1, 14 (t, 3 H), 1, 15 (d, 3 H), 1, 22 (m, 1 H), 2.31 (m, 3 H), 4.79 (sextuplet, 1 H), 5.64 (br s, 1 H), 6.44 (d, 1H), 6.81-6.92 (m, 3H), 7.10-7.22 (m, 4H), 7.43 (d, 1H), 7.72 (dd, 1 H), 8.50 (d, 1H). MS m / z: 452 (M + 1). (±) -C / sN- (4-chloro-phenyl) -N- [1- (4-methoxy-benzoyl) -2,5-dimethyl-1,2,3,4-tetrahydro-quinolin-4-yl ] -acetamide (B-55) was prepared (±) -c / sN- (4-chloro-phenyl) -N- [1- (4-methoxy-benzoyl) -2,5-dimethyl-1, 2 , 3,4-tetrahydro-quinolin-4-yl] -acetamide following the general procedure B, substituting aniline for 3-toluidine and 4-dimethylaminobenzoyl chloride for 4-methoxybenzoyl chloride. The reaction was not selective and (±) -c / sN- (4-chloro-phenyl) -N- [1- (4-methoxy-benzoyl) -2,7-dimethyl-1,2, was also obtained. 3,4-tetrahydro-quinolin-4-yl] -acetamide in a 1: 1 mixture with the product. 1 H NMR (CDCl 3) d: 1, 07 (d, 3 H), 1, 25 (t, 1 H), 1.91 (s, 3 H), 2.15 (m, 1 H), 2.43 (s, 3H), 3.76 (s, 3H), 4.26 (sextuplet, 1 H), 6.28 (d, 1 H), 6.33 (t, 1 H), 6.58 (t, 1 H) ), 6.62 (d, 2H), 6.77 (t, 1 H), 6.88 (d, 3H), 7.28 (m, 2H), 7.44 (d, 1 H). MS m / z: 463.0 (M + 1) (±) -C / sN- (4-chloro-phenyl) -N- [1- (4-methoxy-benzoyl) -2,7-dimethyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide (B-56) was prepared (±) -c / sN- (4-chloro-phenyl) -N- [1- (4-methoxy -benzoyl) -2,7-dimethyl-1, 2,3,4-tetrahydro-quinolin-4-yl-acetamide following general procedure B, substituting aniline for 3-toluidine and 4-dimethylaminobenzoyl chloride for 4-chloride methoxybenzoyl. The reaction was not selective and (±) -c / sN- (4-chloro-phenyl) -N- [1- (4-methoxy-benzoyl) -2,5-dimethyl-1, 2,3 was also obtained. 4-tetrahydroquinolin-4-yl] -acetamide in a 1: 1 mixture with the title compound. Separated (±) -c / sN- (4-chloro-phenyl) -N- [1- (4-methoxy-benzoyl) -2,7-dimethyl-1, 2,3,4-tetrahydro-quinolin-4 -yl] -acetamide by chiral HPLC using a cel column Chiral OD and eluting with an isocratic system of 90% hexane / 10% ethanol to give (2R, 4S) - and (2S, 4R) -c / sN- (4-chloro-phenyl) -N- [1- (4-methoxy-benzoyl) -2,7-dimethyl-1, 2,3,4-tetrahydro-quinolin-4-ill-acetamide (B-58 and B-57, respectively). 1 H NMR (CDCl 3) d: 1, 13 (d, 3 H), 1, 26 (t, 1 H), 2.03 (s, 3 H), 2.05 (s, 3 H), 2.27 (m, 1 H), 3.76 (s, 3H), 4.75 (sextuplet, 1 H), 5.59 (sa, 1 H), 6.35 (s, 1 H), 6.68 (d, 2H) ), 6.95 (d, 1H), 7.18 (m, 1H), 7.20 (d, 2H), 7.37 (d, 2H). MS m / z: 463.5 (M + 1) (±) - C / sN- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -6-methoxy-2-methyl- 1, 2,3,4-tetrahydro-quinolin-4-yl] -propionamide (B-59) was prepared (±) -c / sN- (4-chloro-phenyl) -N- [1- (4-fluoro -benzoyl) -6-methoxy-2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -propionamide following general procedure B, replacing aniline with 4-anisidine, -dimetiIaminobenzoyl by 4-fluorobenzoyl chloride and acetyl chloride by propionyl chloride. 1 H NMR (300 MHz, CDCl 3) d: 1, 08-1, 22 (m, 7 H), 2.09-2.38 (m, 3 H), 3.79 (s, 3 H), 4, 77 (ddd, 1 H), 5.58 (sa, 1 H), 6.41 - 6.50 (m, 2 H), 6.82 - 6.94 (m, 3 H), 7.16 - 7.32 (m, 4 H), 7.35-7.44 (m, 2 H). MS m / z = 481 (M + 1). (±) -C / sN- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -6-hydroxy-2-methyl-1,2,3,4-tetrahydro-quinolin-4 -yl] -propionamide (B-60) was prepared (±) -c / sN- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -6-hydroxy-2-methyl- 1 , 2,3,4-tetrahydro-quinoIin-4-yl] -propionamide from (±) -c / sN- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -6 -methoxy-2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -proponamide using the procedure described above for the preparation of (±) -c / sN- (4- chloro-phenyl) -N- [1- (4-hydroxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -propionamide. 1 H NMR (300 MHz, CDCl 3) d: 1, 04-1, 18 (m, 7 H), 2.07-2.41 (m, 5 H), 4.76 (ddd, 1 H), 5, 50 (sa, 1 H), 6.27 (d, 1 H), 6.36 (d, 1 H), 6.65 (s, 1 H), 6.70 - 6.91 (m, 3 H) ), 7.03-7.44 (m, 4 H). MS m / z: 467 (M + 1). (+) - C / sN- (4-chloro-phenyl) -N- [1 - (4-f luoro-benzoyl) -2,7-dimethyl-1, 2,3,4-tetrahydro-quinolin-4- il] -propionamide (B-61) was prepared (±) -c / sN- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -2,7-dimethyl-1, 2, 3,4-tetrahydro-quinolin-4-yl] -propionamide following general procedure B, substituting aniline for 3-toluidine, 4-dimethylaminobenzoyl chloride for 4-fluorobenzoyl chloride and acetyl chloride for propionyl chloride.
? NMR (300 MHz, CDCl 3) d: 1.10 (m, 7 H), 2.04 (s, 3H), 2.14-2.32 (m, 3 H), 4.74 (ddd, 1H) , 5.57 (sa, 1 H), 6.26 (s, 1 H), 6.81-6.98 (m, 4 H), 7.11-7.33 (, 4 H), 7, 31-7.43 (m, 2 H). MS m / z: 465 (M + 1). Acid methyl ester (±) -c / s- [4 - [(4-chloro-phenyl) -propionyl-amino] -1- (4-fluoro-benzoyl) -2-methyl-1,2,3,4 -tetrahydro-quinolin-6-yloxy] -acetic acid (B-62) (±) -c / s- [4 - [(4-chloro-phenyl) -propionyl-amino] -1- ( 4-fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-6-yloxy] -acetic from (±) -c / sN- (4-chloro-phenyl) -N- [1- (4-Fluoro-benzoyl) -6-hydroxy-2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -propionamide following the alkylation procedure of the phenol used to prepare the ester Ethyl (±) -c / s-4- (4- { 4 - [(4-Chloro-phenyl) -propionyl-amino] -2-methylene-3,4-d-hydro-2H -quinoline-1-carbonyl.}. -phenoxy) -butyric acid. Ethyl 4-bromobutyrate was replaced by ethyl bromoacetate. 1 H NMR (300 MHz, CDCl 3) d: 1, 07-1, 22 (m, 7 H), 2.10-2.38 (m, 3 H), 3.80 (s, 2 H), 4, 58 (s, 3 H), 4.75 (m, 1 H), 5.54 (sa, 1 H), 6.39 (m, 2 H), 6.81 - 6.94 (m, 3 H) ), 7.18-7.35 (m, 5 H, 7.36-7.44 (m, 2 H) MS m / z: 539 (M + 1). (±) -C / sN- ( 4-Chloro-phenyl) -N- [6- (2-diethylamino-ethoxy) -1- (4-fIuoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -propionamide (B-63) was prepared (±) -c / sN- (4-chloro-phenyl) -N- [6- (2-diethylamino-ethoxy) -1- (4-fluoro-benzoyl) -2- methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -propionamide from (±) -c / sN- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl ) -6-hydroxy-2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -propionamide following the alkylation procedure of phenol used to prepare (±) -c / ethyl acid ester s-4- (4- { 4 - [(4-Chloro-phenyl) -propionyl-amino] -2-methylene-3,4-d-H-d-2H-quinoline-1-carbonyl} -phenoxy) -butyric acid was replaced by ethyl 4-bromobutyrate by (2-bromo-ethyl) -diethyl-amine, 1 H NMR (300 MHz, CDCl 3) d: 0.95-1.1 (m, 13 H), 2.09-2.38 (m, 3 H), 2.51-2.77 (m, 4 H), 2.79-2.92 (m, 2 H), 3.86-4.08 ( m, 2 H), 4.76 (ddd, 1 H), 5.58 (sa, 1 H), 6.34 - 6.51 (m, 2 H), 6.78 - 6.94 (m, 3 H), 7.14-7.31 (m, 4 H), 7.37-7.42 (m, 2 H).
MS m / z: 566 (M + 1). Ethyl ester of (±) -c / s-2- [4 - [(4-chloro-phenyl) -propionyl-amino] -1- (4-fluoro-benzoyl) -2-methyl-1,2,3 , 4-tetrahydro-quinolin-6-yloxy] -2-methyl-propionic acid (B-64) Ethyl ester of (±) -c / s-2- [4 - [(4-chloro-phenyl)] was prepared ) -propionyl-amino] -1- (4-fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-6-yloxy] -2-methyl-propionic from (±) - c / sN- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -6-hydroxy-2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -properly following the alkylation procedure of phenol used to prepare (±) -c / s-4- (4- {4 - [(4-chloro-phenyl) -propionyl-amino) ethyl ester ] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl.] - phenoxy) -butyric acid. Ethyl 4-bromobutyrate was replaced by 2-bromo-2-methyl-propionic acid ethyl ester. 1 H NMR (300 MHz, CDCl 3) d: 1, 13-1, 28 (m, 10 H), 1.56 (s, 3 H), 1.58 (s, 3 H), 2.16-2, 29 (m, 3 H), 4.73 (ddd, H), 5.56 (sa, 1 H), 6.31-6.39 (m, 2 H), 6.76 -6.88 (m) , 3 H), 7.16-7.22 (m, 4 H), 7.38-7.41 (m, 2 H). MS m / z: 581 (M + 1). Acid (±) -c / s- [4 - [(4-chloro-phenyl) -propionyl-amino] -1- (4-fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro- quinolin-6-yloxy] -acetic acid (B-65) Acid (±) -c / s- [4 - [(4-chloro-phenyl) -propionyl-amino] -1- (4-fluoro-benzoyl) was prepared -2-methyl-1, 2,3,4-tetrahydro-quinoIin-6-yloxy] -acetic acid from (±) -c / s- [4 - [(4-chloro-phenyl)] - methyl ester - propionyl-amino] -1- (4-fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolyl-6-yloxy-acetic acid. To a solution of (±) -c / s- [4 - [(4-chloro-phenyl) -propionyl-amino] -1- (4-fIuoro-benzoyl) -2-methyl-1, 2-methyl ester. , 3,4-tetrahydro-quinolin-6-yloxy] -acetic acid (83 mg, 0.155 mmol) in methanol (3 ml) was added sodium hydroxide (1 M in water, 310 μl, 0.310 mmol). The reaction was stirred at room temperature for 3 h and concentrated under reduced pressure to remove methanol. The pH of the remaining aqueous solution was adjusted to 6 with 1 M hydrochloric acid. The suspension was extracted twice with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to yield the carboxylic acid (76 mg, 94%). 1 H NMR (300 MHz, CDCl 3) d: 1, 09-1, 26 (m, 7 H), 2.08-2.18 (m, 3 H), 4.58 (AB q, 2 H), 4 , 79 (ddd, 1 H), 5.57 (sa, 1 H), 6.40 (m, 2 H), 6.86 (m, 3 H), 7.09 - 7.30 (m, 4 H), 7.35-7.46 (m, 2 H), 8.18 (s at, 1 H). MS m / z: 523 (M-1). Acid (±) -c / s-2- [4 - [(4-chloro-phenyl) -propionyl-amino] -1- (4-fluoro-benzoyl) -2-methyl-1,2,3,4- tetrahydro-quinolin-6-yloxy] -2-methyl-propionic acid (B-66) Acid (±) -c / s-2- [4 - [(4-chloro-phenyl) -propionyl-amino] -1 was prepared - (4-Fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-6-yloxy] -2-methyl-propionic acid from ethyl ester of (±) - c / s-2- [4 - [(4-chloro-phenyl) -propionyl-amino] -1- (4-fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-6 -iloxy] -2-methyl-propionic. The saponification conditions indicated in the procedure for the synthesis of (±) -c / s- [4 - [(4-chloro-phenyl) -propionyl-amino] -1- (4-fluoro-benzoyl) acid were used. ) -2-methyl-1, 2,3,4-tetrahydro-quinolin-6-yloxy] -acetic. 1 H NMR (300 MHz, CDCl 3) d: 1, 04-1.21 (m, 7 H), 1, 54-1,66 (m, 6 H), 2.12-2.37 (m, 3 H) ), 4.77 (ddd, 1 H), 5.53 (sa, 1 H), 6.37 (d, 1 H), 6.48 (d, 1 H), 6.66 -6.92 ( m, 1 H), 7.12-7.26 (m, 4 H), 7.43 (m, 2 H), 9.00 (s at, 1 H). MS m / z: 553 (M + 1). (±) -C / sN- [6-carbamoylmethoxy-1- (4-fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N- (4-chloro phenyl) -propionamide (B-67) was prepared (±) -c / sN- [6-carbamoylmethoxy-1- (4-fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin -4-yl] -N- (4-chloro-phenyl) -propionamide from (±) -c / s-4 - [(4-cyoro-phenyl) -propionyl-amino] -1- methyl ester (4-Fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-6-yloxy] -acetic. To the solid methyl ester of (±) -c / s- [4 - [(4-chloro-phenyl) -propionyl-amino] -1- (4-fluoro-benzoyl) -2-methyl-1, 2,3 acid , 4-tetrahydro-quinolin-6-yloxy] -acetic acid (76 mg, 0.14 mmol) was added a solution of ammonia in methanol (2 M, 10 mL). The resulting solution was stirred overnight at room temperature and concentrated. The resulting crude amide was purified by chromatography on silica gel (100% gradient of hexanes - 100% ethyl acetate) to yield the pure product (59 mg, 76%). 1 H NMR (300 MHz, CDCl 3) d: 1, 10-1, 23 (m, 7 H), 2.16-2.39 (m, 3 H), 4.44 (s, 2 H), 4, 77 (ddd, 1 H), 5.56 (sa, 1 H), 6.25 (sa, 1 H), 6.40 - 6.62 (m, 3 H), 7.16 -7.26 ( m, 4 H), 7.35-7.48 (m, 2 H). MS m / z: 524 (M + 1). (±) -C / sN- [6-Bromo-1- (4-fluoro-benzoyl) -2-methyl-1,2,354-tetrahydro-quinolin-4-yl] -N- (4-chloro-phenyl) - propionamide (B-69) was prepared (±) -c / sN- [6-bromo-1- (4-fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl ] -N- (4-chloro-phenyl) -propionamide following general procedure B, substituting aniline for 4-bromoaniline, 4-dimethylaminobenzoyl chloride for 4-fluorobenzoyl chloride and acetyl chloride for propionyl chloride. 1 H NMR (CDCl 3) d: 1, 1-1, 2 (7 H, m), 2.1-2.3 (3 H, m), 4.8 (1 H, m), 5.6 (1 H, m), 6.4 (1 H, d), 6.9 (3 H, t), 7.1 (1 H, m), 7.2 (4 H, m), 7.4 (3 H, m). MS m / z: 531 (M + 2). (±) -C / sN- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -2-methyl-6-morpholin-4-yl-1, 2,3,4-tetrahydro -quinolin-4-yl] -propionamide (B-70) was prepared (±) -c / sN- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -2-methyl-6 -morpholin-4-α-1, 2,3,4-tetrahydro-quinolin-4-yl] -propionamide from (±) -c / sN- [6-bromo-1- (4-fluoro-benzoyl ) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N- (4-chloro-phenyl) -propionamide. (±) -c / sN- [6-bromo-1- (4-fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N- (4) was dissolved -chloro-phenyl) -propionamide in toluene, followed by Pd2 (dba) 3, BINAP, sodium tert-butoxide and morpholine. The reaction mixture was heated at 90 ° C for 24 hours. The reaction mixture was cooled to room temperature, filtered through Celite® and concentrated. The crude mixture was purified by flash chromatography on silica gel using an elution gradient of hexane-ethyl acetate (10-50%). 1 H NMR (CDCl 3) d: 1, 1-1, 2 (7 H, m), 2.1-2.3 (3 H, m), 3.1 (4 H, t), 3.8 (4 H, t), 4.8 (1 H, m), 5.6 (1 H, m), 6.3 (1 H, d), 6.4 (1 H, m), 6.7 (1 H, s), 6.9 (3 H, m), 7.1-7.4 (5 H, m). MS m / z: 536 (M + 1). (±) -C s- (4-chloro-phenyl) -N- [6-diethylamino-1- (4-fluoro-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4- il] -propionamide (B-71) was prepared (±) -c / sN- (4-chloro-phenyl) -N- [6-diethylamino-1- (4-fluoro-benzoyl) -2-methyl- 1, 2,3,4-tetrahydro-quinolin-4-yl] -propionamide in the same manner as (±) -c / sN- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) ) -2-methyl-6-morpholin-4-yl-1, 2,3,4-tetrahydro-quinoxy-4-yl] -propionamide with the exception that morpholine was replaced by diethylamine. The reaction was not selective and yielded (±) -c / sN- [6-diethylamino-1- (4-fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinoIin-4-yl] -N- (4-diethylamine-phenyl) -propionamide in addition to the title compound. 1 H NMR (CDCl 3) d: 1, 1-1, 3 (13 H, m), 1.6 (1 H, m), 2.1-2.3 (3 H, m), 3.3 (4 H, m), 4.7 (1 H, m), 5.6 (1 H, m), 6.2 (1 H, m), 6.3 (1 H, m), 6.5 (1 H, s), 6.9 (2 H, m), 7.3 (4 H, m), 7.4 (2 H, m). MS m / z: 523 (M + 2). (±) -C / sN- [6-diethylamino-1- (4-fluoro-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N (4-diethylamino- phenyl) -propionamide (B-72) was prepared (±) -c / sN- [6-diethylamino-1- (4-fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinoline- 4-yl] -N (4-diethylamino-phenyl) -propionamide in the same manner as (±) -c / sN- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -2 -methyl-6-morpholin-4-yl-1, 2,3,4-tetrahydro-quinolin-4-yl] -propionamide with the exception that morpholine was replaced by diethylamine. The reaction was nonselective and yielded (±) -c / sN- (4-chloro-phenyl) -N- [6-diethylamino-1- (4-fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -propionamide in addition to the title compound. 1 H NMR (CDCl 3) d: 1, 1-1, 3 (19 H, m), 2.3 (3 H, m), 3.3 (8 H, m), 4.7 (1 H, m) , 5,6 (1 H, m), 6.1 (1 H, m), 6.2 (1 H, m), 6.6 (3 H, m), 6.9 (1 H, m), 7.1 (3 H, m), 7.3 (2 H, m). MS m / z: 560 (M + 2). Acid (±) -c / s-3- [4 - [(4-cioro-phenyl) -propionyl-amino] -1- (4-fluoro-benzoyl) -2-methyl-1, 2,3,4- tetrahydro-quinolin-6-yl] -acrylic acid (B-73) Acid (±) -c / s-3- [4 - [(4-chloro-phenyl) -propionyl-amino] -1- (4- fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-6-yl] -acrylic from (±) -c / sN- [6-bromo-1- (4-fluoro- benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N- (4-cyoro-phenyl) -propionamide. To a solution of (±) -c / sN- [6-bromo-1- (4-fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N- (4-chloro-phenyl) -propionamide (250 mg, 0.47 mmol), TEA (0.2 mL, 1.4 mmol), palladium acetate (11 mg, 0.047 mmol) and 1,3-bis (diphenylphosphino) propane (39 mg, 0.094 mmol) in 10 ml of DMF was added 0.13 ml of methyl acrylate (1.41 mmol). The resulting reaction mixture was heated at 80 ° C overnight. The mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with ethyl acetate-hexane (2: 3) to give (±) -c / s-3- [4 - [(4-chloro-phenyl)] methyl ester. -propionyl-amino] -1- (4-fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-6-yl] -acrylic (110 mg, 44% ). To a solution of (±) -c / s-3- [4 - [(4-chloro-phenyl) -propionyl-amino] -1- (4-fluoro-benzoyl) -2-methyl-1-methyl ester , 2,3,4-tetrahydro-quinolin-6-yl] -acrylic acid (110 mg, 0.21 mmol) in 4 mL of methanol was added 50 mg of K2CO3 (0.36 mmol, in 2 mL water). The resulting reaction mixture was stirred at room temperature overnight. The methanol was removed in vacuo. 1 M HCl was added until the mixture became acidic. Dichloromethane (25 ml) was added. The organic layer was dried with magnesium sulfate. The dichloromethane was removed in vacuo. The residue was purified by HPLC to give 10 mg of the title compound. 1 H NMR (CDCl 3) d: 1, 0-1, 2 (7 H, m), 2.4 (2 H, m), 2.5 (1 H, m), 3.3 (1 H, a) , 4.8 (1 H, m), 5.6 (1 H, m), 6.4 (1 H, d), 6.6 (1 H, d), 7.0 (2 H, t) , 7.2-7.6 (9 H, m). MS m / z: 522 (M + 2). (±) -C / sN- (4-chloro-phenyl) -N- [1- (3-methoxy-benzoyl) -2,8-dimethyl-1,2,3,4-tetrahydro-quinolin-4-yl ] -acetamide (B-74) was prepared (±) -c / sN- (4-chloro-phenyl) -N- [1- (3-methoxy-benzoyl) -2,8-dimethyl-1, 2,3 , 4-tetrahydro-quinolin-4-yl] -acetamide following general procedure B, aniline by 2-toluidine and 4-dimethylaminobenzoyl chloride by 3-methoxybenzoyl chloride. 1 H NMR (CDCl 3) d: 1, 11 (3 H, d; overlap of 1 H, t), 1, 76 (3 H, s), 2.00 (3 H, s), 2.35 (1 H, m), 3.55 (3H, s), 5.00 (1 H, m), 5.60 (1 H, m), 6.65 (1 H, s), 6.80 (1 H, t), 6 , 85 (1 H, t), 6.95 (1 H, t), 7.15 (1 H, t), 7.25 (1 H, t), 7.25-7.55 (6H, m ) MS m / z: 429 (M + 1).
(± JC / sN ^ -chloro-phenyl-N-tl-SS-methoxy-benzoyl ^. Β-dimethyl-l ^^^ - tetrahydro-quinolin-4-yl] -acetamide (B-75) Prepared (± ) -c / sN- (4-chloro-phenyl) -N- [1 - (3-methoxy-benzoyl) -2,6-dimethyl-1, 2,3,4-tetrahydro-quinolin-4-yl] - acetamide following general procedure B, substituting aniline for 4-toluidine and 4-dimethylaminobenzoyl chloride for 3-methoxybenzoyl chloride: H NMR (CDCl 3) d: 1, 12 (3H, d; overlap of 1 H, t), 2 , 02 (3H, s), 2.33-2.35 (3H, s, overlap of 1H,), 3.63 (3H, s), 4.80 (1H, m), 5.60 (1H , m), 6.44 (1H, d), 6.70-6.85 (3H, complex), 7.05 (1H, t), 7.15 (1H, s), 7.25-7 55 (6H, complex) MS m / z: 429 (M + 1). (±) -C / sN- (4-chloro-phenyl) -N- [1- (3-methoxy-benzoyl) -2 -methyl-6-trifluoromethyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide (B-76) was prepared (±) -c / sN- (4-chloro-phenyl) -N- [1- (3-methoxy-benzoyl) -2-methyl-6-trifluoromethyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide following the general procedure B, substituting aniline for 4-trifluoromethylaniline and cl 4-dimethylaminobenzoyl chloride by 3-methoxybenzoyl chloride. 1 H NMR (CDCl 3) d: 1, 15 (3 H, d; overlap of 1 H, t), 2.03 (3 H, s), 2.38 (1 H, m), 3.63 (3 H, s) , 4.80 (1 H, m), 5.60 (1 H, m), 6.60 (1 H, d), 6.70 (1 H, d), 6.80 (1 H, dd), 7.15 (1 H, t), 7.25-7.40 (6H, m), 7.60 (1H, s). MS m / z: 483 (M + 1). (±) -C / sN- (4-chloro-phenyl) -N- [6-methoxy-1- (3-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4 -yl] -acetamide (B-77) was prepared (±) -c / sN- (4-chloro-phenyl) -N- [6-methoxy-1- (3-methoxy-benzoyl) -2-methyl-1 , 2,3,4-tetrahydro-quinolin-4-yl] -acetamide following the general procedure B, substituting aniline for 4-methoxyaniline and 4-dimethylaminobenzoyl chloride for 3-methoxybenzoyl chloride. 1 H NMR (CDCl 3) d: 1, 12 (3H, d; overlap of 1 H, t), 2.02 (3H, s), 2.35 (1H, m), 3.63 (3H, s), 3.76 (3H, s), 4.80 (1 H , m), 5.60 (1 H, m), 6.44 (1 H, s), 6.70-6.95 (4H, complex), 7.15 (1 H, t), 7.25 -7.55 (6H, m). MS m / z: 445 (M + 1).
(±) -C / sN- (4-chloro-phenyl) -N- [2-methyl-1- (thiophene-2-carbonyl) -6-trifluoromethyl-1, 2,3,4-tetrahydro-quinolin-4 -yl] -acetamide (B-78) was prepared (±) -c sN- (4-chloro-phenyl) -N- [2-methyl-1 - (thiophene-2-carbonyl) -6-trifluoromethyl-1, 2,3,4-tetrahydro-quinolyl-4-yl] -acetamide following the general procedure B, substituting aniline for 4-trifluoromethylaniline and 4-dimethylaminobenzoyl chloride for 2-thiophene carbonyl chloride. 1 H NMR (CDCl 3) d: 1, 14 (3 H, d; overlap of 1 H, t), 2.02 (3 H, s), 2.35 (1 H, m), 4.80 (1 H, m ), 5.65 (1 H, m), 6.65 (1 H, d), 6.80 (1 H, d), 7.00 (1 H, d), 7.20 (overlap of 2 x 1H, d), 7.24-7.42 (3H, m), 7.60 (1H, s). MS m / z: 539 (M + 1). (±) -C / sN- (4-chloro-phenyl) -N- [2-methyl-1- (5-methyl-thiophene-2-carbonyl) -6-trifluoromethyl-1,2,3,4-tetrahydro -quinolin-4-yl] -acetamide (B-79) was prepared (±) -c / sN- (4-chloro-phenyl) -N- [2-methyl-1 - (5-methyl-thiophene-2- carboni I) -6-trifluoromethyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide following the general procedure B, substituting aniline for 4-trifluoromethylaniline and 4-dimethylaminobenzoyl chloride for 5-methyl chloride. 2-thiophene carbonyl. 1 H NMR (CDCl 3) d: 1, 14 (3 H, d; overlap of 1 H, t), 2.02 (3 H, s), 2.35 (1 H, m), 2.40 (3 H, s), 4.80 (1 H, m), 5.65 (1 H, m), 6.45 (1 H, d), 6.55 (1 H, d), 7.00 (1 H, d), 7.20 (overlap of 2 x 1 H, d), 7.24-7.42 (3H, m), 7.55 (1H, s). MS m / z: 554 (M + 1). (±) -C / sN- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -2-methyl-7-trifluoromethyl-1, 2,3,4-tetrahydro-quinolin-4 -yl] -propionamide (B-80) was prepared (±) -c / sN- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -2-methyl-7-trifluoromethyl-1 , 2,3,4-tetrahydro-quinolin-4-yl] -proponamide following general procedure B, substituting aniline for 3-trifluoromethylaniline, 4-dimethylaminobenzoyl chloride for 4-fluorobenzoyl chloride and acetyl chloride for chloride of propionyl. A mixture of the isomer was obtained at positions 5 and 7. 1 H NMR (CDCl 3) d: 1.15 (3H, d; overlap of 1H, t), 2.20-2.40 (2H, c; 1H, m ), 4.80 (1 H, m), 5.65 (1 H, m), 6.70 (1 H, s), 6.95 (2 x 1 H, t), 7.10-7, 60 (8H, m) MS m / z: 519 (M + 1).
(±) -C / sN- [7-bromo-1- (4-dimethylamino-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N- (4-chloro phenyl) -acetamide (B-81) was prepared (±) -c / sN- [7-bromo-1- (4-dimethylamino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin -4-yl] -N- (4-chloro-phenyl) -acetamide following the general procedure B, substituting aniline for 3-bromoaniline. A mixture of the isomer was obtained in positions 5 and 7. (±) -C / sN- (4-chloro-phenyl) -N- [1- (4-dimethylamino-benzoyl) -7-isopropyl-2-methyl- 1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide (B-82) was prepared (±) -c / sN- (4-chloro-phenyl) -N- [1- (4-dimethylamino -benzoyl) -7-isopropyl-2-methyl-1, 2,3,4-tetrahydro-quinolyl-4-yl] -acetamide following the general procedure B, substituting aniline for 3-isopropylaniline. A mixture of the isomer was obtained in positions 5 and 7. 1 H NMR (CDCl 3) d: 0.89 (2 x 3 H, t), 1, 15 (3 H, d; overlap of 1 H, t), 2.01 ( 3 H, s), 2.33 (1 H, m), 2.60 (1 H, m), 2.87 (2 x 3 H, s), 4.80 (1 H, m), 5.65 ( 1 H, m), 6.40 (overlap of 1H, s, 2H, d), 6.90 (1H, d), 7.10 (1H, d), 7.15-7.35 (5H, m 7.40 (1 H, d). MS m / z: 505 (M + 1). (±) -Cis-N- (4-chloro-phenyl) -N- [1- (4-dimethylamino-benzoyl) -2-methyl-7-morpholin-4-yl-1, 2,3,4-tetrahydro -quinolin-4-yl] -acetamide (B-83) was prepared (±) -c / sN- (4-chloro-phenyl) -N- [1- (4-dimethylamino-benzoyl) -2-methyl-7 -morpholin-4-yl-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide from (±) -c / sN- [7-bromo-1- (4-dimethylamino- benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N- (4-chloro-phenyl) -acetamide. It was dissolved (±) -c / sN- [7-bromo-1- (4-dimethylamino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolyl-4-yl] -N - (4-chloro-phenyl) -acetamide in toluene, followed by Pd2 (dba) 3, BINAP, sodium tert-butoxide and morpholine. The reaction mixture was heated at 90 ° C for 24 hours. The reaction mixture was cooled to room temperature and filtered through Celite® and concentrated. The crude mixture was purified by flash chromatography on silica gel using an elution gradient of hexane-ethyl acetate (10-50%). 1 H NMR (CDCl 3) d: 1, 11 (3H, d; overlap of 1 H, t), 1, 99 (3H, s), 2.33 (1 H, m), 2.60-2.80 (2 x 2H, m), 2.89 (2 x 3H, s), 3.70 (2 x 2H, m), 4.70 (1 H, m), 5.60 (1 H, m), 6.10 (1 H, s), 6.44 (2 x 1 H, d), 7.00-7.40 (8H, m). MS m / z: 548 (M + 1). (±) -C / sN- [7-diethylamino-1- (4-dimethylamino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N- (4-diethylamino phenyl) -acetamide (B-84) was prepared (±) -c / sN- [7-diethylamino-1- (4-dimethylamino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinol N-4-yl] -N- (4-d-ethylamino-phenyl) -acetamide in the same manner as (±) -c / sN- (4-chloro-phenyl) -N- [1- (4- dimethylamino-benzoyl) -2-methy1-7-morpholin-4-yl-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide with the exception that morpholine was replaced with diethylamine. The reaction was not selective and yielded (±) -c / sN- (4-chloro-phenyl) -N- [7-diethylammon-1- (4-dimethylamino-benzoyl) -2-methyl- 1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide in addition to the title compound. 1 H NMR (CDCl 3) d: 0.78 (2 x 3 H, t), 1, 15 (overlap of 3 H, d; 1 H, t), 1, 98 (3 H, s), 2.33 (1 H, m) , 2.87 (2 x 3H, s), 2.90-3.10 (2 x 2H, c), 4.70 (1H, m), 5.60 (1H, m), 5.90 (1 H, s), 6.46 (3 x 1 H, d), 7.00-7.40 (7H, m). MS m / z: 557 (M + 1). (±) -C / sN- (4-chloro-phenyl) -N- [7-diethylamino-1- (4-dimethylamino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4 -yl] -acetamide (B-85) was prepared (±) -c / sN- (4-chloro-phenyl) -N- [7-diethylamino-1- (4-dimethylamino-benzoyl) -2-methyl -1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide in the same manner as (±) -c / sN- (4-cioro-phenyl) -N- [1- (4-dimethylamino- benzoyl) -2-methyl-7-morpholin-4-yl-1, 2,3,4-tetrahydro-quino-4-yl] -acetamide, with the exception that morpholine was replaced by diethylamine. The reaction was not selective and yielded (±) -c / sN- [7-diethylamino-1- (4-dimethylamino-benzoyl) -2-methyl-1, 2,3,4-tetrahydroquinoline-4- L] -N- (4-diethylamino-phenyl) -acetamide in addition to the title compound. 1 H NMR (CDCl 3) d: 0.78 (2 x 3 H, t), 1.15 (overlap of 2 x 3 H, t; 3 H, d; 1 H, t), 2.00 (3 H, s), 2 , 33 (1 H, m), 2.76 (2 x 3H, s), 2.80-3.00 (2 x 2H, c), 3.24 (2 x 2H, c), 4.60 ( 1H, m), 5.60 (1H, m), 5.90 (1H, s), 6.46 (2 x 1H, d), 6.60 (1H, m), 6.90 (2 x 1 H, d), 7.00-7.20 (6H, m). MS m / z: 609 (M + 1).
(±) -C / sN- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -5-methoxy-2-methyl-1,2,3,4-tetrahydro-quinolin-4 -yl] -propionamide (B-86) was prepared (±) -c / sN- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -5-methoxy-2-methyl-1 , 2,3,4-tetrahydro-quinolin-4-yl] -propionamide following general procedure B, substituting aniline for 3-anisidine, 4-dimethylaminobenzoyl chloride for 4-fluorobenzoyl chloride and acetyl chloride for propionyl chloride. 1 H NMR (CDCl 3) d: 1, 09-1, 14 (6H, m), 1, 50-1, 66 (1 H, m), 1, 97-2.34 (3H, m), 3.83 (3 H, s), 4.65 (1 H, c), 5.70-5.80 (1 H, a), 6.08 (1 H, d), 6.68 (1 H, d). 6.81-6.89 (3H, m), 7.14-7.18 (4H, m), 7.33-7.36 (2H, m). MS m / z: 481 (M + 1). 4- [Acetyl- (4-chloro-phenyl) -amino] -1- (4-dimethylamino-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-7-yl ester of the acid (± ) -c / s-2,2-dimethyl-propionic (B-87) 4- [Acetyl- (4-chloro-phenyl) -amino] -1 - (4-dimethylamino-benzoyl) -2-methyl- was prepared 1, 2,3,4-tetrahydro-quinolin-7-yl ester of (±) -c / s-2,2-dimethyl-propionic acid following general procedure B, substituting aniline for 3-amino-phenyl ester of the acid 2,2-dimethyl-propionic. 1 H NMR (CDCl 3) d: 1, 11-1, 25 (13H, m), 2.02 (3H, s), 2.20-2.40 (1H, m), 2.92 (6H, s) , 4.60-4.72 (1 H, m), 5.45-5.55 (1 H, a), 6.26 (1 H, s), 6.46 (2H, d), 6, 85 (1H, d), 7.09-7.39 (7H, m). MS m / z: 562 (M + 1). (±) -C / sN- (4-chloro-phenyl) -N- [1- (4-dimethylamino-benzoyl) -7-hydroxy-2-methyl-1, 2,3,4-tetrahydro-quinolin-4 -yl] -acetamide (B-88) was prepared (±) -c / sN- (4-chloro-phenyl) -N- [1- (4-dimethylamino-benzoyl) -7-hydroxy-2-methyl-1 , 2,3,4-tetrahydro-quinolin-4-yl] -acetamide from 4- [acetyl- (4-chloro-phenyl) -amino] -1- (4-dimethylamino-benzoyl) -2-methyl- 1, 2,3,4-tetrahydro-quinolin-7-yl ester of (±) -c / s-2,2-dimethyl-propionic acid. 4- [Acetyl- (4-chloro-phenyl) -amino] -1- (4-dimethylamino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-7-yl ester of the acid was dissolved (±) -c / s-2,2-dimethyl-propionic acid (100 mg, 0.178 mmol) in tetrahydrofuran and sodium hydroxide (1 M, 356 μl, 0.356 mmol) was added. The mixture was stirred at room temperature for 4 hours and then heated to reflux for 2 h. The mixture was cooled to rt, acidified, concentrated and purified by chromatography on silica gel (20 mg, 23%). 1 H NMR (MeOD) d: 1, 06-1, 08 (4H, m), 2.00 (3H, s), 2.35-2.45 (1H, m), 2.93 (6H, s) , 4.65-4.68 (1 H, m), 5.42-5.50 (1 H, a), 6.07 (1 H, s), 6.53 (2H, d), 6, 63 (1 H, d), 7.10-7.20 (3H, m), 7.35-7.48 (4H, m). MS m / z: 478 (M + 1). Ethyl acid ester (±) -c / s- [4- [Acetyl- (4-chloro-phenyl) -amino] -1- (4-dimethylamino-benzoyl) -2-methyl-1,2,3,4 -tetrahydro-quinolin-7-yloxy] -acetic acid (B-89) (±) -c / s- [4- [Acetyl- (4-chloro-phenyl) -amino] -1- ( 4-dimethylamino-benzoyl) -2-methylene-1, 2,3,4-tetrahydro-quinolin-7-yloxy] -acetic from (±) -c / sN- (4-chloro-phenyl) - N- [1- (4-dimethylamino-benzoyl) -7-hydroxy-2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide, following the alkylation conditions described for the synthesis of ethyl ester of (±) -c / s-4- (4- { 4 - [(4-chloro-phenyl) -propionl-amino] -2-methyl-3,4-dihydro-2H- quinoline-1-carbonyl.] - phenoxy) -butyric, substituting ethyl 4-bromobutyrate for ethyl bromoacetate. 1 H NMR (MeOD) d: 1, 10-1, 38 (7H, m), 2.00 (3H, s), 2.39-2.45 (1 H, m), 2.94 (6H, s) ), 4.04-4.20 (2H, m), 4.29 (2H, s), 4.60-4.75 (1H, m), 5.40-5.50 (1H, a ), 6.16 (1H, s), 6.54 (2H, d), 6.79 (1H, d), 7.08 (2H, d), 7.20-7.48 (5H, m). MS m / z: 564 (M + 1). (±) -C / s-2- [4- [Acetyl- (4-chloro-phenyl) -amino] -1- (4-dimethylamino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro -quinolin-7-yloxy] -acetamide (B-90) was prepared (±) -c / s-2- [4- [acetyl- (4-chloro-phenyl) -amino] -1- (4-dimethylamino- benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-7-yloxy] -acetamide from ethyl ester of (±) -c / s- [4- [acetyl- (4-chloro phenyl) -amino] -1- (4-d-methmetlamino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-7-yloxy] -acetic, by the same amidation process used in the synthesis of (±) -c / sN- [6-carbamoylmethoxy-1- (4-fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N - (4-chloro-phenyl) -propionamide. 1 H NMR (MeOD) d: 1, 09-1, 15 (4H, m), 2.00 (3H, s), 2.39-2.45 (1H, m), 2.94 (6H, s), 4.04-4.20 (2H, m), 4.60-4.75 (1H, m), 5.40-5.50 (1H, a), 6.14 (1H, s), 6.53 (2H, d), 6.81 (1H, d), 7.09 (2H, d), 7.20-7.48 (5H, m). MS m / z: 535 (M + 1). Acid (±) -c / s- [4- [Acetyl- (4-chloro-phenyl) -amino] -1- (4-dimethylamino-benzoyl) -2-methyl-1,2,3,4-tetrahydro- quinolin-7-yloxy] -acetic acid (B-91) Acid (±) -c / s- [4- [acetyl- (4-chloro-phenyl) -amino] -1- (4-dimethylamino-benzoyl) was prepared -2-methyl-1, 2,3,4-tetrahydro-quinolin-7-yloxy] -acetic acid from (±) -c / s- [4- [acetyl-] 4- ethyl ester chloro-phenyl) -amino] -1- (4-dimethylamino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-7-yloxy] -acetic following the saponification procedure described above for the synthesis of acid (±) -c / s- [4 - [(4-chloro-phenyl) -propionyl-amino] -1- (4-fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro -quinolin-6-iloxij-acetic. 1 H NMR (MeOD) d: 1, 08-1, 10 (4H, m), 1, 98 (3H, s), 2.39-2.45 (1 H, m), 2.93 (6H, s) ), 4.20 (2H, s), 4.61-4.70 (1 H, m), 5.40-5.50 (1 H, a), 6.17 (1 H, s), 6 , 53 (2H, d), 6.79 (1H, d), 7.08 (2H, d), 7.28-7.48 (5H, m). MS m / z: 536 (M + 1). (±) -C / sN- (4-chloro-phenyl) -N- [1- (4-dimethylamino-benzoyl) -7- (2-hydroxy-2-methyl-propoxy) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide (B-92) was prepared (±) -c / sN- (4-chloro-phenyl) -N- [1- (4-dimethylamino-benzoyl ) -7- (2-hydroxy-2-methyl-propoxy) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide from ethyl ester of the acid ( ±) -c / s- [4- [Acetyl- (4-chloro-phenyl) -amino] -1- (4-dimethylamino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinoline- 7-yloxy] -acetic using the same alkylation procedure described for the synthesis of (±) -c / sN-. { 1- [4- (2-hydroxy-2-methyl-propoxy) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinoIin-4-yl} -N-phenyl-propionamide. 1 H NMR (CDCl 3) d: 1, 01-1, 20 (4H, m), 1, 30 (6H, s), 2.01 (3H, s), 2.20-2.40 (1H, m ), 2.92 (6H, s), 3.70 (2H, s), 4.65-4.72 (1H, m), 5.45-5.55 (1H, a), 6, 13 (1 H, s), 6.45 (2H, d), 6.65 (1H, d), 7.12-7.46 (7H,). MS m / z: 551 (M + 1). (±) -C / sN- (4-chloro-phenyl) -N- [1- (4-dimethylamino-benzoyl) -7-ethoxy-2-methyl-1, 2,3,4-tetrahydro-quinolin-4 -yl] -acetamide (B-93) was prepared (±) -c / sN- (4-chloro-phenyl) -N- [1- (4-dimethylamino-benzoyl) -7-ethoxy-2-methyl- 1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide from (±) -c / sN- (4-chloro-phenyl) -N- [1- (4-dimethylamino -benzoyl) -7-hydroxy-2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide using the same alkylation procedure described for the synthesis of (±) -c acid ethyl ester / s-4- (4- { 4 - [(4-Chloro-pheny] -propionyl-amino] -2-methyl-3,4-dihydro-2H-quinoline-1 -carbonyl.}. -phenoxy) -butyric, substituting ethyl 4-bromobutyrate for ethyl iodide. 1 H NMR (CDCl 3) d: 1, 01-1, 20 (7H, m), 2.01 (3H, s), 2.20-2.40 (1H, m), 2.92 (6H, s) , 3.60 (2H, c), 4.65-4.72 (1 H, m), 5.45-5.55 (1H, a), 6.15 (1 H, s), 6.44 (2H, d), 6.69 (1H, d), 7.11-7.46 (7H, m). MS m / z: 506 (M + 1). Ethyl ester of the acid (±) -c / s-4- [4- [acetyl- (4-chloro-phenyl) -amino] -1- (4-dimethylamino-benzoyl) -2-methyl-1,2,3 , 4-tetrahydro-quinolin-7-yloxy] -butyric acid (B-94) Ethyl ester of (±) -c / s-4- [4- [acetyl- (4-chloro-phenyl) -amino]] was prepared] -1- (4-dimethylamino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-7-yloxy] -butyric from (±) -c / sN- (4-chloro-phenyl) ) -N- [1 - (4-dimethylamino-benzoyl) -7-hydroxy-2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide using the same alkylation procedure described for the synthesis of (±) -c / s-4- (4-. {4 - [(4-chloro-phenyl) -propionl-amino] -2-methyl-3-ethyl ester, 4-dihydro-2H-quinoline-1-carbonyl] -phenoxy) -butyric acid. 1 H NMR (CDCl 3) d: 1, 09-1, 11 (4 H, m), 1, 23 (3 H, t), 1, 81-1, 85 (2 H, m), 2.01 (3 H, s), 2.30-2.33 (3 H, m), 2.92 (6 H, s), 3.50-3.54 (1 H, m), 3.72-3.76 (1 H, m), 4.09 (2 H, c), 4.66-4.73 (1 H, m), 5.57-5.63 (1 H, m), 6.14 (1 H, s), 6.46 (2 H, d), 6.68 (1 H, d), 7.11-7.39 (7 H, m). MS m / z: 593 (M + 1). Acid (±) -c / s-4- [4- [Acetyl- (4-cioro-phenyl) -amino] -1- (4-dimethylamino-benzoyl) -2-methyl-1,2,3,4- tetrahydro-quinolin-7-yloxy] -butyric acid (B-95) Acid (±) -c / s-4- [4- [acetyl- (4-chloro-phenyl) -amino] -1- (4- d-methylamino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-7-yloxy] -butyric acid from (±) -c / s-4- [4- [acetyl- (4-chloro-phenyl) -amino] ethyl ester] -1- (4-dimethylamino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-7-yloxy] -butyric acid following the saponification conditions described for the synthesis of acid ( ±) -c / s- [4 - [(4-chloro-phenyl) -propionyl-amino] -1- (4-fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinoline- 6 -loxy] -acetic. 1 H NMR (CDCl 3) d: 1, 08-1, 11 (4H, m), 1, 80-1, 86 (2H, m), 1, 99 (3H, s), 2.28-2.35 ( 3H, m), 2.89 (6H, s) 3.37-3.46 (1H, m), 3.66-3.73 (1H, m), 4.64-4.72 (1 H, m), 5.54-5.63 (1H, m), 6.07 (1H, s), 6.52 (2H, d), 6.67 (1H, d), 7.08-7 , 36 (7H, m). MS m / z: 564 (M + 1). (±) -C / sN- (4-chloro-phenyl) -N- [1- (4-dimethylamino-benzoyl) -2,7-dimethyl-1, 2,3,4-tetrahydro-quinoiin-4-yl ] -acetamide (B-96) was prepared (+) - c / sN- (4-chloro-phenyl) -N- [1- (4-dimethylamino-benzoyl) -2,7-dimethyl-1, 2,3 , 4-tetrahydro-quinolin-4-yl] -acetamide following general procedure B, substituting 3-toluidine for aniline. Both isomers were obtained at positions 5 and 7 in this procedure. 1 H NMR (CDCl 3) d: 1, 11 (3H, d), 1, 45-1, 59 (4H, m), 2.02-2.07 (3H, m), 2.24-2.28 ( 1 H, m), 2.92 (6H, s) 4.67-4.74 (1 H, m), 5.52-5.59 (1 H, m), 6.43-6.45 ( 3H, m), 6.95 (1H, d), 7.13-7.22 (6H, m), 7.35-7.43 (1H, m). MS m / z: 307 (M). (±) -C / sN- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -2-phenethyl-1, 2,3,4-tetrahydro-quinolin-4-yl] - propionamide (B-97) was prepared (±) -c / sN- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -2-phenetii-1, 2,3,4-tetrahydro -quinolin-4-yl] -propionamide following general procedure B, substituting 4-dimethylaminobenzoyl chloride for 4-fluorobenzoyl chloride, acetaldehyde for 3-phenyl-propionaldehyde and acetyl chloride for propionyl chloride. 1 H NMR (CDCl 3) d: 1, 16 (dt, 3 H), 1.25 (m, 1 H), 1.54 (m, 1 H), 1.97 (m, 1 H), 2.30 (m, 3H), 2.56 (t, 2H), 4.85 (sextuplet, 1 H), 5.66 (sa, 1 H), 6.44 (d, 1 H), 6.86 (t, 2H) , 6.93 (m, 2H), 7.03 (d, 2H), 7.12-7.29 (m, 8H), 7.37 (d, 2H). MS m / z: 542 (M + 1).
(±) -C / sN- (4-chloro-phenyl) -N- [2- (2-cyano-ethyl) -1- (4-fluoro-benzoyl) -1,2,3,4-tetrahydro-quinolin -4-yl] -propionamide (B-98) was prepared (±) -c / sN- (4-chloro-phenyl) -N- [2- (2-cyano-ethyl) -1 - (4-fluoro- benzoyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -propionamide following general procedure B, substituting 4-dimethylaminobenzoyl chloride for 4-fluorobenzoyl chloride, acetaldehyde for 4-oxobutyrylnitrile and acetyl chloride for propionyl chloride. H NMR (300 MHz, CDCl 3) d: 1, 19-1, 23 (m, 4 H), 1, 65-1, 79 (m, 2 H), 2.07 -2.57 (m, 5 H) ), 4.90 (ddd, 1 H), 5.61 (sa, 1 H), 6.61 (d, 1 H), 6.86 (m, 2 H), 6.95 (dd, 1 H) ), 7.14-7.43 (m, 8 H). MS m / z = 490 (M + 1). (±) -C / sN- [2-ethyl-1- (3-methoxy-benzoyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide (B-99) (±) -c / sN- [2-ethyl-1- (3-methoxy-benzoyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide was prepared following the procedure B, substituting 4-dimethylaminobenzoyl chloride for 3-methoxybenzoyl chloride, acetaldehyde for propionyl aldehyde and 4-chlorophenylboronic acid for phenylboronic acid. 1 H NMR (CDCl 3) d: 0.8 (3H, t), 1.3 (2H, m), 1.6 (1H, m), 2.0 (3H, s), 2.3 (1H, m), 3.7 (3H, s), 4.7 (1H, m), 5.7 (1H, m), 6.5 (1H, d), 6.7 (1H, s), 6, 8 (2H, m), 6.9-7.4 (9H, m) MS m / z: 429 (M + 1). (±) -C / sN- [1- (3-methoxy-benzoyl) -2-phenyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide (B-100) (±) -c / sN- [1- (3-methoxy-benzoyl) -2-phenyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide was prepared following the procedure B, substituting 4-dimethylaminobenzoyl chloride for 3-methoxybenzoyl chloride, acetaldehyde for benzaldehyde and 4-chlorophenylboronic acid for phenylboronic acid. 1 H NMR (CDCl 3) d: 1.5 (1 H, m), 2.0 (3 H, s), 2.5 (1 H, m), 3.6 (3 H, s), 5.7 (1 H , t) 5.8 (1 H, m), 6.6 (1 H, d), 6.9 (2H, m), 6.9-7.4 (15H, m). MS m / z: 494 (M-18). Ethyl ester of (±) -c7s-4- (acetyl-phenyl-amino) -1- (4-fluoro-benzoyl) -1,2,4,4-tetrahydro-quinoline-2-carboxylic acid (B-101) (±) -c / s-4- (Acetyl-phenyl-amino) -1- (4-fluoro-benzoyl) -1,2,3,4-tetrahydro-quinoline-2-carboxylic acid ethyl ester was prepared following the general procedure B, substituting 4-dimethylaminobenzoyl chloride for 4-fluorobenzoyl chloride, acetaldehyde for ethyl glyoxylate and 4-chlorophenylboronic acid for phenylboronic acid. 1 H NMR (CDCl 3) d: 1, 2 (3 H, t), 1, 2 (1 H, m), 2.0 (3 H, s), 2.5 (1 H, m), 4.1 (2 H , c), 5.0 (1H, t), 5.7 (1H, m), 6.6 (1H, d), 6.8-7.0 (4H, d), 7.1-7 , 4 (8H, m). MS m / z: 461 (M + 1). Acid (±) -c / s-4- (acetyl-phenyl-amino) -1- (4-fluoro-benzoyl) -1, 2,3,4-tetrahydro-quinoline-2-carboxylic acid (B-102) prepared (±) -c / s-4- (acetyl-phenylamino) -1- (4-fluoro-benzoyl) -1,2,3,4-tetrahydro-quinoline-2-carboxylic acid from (±) -c / s-4- (Acetyl-phenyl-amino) -1 - (3-methoxy-benzoyl) -1,2,3,4-tetrahydro-quinoline-2-carboxylic acid ethyl ester by basic hydrolysis with 1 N sodium hydroxide, ethanol and water. 1 H NMR (CDCl 3) d: 1.2 (1 H, m), 2.0 (3 H, s), 2.6 (1 H, m), 5.0 (1 H, t), 5.6 (1 H, m), 6.6 (1 H, d), 6.9-7.0 (3H, m), 7.2 (2H, m), 7.3-7.5 (7H, m). MS m / z: 433 (M + 1). (±) -C / sN- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -2-propyl-1,2,3,4-tetrahydro-quinolin-4-yl] - propionamide (B-103) was prepared (±) -c / sN- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -2-propyl-1, 2,3,4-tetrahydro -quinolin-4-yl] -proponamide following general procedure B, substituting 4-dimethylaminobenzoyl chloride for 4-fluorobenzoyl chloride, acetaldehyde for butyryl aldehyde and acetyl chloride for propionyl chloride. 1 H NMR (CDCl 3) d: 0.8 (3H, t), 1, 1-1, 2 (7H, m), 1.4 (1 H, m), 2.1-2.3 (3H, m ), 4.8 (1 H, m), 5.6 (1 H, m), 6.7 (1 H, d), 6.9-7.1 (4H, m), 7.2-7 , 5 (7H, m). MS m / z: 479 (M + 1). 4 - [(4-Chloro-phenyl) -propionyl-amino] -1- (4-fluoro-benzoyl) -1,2,4,4-tetrahydro-quinolin-2-ylmethyl ester of (±) -c / s-propionic (B-104) 4 - [(4-Chloro-phenyl) -propionyl-amine] -1- (4-fluoro-benzoyl) -1,2,3,4-tetrahydro-quinoline- 2-ylmethyl ester of (±) -c / s-propionic acid following general procedure B, substituting acetaldehyde for 2-oxo-ethyl ester of propionic acid, 4-dimethylaminobenzoyl chloride for 4-fluorobenzoyl chloride and acetyl chloride for propionyl chloride. H NMR (CDCl 3) d: 0.8 (3H, t), 1.1 (3H, t), 1.1 (1 H, m), 2.1 (2H, m), 2.2 (3H, s), 3.8 (1H,), 4.2 (1H, m), 5.0 (1H, m), 5.4 (1H, m), 6.4 (1H, d), 6.8 (3H, m ), 7.1-7.4 (8H, m). MS m / z: 523 (M + 1). (±) -C / sN- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -2-hydroxymethyl-1,2,3,4-tetrahydro-quinolin-4-yl] - propionamide (B-105) Prepared (±) -c / sN- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -2-hydroxymethyl- 1, 2,3,4-tetrahydro -quinolin-4-yl] -propionamide from 4 - [(4-chloro-phenyl) -propionyl-amino] -1- (4-fluoro-benzoyl) -1, 2,3,4-tetrahydro- cinnamyl-2-methyl ester of (+) - c / s-propionic acid using the saponification conditions used in the synthesis of acid (±) -c / s- [4 - [(4-chloro-phenyl)] -propionyl-amino] -1- (4-fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinoIin-6-yloxy] -acetic. 1 H NMR (CDCl 3) d: 1.1 (3H, t), 1.3 (1 H, m), 1.8 (1 H, m), 2.1 (2 H, m), 3.4 (1 H, t), 3.6 (2H, m), 4.2 (1 H, m), 6.2 (1 H, m), 6.4 (1 H, d), 6.7 (2H, t), 6.8-7 , 0 (5H, m), 7.1-7.3 (4H, m). MS m / z: 367 (M-99). (±) -C / sN- (4-chloro-phenyl) -N- [2-diethylaminomethyl-1- (4-fluoro-benzoyl) -1,2,4,4-tetrahydro-quinolin-4-yl] - propionamide (B-106) (±) -c / sN- (4-chloro-phenyl) -N- [2-diethyl-amnomethyl-1- (4-fluoro-benzoyl) -1,2,3,4 was prepared -tetrahydro-quinolin-4-yl] -propionamide following general procedure B, substituting acetaldehyde for diethylamino-acetaldehyde, 4-dimethylaminobenzoyl chloride for 4-fluorobenzoyl chloride and acetyl chloride for propionyl chloride. 1 H NMR (CDCl 3) d: 0.8 (6H, m), 1.1 (3H, t), 1.1 (1 H, m), 1.8 (2H, m), 2.2-2, 5 (6H, m), 2.6 (1H, m), 4.8 (1H, m), 5.7 (1H, m), 6.4 (1H, d), 6.9 (3H, m ), 7.1-7.4 (8H, m). MS m / z: 523 (M + 2).
(±) -C / sN- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -2-methoxymethyl-1,2,3,4-tetrahydro-quinolin-4-yl] - propionamide (B-107) was prepared (±) -c / sN- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -2-methoxymethyl- 1, 2,3,4-tetrahydro -quinolin-4-yl] -propionamide following general procedure B, substituting acetaldehyde for methoxyacetaldehyde, 4-dimethylamino-benzoyl chloride for 4-fluorobenzoyl chloride and acetyl chloride for propionyl chloride. 1 H NMR (CDCl 3) d: 1.1 (3 H, t), 1.3 (1 H, m), 1.8 (1 H, m), 2.1 (1 H, m), 3.4 (4 H, m ), 3.6 (2H, m), 4.2 (1 H, m), 6.3 (1 H, m), 6.5 (1H, d), 6.7 (1 H, m), 6.8-7.0 (4H, m), 7.1-7.4 (6H, m). MS m / z: 381 (M-99). (±) -C / sN- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -2-phenyl-1,2,3,4-tetrahydro-quinolin-4-yl] - propionamide (B-108) was prepared (±) -c / sN- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -2-phenyl-1, 2,3,4-tetrahydro -quinolin-4-yl] -propionamide following general procedure B, substituting acetaldehyde for benzaldehyde, 4-dimethylaminobenzoyl chloride for 4-fluorobenzoyl chloride and acetyl chloride for propionyl chloride. 1 H NMR (CDCl 3) d: 1, 1-1, 2 (3 H, m), 1, 2 - 1, 4 (1 H, m), 2,2 - 2,4 (2 H, m), 2 , 4-2.6 (1 H, m), 5.6 (1 H, t), 5.8 (1 H, m), 6.6 (1 H, d), 6.8 (2 H, m), 7.0 (1 H, m), 7.2-7.4 (13 H, m). MS m / z: 513 (M + 1). (±) -C / sN- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -6-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydro-quinolin -4-yl] -propionamide (B-109) was prepared (±) -c / sN- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -6-methoxy-2- trifluoromethyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -propionamide following general procedure B, replacing N-vinylcarbamic acid benzyl ester with N- (4-chloro-phenyl) -N-vinyl-propionamide and acetaldehyde by trifluoroacetaldehyde in the synthesis of 11, 4-dimethylaminobenzoyl chloride by 4-fluorobenzoyl chloride and acetyl chloride by propionyl chloride. 1 H NMR (CDCl 3) d: 1, 1-1, 2 (3 H, m), 1, 6 (1 H, a), 2,2-2,4 (3 H, m), 3.8 (3 H, s), 5.5 (1 H, m), 5.6 (1 H, m), 6.5 (1 H, s), 6.8 (1 H, s), 6.9 (2 H, t), 7.1 - 7.3 (4 H, m), 7.4 (2 H, d). MS m / z: 535 (M + 1). (±) -C / sN- (4-chloro-phenyl) -N- [6-methoxy-1- (3-methoxy-benzoyl) -2-trifluoromethyl-1, 2,3,4-tetrahydro-quinolin-4 -yl] -propionamide (B-110) was prepared (±) -c / sN- (4-chloro-phenyl) -N- [6-methoxy-1- (3-methoxy-benzoyl) -2-trifluoromethyl-1 , 2,3,4-tetrahydro-quinolin-4-yl] -propionamide following the procedure for the synthesis of (±) -N- (4-chloro-phenyl) -N- [1- (4-fluoro- benzoyl) -6-methoxy-2-trifluoromethyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -propionamide, substituting 4-fluorobenzoyl chloride for 3-methoxybenzoyl chloride. 1 H NMR (CDCl 3) d: 1, 1 - 1, 2 (3 H, m), 1.6 (1 H, a), 2.2 - 2.4 (3 H, m), 3.7 (3 H, s), 3.8 (3 H, s), 5.5 (1 H, m), 5.6 (1 H, m), 6.5 (2 H, m), 6.6 (1 H, m), 6.8 (3 H, m), 7.1 (1H, t), 7.2 (2H, d), 7.4 (2H, d). MS m / z: 547 (M + 1). (±) -C / sN- (4-chloro-phenyl) -N- [1- (furan-2-carbonyl) -6-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4 -yl] -propionamide (B-111) was prepared (±) -c / sN- (4-chloro-phenyl) -N- [1- (furan-2-carbonyl) -6-methoxy-2-trifluoromethyl-1 , 2,3,4-tetrahydro-quinolin-4-yl] -propionamide propionamide following the procedure for the synthesis of (±) -c / sN- (4-cyoro-phenyl) -N- [1- (4- fluoro-benzoyl) -6-methoxy-2-trifluoromethyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -propionamide, substituting 4-fluorobenzoyl chloride for 2-furoyl chloride chloride. 1 H NMR (CDCl 3) d: 1, 1 - 1, 2 (3 H, m), 1.6 (1 H, a), 2.2 - 2.4 (3 H, m), 3.8 (3 H, s), 5.4 (2 H, m), 6.0 (1 H, m), 6.3 (1 H, m), 6.8 (1 H, m), 6.9 (1 H, s), 7.0 (1 H, m), 7.2 (2 H, m), 7.4 (3 H, m). MS m / z: 507 (M + 1). (±) -C / sN- [2-benzyl-1- (4-fluoro-benzoyl) -1,2,3,4-tetrahydro-quinolin-4-yl] - N- (4-chloro-phenyl) - propionamide (B-112) was prepared (±) -c / sN- [2-benzyl-1- (4-fluoro-benzoyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] -N- (4-chloro-phenyl) -propionamide following general procedure B, substituting acetaldehyde for phenylacetaldehyde, 4-dimethylaminobenzoyl chloride for 4-fluorobenzoyl chloride and acetyl chloride for propionyl chloride. 1 H NMR (CDCl 3) d: 1, 14 (3 H, t), 2.05-2.52 (5 H, m), 3.18 - 3.24 (1 H, m), 4.89 -, 93 (1 H, m) 5.45-5.55 (1 H, a), 6.46 (1 H, d), 6.83-7.37 (16 H, m). MS m / z: 528 (M + 1). (±) -C / sN- (4-chloro-phenyl) -N- [2-methyl-1- (3-methyl-isoxazole-5-carbonyl) -1,2,3,4-tetrahydro-quinoline-4 -yl] -acetamide (B-113) was prepared (±) -cs-N- (4-chloro-phenyl) -N- [2-methyl-1- (3-methyl-isoxazole-5-carbonyl) -1 , 2,3,4-tetrahydro-quinolin-4-yl] -acetamide following the general procedure B, substituting 4-dimethylammonium-benzoyl chloride for 3-methylisoxazole-5-carbonyl chloride. Separated (±) -c / sN- (4-chloro-phenyl) -N- [2-methyl-1- (3-methyl-isoxazole-5-carbonyl) -1, 2,3,4-tetrahydro-quinolin -4-yl] -acetamide by chiral HPLC using a chiral OD cell column and eluting with an isocratic system of 90% hexane / 10% ethanol to give (2R, 4S) - and (2S, 4R) -c / sN - (4-chloro-phenyl) -N- [2-methyI-1- (3-methyl-5-oxazole-5-carbonyl), 2,3,4-tetrahydro-quinolin-4-yl] -acetamide ( B-42 and B-36, respectively) 1 H NMR (CDCl 3) d: 1, 1 (3 H, d), 1, 1 (1 H, m), 2.0 (3 H, s), 2.2 (3 H , s), 2.3 (1 H, m), 4.7 (1 H, m), 5.4 (1 H, m), 5.8 (1 H, s), 6.8 (1 H, d), 7.1-7.4 (7H, m). MS m / z: 424 (M + 1). The compounds B-114-B-147 can be prepared by the schemes indicated in Schemes 13 and 14 and by the general procedures B and others described herein. Those skilled in the art will be able to recognize, or determine, using only conventional experimentation, many equivalents of the specific embodiments of the invention described herein.
Table 2: Compounds Obtained from General Procedure B Scheme 13 ! ÜH2 1 B CaO? B8 NaON NHBoc 1.MeSQ3H (O »: * • / s ^ OMs - ^ \ ^ CN THF ^^ 2. MsCI, TMEDA DMF, Bu4NBr (S) 16 17 ¿toa ?? - 1 8 . { Exclusive cls) 2- (S) -terc-butoxycarbonylamino-propyl ester of methanesulfonic acid (16) To a room temperature solution of S-2-amino-propan-1-ol (28.23 g, 0.375 mo!) In ethyl acetate (300 ml) was added anhydrous BOC (86.13 g, 0.395 mol) dissolved in 30 ml of ethyl acetate via an addition funnel (exothermic). The solution became turbid and then transparent. The reaction mixture was stirred for about 30 minutes. Tetramethylethylenediamine (TMEDA) (59.6 ml, 0.395 mol) was added and the reaction mixture was cooled to about 0 ° C. Methanesulfonyl chloride (30.6 ml, 0.395 mol) was added to the reaction mixture over a period of 30 minutes. After stirring for 2.5 hours at 0 ° C, a white precipitate formed. The reaction mixture was filtered and the filtrate was concentrated to half the volume, poured into hexanes (800 ml) and stirred rapidly. The mixture was cooled in an ice bath for 2 h and then filtered to give 82 g (86%) of 2- (S) -tert-butoxycarbonylamino-propyl ester of methanesulfonic acid. 1 H NMR (300 MHz, CDCl 3) d 1, 23 (d, 3H), 1.44 (s, 9 H), 3.03 (s, 2 H), 3.96 (m, 1 H), 4.15 (dd, 1 H), 4.23 (dd, 1 H), 4.58 (s at, 1 H). (S) - (2-Cyano-1-methyl-ethyl) -carbamic acid tert-butyl ester (17) Sodium cyanide (48.92 g, 0.421 mol) was added to dimethylformamide (DMF) (420 ml) and the The mixture was stirred at 35 ° C for 30 minutes. Tetrabutylammonium bromide (5.22 g, 0.016 mol) was added and the reaction mixture was stirred for a further 2 h at 35 ° C. 2- (S) -tert-butoxycarbonylamino-propyl ester of methanesulfonic acid (82.03 g, 0.324 mol) was added and the reaction mixture was stirred at 35 ° C overnight. An additional 5.22 g of tetrabutylammonium bromide (0.016 mol) was added and stirred overnight at 35 ° C. Then, the mixture was partitioned between 1200 ml of water and 1600 ml of ethyl acetate. The resulting organic extract and the aqueous phases were separated and extracted sequentially 2 times with 800 ml of ethyl acetate. The combined extracts were washed 3 times with 500 ml of water and a saturated solution of sodium chloride in water. The organic layer was dried over magnesium sulfate, filtered and concentrated to yield an 84% solid of (S) - (2-cyano-1-methyl-ethyl) -carbamic acid tert-butyl ester. (S) -3-Amino-butyronitrile (18) To a solution of (S) - (2-cyano-1-methyl-ethyl) -carbamic acid tert-butyl ester (50.29 g, 0.273 mol) dissolved in THF (550 ml) was added methanesulfonic acid (44 ml, 0.682 mol) and stirred for 20 minutes. The reaction mixture was heated at 65 ° C for about 3 h (make sure the reaction is ventilated during this time). The mixture was allowed to cool to room temperature. The resulting solids were isolated by filtration to yield the title compound. The solids were suspended in dichloromethane and 300 ml of sat Na2CO3. and the pH was adjusted to 13 with 6 M NaOH (-20 ml). Extract 2 x 500 ml of dichloromethane. Combine the organic extracts and wash with a saturated solution of sodium chloride in water. The organic layer was dried over sodium sulfate, filtered and concentrated to give (S) -3-amino-butyronitrile in 64% yield. 1 H NMR (300 MHz, CDCl 3) d 1, 23 (d, 3 H), 1.46 (sa, 2 H), 2.34 (dd, 1 H), 2.43 (dd, 1 H), 3 , 34 (sextuplete, 1 H). (S) -3-Phenylamino-butyronitrile (19) (S) -3-Amino-butyronitrile (2.51 g, 0.030 mol) was dissolved in 40 ml of DMF, phenylboronic acid (4.73 g, 0, 0389 mol), Cu (OAc) 2 (7.06 g, 0.0389 mol) and pyridine (6.29 ml, 0.077 mol) and the reaction was heated to 65 ° C open to the air until no starting material remained by LCMS (It is very important that this reaction does not take place under an argon or nitrogen atmosphere, air is needed to catalyze the reaction, and the reaction must be stirred very vigorously to allow the air to mix with the reaction.). After removing the starting material (~18 h), the reaction was allowed to cool to room temperature, poured into ethyl acetate and filtered. The precipitate was washed well with ethyl acetate. The filtrate was washed 2 times with H2O, dried over Na2SO4, filtered and concentrated. Isco chromatography (gradient from 100% hexane to 30% ethyl acetate / 70% hexane) yielded the N-phenylnitrile in 2.13 g (41%) as a white solid. 1 H NMR (300 MHz, CDCl 3) d 1, 44 (d, 3 H), 2.61 (d, 2 H), 3.64 (br s, 1 H), 3.90 (br s, 1 H), 6, 60 (d, 2 H), 6.77 (t, 1 H), 7.18-7.26 (m, 2 H) (S) -3-Phenylamino-butyramide (20) To a solution of (S) 3-phenylamino-butyronitrile (6.06 g, 0.0378 mol) in toluene (150 ml) was added a cooled solution of conc. Sulfuric acid. in H2O (20.12 ml H2S04 / 3 ml) (the ratio of toluene to acid / H2O is very important and must be strictly followed). Stir the biphasic mixture at room temperature for 0.5 h, warm to 35 ° C and stir for 22 h. The reaction was cooled to room temperature and quenched with 13 g of Na2CO3 in water (slowly add a little foaming agent). Separate the organic extract and extract 2 x EtOAc. Combine all the organic extracts and wash the organic extracts with brine, dried over MgSO4, filtered and concentrated to give the desired product in 2.11 g (90%) 1 H NMR (300 MHz, CDCl 3) d: 1.29 (d, 3 H), 2.40 (dd, 1 H ), 2.48 (dd, 1 H), 3.73 (sa, 1 H), 3.92 (sextuplet, 1 H), 5.52 (sa, 1 H), 6.00 (sa, 1 H) ), 6.66 (d, 2 H), 6.74 (t, 1 H), 7.19 (m, 2 H) Benzyl ester of (S) - (3-phenylamino-butyral) -carbamic acid (21) A clean, dry flask purged with nitrogen gas was charged with (S) -3-phenylamino-butyramide (3.25 g, 0.018 mmol) in THF (65 ml) and the mixture was cooled to -10 ° C. Then, benzyl chloroformate (3.12 ml, 0.022 mmol) was added followed by the slow addition of 1.0 M lithium tert-butoxide in a THF solution (18 ml). The solution of lithium tert-butoxide was added at such a rate that the internal temperature remained below 0 ° C. Fifteen minutes after the addition of the base was complete, the reaction (starting material removed by TLC) was stopped by the addition of EtOAc (65 ml) and 1.0 M hydrochloric acid (10 ml). Then, the aqueous phase was basified with 1 N NaOH. The aqueous phase was extracted 3 x EtOAc. The organic extracts were collected together and with a saturated aqueous sodium chloride solution (130 ml). The phases were separated and the organic layer was dried (MgSO), filtered and concentrated. Flash chromatography using a Biotage system (10% EtOAc / 10% hexane to 20% EtOAc / 80% hexane) afforded the title compound in 82% yield. H NMR (300 MHz, CDCl 3) d: 1, 30 (d, 3 H), 2.87 (dd, 1 H), 3.04 (dd, 1 H), 3.80 (br s, 1 H), 4.02 (m, 1 H), 5.17 (s, 2 H), 6.62 (d, 2 H), 6.73 (t, 1 H), 7.17 (t, 2 H), 7.37 (s, 5 H), 8.13 (sa, 1 H). Benzyl ester of (2S, 4R) - (2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl) -carbamic acid (22) A clean, dry flask was charged with benzyl ester of the acid (S) ) - (3-phenylamino-butyryl) -carbamic acid (0.821 g, 2.63 mmol) followed by quality ethanol for use as a reagent (20 ml) and cooled to -10 ° C. To the solution was added sodium borohydride (0.070 g, 1.84 mmol) in one portion. Purging with nitrogen gas was maintained for 5 minutes. A 3.3 M solution of aqueous magnesium chloride (0.561 g MgCl2 6H2O in 1.5 ml of water) was added at such a rate that the internal temperature did not exceed -5 ° C. After the addition was complete, the reaction solution was heated at 0 ° C for 30 min. The reaction was quenched with methylene chloride (10 ml) and a 1 M solution of hydrochloric acid / citric acid (10.52 ml of 1 N HCl, and 1.38 g of citric acid). This bilayer was stirred at room temperature for six hours. The reaction mixture was diluted with ethyl acetate (200 ml) and neutralized with an aqueous sat. NaHCO3 solution. (pH = 10). The organic extracts were collected together, washed with a solution of NaCl sat, dried over Na2SO4, filtered and concentrated. Flash chromatography using an Isco system (gradient of 100% hexane to 50% EtOAc / 50% hexane) yielded the title compound (0.733 g). (91%) 1 H NMR (300 MHz, CDCl 3) d: 7.38 (m, 5 H), 7.17 (d, 1 H), 7.02 (t, 1 H), 6.68 (t, 1 H, C6 -H), 6.47 (d, 1 H), 5.17 (sa, 2H), 5.07 (m, 1 H), 4.92 (d, 1H), 3.78 (sa, 1H) , 3.57 (m, 1 H), 2.30 (m, 1 H), 1.47 (c, 1 H), 1, 21 (d, 3H). General Procedure C Scheme 15 (2S, 4R) -N- (4-Chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -2-methyl-152,3,4-tetrahydro-quinolin-4-yl] -acetamide ( 25) To a solution of (2S, 4R) - (2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl) -carbamic acid benzyl ester (1.0 g, 3.38 mmol) in methylene chloride (50 ml) at room temperature was added diisopropylethylamine (650 μl, 3.72 mmol) followed by 4-fluorobenzoyl chloride. The reaction was stirred overnight at room temperature. The mixture was poured into water and extracted with ethyl acetate. The extracts were washed with 1 M NaOH (aq.) And brine, dried over magnesium sulfate, filtered, dried and concentrated. The crude residue was purified by chromatography on silica gel (75% hexanes / 25% ethyl acetate) to yield pure amide (720 mg, 51%). Benzyl ester of (2S, 4R) - [1- (4-fluorobenzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -carbamic acid (720 mg, 1.73 mmol) in ethanol (30 ml). The vessel in which the resulting solution was found was evacuated and charged with argon. A catalytic amount of Palladium on Carbon (10%) was added. The vessel was evacuated one more time and this time charged with hydrogen and stirred in a Parr vessel at 275,790 kPa (40 psi) of hydrogen. The reaction was complete after 4 h. The mixture was carefully filtered and concentrated to 10% of the volume. The resulting concentrated solution was filtered through a Celite® and concentrated to yield the crude amine. To a solution of (2S, 4R) - (4-amino-2-methyl-3,4-dihydro-2H-quinolin-1-yl) - (4-fluoro-phenyl) -methanone (1.0 g, 3.5 mmol) in DMF (20 ml, dry) was added 4-chlorophenylboronic acid (1.1 g, 7.0 mmol), pyridine (850 μl, 10.5 mmol) and copper (II) acetate ( 1.27 g, 7.0 mmol). The heterogeneous green mixture was stirred open in the air for 1 h, then heated to 60 ° C and stirred overnight (14 h). After the mixture was cooled to rt, it was poured into rapidly stirred ethyl acetate (150 ml); and the solids were removed by filtration through Celite®. The extracts were washed several times with water and then once with brine. Then, the extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel (95% methylene chloride / 5% ethyl acetate) to yield the aniline product (250 mg, 18%) as a yellow oil. To a solution of (2S, 4R) - [4- (4-chloro-phenylamino) -2-methyl-3,4-dihydro-2H-quinolin-1-yl] - (4-fluoro-phenyl) -methanone ( 250 mg, 0.636 mmol) in methylene chloride (5 ml) was added diisopropylethylamine (120 μl, 0.70 mmol) followed by acetyl chloride (90 μl, 1.27 mmol). The mixture was stirred at rt for 4 h. The mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with sat. Aqueous sodium bicarbonate. and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (gradient of 25/75 hexanes / ethyl acetate) to yield N- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -2- pure methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide (200 mg, 71%). 1 H NMR (CDCl 3) d: 1.1 (3H, d), 1.1 (1 H, m), 2.0 (3H, d), 2.3 (1 H, m), 4.7 (1 H, m), 5.6 (1 H, m), 6.5 (1H, d), 6.7-7.0 (3H, m), 7.1-7.4 (8H, m). MS m / z: 436 (M + 1). (2S54?) - N- (4-Chloro-phenyl) -N- [2-methyl-1- (4-morpholin-4-yl-benzoyl) -1, 2,354-tetrahydro-quinolin-4-yl] -acetamide (C-1) was prepared (2S, 4:?) - N- (4-chloro-phenyl) -N- [2-methyl-1 - ( 4-morpholin-4-yl-benzoyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide following the general procedure C, substituting 4-bromobenzoyl chloride for 4-fluorobenzoyl chloride. Another elaboration of the morpholine was carried out following the same procedure described for (±) -N- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -2-methyl-6-morpholin-4- il-1, 2,3,4-tetrahydro-quinolin-4-yl] -propionamide. 1 H NMR (CDCl 3) d: 1, 13 (d, 3 H), 1, 22 (t, 1 H), 2.03 (s, 3 H), 2.29 (s, 1 H), 3.31 (t, 4H), 3.80 (t, 4H), 4.75 (sextuplet, 1 H), 5.61 (sa, 1 H), 6.58 (d, 1 H), 6.64 (d, 2H) , 6.94 (t, 1 H), 7.15 (d, 2H), 7.18 (t, 1 H), 7.21 (d, 2H), 7.28-7.39 (m, 3H) ). MS m / z: 505.4 (M + 1). (2S, 4R) -4- (4- {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl} .-phenoxy) -butyric acid (C-2). Preparation was prepared (2S, 4R) -4- (4-. {4- [acetyl- (4-cioro-phenyl) -amino] -2-methyl- 3,4-dihydro-2H-quinoline-1-carbonyl.] - phenoxy) -butyric following general procedure C, substituting 4-fluorobenzoyl chloride for 4-methoxybenzoyl chloride. Further elaboration of the acid was carried out following the same procedure described for (±) -4- (4-. {4 - [(4-chloro-phenyl) -propionyl-amino] -2-methylene-3,4) -dihydro-2H-quinol-1-carbonyl-] -phenoxy) -butyric acid. 1 H NMR (CDCl 3) d: 1.1 (3 H, d), 1.1 (1 H, m), 2.0 (3 H, s), 2.1 (2 H, m), 2.3 (1 H , m), 2.5 (2H, m), 3.9 (2H, m), 4.7 (1 H, m), 5.6 (1 H, m),), 6.5 (1 H , d), 6.7 (2H, d), 6.9 (1H, t), 7.1-7.3 (7H, m), 7.4 (1H, d). MS m / z: 522 (M + 2). (2S, 4f?) - N- (4-Chloro-phenyl) -N- [1- (4-dimethylamino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide (C-3) was prepared (2S, 4R) -N- (4-chloro-phenyl) -N- [1- (4-dimethylamino-benzoyl) -2-methyl-1, 2,3,4- tetrahydro-quinolin-4-yl] -acetamide following general procedure C, substituting 4-fluorobenzoyl chloride for 4-dimethylaminobenzoyl chloride. 1 H NMR (300 MHz, CDCl 3) d: 1, 14-1, 33 (m, 4 H), 2.13 (s, 3 H), 2.24-2.39 (m, 1 H), 2, 94 (s, 6 H), 4.75 (ddd, 1 H), 5.61 (sa, 1 H), 6.44 (d, 2 H), 6.63 (d, 1 H), 6, 96 (dd, 1 H), 7.07-7.36 (m, 6 H), 7.40 (d, 2 H). MS m / z: 420 (M + 1). (2S, 4R) -N- (4-Chloro-phenyl) -N- [1- (4-isopropoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] - acetamide (C-4) was prepared (2S, 4R) -N- (4-chloro-phenyl) -N- [1- (4-isopropoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro -quinolin-4-yl] -acetamide following the general procedure C, substituting 4-fluorobenzoyl chloride for 4-isopropoxybenzoyl chloride. H NMR (300 MHz, CDCl 3) d: 1, 14 (d, 3 H), 1, 23-1, 31 (m, 7 H), 2.03 (s, 3 H), 2.23-2, 35 (m, 1 H), 4.48 (sept., 1 H), 4.74 (ddd, 1 H), 5.61 (sa, 1 H), 6.55 (d, 1 H), 6 , 64 (d, 2 H), 6.92 (dd, 1 H), 7.09 - 7.24 (m, 5 H), 7.29 (d, 1 H), 7.34 - 7.41 (m, 2 H). MS m / z: 477 (M + 1). (2S, 4R) -N- (4-Chloro-phenyl) -N- [2-methyl-1- (6-morpholin-4-yl-pyridine-3-carbonyl) -1,2,3,4-tetrahydro -quinolin-4-yl] -acetamide (C-5) was prepared (2S, 4R) -N- (4-chloro-phenyl) -N- [2-methyl-1- (6-morpholin-4-yl- pyridine-3-carbonyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide following the general procedure C, substituting 4-fluorobenzoyl chloride for 2-chloronicotinoyl chloride. Before removal of the benzyl carbamate, chloronicotinamide was converted to 2-morpholinonicotinamide as indicated below. A solution of the benzyl ester of (2S, 4R) - [1- (6-cyclo-nicotinoyl) -2-methyl-1, 2,3,4-tetrahydro-quino-4-yl] -carbam Co (525 mg, 1.20 mol) was dissolved in morpholine (5 ml). The resulting solution was heated at 70 ° C overnight. After the reaction was complete (12 h), the solution was concentrated under reduced pressure; and the crude residue was dissolved in ethyl acetate and washed with water and brine to remove the remaining morpholine. The extracts were dried over sodium sulfate, filtered and concentrated to yield crude morpholinonicotinate (639 mg,> 100%). The resulting product was converted to (2S, 4R) -N- (4-chloro-phenyl) -N- [2-methyl-1- (6-morpholin-4-yl-pyridine-3-carbonyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide fully worked-up as described in general procedure C. 1 H NMR (300 MHz, CDCl 3) d: 1, 11 -1, 22 (m , 4 H), 2.03 (s, 3 H), 2.24 - 2.38 (m, 1 H), 3.48 - 3.56 (m, 4 H), 3.74 - 3.80 (m, 4 H), 4.73 (ddd, 1 H), 5.56 (sa, 1 H), 6.30 (d, 1 H), 6.66 (d, 1 H), 7.02 (dd, 1 H), 7.12 (dd, 1 H), 7.16 - 7.25 (m, 3 H), 7.32 (d, 1 H), 7.40 (d, 2 H) , 8.24 (sa, 1 H). MS m / z: 505 (M + 1). (2S, 4?) - N- (4-Chloro-phenyl) -N- [1- (3-ethyl-isoxazole-5-carbonyl) -2-methylene-1,2,3,4- tetrahydro-quinoline-4-irylacetamide (C-6) was prepared (2S, 4R) -N- (4-chloro-phenyl) -N- [1- (3-ethyl-isoxazole-5-carbonyl) -2 -methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide following the general procedure C, substituting 4-fluorobenzoyl chloride for 3-ethylisoxazole-carbonyl chloride. 1 H NMR (300 MHz, CDCl 3) d: 1, 06-1, 23 (m, 7 H), 2.02 (s, 3 H), 2.21-2.37 (m, 1 H), 2, 52 - 2.66 (m, 2 H), 4.72 (ddd, 1 H), 5.34 - 5.56 (sa, 1 H), 5.88 (s, 1 H), 6.80 ( d, 1 H), 7.11 (dd, 1 H), 7.20 (d, 2 H), 7.28-7.43 (m, 4 H). MS m / z: 438 (M + 1). (2S, 4 /?) - N- [1- (3-Benzyl-isoxazole-5-carbonyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N- (4-chloro-phenyl) -acetamide (C-7) Prepared (2S, 4R) -N- [1- (3-benzyl-isoxazole-5-carbonyl) -2-methyl-1, 2,3,4 -tetrahydro-quinolin-4-yl] -N- (4-chloro-phenyl) -acetamide following the general procedure C, substituting 4-fluorobenzoyl chloride for 3-benzisoxazole-carbonyl chloride. 1 H NMR (300 MHz, CDCl 3) d: 1, 06-1, 43 (m, 4 H), 2.01 (s, 3 H), 2.16-2.35 (m, 1 H), 3, 81 - 4.01 (m, 2 H), 4.70 (ddd, 1 H), 5.40 (sa, 1 H), 5.83 (s, 1 H), 6.75 (d, 1 H) ), 7.02 (dd, 1 H), 7.10 (m, d, 2 H), 7.14-7.22 (m, 2 H), 7.22-7.34 (m, 5 H) ), 7.38 (d, 2 H). MS m / z: 500 (M + 1). (2S, 4R) -N- (4-Chloro-phenyl) -N- [1- (3-methoxymethyl-isoxazole-5-carbonyl) -2-methyl-1, 2,3,4-tetrahydro-quinoline-4 -yl] -acetamide (C-8) was prepared (2S, 4f?) - N- (4-chloro-phenyl) -N- [1- (3-methoxymethyl-isoxazole-5-carbonyl) -2-methyl- 1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide following general procedure C, substituting 4-fluorobenzoyl chloride for 3-methoxymethyl ether isoxazolo-carbonyl chloride. 1 H NMR (300 MHz, CDCl 3) d: 1, 11-1, 24 (m, 4 H), 2.02 (s, 3 H), 2.22-2.39 (m, 1 H), 3, 28 (s, 3 H), 4.42 (s, 2 H), 4.73 (ddd, 1 H), 5.46 (sa, 1 H), 6.09 (s, 1 H), 6, 79 (d, 1 H), 7.10 (d, 1 H), 7.10 (d, 2 H), 7.27-7.42 (m, 4 H). MS m / z: 454 (M + 1). (2S, 4?) - 4- (4-. {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-ethyl ester -carbonyl.}. -phenoxy) -piperidine-1-carboxylic acid (C-9) (2S, 4R) -4- (4-. {4- [acetyl- (4-chloro-phenyl) ethyl ester was prepared. ) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl.) -phenoxy) -piperidine-1-carboxylic acid following the general procedure C, substituting chloride of 4-fluorobenzoyl by 4- (4-chlorocarbonyl-phenoxy) -piperidine-1-carboxylic acid ethyl ester. 1 H NMR (CDCl 3) d: 1.1 (3H, d), 1.1 (1 H, m), 1.2 (3H, t), 1.7 (2H, m), 1.9 (2H, m), 2.0 (3H, s), 2.3 (1H, m), 3.3 (2H, m), 3.7 (2H, m), 4.1 (2H, c), 4 , 4 (1H, m), 4.8 (1H, m), 5.6 (1H, m), 6.5 (1H, d), 6.7 (2H, d), 6.9 (1 H, t), 7.1-7.3 (7H, m), 7.4 (1 H, d). MS m / z: 590 (M). (2S, 4 /?) -2- (4-. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1 -carbonyl} -phenoxy) -acetamide (C-10) Prepared (2S, 4R) -2- (4-. {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3, 4-dihydro-2H-quinoline-1-carbonyl.]. -phenoxy) -acetamide from (2S, 4R) -N- (4-chloro-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide. Prepared (2S, 4R) -N- (4-chloro-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl ] -acetamide following the general procedure C, substituting 4-fluorobenzoyl chloride for 4-methoxybenzoyl chloride. Another elaboration of the amide was carried out following the same procedure described for (±) -N- [1- (4-carbamoylmethoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide. 1 H NMR (CDCl 3) d: 1.1 (3H, m), 1.8 (1H, s), 2.0 (3H, s), 2.3 (1H, m), 4.4 (2H, s), 4.7 (1 H, m), 5.6 (1 H, a), 5.9 (2H, sa), 6.5 (2H, d), 6.7 (2H, d), 6.9 (1 H, t), 7.2-7.4 (7H, m). MS m / z: 492 (M + 1). (2S, 4R) -N- (4-Chloro-phenyl) -N-. { 2-methyl-1- [4- (2-morpholin-4-yl-ethoxy) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -acetamide (C-11) was prepared (2S, 4R) -N- (4-chloro-phene) -N-. { 2-methyl-1- [4- (2-morpholin-4-yl-ethoxy) -benzoyl] -1, 2,3,4-tetrahydro-quinolin-4-yl} -acetamide from (2S, 4R) -N- (4-chloro-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinoline- 4-l] -acetamide. Prepared (2S, 4R) -N- (4-chloro-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl. ] -acetamide following general procedure C, substituting 4-fluorobenzoyl chloride for 4-methoxybenzoyl chloride. Another elaboration of the morpholine was carried out following the same procedure described for (±) -N-. { 2-methyl-1- [4- (2-morfoin-4-yl-ethoxy) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -N-phenyl-propionamide. 1 H NMR (CDCl 3) d: 1.1 (3 H, d), 1.1 (1 H, m), 2.0 (3 H, s), 2.3 (1 H, m), 2.6 (4 H, m), 2.8 (2H, m), 3.7 (4H, m), 4.1 (2H, m), 4.7 (1H, m), 5.6 (1H, m), 6, 5 (1H, d), 6.7 (2H, d), 6.9 (1H, t), 7.1-7.3 (7H, m), 7.4 (1H, d). MS m / z: 549 (M + 2). (2S, 4?) - (4. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}. -phenoxy) -acetic acid (C-13) (2S, 4R) - (4-. {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro) was prepared -2H-quinoline-1-carbonyl] -phenoxy) -acetic acid from (2S, 4R) -N- (4-cyclo-phenyl) -N- [1- (4-methoxy) benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolyl-4-yl] -acetamide. Prepared (2S, 4R) -N- (4-chloro-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl. ] -acetamide following general procedure C, substituting 4-fluorobenzoyl chloride for 4-methoxybenzoyl chloride. Another elaboration was carried out for the acid following the same procedure described for acid. { (±) -4- [2-methyl-4- (phenyl-propionyl-amino) -3,4-dihydro-2H-quinoline] -carbonyl] -phenoxy} -acetic. 1 H NMR (CDCl 3) d: 1.1 (3 H, d), 1.1 (1 H, m), 2.0 (3 H, s), 2.3 (1 H, m), 4.3 (2 H , s), 4.6 (1 H, m), 5.6 (1 H, m), 6.4-6.9 (5H, m), 7.0-7.4 (7H, m). MS m / z: 494 (M + 2). (2S, 4f?) - N- (4-Chloro-phenyl) -N-. { 2-methyl-1 - [4- (1 H-tetrazol-5-ylmethoxy) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -acetamide (C-14) was prepared (2S, 4R) -N- (4-chloro-phenyl) -N-. { 2-methyl-1- [4- (1 H-tetrazol-5-ylmethoxy) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -acetamide from (2S, 4R) -N- (4-chloro-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinoline- 4-il] -acetamida. Prepared (2S, 4R) -N- (4-chloro-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl ] -acetamide following general procedure C, substituting 4-fluorobenzoyl chloride for 4-methoxybenzoyl chloride. Another elaboration was carried out for the tetrazole following the same procedure described for (±) -N- (4-chloro-phenyl) -N-. { 2-methyl-1 - [4- (1 H-tetrazol-5-ylmethoxy) -benzoyl] -1,2,3,4-tetrahydro-quinoIin-4-yl} -propionamide. 1 H NMR (CDCl 3) d: 1.1 (3H, d), 1.1 (1H, m), 2.0 (3H, s), 2.3 (1H, m), 4.8 (1H, m ), 5.2 (2H, dd), 5.6 (1 H, m), 6.4 (1 H, m), 6.5 (1H, d), 7.0 (2H, m), 7 , 1-7.4 (8H, m). MS m / z: 517 (M + 1). (2S, 4R) -N-. { 1 - [4- (1-Acetyl-piperidin-4-yloxy) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -N- (4-chloro-phenyl) -acetamide (C-15) was prepared (2S, 4R) -N-. { 1 - [4- (1-Acetyl-piperidin-4-yloxy) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -N- (4-chloro-phenyl) -acetamide from ethyl ester of (2S, 4R) -4- (4-. {4- [acetyl- (4-chloro-phenyl) -amino]] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl.] - phenoxy) -piperidine-1-carboxylic acid, followed by removal of the ethoxycarbamate using basic hydrolysis and then acetylation. 1 H NMR (CDCl 3) d: 1, 1 (3H, d), 1, 1 (1H, m), 1, 6-2.1 (4H, m), 2.0 (6H, s), 2.3 (1H, m), 3.4 (1H, m), 3.5-3.8 (3H, m), 4.4 (1H, m), 4.7 (1H, m), 5.6 (1H, m ), 6.5 (1 H, d), 6.7 (2H, d), 6.9 (1 H, t), 7.1-7.3 (7H, m), 7.4 (1H, d). MS m / z: 560 (M + 1). (2S, 4R) -N- (4-Chloro-phenyl) -N-. { 2-methyl-1- [4- (pyridin-4-ylmethoxy) -benzoyl] -1,2,4,4-tetrahydro-quinolin-4-yl} -acetamide (C-16) (2S, 4R) -N- (4-chloro-phenyl) -N- were prepared. { 2-methyl-1 - [4- (pyridin-4-ylmethoxy) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -acetamide and (2S, 4R) -N- (4-chloro-phenyl) -N-. { 2-methyl-1- [4- (1 H-tetrazol-5-ylmethoxy) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -acetamide from (2S, 4R) -N- (4-chloro-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinoI n-4-l] -acetamida. Prepared (2S, 4R) -N- (4-chloro-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl. ] -acetamide following general procedure C, substituting 4-fluorobenzoyl chloride for 4-methoxybenzoyl chloride. It was dissolved (2S, 4R) -N- (4-chloro-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl. ] -acetamide in dichloromethane and a solution of BBr3 (1.0 M in dichloromethane, 10 ml) was added; the reaction was allowed to stir at room temperature until no starting material remained. The reaction was carefully washed with sat. NaHCO3. and brine. The organic extracts were dried over MgSO, filtered and concentrated. The residue was purified by flash chromatography Biotage using 100% EtOAc to give a white solid. The phenol was dissolved in DMF (5 ml) at room temperature. Sodium hydride (60% in oil) was added and the mixture was allowed to stir for 30 min. 4-Bromomethyl-pyridine was added and the reaction was allowed to stir overnight. Ethanol was added and the reaction was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO 4, filtered and concentrated. The crude residue was purified by chromatography on silica gel (gradient 2/98 methanol / dichloromethane-5/95 methanol / dichloromethane) to produce the product. 1 H NMR (CDCl 3) d: 1.1 (3 H, d), 1.1 (1 H, m), 2.0 (3 H, s), 2.3 (1 H, m), 4.7 (1 H, m), 5.0 (2H, s), 5.6 (1 H, m), 6.5 (1 H, d), 6.7 (2H, d), 6.9 (1 H, t), 7.0-7.4 (10H, m), 8.6 (2H, d). MS m / z: 526 (M + 1). (2S, 4R) -4- (3- {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl} .-phenoxy) -butyric acid (C-17) (2S, 4R) -4- (3. {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3) acid was prepared, 4-dihydro-2H-quinoline-1-carbonyl) -phenoxy) -butyric following general procedure C, substituting 4-fluorobenzoyl chloride for 3-methoxybenzoyl chloride. Another elaboration was carried out for the acid following the same procedure described for (±) -4- (4-. {4 - [(4-chloro-phenyl) -proponyl-amino] -2-methyl-3 acid, 4-dihydro-2H-quinoline-1-carbonyl] -phenoxy) -butyric acid. ? NMR (CDCl 3) d: 1.1 (3H, d), 1.1 (1 H, m), 1.8-2.0 (2H, m), 2.0 (3H, s), 2.3 (1 H, m), 2.4 (2 H, m), 3.8 (2 H, m), 4.8 (1 H, m), 5.7 (1 H, m), 6.4 (1 H, m ), 6.5 (1H, d), 6.8 (1 H, m), 7.0 (1 H, t), 7.1-7.4 (7H, m), 7.5 (1H, m). MS m / z: 521 (M + 1). (2S, 4R) - N- (4-Chloro-phenyl) -N- [1- (4-hydroxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] - acetamide (C-18) was prepared was prepared (2S, 4R) -N- (4-chloro-phenyl) -N- [1- (4-hydroxy-benzoyl) -2-methyl-1, 2,3, 4-tetrahydro-quinolin-4-yl] -acetamide following the general procedure C, substituting 4-fluorobenzoyl chloride for 3-methoxybenzoyl chloride. Another elaboration was carried out for the phenol following the same procedure described for (±) -N- [1- (4-hydroxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide. 1 H NMR (CDCl 3) d: 1.1 (3 H, d), 1.1 (1 H, m), 2.0 (3 H, s), 2.3 (1 H, m), 4.7 (1 H , m), 5.6 (1 H, m), 6.4 (2H, d), 6.5 (1 H, d), 6.9 (3H, m), 7.1-7.3 ( 4H, m), 7.4 (2H, m), 8.0 (1 H, a). MS m / z: 435 (M + 1). Ethyl ester of (2S, 4R) -4- (4-. {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1 - carbonyl, phenyl) -piperidine-1-carboxylic acid (C-19) (2S, 4R) -4- (4-. {4- [acetyl- (4-chloro-phenyl)) ethyl ester was prepared -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl.} - phenyl) -piperidine-1-carboxylic acid following general procedure C, substituting 4-fluorobenzoyl chloride for ethyl ester of acid 4- (4-chlorocarbonyl-phenyl) -piperidine-1-carboxylic acid. ? NMR (CDCl 3) d: 1.1 (4 H, m), 1.3 (3 H, m), 1.5 (2 H, m), 1.7 (2 H, m), 2.0 ( 3 H, s), 2.3 (1 H,), 2.6 (1 H, m), 2.8 (2 H, t), 4.1 (2 H, m), 4.2 (2 H, m), 4.8 (1 H, m), 5.6 (1 H, a), 6.5 (1 H, d), 6.9 (1 H, m), 7.0 (2 H, d), 7.1 (2 H, d), 7.3 (5 H, m), 7.4 ( 2H, m). MS m / z: 474 (M + 1). (2S, 4R) -N- (4-chloro-phenyl) -N- [1 - (3-ethoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide (C-20) was prepared (2S, 4R) -N- (4-chloro-phenyl) -N- [1- (3-ethoxy-benzoyl) -2-methylene-1, 2.3, 4-tetrahydro-quinolin-4-yl] -acetamide following general procedure C, substituting 4-fluorobenzoyl chloride for 3-ethoxybenzoyl chloride. 1 H NMR (CDCl 3) d: 1, 2 (3 H, m), 1.3 (4 H, m), 2.0 (3 H, s), 2.2 (1 H, m), 3.9 (2 H, m), 4.8 (1 H, m), 5.6 (1 H, a), 6.5 (1 H, d), 6.7 (1 H, d), 6.8 ( 2 H, m), 6.9 (1 H, m), 7.0 (1 H, m), 7.1-7.3 (4 H, m), 7.4 (2 H, d). MS m / z: 463 (M + 1). Ethyl ester of (2S, 4R) - (4- 4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1 -carbonyl} - phenyl) -carbamic acid (C-22) (2S, 4R) - (4-. {4- [acetyl- (4-chloro-phenyl] -amino] -2-methyl-3-ethyl ester was prepared , 4-dihydro-2H-quinoline-1-carbonyl.} - phenyl) -carbamic acid following general procedure C, substituting 4-fluorobenzoyl chloride for (4-chlorocarbonyl-phenyl) -carbamic acid ethyl ester. ? NMR (CDCl 3) d: 1.1 (3 H, m), 1.3 (4 H, m), 2.0 (3 H, s), 2.3 (1 H, m), 4.2 ( 2 H, m), 4.8 (1 H, m), 5.6 (1 H, a), 6.5 (1 H, d), 6.9 (1 H, m), 7.1- 7.3 (8 H, m), 7.4 (2 H, d). MS m / z: 506 (M + 1). (2S, 4R) -N- (4-Chloro-phenyl) -N- [2-methyl-1- (4-oxazol-5-yl-benzoyl) -1,2,3,4-tetrahydro-quinolin-4 -yl] -acetamide (C-24) was prepared (2S, 4R) -N- (4-chloro-phenyl) -N- [2-methyl-1- (4-oxazol-5-yl-benzoyl) -1 , 2,3,4-tetrahydro-quinolin-4-yl] -acetamide following general procedure C, substituting 4-fluorobenzoyl chloride for 4-oxazol-5-yl-benzoyl chloride. ? NMR (CDCl 3) d: 1.2 (3 H, m), 1.3 (1 H, m), 2.1 (3 H, s), 2.3 (1 H, m), 4.8 ( 1 H, m), 5.6 (1 H, a), 6.5 (1 H, d), 6.9 (1 H, m), 7.1-7.3 (8 H, m), 7.4 (1 H, d), 7.5 (2 H, d), 7.9 (1 H, s). MS m / z: 486 (M + 1). (2S, 4R) -N- (3,4-Dichloro-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl ] -acetamide (C-25) was prepared (2S, 4R) -N- (3,4-dichloro-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl- 1, 2,3 , 4-tetrahydro-quinolin-4-yl] -acetamide following the general procedure C, substituting 4-chlorophenyl boronic acid for 3,4-dichlorophenylboronic acid and 4-fluorobenzoyl chloride for 4-methoxybenzoyl chloride. 1 H NMR (CDCl 3) d: 1, 2 (3 H, m), 1, 3 (1 H, m), 2.0 (3 H, s), 2.3 (1 H, m), 3.7 (3 H, s), 4.8 (1 H, m), 5.6 (1 H, a), 6.6 (1 H, d), 6.7 (2 H, d), 7.0 (1 H, m), 7.2 (3 H, m), 7.3 (2 H, d), 7.4 (1 H, s), 7.5 (1 H, d). MS m / z: 483 (M + 1). (2S, 4R) -N- (2,3-Di-idro-benzo [1,4] dioxin-6-yl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2, 3,4-tetrahydro-quinolin-4-yl] -acetamide (C-26) was prepared (2S, 4R) -N- (2,3-dihydro-benzo [1,4] dioxin-6-I) - N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide following the general procedure C, substituting 4-chlorophenylboronic acid for acid 2, 3-dihydro-benzo [1,4] dioxane-6-carboxylic acid and 4-fluorobenzoyl chloride per chloride 4-methoxyphenylbenzoyl. ? NMR (CDCl 3) d: 1.2 (3 H, m), 1.3 (1 H, m), 2.0 (3 H, s), 2.4 (1 H, m), 3.7 ( 3 H, s), 4.3 (4 H, s), 4.8 (1 H, m), 5.6 (1 H, a), 6.5 (1 H, d), 6.68 (2 H, d), 6.7-6.9 (3 H, m), 7.10-7.3 (5 H, m). MS m / z: 474 (M + 2). (2S, 4R) -N- [1- (4-ethoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -Np-tolyl-acetamide (C-27) Prepared (2S, 4R) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -Np-toI-yl-acetamide following the general procedure C, substituting 4-fluorobenzoyl chloride for 4-methoxybenzoyl chloride and 4-chlorophenylboronic acid for 4-toluenoboric acid. 1 H NMR (CDCl 3) d: 1, 15 (3 H, d; overlap of 1 H, t), 2.01 (3 H, s), 2.33-2.36 (overlap of 1H, m, 1H, s), 3.73 (3H, s), 4.70 (1H, m), 5.65 (1H, m), 6.50 (1H, d), 6.68 (2 x 1H, d), 6.95 (1H, t), 7.00-7.40 (8H, m). MS m / z: 429 (M + 1). (2S, 4R) -N- (4-Chloro-phenyl) -N- [2-methyl-1- (4-pyrrole-din-1-yl-benzoyl) -1, 2,3,4-tetrahydro-quinoline -4-yl] -acetamide (C-28) Prepared (2S, 4R) -N- (4-chloro-phenyl) -N- [2-methyl-1- (4-pyrrolidin-1-yl-benzoyl) -1, 2,3,4-tetrahydro-quinoIin-4-yl] -acetamide following the general procedure C, substituting 4-fluorobenzoyl chloride for 4-pyrrolidin-1-yl-benzoyl chloride. 1 H NMR (CDCl 3) d: 1, 11-1, 15 (4H, m), 1, 94-1, 98 (4H, m), 2.03 (3H, s), 2.24-2.34 ( 1 H, m), 3.21-3.25 (4H, m), 4.68-4.75 (1H, m), 5.61-5.65 (1H, a), 6.30 (2H , d), 6.63 (1 H, d), 6.92-7.52 (9H, m). MS m / z: 488 (M + 1). (2S, 4R) -N- (4-Chloro-phenyl) -N- [1 - (1-isopropyl-1 H-benzotriazole-5-carbonyl) -2-methyl-1,2,3,4-tetrahydro- quinolin-4-yl] -acetamide (C-29) was prepared (2S, 4R) -N- (4-chloro-phenyl) -N- [1- (1-isopropyl-1 H-benzotriazole-5-carbonyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide following the general procedure C, substituting 4-fluorobenzoyl chloride for 1-isopropyl-1 H-benzotriazole-5-carbonyl chloride . 1 H NMR (CDCl 3) d: 1, 19-1, 27 (4 H, m), 1, 68 (6 H, d), 2.04 (3 H, s), 2.30-2.40 (1 H, m), 4.83 (1 H, c), 4.98 (1 H, c) 5.45-5.55 (1 H, a), 6.48 (1 H, d), 6, 83 (1 H, t), 7.10-7.41 (8 H, m), 8.13 (1 H, a). MS m / z: 503 (M + 1). (2S, 4R) -N- (4-Chloro-phenyl) -N-. { 1 - [4- (1-Hydroxy-1-methyl-ethyl) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -acetamide (C-30) was prepared (2S, 4R) -N- (4-chloro-phenyl) -N-. { 1- [4- (1-hydroxy-1-methyl-ethyl) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -acetamida starting from (2S, 4R) -N- [1- (4-acetyl-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N - (4-chloro-phenyl) -acetamide. It was dissolved (2S, 4R) -N- [1- (4-acetyl-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N- (4-chloro-phenyl) ) -acetamide (112 mg, 124 mmol) in THF (5 ml) and cooled to 0 ° C. Methylmagnesium bromide (1.4 M in ether, 2 mL, 2.4 mmol) was added and the mixture was stirred at 0 ° C for 2 h. The reaction was warmed to rt and stirred for a further 2 h. The reaction was poured into saturated aqueous ammonium chloride. The phases were separated and the aqueous phase was extracted with ethyl acetate. The extracts were washed with brine, dried over magnesium sulfate, filtered, dried and concentrated. The crude alcohol was purified by chromatography on silica gel to yield the pure product (20 mg, 24%). 1 H NMR (CDCl 3) d: 1, 12-1, 21 (4 H, m), 1, 48 (6 H, d), 2.02 (3 H, s), 2.25-2.34 (1 H, m), 4.70-4.80 (1 H, m), 5.45-5.54 (1 H, a), 6.50 (1 H, d), 6.88 (1 H, t), 7.11-7.38 (10 H, m). MS m / z: 478 (M + 1). (2S, 4R) -N- (4-Chloro-phenyl) -N- [1- (3-ethoxy-isoxazole-5-carbonyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4 -yl] -acetamide (C-31) was prepared (2S, 4R) -N- (4-cyoro-phenyl) -N- [1- (3-ethoxy-isoxazole-5-carbonyl) -2-methyl-1 , 2,3,4-tetrahydro-quinolin-4-yl] -acetamide following the general procedure C, substituting 4-fluorobenzoyl chloride for 3-ethoxy-isoxazoyl-5-carbonyl chloride. 1 H NMR (CDCl 3) d: 1, 16 (3 H, d), 1, 33 (3 H, t), 1, 69 (1 H, s), 2.00 (3 H, s), 2.21-2.38 (1 H, m), 4.21 (2 H, c), 4.66-4.73 (1 H, m), 5.65 (1 H, s), 6.86 (1 H, d), 7.13-7.39 (8H, m). MS m / z: 454 (M). Acid (2S, 4R) -3- (4-. {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3, 4-dihydro-2H-quinoline-1 -carbonyl} phenyl) -propionic (C-32) (2S, 4R) -3- (4-. {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4- acid was prepared -dihydro-2H-quinoline-1-carbonyl.}. -phenyl) -propionic acid from (2S, 4R) -3- (4-. {4- [acetyl- (4-chloro-phenyl) -amino] ] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl, phenyl) -acrylic. A solution of (2S, 4R) -3- (4- {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline- 1-carbonyl.}. Phenyl) -acrylic (50 mg, 0.102 mmol) in EtOH (2 ml) and CH2Cl2 (10 drops to promote solubility) was subjected to Pd-C (10%, ca. 50 mg) and 1 atm of H2 gas. After 1 hour, the mixture was filtered, concentrated and chromatographed on silica gel (2% MeOH in EtOAc to 10% MeOH in EtOAc), yielding the title compound (50 mg, 99%). ? NMR (CDCl 3 300 MHz) d 1, 09 (3H, d), 1, 17-1.18 (1 H, m), 2.00 (3H, s), 2.20-2.35 (1H, m ), 2.46-2.60 (2H, m), 2.80-2.90 (2H, m), 4.65-4.80 (1H, m), 5.40-5.71 (1 H, m), 6.48 (1 H, d), 6.89 (1 H, t), 7.0 (2H, d), 7.12 (2H, d), 7.20-7.48 (5H, m), 7.72 (1 H, d).
MS m / z: 322 (M-C8H7NO). (2S, 4R) -3- (4-. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl} acid phenyl) -acrylic (C-33) (2S, 4R) -3- (4-. {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3) acid was prepared, 4-dihydro-2H-quinoline-1-carbonyl} -phenyl) -acrylic following general procedure C, substituting 4-fluorobenzoyl chloride for 3- (4-chlorocarbonyl-phenyl) -acrylic acid methyl ester. The ester was hydrolyzed as indicated below. To a solution of (2S.4R) -3- (4-. {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H- methyl ester quinoline-1-carbonyl.}. phenyl) -acrylic acid (112 mg, 0.239 mmol) in THF / MeOH (2 mL, 2 mL) was added LiOH (4 mL: 1.0 M in H2O). After the starting unit was consumed (1 hour), the mixture was neutralized with ac HCl. (1.0 M), partitioned with EtOAc (10 mL) and separated. The organic layer was separated and concentrated so that the resulting oil was chromatographed on silica gel (2% MeOH in EtOAc to 10% MeOH in EtOAc) to yield the title compound (110 mg, 99% ). ? NMR (MeOD, 300 MHz) d 0.85-0.95 (1 H, m), 1.12 (3H, d), 2.04 (3H, s), 2.40-2.53 (1 H , m), 4.70-4.80 (1 H, m), 5.50-5.71 (1 H, m), 6.46 (1 H, d), 6.57 (1H, d) , 6.96 (1 H, t), 7.20-7.55 (8H, m), 7.60 (2H, d), 7.81 (1 H, d). MS m / z: 320 (M-C8H7NO). (2S, 4R) -N- [1 - (4-Methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] - N- (4-methoxy-phenyl) - acetamide (C-34) was prepared (2S, 4R) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N- (4-methoxy-phenyl) -acetamide following the general procedure C, substituting 4-fluorobenzoyl chloride for 4-methoxybenzoyl chloride and 4-chlorophenylboronic acid for 4-methoxyphenylboronic acid. ? NMR (CDCl 3 300 MHz) d 1.12 (3H, d), 1, 20-1, 23 (1 H, m), 2.09 (3H, s), 2.30-2.42 (1 H, m), 3.71 (3H, s), 3.81 (3H, s) 4.70-4.81 (1H, m), 5.50-5.80 (1H, m), 6.52 (1 H, d), 6.67 (2H, d), 6.80-6.94 (4H, m), 7.10-7.40 (5H, m). MS m / z: 280 (M- C9H10NO2). (2S, 4R) -N- (4-lsopropyl-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] - acetamide (C-35) was prepared (2S, 4R) -N- (4-isopropyl-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro -quinolin-4-yl] -acetamide following the general procedure C, substituting 4-fluorobenzoyl chloride for 4-methoxybenzoyl chloride and 4-chlorophenylboronic acid for 4-isopropylphenylboronic acid. 1 H NMR (CDCl 3 300 MHz) d 1, 21 (6H, d), 1, 20-1, 23 (1H, m), 1.23 (3H, d), 2.09 (3H, s), 2, 30-2.42 (1 H, m), 2.80-2.95 (1 H, m), 3.74 (3 H, s), 4.65-4.83 (1 H, m), 5 , 50-5.80 (1 H, m), 6.53 (1 H, d), 6.67 (2H, d), 6.72 (2H, d), 6.92 (1 H, t) , 7.02-7.12 (3H, m), 7.21 (2H, d), 7.38 (1H, d). MS m / z: 280 (M- CnH14NO). (2S, 4R) -N- (4-Bromo-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] - acetamide (C-36) was prepared (2S, 4R) -N- (4-bromo-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro -quinolin-4-yl] -acetamide following the general procedure C, substituting 4-fluorobenzoyl chloride for 4-methoxybenzoyl chloride and 4-chlorophenylboronic acid for 4-bromopheniomeric acid. ? NMR (300 MHz CDCl 3) d 1, 12 (3H, d), 1, 20-1, 24 (1H, m), 2.05 (3H, s), 2.20-2.38 (1H, m ), 3.72 (3H, s), 4.66-4.81 (1H, m), 5.50-5.75 (1H, m), 6.52 (1H, d), 6 , 67 (2H, d), 6.92 (1H, t), 7.10-7.18 (5H, m), 7.26 (1H, t), 7.48-7.58 (2H , m). MS m / z: 493 (M + 1). Acid (2S, 4R) -4-. { acetyl- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -amino} -benzoic acid (C-37) (2S, 4R) -4- acid was prepared. { acetyl- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -amino} -benzoic acid from (2S, 4R) -4- methyl ester. { acetyl- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -amino} -benzoic. Methyl ester of (2S, 4R) -4- acid was prepared. { acetyl- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -amino} -benzoic following general procedure C, substituting 4-fluorobenzoyl chloride for 4-methoxybenzoyl chloride and 4-chlorophenylboronic acid for 4-phenylboronic acid methyl ester. It became methyl ester of acid (2S, 4R) -4-. { acetyl- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -amino} -benzoic in the acid using the following procedure. To a solution of 4-methyl ester. { acetyl- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinoIin-4-yl] -amino} -benzoic acid (10 mg, 0.038 mmol) in 4 ml of methanol was added 100 mg of K2CO3 (0.72 mmol, in 0.5 ml of water). The resulting reaction mixture was stirred at room temperature overnight. The methanol was removed in vacuo. 1 M HCl was added until the mixture became acidic. Dichloromethane (20 ml) and 5 ml of water were added. The organic layer was dried with magnesium sulfate. The dichloromethane was removed in vacuo to give the title compound (15 mg, 86%)? NMR (CDCl 3) d: 1.1 (3H, d), 1.1 (1 H, m), 2.0 (3H, s), 2.3 (1 H, m), 3.8 (3H, s), 4.8 (1 H, m), 5.6 (1 H, m), 6.5 (1 H, d), 6.6 (2 H, d), 6.9 (1 H, t) , 7.1-7.4 (6H, m), 8.1 (2H, d). MS m / z: 460 (M + 2). (2S, 4R) -N- (3-Aminomethyl-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] - acetamide (C-38) was prepared (2S, 4R) -N- (3-aminomethyl-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro -quinolin-4-yl] -acetamide from (2S, 4R) -N- (3-cyano-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3 , 4-tetrahydro-quinoIin-4-yl] -acetamide. Prepared (2S, 4R) -N- (3-cyano-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinoiin-4-; I] -acetamide following the conventional procedure C, substituting 4-fluorobenzoyl chloride for 3-cyanophenylboronic acid. To a mixture of (2S, 4R) -N- (3-cyano-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinoline -4-yl] -acetamide (48 mg, 0.11 mmol) in 2 ml of ethanol was added cobalt chloride (14 mg, 0.11 mmol). Sodium borohydride (12 mg, 0.33 mmol) was added at 0 ° C and the temperature was maintained at 0 ° C for 30 min. Then, the mixture was heated to rt and stirred overnight. The reaction was stopped by the addition of saturated aqueous ammonium chloride. The saturated aqueous layer was extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude oil was purified by HPLC to give the title compound (10 mg, 10%).
H NMR (CDCl 3) d: 1, 1-1, 2 (4 H, m), 2.0 (3 H, s), 2.3 (1 H, m), 3.4 (2 H, a) , 3.8 (3 H, s), 4.3 (1 H, d), 4.8 (2 H, d), 5.6 (1 H, a), 6.4 (1 H, m) , 6.6 (2 H, m), 6.9 (1 H, m), 7.1-7.4 (8H, m). MS m / z: 444 (M + 1) (2S, 4R) -N- (4-Butyl-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3, 4-tetrahydro-quinolin-4-yl] -acetamide (C-39) Prepared (2S, 4R) -N- (4-butyl-phenyl) -N- [1- (4-methoxy-benzoyl) -2- methylene-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide following general procedure C, substituting 4-fluorobenzoyl chloride for 4-methoxybenzoyl chloride and 4-chlorophenylboronic acid for 4 -butyl phenylboronic. 1 H NMR (CDCl 3) d: 0.9 (3 H, m), 1.2 (3 H, d), 1.4 (3 H, m), 1.6 (2 H, m), 2.0 (3 H, s), 2.4 (1 H, m), 2.6 (2 H, m), 3.8 (3 H, s), 4.8 (1 H, m), 5.6 (1 H, a), 6.5 (1 H, d), 6.7 (2 H, d), 7.0 (1 H, m), 7.1-7.2 (7 H, m) 7.4 (1 H, d). MS m / z: 471 (M + 1). The C-40-C-147 compounds can be prepared by the schemes indicated in Schemes 15-16 and by the general procedures C and others described herein. Those skilled in the art will be able to recognize, or determine, using only conventional experimentation, many equivalents of the specific embodiments of the invention described herein.
Table 3: Compounds Obtained from General Procedure C General Procedure D Scheme 15 Methyl ester of (2S, 4 /?) - ((4 - { Acetyl- [1- (4-methoxy-benzoyl) -2-methyl-1,2J3,4-tetrahydro-quinolin-4-yl] -amino.}.-phenoxy) -acetic acid (D-9) (2S, 4f?) - ((4 - { acetyl- [1- (4-methoxy-benzoyl) -2-) methyl ester was prepared methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -amino.}. -phenoxy) -acetic acid from benzyl ester of (2S, 4R) - (2-methyl-1, 2, 3,4-tetrahydro-quinolin-4-yl) -carbamic acid as shown below. (2S, 4) - (2-methyl-1, 2,3,4-tetrahydro-quinolyl) benzyl ester was dissolved. -4-yl) -carbamic acid (7.6 g, 25.65 mmol) in dichloromethane (50 ml) and the resulting solution was cooled to 0 ° C. Triethylamine (14.3 ml) was added dropwise to this solution. ) followed by freshly distilled anisoyl chloride (8.75 ml, 51.3 mmol) dissolved in dichloromethane (15 ml) The resulting reaction mixture was allowed to warm to room temperature and allowed to stir overnight. divided between dichloromethane and sodium hydroxide 1 M. The extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude amide was purified by chromatography on silica gel (2: 1 hexane: ethyl acetate) to yield the pure product (10 g, 91%). The benzyl ester of (2S, 4R) - [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -carbamic acid formed in this manner g) was dissolved in ethanol (400 ml). Palladium (10% on Carbon) was added. The black suspension was stirred under a hydrogen atmosphere for 3 h. The mixture was filtered and concentrated. The crude amine was purified by filtration through a silica plug (gradient elution with ethyl acetate to 90/10 ethyl acetate / methanol) to yield the pure amine (5.17 g, 72%). (2S, 4R) - (4-amino-2-methyl-3,4-dihydro-2H-quinolin-1 -yl) - (4-methoxyphenyl) -methanone (100 mg, 0.34 mmol), was collected. - (methyl 4-bromophenoxy) -acetate (91 mg, 0.37 mmol), Pd2 (dba) 3 (17 mg, 0.02 mmol), 2-dicyclohexosphino-2 '- (N, N-dimethylamino) biphenyl (8 mg, 0.00002 mol) and cesium carbonate (0.163 g, 0.0005 mol) in a round bottom flask which was then flushed with nitrogen gas through a rubber septum. Toluene (2 ml) was injected into the flask through the rubber septum and the reaction mixture was stirred at 100 ° C for 24 h. After cooling to room temperature, the reaction mixture was filtered through Celite® and evaporated to give the crude product (0.236 g). This crude product was purified by chromatography on silica gel eluting with a gradient of 100% hexanes to 50/50 hexanes / ethyl acetate to give the title compound (37 mg, 24%). To a solution of the aniline formed in this manner (0.037 g, 0.00008 mol) was added freshly distilled acetyl chloride (0.5 ml) followed by diisopropylethylamine (0.0114 g, 0.015 ml, 0.088 mmol) in dichloromethane (0.5 ml); the mixture was stirred at room temperature for 2 days. The reaction mixture was neutralized with 1 M sodium bicarbonate. The organic layer was separated, washed three times with water and brine, dried over magnesium sulfate and evaporated. The resulting crude product was purified by chromatography on silica gel eluting with (0% to 70% ethyl acetate in hexanes) to yield the title compound (15 mg, 38%). 1 H-NMR (CDCl 3) d: 1, 12-1, 14 (4 H, m), 2.02 (3 H, s), 2.18-2.43 (1 H, m), 3.75 ( 3 H, s) 3.82 (3 H, s), 4.65 (2 H, s), 4.67 - 4.82 (1 H, m), 5.45 - 5.73 (1 H, width), 6.52 (1 H), 6.68 (2 H, d), 6.89 - 6.95 (3 H, m), 7.13 - 7.21 (5 H, m), 7 , 32 (1 H, d).
MS m / z: 504 (M + 1). (2S, 4?) - (4. {Acetyl- [1- (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetra idroquinolin-4-yl] -amino}. phenoxy) -acetic (D-10) (2S, 4R) - (4 -. {acetyl- [1- (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinoline) -4-yl] -amino.}.-Phenoxy) -acetic acid from (2S, 4R) - (4-. {Acetyl- [1- (4-methoxybenzoyl) -2- methyl-1, 2,3,4-tetrahydroquinolin-4-yl] -amino.}. -phenoxy) -acetic acid (15 mg, 0.03 mmol). The methyl ester was dissolved in methanol (1 ml), sodium hydroxide (1 ml, 0.1 M in water) was added and the resulting solution was stirred at room temperature for 18 h. The reaction mixture was acidified with hydrochloric acid (1 M) and concentrated under reduced pressure. The residue was extracted with ethyl acetate and the extract was washed three times with water and brine, dried over sodium sulfate, filtered and concentrated to yield the title compound (13 mg, 89%). 1 H- NMR (CDCl 3) d: 1, 07 (4 H, m), 1, 99 (3 H, s), 2.12 - 2.38 (1 H, broad), 3.7 (3 H, s ), 4.61 (2 H, s), 4.66 - 4.78 (1 H, m), 5.47 - 5.75 (1 H, broad), 6.49 (1 H, d), 6.64 (2 H, d), 6.86-6.9 (3 H, m), 7.09-7.16 (5 H, m), 7.27 (1 H, d). MS m / z 489 (M +), 490 (M + 1) Acid (2S, 4K) -2- (4- { Acetyl- [1- (4-methoxy-benzoyl) -2-methyl-1, 2 , 3,4-tetrahydro-quinolin-4-yl] -amino} -phenyl) -2-methyl-propionic acid (D-1) (2S, 4R) -2- (4-. { acetyl- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -amino.} - phenyl) -2-methylene-propionic by saponification of 2- (4- { acetyl- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -amino acid methyl ester .}.-.phenyl] -2-methyl-propionic acid, as described in the synthesis of (2S, 4R) - (4- { acetyl- [1- (4-methoxybenzoyl)) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] -amino,} -phenoxy) -acetic acid. The methyl ester was prepared following the general procedure D, substituting methyl 2- (4-bromophenoxy) -acetate for 2- (4-bromo-phenyl) -2-methyl-propionic acid. 1 H NMR (300 MHz, CD 3 OD) d: 1, 07-1, 18 (m, 4 H), 1.58 (s, 6 H), 2.02 (s, 3 H), 2.42-2, 56 (m, 1 H), 3.76 (s, 3 H), 4.74 (ddd, 1 H), 5.55 (sa, 1 H), 6.56 (d, 1 H), 6, 75 (d, 2 H), 6.97 (dd, 1 H), 7.13-7.27 (m, 3 H), 7.36 (d, 2 H), 7.42-7.55 (d. m, 3 H).
Acid (2S, 4R) -4- (4- { Acetyl- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -amino .} -2-Chloro-phenyl) -4-oxo-butyric acid (D-2) (2S, 4R) -4- (4- { Acetyl- [1- (4-methoxy-benzoyl) was prepared -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -amino.} -2-chloro-phenyl) -4-oxo-butyric acid from the corresponding methyl ester following the procedure described above for the synthesis of (2S, 4R) - (4-. {acetyl- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydroquinol-4) acid -yl] -amino.}.-phenoxy) -acetic acid. The corresponding methyl ester was prepared following the general procedure D, substituting methyl 2- (4-bromophenoxy) -acetate for 4- (4-bromo-2-cyoro-phenyl) -4-oxo-butyric acid methyl ester. 1 H NMR (300 MHz, CD 3 OD) d: 1, 10 -1, 19 (m, 4 H), 2.08 (br s, 3 H), 2.41-2.56 (, 1 H), 2.69. - 2.74 (m, 2 H), 3.20 - 3.26 (m, 2 H), 3.75 (s, 3 H), 4.74 (ddd, 1 H), 5.45 - 5 , 62 (sa, 1 H), 6.57 (d, 1 H), 6.74 (d, 2 H), 6.98 (dd, 1 H), 7.16 (d, 2 H), 7 , 20-7.27 (m, 1 H), 7.42-7.49 (m, 2 H), 7.60 (s at, 1), 7.73 (d, 1 H). MS m / z: 549 (M + 1). (2S, 4R) -N- (4-Dimethylsulfamoyl-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] - acetamide (D-3) was prepared (2S, 4R) -N- (4-dimethylsulfamoyl-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro -quinolin-4-yl] -acetamide following the general procedure D, substituting methyl 2- (4-bromophenoxy) -acetate for 4-bromo-N, N-dimethyl-benzenesulfonamide. 1 H NMR (CDCl 3) d: 1.1 (3 H, d), 1.1 (1 H, m), 2.0 (3 H, s), 2.3 (1 H, m), 2.8 (6 H, s), 3.8 (3 H, s), 4.8 (1 H, m), 5.6 (1 H, m), 6.6 (1 H, d), 6.7 (2 H, d), 6.9 (1 H, t), 7.2 (3 H, m), 7.3 (1 H, m), 7.5 (2 H, d), 7.8 (2 H, d). MS m / z: 522 (M + 1). (2S, 4R) -N- [1- (4-Methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N- [4- (pyrrolidine-1 - sulfonyl) -phenyl] -acetamide (D-4) was prepared (2S, 4R) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinoline- 4-yl] -N- [4- (pyrrolidin-1-sulfonyl) -phenyl] -acetamide following the general procedure D, substituting methyl 2- (4-bromophenoxy) -acetate for 1- (4- bromo-benzenesulfonyl) -pyrrolidine. 1 H NMR (CDCl 3) d: 1.1 (3 H, d), 1.1 (1 H, m), 1.7 (4 H, m), 2.0 (3 H, s), 2.3 (1 H, m), 3.3 (4 H, m), 3.7 (3 H, s), 4.7 (1 H, m), 5.6 (1 H, m), 6.5 (1 H, d), 6.6 (2 H, d), 6.9 (1 H, t), 7.3 (4 H, m), 7.4 (2 H, d), 7.9 (2 H, d). MS m / z: 548 (M + 1). (2S, 4R) -N- (4-Methanesulfonyl-phen-N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl ] -acetamide (D-5) was prepared (2S, 4R) -N- (4-methanesulfonyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3 , 4-tetrahydro-quinolin-4-yl] -acetamide following general procedure D, substituting methyl 2- (4-bromophenoxy) -acetate for 1-bromo-4-methanesulfonyl-benzene. 1H NMR (CDCl3) d: 1 , 1 - 1, 2 (3 H, m), 2.0 - 2.2 (4 H, m), 2.3 (1 H, m), 3.1 (3 H, s), 3.7 (3 H, s), 4.8 (1 H), 5.6-5.8 (1 H, a), 6.5 (1 H, d), 6.6 (2 H, d ), 6.9 (1 H, t), 7.1-7.3 (4 H, m), 7.4 (2 H, d), 8.0 (2 H, d). MS m / z: 493 (M + 1). Acid (2S, 4 /?) - 3- (4- { Acetyl- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -amino.}.-phenyl) -propionic (D-6). (2S, 4R) -3- (4- { acetyl- [1- (4-methoxy-benzoyl) -2-methyl-1) acid was prepared. , 2,3,4-tetrahydro-quinolin-4-yl] -amino.}. -phenyl) -propionic from (2S, 4R) -N- (4-bromo-phenyl) -N- [1 - (4-methoxy-benzoyl) -2-methyI-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide. It was converted (2S, 4R) -N- (4-bromo-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl. ] -acetamide in acrylic acid using the same procedure described in the synthesis of (±) -3- [4 - [(4-chloro-phenyl) -propionyl-amino] -1- (4-fluoro-benzoyl) - 2-methyl-1, 2,3,4-tetrahydro-quinolin-6-yl] -acrylic. The reduction and saponification were carried out as in the procedure which describes the preparation of (2S, 4R) -3- (4-. {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl] acid. -3,4-dihydro-2H-quinoline-1-carbonyl.] - phenyl) -propionic acid. 1 H NMR (CDCl 3 300 MHz) d 1, 12 (3 H, d), 1, 20-1, 24 (1 H, m), 2.00 (3 H, s), 2.22-2.38 (1 H, m), 2.52 (2H, t), 3.00 (2H, t), 3.72 (3H, s), 4.64-4.79 (1H, m), 5.44-5.70 (1H, m), 6.50 (1H, d), 6.65 (2H, d), 6.90 (1H, t), 7.10-7.28 (7H, m), 7.32 ( 1 H, d). (2S, 4R) -3- (4-. {Acetyl- [1- (4-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -amino}-phenyl) -propionamide (D-7) was prepared (2S, 4R) -3- (4- { acetyl- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3 , 4-tetrahydro-quinolin-4-yl] -amino.}.-Phenyl) -propionamide from (2S, 4R) -3- (4- { Acetyl- [1- (4-methoxy-benzoyl ) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -amino.} - phenyl) -propionic acid. To a solution of 3- (4. {Acetyl- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -amino}. .-phenyl) -propionic acid (21 mg, 0.042 mmol) in dimethylformamide (200 μl) were added HATU (24 mg, 0.063 mmol), HOBt (8.5 mg, 0.063 mmol), NH4CI (4.5 mg, 0.084 mmol). mmol) and DIPEA (29 μl, 0.168 mmol). After the starting unit was consumed (2.5 hours), the mixture was diluted with EtOAc (10 ml) and washed with sat. NaHCO3. (4 x 10 ml). The EtOAc layer was collected, dried over Na2SO, filtered and concentrated to yield the title compound (17.2 mg, 82%). 1 H NMR (CDCl 3 300 MHz) d 1, 09 (3 H, d), 1, 20-1, 24 (1 H, m), 2.02 (3 H, s), 2.22-2.38 (1 H , m), 2.52 (2H, t), 3.00 (2H, t), 3.73 (3H, s), 4.64-4.79 (1H, m), 5.30-5, 70 (3H, m), 6.50 (1H, d), 6.68 (2H, d), 6.91 (1H, t), 7.10-7.28 (7H, m), 7 , 32 (1 H, d). (2S, 4R) -N- [1- (4-Methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N- (4-nitro-phenyl) - acetamide (D-8) was prepared (2S, 4R) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N- (4-Nitro-phenyl) -acetamide following the general procedure D, substituting methyl 2- (4-bromophenoxy) -acetate for 4-bromonitrobenzene. 1 H NMR (CDCl 3 300 MHz) d 1, 12 (3H, d), 1, 20-1, 24 (1H, m), 2.07 (3H, s), 2.20-2.35 (1H, m), 3.73 (3H, s), 4.66-4.81 (1H, m), 5.50-5.78 (1H, m), 6.55 (1H, d), 6.68 (2H, d), 6.96 (1H, t), 7.10-7.32 (4H, m), 7.46 (2H, d), 8.28 (2H, d). MS m / z: 460 (M + 1). Table 4: Compounds Obtained from General Procedure D General Procedure E Scheme 16 (±) -N- (7-Acetyl-6-methyl-4,5,6,7-tetrahydrohetero [2,3-b] pyridin-4-yl) -N-substituted phenylacetamides (45) Ethyl acid ester 2 - (2-ethoxycarbonyl-1-methyl-ethylamino) -furan-3-carboxylic acid (38) 2-Amino-furan-3-carboxylic acid ethyl ester and butyl-2-enoic acid ethyl ester are dissolved in ethanol, heat to reflux in the presence of AI2? 3 until no starting material remains, filter and concentrate. The residue is purified by flash chromatography to produce the corresponding diketone. 2- [Benzyl- (2-ethoxycarbonyl-1-methyl-ethyl) -amino] -furan-3-carboxylic acid ethyl ester (39) The synthesis is carried out using the alkylation described for the synthesis of A-164, substituting bromide of 3-methoxybenzyl by benzyl bromide. 7-Benzyl-6-methyl-4-oxo-4,5,6,7-tetrahydro-furo [2,3-b] pyridine-5-carboxylic acid ethyl ester (40) To a solution of the diester in ethyl ether at room temperature, potassium tert-butoxide is added and the mixture is left stirring for 1 hour. The mixture is filtered to remove any hydrolyzed material. The solvent was removed in vacuo to yield the potassium salt of the bicyclic ester. 7-Benzyl-6-methyl-6,7-dihydro-5H-furo [2,3-b] pyridin-4-one (41) The -ceto-ester is dissolved in 4M HCl in dioxane and stirred for 2 hours. hours at room temperature. Then, 4 N HCl is added and the mixture is heated in an oil bath at 100 ° C for 12 hours. The mixture is then cooled to room temperature and neutralized with 1 N NaOH. The aqueous layer is extracted with ethyl acetate, dried over magnesium sulfate and filtered. Evaporate the solvent in vacuo and purify the residue by flash chromatography to produce the corresponding ketone. (±) - (7-Benzyl-6-methyl-4,5,6,7-tetrahydro-furo [2,3-b] pyridin-4-yl) -phenyl-substituted amine (42) The synthesis of the substituted phenylamine is carried out using the procedure described for F-1, substituting the corresponding aniline for aniline. (±) -N- (7-Benzyl-6-methyl-4,5,6,7-tetrahydro-furo [2,3-b] pyridin-4-yl) -N-substituted phenyl-substituted amide ( 45) The synthesis of the corresponding phenylamide is carried out using the hydrogenation and acylation processes described in general procedure B with the corresponding acid chlorides. Representative examples of compound 45 are shown in the following table. The compounds E-1-E-30 can be prepared by the schemes indicated in Schemes 18 and by the general procedures E and others described herein. Those skilled in the art will be able to recognize, or determine, using only conventional experimentation, many equivalents of the specific embodiments of the invention described herein.
Table 5: Examples using General Procedure E General Procedure F N- [1- (3-Wletoxy-benzoyl) -2,2-dimethyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide (F-1) synthesized N- [1- (3-methoxy-benzoyl) -2,2-dimethyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide from 4- (hydroxy) 2,2-dimethyl-3,4-dihydro-2H-quinolin-1-yl) - (3-methoxy-phenyl) -methanone according to the reference Hamann, LG; Higuchi, R. I.; Zhi, L .; Edwards, J. P .; Wang, X .; Marrschke, K. B.; Kong, J. W .; Farmer, L. J .; Jones, TDJ Med. Chem 1998, 41, 623. It was further elaborated to obtain N- [1- (3-methoxy-benzoyl) -2,2-dimethyl-1, 2,3,4-tetrahydro-quinolin-4 -yl] -N-phenyl-acetamide using an in-situ iodide formation and displacement with the aniline according to the following procedure. To a cooled solution of (4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-quinolin-1-yl) - (3-methoxy-phenyl) -methanone (500 mg, 1.6 mmol) in 10 ml of dichloromethane was slowly added 0.8 ml of iodotrimethylsilane (5.6 mmol) at 0 ° C. The resulting reaction mixture was stirred at 0 ° C for 6 hours. Then, the mixture was concentrated in vacuo. The residue was dissolved in 12 ml of THF. BaCO3 (630 mg, 3.2 mmol) and aniline (0.17 mL, 1.92 mmol) were added. The mixture was stirred at RT overnight. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with ethyl acetate-hexane (1: 4) to give (2,2-dimethyI-4-phenylamino-3,4-dihydro-2H-quinolin-1-) il) - (3-methoxy-phenyl) -methanone (150 mg, 24%). To a solution of (2,2-d.methyl-4-phenylamino-3, 4-dihydro-2H-quino-1-yl) - (3-methoxy-phenyl) -methanone in methylene chloride (5 ml) was added diisopropylethylamine followed by acetyl chloride. The mixture was stirred at room temperature overnight. The mixture was poured into water and extracted with dichloromethane. The extracts were washed with 1 M NaOH (aq.) And brine, dried over magnesium sulfate, filtered, dried and concentrated. The crude residue was purified by chromatography on silica gel (50% hexanes / 50% ethyl acetate) to yield N- [1- (3-methoxy-benzoyl) -2,2-dimethyl-1, 2,3 , 4-tetrahydro-quinoIin-4-yl] -N-phenyl-acetamide. 1 H NMR (CDCl 3) d: 1.5 (1 H, m), 1.6 (3 H, s), 1.7 (3 H, s), 1.9 (1 H, m), 2.0 (3 H, 3), 3.7 (3H, m), 5.8 (1H, m), 6.5 (1H, d), 6.6-7.1 (8H, m), 7.2 (1 H, m), 7.3-7.5 (3H, d). MS m / z: 429 (M + 1). (2S, 4 /?) - 4-Chloro-N-ethyl-N- [1- (4-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] - Benzamide (F-2) It was synthesized (2S, 4R) -4-chloro-N-ethyl-N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin -4-yl] -benzamide as described in general procedure C, except that after removal of the benzyl carbamate, the amine was modified in the following manner. To a solution of (2S, 4R) - (4-amino-2-methyl-3,4-dihydro-2H-quinolin-1-yl) - (4-methoxy-phenyl) -methanone (200 mg, , 68 mmol) in 20 ml of dichloromethane was added acetaldehyde (0.042 ml, 0.75 mmol). The reaction mixture was stirred for 30 min at room temperature. Then, sodium triacetoxyborohydride (0.156 g, 0.75 mmol) was added and the resulting reaction mixture was stirred at room temperature for 6 hours. ? /, / V-diisopropylethylamine (0.3 ml, 2.3 mmol) and 4-chlorobenzoyl chloride (0.4 ml, 3.1 mmol) were added and the mixture was stirred at room temperature overnight. Dichloromethane (40 ml) was added. The mixture was washed with 30 ml of sodium hydroxide (1 N). The organic layer was dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with ethyl acetate-dichloromethane (1: 4) to give 80 mg (24%) of the title compound. 1 H NMR (CDCl 3) d: 1, 2-1, 4 (7H, m), 1.7 (1 H, m), 2.7 (1 H, m), 3.1 (1 H, m), 3.8 (3H, s), 4.2 (1 H, m), 4.8 (1 H, m), 6.5 (1 H, d), 6.6 (2H, d), 6, 8 (2H, m), 6.9 (1 H, m), 7.1-7.5 (6H, m) MS m / z: 463 (M + 1). N- [1- (3-Methoxy-benzoyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide (F-3) N- [1- (3- methoxy-benzoyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide from 1- (4-methoxy-benzoyl) -2,3-dihydro-1 H-quinolin -4-one that was synthesized according to the reference Bellassou-Fargeau, M. C; Graffe, B .; Sacquet, M. C; Maitte, P. J. of Heter. Chem. 1985, 22 (3), 713. It was further elaborated to produce (4-hydroxy-3,4-dihydro-2H-quinolin-1-yl) - (3-methoxy-phenyl) -methanone by reduction of the ketone in the alcohol and in-situ formation of the iodide and displacement with the aniline according to the following procedure. To a solution of 1- (3-methoxy-benzoyl) -2,3-dihydro-1H-quinolin-4-one (310 mg, 1.1 mmol) in 5 mL methanol was added 410 mg of sodium borohydride (4 mg). 4 mmol). The resulting reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated in vacuo and the residue was purified by chromatography on silica gel, eluting with ethyl acetate-hexane (1: 2) to give (4-hydroxy-3,4-dihydro-2H-quinolin-1-yl). ) - (3-methoxy-phenyl) -methanone (215 mg, 69%). This was further elaborated to produce (3-methoxy-phenyl) - (4-phenylamino-3,4-dihydro-2H-quinolin-1-yl) -methanone using the following procedure. To a cooled solution of (4-hydroxy-3,4-dihydro-2H-quinolin-1-yl) - (4-methoxy-phenol) -methanone in dichloromethane was slowly added iodotrimethylsilane 0 ° C. The resulting reaction mixture was stirred at 0 ° C for 6 hours. Then, the mixture was concentrated in vacuo. The residue was dissolved in THF. BaCO3 and aniline were added. The mixture was stirred at room temperature overnight. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with ethyl acetate-hexane (1: 4) to give (4-phenylamino-3,4-dihydro-2H-quinolin-1-yl) - (3- methoxy-phenyl) -metanone. To a solution of (4-phenylamino-3,4-dihydro-2H-quinolin-1-yl) - (4-methoxy-phenyl) -methanone in methylene chloride was added diisopropylethylamine followed by acetyl chloride. The mixture was stirred at room temperature overnight. The mixture was poured into water and extracted with dichloromethane. The extracts were washed with 1 M NaOH (aq.) And brine, dried over magnesium sulfate, filtered, dried and concentrated. The crude residue was purified by chromatography on silica gel (50% hexanes / 50% ethyl acetate) to yield (±) -N- [1- (3-methoxy-benzoyl) -1, 2,3,4 -tetrahydro-quinolin-4-ylj-N-phenyl-acetamide. 1 H NMR (CDCl 3) d: 1.2 (1 H, m), 1.9 (3 H, s), 2.1 (1 H, m), 2.3 (1 H, m), 3.5 (1 H , m), 3.7 (3H, m), 4.1 (1H, m), 6.4 (2H, m), 6.6 (1H, m), 6.8-7.3 (6H , m), 7.4 (3H, m), 7.5 (1 H, d). MS m / z: 401 (M + 1). Table 6: Structurally Diverse Series The Described Compounds Inhibit the Binding of PGD2 to CRTH2 This membrane radioligand binding assay evaluated the ability of compounds to inhibit the binding of [3H] Prostaglandin D2 (PGD2) to the cloned human CRTH2 receptor which is stably expressed in the HEK-293 cells (expressing the human CRTh2 receptor and the a subunit of heterotrimeric G protein 16, were prepared by Biosignal Company) using a Scintillation Proximity Assay. A binding buffer containing 50 mM Tris-HCl (pH 7.5), 5 mM MgCl2 and 1 mM EDTA was prepared immediately prior to performing the assay. A bead / membrane solution was prepared at a concentration twice the final assay concentration comprising the membranes (membranes acquired from Biosignal) of the HEK-293 cells cloned to express the CRTH2 receptor bound to [3 H] PGD2 at two times the final test concentration and stored on ice before being added to the wells. Cold PGD2 was prepared at twenty times the final assay concentration and stored on ice before being added to the wells defining the non-specific binding (UNE) plates n ° 3653 that were used for this assay. 10 mM stock concentrations of compounds were prepared in 100% DMSO and stored at room temperature. Then, a 10-point concentration response curve was constructed for each compound, starting at 10 μM (final test concentration). The compounds were prepared at a concentration of 40 times the final test concentration with nine subsequent 3-fold dilutions. 0.1 μl of each concentration of compound was added to the appropriate well of plate 384 and 2 μl of cold PGD2 was added to the wells defining UNE. Then, to each well was added 20 μl of [3 H] PGD2 and then 20 μl of 2 x bead / membrane solution. Plates were allowed to incubate at room temperature for approximately 2 hours and then counted in a Packard Topcount using SPA tritium protocol for 1 minute / well.
The percentage of inhibition of the binding of PGD2 (PGD2 used in the lower KD O value) to the membranes of the HEK-293 cells was determined, the test was always carried out in duplicate for n = 1 for a total of n = 2. Compounds A-3, A-11, A-16, A-17, A-20, A-24, A-35, A-49, A-51, A-54, A-55, A-67, A-70, A-72, A-73, A-81, A-82, A-120, A-130, A-131, A-132, A-143, A-144, A-147, A- 153, A-156, A-157, A-159, B-7, B-9, B-11, B-13, B-18, B-20, B-26, B-28, B-34, B-39, B-40, B-47, B-51, B-58, B-59, B-63 to B-66, B-68, B-70, B-73, B-74, B- 84, B-86, B-97, B-101 to B-112, C-33, C-37, C-38, D-1, D-2, D-6, D-10, F-3 have a value of K < 10 uM. Compounds A-8, A-53, A-58, A-124, A-126, A-154, B-53, B-100, F-1 have a value of K < 60 uM. All the remaining compounds have a value of K < 1 uM Conventional conditions-Ammonium acetate:% A (Water) 95.0 % B (Acetonitrile) 5.0 % Ammonium Acetate 0.1 Flow (ml / min) 2,500 Detention time (min) 3.8 Pressure min (bar) 0 Max pressure (bar) 400 Left oven temperature (° C) 10.0 Right oven temperature (° C) 10.0 Pump Gradient Time Table HP1100 LC The gradient time table contains 4 inputs that are: Time% A% B% C% D Presic Flow 0.00 95.0 5.0 0.0 0.0 2,500 400 2 , 00 0,0 100,0 0,0 0,0 2,500 400 3,00 0,0 100,0 0,0 0,0 2,500 400 3,05 95,0 5,0 0,0 0,0 2,500 400 The LC-MS data were acquired using an "ammonium acetate standard" method unless otherwise indicated.
SCHEME 17 • 93.7% ee 1, yield of 72% 94% ee 2, gross yield of 92% 3, rend. gross 85% 94% ee NHCbz Recrystallization EtOAC / heptapo c% o '"99 ee 60% recovery Scheme 18 2 eq. of aniline NH 20 vol H20 2) K2C03 at pH 10 and then extract with MTBE ^^ 2 3) 6 N HCl at pH 5 and then extract with EtOAc ^ Mass recovery of 72% 94% ee (S) -3-phenylaminobutyral acid (1) A cylindrical reactor with a 3-port, 30-valve, bottom valve, equipped with an overhead stirrer, reflux condenser, addition funnel, and N2 inlet. washed abundantly with N2. Water (8.7 I) was charged followed by aniline (423 I, 4.9 mol). Agitation was started and the internal temperature was set at 80 ° C. After the internal temperature reached 77 ° C, (R) -β-butyrolactone was charged for 1.5 h by means of an addition funnel. The internal temperature was maintained between 80-81, 7 ° C during the course of the addition. When the addition was complete, the reaction was cooled to 20 ° C for 1 h. K2CO3 (250 g, 1.8 mole, 0.75 equiv.) Was charged in the form of a solid and the pH was determined to be 10. The aqueous phase was extracted with MTBE (3 x 2 L) and the extracts were extracted. they discarded. After adjusting the pH of the aqueous phase to 5 with 6 N HCl (225 mL), it was extracted with EtOAc (3 x 2 I). After each extraction, the pH was checked and adjusted again to 5 with 6 N HCl as necessary. The combined EtOAc extracts were washed with saturated brine (2 L), dried with MgSO 4 and concentrated by rotary evaporation to yield a pink oil. Recovery: 300 g (72%). It was determined that enantiomeric excess by chiral HPLC was 94%. 1 H NMR (CDCl 3) d: 7.24 (t, 2 H); 6.81 (t, 1 H); 6.73 (d, 2 H); 3.93 (m, 1 H); 2.68 (dd, 1 H); 2.51 (dd, 1 H); 1, 30 (d, 3 H). Scheme 19 3) 1.5 equiv 1 M iOfBu in THF crude yield of 98% (S) - (phenylamino-butyryl) -carbamic acid benzyl ester (2) A 5 I glass reactor coated with a jacket, equipped with stirrer in the top, addition funnel and thermocouple was flushed with N2. A solution of (S) -3-phenylaminobutyric acid (1.100 g, 558 mmol) in 800 ml of THF (8 volumes relative to the amino acid) was charged to the reactor. The internal temperature of the reaction mixture was set at 20 ° C. 1, 1'-Carbonyldiimidazole (99.5 g, 614 mmol) was charged into the stirred solution to produce a clean solution together with a medium exotherm (5 ° C) and much gas evolution. After 1 h, benzyl carbamate (84.3 g, 558 mmol) was charged and the internal temperature was set at -15 ° C. At -15 ° C, a 1 M solution of LiOt-Bu in THF (837 mL, 837 mmol) was charged into the reaction by an addition funnel in 30 min to maintain the internal temperature between -10 and -15 ° C. The solution turned opaque pale brown and was more viscous. The internal temperature is maintained at approximately -10 ° C for 15 more minutes and then it is allowed to warm to room temperature. After 16 h, the reaction was quenched by the addition of 1000 ml of EtOAc (10 volumes) followed by 280 ml of 1 N HCl and 1000 ml of H 2 O (10 volumes). The resulting aqueous phase was pH 9. The phases were separated and the aqueous phase was extracted with an additional 600 ml of EtOAc (6 volumes). The organic phases were combined and washed with 1000 ml of 10% brine (10 volumes). The resulting organic solution of the crude product is distilled to a minimum volume of 500 to 700 ml at 170 to 200 torr (22.61 - 26.60 kPa) and at a container temperature of 35 to 40 ° C. This crude product was partitioned between 2.0 I of 1 N HCl (20 volumes) and 1.0 I of MTBE. The amber oil phase formed which was the HCl salt of the product was maintained with the aqueous acid phase. The MTBE phase was extracted with an additional 1000 ml of 1 N HCl (10 volumes) and the combined HCl phases were washed again with an additional 500 ml of MTBE. The pH of the aqueous solution was adjusted to 9-10 by the addition of 495 ml of saturated aqueous K2CO3. The basic aqueous solution was extracted twice with 800 ml of EtOAc (8 volumes) and the organic phases were combined, washed with 500 ml of brine, dried over Na 2 SO 4 and evaporated to yield 161 g (92%) of amber oil. stupid. 1 H NMR (CDCl 3) d: 7.35 (m, 5 H); 7.15 (t, 2 H); 6.72 (t, 1 H); 6.61 (d, 2 H); 5.15 (s, 2 H); 4.03 (m, 1 H); 3.02 (dd, 1 H); 2.84 (dd, 1 H); 1, 28 (d, 3 H). Scheme 20 O 1) 10 vol EtOH, 0.7 equiv NaBH4l-10 C? I J 2) 1.05 eq. of aqueous WlgCl2 N Me 2 3) CH 2 Cl 2, 1 N HCl, 2.5 eq. of citric acid "......? ... 3, 85%, 94% ee Benzyl Ester of (2S, 4R) - (2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl) -carbamic acid (3) A 5 I glass reactor, coated with a jacket and equipped with agitator in the upper part, addition funnel and thermocouple was washed abundantly with N2. A solution of (S) - (phenylamino-butyryl) -carbamic acid benzyl ester (2) (160 g, 512 mmol) in EtOH (960 ml, 6 volumes) was charged to the reactor and the internal temperature was established at - 15 ° C. NaBH 4 (13.6 g, 359 mmol) was charged to the stirred solution in 3 portions. An aqueous solution of MgCl2-6H2O (109 g, 538 mmol in 110 ml of water) was charged to the reactor by means of an addition funnel for 1 h to maintain the internal temperature between -10 and -5 ° C. After the addition was complete, the internal temperature was adjusted to 0 ° C and the mixture was allowed to stir for a further 30 min. The reactor was charged with 960 ml of CH2Cl2 (6 volumes), citric acid (246 g, 1280 mmol) and 960 ml of 1 N HCl (6 volumes). The internal temperature was set at 20 ° C and the mixture was allowed to stir for 16 h. The reaction mixture was diluted with 960 mL of EtOAc and the aqueous pH was adjusted to 9 by the addition of 470 mL of saturated aqueous K2C? 3. The phases were separated and the organic phase was washed twice with 640 ml of water and then with 640 ml of brine. The organic phase was dried over Na2SO4 and evaporated to provide 130 g of a solid (86% yield). The crude product was recrystallized from 20 volumes of a 9/1 mixture of heptane / EtOAc. The solid was suspended with 260 ml of EtOAc (2 volumes) and 780 ml of heptane (6 volumes) and heated to 75 ° C to provide a clear solution. At 75 ° C, an additional 260 ml of heptane (2 volumes) was slowly added followed by gradual cooling. Crystallization normally begins around 58 to 68 ° C. At room temperature, an additional 1300 ml of heptane (10 volumes) was slowly added. After stirring at room temperature for a further 2 h, the solids are filtered and washed with 4 volumes of 9/1 heptane / EtOAc. The solids were dried in a vacuum oven to provide 90 g (60% recovery). The product had an enantiomeric excess of 99.2% as determined by chiral HPLC. 1 H NMR (CDCl 3) d: 7.38 (m, 5H); 7.22 (d, 1 H); 7.07 (t, 1 H); 6.78 (t, 1 H); 6.69 (d, 1 H); 5.17 (s, 2 H); 5.07 (m, 1 H); 4.94 (d, 1 H); 3.58 (m, 1 H); 2.33 (m, 1 H); 1.60 (c, 1 H); 1, 30 (d, 3 H). Scheme 21 General Procedure G: (2S, 4?) -? / - (4-Chloro-phenyl) -? / - [1- (4-fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro- quinolin-4-yl] -acetamide (6) To a solution of (2S, 4R) - (2-methyI-1, 2,3,4-tetrahydro-quinolin-4-yl) -carbamic acid benzyl ester (1) , 0 g, 3.38 mmol) in methylene chloride (50 ml) at room temperature was added diisopropylethylamine (650 μl, 3.72 mmol) followed by 4-fluorobenzoyl chloride. The reaction was stirred overnight at room temperature. The mixture was poured into water and extracted with ethyl acetate. The extracts were washed with 1 M NaOH (aq) and brine, dried over magnesium sulfate, filtered, dried and concentrated. The crude residue was purified by chromatography on silica gel (75% hexanes / 25% ethyl acetate) to yield pure amide (720 mg, 51%). Benzyl ester of (2S, 4R) - [1- (4-fluorobenzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -carbamic acid (720 mg, 1.73 mmol) in ethanol (30 ml). The vessel in which the resulting solution was was evacuated and refilled with argon. A catalytic amount of Palladium on Carbon (10%) was added. The vessel was again evacuated once more and at this time it was again filled with hydrogen and stirred in a Parr bottle at 275,790 kPa of hydrogen. The reaction was complete after 4 h. The mixture was carefully filtered and concentrated to 10% volume. The resulting concentrated solution was filtered through Celite® and concentrated to yield the crude amine.
To a solution of (2S, 4R) - (4-amino-2-methyl-3,4-dihydro-2H-quinolin-1-yl) - (4-fluoro-phenyl) -methanone (1 , 0 g, 3.5 mmol) in DMF (20 ml, dry) was added 4-chlorophenylboronic acid (1.1 g, 7.0 mmol), pyridine (850 μl, 10.5 mmol) and copper acetate (II) (1.27 g, 7.0 mmol). The heterogeneous green mixture was stirred open in the air for 1 h and then heated to 60 ° C and stirred overnight (14 h). The mixture was then cooled to rt and poured into stirred ethyl acetate rapidly (150 ml); the solids were removed by filtration through Celite®. The extracts were washed several times with water and then once with brine. Then, the extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel (95% methylene chloride / 5% ethyl acetate) to yield the aniline product (250 mg, 18%) as a yellow oil. To a solution of (2S, 4R) - [4- (4-chloro-phenylamino) -2-methyl-3,4-dihydro-2H-quinolin-1-yl] - (4-fluoro-phenyl) -methanone ( 250 mg, 0.636 mmol) in acetyl chloride (5 ml) was added diisopropylethylamine (120 μl, 0.70 mmol). The mixture was stirred at rt for 4 h. The mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with sat. Sodium bicarbonate. aqueous and brine and dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (gradient of 25/75 hexanes / ethyl acetate) to produce? / - (4-chloro-phenyl) -? / - [1- (4-fluoro-benzoyl) - Pure 2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide (200 mg, 71%). 1 H NMR (CDCl 3) d: 1.1 (d, 3 H), 1.1 (m, 1 H), 2.0 (d, 3 H), 2.3 (m, 1 H), 4.7 (m , 1 H), 5.6 (m, 1 H), 6.5 (d, 1H), 6.7-7.0 (m, 3H), 7.1-7.4 (m, 8H). MS m / z: 436 (M + 1). Ethyl ester of (2S, 4R) -4- (4-. {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1 - carbonyl, .phenyl) -piperazine-1-carboxylic acid (G-1) (2S, 4R) -4- (4-. {4- [acetyl- (4-chloro-phenyl)) ethyl ester was obtained -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}. phenyl) -piperazine-1-carboxylic acid following general procedure G, substituting 4-fluorobenzoyl chloride for ethyl ester of acid 4- (4-chlorocarbonyl-phenyl) -piperazine-1-carboxylic acid. The remainder of the procedure is followed as indicated in general procedure G to produce (2S, 4R) -4- (4. {4- [acetyl- (4-chloro-phenyl) -amino] - ethyl ester - 2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl.] - phenyl] -piperazine-1-carboxylic acid. 4- (4-Chlorocarbonyl-phenyl) -piperazine-1-carboxylic acid ethyl ester was prepared by the following procedure. Piperidine and 4-fluoro-benzoic acid methyl ester were heated at 65 ° C in DMSO for 48 h (U.S. Patent 6069143). The reaction was quenched with NaHCO3 and 3 x ethyl acetate was extracted, dried over MgSO4, filtered and concentrated. The ester was used directly. 4-Piperazin-1-yl-benzoic acid methyl ester was acetylated with ethyl chloroformate and DIEA in CH 2 Cl 2 to give 4- (4-methoxycarbonyl-phenyl) -piperazine-1-carboxylic acid ethyl ester. The methyl ester was hydrolyzed with the acid by dissolving in tetrahydrofuran and ethanol and sodium hydroxide (1 N) was added thereto. The mixture was stirred at room temperature for 2 hours. The mixture was cooled to 0 ° C and acidified to form a white precipitate. The solid was filtered to give 4- (4-methoxycarbonyl-phenyl) -piperazine-1-carboxylic acid. The acid was converted to the acid chloride by reaction with oxalyl chloride. 1 H NMR (CDCl 3) d: 1, 10 (d, 3 H), 1, 24 (m, 4 H), 2.00 (s, 3 H), 2.27 (m, 1 H), 3.13 (t, 4H), 3.55 (t, 4H), 4.12 (c, 2H), 4.70 (m, 1 H), 5.56 (sa, 1H), 6.54 (d, 1H), 6 , 62 (d, 2H), 6.91 (t, 1 H), 7.09 (d, 2H), 7.14 (d, 2H), 7.27 (m, 2H), 7.36 (d, 2H). MS m / z: 575.16 (M + 1). N-. { 3 - [(Glycoloylamino) methyl] phenyl} -W - [(2S, 4R) -1- (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] acetamide (G-2) / V- was prepared. { 3 - [(glycolylamino) methyl] phenyl} -? / - [(2S, 4R) -1 - (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] acetamide following the general procedure G, substituting 4-fluorobenzoyl chloride for 4-methoxybenzoyl chloride and 4-chlorophenylboronic acid for (3-cyanophenyl) boric acid. The rest of the procedures were followed as indicated in general procedure A to produce? / - (3-cyanophenyl) -? / - [(2S, 4R) -1 - (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] acetamide. It was further treated? / - (3-cyanophenyl) -? / - [(2S, 4R) -1- (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] acetamide with cobalt (II) chloride and sodium borohydride (1 equiv., 3 equiv.) to produce? / - [3- (aminomethyl) phenyl] -? / - [(2S, 4R) -1- (4-methoxybenzoyl) ) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] acetamide. Then, it was coupled / V- [3- (aminomethyl) phenyl] -? / - [(2S, 4R) -1- (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinol n-4-yl] acetamida with glycolic acid using a coupling reagent such as EDCI with HOBt to produce? / -. { 3- [(glycolylamino) methyl] phenyl} -? - [(2S, 4R) -1- (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolyl-4-yl] acetamide 1H NMR (CDCl3) d: 1, 1- 1, 2 (m, 4H), 2.0 (s, 3H), 2.3 (m, 1H), 3.8 (s, 3H), 4.2 (m, 1 H), 4.5 (m, 2H), 4.7 (m, 2H), 5.6 (a, 1H), 6.5 (m, 1 H), 6.6 (m, 2H), 6.9 (m, 1 H), 7.1-7.4 (m, 8H). MS m / z: 502 (M + 1). W ^ -chloro ^ -fluoropheni-W- ^ S ^ RJ-l ^ -methoxybenzoi ^ -methyl-l ^^^ -tetrahydroquinolin-4-yl] acetamide (G-3) Obtained? / - (4-chloro- 2-fluorophenyl) -? / - [(2S, 4R) -1 - (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] acetamide following the general procedure G, substituting chloride of 4-fluorobenzoyl by 4-methoxybenzoyl chloride. The amine-aryl coupling was performed in a different manner to that described in procedure G. Therefore, (2S, 4R) -1- (4-methoxybenzoyl) -2-methyl-1, 2,3,4- was dissolved. tetrahydroquinolin-4-amine (obtained from the hydrogenation step, 200 mg, 0.6 mmol, 1 equiv.) in ethylene glycol dimethyl ether (1 ml) in a Schlenk tube. To this solution were sequentially added 1-bromo-4-chloro-2-fluorobenzene (105 μL, 0.84 mmol, 1.4 equiv.), Cesium carbonate (274 mg, 0.84 mmol, 1.4 equiv. .), palladium acetate (16 mg, 0.024 mmol, 0.04 equiv.) and 2- (dicyclohexylphosphine) -2 \ 4 \ 6: ri-i-propyl-1, rb-phenyl (23 mg , 0.048 mmol, 0.08 equiv.). The reaction mixture was flushed with nitrogen and heated at 95 ° C in the Schlenk tube for 48 h. The reaction mixture was concentrated to leave a residue which was partitioned between water and ethyl acetate and extracted. The aqueous phase was separated and the organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give a black oil. The crude product was purified by chromatography on silica gel (methylene chloride / methanol: gradient from 100/0 to 99/1) to provide (2S, 4R) -? / - (4-chloro-2-fluorophenyl) -1 - (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-amine (60 mg, 24%). To a solution of (2S, 4f?) -? / - (4-chloro-2-fluorophenyl) -1- (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-amine ( 60 mg, 0.14 mmol, 1 equiv.) In acetyl chloride (0.5 ml) was added diisopropylethylamine (25 μl, 0.14 mmol, 1 equiv.). The mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with sat. Sodium bicarbonate. aqueous and brine and dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (99.5 / 0.5 methylene chloride / methanol) to yield / V- (4-chloro-2-fluorophenyl) -? / - [(2S, 4R) - Pure 1- (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl-acetamide (140 mg, 92%). 1 H NMR (CDCl 3) d: 1, 15 (d, 3 H), 2.05 (s, 3 H), 2.30 (m, 1 H), 3.75 (s, 3 H), 4.75 (m, 1H), 5.65 (m, 1 H), 6.50 (d, 1 H), 6.70 (d, 2H), 7.00 (t, 1 H), 7.15-7.20 ( m, 4H), 7.25-7.40 (m, 3H).
MS m / z: 467 (M + 1). 4-. { [(2S, 4?) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl} benzamide (G-4)? / - (4-chlorophenyl) -? / - [(2SJ4R) -1- (4-cyanobenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-y were dissolved. ] acetamide (143 mg, 0.33 mmol) and potassium hydroxide (55 mg, 1.00 mmol) in water (150 ml) and ethanol (3 ml) and heated at 70 ° C for 4 h. The suspension was partitioned between 1 N HCl (until acid was made) and methylene chloride. The organic layer was collected, concentrated and subjected to flash chromatography (from EtOAc to 20% MeOH, EtOAc) to give the title compound as a white solid. 1 H NMR (CDCl 3) d: 1, 15-1, 25 (m, 1 H), 1, 17 (d, 3 H), 2.11 (s, 3 H), 2.20-2.34 (m, 1 H), 4.70-4.84 (m, 1H), 5.50-5.80 (m, 1H), 5.80-6.00 (, 1H), 6.40-6.60 (m , 1H), 6.40 (d, 1 H), 6.83 (t, 1 H), 7.08-7.30 (m, 8H), 7.60 (d, 2H). MS m / z: 462 (M + 1) (2S, 4R) -4- (4. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3-methyl ester , 4-dihydro-2H-quinoline-1-carbonyl} -2-fluoro-phenoxy) -2,2-dimethyl-butyric (G-5) To a solution of (2S, 4R) - (2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl) -carbamic acid benzyl ester in methylene chloride at room temperature was added diisopropylethylamine followed by 3-fluoro-4-methoxy-benzoyl chloride. The reaction was stirred overnight at room temperature. The mixture was poured into water and extracted with ethyl acetate. The extracts were washed with 1 M NaOH (aq) and brine, dried over MgSO 4, filtered, dried and concentrated. The crude residue was purified by chromatography on silica gel (75% hexanes / 25% ethyl acetate) to yield the pure amide. (2S34f? J- [1- (3-Fluoro-4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -carbamic acid benzyl ester was dissolved in ethanol (30 ml) The vessel in which the resulting solution was was evacuated and refilled with argon, a catalytic amount of Palladium on Carbon (10%) was added, the vessel was evacuated once again and in this moment was again filled with hydrogen and stirred in a Parr bottle at 275,790 kPa of hydrogen The reaction was completed after 4 hours The mixture was carefully filtered and concentrated to 10% volume The resulting concentrated solution was filtered through Celite® and concentrated to yield the crude amine To a solution of (2S, 4R) - (4-amino-2-methyl-3,4-dihydro-2H-quinolin-1-yl) - (3 -fluoro-4-methoxy-phenyl) -methanone in DMF (dry) were added 4-chlorophenylboronic acid, pyridine and copper (II) acetate.The heterogeneous green mixture was stirred open in the air for 1 hour and then it was heated to 60 ° C and stirred overnight (14 h). Then, the mixture was cooled to room temperature and poured into stirred ethyl acetate rapidly (150 ml); the solids were removed by filtration through Celite®. The extracts were washed several times with water and then once with brine. Then, the extracts were dried over anhydrous MgSO 4, filtered and concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel (95% methylene chloride / 5% ethyl acetate) to yield the aniline product as a yellow oil. To a solution of (2S, 4R) - [4- (4-chloro-phenylamino) -2-methyl-3,4-dihydro-2H-quinolin-1-yl] - (3-fluoro-4-methoxy-phenyl) ) -metanone in methylene chloride was added diisopropylethylamine followed by acetyl chloride. The mixture was stirred at rt for 4 h. The mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with sat. NaHCO 3. ac. and brine and dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (gradient of 25/75 hexanes / ethyl acetate) to produce the pure final product. It was dissolved? / - (4-chloro-phenyl) -? / - [1- (3-fluoro-4-hydroxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl ] -acetamide (115 mg, 0.256 mmol) in DMF (5 ml) at room temperature. K2CO3 (175 mg, 1.28 mmol) and 5-bromo-2,2-dimethyl-pentanoic acid ethyl ester (100 mg, 0.511 mmol) were added and the reaction mixture was allowed to stir overnight. The mixture was partitioned between methylene chloride and water; The methylene chloride layer was dried over MgSO 4, filtered and concentrated. The crude residue was purified by chromatography on silica gel (gradient 2/1 hexanes / ethyl acetate-ethyl acetate) to produce the product. 1 H NMR (CDCl 3) d: 1, 1 (d, 3 H), 1, 2 (s, 6 H), 1, 2 (m, 1 H), 2.0 (s, 3 H), 2.0 (t, 1 H), 2.3 (m, 1 H), 3.8 (s, 3 H), 4.0 (t, 2 H), 4.7 (m, 2 H), 5.6 (sa, 1 H) , 6.5 (d, 1H), 6.6 (t, 1H), 6.7 (d, 1 H), 6.9 (t, 1 H), 7.2 (m, 5H), 7, 4 (d, 2H). MS m / z: 581 (M + 1). (2S, 4R) -W- (4-chloro-phenyl) -? / - [1- (354-dihydro-2H-benzo [1,4] oxazine-6-carbonyl) -2-methyl-1, 2, 3,4-tetrahydro-quinolin-4-yl] -acetamide (G-6) 6-ethyl ester was dissolved. { 4- [Acetyl- (4-cioro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl} -2,3-dihydro-benzo [1,4] oxazine-4-carboxylic acid in methylene chloride (3 ml) and iodotrimethylsilane (1 ml). After 4 days, the reaction was quenched with NaHC? 3 sat. ac. . The residue was partitioned between methylene chloride and water, then extracted three times with methylene chloride, dried over MgSO, filtered and concentrated. The crude residue was purified by chromatography on silica gel (ethyl acetate) to produce the product. 1 H NMR (CDCl 3) d: 1.1 (d, 3 H), 1.2 (m, 1 H), 2.0 (s, 3 H), 2.3 (m, 1 H), 3.3 (m, 2H), 4.2 (m, 2H), 4.7 (m, 1 H), 5.5 (m, 1 H), 6.4 (d, 1 H), 6.5 (d, 1 H) ), 6.6 (d, 2H), 6.96 (t, 1 H), 7.2 (m, 5H), 7.4 (d, 2H). MS m / z: 476 (M + 1). N- (4-chlorophenyl) - / V - ((2S, 4?) - 2-methyl-1 -. {4- [3- (trifluoromethyl) -1 W -pyrazol-1-yl] benzoyl}. -1, 2,3,4-tetrahydroquinolin-4-yl) acetamide (G-7)? / - (4-chlorophenyl) -? / - ((2S, 4 /:) - 2-methyl-1 was prepared - { 4- [3- (trifluoromethyl) -1 H -pyrazol-1-yl] benzoyl] -1, 2,3,4-tetrahydroquinolin-4-yl) acetamide following the general procedure A, substituting chloride of 4-fluorobenzoyl by 4- [3- (trifluoromethyl) -1-pyrazol-1-yl] benzoyl chloride. (4- [3- (Trifluoromethyl) -1-pyrazol-1-yl] benzoyl chloride was prepared in a step of 4- [3- (trifluoromethyl) -1H-pyrazol-1-yl] benzoic acid. treated 4- [3- (trifluoromethyl) -1H-pyrazol-1-yl-benzoic acid with oxalyl chloride in DCM and catalytic DMF to produce 4- [3- (trifluoromethyl) -1H-pyrazol-1-yl] benzoyl chloride with a decent performance). The rest of the procedures were followed as indicated in general procedure A to produce? / - (4-chlorophenyl) - / V - ((2S, 4R) -2-methyl-1 -. {4- [3- (trifluoromethyl) -1 H -pyrazol-1-ylbenzoyl} -1, 2,3,4-tetrahydroquinolin-4-yl) acetamide. 1 H NMR (CDCl 3) d: 1, 20 (d, 3H; t, 1 H), 2.03 (s, 3H), 2.33 (m, 1 H), 4.80 (m, 1 H), 5.62 (m, 1H), 6.47 (d, 1 H), 6.77 (d, 1 H), 6.90 (t, 1 H), 7.00-7.40 (m, 10H), 7.66 (d, 1 H) MS m / z: 553 (M + 1). (2S, 4R) -W- (4-Chloro-phenyl) -W- [2-methyl-1- (4-methyl-3,4-dihydro-2H-benzo [1,4] oxazine-7-carbonyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide (G-8) To a solution of (2S, 4R) - (2-methyl-1, 2,3,4) benzyl ester -tetrahydro-quinoline-4-yl) -carbamic acid (400 mg, 1.36 mmol) in methylene chloride (4 ml) at room temperature was added triethylamine (0.320 ml, 2.3 mmol) followed by 4-chloride. methyl-3,4-dihydro-2H-benzo [1,4] oxazine-7-carbonyl (1.5 mmol). The reaction was stirred overnight at room temperature. The mixture was poured into water and extracted with ethyl acetate. The extracts were washed with 1 M NaOH (aq) and brine, dried over MgSO4, filtered and concentrated. The crude residue was purified by chromatography on silica gel (75% hexanes / 25% ethyl acetate) to yield the pure amide. Benzyl ester of (2S, 4R- [2-methyl-1- (4-methyl-3,4-dihydro-2H-benzo [1,4] oxazine-7-carbonyl) -1,3,3-benzyl ester was dissolved. 4-tetrahydro-quinolin-4-yl] -carbamic acid (300 mg) in ethanol.The vessel in which the resulting solution was was evacuated and refilled with argon.A catalytic amount of Palladium on Carbon (10%) was added. %) .The vessel was again evacuated once more and at this time it was again filled with hydrogen and stirred in a Parr bottle at 275,790 kPa hydrogen.The reaction was completed after 4 hours.The mixture was carefully filtered and it was concentrated to 10% of the volume The resulting concentrated solution was filtered through Celite® and concentrated to give the crude amine to a solution of (2S, 4R) - (4-amino-2-methyl-3,4). -dihydro-2H-quinolin-1-yl) - (4-methyl-3,4-dihydro-2H-benzo [1,4] oxazin-7-yl) -methanone (662 mg, 1.87 mmol) in methylene chloride (8 ml) was added 4-chlorophenylboronic acid (583 mg, 3.74 mmol) , triethylamine (1.81 ml, 13.09 mmol) and copper (II) acetate (681 mg, 3.74 mmol). The heterogeneous green mixture was stirred open in air for 1 hour and then heated to 60 ° C and stirred overnight (14 h). Then, the mixture was cooled to room temperature and poured into stirred ethyl acetate rapidly (150 ml); the solids were removed by filtration through Celite®. The extracts were washed several times with water and then once with brine. Then, the extracts were dried over anhydrous MgSO, filtered and concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel (95% methylene chloride / 5% ethyl acetate) to yield the aniline product as a yellow oil. To a solution of (2S, 4R) - [4- (4-chloro-phenylamino) -2-methyl-3,4-dihydro-2H-quinolin-1-yl] - (4-methyl-3,4-dihydro) -2H-benzo [1,4] oxazin-7-yl) -methanone (540 mg, 1.25 mmol) in methylene chloride (5 mL) was added diisopropylethylamine (0.240 mL, 1.37 mmol) followed by chloride of acetyl (2 ml). The mixture was stirred at room temperature 4 hours. The mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with sat. NaHCOs. ac. and brine and dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (gradient of 25/75 hexanes / ethyl acetate) to produce the final product. 1 H NMR (CDCl 3) d: 1.1 (d, 3 H), 1.1 (m, 1 H), 2.0 (d, 3 H), 2.3 (m, 1 H), 2.8 (s, 3H), 3.2 (t, 2H), 4.2 (t, 2H), 4.7 (m, 1 H), 5.6 (m, 1H), 6.3 (d, 1 H), 6.5 (d, 1 H), 6.6 (d, 1 H), 6.8 (s, 1 H), 6.9 (t, 1 H), 7.2 (m, 5H), 7 , 4 (d, 2H). MS m / z: 490 (M + 1). (2S, 4R) -? / - (4-Chloro-phenyl) -W- [1- (2,2-difluoro-benzo [1,3] dioxol-5-carbonyl) -2-methyl-1, 2, 3,4-tetrahydro-quinolin-4-yl] -acetamide (G-9) Prepared (2S, 4R) - / V- (4-chloro-phenyl) -? / - [1- (2,2-difluoro -benzo [1,3] dioxol-5-carbonyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide following the general procedure G, substituting 4-fluorobenzoyl chloride for chloride of 2,2-difluoro-1,3-benzodioxol-5-carbonyl. The rest of the procedures were followed as indicated in general procedure G to produce (2S, 4R) -N- (4-Chloro-phenyl) - / V- [1 - (2,2-difluoro-benzo [1, 3] dioxol-5-carbonyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide. 1 H NMR (CDCl 3) d: 1.15 (3H, d; overlap 1 H, t), 2.02 (3 H, s), 2.33 (1 H, m), 4.78 (1 H, m), 5.60 (1 H, m), 6.44 (1 H, d), 6.68 (1 H, d), 6.95 (1 H, t), 7 , 00-7.40 (8H, complex). MS m / z: 499 (M + 1). 5- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl. phenyl) pentanamide (G-10) [(2S, 4R) -1- (4-iodobenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-ylcarbamic acid benzyl ester was prepared following the general procedure G, substituting 4-fluorobenzoyl chloride for 4-iodo-benzoyl chloride. To a solution of benzyl [(2S, 4R) -1- (4-iodobenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-ylcarbamate (0.6 g, 1.14 mmol ) in DMF (15 ml) at room temperature was added pent-4-enoic acid ethyl ester (0.292 g, 2.28 mmol), potassium acetate (0.67 g, 6.84 mmol), palladium acetate ( 0.05 g, 0.228 mmol), tetrabutylammonium chloride (0.32 g, 1.14 mmol) and triphenylphosphine (0.06 g, 0.228 mmol). The mixture was stirred at room temperature for 1 hour and then heated at 70 ° C for 3 hours. The mixture was concentrated and ethyl acetate was added thereto. The solution was washed with water, dried and concentrated. The residue was purified by chromatography on silica gel (70% CH2CI2 / 30% EtOAc) to yield (4E) -5- (4- {[[2S, 4R) -4-. {[[(Benzyloxy ) carbon.l] amino.} -2-methyl-3,4-dihydroquinolyl-1 (2H) -yl] carbonyl, phenyl-pent-4-enoate ethyl (0.5 g, 83% ), which was converted to 5- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] ethyl carbonyl) phenyl) pentanoate following the general procedure G. Hydrolyzed 5- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3, Ethyl 4-dihydroquinolin-1 (2H) -yl] carbonyl, phenyl) pentanoate (0.135 g, 0.25 mmol) in the acid was dissolved in 6 ml of methanol and potassium carbonate (0.2 g in methanol) was added thereto. 4 ml of water). The mixture was heated at 40 ° C for 24 hours and the methanol was removed in vacuo. The mixture was acidified to form a white precipitate. The solid was filtered to give the acid. To a solution of the acid in DMF (10 ml) at room temperature were added HATU (0.143 g, 0.375 mmol), DIEA (0.18 ml, 1 mmol), HOBt (0.057 g, 0.375 mmol) and chloride added. Ammonium (0.027 g, 0.5 mmol). The mixture was stirred for 18 hours and concentrated. The residue was dissolved in CH2Cl2 and washed with water. The organic layer was concentrated and purified by chromatography on silica gel (87% CH2CI2 / 13% methanol) to yield 5- (4- {[[2S, 4R} -4- [acetyl (4-chlorophenyl) ) amino] -2-methyl-3,4-d-hydroquinolin-1 (2H) -yl] carbonyl, phenyl) pentanamide. 1 H NMR (CDCl 3) d: 1, 16 (d, 3 H), 1, 18 (m, 1 H), 1.56 (m, 3 H), 1.98 (s, 3 H), 2.05 (m, 1 H ), 2.14 (m, 2H), 2.26 (m, 1H), 2.53 (m, 2H), 4.74 (m, 1H), 5.59 (a, 2H), 5.76 (m, 1 H), 6.48 (d, 1 H), 6.88 (t, 1 H), 6.94 (m, 2H), 7.19 (m, 6H), 7.32 (d) , 2H). MS m / z: 519 (M + 1) (2S, 4R) -? / - (4-Chloro-phenyl) - V- [1- (2,3-dihydro-benzofuran-5-carbonyl) -2-methyl -1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide (G-11) Obtained (2S, 4R) -? / - (4-cyoro-phenyl) - / V- [1 - ( 2,3-dihydro-benzofuran-5-carbonyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide following the general procedure G, substituting 4-fluorobenzoyl chloride for chloride of 2,3-dihydro-benzofuran-5-carbonyl chloride. The remainder of the procedure is followed as indicated in general procedure G to produce (2S, 4R) - / V- (4-chloro-phenyl) - / V- [1- (2,3-dihydro-benzofuran-5- carbon I) -2-methyl-1, 2,3,4-tetrahydro-quinoyl-4-yl] -acetamide. 1 H NMR (CDCl 3) d: 1, 09 (d, 3 H), 1, 22 (t, 1 H), 1, 99 (s, 3 H), 2.25 (s, 1 H), 3.04 (m , 2H), 4.49 (t, 2H), 4.70 (m, 1 H), 5.61 (sa, 1 H), 6.50 (m, 2H), 6.88 (m, 2H) , 7.10 (d, 2H), 7.18 (d, 2H), 7.26 (d, 1 H), 7.34 (d, 2H). MS m / z: 461, 2 (M + 1). W- (4-chlorophenyl) -W - [(2S, 4 /?) -2-methyl-1- (pyridin-3-ylcarbonyl) -1,253,4-tetrahydroquinolin-4-yl] acetamide (G-12) prepared? / - (4-chlorophenyl) - / V - [(2S, 4R) -2-methyl-1- (pyridin-3-ylcarbonyl) -1, 2,3,4-tetrahydroquinolin-4-yl] acetamide following General procedure G, substituting 4-fluorobenzoyl chloride for nicotinoyl chloride hydrochloride. The rest of the procedures were followed as indicated in general procedure G to produce / V- (4-chloropheni) -? / - [(2S, 4R) -2-meth1l-1- (pyridin-3-ylcarbonyl) -1, 2,3,4-tetrahydroquinolin-4-yl] acetamide with a decent yield. 1 H NMR (CDCl 3, 300 MHz) d: 1, 07-1, 09 (d, 3 H), 2.01 (s, 3 H), 2.21-2.33 (m, 2 H), 4.05-4 , 12 (c, 1 H), 4.76-4.81 (m, 1 H), 6.54-6.74 (d, 1 H), 6.93-7.38 (m, 9H), 8.49-8.56 (d, 2H). MS m / z: 420 (M + 1). W - [(2S, 4?) - 1- (4-methoxybenzoyl) -2-methyl-1,2,354-tetrahydroquinolin-4-yl] -W-phenylacetamide (G-13)? / - (4-chlorophenyl) was prepared ) - / V - [(2S, 4R) -1- (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] acetamide following the general procedure G, substituting 4- fluorobenzoyl by 4-methoxybenzoyl chloride. The rest of the procedures were followed as indicated in general procedure G to produce (2S, 4R) -? / - (4-cyoro-phenyl) - / V- [1- (4-methoxy-benzoyl) -2- methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide which was obtained in a decent yield. It was dissolved (2S, 4R) -? / - (4-cyoro-phenyl) -? / - [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4 -yl] -acetamide (200 mg, 0.36 mmol) in MeOH and a catalytic amount of Palladium on Carbon (10%) was added. The round bottom flask in which the resulting solution was was evacuated and refilled with hydrogen. The reaction was stirred in the hydrogen atmosphere overnight. The mixture was carefully filtered through a pad of Celite® and concentrated to yield the crude product. The crude product was purified by chromatography on silica gel (hexanes / ethyl acetate system) to yield? / - [(2S, 4R) -1 - (4-methoxybenzoyl) -2-methyl-1, 2,3, 4-tetrahydroquinolin-4-yl] -? / - phenylacetamide (142 mg, 95%). 1 H NMR (CDCl 3) d: 1, 10 (d, 3 H), 1, 60 (s, 1 H), 2.02 (s, 3 H), 2.30 (m, 1 H), 3.74 (s) , 3H), 4.75 (m, 1 H), 5.45 (a, 1 H), 6.50 (d, 1 H), 6.67 (d, 2H), 6.92 (t, 1 H) 7.13-7.18 (m, 3H), 7.28 (d, 1 H), 7.32-7.40 (m, 5H). MS m / z: 415 (M + 1) (2S, 4R) -4- (4. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methylene-3, 4-dihydro-2H-quinolin-1-carbonyl] -2-fluoro-phenoxy) -2,2-dimethyl-butyric acid (G-14) (2S, 4R) - methyl ester was dissolved - 4- (4-. {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl} -2-fluoro -phenoxy) -2,2-dimethyl-butyric acid (100 mg) in methanol / THF (1: 1, 5 ml) and lithium hydroxide (1.0 N, 1 ml) was added thereto. After 1 hour, the reaction was acidified (HCl) and extracted with methylene chloride. The organic layer was dried, filtered and concentrated. The crude residue was purified by chromatography on silica gel (gradient of ethyl acetate-5% MeOH / ethyl acetate) to yield the product. 1 H NMR (CDCl 3) d: 1.1 (d, 3 H), 1, 2 (s, 6 H), 1, 2 (m, 1 H), 2.0 (s, 3 H), 2.0 (t, 1 H ), 2.3 (m, 1 H), 4.0 (t, 2H), 4.7 (m, 2H), 5.6 (sa, 1 H), 6.5 (d, 1 H), 6.6 (t, 1H), 6.7 (d, 1 H), 6.9 (t, 1 H), 7.2 (m, 5H), 7.4 (d, 2H), 11, 1 (sa, 1 H). MS m / z: 567 (M + 1). (2S, 4R) -? / - (4-Chloro-phenyl) -? / - [1 - (1-isopropyl-1 H -indazol-5-carbonyl) -2-methyl-1, 2,3,4- tetrahydro-quinolin-4-yl] -acetamide (G-15) was prepared (2S, 4R) -? / - (4-cyoro-phenyl) -? / - [1 - (1-isopropyl-1 H-indazole- 5-carbonyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide following general procedure G, replacing 4-fluorobenzoyl chloride with 1-ylpropyl chloride 1 - / - indazole-5-carbonyl. (1-isopropyl-1 - / - indazole-5-carbonyl chloride was prepared in three steps from 1H-indazole-5-carboxylic acid ethyl ester) 1-endanzole-5-carboxylic acid ethyl ester was alkylated using 2-bromopropane in the presence of sodium hydride in DMF at room temperature to produce the desired 1-isopropyl-1H-indazole-5-carboxylic acid ethyl ester.The hydrolysis of the ester using 1N sodium hydroxide in ethanol at 80 ° C gave 1-isopropyl-1H-indazole-5-carboxylic acid and the subsequent treatment of this carboxylic acid with oxalyl chloride and catalytic DMF yielded 1-isopropyl-1H-indazole-5-carbonyl chloride in a decent yield). The rest of the procedures were followed as indicated in general procedure G to produce (2S, 4R) - / V- (4-Chloro-phenyl) -? / - [1 - (1-isopropyl-1 H-indazole- 5-carbonl) -2-methl-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide. (The first exception being the deprotection of the benzyloxycarbonyl group by treatment with 30% HBr in AcOH substituting palladium on carbon (10%) and the other in the N-arylation stage of (2S, 4R) - (4- amino-2-methyl-3,4-dihydro-2H-quinolin-1 -yl) - (1-isopropyl-1 H -indazol-5-yl) -methanone with 4-chlorophenylboronic acid, in the presence of copper, pyridine was replaced by triethylamine and the reaction was carried out in dichloromethane at room temperature to yield (2S, 4R) -? / - (4-chloro-phenyl) - / V- [1 - (1-isopropyl-1H -indazole-5-carbonyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl-acetamide). H NMR (CDCl 3) d: 1.15 (3H, d; overlap 1 H, t), 1, 60 (2 x 3H, d), 2.02 (3H, s), 2.33 (1 H, m), 4.78 (2 x 1 H, m, overlap), 5.60 (1 H, m), 6.44 (1 H, d), 6.95 (1 H, t), 7.00-7.40 (9H, complex). ESl-MS m / z: 501 (M + 1). ? / - (4-Chlorophenyl) - / V - [(2S, 4?) - 1- (4-methoxybenzoyl) -2-methyl-152,3,4-tetrahydroquinolin-4-yl] -2-methylpropanamide (G -16) was synthesized / V- (4-chlorophenyl) -? / - [(2SJ4R) -1- (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolyl-4-yl] -2-methylpropanamide according to general procedure A replacing 4-fluorobenzoyl chloride with 4-methoxybenzoyl chloride and substituting acetyl chloride for 2-methylpropanoyl chloride.
The remainder of the procedure was followed as indicated in general procedure G to produce? / - (4-chlorophenyl) -? / - [(2S, 4R) -1- (4-methoxybenzoyl) -2-methyl-1, 2 , 3,4-tetrahydroquinolin-4-yl] -2-methylpropanamide. 1 H NMR (CDCl 3) d: 1, 12-1, 26 (m, 10H), 2.20-2.28 (m, 1 H), 2.61 (overlap, 1 H), 3.72 (s, 3 H), 4.69-4.79 (m, 1 H), 5.61 (sa, 1 H), 6.52 (d, 1 H), 6.67 (d, 2H), 6.92 (t, 1H), 7.11-7.41 (m, 8H). MS m / z: 477 (M + 1). W- (4-Chlorophenyl) -W-. { (2S, 4K) -1 - [(1,3-DimetiM H -thieno [2,3-c] pyrazol-5-yl) carbonyl] -2-methyl-1,2J3,4-tetra idroquinolin-4-yl } Acetamide (G-17) - (4-Chlorophenyl) -? / - was prepared. { (2S, 4R) -1 - [(1,3-dimethyl-1H-thieno [2,3-firazol-5-yl) carbonyl] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl } acetamide following the procedure for? / - (4-chlorophenyl) -? / -. { (2S, 4R) -1 - [(1-isopropyl-1 / - / - pyrazol-4-yl) carbonii] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} acetamide substituting 1-isopropyl-1 - / - pyrazole-4-carbonyl chloride for 1,3-dimethyl-1 / - / - thieno [2,3- c] pyrazole-5-carbonyl chloride. (1,3-Dimethyl-1H-thieno [2,3-c] pyrazole-5-carbonyl chloride was prepared from 1,3-dimethyl-1H-thieno [2,3-c] pyrazole-5-acid. carboxylic acid available commercially by treatment with oxalyl chloride and catalytic DMF in dichloromethane). 1 H NMR (CDCl 3) d: 1, 15 (d, 3 H), 1, 17 (t, 1 H), 2.02 (s, 3 H), 2.25 (s, 3 H), 2.25 (m, 1 H), 3.80 (s, 3 H), 4.62-4.74 (m, 1 H), 5.48 -5.60 (m, 1 H), 6.55 (s, 1 H) , 7.00-7.40 (m, 8H). MS m / z: 493 (M + 1). W- (4-chlorophenyl) -? H (2S, 4R) -1 - [(1-isopropyl-1W-pyrazol-4-yl) carbonyl] -2-methyl-1,2,3,4-tetrahydroquinoline- 4-il} acetamide (G-18) A / - (4-chlorophenyl) -? / - was prepared. { (2S, 4R) -1 - [(1-isopropyl-1 H -pyrazol-4-yl) carbonyl] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} acetamide following general procedure G, substituting 4-fluorobenzoyl chloride for 1-isopropyl-1H-pyrazole-4-carbonyl. Commercially available (1-isopropyl-1H-pyrazole-4-carbonyl chloride from 1-isopropyl-1H-pyrazole-4-carboxylic acid was prepared by treatment with oxalyl chloride and catalytic DMF in dichloromethane).
Other modifications of general procedure A included the deprotection of the benzyloxycarbonyl group by treatment with 30% HBr in acetic acid instead of palladium on carbon (10%) and the use of triethylamine in place of pyridine using dichloromethane as solvent at room temperature during the sequence of? / - arylation. 1 H NMR (CDCl 3) d: 1, 11 (d, 3 H), 1, 13 (t, 1 H), 1, 36 (d, 6 H), 2.00 (s, 3 H), 2.21-2.28 (m, 1 H), 4.25-4.34 (m, 1 H), 4.65-4.76 (m, 1 H), 5.36-5.56 (m. a, 1 H), 6.95 (d, 1 H), 7.00-7.40 (m, 9H). MS m / z: 451 (M + 1). ? H-indol-4-yl-W - [(2S, 4R) -1 - (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] acetamide (G-19) obtained? / - 1H-indol-4-yl -? / - [(2S, 4R) -1- (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] acetamide following General procedure G, substituting 4-fluorobenzoyl chloride for 4-methoxybenzoyl chloride.
A mixture of (2S, 4R) -1- (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-amine (0.12 g, 0.4 mmol) (obtained after the hydrogenation step), 4-bromo-1 H-indole-1-carboxylic acid-butyl ester (0.099 g, 0.39 mmol), palladium dba (0.018 g, 0.02 mmol), biphenyl-2-yl (di -erc-butyl) phosphine (0.006 g, 0.02 mmol) and cesium carbonate (0.13 g, 0.4 mmol) in dimethoxyethane (3 ml) was stirred at 80 ° C under a nitrogen atmosphere for 15 h. The reaction mixture was filtered. The filtrate was evaporated to produce the crude product (0, 222 g) which was then cleaned by chromatography on silica gel (10% ethyl acetate: hexane) to give 4-. { [(2S, 4R) -1 - (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] amino} -1 H-Indole-1-desired fer-butyl carboxylate (0.054 g, 32%). 1 H NMR (CDCl 3) d: 1, 32 (d, 3 H), 1, 47-1, 57 (m, 1 H), 1.71 (s, 9 H), 2.87-2.96 (m, 1 H), 3.81 (s, 3H), 4.63-4.69 (m, 1 H), 4.88-5.01 (m, 1 H), 6.46 (d, 1 H), 6.56-6.63 (m, 2H), 6.75-6.78 (m, 2H), 6.94-7.09 (m, 2H), 7.2-7.36 (m, 4H) ), 7.59-7.66 (m, 2H). MS m / z: 512 (M + 1) A mixture of 4-. { [(2S, 4R) -1- (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolyl-4-yl] amino} 1 H -indole-1-methyl-ert-butyl carboxylate (0.054 g, 0.1 mmol), freshly distilled acetyl chloride (0.5 ml), diisopropylethylamine (0.015 g, 0.12 mmol) and 4-N , N-dimethylaminopyridine (catalytic amount) was stirred at room temperature for 43 h. Ice was added to the reaction mixture and stirred for 1 h. The reaction mixture was neutralized with solid sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate extract was washed twice with water and brine, dried over sodium sulfate and evaporated. The crude product (0.055 g) obtained in this way was cleaned by chromatography on silica gel (ethyl acetate: hexane) to give 4-. { acetyl [(2S, 4R) -1- (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] amino} -1 H-Indole-1-clean urea-butyl carboxylate (0.035 g, 60%). 1 H NMR (CDCl 3) d: 1, 04 (d, 3 H), 1, 47-1, 57 (m, 1 H), 1.69 (s, 9 H), 1, 97 (s, 3 H), 2, 87-2.96 (m, 1H), 3.75 (s, 3H), 4.64-4.77 (m, 1H), 4.88-5.01 (m, 1H), 6.53 ( d, 1H), 6.66 (d, 1H), 6.69 (d, 2H), 6.92-6.97 (m, 1 H), 7.14-7.29 (m, 5H), 7.45 (d, 1 H), 7.73 (d, 1 H), 8.21 (d, 1 H).
MS m / z: 411, 280. Stirred 4-. { acetyl [(2S, 4R) -1- (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] amino} 1 H -indole-1-tert-butylcarboxylate (0.035 g, 0.068 mmol) in 4 N HCl in dioxane (1 mL) for 24 h and then evaporated to dryness. The residue was dissolved in ethyl acetate, washed with 1 N NaOH, water and brine, dried over sodium sulfate and evaporated to dryness to give the crude product (0.023 g). The crude product was cleaned by chromatography on silica gel to give? / - 1H-indol-4-yl- / V - [(2S, 4R) -1- (4-methoxybenzoyl) -2-metii-1, 2, 3,4-tetrahydroquinolin-4-yl] acetamide clean (0.008 g, 28%). 1 H NMR (CDCl 3) d: 1, 03 (d, 3 H), 2.01 (s, 3 H), 3.75 (s, 3 H), 4.08-4.16 (m, 1 H), 4.61 -4.79 (m, 1H), 6.52-6.55 (m, 2H), 6.67-6.7 (m, 2H), 6.92-7.51 (m, 9H), 8 , 62 (sa, 1 H). MS m / z: 454 (M + 1). 4 - [(4. {[[(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl}. phenyl) (methyl) amino] -2,2-dimethylbutanoic acid (G-20) 4 - [(4- {[[2S, 4R) -4- [acetyl (4-chlorophenyl) amino] was dissolved ] -2-methyl-3,4-dihydroquinolin-1 (2H) -iI] carbonyl, phenyl) (methyl) amino] -2,2-dimethylbutanoate methyl in methanol / tetrahydrofuran / water (2/1/1 ), then sodium hydroxide (3 equivalents) was added and the reaction mixture was heated at 40 ° C for 2 h. The mixture was concentrated, the residue was acidified with a 1 N aqueous solution of HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give 4 - [(4- {[[(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino]] -2-methyl-3,4-dihydroquinolin-1 (2 -) -yl] carbonyl, phenyl) (methyl) amino] -2,2-dimethylbutanoic acid. 1 H NMR (CDCl 3) d: 1, 09-1, 12 (m, 1 H), 1, 11 (d, 3 H), 1, 22 (d, 6 H), 1, 69-1, 74 (m, 2H), 2.01 (s, 3H), 2.24-2.31 (m, 1 H), 2.83 (s, 3H), 3.27 (t, 2H), 4.65 -4.76 (m, 1 H), 5.60 (sa, 1 H), 6.39 (d, 2H), 6.62 (d, 1 H), 6.95 (t, 1 H), 7.07-7.16 (m, 3H), 7.18-7.28 (m, 3H), 7.37 (d, 2H). MS m / z: 562 (M + 1). ? / - (4-chlorophenyl) -2-hydroxy -? / - [(2S, 4R) -1- (4-methoxybenzoyl) -2-methyl-1,2,3,4-tetrahydroquinolin-4-yl] acetamide (G-21) Obtained? / - (4-chlorophenyl) -2-hydroxy -? / - [(2S, 4R) -1 - (4-methoxybenzoyl) -2-methylene-1, 2,3, 4-tetrahydroquinolin-4-yl] acetamide following the general procedure G, substituting 4-fluorobenzoyl chloride for 4-methoxybenzoyl chloride. Process A was followed by also replacing acetyl chloride with acetoxyacetyl chloride in the last step to produce 2- acetate. { (4-chlorophenyl) [(2S, 4R) -1- (4-methoxybenzoyl) -2-methyl-1,2,3,4-tetrahydroquinolyl-4-yl] amino} -2-oxoetllo. 2- acetate was dissolved. { (4-chlorophenyl) [(2S, 4R) -1- (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] amino} -2-oxoethyl (496 mg, 0.98 mmol, 1 equiv.) In methanol (12 ml). A solution of potassium carbonate (1.08 g, 7.84 mmol, 8 equiv.) In water (5 ml) was added and the reaction mixture was stirred at room temperature for 4 h. The mixture was concentrated and the residue was dissolved in ethyl acetate and washed with water and brine and then dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by chromatography on silica gel (methylene chloride / methanol: 98/2) to produce? / - (4-chlorophenyl) -2-hydroxy -? / - [(2S, 4R) -1- ( 4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] acetamide (380 mg, 84%). 1 H NMR (DMSO) d: 1, 05 (d, 3 H), 2.45 (m, 1 H), 3.70 (s, 3 H), 3.80-3.95 (dd, 2 H), 4, 60 (m, 1 H), 4.80 (m, 1 H), 5.40 (m, 1 H), 6.55 (d, 1 H), 6.75 (d, 2H), 6.95 (t, 1 H), 7.10 (d, 2H), 7.20 (t, 1H), 7.40-7.60 (m, 5H). MS m / z: 465 (M + 1). Ethyl ester of (2S, 4R) -6- acid. { 4- [Acetyl- (4-chloro-phenyI) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl} -2,3-dihydro-benzo [1,4] oxazine-4-carboxylic acid (G-22) To a solution of (2S, 4R) - (2-methyl-1, 2,3,4-) benzyl ester tetrahydro-quinolin-4-yl) -carbamic acid (990 mg, 3.49 mmol) in methylene chloride at room temperature was added triethylamine (1.21 ml, 8.71 mmol) followed by 6-chlorocarbonyl ethyl ester -2,3-dihydro-benzo [1,4] oxazine-4-carboxylic acid (349 mmol). The reaction was stirred overnight at room temperature. The mixture was poured into water and extracted with ethyl acetate. The extracts were washed with 1 M NaOH (aq) and brine, dried over MgSO 4, filtered, dried and concentrated. The crude residue was purified by chromatography on silica gel (75% hexanes / 25% ethyl acetate) to yield the pure amide. Ethyl ester of (2S, 4RJ-6- (4-benzyloxycarbonylamino-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl) -2,3-dihydro-benzo [1, 4] was dissolved. ] oxazine-4-carboxylic acid (697 mmol) in ethanol (30 ml) The vessel in which the resulting solution was was evacuated and refilled with argon, a catalytic amount of palladium on carbon (10%) was added. %) .The vessel was again evacuated once more and at this time it was again filled with hydrogen and stirred in a Parr bottle at 275,790 kPa hydrogen.The reaction was completed after 4 hours.The mixture was carefully filtered and it was concentrated to 10% of the volume The resulting concentrated solution was filtered through Celite® and concentrated to give the crude amine to a solution of (2S, 4R) -6- (4-amino-2-ethyl ester. -methyl-3,4-dihydro-2H-quinoline-1-carbonyl) -2,3-dihydro-benzo [1,4] oxazine-4-carboxylic acid (470 mg, 1.18 mmol) in methylene chloride was they added 4-chlor acid ofhenylboronic acid (368 mg, 2.36 mmol), triethylamine (1.31 ml, 9.42 mmol) and copper (II) acetate (429 mg, 2.36 mmol). The heterogeneous green mixture was stirred open in air for 1 hour and then heated to 60 ° C and stirred overnight (14 hours). Then, the mixture was cooled to room temperature and poured into stirred ethyl acetate rapidly (150 ml); the solids were removed by filtration through Celite®. The extracts were washed several times with water and then once with brine. Then, the extracts were dried over anhydrous MgSO, filtered and concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel (95% methylene chloride / 5% ethyl acetate) to yield the aniline product as a yellow oil. To a solution of (2S, 4R) -6- [4- (4-chloro-phenylamino) -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl] -2.3- ethyl ester. dihydro-benzo [1,4] oxazine-4-carboxylic acid (343 mg, 0.673 mmol) in methylene chloride (2 mL) was added diisopropylethylamine (0.129 mL, 0.739 mmol) followed by acetyl chloride (2 mL) . The mixture was stirred at room temperature 4 hours. The mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with sat. NaHCO 3. ac. and brine and dried over MgSO, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (gradient of 25/75 hexanes / ethyl acetate) to yield the pure product. 1 H NMR (CDCl 3) d: 1, 1 (d, 3 H), 1, 2 (m, 1 H), 1.3 (t, 3 H), 2.0 (s, 3 H), 2.3 (m, 1 H), 3.3 (m, 2H), 4.0 (m, 2H), 4.3 (m, 2H), 4.7 (m, 1H), 5.5 (m, 1H), 6.4 (d, 1H) , 6.5 (d, 1H), 6.6 (d, 2H), 6.96 (t, 1H), 7.2 (m, 4H), 7.4 (d, 2H). MS m / z: 548 (M + 1). ? / - [(2S, 4R) -6-chloro-1- (4-methoxybenzoyl) -2-methyl-1,2,3,4-tetrahydroquinolin-4-yl] -? / - (4-chlorophenyl) acetamide (G-23) It was synthesized / V - [(2S, 4R) -6-cyoro-1- (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] -? - (4-chlorophenyl) acetamide as described for (2S, 4R) - (2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl) -carbamic acid benzyl ester, substituting aniline for 4 -cyooaniline. Another preparation following general procedure A, substituting 4-fluorobenzoyl chloride for 4-methoxy-benzoyl chloride produced? / - [(2S, 4R) -6-cyoro-1- (4-methoxybenzoyl) -2-methyl-1 , 2,3,4-tetrahydroquinolin-4-yl] - / V- (4-chlorophenyl) acetamide. 1 H NMR (CDCl 3) d: 1, 13 (d, 3 H), 1, 15 (t, 1 H), 2.03 (s, 3 H), 2.27 (m, 1 H), 3.76 (s) , 3H), 4.72 (sextuplet, 1 H), 5.58 (sa, 1 H), 6.43 (d, 1 H), 6.71 (d, 2H), 6.93 (d, 1H) , 7.14-7.29 (m, 5H), 7.41 (d, 2H). MS m / z: 483 (M + 1) Acid [(5- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinoline-1 ( 2H) -yl] carbonyl.] Isoxazol-3-yl) oxy] acetic acid (G-24) [(5- {[[2S, 4R) -4- [acetyl (4-chlorophenyl) amino] 2-methyl-3,4-dihydroquinolin-1 (2 / - /) - yl] carbonyl] isoxazol-3-yl) oxy] ethyl acetate following the procedure for / V- (4-chlorophenyl) -? / -. { (2S, 4R) -1 - [(1-isopropyl-1 H -pyrazol-4-yl) carbonyl] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} acetamide substituting 1-isopropyl-1H-pyrazole-4-carbonyl chloride for. { [5- (chlorocarbonyl) isoxazol-3-yl] oxy} ethyl acetate. It was prepared. { [5- (chlorocarbonyl) isoxazol-3-yl] oxy} ethyl acetate in 4 steps from methyl 3-hydroxy-5-isoxazole carboxylate. Methyl 3-hydroxy-5-isoxazole carboxylate (1.00 g, 6.95 mmol) was alkylated using ethyl bromoacetate (0.850 mL, 7.64 mmol) in the presence of potassium carbonate (1.05 g, 7%). 64 mmol) and catalytic potassium iodide in DMF (3.00 ml) at room temperature overnight. Water was added to the reaction mixture and extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the desired methyl 3- (2-ethoxy-2-oxoethoxy) isoxazole-5-carboxylate (60%). (Ref: WO 03/063800 PCT / US03 / 03224). Methyl 3- (2-ethoxy-2-oxoethoxy) isoxazole-5-carboxylate was also treated with 5% aqueous sodium hydroxide in methanol to give 3- (carboxymethoxy) isoxazole-5-carboxylic acid (86%). This diacid (0.700 g, 3.76 mmol) was selectively esterified in the presence of catalytic p-toluenesulfonic acid monohydrate (100 mg) in ethanol at room temperature. Water was added to the reaction and the mixture was extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the desired 3- (2-ethoxy-2-oxoethoxy) isoxazole-5-carboxylic acid (90%). 3- (2-Ethoxy-2-oxoethoxy) isoxazole-5-carboxylic acid was treated with oxalyl chloride and catalytic DMF in dichloromethane to yield the. { [5- (chlorocarbonyl) isoxazol-3-yl] oxy} ethyl acetate desired. [(5- {[[2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl was treated. isoxazol-3-yl) oxy] ethyl acetate with a solution of lithium hydroxide monohydrate (aq.) in methanol at room temperature overnight to produce [(5- ({(2S, 4R) -4]] - [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl] -isoxazol-3-yl) oxy] acetic in a yield of 60%. 1 H NMR (CDCl 3) d: 1, 15 (d, 3 H), 1, 17 (t, 1 H), 2.02 (s, 3 H), 2.42-2.68 (m, 1 H), 4 , 69 (s, 1 H) 4.72-4.78 (m, 1 H), 5.44-5.58 (a, 1 H), 6.80 (d, 1 H), 7.00- 7.40 (m, 8H). MS m / z: 484 (M + 1). ? / - (4-chlorophenyl) -W - [(2S, 4R) -1- (4-cyanobenzoyl) -2-methyl-1,2,3,4-tetrahydroquinolin-4-yl] acetamide (G-25) Obtained? / - (4-chlorophenyl) -A / - [(2S, 4R) -1- (4-cyanobenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] acetamida following the general procedure G, replacing 4-fluorobenzoyl chloride with 4-cyanobenzoyl chloride. The remainder of the procedure is followed as indicated in general procedure G to produce? / - (4-chlorophenyl) -? / - [(2S, 4R) -1 - (4-cyanobenzoyl) -2-methyl-1, 2 , 3,4-tetrahydroquinol-4-yl] acetamide. 1 H NMR (CDCl 3) d: 1, 10-1, 20 (m, 1 H), 1, 16 (d, 3 H), 2.03 (s, 3 H), 2.20-2.36 (m, 1 H), 4.70-4.84 (m, 1H), 5.48-5.70 (m, 1 H), 6.40 (d, 1 H), 6.91 (t, 1 H), 7.16-7.32 (m, 6H), 7.38 (d, 2H), 7.47 (d, 2H). MS m / z: 444 (M + 1) 4 - [(5- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl.}. Isoxazol-3-yl) oxy] -2,2-dimethylbutanoate ethyl (G-26) 4 - [(5- {(2S, 4R) -4 was prepared - [ethyl acetyl (4-cyanophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2 -) -yl] carbonyl] -isoxazol-3-yl) oxy] -2,2-dimethylbutanoate following the procedure for? / - (4-chlorophenyl) - / V-. { (2SJ4R) -1 - [(1-isopropyl-1H-pyrazol-4-yl) carbonyl] -2-methylene-1, 2,3,4-tetrahydroquinolyl-4-yl} acetamide, substituting 1-α-propyro-1-pyrazol-4-carbonyl chloride for 4-. { [5- (chlorocarbonyl) isoxazol-3-yl] oxy} Ethyl -2,2-dimethylbutanoate. He prepared 4-. { [5- (chlorocarbonyl) isoxazol-3-yl] oxy} Ethyl -2,2-dimethylbutanoate in three steps from methyl 3-hydroxy-5-isoxazole carboxylate. Methyl 3-hydroxy-5-isoxazole carboxylate (1.00 g, 6.94 mmol) was alkylated using ethyl 4-bromo-2,2-dimethylbutanoate (1.59 g, 7.63 mmol) in the presence of potassium carbonate (1.05 g, 7.64 mmol) and catalytic potassium iodide in DMF (5.00 ml) at room temperature overnight. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and purified on silica gel by flash chromatography using hexane / ethyl acetate (gradient of 10-50%) to produce 3- (4-Ethoxy-3,3-dimethyl-4-oxobutoxy) isoxazole-5-carboxylic acid methyl ester with a yield of 35%. Selective hydrolysis of the methyl ester by subsequent treatment with lithium hydroxide (aq.) (1.50 equiv.) In methanol at room temperature afforded 3- (4-ethoxy-3,3-dimethyl-4-oxobutoxy) isoxazole acid. -5-carboxylic acid which was then treated with oxalyl chloride and catalytic DMF in dichloromethane to yield 4-. { [5- (cyclocarbonyl) isoxazol-3-yl] oxy]} Desired ethyl -2,2-dimethylbutanoate. 1 H NMR (CDCl 3) d: 1, 18 (d, 3 H), 1, 18 (t, 1 H), 1, 19 (s, 6 H), 1, 20 (t, 3 H), 1, 99-2, 02 (s, 3H; m, 1H), 2.24-2.36 (m, 1H), 4.15 (c, 2H), 4.17-4.22 (m, 2H), 4.64-4.74 (m, 1H), 5.60-5.68 (a, 1 H), 6.80 (d, 1 H), 7.00-7.40 (m, 8H). MS m / z: 568 (M + 1). 4- Acid. { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl} benzoic acid (G-27) 4 - ((2S, 4R) -4- (N- (4-chlorophenyl) acetamido) -2-methyl-1, 2,3,4-tetrahydroquinoline-1-carbonyl) benzoate was obtained from methyl followed by general procedure G, substituting 4-fluorobenzoyl chloride for methyl 4- (chlorocarbonyl) benzoate. The rest of the procedure is followed as indicated in general procedure A to produce 4 - ((2S, 4R) -4- (N- (4-chlorophenyl) acetamido) -2-methyl-1, 2,3,4- methyl tetrahydroquinoline-1-carbonyl) benzoate, which was saponified with excess lithium hydroxide in MeOH / THF / H 2 O (2: 1: 2). The suspension was acidified with 1 N HCl and the crude product was extracted using methylene chloride. The organic portion was concentrated and the resulting suspension was subjected to preparative HPLC to yield the title compound as a white solid. 1 H NMR (CDCl 3) d: 1, 15-1, 22 (m, 1 H), 1, 16 (d, 3 H), 2.06 (s, 3 H), 2.20-2.36 (m, 1 H), 3.50-4.05 (sa, 1 H), 4.72-4.88 (m, 1 H), 5.50-5.75 (m, 1 H), 6.45 (d) , 1 H), 6.85 (t, 1H), 7.08-7.30 (m, 6H), 7.40 (d, 2H), 7.87 (d, 2H). MS m / z: 463 (M + 1) W- (4-chlorophenyl) -W - [(2S, 4R) -1- (4-methoxybenzoyl) -2-methyl-1,2,3,4-tetrahydroquinoline- 4-yl] cyclopropanecarboxamide (G-28) Obtained? / - (4-chlorophenyl) - / V - [(2SJ4R) -1- (4-methoxybenzoyl) -2-methyl-1, 2,3,4 tetrahydroquinol-4-yl] cyclopropanecarboxamide following the general procedure G, substituting 4-fluorobenzoyl chloride for 4-methoxybenzoyl chloride. Process G was followed by replacing acetyl chloride with cyclopropanecarbonyl chloride in the last step to produce? / - (4-chlorophenyl) -? / - [(2S, 4R) -1 - (4-methoxybenzoyl) -2-methyl -1, 2,3,4-tetrahydroquinolin-4-yl-cyclopropanecarboxamide. 1 H NMR (CDCl 3) d: 0.75 (m, 2 H), 1, 00-1, 20 (m, 5 H), 1.45 (m, 1 H), 2.30 (m, 1 H), 3, 75 (s, 3H), 4.75 (m, 1 H), 5.60 (m, 1 H), 6.50 (d, 1 H), 6.60 (d, 2H), 6.90 ( t, 1 H), 7.10-7.45 (m, 8H). MS m / z: 475 (M + 1). W - [(2S, 4R) -1- (4-methoxybenzoyl) -2-methyl-1,2,3,4-tetrahydroquinolin-4-yl] -W- [4- (1H-pyrrol- 1-phenyl) acetamide (G-29)? / - (4-Amino-phenyl) -? / - [(2S, 4R) -1 - (4-methoxy-benzoyl) -2-methyl-1 was prepared , 2,3,4-tetrahydro-quinolin-4-yl] -acetamide in a similar manner to General Procedure G: To a solution of (2S, 4R) - (2-met? 'M, 2,3) benzyl ester , 4-tetrahydro-quinolin-4-yl) -carbamic acid (1.00 equiv.) In methylene chloride at room temperature was added diisopropylethylamine (1.50 equiv.) Followed by 4-anisoyl chloride (1.15 equiv. .). The reaction was stirred overnight at room temperature. The mixture was poured into water and extracted with ethyl acetate. The extracts were washed with 1 M NaOH (aq) and brine, dried over magnesium sulfate, filtered, dried and concentrated. The crude residue was purified by chromatography on silica gel (75% hexanes / 25% ethyl acetate) to yield benzyl ester of 2S, 4R) - [1- (4-methoxybenzo) - 2-methyl ester. l-1, 2,3,4-tetrahydro-quinolin-4-yl] -carbamic acid. Benzyl ester of (2S, 4R) - [1- (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -carbamic acid (1.00 equiv.) Was dissolved. in ethanol (30 ml). The vessel in which the resulting solution was was evacuated and refilled with argon. A catalytic amount of Palladium on Carbon (10%, 0.10 equiv. By weight) was added. The vessel was again evacuated once more and at this time it was again filled with hydrogen and stirred in a Parr bottle at 275,790 kPa of hydrogen. The reaction was complete after 4 h. The mixture was carefully filtered and concentrated to 10% volume. The resulting concentrated solution was filtered through Celite® and concentrated to yield the crude amine, (2S, 4R) - (4-amino-2-methyl-3,4-dihydro-2H-quinolin-1-yl) - (4-methoxy-phenyl) -methanone. To a solution of (2S, 4R) - (4-amino-2-methyl-3,4-dihydro-2H-quinolin-1-yl) - (4-methoxy-phenyl) -methanone (1.00 equiv.) in DMF were added 4-nitrophenylboronic acid (2.00 equiv.), pyridine (2.50 equiv.) and copper (II) acetate (2.00 equiv.). The heterogeneous green mixture was stirred open in the air for 1 h and then heated to 60 ° C and stirred overnight (14 h). Then, the mixture was cooled to rt and poured into stirred ethyl acetate rapidly (150 ml); the solids were removed by filtration through Celite®. The extracts were washed several times with water and then once with brine. Then, the extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel (95% methylene chloride / 5% ethyl acetate) to yield (4-methoxy-phenyl) - [(2S, 4R) -2-methyl-4- ( 4-nitro-phenylamino) -3,4-dihydro-2H-quinolin-1-yl] -methanone as a yellow solid. To a solution of (2S, 4R) - [4- (4-nitro-phenylamino) -2-methyl-3,4-dihydro-2H-quinolin-1-yl] - (4-methoxy-phenyl) -methanone ( 1.00 equiv.) In methylene chloride was added diisopropylethylamine (1.05 equiv.) Followed by acetyl chloride (1.00 equiv.). The mixture was stirred at 48 h. The mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with sat. Sodium bicarbonate. aqueous and brine and dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (gradient of 25/75 hexanes / ethyl acetate) to yield? - (4-nitro-phenyl) -? / - [1- (4-methoxy-benzoyl) -2 -methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide pure, which was reduced to? / - (4-amino-phenyl) -? / - [1- (4-methoxy-benzoyl ) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide using excess NH 2 CO 2 H, Pt (sulphide) catalytic, in ethanol at reflux temperature for 30 m, followed by filtration and concentration. The amine was used without further purification due to the inherent chemical instability.
It was dissolved? / - (4-amino-phenyl) -? / - [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide ( 22 mg, 0.05 mmol) in MeOH: THF (1 ml each) and cooled to 10 ° C. 2,5-Dimethoxy-tetrahydrofuran (1.25 equiv.) Was dissolved in THF and catalytic H2SO and added dropwise to the aniline mixture. The mixture was poured into sat. NaHC? 3 sat. and extracted with ethyl acetate. The organic layer was dried, filtered and concentrated and the crude residue was purified by preparative HPLC to yield the title compound as an off-white solid. 1 H NMR (CDCl 3) d: 1.00-1.22 (m, 1H), 1.12 (s, 3H), 2.04 (s, 3H), 2.22-2.42 (m, 1H) , 3.72 (s, 3H), 4.64-4.84 (m, 1 H), 5.50-5.80 (m, 1 H), 6.38 (s, 2H), 6.53 (d, 1 H), 6.67 (d, 2H), 6.94 (t, 1 H), 7.05-7.48 (m, 10H). MS m / z: 480 (M + 1) 4 - [(4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinoline-1 (2 H) -yl] carbonyl, phenyl) (methyl) amino] -2,2-dimethylbutanoate methyl (G-30) 4 - [(4- {[(2S, 4R) -4- [Acetyl (4-chlorophenii) amino] -2-methyl-3,4-dihydroquinolin-1 (2 - /) - yl] carbonyl} phenyl) (methyl) amino] -2,2-dimethylbutanoate methyl in accordance with the procedure G substituting 4-fluorobenzoyl chloride for 4-nitrobenzoyl chloride in the first stage and, to avoid complications, the protective group CBZ was excised by treatment of a solution of the protected amine, [(2S, 4R) - 2-methyl-1- (4-nitrobenzoyl) -1,2,3,4-tetrahydroquinolin-4-benzylcarbamate, in dichloromethane with hydrogen bromide in acetic acid (30% by weight) followed by precipitation of the product of the reaction mixture by the addition of hexanes. The remainder of general procedure A was followed as indicated to produce? / - (4-chlorophenyl) -? / - [(2S, 4R) -2-methyl-1- (4-nitrobenzoyl) -1, 2,3 , 4-tetrahydroquinolin-4-yl] acetamide. This material was reduced by exposure to sulfurized platinum (at 10% by weight) and ammonium formate (4.0 equivalents) in ethanol at 70 ° C until all the starting material was consumed to produce? / - [(2S, 4R ) -1- (4-aminobenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] - / V- (4-chlorophenyl) acetamide. This material underwent a first reductive alkylation with methyl 2,2-dimethyl-4-oxobutanoate and then with formaldehyde. (Methyl 2,2-dimethyl-4-oxobutanoate was prepared in 3 steps from methyl 4,4-dimethoxybutanoate.) Methyl 4,4-dimethoxybutanoate underwent the formation of lithium enolate with lithium diisopropylamide (1, 1 equivalent) in THF at -78 ° C followed by inactivation with methyl iodide (2.0 equivalents) and aqueous treatment, the repetition of the same protocol produced, after conventional chromatography (5% ethyl acetate / hexanes), Methyl 4,4-dimethoxy-2,2-dimethylbutanoate The subsequent treatment of this material with 6-normal aqueous hydrochloric acid in acetone produced, after the conventional aqueous treatment, methyl 2,2-dimethyl-4-oxobutanoate). A solution of methyl 2,2-dimethyl-4-oxobutanoate (1.0 equivalent), sodium triacetoxyborohydride (1.2 equivalents) and aniline in THF with acetic acid (1.0 equivalent) was stirred until all the departure had been consumed. The reaction was then diluted with methanol, acidified with concentrated hydrochloric acid (3 drops) and an excess of formaldehyde (37% by weight in H2O) and sodium cyanoborohydride (5 equivalents) added. The reaction mixture was stirred at room temperature until all the starting material had been consumed and then the conventional aqueous workup followed by chromatography (50% ethyl acetate / hexanes) yielded 4 - [(4- {[[( 2S, 4R) -4- [acetyl (4-cyanophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl} phenyl) (methyl) amino] -2.2- methyl dimethylbutanoate. 1 H NMR (CDCl 3) d: 1, 09-1, 14 (m, 1 H), 1, 13 (d, 3 H), 1, 20 (d, 6 H), 1, 71-1, 79 (m, 2 H ), 1.98 (s, 3H), 2.24-2.28 (m, 1 H), 3.02 (s, 3H), 3.30 (t, 2H), 3.57 (s, 3H) ), 4.69-4.76 (m, 1 H), 5.51 (sa, 1H), 6.39 (d, 1 H), 6.84 (t, 1 H), 7.16 (d) , 2H), 7.24-7.29 (m, 4H), 7, 34 (d, 2H), 7.54 (d, 2H). MS m / z: 576 (M + 1). N- [3- (acetylamino) phenyl] -W - [(2S, 4R) -1 - (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] acetamide (G-) 31)? / - [3- (Acetylamino) phenyl] -? / - [(2S, 4R) -1 - (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinoline-4- was prepared il] acetamide following general procedure G, substituting 4-fluorobenzoyl chloride for 4-methoxybenzoyl chloride and 4-chlorophenylboronic acid 3-acetamidophenylboronic acid. The rest of the procedures were followed as indicated in general procedure G to produce? / - [3- (acetylamino) phenyl] -? / - [(2SJ4R) -1- (4-methoxybenzoyl) -2 -methyl-1, 2,3,4-tetrahydroquinolin-4-yl] acetamide. 1 H NMR (CDCl 3) d: 1, 1-1, 2 (m, 4 H), 2.0 (s, 3 H), 2.3 (m, 4 H), 3.7 (s, 3 H), 4.8 (m, 1 H), 5.6 (a, 1 H), 6.5 (d, 1 H), 6.7 (m, 2H), 6.9 (m, 1 H), 7.1- 7.4 (m, 7H), 7.5 (m, 1 H) MS m / z: 472 (M + 1). ? - [(2S, 4R) -1- (4-methoxybenzoyl) -2-methyl-1,2,3,4-tetrahydroquinolin-4-yl] -? / -. { 4 - [(methylsulfonyl) amino] phenyl} acetamide (G-32)? / - (4-Amino-phenyl) -? / - [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinoline-4 was dissolved -yl] -acetamide (32 mg, 0.075 mmol) in methylene chloride (1 ml) and triethylamine (10 equiv.) and then cooled to -3.0 ° C. Methanesulfonyl chloride (5 equiv.) Was added; After 30 min, the TLC showed the complete consumption of the starting aniline. The mixture was poured into water and extracted with EtOAc. The organic layer was dried, filtered and concentrated to yield the corresponding b / s-methanesulfonated adduct. The crude residue was dissolved in MeOH and -20 equiv. of Cs2CO3. After stirring for 5 min, the mixture was poured into aHC? 3 sat. and EtOAc. The organic layer was dried, filtered and concentrated. The resulting crude material was subjected to flash chromatography (EtOAc) to yield the title compounds as a white solid. 1 H NMR (CDCl 3) d: 1, 00-1, 22 (m, 1 H), 1, 11 (s, 3 H), 1, 20-1, 28 (m, 1 H), 2.01 (s, 3H), 2.20-2.40 (m, 1 H), 3.01 (s, 3H) 3.72 (s, 3H), 4.64-4.82 (m, 1 H), 5, 45-5.75 (m, 1 H), 6.51 (d, 1 H), 6.63 (d, 2H), 6.91 (t, 1 H), 7.10-7.35 (m , 7H), 7.38-7.44 (m, 1H). MS m / z: 508 (M + 1)? / - [(2S, 4R) -1 - (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] - / V -pyridin-4-ylacetamide (G-33) Obtained? / - [(2SJ4R) -1- (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] - / V -pyridin-4-ylacetamide following the general procedure G, substituting 4-fluorobenzoyl chloride for 4-methoxybenzoyl chloride. The amine-aryl coupling was performed in a different manner to that described in procedure G. Therefore, (2S, 4R) -1- (4-methoxybenzoyl) -2-methyl-1, 2 was dissolved, 3,4-tetrahydroquinolin-4-amine (obtained from the hydrogenation step, 356 mg, 1.2 mmol, 1 equiv.) In dimethyl ether of ethylene glycol (4 ml) in a Schlenk tube. To this solution were sequentially added 4-bromopyridine hydrochloride (280 mg, 1.44 mmol, 1.2 equiv.), Cesium carbonate (940 mg, 2.88 mmol, 2.4 equiv.), Palladium acetate. (32 mg, 0.048 mmol, 0.04 equiv.) And 2- (dicyclohexylphosphino) -2,, 4 ', 6, -tri-i-propyl-1, 1'-b-phenyl (48 mg, 0.096 mmol, 0.08 equiv.). The reaction mixture was flushed with nitrogen and heated at 100 ° C in the Schlenk tube for 48 h. The reaction mixture was concentrated to leave a residue which was partitioned between water and ethyl acetate and extracted. The aqueous phase was separated and the organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give a brown oil. The crude product was purified by chromatography on silica gel (methylene chloride / methanol: gradient 99/1 to 90/10) to provide (2S, 4R) -1- (4-methoxybenzoyl) -2-methyl-? / -pyridin-4-yl-1, 2,3,4-tetrahydroquinolin-4-amine (125 mg, 28%). To a solution of (2S, 4R) -1- (4-methoxybenzoyl) -2-methiI- / V-pyridin-4-yl-1, 2,3,4-tetrahydroquinolin-4-amine (90 mg, 0.24 mmol, 1 equiv.) In methylene chloride (0.8 ml) was added diisopropylethylamine (84 μl, 0.48 mmol, 2 equiv.) Followed by acetyl chloride (340 μl, 4.80 mmol, 20 equiv.). The mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with sat. Sodium bicarbonate. aqueous and brine and dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (97/3 methylene chloride / methanol) to produce? / - [(2S, 4R) -1- (4-methoxybenzoyl) -2-methyl-1, 2,3 4-tetrahydroquinolin-4-yl] -? - pyridin-4-ylacetamide (60 mg, 61%). 1 H NMR (CDCl 3) d: 1, 20 (d, 3H), 2.20 (s, 3H), 2.30 (m, 1H), 3.75 (s, 3H), 4.80 (m, 1 H), 5.65 (m, 1 H), 6.60 (d, 1 H), 6.70 (d, 2H), 7.05 (t, 1 H), 7.10-7.20 ( m, 4H), 7.25-7.40 (m, 2H), 8.70 (d, 2H). MS m / z: 416 (M + 1). ? / - (4-chloro-2-methylphenyl) - / V - [(2S, 4R) -1- (4-methoxybenzoyl) -2-methyl-1,2,3,4-tetrahydroquinolin-4-yl] acetamide (G-34) Obtained / V- (4-chloro-2-methylphenyl) - / V - [(2S, 4R) -1 - (4-methoxybenzoyl) -2-methyl-1, 2,3,4- tetrahydroquinolin-4-yl] acetamide following the general procedure G, substituting 4-fluorobenzoyl chloride for 4-methoxybenzoyl chloride. The amine-aryl coupling was performed in a different manner to that described in procedure G. Therefore, (2S, 4R) -1- (4-methoxybenzoyl) -2-methyl-1,2 was dissolved, 3,4-tetrahydroquinolyl-4-amine (obtained from the hydrogenation step, 500 mg, 1.5 mmol, 1 equiv.) In ethylene glycol dimethyl ether (5 ml) in a Schlenk tube. To this solution were sequentially added 2-bromo-5-chlorotoluene (400 mg, 1.95 mmol, 1.3 equiv.), Cesium carbonate (684 mg, 2.10 mmol, 1.4 equiv.), Acetate of palladium (40 mg, 0.06 mmol, 0.04 equiv.) and 2- (dicyclohexylphosphino ^ '^'. ß'-tri-i-propyl-l .l'-biphenyl (60 mg, 0.12 mmol 0.08 equiv.) The reaction mixture was flushed with nitrogen and heated at 90 ° C in the Schlenk tube for 48 h.The reaction mixture was concentrated to leave a residue which was partitioned between water and ethyl acetate. The aqueous phase was separated and the organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to a black oil.The crude product was purified by chromatography on silica gel (chloride methylene / methanol: 99/1) to provide (2S, 4R) -? / - (4-chloro-2-methylphenyl) -1- (4-methoxybenzoyl) -2-methyl-1, 2,3,4- tetrahydroquinolin-4-amine (200 mg, 32%). To a solution of (2S, 4R) - / V- (4-chloro-2-methylphenyl) -1- (4-methyl) toxibenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-amino (140 mg, 0.33 mmol, 1 equiv.) in acetyl chloride (1.0 ml) was added diisopropylethylamine ( 58 μl, 0.33 mmol, 1 equiv.). The mixture was stirred at room temperature for 5 h. The mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with sat. Sodium bicarbonate. aqueous and brine and dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (99/1 methylene chloride / methanol) to yield? / - (4-chloro-2-methylphenyl) -? / - [(2S, 4R) -1- (4 -methoxybenzoyl) -2-methyl-1,2,3,4-tetrahydroquinolin-4-yl] acetamide (140 mg, 92%). 1 H NMR (CDCl 3) d: 1.10 (d, 3 H), 1.95 (s, 3 H), 2.15 (m, 1 H), 2.35 (s, 3 H), 3.70 (s, 3H), 4.75 (m, 1H), 5.60 (m, 1H), 6.50 (d, 1H), 6.65 (d, 2H), 6.95 (t, 1H), 7, 15-7.30 (m, 6H), 7.40 (s, 1H). MS m / z: 463 (M + 1). Table 7: Exemplary Compounds: Table 2: Names of the Compounds Exemplified in Table 1: G-1 4- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl -3,4-dihldroquinolin-1 (2H) -yl] carbonyl, phenyl) piperazine-1-ethyl carboxylate G-2? / -. { 3 - [(Glycolylamino) meth] I] phenyl} -? / - [(2SJ4R) -1- (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] acetamide G-3? / - (4-Chloro-2-fluorophen L) -? / - [(2S, 4f?) - 1- (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] acetamide G-4 4-. { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methylene-3,4-dihydroquinolin-1 (2 - /) - yl] carbonyl} benzamide G-5 4- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolyl-1 (2H) -yl] carbonyl.) -2-fIuorophenoxy) -2,2- methyl dimethylbutanoate G-6 N- (4-chlorophenyl) -? / - [(2S, 4R) -1 - (3,4-dihydro-2r / -1,4-benzoxazin-6-ylcarbonyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] acetamide G-7? / - (4-Chlorophenyl) -? / - ((2S , 4R) -2-methyl-1 - { 4- [3- (trifluoromethyl) -1H-pyrazol-1-yl] benzoyl} -1, 2,3,4-tetrahydroquinolyl- 4-yl) acetamide G-8? / - (4-Chlorophenyl) - / V-. { (2S, 4R) -2-methyl-1 - [(4-methyl-3,4-dihydro-2H-1, 4-benzoxazin-7-yl) carbonyl] -1, 2,3,4-tetra idroquinolin- 4-il} Acetamide G-9? / - (4-Chlorophene) -? / -. { (2S, 4R) -1 - [(2,2-difiuoro-1,3-benzodioxol-5-yl) carbonyl] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} acetamide G-10 5- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -l] carbonyl .}. phenyl) pentanamide G-11? / - (4-Chlorophenyl) -? / - [(2S, 4R) -1 - (2,3-dihydro-1-benzofuran-5-l-carbonyl) -2-methyl-1, 2,3,4-tetrahydroquinoline-4-yl] acetamide G-12? / - (4-Chlorophenyl) -? / - [(2S, 4R) -2-methyl-1- (pyridin-3-ylcarbonyl) -1, 2,3,4-tetrahydroquinolin-4-yl] acetamide G- 13? / - [(2S, 4R) -1 - (4-Methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] - / V-phenylacetamide G-14 Acid 4- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl} -2-fluorophenoxy) -2,2- dimethylbutanoic G-15? / - (4-Chlorophenyl) - / V-. { (2S, 4R) -1 - [(1-isopropyl-1 H -indazol-5-yl) carbonyl] -2-methyl-1, 2,3,4-tetrahydroquinoline-4-yl} acetamide G-16? / - (4-Chlorophenyl) -? / - [(2S, 4R) -1 - (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinoline-4-yl] - 2-methylpropanamide G-17? / - (4-Chlorophenyl) -? / -. { (2S, 4R) -1 - [(1,3-d.methyl-1H-thieno [2,3-c] p¡razol-5-yl) carbonyl] -2-methyl-1, 2,3,4 -tetrahydroquinolin-4-yl} acetamide G-18? / - (4-Chlorophenyl) -? / -. { (2S, 4R) -1 - [(1-isopropyl-1 H -pyrazol-4-yl) carbonyl] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} Acetamida G-19? / - 1H-lndol-4-1 -? / - [(2S, 4R) -1- (4-methoxybenzoyl) -2-methylene-1, 2,3,4- tetrahydroquinolin-4-yl] acetamide G-20 4 - [(4- {[[(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4- dihydroquinolin-1 (2H) -yl] carbonyl, phenyl) (methyl) amino] -2,2-dimethylbutanoic G-21? / - (4-chlorophenyl) -2-hydroxy -? / - [(2S, 4R ) -1- (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] acetamide G-22 6-. { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolyl-1 (2H) -yl] carbonyl} -2,3-dihydro-4H-1,4-benzoxazine-4-carboxylic acid ethyl ester G-23? / - [(2S, 4R) -6-Chloro-1- (4-methoxybenzoyl) -2-methyl-1 , 2,3,4-tetrahydroquinolin-4-yl] - / V- (4-chlorophenyl) acetamide G-24 Acid [(5- {[[2S, 4R) -4- [acetyl (4-chlorophenyl)] amino] -2-methyl-3,4-dihydroquinolin-1 (2 -) -yl] carbonyl}. isoxazoI-3-yl) oxy] acetic acid G-25? / - (4-Chlorophenyl) - / V- [(2S, 4R) -1 - (4-cyanobenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] acetamide G-26 4 - [(5- { [(2S, 4R) -4- [Acetyl (4-cyanophenyl) amino] -2-methylene-3,4-dihydroquinone-1 (2 - /) - 1] carbonyl.] Isoxazole-3-yl ) oxy] -2,2- ethyl dimethylbutanoate G-27 4- acid. { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl} benzoic G-28? / - (4-Chlorophen-I) -? / - [(2S, 4R) -1 - (4-methoxybenzoyl) -2-methyI-1, 2,3,4-tetrahydroquinoline-4 - I] cyclopropanecarboxamide G-29? / - [(2S, 4R) -1 - (4-Methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolyl-4-yl] -? / - [4 - (1 H-pyrrol-1 -yl) phenyl] acetamide G-30 4 - [(4- {[[2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3 , 4- dihydroquinolin-1 (2H) -yl] carbonyl, phenyl) (methyl) amino] -2,2-methyl dimethylbutanoate G-31 / V- [3- (Acetylamino) phenyl] -? / - [ (2S, 4R) -1- (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolyl-4-yl] acetamide G-32? / - [(2S, 4R) - 1- (4-Methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolyl-4-yl] -? / -. { 4 - [(methylsulfonyl) amino] phenyl} acetamide G-33 / V - [(2Sf4R) -1- (4-Methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] -? / - pyridin-4-ylacetamide G -34? / - (4-Chloro-2-methylphenyl) -? / - [(2S, 4R) -1- (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinoline-4 -il] acetamide Scheme 22 Yield 57% in 3 steps General Procedure H: W- (4-chlorophenyl) -W - ((2S, 4R) -2-methyl-1- { [6- (trifluoromethyl) pyridin-3-yl] carbonyl .} -1, 2,3,4-tetrahydroquinolin-4-yl) acetamide (H-83) To a solution of (2S, 4R) - (2-methyl-1, 2,3,4) benzyl ester -tetrahydro-quinoIin-4-yl) -carbamic acid (20.0 g, 0.067 mol) in methylene chloride (150 ml) at room temperature was added diisopropylethylamine (40.2 ml, 0.288 mol) at 0 ° C followed by addition of 3,5-bis (trifluoromethyl) benzylchloride (24.2 g, 15.8 ml, 0.087 mol). A catalytic amount of 4-dimethylaminopyridine was added and the reaction turned dark brown and was allowed to stir overnight at room temperature. The mixture was partitioned between sodium bicarbonate (saturated) and methylene chloride. The organic layer was separated and dried over sodium sulfate, filtered and concentrated to a brown solid. The crude material was taken up in 150 ml of methanol and stirred with 15 g of cesium carbonate for 20 min. To the solution was added 160 ml of methylene chloride and 150 ml of water and separated. The aqueous phase was extracted 2 more times with methylene chloride. The organic extracts were collected together and dried over sodium sulfate, filtered and concentrated to give a light orange solid (36 g, quant). It was dissolved (2S, 4R) -1- (3,5-bis (trifluoromethyl) benzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-ylcarbamate benzyl (36 g, 0.067 mol) in ethanol (135 ml). The vessel in which the resulting solution was was evacuated and refilled with argon. A catalytic amount of Palladium on Carbon (10%) was added. The vessel was again evacuated once more and at this time it was again filled with hydrogen and stirred in a Parr bottle at 68.94 kPa hydrogen. The reaction was allowed to stir until no starting material remained (1 day). The mixture was carefully filtered through a pad of Celite® and concentrated to yield the crude amine (26.6 g, 99%). It was dissolved (3,5-bis (trifluoromethyl) phenyl) ((2S, 4R) -4-amino-2-methyl-3,4-dihydroquinolin-1 (2H) -yl) methanone (26.6 g, 0.066 mol) in 1.0 I of dry methylene chloride. To the solution were also added 4-chlorophenylboronic acid (20.7 g, 0.132 mol, 2 equiv.), Triethylamine (71.2 ml, 0.496 mol, 7.5 equiv.) And copper (II) acetate (24). g, 0.132 mol, 2 equiv.). Finally, 20 g of molecular sieves were added. The heterogeneous green mixture was stirred open in air for 1 h and 2 more equivalents of 4-chlorophenylboronic acid (20.7 g, 0.132 mol) were added. The mixture was allowed to stir at room temperature overnight and then filtered through Celite®. The filtrate was diluted with ethyl acetate to precipitate the copper salts and the mixture was filtered a second time through Celite® to give a brown solution which was concentrated. The residue was purified by flash chromatography (95% methylene chloride / 5% ethyl acetate) to yield 19.54 g of the product in 57% yield as a white solid. A solution of (3,5-bis (trifluoromethyl) phenyl) ((2S, 4R) -4- (4-chlorophenylamino) -2-methyl-3,4-dihydroquinoline-1 (2H) -yl) methanone (19, 44 g, 0.037 mol) in acetyl chloride (5 ml) was cooled to 0 ° C and triethylamine (6.59 ml, 0.037 mol) was added dropwise during -30 min, during which time a precipitate formed. An additional 250 ml of methylene chloride was added to completely dissolve all the precipitate. The reaction was allowed to stir overnight at room temperature. The mixture was concentrated under reduced pressure, partitioned between ethyl acetate and 1 N sodium hydroxide while cooling to 0 ° C. The aqueous phase was extracted 3 times with ethyl acetate, washed with sat. Sodium bicarbonate. aqueous and brine and dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (gradient of 25/75 hexanes / ethyl acetate) to yield / V - ((2S, 4R) -1- (3,5-bis (trifluoromethyl) benzoyl) -2-metl-1, 2,3,4-tetrahydroquinoline-4-yl) -A- (4-chloropheni) pure acetamide (H-31) (18.2 g, 86%). 1 H NMR (CDCl 3) d: 1, 20 (d, 3 H), 1, 10-1, 20 (m, 1 H), 2.03 (s, 3 H), 2.24-2.40 (m, 1 H), 4.72-4.86 (m, 1H), 5.40-5.70 (m, 1H), 6.41 (d, 1H), 6.94 (t, 1H), 7, 18-7.28 (m, 4H), 7.37 (t, 2H), 7.59 (s, 2H), 7.76 (s, 1 H). MS m / z: 555 (M + 1). To a solution of? / - ((2S, 4R) -1- (3,5-bis (trifluoromethyl) benzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl) -? / - (4-chlorophenyl) acetamide (5.5 g, 9.9 mmol) in ethanol (60 ml) and water (10 ml) was added potassium hydroxide (3.00 g, 53.5 mmol). The mixture was heated to 70 ° C. After 1 hour, a further portion of potassium hydroxide (3.00 g, 53.5 mmol) was added and the reaction was stirred for a further 30 min. The mixture was partitioned between ethyl acetate and sodium bicarbonate (sat.c.). The organic layer was separated, washed twice with brine, dried over sodium sulfate, filtered and concentrated. The crude material was subjected to flash chromatography (gradient 2/1 hexanes / ethyl acetate), resulting in? / - (4-chlorophenii) -? / - ((2S, 4R) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl) acetamide in the form of a white solid (2.85 g, 91%). 1 H NMR (CDCl 3) d: 1, 10 (d, 3 H), 1, 30 (m, 1 H), 1.80 (m, 1 H), 1, 90 (s, 3 H), 3.50 (m, 1 H), 3.60 (m, 1 H), 6.30 (broad s, 1 H), 6.45 (d, 1 H), 6.70 (t, 1 H), 6.90 (d) , 2H), 7.00 (t, 1 H), 7.15-7.25 (m, 3H). MS m / z: 315 (M + 1). To a solution of? / - (4-chlorophenyl) -V - ((2S, 4R) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl) acetamide (104 mg, 0.33 mmol, 1 equiv.) In methylene chloride (2.0 ml) at room temperature was added diisopropylethylamine (86 μl, 0.49 mmol, 1.50 equiv.) Followed by 6-trifluoromethyl-nicotinyl chloride (104 mg, 0.49 mmol, 1.50 equiv.). The reaction was stirred overnight at room temperature. The mixture was concentrated, then poured into water and extracted with ethyl acetate. The extracts were washed with 1 M NaOH (aq) and brine, dried over magnesium sulfate, filtered, dried and concentrated. The crude residue was purified by chromatography on silica gel (1: 1 ethyl acetate / hexane) to yield the α / - (4-chlorophenyl) - / V - ((2S, 4R) -2-methyl-1- { [6- (trifluoromethyl) pyridin-3-yl] carbonyl} - 1,2,3,4-tetrahydroquinolin-4-yl) acetamide pure (140 mg, 87%). 1 H NMR (CDCl 3) d: 1.16-1.18 (m, 1H), 1.17 (d, 3H), 1.99 (s, 3H), 2.20-2.28 (m, 1H), 4.77 (sextuplet, 1H), 5.50 (s a, 1H), 6.44 (d, 1H), 6.93 (t, 1H), 7.16-7.22 (m, 3H), 7.45-7.30 (m, 5H), 8.65 (s, 1H). MSm / z = 465 (M + 1).
Scheme 23 General Procedure I: (2S, 4?) -? Í- (4-Chloro-phenyl) -W- [1- (4-hydroxy-benzoyl) -2-methyl-1) 2J3,4-tetrahydro-quinolin-4 -yl] -acetamide (13) Was prepared (2S, 4R) -? - (4-Chloro-phenyl) -? - [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinoIin-4-yl] -acetamide following the general procedure G, substituting 4-fluorobenzoyl chloride for 4-methoxybenzoyl chloride. It was dissolved (2S, 4R) -? / - (4-chloro-phenyl) - / V- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4 -yl] -acetamide in dichloromethane and a solution of BBr3 (1.0 M in dichloromethane, 10 ml) was added thereto; the reaction was allowed to stir at room temperature until no starting material remained. The reaction was washed carefully with sat. NaHCO 3. and brine. The organic extracts were dried over MgSO 4, filtered and concentrated. The residue was purified by flash chromatography Biotage using 100% EtOAc to give (2S, 4R) - / V- (4-chloro-phenyl) -A / - [1- (4-hydroxy-benzoyl) -2-methyl -1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide. Ethyl ester of (2S, 4R) - (4-. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1- carbonyl.}. -phenoxy) -acetic (14) was dissolved (2SJ4R) -? / - (4-chloro-phenyl) -? / - [1- (4-hydroxy-benzoyl) -2-methyl-1, 2 , 3,4-tetrahydro-quinolin-4-yl] -acetamide (0.147 g) in DMF at room temperature and K2CO3 was added. Ethyl 4-bromoacetate (0.065 g) was added and the reaction was allowed to warm to 80 ° C overnight. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO, filtered and concentrated. The crude residue was purified by chromatography on silica gel (gradient of 80/20 hexanes / ethyl acetate-50/50 hexanes ethyl acetate) to yield the product in 130 mg, 73%. (2S, 4?) - 3- (4-. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl} .-phenylamino) -propionamide (H-1) was prepared (2S, 4R) -3- (4-. {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4 -dihydro-2H-quinoline-1-carbonyl.}. -phenylamino) -propionamide from (2S, 4R) -3- (4-. {4- [acetyl- (4-chloro-phenyl) -amino] ] -2-methyl-3,4-dihydro-2H-quinol-1-carbonyl.] - phenylamino) -propionic acid. The acid (0.060 g, 0.118 mmol) was dissolved in DMF (1.5 mL) at room temperature and HOBt (0.024 g, 0.177 mmol), HATU (0.068 g, 0.177 mol) and diisopropylethylamine (0.082 mL, 0.472) were added thereto. mmol) followed by ammonium chloride (0.014 g, 0.236 mmol) and stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate, washed with 1 N NaOH, 1 N HCl and brine. The organic extracts were dried over MgSO 4, filtered and concentrated. The crude residue was purified by purification by HPLC. 1 H NMR (CDCl 3) d: 1, 10 (d, 3 H), 1, 23 (m, 1 H), 1.64 (a, 1 H), 2.01 (s, 3 H), 2.27 (m , 1 H), 2.44 (t, 2H), 3.37 (t, 2H), 4.69 (m, 1 H), 5.40 (a, 1H), 5.61 (s, 1 H ), 5.80 (a, 1 H), 6.31 (d, 2H), 6.59 (d, 1 H), 6.94 (t, 1 H), 7.02 (d, 2H), 7.10-7.23 (m, 4H), 7.36 (d, 2H). MS m / z: 505.3 (M + 1). 4- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolyl-1 (2H) -Hlcarbonyl}. 2-fluorophenoxy) -2,2-dimethylbutanoic acid (H-2) To the solution of 4- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl- Methyl 3,4-dihydroquinolin-1 (2 -) -yl] carbonyl} -2-fIuorophenoxy) -2,2-dimethylbutanoate (176 mg, 0.30 mmol) in MeOH / THF (1 ml / 1 ml ) excess LiOH (1 N aqueous solution) was added. The reaction mixture was stirred at rt overnight. The reaction was stopped by the addition of 6N HCl to pH 2. The mixture was concentrated under reduced pressure to remove MeOH and THF. DCM (30 ml) was added. The reaction mixture was washed with brine (30 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel (hexanes-ethyl acetate system) to yield a slightly yellow solid product (120 mg, 70%). 1 H NMR (CDCl 3, 300 MHz) d: 1, 11-1, 13 (d, 3 H), 1.25 (s, 6 H), 2.02-2.08 (m, 5 H), 2.22-2 , 40 (m, 2H), 3.99-4.04 (t, 2H), 4.71-4.76 (c, 1H), 5.46 (a, 1H), 6.51-6.75 (m, 3H), 6.92-7.06 (m, 2H), 7.16-7.38 (m, 5 H). MS m / z: 567 (M + 1). Ethyl ester of (2S, 4R) - (4-. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl ester}-phenoxy) -fluoroacetic acid (H-3) It was dissolved (2S, 4R) - / V- (4-chloro-phenyl) -? / - [1- (4-hydroxy-benzoyl) -2-methyl -1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide (202 mg, 0.46 mmol) in DMF (2 mL) at room temperature. Cs 2 CO 3 (760 mg, 2.33 mmol) was added followed by bromo-fluoroacetic acid ethyl ester (0.070 ml, 0.583 mmol) and the reaction was allowed to stir overnight. The mixture was partitioned between methylene chloride and water; the organic layer was dried over Na2SO, filtered and concentrated. The crude residue was purified by chromatography on silica gel (2/1 hexanes / ethyl acetate) to produce the product. 1 H NMR (CDCl 3) d: 1, 1 (d, 3 H), 1, 2 (m, 1 H), 1.3 (t, 3 H), 2.0 (s, 3 H), 2.3 (m, 1 H), 4.3 (c, 2H), 4.8 (m, 1 H), 5.6 (sa, 1 H), 5.9 (d, 1 H), 6.5 (d, 1 H), 6.9 (m, 3H), 7.2 (m, 6H), 7.4 (d, 2H). MS m / z: 539 (M + 1). (2S, 4R) -2- [4- (4- { 4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3J4-dihydro-2H-quinoline-1 -carbonyl.} .-phenyl) -piperazin-1-yl] -acetamide (H-4) Obtained (2S, 4R) -2- [4- (4-. {4- [acetyl- (4-chloro-phenyl) - amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl.} - phenyl) -piperazin-1-yl] -acetamide from (2S, 4R) - [4- (4- {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl} -phenyl) -piperazin-1- il] -acetic. The acid (0.120 g, 0.21 mmol) was dissolved in DMF (2 ml) at room temperature and HOBt (0.043 g, 0.32 mmol), HATU (0.122 g, 0.32 mol) and diisopropylethylamine ( 0.15 ml, 0.64 mmol) followed by ammonium chloride (0.023 g, 0.42 mmol) and stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate, washed with 1 N NaOH, 1 N HCl and brine. The organic extracts were dried over MgSO 4, filtered and concentrated. The crude residue was purified by purification by HPLC. 1 H NMR (CDCl 3) d: 1, 10 (d, 3 H), 1, 20 (m, 1 H), 2.00 (s, 3 H), 2.24 (m, 1 H), 3.04 (t , 4H), 3.50 (m, 6H), 4.70 (m, 1H), 5.40 (a, 1H), 5.56 (sa, 1H), 5.80 (a, 1H), 6 , 51 (d, 1H), 6.63 (d, 2H), 6.89 (t, 1 H), 7.07-7.25 (m, 6H), 7.35 (d, 2H). MS m / z: 560 (M + 1) 4- (4- { [(2S, 4R) -4 - [(4-chlorophenyl) (isobutyryl) amino] -2-methyl-3,4-dihydroquinoline -1 (2H) -yl] carbonyl.}. Phenoxy) -2,2-dimethylbutanoic (H-5) 4- (4 { [(2S, 4R) -4 - [(4-chlorophenyl) was dissolved (isobutyryl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -iI] carbonyl, phenoxy) -2,2-dimethylbutanoate methyl in methanol / tetrahydrofuran / water (2/1/1) and then sodium hydroxide (3 equivalents) was added and the reaction mixture was stirred at 40 ° C overnight. The mixture was concentrated, the residue was acidified with a 1 N aqueous solution of HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give 4- (4 { [(2S, 4R) -4 - [(4-Chlorophene) ( sobutyryl) amino] -2-methyl-3,4-dihydroquinolin-1 (2 - /) - I] carbonyl] phenoxy) -2,2-dimethylbutanoic acid. 1 H NMR (CDCl 3) d: 1, 11-1, 21 (m, 10 H), 1.25 (s, 6 H), 2.03 (t, 2 H), 2.21-2.29 (m, 1 H ), 2.61 (sp, 1 H), 3.95 (t, 2H), 4.69-4.76 (m, 1H), 5.60 (sa, 1H), 6.51 (d, 1) H), 6.62 (d, 2H), 6.91 (t, 1 H), 7.11-7.43 (m, 8H). MS m / z: 577 (M + 1). Acid { [3- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl} phenoxy ) propyl] amino} acetic acid (H-6) Acid was prepared. { [3- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2 - /) - yl] carbonyl. phenoxy) propyl] amino} acetic acid from (2S, 4R) -N-. { 1 - [4- (3-Amino-propoxy) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} - / V- (4-Chloro-phenyl) -acetamide. It was dissolved (2S, 4R) -? / -. { 1- [4- (3-amino-propoxy) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -? / - (4-Chloro-phenyl) -acetamide (0.032 g, 0.065 mmol) in dimethylformamide and ethyl bromoisobutyrate (0.05 mL, 0.26 mmol) and potassium carbonate (0.018 g, 0.13 g) were added. mmol). The reaction was heated at 50 ° C for 17 h. The reaction was concentrated and purified using 50% ethyl acetate / hexane to 100% ethyl acetate to give 0.007 g, 12% yield of ethyl ester of the acid. { [3- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2 -) -yl] carbonyl}. phenoxy) propyl] amino} acetic. 1 H NMR (CDCl 3) d: 1, 13 (d, 3 H), 1, 17 (t, 3 H), 1, 23 (m, 1 H), 1.55 (s, 6 H), 2.02 (s, 3H), 2.06 -2.12 (m, 1 H), 2.28 (m, 1 H), 3.63 (c, 2H), 3.70-3.77 (m, 2H), 3 , 91 -3.95 (m, 1 H), 4.13 (c, 2H), 4.74 (sextuplet, 1 H), 5.58 (sa, 1 H), 6.49-6.68 ( m, 3H), 6.92 (t, 1 H), 7.05-7.28 (m, 6H), 7.37 (d, 1 H). MS m / z = 606.1 (M + 1). Acid ethyl ester was hydrolysed. { [3- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2 - /) - yl] carbonyl} phenoxy) propyl] amino} acetic acid in the acid by dissolving in tetrahydrofuran and ethanol and sodium hydroxide (1N) was added thereto. The mixture was stirred at room temperature overnight. The mixture was cooled to rt and acidified to form a white precipitate. The solid was filtered to give acid. { [3- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolyl-1 (2H) -yl] carbonyl .}. phenoxy) propyl] amino} acetic 0.005 g, 75% yield. MS m / z: 578.3 (M + 1). W - [(2S, 4R) -1- (4-Ierc-butylbenzoyl) -2-methyl-1,2,3,4-tetrahydroquinolin-4-yl] -W- (4-chlorophenyl) acetamide (H-7 ) It was synthesized / V - [(2S, 4R) -1- (4-Ierc-butylbenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] -? / - (4-chlorophenyl) acetamide according to general procedure H substituting 6-trifluoromethyl-nicotinyl chloride for 4-urea-butylbenzoyl chloride. The remainder of the procedure was followed as indicated in general procedure H to produce A / - [(2S, 4R) -1- (4-urea-butylbenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinoline- 4-yl] -? / - (4-chlorophenol) acetamide. 1 H NMR (CDCl 3) d: 1, 13-1, 22 (m, 1 H), 1, 14 (d, 3 H), 1, 22 (s, 9 H), 2.03 (s, 3 H), 2, 24-2.35 (m, 1 H), 4.72-4.80 (m, 1 H), 5.61 (sa, 1H), 6.52 (d, 1H), 6.89 (t, 1H), 7.10-7.29 (m, 8H), 7.37 (d, 2H). MS m / z: 475 (M + 1). (2S, 4R) -W- (4-Chloro-phenyl) -W-. { 1- [4- (3-hydroxy-3-methyl-butoxy) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -acetamide (H-8) (2S, 4R) -? / - (4-chloro-phenyl) -? / - [1- (4-hydroxy-benzoyl) -2-methyl-1, 2,3 was dissolved 4-tetrahydro-quinolin-4-yl] -acetamide in DMF (5 ml) at room temperature. K2CO3 was added followed by 4-bromo-2-methyl-butan-2-ol and the reaction was allowed to stir at 90 ° C overnight. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO 4, filtered and concentrated. The crude residue was purified by HPLC to produce the product. 4-Bromo-2-methyl-butan-2-ol was prepared from 3-bromo-propionic acid ethyl ester. 3-Bromo-propionic acid ethyl ester (1.0 g, 5.5 mmol) was dissolved in 10 ml of ether and 3.7 ml of methylmagnesium bromide (3.0 M in ether) was added at 0 °. C. The reaction was stirred at 0 ° C until no starting material remained. The reaction was quenched with a saturated solution of ammonium chloride and 3 x extracted with ether. The organic extracts were collected together and dried over MgSO 4, filtered and concentrated to give 4-bromo-2-methyl-butan-2-ol. 1 H NMR (CDCl 3) d: 1, 12 (d, 3 H), 1, 24 (s + m, 7 H), 1, 90 (t, 2 H), 2.01 (s, 3 H), 2.22 (m , 2H), 4.07 (t, 2H), 4.72 (m, 1 H), 5.60 (sa, 1H), 6.50 (d, 1H), 6.65 (d, 2H), 6.90 (t, 1 H), 7.10-7.20 (m, 5H), 7.25 (t, 1 H), 7.35 (d, 2H). MS m / z: 521 (M + 1). W- (4-chlorophenyl) -W - [(2S, 4 /?) - 1- (4-iodobenzoyl) -2-methyl-1,2J3,4-tetrahydroquinoin-4-yl] acetamide (H-9) purification of the crude material from the last step of the synthesis of acid 5- (4- { (2S, 4R) -4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4 -dihydro-2H-quinoline-1-carbonyl.} - phenyl) -2,2-dimethyl-pentanoic also left to isolate? / - (4-chlorophenyl) - / V- [(2S, 4R) -1 - (4 -iodobenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] acetamide in the form of a by-product of the synthesis (45 mg). 1 H NMR (MeOD) d: 1, 15 (d, 3 H), 2.05 (s, 3 H), 2.45 (m, 1 H), 4.75 (m, 1 H), 5.55 (m , 1 H), 6.55 (d, 1 H), 6.95 (t, 1 H), 7.25 (m, 5H), 7.30-7.55 (m, 5H). MS m / z: 545 (M + 1). (2S, 4R) -? -. { 1- [4- (3-Acetylamino-propoxy) -benzoyl] -2-methyl-1,253,4-tetrahydro-quinolin-4-yl} -W- (4-chloro-phenyl) -acetamide (H-10) It was dissolved (2S, 4R) -? / -. { 1- [4- (3-amino-propoxy) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -? / - (4-chloro-phenyl) -acetamide (99 mg, 0.202 mmol) in methylene chloride (2 ml) and triethylamine (0.056 ml, 0.404 mmol) and cooled to -40 ° C. Acetyl chloride (15 drops by pipette) was added and the mixture was heated at 0 ° C for 30 minutes. The mixture was partitioned between methylene chloride and water; The methylene chloride layer was dried over MgSO 4, filtered and concentrated. The crude residue was purified by chromatography on silica gel (gradient of 1/1 hexanes / ethyl acetate to ethyl acetate) to produce the product. 1 H NMR (CDCl 3) d: 1.1 (s, 3 H), 1, 2 (m, 1 H), 1.9 (s, 3 H), 2.0 (m, 2 H), 2.0 (s, 3H), 2.3 (m, 1H), 3.4 (c, 2H), 4.0 (t, 2H), 4.7 (m, 1H), 5.6 (sa, 1H), 5, 7 (br s, 1H), 6.5 (d, 1 H), 6.6 (d, 2H), 6.9 (t, 1H), 7.2 (m, 6H), 7.4 (d, 2H). MS m / z: 534 (M + 1). (2S, 4R) -W- (4-Chloro-phenyl) -? / -. { 2-methyl-1- [4- (4J4,4-trifluoro-3-hydroxy-3-trifluoromethyl-butoxy) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -acetamide (H-11) It was dissolved (2S, 4R) - / V- (4-chloro-phenyl) - / V- [1- (4-hydroxy-benzoyl) -2-methyl-1, 2,3, 4-tetrahydro-quinolin-4-yl] -acetamide in DMF (5 ml) at room temperature. K2CO3 was added followed by 4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-butyl ester of toluene-4-sulfonic acid and the reaction was allowed to stir at 90 ° C overnight. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO 4, filtered and concentrated. The crude residue was purified by HPLC to produce the product. 4,4,4-Trifluoro-3-hydroxy-3-trifluoromethyl-butyl ester of toluene-4-sulfonic acid was prepared from 4,4,4-trifluoro-3-hydroxy-3-acid. -trifluoromethyl-butyric. 4,4,4-Trifluoro-3-hydroxy-3-trifluoromethyl-butyric acid (1.74 g, 7.0 mmol) was dissolved in THF (2 ml) at 0 ° C and BH3SMe3 was added dropwise ( 2.6 ml, 26 mmol) (Ref: Tetrahedron, 2002, 9839). The reaction was allowed to warm to room temperature and was stirred for 16 h. The reaction was quenched with methanol and the solvent was removed to give crude 4,4,4-trifluoro-3-trifluoromethyl-butane-1,3-diol. The alcohol was converted to tosylate by the addition of 4,4,4-trifluoro-3-trifluoromethyl-butane-1,3-diol dissolved in pyridine (2 ml) to tosyl chloride (1.39 ml) in 2 ml of CH2Cl2 and a catalytic amount of DMAP. The reaction was stirred at room temperature for 2 h and was stopped. 1 H NMR (CDCl 3) d: 1.12 (m, 4 H), 2.01 (s, 3 H), 2.24 (m, 1 H), 2.25 (t, 2 H), 3.94 (t, 2H), 4.70 (m, 1 H), 5.53 (sa, 2H), 6.48 (d, 1H), 6.61 (d, 2H), 6.93 (t, 1 H), 7.09-7.27 (m, 6H), 7.37 (d, 2H). MS m / z: 629 (M + 1). Amide of (2S, 4R) -4- (4- {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl) .}.-phenoxy) -cyclohexanecarboxylic acid (H-12) (2S, 4R) -4- (4-. {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl- 3,4-dihydro-2H-quinoline-1-carbonyl.]. Phenoxy) -cyclohexanecarboxylic acid (0.070 g, 0.125 mmol) in the amide was dissolved in THF (1 ml) at room temperature. HOBt (0.025 g), EDCI (0.035 g) and ammonium chloride (0.014 g, 0.25 mmol) were added together with 2 drops of DMF and stirred at room temperature for 11 h. The reaction was diluted with ethyl acetate and washed with 1 N NaOH, 1 N HCl and brine. The organic extracts were dried over MgSO, filtered and concentrated. The crude residue was purified by chromatography on silica gel (50% ethyl acetate / 50% methanol) to yield the product as a white powder in 71% yield. 1 H NMR (CDCl 3) d: 1, 13 (d, 4 H), 1, 19-1, 60 (m, 7 H), 2.01 (s, 4 H), 2.20-2.39 (m, 2 H) , 4.72 (sextuplet, 1 H), 5.60 (sa, 1 H), 6.54 (d, 1 H), 6.63 (d, 2H), 6.91 (t, 1 H) 7 , 11-7.38 (m, 8H).
MS m / z: 560 (M + 1). (2S, 4R) -W- (4-Chloro-phenyl) - / V- (2-methyl-1- { 4- [3- (1H-tetrazol-5-yl) -propoxy] -benzoyl. -1, 2,3,4-tetrahydro-quinolin-4-yl) -acetamide (H-13) Nitrite was prepared from (2S, 4R) -? / - (4-chloro-phenyl) -? / -. { 1- [4- (3-cyano-propoxy) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} The acetone was dissolved in toluene, sodium azide and triethylammonium hydrochloride were added and the mixture was heated at 80 ° C overnight. The reaction was cooled to room temperature and water was added thereto, followed by hydrochloric acid (1 N) until it became acidic. The aqueous solution was extracted three times with dichloromethane. The combined extracts were dried over magnesium sulfate, filtered, dried and concentrated. The crude product was triturated with ethyl ether / hexanes to yield a white solid in 63% yield. 1 H NMR (CDCl 3) d: 1, 02 (d, 3 H), 1, 19 (m, 1 H), 1.89 (s, 3 H), 1, 96 (m, 2 H), 2.11 (m, H), 2.79 (m, 2H), 3.63 (m, 2H), 4.59 (sextuplet, 1H), 5.42 (sa, 1H), 6.35 (m, 3H), 6, 77 (t, 1 H), 6.91-7.08 (m, 7H), 7.22 (d, 1 H). MS m / z: 545 (M + 1). 4- (4- { [(2S, 4R) -4 - [(4-Chlorophenyl) (cyclopropylcarbonyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2/7) -yl] carbonyl} phenoxy) -2,2-dimethylbutanoate methyl (H-14) To a solution of? / - (4-chlorophenyl) - / V - [(2S, 4R) -1- (4-methoxybenzoyl) -2- methyl-1, 2,3,4-tetrahydroquinolin-4-yl] cyclopropanecarboxamide (200 mg, 0.42 mmol, 1 equiv.) in methylene chloride (0.3 ml) was added a 1 M solution of tribromide boron in methylene chloride (1.2 ml, 1.26 mmol, 3 equiv.). The reaction mixture was stirred at room temperature for 4 h and then the reaction was quenched with methanol and concentrated. The residue was partitioned between water and ethyl acetate and extracted. The aqueous phase was separated and the organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give N- (4-chlorophenyl) -A / - [(2S, 4R) -1- (4-hydroxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinoline- 4-ylcyclopropanecarboxamide in the form of a beige powder (190 mg, 98%). 4- (4- { [(2S, 4R) -4 - [(4-chlorophenol) (cyclopropycarbonyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] was obtained. methyl carbonyl, phenoxy) -2,2-dimethylbutanoate from? / - (4-chlorophenyl) -? / - [(2S, 4R) -1 - (4-hydroxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] -cyclopropanecarboxamide following general procedure I, substituting ethyl 4-bromoacetate for methyl 4-bromo-2,2-dimethylbutanoate to produce 4- (4- { [ (2S, 4R) -4 - [(4-chlorophenyl) (cyclopropylcarbonyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl, phenoxy) -2,2-dimethylbutanoate methyl. 1 H NMR (CDCl 3) d: 0.75 (m, 2 H), 1, 10 (m, 2 H), 1, 20 (d, 3 H), 1, 25 (s, 6 H), 1.45 (m, 1 H), 2.05 (t, 2H), 2.30 (m, 1 H), 3.65 (s, 3H), 3.95 (t, 2H), 4.75 (m, 1 H), 5.60 (m, 1 H), 6.50 (d, 1H), 6.60 (d, 2H), 6.90 (t, 1 H), 7.10-7.45 (m, 8H) . MS m / z: 589 (M + 1). 5- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-354-dihydroquinolin-1 (2W) -yl] carbonyl} -2-fluorophenyl Methyl) -2,2-dimethylpentanoate (H-15) 5- (4 { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4 was prepared methyl-dihydroquinolin-1 (2 / -) -yl] carbonyl} -2-fluorophenyl) -2,2-dimethylpentanoate following general procedure B, substituting 6-trifluoromethyl-nicotinyl chloride for 5- [4- (cyclocarbonyl)] -2-fluorophenyl] -2,2-dimethylpentanoate methyl. (Methyl 5- [4- (cyclocarbonyl) -2-fluorophenyl] -2,2-dimethylpentanoate was prepared in five steps from 4-bromo-3-fluorobenzoic acid to a solution of 3-bromo-3-acid. fluorobenzoic in toluene / methanol a 2 M solution of trimethylsilyldiazomethane was added dropwise until a slightly yellow coloration persisted indicating that the reaction was complete The reaction mixture was concentrated to give methyl 3-bromo-3-fluorobenzoate To a solution of methyl 3-bromo-3-fluorobenzoate in dimethylformamide were added sequentially palladium acetate, triphenylphosphine, tetrabutylammonium chloride, potassium acetate and methyl 2,2-dimethylpent-4-enoate. heated under microwave irradiation at 130 ° C for 10 min to give methyl 3-fluoro-4 - [(1E) -5-methoxy-4,4-dimethyl-5-oxopent-1-en-1-yl] benzoate. Hydrogenation of this diester gave methyl 3-fluoro-4- (5-methoxy-4,4-dimethyl-5-oxopentyl) benzoate whose benzoic ester was hydrolyzed selectively using lithium hydroxide to give 3-fluoro-4- (5-methoxy-4,4-dimethyl-5-oxopentyl) benzoic acid. Subsequent treatment of this carboxylic acid with oxalyl chloride and catalytic DMF produced methyl 5- [4- (chlorocarbonyl) -2-fluorophenyl] -2,2-dimethylpentanoate in a decent yield). The rest of the procedures were followed as indicated in general procedure H to produce 5- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3, Methyl 4-dihydroquinolin-1 (2 - /) - yl] carbonyl] -2- fluorophenyl) -2,2-dimethylpentanoate. H NMR (CDCl 3) d: 1, 15 (d, 3 H), 1.45 (m, 4 H), 2.05 (s, 3 H), 2.30 (m, 1 H), 2.55 (m, 2 H) ), 3.65 (s, 3H), 4.80 (m, 1 H), 5.60 (m, 1 H), 6.55 (d, 1H), 6.75 (d, 1 H), 6.90-7.05 (m, 3H), 7.15-7.25 (m, 3H), 7.30-7.40 (m, 3H). MS m / z: 579 (M + 1). Acid (2S, 4R) -? F -3- (4-. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1 - carbonyl.). -phenoxy) -2,2-dimethyl-propionic (H-16) (2S, 4R) -? / - (4-Chloro-phenyl) -? / - [1- (4-hydroxy) was dissolved benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide (0.32 g, 0.74 mmol) in 10 ml of DMF at room temperature and K2C03 ( 0.51 g, 3.7 mmol). 3-Chloro-2,2-dimethyl-propionic acid ethyl ester (0.25 g, 1.52 mmol) was added and the reaction allowed to warm to 90 ° C for 6 days. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO 4, filtered and concentrated. The crude residue was purified by chromatography on silica gel (60% EtOAc / 40% Hexane) to yield the ethyl ester of the acid (2S), 4R) -3- (4- { 4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl} -phenoxy ) -2,2-dimethyl-propionic (0.13 g, 32%). The ester was hydrolyzed in the acid by dissolving in 8 ml of tetrahydrofuran / methanol (1/1) and potassium hydroxide (0.052 g in 2.5 ml of water) was added thereto. The mixture was heated at 40 ° C for 3 hours. The mixture was cooled to rt and acidified to form a white precipitate. The solid was filtered to give the product (0.098 g, 79%). 1 H NMR (CDCl 3) d: 1, 13 (d, 3 H), 1, 15 (t, 1 H), 1, 31 (s, 6 H), 2.03 (s, 3 H), 2.27 (m, 1 H), 3.88 (c, 2H), 4.72 (sextuplet, 1H), 5.58 (sa, 1H), 6.52 (d, 1H), 6.69 (d, 2H), 6 , 83 (t, 2H), 7.08-7.35 (m, 6H), 7.38 (d, 2H).
MS m / z: 535 (M + 1) (2S, 4R) -3- (4-4 4 - [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro} -2H-quinoline-1 -carbonyl.}. -phenoxy) -propane-1-sulfonic acid (H-17) (2S, 4R) - / V- (4-cyclo-phenyl) -? / - [1 - (4-hydroxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide (207 mg, 0.481 mmol) in DMF (5 ml) at room temperature. NaH (58 mg, 2.40 mmol) was added followed by 3-chloro-propane-1-sulfonic acid (sodium salt, 135 mg, 0.60 mmol) and the reaction was allowed to stir overnight. The mixture was partitioned between methylene chloride and HCl (1.0 N / water), then extracted three times with methylene chloride, dried over MgSO4, filtered and concentrated. The crude residue was purified by preparative HPLC to produce the product. 1 H NMR (CDCl 3) d: 1.1 (d, 3 H), 1.1 (m, 1 H), 2.0 (s, 3 H), 2.2 (m, 3 H), 3.2 (t, 2 H) ), 3.9 (t, 2H), 4.8 (d, 1 H), 5.6 (sa, 1 H), 6.5 (d, 1 H), 6.6 (d, 2H), 6.9 (t, 1 H), 7.2 (m, 6H), 7.4 (d, 2H), 10.6 (br s, 1 H). MS m / z: 557 (M + 1). 4- (5- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl} -2 -fluorophenoxy) -2,2-dimethylbutanoate methyl (H-18) was dissolved / V- (4-chlorophenyl) - / V - [(2S, 4R) -1- (4-fluoro-3-hydroxybenzoyl) -2 methyl-1, 2,3,4-tetrahydroquinolin-4-yl] acetamide (476 mg, 1.05 mmol) in DMF at room temperature and Cs2CO3 (854 mg, 2.63 mmol) was added thereto. Methyl 4-bromo-2,2-dimethylbutanoate (702 mg, 1.58 mmol) was added and the reaction was stirred at rt overnight. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO, filtered and concentrated. The crude residue was purified by chromatography on silica gel (hexanes-ethyl acetate system) to yield 4- (5- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2 methyl-3,4-dihydroquinolin-1 (2 -) -yl] carbonyl} -2-fluorophenoxy) -2,2-dimethylbutanoate (286 mg, 52%).
H NMR (CDCl 3, 300 MHz) d: 1, 11-1, 14 (d, 3H), 1, 18-1, 19 (d, 6H), 2.00 (s, 3H), 2, 22-2 , 27 (m, 1 H), 3.64 (s, 3H), 3.88-3.95 (m, 1 H), 4.69-4.77 (m, 1H), 5.57 (a , 1 H), 6.48-6.50 (d, 1 H), 6.72-6.84 (m, 3 H), 6.91-6.96 (m, 1 H), 7.12 -7.37 (m, 6H). MS m / z: 581 (M + 1). ? / - (4-Chlorophenyl) -W - [(2S, 4R) -1 - (4-fluoro-3-hydroxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] acetamide ( H-19) was dissolved? / - [(2S, 4R) -1 - (3 { [Ferc-butyl (dimethyl) silyl] oxy] -4- fluorobenzoyl) -2-methyl-1, 2 , 3,4-tetrahydroquinolin-4-yl] -? / - (4-chlorophenol) acetamide (543 mg, 0.95 mmol) in dichloromethane and a solution of TBAF (1.0 M in HCl) was added thereto. THF, 5.0 ml); the reaction mixture was stirred at room temperature until no starting material remained. The reaction was carefully washed with sat. NaHCO3. and brine. The organic layer was dried over MgSO 4, filtered and concentrated. The residue was purified by flash chromatography using a Hexane-EtOAc system to give N- (4-chlorophenyl) -? / - [(2S, 4R) -1- (4-fluoro-3-hydroxybenzoyl) -2-methyl- 1, 2,3,4-tetrahydroquinolin-4-yl] acetamide (477 mg, 100%). 1 H NMR (CDCl 3) d: 1, 15 (d, 3 H), 1, 25 (m, 2 H), 2.07 (s, 3 H), 2.30 (a, 1 H), 4.75 (m, 1 H), 6.55 (d, 1 H), 6.68 (d, 1 H), 6.62-6.70 (m, 3H) 7.15-7.25 (m, 4H), 7, 35-7.42 (m, 2H). MS m / z: 453 (M + 1) (2S, 4R) -4- (4-. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro] -2H-quinoline-1 -carbonyl.}. -phenoxy) -N, N-diethyl-butyramide (H-20) was prepared (2S, 4R) -4- (4-. {4- [acetyl- (4 -chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}. -phenoxy) -N, N-diethyl-butyramide from ethyl ester of (2S, 4R) -4- (4-. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinol-1-carbonyl} .-phenoxy) -butyric acid. Hydrolyzed (2S, 4R) -4- (4. {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H- ethyl ester 1-carbonyl-] -phenoxy) -butyric acid (0.511 g, 0.93 mmol) in the acid was dissolved in tetrahydrofuran and ethanol and sodium hydroxide (1 N) was added. The mixture was stirred at room temperature 4 hours. The mixture was cooled to rt and acidified to form a white precipitate. The solid was filtered to give acid (2S, 4R) -4- (4-. {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1 -carbonyl. -etide-penta-2,4-dienyloxy) -butyric with a yield of 74%. The acid (0.050 g, 0.09 mmol) was converted to the amide by dissolving in THF (2 mL) at room temperature. HOBt (0.019 g), EDCI (0.022 g) and diethylamine (0.010 ml) were added together with 2 drops of DMF and stirred at room temperature for 11 h. The reaction was diluted with ethyl acetate, washed with 1 N NaOH, 1 N HCl and brine. The organic extracts were dried over MgSO, filtered and concentrated. The crude residue was purified by chromatography on silica gel (50% ethyl acetate / 50% hexane to 100% ethyl acetate) to yield the product (0.023 mg, 54%). 1 H NMR (CDCl 3) d: 0.91 (d, 3 H), 0.96 (t, 6 H), 1, 06 (m, 1 H), 1.58 (m, 2 H), 1.86 (s, 3H), 2.11 (m, 1 H), 2.29 (m, 2H), 3.11-3.17 (m, 4H), 3.78 (m, 2H), 4.56 (sextuplet, 1 H), 5.43 (sa, 1 H), 6.34 (d, 1 H), 6.48 (d, 2 H), 6.76 (t, 1 H), 6.59-7.19 (m, 8H). MS m / z: 576 (M + 1). N-. { (2S, 4R) -6-chloro-2-methyl-1 - [(3-methylisoxazol-5-yl) carbonyl] -1,2,3,4-tetrahydroquinolin-4-yl} -N- (4-chlorophenyl) acetamide (H-21)? / - was prepared. { (2S, 4R) -6-chloro-2-methyl-1 - [(3-methylisoxazol-5-yl) carbonyl] -1,2,3,4-tetrahydroquinolin-4-yl} -? / - (4-chlorophenyl) acetamide following the procedure described for? / -. { (2S, 4R) -1- [3,5-bis (trifluoromethyl) benzoyl] -6-chloro-2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} -? / - (4-cyclophenol) acetamide by substituting 3,5-bistrifluoromethylbenzoyl chloride for 3-methylisoxazoyl-5-carbonyl chloride. 1 H NMR (CDCl 3) d: 1, 10 (d, 3 H), 1, 10 (1 H, m), 2.02 (s, 3 H), 2.20 (s, 3 H), 2.24-2, 32 (m, 1 H), 4.68-4.74 (m, 1 H), 5.45-5.50 (m, 1 H), 5.80 (s, 1H), 6.80 (d , 1 H), 7.10-7.40 (m, 7H). MS m / z: 458 (M + 1). (2S, 4R) -4- (4- {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl} .-phenoxy) -cyclohexanecarboxylic acid (H-22) (2S, 4R) -4- (4. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl) ethyl ester was hydrolysed -3,4-dihydro-2H-quinoline-1-carbonyl.]. Phenoxy) -cytohexanecarboxylic acid (0.060, 0.10 mmol) in the acid was dissolved in tetrahydrofuran and ethanol and sodium hydroxide (1 N) was added thereto. The mixture was stirred at room temperature for 10 hours. The mixture was cooled to room temperature and acidified to form a white precipitate. The solid was filtered to give (2S, 4R) -4- (4-. {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H) acid. -quinoline-1-carbonyl.}. -phenoxy) -cyclohexanecarboxylic acid in the form of a white powder with a yield of 62%. 1 H NMR (CDCl 3) d: 1.13 (d, 4 H), 1, 24-1, 60 (m, 5 H), 2.01 (s, 6 H), 2.20-2.39 (m, 2 H) , 4.72 (sextuplet, 1 H), 5.60 (sa, 1H), 6.53 (d, 1 H), 6.64 (d, 2H), 6.91 (t, 1 H) 7, 11-7.38 (m, 8H). MS m / z: 561 (M + 1). 5- (4- { [(2S, 4R) -4 - [[(Acetyloxy) acetyl] (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl Phenyl) -2,2-dimethylpentanoate methyl (H-23) 5- (4- { [(2S, 4R) -4 - [[(acetyloxy) acetyl] (4-cyranophene) amino] -2-methyl-3,4-dihydroquinoline-1 was prepared (2 H) -yl] carbonyl, phenyl) -2,2-dimethylpentanoate following the general procedure B, substituting acetyl chloride for acetoxyacetyl chloride in step 3 to provide 2- [acetate. { (2S, 4R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} (4-chlorophenyl) amino] -2-oxoethyl. To a solution of 2- [acetate. { (2S, 4R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2-methyl-1, 2,3,4-tetrahydroquinoline-4-yl} (4-chlorophenyl) amino] -2-oxoethyl (500 mg, 0.82 mmol, 1 equiv.) In ethanol (6 ml) and water (1 ml) was added potassium hydroxide (229 mg, 4.1 mmol, 5 equiv.). The mixture was heated at 70 ° C for 4 h. The mixture was neutralized with 1N aqueous HCl and extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous sodium bicarbonate solution and twice with brine, dried over sodium sulfate, filtered and concentrated to give? / - (4-chlorophenyl) -2-hydroxy -? - [(2S, 4R) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl-acetamide crude which was used as such in the next step. It was dissolved? / - (4-chlorophenyl) -2-hydroxy -? / - [(2SJ4R) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] acetamide (300 mg, 0.91 mmol , 1 equiv.) In methylene chloride (3 ml). To this solution were added EDC (464 mg, 2.7 mmol, 3 equiv.) And acetic acid (164 mg, 2.7 mmol, 3 equiv.) And the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate and washed with water and brine and then dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by chromatography on silica gel (methylene chloride / methanol: gradient 99/1 to 98/2) to produce 2- acetate. { (4-chlorophenyl) [(2S, 4R) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] amino} -2-oxoethyl (240 mg, 84%). To a solution of 2- acetate. { (4-chlorophenyl) [(2S, 4R) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] amino} -2-oxoethyl (170 mg, 0.45 mmol, 1 equiv.) In methylene chloride (2.0 ml) at room temperature was added diisopropylethylamine (127 μl, 0.73 mmol, 1.60 equiv.) Followed methyl 5- [4- (chlorocarbonyl) phenyl] -2,2-dimethylpentanoate (196 mg, 0.73 mmol, 1.60 equiv.). The reaction was stirred overnight at room temperature. The mixture was concentrated, then poured into water and extracted with ethyl acetate. The extracts were washed with brine, dried over magnesium sulfate, filtered, dried and concentrated. The crude residue was purified by chromatography on silica gel (gradient from 25/75 to 1: 1 ethyl acetate / hexane) to yield 5- (4- { [(2S, 4R) -4 - [[ (acetyloxy) acetyl] (4-cyorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -iI] carbonyl, phenyl) -2,2-dimethylpentanoate, pure methyl (110 mg, 40 mg). %). 1 H NMR (CDCl 3) d: 1, 10 (s, 6 H), 1, 15 (d, 3 H), 1, 45 (m, 4 H), 2.15 (s, 3 H), 2.35 (m, 1 H), 2.50 (m, 2H), 3.65 (s, 3H), 4.40-4.55 (c, 2H), 4.80 (m, 1 H), 5.55 (m, 1H), 6.55 (d, 1 H), 6.90-7.0 (m, 3H), 7.05-7.20 (m, 3H), 7.30-7.55 (m, 5H) ). MS m / z: 619 (M + 1). 4- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl} phenoxy ) -1-methylpyrrolidine-2-carboxylic acid (H-24) 4-Hydroxy-1-methyl-pyrrolidine-2-carboxylic acid (0.27 g, 1.85 mmol) was dissolved in 5 ml of methanol at room temperature and (trimethylsilyl) diazomethane (2 M solution in hexane) was added until the solution became yellow. The mixture was concentrated to yield crude 4-hydroxy-1-methyl-pyrrolidine-2-carboxylic acid methyl ester, which was converted to 4- (4- { [(2S, 4R) -4- [acetyl ( 4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2 - /) - il] carbonyl] phenoxy) -1-methylpyrrolidine-2-carboxylic acid following the same procedure as for the preparation of (1R, 2R) -2 - [(4- {[[2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinoline-1 ( 2 -) -yl] carbonyl, phenoxy) methyl] cyclopentanecarboxylic acid. (2S, 4R) -W-4- (4- { 4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3, 4-dihydro-2H-quinoline-1 -carbonyl} -phenoxy) -2,2-dimethyl-butyramide (H-25) was prepared (2S, 4R) -? / - 4- (4-. {4- [acetyl- (4-chloro-phenyl) - amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl.} - phenoxy) -2,2-dimethyl-butyramide from (2S, 4R) -? / - 4- ( 4- {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl} -phenoxy) -2,2-dimethyl -butyric coupling NH4CI, HATU, DIEA, HOBt in DMF at room temperature to produce (2S, 4R) -? / - 4- (4-. {4- [acetyl- (4-cioro-phenyl) -amino] - 2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl.] - phenoxy) -butyramide. The reaction mixture was concentrated and partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over magnesium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel (10% methanol / 90% dichloromethane) to yield (2S, 4R) -? / - 4- (4-. {4- [acetyl- (4- pure (phenyl-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl, phenoxy) -butyramide (63%). 1 H NMR (CDCl 3) d: 1, 13 (d, 3 H), 1, 15 (t, 1 H), 1, 25 (s, 6 H), 1, 98 (t, 2 H), 2.04 (s, 3 H) ), 2.27 (m, 1 H), 3.96 (t, 2H), 4.72 (sextuplet, 1 H), 5.52 (a, 2H), 5.58 (sa, 1 H), 6.52 (d, 1 H), 6.67 (d, 2H), 6.86 (t, 1 H), 7.08-7.35 (m, 6H), 7.38 (d, 2H) . MS m / z: 548 (M + 1) (2S, 4R) -? / - (4-Chloro-phenyl) -? / -. { 2-methyl-1- [4- (3-pyridin-3-yl-propoxy) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -acetamide (H-26) was dissolved (2S, 4R) -? / - (4-chloro-phenyl) -? / - [1- (4-hydroxy-benzoyl) -2-methyl-1, 2,3, 4-tetrahydro-quinolin-4-yl] -acetamide in DMF (5 ml) at room temperature. K 2 C 3 was added followed by 3- (3-bromo-propyl) -pyridine and the reaction was allowed to stir at 90 ° C overnight. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO 4, filtered and concentrated. The crude residue was purified by HPLC to produce the product. 1 H NMR (CDCl 3) d: 1.12 (m, 4 H), 1.83 (m, 2 H), 2.01 (s, 3 H), 2.24 (m, 1 H), 2.76 (t, 2H), 3.89 (t, 2H), 4.73 (m, 1 H), 5.60 (sa, 1H), 6.52 (d, 1 H), 6.64 (d, 2H), 6.93 (t, 1H), 7.12-7.29 (m, 7H), 7.37 (d, 2H), 7.48 (d, 1 H), 8.45 (m, 2H). MS m / z: 554.36 (M + 1). Amide of (2S, 4R) -5- (4-. {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl) .}. - phenoxymethyl) -furan-2-carboxylic acid (H-27) It was converted to (2S34R) -5- (4-. {4- [acetyl- (4-chloro-phenyl) -amino] -2- methyl-3,4-dihydro-2H-quinoline-1-carbonyl.] - phenoxymethyl) -furan-2-carboxylic acid (0.065 g, 0.12 mmol) in the amide was dissolved in THF (1 ml) at room temperature. HOBt (0.024 g), EDCI (0.033 g) and ammonium chloride (0.013 g, 0.232 mmol) were added together with 2 drops of DMF and stirred at room temperature for 11 h. The reaction was diluted with ethyl acetate, washed with 1 N NaOH, 1 N HCl and brine. The organic extracts were dried over MgSO 4, filtered and concentrated. The crude residue was purified by chromatography on silica gel (10 ethyl acetate: 1 methanol) to yield the product as a white solid in 61% yield. 1 H NMR (CDCl 3) d: 1, 13-1, 20 (m, 4 H), 2.01 (s, 3 H), 2.23-2.29 (m, 1 H), 4.72-4.74 (m, 1 H), 4.99 (s, 2H), 5.59 (sa, 1 H) 6.47-6.51 (m, 2H), 6.71 (d, 2H), 6.91 (t, 1 H), 7.09-7.38 (m, 9H). MS m / z: 558 (M + 1). (2S, 4R) -? / - (4-Chloro-phenyl) - / V-. { 2-methyl-1- [4- (3-piperazin-1-yl-propoxy) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -acetamide (H-28) was prepared (2S, 4R) -? / - (4-chloro-phenyl) -? / -. { 2-methyl-1 - [4- (3-piperazin-1-yl-propoxy) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -acetamide from (2S, 4R) -4- [3- (4. {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3-tert-butyl ester, 4-dihydro-2H-quinoline-1-carbonyl] -phenoxy) -propyl] -piperazine-1-carboxylic acid. It was dissolved (2S, 4R) -? / - (4-chloro-phenyl) -? / - [1- (4-hydroxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4 -yl] -acetamide (0.40 g, 0.92 mmol) in DMF at room temperature and K2CO3 (0.127 g, 0.921 mmol) was added thereto. 4- (3-Chloro-propyl) -piperazine-1-carboxylic acid-butyl ester (0.242 g, 0.921 mmol) was added and the reaction allowed to warm to 80 ° C overnight. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO 4, filtered and concentrated. The crude residue was purified by chromatography on silica gel to yield the product as a colorless oil in 50% yield. (2S34R) -4- [3- (4. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-e-butyl ester was dissolved. -quinoline-1-carbonyl.}. -phenoxy) -propyl] -piperazine-1-carboxylic acid (246 mg) in 4 M HCl in dioxane (2 ml). The mixture was stirred for 2 h at room temperature. After concentration, the white solid was washed with EtOAc to give the title compound in 100% yield. 1 H NMR (DMSO, 2 HCl salt) d: 1, 00-1, 02 (m, 4H), 1, 88-1, 94 (m, 3H), 2.10-2.15 (m, 1H), 3 , 15-3.80 (m, 12H), 4.02 (t, 2H), 4.56-4.59 (m, 1 H), 5.49 (s, 1 H), 6.50 (d , 1 H), 6.76 (d, 2H), 6.96 (t, 1 H), 7.04 (d, 2H), 7.16 (t, 1 H), 7.39-7.53 (m, 5H). MS m / z: 561 (M + 1). 4- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2W) -yl] carbonyl.} -2 , 6-difluorophenoxy) -2,2-dimethylbutanoate methyl (H-29) A / - (4-chlorophenyl) -A / - [(2S, 4R) -1 - (3,5-difluoro-4- methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolyl-4-yl] acetamide following the general procedure H, substituting 6-trifluoromethylnicotinyl chloride for 3,5-difluoro-4-methoxybenzoyl chloride. The rest of the procedures were followed as indicated in general procedure H to produce? / - (4-chlorophenyl) - / V - [(2S, 4R) -1- (3,5-difiuoro-4-methoxybenzoyl) - 2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] acetamide which was obtained in a decent yield. Was dissolved? / - (4-chlorophenyl) -? / - [(2S, 4R) -1 - (3,5-difluoro-4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinoline-4 -yl] acetamide (200 mg, 0.41 mmol) in dichloromethane and a solution of BBr3 (1.0 M in dichloromethane, 10 ml) was added thereto.; the reaction was allowed to stir at room temperature until no starting material remained. The reaction was washed with sat. NaHCO3. and brine. The organic layer was dried over MgSO 4, filtered and concentrated. The residue was purified by flash chromatography using a system of hexanes-ethyl acetate to give? / - (4-chlorophenyl) -? / - [(2S, 4R) -1- (3,5-difluoro-4-hydroxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] acetamide (152 mg, 78%). It was dissolved? / - (4-chlorophenyl) - / V - [(2S, 4R) -1 - (3,5-difluoro-4-hydroxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin -4-yl] acetamide (150 mg, 0.32 mmol) in DMF at room temperature and Cs2CO3 (259 mg, 0.80 mmol) was added thereto. Methyl 4-bromo-2,2-dimethylbutanoate (157 mg, 0.48 mmol) was added and the reaction was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO), filtered and concentrated. The crude residue was purified by chromatography on silica gel (hexanes-ethyl acetate system) to yield the product (118 mg, 61%). 1 H NMR (CDCl 3, 300 MHz) d: 1, 12-1, 14 (d, 3H), 1, 21-1, 24 (m, 6H), 1, 48-1, 55 (m, 2H), 2 , 02 (s, 3H), 2.20-2.32 (m, 1 H), 3.64 (s, 3H), 4.11-4.16 (m, 1 H), 4.65-4 , 75 (m, 1H), 5.45-5.55 (m, 1H), 6.51-6.54 (d, 1 H), 6.70-6.73 (m, 1H), 6, 76-6.90 (m, 1H), 7.18-7.39 (m, 7H). MS m / z: 599 (M + 1). Amide of (2S, 4R) -1- (4. {4 - [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl) .}. -phenyl) -piperidine-4-carboxylic acid (H-30) (2S, 4R) -1- (4-. {4- [acetyl- (4-chloro-phenyl) -amino] amide was prepared ] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl] -phenyl) -piperidine-4-carboxylic acid from (2S, 4R) -1- (4- {. 4- [acetyl- (4-cioro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl] -phenyl} -piperidine -4-carboxylic acid The acid (0.120 g, 0.22 mmol) was dissolved in DMF (2.5 ml) at room temperature and HOBt (0.044 g, 0.33 mmol), HATU (0.125 g, 0.33 mol) were added thereto and diisopropylethylamine (0.15 ml, 0.88 mmol) followed by ammonium chloride (0.024 g, 0.44 mmol) and stirred at room temperature for 16 h. The reaction was diluted with ethyl acetate, washed with 1 N NaOH, 1 N HCl and brine. The organic extracts were dried over MgSO 4, filtered and concentrated. The crude residue was purified by purification by HPLC. 1 H NMR (CDCl 3) d: 1, 10 (d, 3 H), 1, 23 (m, 1 H), 1.79 (m, 4 H), 2.01 (m, 3 H), 2.27 (m, 1 H), 2.48 (m, 1 H), 2.96 (m, 1 H), 3.13 (m, 1 H), 3.35 (m, 1 H), 3.52 (m, 1 H), 4.70 (m, 1 H), 5.50 (a, 2 H), 6.24 (a, 1 H), 6.56 (d, 1 H), 6.67 (d, 2 H) ), 6.92 (t, 1H), 7.08-7.28 (m, 6H), 7.37 (d, 2H). MS m / z: 545.4 (M + 1). Acid 2-. { [3- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl} phenyl propanoyl] amino} -2-methylpropanoic (H-32) 3- (4- { [(2SJ4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2 - /) - il was dissolved ] methyl carbonyl. phenyl) propanoate (90 mg, 0.15 mmol, 1 equiv.) in methanol / tetrahydrofuran (2/1) (1 ml). A solution of sodium hydroxide (12 mg, 0.30 mmol, 2 equiv.) In water (0.5 ml) was added and the reaction mixture was stirred at room temperature for 20 h. The mixture was concentrated and the residue was acidified with a 1 N aqueous solution of HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give 2- acid. { [3- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinoline-1 (2H) -yl] carbonyl} phenyl) propanoyl] amino} -2-methylpropanoic acid (76 mg, 87%). 1 H NMR (CDCl 3) d: 1, 15 (d, 3 H), 1, 45 (d, 6 H), 2.05 (s, 3 H), 2.30 (m, 1 H), 2.40 (t, 2H), 2.85 (t, 2H), 4.75 (m, 1 H), 5.60 (m, 1 H), 6.30 (s, 1 H), 6.55 (d, 1H) 6.90 (t, 1 H), 6.90-7.15 (m, 8H), 7.40 (d, 2H). MS m / z: 576 (M + 1). 4- [5-. { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl} Methyl -2-oxopyridin-1 (2H) -yl] -2,2-dimethylbutanoate (H-33) and 4 - [(5 { [(2S, 4R) -4- [acetyl (4-chlorophenyl) ) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl} pyridin-2-yl) oxy] -2,2-dimethylbutanoate methyl (H-143) 4- was prepared [(5- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolyl-1 (2H) -l] carbonyl}. methyl pyridin-2-yl) oxy] -2,2-dimethylbutanoate from (2S, 4R) - / V- (4-chloro-phenyl) -? / - [1 - (6-methoxy) pyridine-3-carbonyl) -2-methyl-1, 2,3,4-tetrahydro-quinoline-4-irylacetamide by deprotection of the methoxy and working-up. It was dissolved (2S, 4R) -? / - (4-chloro-phenyl) - / V- [1- (6-methoxy-pyridine-3-carbonyl) -2-methyl-1, 2,3,4-tetrahydro -quinolin-4-yl] -acetamide (0.062 g, 0.13 mmol) in methylene chloride, TMSI (0.020 mL, 0.13 mmol) was added and stirred at room temperature for 14 h. The reaction mixture was concentrated, methanol was added and stirring was continued for 10 h, concentrated and used directly. It was dissolved? / - (4-chlorophenyl) -? / -. { (2S, 4R) -1 - [(6-hydroxypyridin-3-yl) carbonyl] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} acetamide (0.060 g, 0.13 mmol) in 2 ml of dimethylformamide, followed by 0.046 g of methyl 4-bromo-2,2-dimethylbutanoate (0.20 mmol) and 0.057 g of silver carbonate (0.20 mmol ). The flask was covered with aluminum foil and the light was extinguished in the enclosure. The reaction was allowed to warm to 80 ° C for 24 h. Additional methyl 4-bromo-2,2-dimethylbutanoate (0.046 g, 0.20 mmol) was added and stirring was continued at 80 ° C for 24 h. The reaction was concentrated and partitioned between ethyl acetate and water. The organic extracts were collected together and dried over MgSO, filtered and concentrated. The residue was purified with 2% methanol / 98% methylene chloride to 5% methanol / 95% methylene chloride to 10% methanol / 90% methylene chloride. Two products were obtained, the O- and N-alkylated product, 4 - [(5 { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4- methyl dhydroquinolin-1 (2H) -yl] carbonyl] pyridin-2-yl) oxy] -2,2-dimethylbutanoate (0.025 g, 32%) and 4- [5-. { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -l] carbonyl} Methyl -2-oxopyridin-1 (2H) -yl] -2,2-dimethylbutanoate (0.025 g, 32%). O-alkylated 1 H NMR (CDCl 3) d: 1, 13 (m, 1 H), 1, 14 (d, 3 H), 1, 22 (s, 6 H), 1, 99 (t, 2 H), 2.01 (s, 3H), 2.29 (m, 1 H), 3.62 (s, 3H), 4.27 (t, 2H), 4.74 (sextuplet, 1 H), 5.58 (sa, 1 H), 6.37 (d, 1 H), 6.56 (d, 1 H), 7.00 (t, 1H), 7.28-7.16 (m, 5H), 7.37 ( d, 2H), 8.14 (br s, 1H). MS m / z = 564 (M + 1). N-alkylated 1 H NMR (CDCl 3) d: 1, 11 (m, 1 H), 1, 12 (d, 3 H), 1, 22 (s, 6 H), 1, 72-1, 90 (m, 2 H) , 2.01 (s, 3H), 2.25 (m, 1H), 3.67 (s, 3H), 3.71-3.88 (m, 2H), 4.64 (, sextuplet, 1 H) ), 5.51 (sa, 1 H), 6.15 (d, 1 H), 6.74 (d, 2H), 7.09 (t, 1 H), 7.15 -7.33 (m) , 4H), 7.37 (d, 2H), 7.57 (s, 1 H).
MS m / z: 564 (M + 1). W-. { (2S, 4R) -1- [4- (aminomethyl) benzoyl] -2-methyl-1,2,3,4-tetrahydroquinolin-4-yl} - / V- (4-chlorophenyl) acetamide (H-34)? / - was obtained. { (2S, 4R) -1- [4- (aminomethyl) benzoyl] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} -? / - (4-chlorophenyl) acetamide following the general procedure H, substituting 6-trifluoromethylnicotinium chloride for 4-cyanobenzoyl chloride. The remainder of the procedure is followed as indicated in general procedure H to produce the corresponding nitrite, / V- (4-chloro-phenyl) -? / - [(2S, 4R) -1- (4-cyano-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide. It was dissolved? / - (4-chloro-phenyl) - / V - [(2S, 4R) -1- (4-cyano-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin -4-yl] -acetamide (225 mg, 0.51 mmol) in ethanol (7 ml) and cobalt dichloride (0.079 g, 0.61 mmol) and NaBH 4 (0.059 g, 1.57 mmol) were added thereto and The mixture was stirred at room temperature for 2 h. The suspension was filtered, concentrated and subjected to flash chromatography (1% NH 4 OH, 15% MeOH, EtOAc) to yield the title compound (188 mg, 83%) as a white solid. 1 H NMR (CDCl 3) d: 1, 00-1, 20 (m, 1 H), 1, 14 (s, 3 H), 1, 48 (sa, 2 H), 2.02 (s, 3 H), 2, 20-2.36 (m, 1 H), 3.79 (s, 2H), 4.73-4.83 (m, 1 H), 5.35-5.70 (m, 1 H), 6 , 49 (d, 1H), 6.89 (t, 1H), 7.11-7.29 (m, 8H), 7.37 (d, 2H). MS m / z: 448 (M + 1) (2S, 4R) -W- [3- (4-. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl- 3,4-dihydro-2H-quinoline-1-carbonyl.] - phenoxy) -propyl] -2,2-dimethyl-propionamide (H-35) (2S, 4R) -? / - was dissolved. { 1- [4- (3-amino-propoxy) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -? / - (4-Ctoro-phenyl) -acetamide (60 mg, 0.122 mmol) in methylene chloride (2 ml) and triethylamine (0.034 ml, 0.243 mmol) and cooled to -40 ° C. Pivaloyl chloride (10 drops by pipette) was added and the mixture was heated at 0 ° C for 30 minutes. The mixture was partitioned between methylene chloride and water; The methylene chloride layer was dried over MgSO, filtered and concentrated. The crude residue was purified by chromatography on silica gel (gradient 1/1 hexanes / ethyl acetate-ethyl acetate) to produce the product. 1 H NMR (CDCl 3) d: 1.1 (s, 3 H), 1.1 (s, 9 H), 1.2 (m, 1 H), 2.0 (m, 2 H), 2.0 (s, 3H), 2.3 (m, 1 H), 3.4 (c, 2H), 4.0 (t, 2H), 4.7 (m, 1 H), 5.6 (sa, 1 H) , 6.0 (s, 1H), 6.5 (d, 1H), 6.6 (d, 2H), 6.9 (t, 1 H), 7.2 (m, 6H), 7.4 (d, 2H). MS m / z: 576 (M + 1). 4- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl} -2 -fluorophenoxy) -2,2-dimethylbutanoate methyl (H-36)? / - (4-chlorophenyl) -? / - [(2S, 4R) -1 - (3-fluoro-4-methoxybenzoyl) -2 was prepared -methyl-1, 2,3,4-tetrahydroquinolin-4-yl] acetamide following the general procedure H, substituting 6-trifluoromethylnicotinyl chloride for 3-fluoro-4-methoxybenzoyl chloride. The rest of the procedures were followed as indicated in general procedure H to produce? / - (4-chlorophenyl) -? / - [(2S, 4R) -1- (3-fluoro-4-methoxybenzoyl) -2- methyl-1, 2,3,4-tetrahydroquinolin-4-yl] acetamide. It was dissolved / V- (4-chlorophenyl) - / V - [(2S, 4R) -1- (3-fluoro-4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl ] acetamide in dichloromethane and a solution of BBr3 (1.0 M in dichloromethane, 10 ml) was added thereto; the reaction was allowed to stir at room temperature until no starting material remained. The reaction was washed with sat. NaHCO 3. and brine. The organic layer was dried over MgSO, filtered and concentrated. The residue was purified by flash chromatography using a system of hexanes-ethyl acetate to give? / - (4-chlorophenyl) -? / - [(2S, 4R) -1- (3-fluoro-4-hydroxybenzoyl) -2 -methyl-1, 2,3,4-tetrahydroquinolin-4-yl] acetamide with a decent yield. It was dissolved / V- (4-chloropheni) -? / - [(2S, 4R) -1 - (3-fluoro-4-hydroxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl ] acetamide (317 mg, 0.70 mmol) in DMF at room temperature and Cs2CO3 (567 mg, 1.75 mmol) was added thereto. Methyl 4-bromo-2,2-dimethylbutanoate (465 mg, 1.05 mmol) was added and the reaction was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO, filtered and concentrated. The crude residue was purified by chromatography on silica gel (hexanes / ethyl acetate system) to produce the product (176 mg, 43%). 1 H NMR (CDCl 3, 300 MHz) d: 1, 11-1, 13 (d, 3 H), 1, 22-1, 29 (m, 6 H), 1, 51-1, 64 (m, 2 H), 2 , 07-2.09 (m, 5H), 2.25-2.29 (m, 2H), 3.65 (s, 3H), 3.95-3.99 (m, 2H), 4.70 -4.75 (c, 1H), 5.27 (a, 1H), 6.51-6.75 (m, 3H), 6.92-7.03 (m, 2H), 7.14-7 , 38 (m, 6 H). MS m / z: 581 (M + 1). (2S, 4R) - / V- (4-chloro-phenyl) -W-. { 2-methyl-1 - [4- (2-oxo-imidazolidin-1-yl) -benzoyl] -1, 2,3,4-tetrahydro-quinolin-4-yl} -acetamide (H-37) was dissolved? / - [1- (4-amino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -? / - (4- chloro-phenyl) -acetamide (156 mg, 0.373 mmol) in methylene chloride (3 ml) and triethylamine (0.078 ml, 0.559 mmol) and 1-chloro-2-isocyanatoethane 0.038 ml, 0.448 mmol) were added thereto. The reaction was stirred at room temperature overnight and the reaction was quenched with sat. NaHCO3. ac. The residue was partitioned between methylene chloride and water, then extracted three times with methylene chloride, dried over MgSO 4, filtered and concentrated. The crude residue was purified by chromatography on silica gel (ethyl acetate) to produce the product. 1 H NMR (CDCl 3) d: 1, 2 (d, 3 H), 1, 2 (m, 1 H), 2.0 (s, 3 H), 2.3 (m, 1 H), 4.0 (t , 2H), 4.4 (t, 2H), 4.8 (m, 1 H), 5.6 (m, 1 H), 6.5 (d, 1 H), 6.9 (t, 1 H), 7.2 (m, 9H), 7.4 (d, 2H). MS m / z: 503 (M + 1). Acid (2S, 4R) -4 - [(4- {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1 -carbonyl}-phenyl) -methyl-amino] -butyric (H-38) (2S, 4R) -4 - [(4- {4- [acetyl- (4-chloro-phene) -amino]] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl.] - phenyl] -methyl-amino] -butyric acid from (2S54R) - methyl ester 4 - [(4- {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl} -phenyl) -methyl-amino] -butyric acid was hydrolyzed in the acid by dissolving in tetrahydrofuran and ethanol, lithium hydroxide (1 N) was added and it was heated at 50 ° C for 2 h. The mixture was cooled to room temperature and acidified to form a white precipitate. The solid was filtered to give to produce the product after purification by HPLC. 1 H NMR (CDCl 3) d: 1, 10 (d, 3 H), 1, 18 (m, 1 H), 1.81 (t, 2 H), 2.02 (s, 3 H), 2.28 (m, 3 H) ), 2.86 (s, 3H), 3.28 (t, 2H), 4.70 (m, 1 H), 5.58 (sa, 1 H), 6.39 (d, 2H), 6 , 61 (d, 1 H), 6.94 (t, 1 H), 7.06-7.27 (m, 6H), 7.36 (d, 2H), 8.90 (a, 1 H) .
MS m / z: 534 (M + 1). (2S, 4R) -N- (4-Chloro-phenyl) -W-. { 1- [4- (4-hydroxy-4-methyl-pentyloxy) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -acetamide (H-39) was dissolved (2S, 4R) -? / - (4-chloro-phenyl) -? / - [1- (4-hydroxy-benzoyl) -2-methyl-1, 2,3, 4-tetrahydro-quinolin-4-yl] -acetamide (0.1 g, 0.23 mmol) in DMF (5 ml) at room temperature. K 2 C 3 (0.317 g, 2.3 mmol) was added. 5-Bromo-2-methyl-pentan-2-ol (0.092 g, 0.51 mmol) was added and the reaction was allowed to warm to 80 ° C overnight. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO, filtered and concentrated. The crude residue was purified by chromatography on silica gel (70% EtOAc / 30% Hexane) to yield the product (0.097 g, 79%). 1 H NMR (CDCl 3) d: 1, 13 (d, 3 H), 1, 15 (t, 1 H), 1, 26 (s, 6 H), 1, 52-1, 90 (m, 5 H), 2, 04 (s, 3H), 2.27 (m, 1 H), 3.91 (t, 2H), 4.72 (sextuplet, 1 H), 5.48 (sa, 1 H), 6.52 ( d, 1 H), 6.67 (d, 2H), 6.86 (t, 1 H), 7.08-7.35 (m, 6H), 7.38 (d, 2H). MS m / z: 535 (M + 1) (2S, 4R) -1- [3- (4. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl] -amide -3,4-dihydro-2H-quinoline-1-carbonyl.}. -phenoxy) -propyl] -1H-imidazole-2-carboxylic acid (H-40) (2S, 4R) -1- amide was prepared [3- (4-. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyI-3,4-dihydro-2H-quinoline-1-carbonyl] -.-phenoxy) - propyl] -1- -imidazole-2-carboxylic acid from (2S, 4R) -1- [3- (4-. {4- [acetyl- (4-chloro-phenyl)] - ethyl ester amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl.] - phenoxy) -propyl] -1H-imidazole-2-carboxylic acid. The ester (0.100 g, 0.16 mmol) was hydrolyzed in the acid by dissolving in tetrahydrofuran and ethanol and sodium hydroxide (1 N) was added thereto. The mixture was stirred at room temperature for 4 hours. The mixture was cooled to rt and acidified to form a white precipitate. The solid was filtered to give acid (2S, 4R) -1- [3- (4-. {4- [Acetyl- (4-cioro-phenyl) -amino] -2-methi-3,4-dihydro-2H-quinoline -1-carbonyl.}. -phenoxy) -propyl] -1 / - / - imidazole-2-carboxylic acid with a 65% yield. The acid (0.066 g, 0.09 mmol) was converted to the amide by dissolving in DMF (2 mL) at room temperature. HATU (0.061 g, 0.16 mmol), HOBt (0.021 g, 0.15 mmol) and diisopropylethylamine (0.074 mL, 0.43 mmol) were added and stirred for 5 min followed by ammonium chloride (0.011 g, 0, 20 mmol). The reaction was stirred at room temperature for 12 h and concentrated. The residue was diluted with ethyl acetate and washed with 1 N HCl and dried over MgSO, filtered and concentrated. The crude residue was purified by chromatography on silica gel (5% MeOH / 95% CH 2 Cl 2 / NH 4 OH to 10% MeOH / 90% CH 2 Cl 2 / NH 4 OH to 15% MeOH / 85% CH 2 Cl 2 / NH 4 OH) produce the product (0.050 mg, 81%). 1 H NMR (CDCl 3) d: 1, 11 (d, 3 H), 1, 37 (m, 1 H), 2.00 (s, 3 H), 2.22 (m, 3 H), 3.82 (t, 2 H) ), 4.57 (t, 2H), 4.72 (sextuplet, 1 H), 5.56 (sa, 1 H), 6.49 (d, 1H), 6.60 (d, 2H), 6 , 90 (t, 1 H), 6.89 (t, 1 H), 6.93 (d, 2H), 7.11 (d, 2H), 7.15-7.27 (m, 5H), 7.34 (d, 1 H).
MS m / z: 586 (M + 1). (2S, 4R) - V- (4-Chloro-phenyl) -? -. { 2-methyl-1- [4- (2-oxo-oxazolidin-5-ylmethoxy) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -acetamide (H-41) was dissolved (2S, 4R) - / V- (4-chloro-phenyl) - / V- [1- (4-hydroxy-benzoyl) -2-methyl-1, 2,3, 4-tetrahydro-quinolin-4-yl] -acetamide (0.5 g, 1.14 mmol) in DMF at room temperature and K2CO3 (1.26 g, 9.13 mmol) was added thereto. 2-Chloromethyl-oxirane (0.42 g, 4.57 mmol) was added and the reaction was allowed to warm to 80 ° C overnight. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO, filtered and concentrated. The crude residue was purified by chromatography on silica gel (50% EtOAc / 50% Hexane) to yield (2S, 4R) -? / - (4-ctoro-pheny) -? / - [2-methyl] -1- (4-oxiranylmethoxy-benzoyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide (0.55 g, 77%), which was also prepared in the product following the ref. (Tetrahedron Lett 2002, 43 (46), 8327). 1 H NMR (CDCl 3) d: 1, 13 (d, 3 H), 1, 15 (t, 1 H), 2.03 (s, 3 H), 2.27 (m, 1 H), 3.57 (m , 1 H), 3.68 (m, 1 H), 4.05 (m, 2H), 4.73 (m, 1 H), 4.86 (m, 1 H), 5.58 (sa, 1 H), 6.52 (d, 1 H), 6.67 (d, 2H), 6.86 (t, 1H), 7.08-7.35 (m, 6H), 7.38 (d , 2H). MS m / z: 535 (M + 1) 5- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinoline-1 acid (2H) -yl] carbonyl.}. Phenyl) -2,2-d.methylpentanoic acid (H-42) 5- (4- (4S) -4- [acetyl-] acetic acid methyl ester was dissolved. (4-Chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2-quinoline-1-carbonyl.} - phenyl) -2,2-dimethyl-pentanoic acid (500 mg, 0.89 mmol, 1 equiv.) in methanol / tetrahydrofuran (2/1) (4 ml). A solution of sodium hydroxide (71 mg, 1.8 mmol, 2 equiv.) In water (1 mL) was added and the reaction mixture was heated at 60 ° C for 20 h. The mixture was concentrated and the residue was acidified with a 1 N aqueous solution of HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give the crude acid. Purification by chromatography on silica gel gave 5- (4- ({(2S, 4R) -4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4- acid. pure dihydro-2H-quinoIine-1-carboniI. phenyl) -2,2-dimethyl-pentane (292 mg, 60%). 1 H NMR (MeOD) d: 1, 10 (d, 3 H), 1, 13 (s, 6 H), 1, 50 (m, 4 H), 2.05 (s, 3 H), 2.45 (m, 1 H), 2.55 (t, 2H), 4.75 (m, 1 H), 5.55 (m, 1 H), 6.55 (d, 1 H), 6.95 (t, 1 H) ), 7.05-7.20 (dd, 4H), 7.25 (t, 1H), 7.40-7.55 (m, 5H). MS m / z: 547 (M + 1). 4- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl} phenyl) Methyl -2,2-dimethylbutanoate (H-43) 4- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3, Methyl 4-dihydroquinolin-1 (2H) -yl] carbonyl, phenyl) -2,2-dimethylbutanoate according to general procedure B, substituting 6-trifluoromethylnicotinyl chloride for 4- [4- (chlorocarbonyl) methyl phenyl] -2,2-dimethylbutanoate. (Methyl 4- [4- (ctorocarbonyl) phenyl] -2,2-dimethylbutanoate was prepared in 5 steps from 4- (4-iodophenyl) butanoic acid. 4- (4-iodophenyl) butanoic acid was converted into 4 Methyl (4-iodophenyl) butanoate by treatment with trimethylsilyldiazomethane (1.5 equivalents) in benzene / methanol (4/1) at room temperature The formation of lithium enolate with lithium diisopropylamide (1.1 equivalents) in THF at -78 ° C followed by inactivation with methyl iodide (2.0 equivalents) and aqueous treatment and then repeating the same protocol yielded, after conventional chromatography (10% ethyl acetate / hexanes), 4- (4-iodophenyl) ) -2,2-dimethylbutanoate methyl The subsequent treatment of this material with catalytic palladium (II) acetate (0.05 equivalents) and 1,3-bis (diphenylphosphino) propane (0.05 equivalents) in the presence of water (5.0 equivalents) and triethylamine (2.0 equivalents) in DMF at 80 ° C in an atmosphere of carbon monoxide produced, after aqueous treatment, 4- (4-methoxy-3,3-dimethyl-4-oxobutyl) benzoic acid. This material was converted directly to 4- [4- (chlorocarbonyl) phenyl] -2, Methyl 2-dimethylbutanoate by treatment with excess thionyl chloride in dichloromethane at room temperature for 2 hours and then removal of the volatiles in vacuo). The rest of the procedures were followed as indicated in general procedure B to produce 4- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3, Methyl 4-dihydroquinolin-1 (2 - /) - 1] carbonyl, phenyl) -2,2-d, methylbutanoate. 1 H NMR (CDCl 3) d: 1, 12-1, 21 (m, 1 H), 1, 13 (d, 3 H), 1, 18 (s, 6 H), 1, 73 (ddd, 2 H), 2.01 (s, 3H), 2.23-2.30 (m, 1 H), 2.43 (ddd, 2H), 3.64 (s, 3H), 4.71-4.79 (m, 1 H) ), 5.60 (sa, 1 H), 6.49 (d, 1 H), 6.89 (t, 1 H), 6.95 (d, 2H), 7.08-7.29 (m) , 6H), 7.37 (d, 2H). MS m / z: 547 (M + 1). 3- (4- { [(2S, 4R) -4- [Acetyl (4-cyanophenyl) amino] -6-chloro-2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl acid .}. phenoxy) -2,2-dimethylpropanoic acid (H-44) 3- (4 { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -6-chloro- 2-methyl-3,4-dihydroquinolyl-1 (2 - /) - il] carbonyl, phenoxy) -2,2-dimethylpropanoic acid from (2SJ4R) -? / - 3- (4-. {4- [acetyl- (4-chloro-phene) -amino] -2-methylene-3,4-dihydro-2H-quinoline-1-carbonyl] -phenoxy) -2, 2-dimethy1-propionate (0.030 g, 0.057 mmol) by the addition of 1 ml of dimethylformamide and TCCA (0.0044 g, 0.018 mmol, 0.33 equiv.) And stirred at room temperature 40 min The reaction mixture was diluted with water and acidified with 1 N HCl to form a white precipitate. The solid was dried over the lyophilizer and purified with 5% methanol / dichloromethane to 10% methanol / 90% dichloromethane to yield 0.400 g, 87% 4- (4 { [(2S, 4R)) -4- [acetyl (4-chlorophenyl) amino] -6-chloro-2-methyl-3,4-dihydroquinoline-1 (2H) -iI] carbonyl, phenoxy) -2,2-dimethylbutane. 1 H NMR (CDCl 3) d: 1, 10 (d, 3 H), 1, 13 (m, 1 H), 1, 29 (s, 6 H), 2.03 (s, 3 H), 2.27 (m, 1 H), 3.92-3.85 (m, 2H), 4.72 (sextuplet, 1 H), 5.51 (sa, 1 H), 6.43 (d, 1H), 6.67 (d) , 2H), 6.90 (d, 1 H), 7.11 (s, 1H), 7.13 (d, 2H), 7.19 (d, 2H), 7.38 (d, 2H). MS m / z: 569 (M + 1). W- (4-aminophenyl) -? H (2S, 4R) -1 - (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] acetamide (H-45) (4- {Acetyl [(2S, 4R) -1- (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] amino} phenyl) carbamate was dissolved in benzyl in MeOH and a catalytic amount of Palladium on Carbon (10%) was added. The system was purged with hydrogen gas and subjected to 1 atm of H2 for 2 h. The reaction was quenched with air and filtered to give the title compound as a white solid. 1 H NMR (CDCl 3) d: 1, 10-1, 60 (m, 1 H), 1, 10 (d, 3 H), 2.01 (s, 3 H), 2.22-2.38 (m, 1 H) , 3.70-3.95 (sa, 2H), 3.72 (s, 3H), 4.64-4.80 (m, 1H), 5.45-5.72 (m, 1H), 6.49 (d, 1 H), 6.54-6.70 (m, 2H), 6.64 (d, 2H), 6.89 (t, 1 H), 6.99 (d, 2H) , 7.08-7.20 (m, 3H), 7.30 (d, 1 H). MS m / z: 430 (M + 1) (2S, 4R) - / V- (4-Chloro-phenyl) -W-. { 1- [4- (4-methanesulfonylamino-3,3-dimethyl-4-oxo-butoxy) -benzoyl] -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl} -acetamide (H-46) Acid (2S, 4R 4- (4-. {4- [acetyl- (4-chloro-phenyl) -amino] -2-mef? -3,4-d) was dissolved hydro-2H-quinoline-1-carbonyl.}. - phenoxy) -2,2-d.methyl-butyric acid (200 mg, 0.37 mmol) in methylene chloride (5 ml) and oxalyl chloride (2 ml) A single drop of DMF was added and the mixture was stirred at room temperature until gas evolution ceased.All volatiles were removed.The suspension was dissolved in methylene chloride (10 ml) and triethylamine (2 ml). methanesulfonamide (200 mg, 2.10 mmol) was added and the reaction mixture was stirred for 3 hours, the mixture was partitioned between methylene chloride and water, the organic layer was dried over Na2SO4, filtered and concentrated. it was purified by preparative HPLC. 1 H NMR (CDCl 3) d: 1, 1 (d, 3 H), 1, 2 (m, 1 H), 1, 2 (s, 3 H), 1, 3 (s, 3 H), 2.0 (s, 3H), 2.1 (t, 1 H), 2.3 (m, 1H), 3.4 (m, 4H), 3.9 (m, 2H), 4.7 (m, 1 H), 5.6 (br s, 1H), 5.9 (d, 1 H), 6.5 (d, 1 H), 6.4 (d, 2H), 6.9 (t, 1 H), 7, 2 (m, 6H), 7.4 (d, 2H). MS m / z: 626 (M + 1). (2S, 4R) -1 - (4. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1 -carbonyl} phenyl) -piperidine-3-carboxylic acid (H-47) (2S, 4R) -1- (4-. {4- [acetyl- (4-chloro-phenyl) -amino] -2- methyl-3,4-dihydro-2H-quinoline-1-carbonyl.] - phenyl) -piperidine-3-carboxylic acid from (2S, 4R) -1- (4- {4- [Acetyl- (4-cioro-phenyI) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}. Phenyl) -piperidine-3-carboxylic acid (0.300 g. , 0.522 mol), hydrolyzed in the acid by dissolving in tetrahydrofuran and ethanol, lithium hydroxide (1 N) was added and 50 ° C was heated for 2 h. The mixture was cooled to room temperature and acidified to form a white precipitate. The solid was filtered to give to produce the product after purification by HPLC. 1 H NMR (CDCl 3) d: 1, 11 (d, 3 H), 1, 23 (m, 1 H), 1.77 (m, 2 H), 1.94 (m, 2 H), 2.02 (s, 3H), 2.27 (m, 1 H), 2.43 (m, 1 H), 2.78 (t, 2H), 3.60 (m, 2H), 4.71 (m, 1 H) , 5.58 (sa, 1 H), 6.57 (d, 1 H), 6.63 (d, 2H), 6.93 (t, 1 H), 7.07-7.28 (m, 6H), 7.37 (d, 2H), 9.30 (a, 1 H). MS m / z: 546.3 (M + 1). ? (2S, 4R) -6-Chloro-1 - [(6-ethylpyridin-3-yl) carbonyl] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} - / V- (4-chlorophenyl) acetamide (H-48) Prepared / V-. { (2S, 4R) -6-chloro-1 - [(6-ethylpyridin-3-yl) carbonyl] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} -? / - (4-chlorophenyl) acetamide following the procedure described for? / -. { (2S, 4R) -1- [3,5-bis (trifluoromethyl) benzoyl] -6-chloro-2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} -? / - (4-chlorophenyl) acetamide substituting 3,5-bistrifluoromethylbenzoyl chloride for 6-ethylnicotinyl chloride. (6-Ethylnicotinyl chloride was prepared in two steps from methyl 6-chloronicotinate as described in the procedure for? / - (4-chlorophenyl) - / V-. {(2S, 4R) -1- [(6-ethylpyridin-3-yl) carbonyl] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl.} Acetamide). < at 1 H NMR (CDCl 3) d: 1, 26 (d, 3H); 1, 28 (t, 3H), 1, 28-1, 31 (m, 1 H), 2.02 (s, 3H), 2.22-2.36 (m, 1 H), 2.81 ( c, 2H), 4.70-4.80 (m, 1 H), 5.42-5.56 (a, 1H), 6.50 (d, 1H), 6.90-7.00 (m , 2H), 7.20-7.40 (m, 7H), 8.50 (br s, 1H). MS m / z: 482 (M + 1). 4- (4- { [(2S, 4R) -4 - [(4-chlorophenyl) (cyclopropylcarbonyl) amino] -2-methyl-3,4-dihydroquinorm-1 (2H) -yl] carbonyl} phenoxy) -2,2-dimethylbutanoic (H-49) 4- (4 { [(2S, 4R) -4 - [(4-chlorophenyl) (cyclopropylcarbonyl) amino] -2-methyl-3 was dissolved , Methyl 4-dihydroquinolin-1 (2 / - /) - il] carbonyl, phenoxy) -2,2-dimethylbutanoate (100 mg, 0.17 mmol, 1 equiv.) In methanol / tetrahydrofuran (2/1 ) (1 ml). A solution of sodium hydroxide (21 mg, 0.51 mmol, 3 equiv.) In water (0.5 ml) was added and the reaction mixture was heated at 40 ° C for 2 h. The mixture was concentrated and the residue was acidified with a 1 N aqueous solution of HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give the crude acid. Purification by chromatography on silica gel (98/2 methylene chloride / methanol) gave 4- (4 { [(2S, 4R) -4 - [(4-chlorophenyl) (cyclopropylcarbonyl) amino] ] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl, phenoxy) -2,2-dimethylbutanoic acid (85 mg, 87%). 1 H NMR (CDCl 3) d: 0.75 (m, 2 H), 1, 10 (m, 2 H), 1, 20 (d, 3 H), 1, 25 (s, 6 H), 1.45 (m, 1 H), 2.05 (t, 2H), 2.30 (m, 1 H), 3.95 (t, 2H), 4.75 (m, 1 H), 5.60 (m, 1 H) , 6.50 (d, 1 H), 6.60 (d, 2H), 6.90 (t, 1 H), 7.10-7.45 (m, 8H). MS m / z: 575 (M + 1). W- (4-Chlorophenyl) -W - [(2S, 4R) -1- (3-ethyl-4-fluorobenzoyl) -2-methyl-1,2,3,4-tetrahydroquinolin-4-yl] acetamide (H -50) was prepared? / - (4-chlorophenyl) -? / - [(2S, 4R) -1 - (3-ethyl-4-fluorobenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinoline- 4-yl] acetamide following general procedure B, substituting 6-trifluoromethylnicotinyl chloride for 4-fluoro-3-ethylbenzoyl chloride. (4-Fluoro-3-ethylbenzoyl chloride was prepared in 5 steps from 3-bromo-4-fluorobenzoic acid.) 3-Bromo-4-fluorobenzoic acid was converted to methyl 3-bromo-4-f! Uorobenzoate by Treatment with trimethylsilyldiazomethane (1.5 equivalents) in benzene / methanol (4/1) at room temperature The subsequent reaction with tributyl (vinyl) tin (1.2 equivalents) in DMF in the presence of dichlorobis (triphenylphosphine) catalytic palladium (II) (0.1 equivalent) at 80 ° C under an argon atmosphere, followed by aqueous treatment and conventional chromatography (10% ethyl acetate / hexanes) yielded methyl 4-fluoro-3-vinylbenzoate. Hydrogenation of the vinyl group by treatment of this material with palladium on carbon (palladium 10% on carbon, 10% by mass) in methanol in a hydrogen atmosphere then produced methyl 3-ethyl-4-fluorobenzoate. in methanol / tetrahydrofuran / water (2/1/1), then lithium hydroxide (5.0 equivalents) and the reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated, the residue was acidified with a 1 N aqueous solution of HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give 4-fluoro-3-ethylbenzoic acid. This material was converted directly to 4-fluoro-3-ethylbenzoyl chloride by treatment with thionyl chloride (2.2 equivalents) in dichloromethane at room temperature for 2 hours followed by removal of the volatiles in vacuo). The rest of the procedures were followed as indicated in general procedure B to produce? / - (4-chlorophenyl) -? / - [(2S, 4R) -1- (3-ethyl-4-fluorobenzoyl) -2- methyl-1, 2,3,4-tetrahydroquinolin-4-yl] acetamide. 1 H NMR (CDCl 3) d: 1.03 (t, 3 H), 1, 15 (d, 3 H), 1, 22-1, 26 (m, 1 H), 2.03 (s, 3 H), 2, 24-2.32 (m, 1 H), 2.42-2.58 (m, 2H), 4.70-4.82 (m, 1 H), 5.61 (sa, 1 H), 6 , 48 (d, 1 H), 6.78 (t, 1 H), 6.92 (t, 1 H), 6.97-7.02 (m, 1H), 7.07 (d, 1 H) ), 7.13-7.30 (m, 4H), 7.38 (d, 2H). MS m / z: 465 (M + 1). (2S, 4R) -W- (4-Chloro-phenyl) -W-. { 1- [4- (3-imidazol-1-yl-3-methyl-butoxy) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -acetamide (H-51) 3-imidazoI-1-yl-3-methyl-butan-1-ol was dissolved in benzene at room temperature with PPh3 (0.088 g, 0.33 mmol), added (2S, 4R ) -? / - (4-chloro-phenyl) - / V- [1- (4-hydroxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide ( 0.133 g, 0.30 mmol) and stirred for 5 min. DEAD (0.058 g, 0.33 mmol) was added and the reaction was stirred for 18 h at room temperature. The reaction was concentrated and purified by chromatography on silica gel (4% MeOH / 96% CH 2 Cl 2 to 5% MeOH / 95% CH 2 Cl 2 to 6% MeOH / 94% CH 2 Cl 2) to produce the product with a yield of 46% Preparation of 3-lmidazol-1-yl-3-methyl-butan-1-ol 3-imidazol-1-yl-3-methyl-butan-1-ol was prepared from 2,2- d? 'ethyl methylacrylate. Ethyl 2,2-dimethylacrylate (2.04 ml, 14.7 mmol) and imidazole (0.500 g, 7.34 mmol) were mixed and heated at 90 ° C for 48 h and cooled to room temperature. The reaction mixture was diluted with CH2Cl2 and water. The aqueous phase was extracted 3 x CH 2 Cl 2 and dried over MgSO 4, filtered and concentrated. The crude residue was purified by chromatography on silica gel (10% MeOH / 90% CH 2 Cl 2) to give a 35% yield of 3-imidazol-1-yl-3-methyl-butyric acid ethyl ester. The ester was reduced in alcohol (U.S. Patent Application WO03047586). 3-Imidazol-1-yl-3-methyl-butyric acid ethyl ester (0.500 g, 2.5 mmol) was dissolved in THF (40 ml) and cooled to 0 ° C and added dropwise 2, 55 ml of LiAlH (1.0 M in ether) for 15 min. The reaction was allowed to warm to room temperature over 1 h and was quenched with the dropwise addition of a sat. of Na2SO4. The resulting suspension was dried over solid Na2SO4 and diluted with ethyl acetate, filtered through a pad of Celite and concentrated. 1 H NMR (CDCl 3) d: 1, 09 (d, 3 H), 1, 11 (m, 1 H), 1, 56 (s, 6 H), 1, 97 (s, 3 H), 2.08 (m, 1 H ), 2.16 (t, 2H), 3.67 (m, 2H), 4.67 (sextuplet, 1 H), 5.51 (sa, 1 H), 6.49 (m, 3H), 6 , 87 (t, 1 H), 6.96-7.61 (m, 10 H), 7.64 (m, 1 H). MS m / z: 568 (M + 1). (2S, 4R) -W- (4-Chloro-phenyl) - / V-. { 1- [4- (1-ethyl-piperidin-4-ylmethoxy) -benzoyl] -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl} -acetamide (H-52) Benzyl ester of (2S, 4R) - / V-4- (4-. {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl- benzyl ester was converted 3,4-dihydro-2H-quinoline-1-carbonyl.}. - phenoxymethyl) -piperidine-1-carboxylic acid (0.25 g) in the piperidine by hydrogenation with Pd / C (0.075 g) in a hydrogen atmosphere in Ethanol (17 ml). The reaction mixture was filtered through celite and concentrated to give (2S, 4R) - / V- (4-Chloro-phenyl) -? / -. { 2-methyl-1- [4- (piperidin-4-ylmethoxy) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -acetamide (0.17 g, 85%). The piperidine was reacted with acetaldehyde and Na (OAc) sBH in dichloromethane at room temperature overnight. Then, it was washed with 1 N NaOH, dried over MgSO, filtered and concentrated. The crude residue was purified by chromatography on silica gel (10% methanol / dichloromethane al 90%) to produce the product (55%). 1 H NMR (CDCl 3) d: 0.98-1, 18 (m, 7H), 1.37 (m, 2H), 1, 72-1, 93 (m, 5H), 2.04 (s, 3H) , 2.27 (m, 1H), 2.37 (c, 2H), 2.95 (m, 2H), 3.73 (d, 2H), 4.72 (sextuplet, 1 H), 5.58 (sa, 1 H), 6.52 (d, 1H), 6.67 (d, 2H), 6.86 (t, 1 H), 7.08-7.35 (m, 6H), 7, 38 (d, 2H). MS m / z: 560 (M + 1) (2S, 4R) -4 - [(4- 4- [Acetyl- (4-chloro-pheny] -amino] -2-methyl-3,4-dihydro -2H-quinoline-1 -carbonyl.} - phenyl) -methyl-amino] -butyramide (H-53) (2S, 4R) -4 - [(4- {4- [acetyl- (4 -chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl.} - phenyl) -methyl-amino] -butyramide from (2S, 4R) -4 - (4-. {4- [Acetyl- (4-ctoro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl) -phenyl) -piperazine -1 -carboxylic. The acid (0.050 g, 0.096 mmol) was dissolved in DMF (1 mL) at room temperature and HOBt (0.020 g, 0.144 mmol), HATU (0.055 g, 0.144 mol) and diisopropylethylamine (0.067 mL, 0.384 mmol) were added thereto. followed by ammonium chloride (0.011 g, 0.192 mmol) and stirred at room temperature for 16 h. The reaction was diluted with ethyl acetate, washed with 1 N NaOH, 1 N HCl and brine. The organic extracts were dried over MgSO 4, filtered and concentrated. The crude residue was purified by purification by HPLC. 1 H NMR (CDCl 3) d: 1, 10 (d, 3 H), 1, 18 (m, 1 H), 1.80 (t, 2 H), 2.00 (s, 3 H), 2.13 (t, 2H), 2.27 (m, 1 H), 2.85 (s, 3H), 3.27 (t, 2H), 4.70 (m, 1 H), 5.65 (a, 2H), 5.85 (sa, 1 H), 6.39 (d, 2H), 6.59 (d, 1 H), 6.93 (t, 1 H), 7.03-7.34 (m, 6H) ), 7.36 (d, 2H). MS m / z: 533 (M + 1). (2S, 4R) -4- (4- {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl} .-phenoxy) -3- (S) -hydroxy-butyric (H-54) It was dissolved (2S, 4R) - / V- (4-chloro-phenyl) -? / - [1- (4-hydroxy) -benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide (200 mg, 0.46 mmol) in DMF (5 ml) at room temperature. Cs2CO3 (374 mg, 1.15 mmol) was added followed by 4-bromo-3- (S) - (urea-butyl-dimethyl-silanyloxy) -butyric acid methyl ester (214 mg, 0.69 mmol) and The reaction was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure and dissolved in ethyl acetate (15 ml). The reaction mixture was washed with sat. NaHCO3. ac. (15 ml), water (15 ml) and brine (15 ml). The organic phase was dried over MgSO 4, filtered and concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel (gradient 5/95 ethyl acetate / hexane-50/50 ethyl acetate / hexane) to yield the light yellow solid product (74 mg, 37%). Ethyl (2S, 4R) -4- (4-. {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H- ethyl ester was dissolved. quinoline-1-carbonyl.]. phenoxy) -3- (S) - (fer-butyl-dimethyl-silanyloxy) -butyric acid (99 mg, 0.148 mmol) in THF (4 ml). To this solution was added tetrabutylammonium fluoride (1.0 M in THF, 1 ml). The reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure and dissolved in DCM (15 ml). The reaction mixture was washed with sat. NaHCO 3. ac. (15 ml), water (15 ml) and brine (15 ml). The organic phase was dried over MgSO 4, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (gradient 2/98 methanol / dichloromethane-10/90 methanol / dichloromethane) to yield the white solid product (41 mg, 51%). Methyl ester of (2S, 4R) -4- (4-. {4- [acetyl- (4-chloro-phenyl) -aminoj ^ -methyl-S ^ -dihydro ^ H-quinoline-1-carbonyl) was dissolved. -phenoxy-S-SS-hydroxy-butyric acid (41.2 mg, 0.075 mmol) in MeOH / THF (2: 1, 3 ml) To this solution was added 2 N LiOH (2 ml) .The reaction was stirred At room temperature for 18 hours, the reaction mixture was concentrated in vacuo to remove MeOH and THF, then a 6 N aqueous solution of HCl was added to acidify the reaction mixture to pH 2-3. it was extracted with DCM (5 ml x 3) The extract was washed with brine (15 ml) and dried over MgSO 4, filtered and concentrated The crude residue was purified by preparative HPLC to produce the product (35 mg, 87%). 1 H NMR (CDCl 3, 300 MHz) d: 1, 05-1, 14 (m, 4 H), 2.0 (s, 3 H), 2.25-2.27 (m, 1 H), 2.60- 2.62 (m, 2H), 3.87-3.88 (m, 2H), 4.28-4.34 (m, 1H), 4.70-4.77 (m, 1 H), , 58-5.62 (broad, 1 H), 6.49-6.93 (m, 4H), 7.12-7.39 (m, 8H). MS m / z: 538 (M + 1). (2S, 4R) -W-3- (4-. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1 -carbonyl} -phenoxy) -2,2-dimethyl-propionamide (H-55) Prepared (2S, 4R) -? / - 3- (4-. {4- [acetyl- (4-chloro-phenyl) - amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl.] - phenoxy) -2,2-dimethyl-propionamide from (2S, 4R) -A / -3 - (4- { 4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl.} - phenoxy) -2 , 2-dimethyl-propionic coupling NH4CI, HATU, DIEA, HOBt in DMF at room temperature to produce (2S, 4R) -? / - 4- (4-. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl.] - phenoxy) -butyramide. The reaction mixture was concentrated and partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over magnesium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel (10% methanol / 90% dichloromethane) to yield the product in 88% yield. 1 H NMR (CDCl 3) d: 1, 13 (d, 3 H), 1, 15 (t, 1 H), 1, 31 (s, 6 H), 1, 71 (sa, 1 H), 2.03 (s) , 3H), 2.27 (m, 1 H), 3.83 (c, 2H), 4.72 (sextuplet, 1H), 5.58 (sa, 1H), 6.17 (a, 1 H) , 6.52 (d, 1 H), 6.69 (d, 2H), 6.83 (t, 2H), 7.08-7.35 (m, 6H), 7.38 (d, 2H) . MS m / z: 534 (M + 1) (2S, 4R) -W- (1 -. {4- [2- (1-Acetyl-piperidin-4-yl) -ethoxy] -benzoyl}. 2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl) -A- (4-cyoro-phenyl) -acetamide (H-56) It was dissolved (2S, 4R) -? / - (4 -chlorine-phenyl) - / V-. { 2-methyl-1 - [4- (2-piperidin-4-yl-ethoxy) -benzoyl] -1, 2,3,4-tetrahydro-quinolin-4-yl} -acetamide (0.085 g, 0.15 mmol) in dichloromethane at room temperature and DIEA (0.1 g, 0.56 mmol) was added. Acetyl chloride (0.2 ml, 2.8 mmol) was added and the reaction was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo. The crude residue was purified by chromatography on silica gel (10% methanol / 90% dichloromethane) to yield the product (0.068 g, 75%). 1 H NMR (CDCl 3) d: 1, 15 (d, 3 H), 1, 15 (t, 1 H), 1, 21 (m, 2 H), 1, 58-1, 77 (m, 5 H), 1, 98 (s, 3H), 2.04 (s, 3H), 2.27 (m, 1 H), 2.51 (t, 1H), 2.98 (t, 1 H), 3.72 (m , 1 H), 3.93 (t, 2H), 4.51 (m, 1 H), 4.72 (sextuplet, 1H), 5.58 (sa, 1 H), 6.52 (d, 1H) ), 6.69 (d, 2H), 6.83 (t, 2H), 7.08-7.35 (m, 6H), 7.38 (d, 2H). MS m / z: 588 (M + 1) 4- (5- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinoline -1 (2H) -yl] carbonyl.} -2-fluorophenoxy) -2,2-dimethylbutanoic (H-57) To the solution of 4- (5- { [(2S, 4R) -4- [ methyl acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl} -2-fluorophenoxy) -2,2-dimethylbutanoate in MeOH / THF ( 1 ml / 1 ml) was added excess LiOH (1 N aqueous solution). The reaction mixture was stirred at rt overnight. The reaction was stopped by the addition of 6N HCl to pH 2. The mixture was concentrated under reduced pressure to remove MeOH and THF. DCM was added. The reaction mixture was washed with brine. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by preparative HPLC to produce the pure product. 1 H NMR (CDCl 3, 300 MHz) d: 0.90-0.94 (m, 2H), 1, 12-1, 14 (d, 3H), 1, 21-1, 24 (m, 3H), 1 , 60-1, 72 (m, 2H), 1, 95-2.03 (m, 1 H), 2.09 (s, 3H), 2.20-2.27 (m, 1 H), 3 , 45-3.59 (m, 1 H), 3.60-3.75 (m, 1 H), 4.65-4.75 (m, 1 H), 5.72-5.80 (m , 1H), 6.31-6.34 (m, 1 H), 6.45-6.47 (m, 1 H), 6.90-6.96 (m, 1H), 7.04-7 , 08 (m, 1 H), 7.15-7.20 (m, 3H), 7.24-7.36 (m, 6H). MS m / z: 567 (M + 1). / V- (4-chlorophenyl) -W - ((2S, 4R) -2-methyl-1 -. {4 - [(methylsulfonyl) amino] benzoyl] -1, 2,3,4-tetrahydroquinoline- 4-yl) acetamide (H-58) To a solution of? / - [(2S, 4R) -1- (4-aminobenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] -A / - (4-chlorophenyl) acetamide (208 mg, 0.48 mmol) in methylene chloride (4.0 ml) at 0 ° C was added methanesulfonic anhydride (175 mg, 1.01 mmol) and? /,? / - diisopropylethylamine (0.460 ml, 2.63 mmol). The reaction was warmed to room temperature and stirred for 4 days. (Analysis by LCMS indicated a mixture of the starting aniline, mono-sulfonamide and bis-sulfonamide). Additional methanesulfonic anhydride (170 mg, 0.98 mmol) was added and the reaction was stirred for a further 2 days at room temperature. The resulting reaction was diluted with dichloromethane (25 ml) and poured into a 1: 1 mixture of water and brine (25 ml). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to yield? / - ((2S, 4R) -1 -. {4- [bis (methylsulfonyl) amino] benzoyl} -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl) - / V- (4-chlorophenyl) acetamide crude (273 mg) as a yellow foam. The raw material was used directly in subsequent reactions. To a solution of? / - ((2S, 4R) -1-. {4- [bis (methylsulphonyl) amino] benzoyl} -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl. ) -? / - (4-chlorophenyl) acetamide (259 mg, 0.44 mmol) in tetrahydrofuran (5.0 ml) at room temperature was added 1.0 M sodium hydroxide (0.880 ml, 0, 88 mmol). The reaction was stirred at room temperature for 2 days. The resulting reaction mixture was poured into a 1: 1 mixture of water and saturated sodium bicarbonate (25 ml) and extracted with ethyl acetate (1 x 25 ml). The aqueous phase was neutralized by the addition of 1 N HCl to pH ~ 8 and extracted with ethyl acetate (2 x 25 ml). The combined organic layers were washed once with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to yield? / - (4-chlorophenyl) -? / - ((2S, 4R) -2- methyl-1 - { 4 - [(methylsulfonyl) amino] benzoyl] -1, 2,3,4-tetrahydroquinolin-4-yl) acetamide (190 mg, 76%) as a pale yellow foamy solid . 1 H NMR (CDCl 3) d: 1, 14 (d, 3 H), 2.04 (s, 3 H), 2.05-2.12 (m, 1 H), 2.20-2.35 (m, 1 H) ), 2.95 (s, 3H), 4.65-4.80 (m, 1 H), 5.44-5.66 (m, 1 H), 6.50 (d, 1 H), 6 , 88-7.01 (m, 3H), 7.07-7.32 (m, 6H), 7.35-7.46 (m, 3H). MS m / z: 512 (M + 1). [S ^^ - lacetil ^ -chloro-phenylJ-aminoJ ^ -methyl-S ^ -dihydro ^ H-quinoline-1-carbonyl} (2S, 4R) -1-methyl-pyrrolidine-2-carboxylic acid (p-phenoxy) -propyl] -amide (H-59) (2S, 4R) -? / - was dissolved. { 1- [4- (3-Amino-propoxy) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinol-4-yl} -? / - (4-chloro-phenyl) -acetamide (100 mg, 0.204 mmol) in methylene chloride (2 ml) and pyridine (2 ml). Add? / - methylproline (33 mg, 0.255 mmol) and EDC (63 mg, 0.255 mmol) were added and the reaction was stirred for 1 hour. The mixture was partitioned between methylene chloride and water; The methylene chloride layer was dried over MgSO 4, filtered and concentrated. The crude residue was purified by chromatography on silica gel (ethyl acetate) to produce the product. 1 H NMR (CDCl 3) d: 1.1 (s, 3 H), 1.2 (m, 1 H), 1.8 (m, 2 H), 2.0 (m, 2 H), 2.0 (s, 3H), 2.2 (m, 2H), 2.3 (m, 1 H), 2.4 (s, 3H), 2.6 (m, 1 H), 3.2 (m, 2H), 3.4 (c, 2H), 4.0 (t, 2H), 4.1 (m, 1 H), 4.8 (m 1 H), 5.6 (sa, 1 H), 6.5 (d, 1 H), 6.6 (d, 2H), 6.9 (t, 1 H), 7.2 (m, 6H), 7.4 (d, 2H). MS m / z: 603 (M + 1). 4- (4- { [(2R, 4S) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl} phenoxy ) -2,2-dimethylbutanoic (H-60) 4- (4 { [(2R, 4S) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4- acid was prepared dihydroquinolin-1 (2H) -yl] carbonyl, phenoxy) -2,2-dimethylbutanoic following the procedure for preparing 4- (4- { [(2S, 4R) -4- [acetiI (4-chlorophenyl) acid ) amino] -2-methyl-3,4-d-hydroquinolin-1 (2 - /) - il] carbonyl] phenoxy) -2,2-dimethylbutanoic acid, substituting? / - (4-chlorophenyl) ) -A / - [(2S, 4R) -1- (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl-acetamide by? / - (4-chlorophenyl) -? / - [(2R, 4S) -1- (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] acetamide. 1 H NMR (CDCl 3) d: 1, 14 (d, 3 H), 1, 15 (t, 1 H), 1, 25 (s, 6 H), 2.02 (t, 2 H), 2.05 (m, 2H), 2.27 (m, 1 H), 3.96 (t, 2H), 4.72 (sextuplet, 1 H), 5.52 (a, 2H), 5.58 (sa, 1 H) , 6.52 (d, 1H), 6.67 (d, 2H), 6.86 (t, 1H), 7.08-7.35 (m, 6H), 7.38 (d, 2H). MS m / z: 549 (M + 1). (2S, 4R) -? / - (1- { 4- [3- (Acetyl-ethyl-amino) -propoxy] -benzoyl.} -2-methyl-1, 2,3,4-tetrahydro- quinolin-4-yl) -? / - (4-chloro-phenyl) -acetamide (H-61) was dissolved (2S, 4R) -? / -. { 1- [4- (3-acetylamino-propoxy) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -? / - (4-chloro-phenyl) -acetamide (30 mg, 0.056 mmol) in DMF (1 ml). Sodium hydride (20 mg, 0.833 mmol) and iodoethane (10 drops by pipette) were added and the reaction was stirred at room temperature overnight. The mixture was partitioned between methylene chloride and water; The methylene chloride layer was dried over MgSO 4, filtered and concentrated. The crude residue was purified by preparative HPLC. 1 H NMR (CDCl 3) d: 1.1 (m, 7H), 2.0 (m, 8H), 2.3 (m, 1 H), 3.3 (c, 1H), 3.4 (c, 1H), 3.4 (t, 2H), 3.9 (t, 2H), 4.7 (m, 1H), 5.6 (sa, 1H), 6.5 (d, 1H), 6, 7 (d, 2H), 6.9 (t, 1 H), 7.2 (m, 6H), 7.4 (d, 2H). MS m / z: 562 (M + 1). N- (4-chlorophenyl) -W-. { (2S, 4R) -1- [4- (4-hydroxy-4-methylpentyl) benzoyl] -2-methyl-1,2,3,4-tetrahydroquinolin-4-yl} acetamide (H-62)? / - (4-chlorophenii) -? / - was prepared. { (2S, 4R) -2-methyl-1 - [4- (4-oxopentyl) benzoyl] -1,2,3,4-tetrahydroquinolin-4-yl} acetamide following general procedure H, substituting 6-trifluoromethylnicotinyl chloride for 4- (4-oxopentyl) benzoyl chloride to produce? / - (4-chlorophenyl) -? / -. { (2S, 4R) -2-methyl-1- [4- (4-oxopentyl) benzoyl] -1,2,3,4-tetrahydroquinolin-4-yl} Acetamida. 1 H NMR (CDCl 3): 1, 14 (d, 4 H), 1.87 (c, 2 H), 2.01 (s, 3 H), 2.04 (m, 1 H), 2.06 (s, 3 H) ), 2.32 (t, 2H), 2.52 (t, 2H), 4.74 (c, 1 H), 5.60 (a, 1 H), 6.47 (d, 1 H), 6.96 (m, 3H), 7.20 (m, 8H). MS m / z: 503 (M + 1). (4- (4-Oxopentyl) benzoyl chloride was prepared in six steps from pent-4-en-2-ol (as indicated below: pent-4-en-2-oI (4, 0 g, 46.44 mmol) in CH 2 Cl 2 (30 mL). TBDMSCI (13.93 g, 92.88 mmol) and imidazole (6.31 g, 92.88 mmol) were added at 0 ° C. The reaction was stirred at RT overnight, the organic phase was washed with sat'd NaHCO3 and brine, dried over MgSO4 and concentrated, The residue was purified by column chromatography (hexane) to give 5.14 g of the desired product. form of a colorless oil (55% yield). 1 H NMR (CDCl 3) d: 0.02 (s, 6H), 0.89 (s, 9H), 1, 11 (d, 3H), 2.14 ( c, 2H), 3.80 (c, 1 H), 5.03 (m, 2H), 5.80 (m, 1H) MS m / z: 200 (M + 1) To a solution of 4- ethyl iodobenzoate (4.15 g, 15.03 mmol) in DMF (20 ml), was added fer-butyl (dimethyl) [(1-methylbut-3-en-1-yl) oxy] silane (3, 0 g, 15.03 mmol) and Pd (OAc) 2 (342 mg, 1.50 mmol), triethylamine (2 mL, 30.06 mmol) and DPPP (1.05 g, 2.55 mmol) in an atmosphere from The mixture was stirred at 80 ° C overnight. After concentrating, the residue was dissolved in EtOAc (20 ml). The organic phase was washed with sat. NaHCO3. and brine, dried over MgSO4 and concentrated. The residue was purified by column chromatography (Hexane: EtOAc, 20: 1) to give 3.15 g of the desired product as a yellow oil (60% yield). 1 H NMR (CDCl 3) d: 0.02 (s, 6 H), 0.86 (s, 9 H), 1, 16 (d, 3 H), 1, 36 (t, 3 H), 2.34 (c, 2 H) ), 3.89 (c, 1 H), 4.34 (c, 2H), 6.38 (m, 2H), 7.36 (d, 2H), 7.95 (d, 2H). MS m / z: 348 (M + 1). To a solution of ethyl 4- (E-4- {[tert-butyl (dimethyl) syl) oxy] phenyl-1-en-1-yl) benzoate (3.15 g, , 07 mmol) in THF (10 ml) was added TBAF (18.15 ml, 18.15 mmol, 1 M solution in THF) at RT. The reaction mixture was stirred at RT for 2 h. The organic phase was washed with sat. NaHCO 3. and brine, dried over MgSO4 and concentrated. The residue was purified by column chromatography (hexane: EtOAc, 4: 1) to give 1.25 g of the desired product as a yellow oil (58% yield). 1 H NMR (CDCl 3) d: 1, 19 (d, 3 H), 1, 25 (t, 3 H), 2.34 (m, 2 H), 3.91 (m, 1 H), 4.34 (c, 2H), 6.38 (m, 2H), 7.36 (d, 2H), 7.93 (d, 2H). MS m / z: 237 (M + 1). A solution of ethyl 4 - [(1E) -4-hydroxypent-1-en-1-yl] benzoate (1.25 g, 5.29 mmol) and Pd / C (10% by weight, 0.125 g) in EtOH (20 ml) was degassed and bubbled through H2. The mixture was stirred at RT overnight. After filtering through celite, the organic solution was concentrated to give a colorless oil which was used in the next step without purification (1.1 g, 88% yield). 1 H NMR (CDCl 3) d: 1, 15 (d, 3 H), 1, 35 (t, 3 H), 2.70 (m, 2 H), 2.66 (t, 2 H), 3.80 (quant, 1 H), 4.33 (c, 2H), 7.23 (d, 2H), 7.94 (d, 2H). MS m / z: 239 (M + 1). To a solution of ethyl 4- (4-hydroxypentyl) benzoate (1.1 g, 4.62 mmol) and triethylamine (1.9 mL, 13.86 mmol) in CH2Cl2 (20 mL) was added trioxide complex. of sulfur and pyridine (2.2 g, 13.86 mmol) in JDMSO (2 ml) at 0 ° C. The mixture was stirred at 0 ° C for 2 h. The reaction mixture was washed with a 1N HCl solution, dried over MgSO and concentrated. The residue was purified by column chromatography (Hexane: EtOAc, 3: 1) to give 0.5 g of the desired product as a colorless oil (50% yield). 1 H NMR (CDCl 3) d: 1.36 (t, 3 H), 1.86 (c, 2 H), 2.09 (s, 3 H), 2.40 (t, 2 H), 2.67 (t, 2 H) ), 4.32 (c, 2H), 7.23 (d, 2H), 7.95 (d, 2H). MS m / z: 237 (M + 1). To a solution of ethyl 4- (4-oxopentyl) benzoate (500 mg, 2.11 mmol) in THF / EtOH / H 2 O (5 mL, 10: 1: 1) was added NaOH (254 mg, 6.33 mmol). mmol). The mixture was heated to reflux overnight. After acidification, the mixture was extracted with EtOAc. The combined organic phases were dried over MgSO4 and concentrated. The residue was purified by column chromatography (EtOAc) to give 0.31 g of the desired product as a white solid (70% yield). 1 H NMR (CDCl 3) 1, 87 (c, 2 H), 2.10 (s, 3 H), 2.50 (t, 2 H), 2.70 (t, 2 H), 7.24 (d, 2 H), 8.01 (d, 2H). MS m / z: 207 (M-1, ES-). To a solution of A / - (4-chlorophenyl) -? / - ((2S, 4R) -2-methyl-1- (4- (4-oxopentyl) benzoyl) -1, 2,3,4-tetrahydroquinoline- 4-μl) acetamide (40 mg, 0.079 mmol) in THF (2 ml) was added MeMgBr (68 μl, 0.095 mmol, 1.4 M solution in THF) at 0 ° C. The mixture was stirred at 0 ° C for 2 h. After inactivating with a sat solution. NH4Cl, the mixture was extracted with EtOAc. The combined organic phases were dried over MgSO4 and concentrated. The residue was purified by column chromatography (EtOAc) to give 16 mg of the desired product as a white solid (40% yield). 1 H NMR (CDCl 3): 1, 14 (m, 10 H), 1.37 (m, 2 H), 1.61 (m, 2 H), 2.01 (s, 3 H), 2.22 (m, 1 H ), 2.49 (t, 2H), 4.74 (c, 1 H), 5.60 (a, 1 H), 6.49 (d, 1 H), 6.97 (m, 3H), 7.20 (m, 8H). MS m / z: 519 (M + 1). ? / - (4-chlorophenyl) -W - [(2S, 4R) -1- (3,5-difluoro-4-hydroxybenzoyl) -2-methyl-1,2,3,4-tetrahydroquinolin-4-yl] acetamide (H-63) was dissolved / V- (4-chlorophenyl) -? / - [(2S, 4R) -1- (3,5-d? -fluoro-4-methoxybenzoyl) -2-methyl-1, 2 , 3,4-tetrahydroquinolin-4-yl] acetamide (200 mg, 0.41 mmol) in dichloromethane and a solution of BBr3 (1, 0 M in dichloromethane, 3.0 ml); the reaction mixture was stirred at room temperature until no starting material remained. The reaction mixture was carefully washed with sat. NaHCOs. and brine. The organic layer was dried over MgSO 4, filtered and concentrated.
The residue was purified by flash chromatography using a Hexane-EtOAc system to give? / - (4-chlorophenyl) -? / - [(2S, 4R) -1- (3,5-difluoro-4-hydroxybenzoyl) -2 -methyl-1, 2,3,4-tetrahydroquinolin-4-yl] acetamide (152 mg, 78%). 1 H NMR (CDCl 3) d: 1, 12 (d, 3 H), 1, 24 (m, 2 H), 2.07 (s, 3 H), 2.25 (a, 1 H), 4.70 (m, 1 H), 6.52 (d, 1 H), 6.78 (d, 2H), 7.18 (t, 1 H), 7.20-7.40 (m, 6H). MS m / z: 471 (M + 1) (2S, 4R) - [3- (4. {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl] -methyl ester l-3,4-dihydro-2H-quinoline-1-carbonyl.]. -phenoxy) -propyl] -carbamic acid (H-64). (2S, 4R) -N- was dissolved. { 1- [4- (3-amino-propoxy) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} - / V- (4-chloro-phenyl) -acetamide (150 mg, 0.30 mmol) in DCM (1 ml). To this solution was added TEA (36.4 mg, 0.36 mmol) followed by methyl chloroformate (34 mg, 0.36 mmol). The reaction mixture was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure and dissolved in DCM (15 mL). The reaction mixture was washed with sat. NaHCO 3. ac. (15 ml), water (15 ml) and brine (15 ml). The organic phase was dried over MgSO, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (gradient 5/95 ethyl acetate / hexane-50/50 ethyl acetate / hexane) to yield a white solid product (71 mg, 52%). 1 H NMR (CDCl 3, 300 MHz) d: 0.68-0.88 (m, 2H), 1, 00-1, 05 (m, 4H), 1, 23 (s, 3H), 1, 61-1 , 64 (width, 1H) 2.02 (s, 3H), 2.22-2.33 (m, 1 H), 3.31-3.37 (m, 1 H), 3.62 (s, 3H), 3.93-3.97 (m, 1 H), 4.73-4.75 (m, 1H), 5.28-5.31 (width, 1H), 6.50-6.93 ( m, 4H), 7.12-7.39 (m, 8H). MS m / z: 551 (M + 1). 5-. { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2W) -yl] carbonyl} methyl thiophene-2-carboxylate (H-65) 5- was prepared. { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yljcarbonyl} methyl thiophene-2-carboxylate following general procedure H, substituting 6-trifluoromethylnicotinyl chloride for methyl 5- (chlorocarbonyl) thiophene-2-carboxylate. (Methyl 5- (chlorocarbonyl) thiophene-2-carboxylate was prepared in one step from thiophene-2,5-dicarboxylic acid monomethyl ester.) Treatment of this carboxylic acid with oxalyl chloride and catalytic DMF yielded 5- ( chlorocarbonyl) thiophene-2-carboxylate methyl with a decent yield). The rest of the procedures were followed as indicated in general procedure H to produce 5-. { [(2S, 4R) -4- [acetyl (4-cyanophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2 - /) - yl] carbonyl} methyl thiophene-2-carboxylate. 1 H NMR (CDCl 3) d: 1, 10 (d, 3 H), 2.05 (s, 3 H), 2.20 (m, 1 H), 3.80 (s, 3 H), 4.65 (m, 1 H ), 5.50 (m, 1H), 6.45 (d, 1H), 6.80 (d, 1H), 7.00 (t, 1H), 7.15 (d, 2H), 7.20 -7.40 (m, 5H). MS m / z: 483 (M + 1). (2S, 4R) -5- (4-. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl} acid .-phenoxymethyl) -furan-2-carboxylic acid (H-66) was dissolved (2S, 4R) -? / - (4-chloro-phenyl) -A / - [1- (4-hydroxy-benzoyl) - 2-methyl-1, 2,3,4-tetrahydro-quinoIin-4-yl] -acetamide (0.28 g, 0.64 mmol) in DMF at room temperature and K 2 C 3 (0.125 g, 0.degree. 89 mmol). 5-Chloromethyl-furan-2-carboxylic acid methyl ester (0.130 g, 0.64 mmol) was added and the reaction was allowed to warm to 80 ° C overnight. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO 4, filtered and concentrated. The crude residue was purified by chromatography on silica gel to yield the product as a colorless oil with a yield of 53%. Hydrolyzed (2SJ4R) -5- (4-. {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H- methyl ester was hydrolyzed. quinoline-1-carbonyl) -phenoxymethyl) -furan-2-carboxylic acid (0.145 g, 0.25 mmol) in the acid was dissolved in tetrahydrofuran and ethanol and sodium hydroxide (1 N) was added thereto. The mixture was stirred at room temperature 4 hours. The mixture was cooled to rt and acidified to form a white precipitate. The solid was filtered to give (2S, 4R) -5- (4. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline) -1-carbonyl.} - phenoxymet [l] -furan-2-carboxylic acid in the form of a white solid. 1 H NMR (CDCl 3) d: 1, 12-1, 19 (m, 4 H), 2.03 (s, 3 H), 2.23-2.29 (m, 1 H), 4.73-4.75 (m, 1H), 4.95 (s, 2H), 5.59 (sa, 1 H) 6.48-6.51 (m, 2H), 6.69 (d, 2H), 6.91 ( t, 1H), 7.12-7.37 (m, 9H). MS m / z: 559 (M + 1). Amide of (2S, 4R) -? / - 5- (4- { 4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline- 1 -carbonyl.}. -phenoxy) -pentanoic acid (H-67) was dissolved (2S, 4R) -? / - (4-chloro-phenyl) -? / - [1- (4-hydroxy-benzoyl) ) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide (0.146 g, 0.34 mmol) in 5 ml of DMF at room temperature and K2CÜ3 (0.186 g, 1.35 mmol). 5-Bromo-pentanoic acid ethyl ester (0.14 g, 0.67 mmol) was added and the reaction was allowed to warm to 80 ° C overnight. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO 4, filtered and concentrated. The crude residue was purified by chromatography on silica gel (50% EtOAc / 50% Hexane) to yield the (2S, 4R) - / V-5- (4-. {4- [acetyl) ethyl ester - (4-Chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl.] - phenoxy) -pentanoic acid (0.148 g, 78%). The ester was hydrolysed in the acid by dissolving in 10 ml of tetrahydrofuran / methanol (1/1) and potassium hydroxide (0.182 g in 5 ml of water) was added thereto. The mixture was heated at 40 ° C for 3 hours. The mixture was cooled to rt and acidified to form a white precipitate. The solid was filtered to give (2S, 4R) - / V-5- (4-. {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4- acid. dihydro-2H-quinoline-1-carbonyl,.,. -phenoxy) -pentanoic acid (0.128 g, 91%). Amide of (2S34R) -? / - 5- (4-. {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline- 1-carbonyl.}. -phenoxy) -pentanoic acid from the coupling by NH CI, HATU, DIEA, HOBt in DMF at room temperature to produce (2S, 4R) -? / - 1- [2- (4- { 4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline] -1-carbonyl.} - phenoxy) - ethyl] -cyclobutanecarboxylic acid. The reaction mixture was concentrated and partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over magnesium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel (10% methanol / 90% dichloromethane) to produce the pure product in 69% yield. 1 H NMR (CDCl 3) d: 1, 13 (d, 3 H), 1, 15 (t, 1 H), 1.68 (m, 4 H), 1.95 (s, 3 H), 2.16-2, 37 (m, 3H), 3.86 (t, 2H), 4.72 (sextuplet, 1 H), 5.58 (sa, 1 H), 5.79 (sa, 1 H), 6.52 ( d, 1H), 6.67 (d, 2H), 6.86 (t, 1H), 7.08-7.35 (m, 6H), 7.38 (d, 2H). MS m / z: 534 (M + 1) W- (4-chlorophenyl) -W-. { (2S, 4R) -2-methyl-1 - [(2-methylpyrimidin-5-yl) carbonyl] -1,2,3,4-tetrahydroquinolin-4-yl} acetamide (H-68) A / - (4-chlorophenyl) -? / - was prepared. { (2S, 4R) -2-methyl-1 - [(2-methylpyrimidin-5-yl) carbonyl] -1,2,3,4-tetrahydroquinolin-4-yl} acetamide following general procedure H, substituting 6-trifluoromethylnicotinyl chloride for 2-methylpyrimidine-5-carbonyl chloride. (2-Methylpyridine-5-carbonyl chloride was prepared in four stages) To a solution of 3,3-dimethoxypropionate in ethylene glycol dimethyl ether was added sodium hydride at 0 ° C and then ethyl formate. The reaction mixture was heated to 50 ° C for 30 min and then stirred at room temperature for 20 h Anhydrous diethyl ether was added and the precipitate was filtered to give 2- (dimethoxymethyl) -3-methoxy-3-oxoprop Sodium -1-en-1-olate To a solution of acetamide hydrochloride in dimethylformamide was added preformed sodium 2- (dimethoxymethyl) -3-methoxy-3-oxoprop-1-ene-1-olate in the reaction mixture. it was heated at 100 ° C for 1 h to give methyl 2-methylpyrimidine-5-carboxylate, hydrolysis of the ester with sodium hydroxide gave 2-methylpyrimidine-5-carboxylic acid, the subsequent treatment of this carboxylic acid with oxalyl chloride and Catalytic DMF produced 2-methylpyrimidine-5-carbonyl chloride with a decent yield). The rest of the procedures were followed as indicated in general procedure H to produce? / - (4-chlorophenii) -? / -. { (2S, 4R) -2-methyl-1 - [(2-methy1-pyrimidin-5-yl) carbonyl] -1,2,3,4-tetrahydroquinolin-4-yl} acetamide. H NMR (CDCl 3) d: 1, 15 (d, 3H), 2.05 (s, 3H), 2.30 (m, 1H), 2.70 (s, 3H), 4.75 (m, 1 H), 5.55 (m, 1H), 6.50 (d, 1H), 7.00 (t, 1H), 7.20-7.45 (m, 6H), 8.40 (s, 2H) ). MS m / z: 435 (M + 1).
V- (4-chlorophenyl) - / V-. { (2S, 4R) -1 - [4- (1,1-dioxy-siazolidin-2-yl) benzoyl] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} acetamide (H-69) To a solution of? / - [(2S, 4R) -1- (4-aminobenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] -? / - (4-chlorophenyl) acetamide (321 mg, 0.74 mmol) in methylene chloride (7.0 mL) at 0 ° C was added triethylamine (0.644 mL, 4.70 mmol) and 3-chloropropane-1 chloride. -sulphonyl (0.610 ml, 4.90 mmol). The reaction was warmed to room temperature and stirred for 2 days. To the resulting reaction were added potassium carbonate (496 mg, 3.59 mmol) and? /,? / - dimethylformamide (2.0 ml). The reaction was stirred overnight (14 h) at room temperature. Then, 1 N sodium hydroxide (1.5 ml) was added and the reaction was stirred for 3 more days at room temperature. The resulting reaction was diluted with methylene chloride (15 ml) and poured into water (25 ml). The aqueous phase was extracted with methylene chloride (2 x 25 ml) and the combined organic layers were washed once with brine. Then, the organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel (gradient of 0-5% methanol / methylene chloride) to yield the 85% pure product (220 mg). A portion of this material (100 mg) was purified by HPLC to produce? / - (4-chlorophenyl) -? / -. { (2S, 4R) -1- [4- (1, 1-dioxidoisothiazolidin-2-yl) benzoyl] -2-methyl-1, 2,3,4-tetrahydroquinolyl-4-yl-acetamide pure (73 mg, 18 %). 1 H NMR (CDCl 3) d: 1, 10-1, 14 (m, 1 H), 1, 14 (d, 3 H), 2.02 (s, 3 H), 2.22-2.34 (m, 1 H), 2.45-2.56 (m, 2H), 3.30-3.40 (m, 2H), 3.66-3.76 (m, 2H), 4.67-4.82 ( m, 1 H), 5.54-5.64 (m, 1H), 6.52 (d, 1H), 6.93 (t, 1 H), 6.98-7.05 (m, 2H) , 7.12-7.31 (m, 5H), 7.34-7.42 (m, 3H). MS m / z: 538 (M + 1). N- (4-chlorophenyl) -N - [(2S, 4R) -1- (3,5-dichloro-4-ethylbenzoyl) -2-methyl-1,2,3,4-tetrahydroquinolin-4-yl] acetamide (H-70)? / - (4-chlorophenyl) -? / - [(2S34R) -1 - (3,5-dichloro-4-ethylbenzoyl) -2-methyl-1, 2,3 was prepared 4-tetrahydroquinolin-4-yl] acetamide following the general procedure H, substituting 6-trifluoromethylnicotinyl chloride for 4-ethyl-3,5-dichlorobenzoyl chloride. (4-Ethyl-3,5-dichlorobenzoyl chloride was prepared in two steps from 3,5-dichlorobenzoic acid.) To a solution of 3,5-dichlorobenzoic acid in tetrahydrofuran was added lithium diisopropylamide at -78. C. After the reaction mixture was stirred at -78 ° C for 1 h, ethyl iodide was added and the reaction mixture was stirred at room temperature for 2 h to give 4-ethyl-3,5- acid. dichlorobenzoic acid The subsequent treatment of this carboxylic acid with oxalyl chloride and catalytic DMF produced 4-ethyl-3,5-dichlorobenzoyl chloride with a decent yield). The rest of the procedures were followed as indicated in general procedure B to produce? / - (4-chlorophenyl) -? / - [(2S, 4R) -1- (3,5-dichloro-4-ethylbenzoyl) - 2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] acetamide. 1 H NMR (CDCl 3) d: 1.00 (t, 3 H), 1, 10 (d, 3 H), 2.05 (s, 3 H), 2.20 (m, 1 H), 2.80 (c, 2H), 4.65 (m, 1 H), 5.50 (m, 1 H), 6.50 (d, 1 H), 6.95 (d, 1H), 7.00 (s, 2H) , 7.2 (m, 3H), 7.25-7.40 (m, 3H). MS m / z: 517 (M + 1). Ethyl ester of (2S, 4R) -4- (4-. {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-) carbonyl.}. -phenoxy) -butyric (H-71) was dissolved (2SJ4R) -? / - (4-chloro-phenyl) -? / - [1- (4-hydroxy-benzoyl) -2-met L-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide in DMF at room temperature and K2CO3 was added thereto. Ethyl 4-bromobutyrate was added and the reaction was allowed to warm to 80 ° C overnight. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO, filtered and concentrated. The crude residue was purified by chromatography on silica gel (50% EtOAc / 50% Hexane) to produce the product. 1 H NMR (CDCl 3) d: 1, 10 (d, 3 H), 1, 11 (m, 1 H), 1, 20 (t, 3 H), 2.43 (t, 2 H), 1, 99 (s, 3 H) ), 2.24 (m, 1 H), 3.90 (t, 2H), 4.09 (c, 2H), 4.72 (sextuplet, 1 H), 5.55 (sa, 1 H), 6.49 (d, 1 H) < 6.62 (d, 2H), 6.90 (t, 1 H), 7.11 (d, 2H), 7.16 (m, 1 H), 7.18 (d, 2H), 7.26 (d, 1 H), 7.34 (d, 2H). MS m / z: 549 (M + 1). (2S, 4R) -3- (4-. {4- [Acetyl- (4-cyoro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-methyl ester carbonyl.}. phenoxymethyl) -benzoic acid (H-72). It was dissolved (2S, 4R) -? / - (4-chloro-phenyl) -? / - [1- (4-hydroxy-benzoyl) -2- methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide (150 mg, 0.35 mmol) in DMF (5 ml) at room temperature. Cs 2 C 3 (283 mg, 0.87 mmol) was added followed by methyl 3- (bromomethyl) benzoate (119 mg, 0.52 mmol) and the reaction was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure and dissolved in ethyl acetate (15 ml). The reaction mixture was washed with sat. NaHCO 3. ac. (15 ml), water (15 ml) and brine (15 ml). The organic phase was dried over MgSO 4, filtered and concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel (gradient 5/95 ethyl acetate / hexane-50/50 ethyl acetate / hexane) to yield the light yellow solid product (111 mg, 54%). 1 H NMR (CDCl 3, 300 MHz) d: 1, 02-1, 08 (d, 3 H), 1.55 (s, 1 H), 2.02 (s, 3 H), 2.24-2.32 ( m, 1 H), 3.88-3.91 (s, 3H), 4.70-4.78 (m, 1 H), 5.02-5.05 (s, 2H), 5.58- 5.61 (a, 1 H), 6.51-6.53 (m, 3H), 6.89-7.29 (m, 8H), 7.36-7.46 (m, 2H), 7 , 56-7.58 (m, 1 H), 7.97-8.04 (m, 2H). MS m / z: 584 (M + 1). Ethyl ester of (2S, 4R) -1- (4-. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1 - carbonii.}. phenyl) -piperidine-4-carboxylic acid (H-73). (2S, 4R) -1- (4-. {4- [acetyl- (4-chloro-phenyl)) ethyl ester was prepared. -amino] -2-methy1-3,4-d, 2-d-2H-quinoline-1-carbonyl, 4-phenyl) -piperidine-4-carboxylic acid from 4. { 4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1 -carbonyl} -phenyl ester of (2S, 4R) -trifluoro-methanesulfonic acid by adding ethyl ester of piperidine-4-carboxylic acid (4 equiv.), Cs2CO3 (3 equiv.), Pd2 (dba) 3 at 10%, BINAP (0 , 20 equiv.) And 18-Corona-6 at 10% (0.10 equiv.) In toluene at 110 ° C overnight. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO 4, filtered and concentrated. The crude residue was purified by HPLC to produce the product. 1 H NMR (CDCl 3) d: 1, 10 (d, 3 H), 1, 24 (m, 4 H), 1.54-1, 74 (mm, 4 H), 2.00 (s, 3 H), 2.27 (m, 1 H), 2.57 (m, 1 H), 2.80 (m, 1 H), 3.01 (m, 1 H), 3.48 (m, 1 H), 3.71 (m, 1H), 4.10 (c, 2H), 4.70 (m, 1 H), 5.56 (sa, 1 H), 6.56 (d, 1 H), 6.64 (d) , 2H), 6.92 (t, 1 H), 7.07-7.28 (m, 6H), 7.35 (d, 2H). MS m / z: 574.31 (M + 1). W- (4-Chlorophen? L) -W-. { (2S, 4R) -1 - [(6-ethylpyridin-3-yl) carbonyl] -2-methyl-1,2,3,4-tetrahydroquinolin-4-yl} acetamide (H-74)? / - (4-chlorophenyl) - / V- was prepared. { (2S, 4R) -1 - [(6-ethylpyridin-3-yl) carbonyl] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} acetamide following general procedure H, substituting 6-trifluoromethyl-nicotinyl chloride for 6-ethy-nicotinyl chloride. (6-Ethylnicotinyl chloride was prepared in two steps from methyl 6-chloronicotinate) To a solution of methyl 6-chloronicotinate (2.50 g, 14.6 mmol) in tetrahydrofuran (80 mL) and? / - methy1rolidone (3 ml) was added iron (III) acetylacetonate (500 mg), followed by the dropwise addition of a solution of ethylmagnesium bromide in ether (9.80 ml, 17.5 mmol) The reaction was stirred at room temperature for 2 hours (JACS 2002, 124, 13856-13863) .The resulting reaction was quenched using aqueous (saturated) ammonium chloride.The mixture was extracted with ethyl acetate and the organic extracts were separated and they were washed with brine, then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo The crude product was purified on silica gel by flash chromatography using hexanes / ethyl acetate (10-30%) to produce 6-ethylnicotinate of methyl with a yield of 66% .Then, the methyl ester was hydrogenated The reaction was carried out in the presence of aqueous lithium hydroxide in methanol at room temperature overnight to give 6-ethylnicotinic acid. Further treatment of 6-ethylnicotinic acid with oxalyl chloride and catalytic DMF in dichloromethane gave the desired 6-ethylnicotinyl chloride). 1 H NMR (CDCl 3) d: 1, 16 (d, 3 H), 1, 24 (t, 3 H), 1, 24-1, 26 (m, 1 H), 2.02 (s, 3 H), 2.24 -2.38 (m, 1 H), 2.70-2.85 (c, 2H), 4.70-4.80 (m, 1 H), 5.44-5.64 (m, 1H) , 6.50 (d, 1H), 6.92-6.98 (t, 2H), 7.20-7.40 (m, 8H), 8.50 (br s, 1 H). MS m / z: 448 (M + 1). (2S, 4R) -W- (4-Chloro-phenyl) - V-. { 2-methyl-1- [4- (3-trifluoromethanesulfonylamino-propoxy) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -acetamide (H-75) It was dissolved (2S, 4R) -? / -. { 1- [4- (3-amino-propoxy) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -? / - (4-Ctoro-phenyl) -acetamide (34 mg, 0.069 mmol) in methylene chloride (0.5 ml) and triethylamine (0.019 ml, 0.138 mmol) and cooled to -40 ° C. Trifluoromethanesulfonic anhydride (0.015 ml, 0.086 mmol) was added and the mixture was heated at 0 ° C for 30 minutes. The mixture was partitioned between methylene chloride and water; The methylene chloride layer was dried over MgSO, filtered and concentrated. The crude residue was purified by chromatography on silica gel (gradient of 1/1 hexanes / ethyl acetate-ethyl acetate) to produce the product. 1 H NMR (CDCl 3) d: 1.1 (s, 3 H), 1.2 (m, 1 H), 1.9 (m, 2 H), 2.0 (s, 3 H), 2.3 (m, 1 H ), 3.6 (m, 2H), 4.0 (t, 2H), 4.7 (m, 1 H), 5.6 (sa, 1 H), 6.5 (d, 1H), 6 , 6 (t, 1 H), 6.7 (d, 1 H), 6.9 (t, 1 H), 7.2 (m, 7H), 7.4 (d, 2H). MS m / z: 624 (M + 1). (2S, 4R) - / V- (4-Chloro-phenyl) -W- (2-methyl-1- { 4- [3- (2-oxo-oxazolidin-3-yl) -propoxy] -benzoyl ., -1, 2,3,4-tetrahydro-quinolin-4-yl) -acetamide (H-76) (2S, 4R) -? / - was dissolved. { 1- [4- (3-amino-propoxy) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -? / - (4-chloro-phenyl) -acetamide (50 mg, 0.102 mmol) in methylene chloride (3 ml) and triethylamine (0.150 ml, 1.08 mmol) and cooled to -40 ° C. 2-Bromoethyl-Ioroformate (0.016 ml, 0.153 mmol) was added and the reaction was allowed to warm to room temperature. After 1 hour at room temperature, DMF (2 ml) and Cs2CO3 (100 mg, 0.307 mmol) were added and the mixture was stirred overnight. The mixture was partitioned between methylene chloride and water; The methylene chloride layer was dried over MgSO, filtered and concentrated. The crude residue was purified by chromatography on silica gel (gradient of 1/1 hexanes / ethyl acetate-ethyl acetate) to produce the product. 1 H NMR (CDCl 3) d: 1.1 (s, 3 H), 1.2 (m, 1 H), 1.9 (m, 2 H), 2.0 (s, 3 H), 2.3 (m, 1 H), 3.4 (t, 2H), 3.5 (t, 2H), 3.9 (t, 2H), 4.3 (t, 2H), 4.7 (m, 1 H), 5.6 (br s, 1 H), 6.5 (d, 1 H), 6.6 (d, 2H), 6.9 (t, 1 H), 7.2 (m, 6H), 7, 4 (d, 2H).
MS m / z: 562 (M + 1). (2S, 4R) -3- (4-. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl} acid phenylamino) -propionic acid (H-77) (2S, 4R) -3- (4-. {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl- acid was prepared. 3,4-dihydro-2H-quinoline-1-carbonyl.] -phenylamino) -propionic following the procedure for (2S, 4R) -1- (4-. {4- [Acetyl- (4-ethyl) ethyl ester -chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1 -carbonyl}. phenyl) -piperidine-4-carboxylic acid, substituting piperidine-4-ethyl ester carboxylic acid by 3-amino-propionic acid methyl ester to produce the (2S, 4R) -3- (4-. {4- [acetyl- (4-chloro-phenyl) -amino] -2- methyl ester methyl-3,4-dihydro-2H-quinoline-1-carbonyl.] - phenylamino) -propionic acid. The ester was hydrolyzed in the acid by dissolving in tetrahydrofuran and ethanol, lithium hydroxide (1 N) was added and the mixture was heated at 50 ° C for 2 h. The mixture was cooled to room temperature and acidified to form a white precipitate. The solid was filtered to give to produce the product after purification by HPLC. 1 H NMR (CDCl 3) d: 1, 10 (d, 3 H), 1, 23 (m, 1 H), 2.03 (s, 3 H), 2.27 (m, 1 H), 2.51 (s) , 2H), 3.30 (t, 2H), 4.71 (m, 1 H), 5.61 (sa, 1 H), 6.27 (d, 2H), 6.59 (d, 1 H) ), 6.93 (t, 1 H), 7.01 (d, 2H), 7.02-7.27 (m, 4H), 7.37 (d, 2H), 8.90 (a, 1) H). MS m / z: 506.3 (M + 1). ? / - (4-chlorophenyl) -? / - [(2S, 4R) -1- (3,5-difluoro-4-methoxybenzoyl) -2-methyl-1,2,3,4-tetrahydroquinolin-4-yl ] acetamide (H-78)? / - (4-chlorophenyl) -? / - [(2S, 4R) -1 - (3,5-difluoro-4-methoxybenzoyl) -2-methyl-1, 2 was prepared 3,4-tetrahydroquinolyl-4-yl] acetamide following the general procedure H, substituting 6-trifluoromethylnicotinyl chloride for 3,5-difluoro-4-methoxybenzoyl chloride. (3,5-Difluoro-4-methoxybenzoyl chloride was prepared in a step of 3,5-difluoro-4-methoxybenzoic acid.) 3,5-Difluoro-4-methoxybenzoic acid was treated with oxalyl chloride and a catalytic amount of DMF to produce 3,5-difluoro-4-methoxybenzoyl chloride with a decent yield). The rest of the procedures were followed as indicated in general procedure H to produce? / - (4-chlorophenyl) -? / - [(2S, 4R) -1- (3,5-difluoro-4-methoxybenzoyl) - 2-methyI-1, 2,3,4-tetrahydroquinolin-4-yl] acetamide with a decent yield. 1 H NMR (CDCl 3) d: 1, 13 (d, 3 H), 1, 24 (m, 2 H), 2.02 (s, 3 H), 2.28 (a, 1 H), 3.94 (s, 3H), 4.70 (m, 1 H), 6.52 (d, 1 H), 6.72 (d, 2H), 6.90 (t, 1H), 7.17-7.23 (m , 3H), 7.28-7.38 (m, 3H). MS m / z: 484 (M + 1). Acid (2S, 4R) -4-. { 4- [4- (Acetyl-phenyl-amino) -2-methyl-3,4-dihydro-2H-quinoline-1 -carbonyl] -phenoxy} -2,2-dimethyl-butyric acid (H-79) 4- (4-. {4- [Acetyl- (4-cyoro-phenyl) -amino] -2-methyl-3,4-dihydro- acid was dissolved. 2H-quinoline-1-carbonyl.] - phenoxy) -2,2-dimethyl-butyric acid (300 mg, 0.545 mmol) in ethanol.
Pd / C (10% palladium) was added, followed by H2 gas (1 atm-balloon). After 3 hours, the reaction mixture was filtered and concentrated. The crude residue was purified by chromatography on silica gel (gradient from 100% ethyl acetate to 5% methanol / ethyl acetate) to yield the product. 1 H NMR (CDCl 3) d: 1, 1 (d, 3 H), 1, 2 (m, 1 H), 1.2 (s, 3 H), 1,3 (s, 3 H), 2.0 (s, 3H), 2.1 (t, 1 H), 2.3 (m, 1 H), 3.9 (m, 2H), 4.7 (m, 1 H), 5.6 (sa, 1 H), 5.9 ( d, 1H), 6.5 (d, 1H), 6.4 (d, 2H), 6.9 (t, 1 H), 7.2 (m, 7H), 7.4 (d, 2H) , 10.8 (sa, 1 H). MS m / z: 515 (M + 1). (2S, 4R) - (4-. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}. phenoxy) -fluoroacetic acid (H-80) (2S, 4R) - (4. {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3-ethyl ester was dissolved. , 4-dihydro-2H-quinoline-1-carbonyl.}. - phenoxy) -fluoro-acetic acid (100 mg) in methanol / THF (1: 1, 5 ml) and potassium hydroxide (1.0 g.) Was added thereto. N, 1 ml). After 1 hour, the reaction was acidified and extracted with methylene chloride. The organic layer was dried, filtered and concentrated. The crude residue was purified by chromatography on silica gel (gradient from 100% ethyl acetate to 5% methanol / ethyl acetate) to yield the product. 1 H NMR (CDCl 3) d: 1.1 (d, 3 H), 1.2 (m, 1 H), 2.0 (s, 3 H), 2.3 (m, 1 H), 4.8 (m, 1 HOUR), 5.6 (br s, 1 H), 5.9 (d, 1 H), 6.5 (d, 1H), 6.9 (m, 3H), 7.2 (m, 6H), 7.4 (d, 2H), 11, 1 (sa, 1 H). MS m / z: 511 (M + 1) (2S, 4R) -4- (4. {4- [Acetyl- (4-cyoro-phenyl) -amino] -2-methyl-3-ethyl ester , 4-dihydro-2H-quinoline-1-carbonyl.}. -phenoxy) -cyclohexanecarboxylic acid (H-81) To a solution of diethylazodicarboxylate (120 mg) in 5 ml of THF at 0 ° C was added PPh3 (181 mg ). The mixture was stirred for 10 min at 0 ° C. Then, (2S, 4R) -? / - (4-chloro-phenyl) -? / - [1- (4-hydroxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinol was added N-4-yl] -acetamide (200 mg). The mixture was stirred for 20 min at 0 ° C. 4-Hydroxy-cyclohexanecarboxylic acid ethyl ester (80 mg) was added. The final reaction mixture was stirred overnight at RT. The mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with sat. Sodium bicarbonate. aqueous and brine and dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (gradient of 30/70 hexanes / ethyl acetate) to produce (2S, 4R) -4- (4-. {4- [acetyl- (4-ethyl) ethyl ester. -chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl.] - phenoxy) -cyclohexanecarboxylic acid (100 mg, 37%). 1 H NMR (CDCl 3) d: 1, 13 (d, 4 H), 1, 22 (t, 3 H), 1, 26-1, 60 (m, 5 H), 2.00-2.18 (m, 5 H) , 2.20-2.39 (m, 3H), 4.11 (c, 2H), 4.72 (sextuplet, 1 H), 5.60 (sa, 1H), 6.53 (d, 1 H) ), 6.64 (d, 2H), 6.91 (t, 1H) 7, 11-7, 38 (m, 8H). MS m / z: 589 (M + 1). Acid (1R, 2R) -2 - [(4. {[[(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) - il] carbonyl.}. phenoxy) methyl] cyclopentanecarboxylic (H-82) The methyl ester of fraA7s-2-hydroxymethyl-cyclopentanecarboxylic acid (0.127 g, 0.81 mmol) was dissolved in 10 ml of toluene at room temperature with PPh3 (0.211 g, 0.81 mmol), then it was added? / - ( 4-chlorophenyl) -? / - [(2S, 4R) -1- (4-hydroxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinol-4-yl] acetamide ( 0.1 g, 0.23 mmol) and stirred for 5 min. DEAD (0.141 g, 0.81 mmol) was added and the reaction was stirred for 18 h at room temperature. The reaction was concentrated and purified by chromatography on silica gel (45% dichloromethane / 55% ethyl acetate) to yield 2 - [(4 { [(2S, 4R) -4- [acetyl (4 Methyl] -2-methyl-3,4-dihydroquinolin-1 (2H) -l] carbonyl, phenoxy) methyl] cyclopentanecarboxylate (0.12 g, 90%). 2 - [(4- {[[2S, 4R) -4- [acetyl (4-chlorophenol) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl was hydrolysed methyl carbonyl) phenoxy) methylene] cyclopentanecarboxylate in the acid was dissolved in 5 ml of methanol and potassium carbonate (0.100 g in 4 ml of water) was added. The mixture was stirred for 2 days. The mixture was cooled to room temperature and the methanol was removed in vacuo. The mixture was acidified to form a white precipitate. The solid was filtered to give acid (1R, 2R) -2 - [(4- {[[2S, 4R) -4- [acetyl (4-cyranophene) amino] -2-methyl-3,4- dihydroquinol-1 (2H) -I] carbonyl, phenoxy) methyl] cyclopentanecarboxylic acid (0.012 g, 10%) 1 H NMR (CDCl 3) d: 1.12 (m, 1H), 1, 18 (d, 3H), 1.51 (m, 1 H), 1.74 (m, 2H), 1.96 (m, 3H), 2.02 (s, 3H), 2.28 ( m, 1 H), 2.65 (m, 2H), 3.89 (m, 2H), 4.77 (m, 1 H), 5.60 (m, 1H), 6.48 (d, 1 H), 6.61 (m, 2H), 6.88 (t, 1 H), 7.19 (m, 6H), 7.37 (d, 2H). MS m / z: 562 (M + 1) (2S, 4R) -W- (4-Chloro-phenyl) -W-. { 2-methyl-1- [4- (3-ureido-propoxy) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -acetamide (H-84) To a solution of (2S, 4R) -? / -. { 1- [4- (3-Amino-propoxy) -benzoylj-2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} - / V- (4-chloro-phenyl) -acetamide (50 mg, 0.10 mmol) in DCM (1 ml) was added trimethylsilyl isocyanate (23 mg, 0.20 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction was stopped by the addition of 0.2 ml of water and concentrated under reduced pressure. The crude residue was purified by preparative HPLC to produce the product (9 mg, 17%). MS m / z: 536 (M + 1). (2S, 4R) -W- (4-Chloro-phenyl) - / V-. { 1 - [4- (2-imidazol-1-yl-ethoxy) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -acetamide (H-85) was dissolved (2S, 4R) -? / - (4-cioro-phenyl) -A / - [1- (4-hydroxy-benzoyl) -2-methyl-1, 2,3, 4-tetrahydro-quinolin-4-yl] -acetamide (0.065 g, 0.15 mmol) in DMF at room temperature and K2CO (0.12 g, 0.87 mmol) was added thereto. 1- (2-Bromo-ethyl) -1 H-imidazole (0.08 g, 0.45 mmol) was added and the reaction was allowed to warm to 80 ° C overnight. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO 4, filtered and concentrated. The crude residue was purified by chromatography on silica gel (10% methanol / 90% dichloromethane) to yield the product (0.06 g, 76%). 1 H NMR (CDCl 3) d: 1, 13 (d, 3 H), 1, 15 (t, 1 H), 1.98 (s, 3 H), 2.27 (m, 1 H), 4.13 (t , 2H), 4.28 (t, 2H), 4.72 (sextuplet, 1 H), 5.58 (sa, 1H), 6.48 (d, 1 H), 6.64 (d, 2H) , 6.91 (t, 1 H), 6.98 (s, 1 H), 7.03 (s, 1 H), 7.08-7.35 (m, 6H), 7.38 (d, 2H), 7.55 (s, 1 H). MS m / z: 529 (M + 1) (2S, 4R) -1- [3- (4. {4- [Acetyl- (4-chloro-phenyl) -amino] -2- ethyl ester methyl-3,4-dihydro-2H-quinoline-1-carbonyl.} - phenoxy) -propyl] -1-W-imidazole-2-carboxylic acid (H-86) was dissolved (2S, 4R) -? / - ( 4-chloro-phenyl) -? / - [1- (4-hydroxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide in DMF at room temperature and he added K2C? 3. 1- (3-Bromo-propyl) -1 / -imidazole-2-carboxylic acid ethyl ester (prepared from the corresponding dibromide and imidazole with NaH in THF) was added and the reaction allowed to warm to 80 ° C during one night. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO 4, filtered and concentrated. The crude residue was purified by chromatography on silica gel (5% MeOH / 95% CH 2 Cl 2 / NH 4 OH to 10% MeOH / 90% CH 2 Cl 2 / NH 4 OH) to produce the product. 1 H NMR (CDCl 3) d: 1, 10 (d, 3 H), 1, 11 (m, 1 H), 1.38 (t, 3 H), 2.01 (s, 3 H), 2.22 (m, 2H), 3.83 (m, 2H), 4.35 (c, 2H), 4.55 (m, 2H), 4.71 (sextuplet, 1 H), 5.58 (sa, 1 H), 6.49 (d, 1 H), 6.63 (d, 2H), 6.90 (t, 1 H), 7.08-7.28 (m, 9H), 7.36 (d, 1H) . Acid (2S, 4R) -W-4- (4-. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1 -carbonyl .}.-phenoxy) -2,2-dimethyl-butyric (H-87) It was dissolved (2S, 4R) -? / - (4-chloro-phenyl) -? / - [1- (4-hydroxy) -benzoii) -2-methylene-1, 2, 3,4-tetrahydro-quinolin-4-yl] -acetamide (0.126 g, 0.242 mmol) in 3 mL of DMF at room temperature and K2C? 3 (0.267 g, 1.94 mmol) was added thereto. 4-Bromo-2,2-dimethyl-butyric acid methyl ester (0.202 g, 0.969 mmol, prepared according to the procedure of Tetrahedron 1994, 50 (32), 9825-30) was added and the reaction was allowed to warm up. 80 ° C for one night. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO 4, filtered and concentrated. The crude residue was purified by chromatography on silica gel (50% EtOAc / 50% Hexane) to yield the methyl ester of (2S, 4R) -4- (4-. {4- [Acetyl] (4-Chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl) -phenoxy) -2,2-dimethyl-butyric acid (0.105 g, 77% ). The ester was hydrolyzed in the acid by dissolving in 6 ml of tetrahydrofuran / methanol (1/1) and potassium hydroxide (0.042 g in 2 ml of water) was added thereto. The mixture was heated at 40 ° C for 3 hours. The mixture was cooled to rt and acidified to form a white precipitate. The solid was filtered to give (2S, 4R) -? / - 4- (4-. {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4- acid. dihydro-2H-quinoline-1-carbonyl.] - phenoxy) -2,2-dimethyl-butyric acid (0.085 g, 83%). 1 H NMR (CDCl 3) d: 1, 14 (d, 3 H), 1, 15 (t, 1 H), 1, 25 (s, 6 H), 2.02 (t, 2 H), 2.05 (m, 2H), 2.27 (m, 1 H), 3.96 (t, 2H), 4.72 (sextuplet, 1 H), 5.52 (a, 2H), 5.58 (sa, 1 H) , 6.52 (d, 1H), 6.67 (d, 2H), 6.86 (t, 1H), 7.08-7.35 (m, 6H), 7.38 (d, 2H). MS m / z: 549 (M + 1). W- (4-Chlorophenyl) -W-. { (2S, 4R) -1 - [4- (1,1-difluoroethyl) benzoyl] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} Acetamide (H-88) - (4-chlorophenyl) -? / - was prepared. { (2S, 4R) -1- [4- (1,1-difluoroethyl) benzoyl] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} acetamide following general procedure H, substituting 6-trifluoromethylnicotinyl chloride for 4- (1,1-difluoroethyl) benzoyl chloride. (4- (1, 1-difluoroethyl) benzoyl chloride was prepared in 3 steps from 1- (4-iodophenyl) ethanone The treatment of 1- (4-iodophenyl) ethanone with trifluoride of [bis (2- methoxyethyl) amino] sulfur (1.7 equivalents) at 85 ° C in an argon atmosphere in the presence of ethanol (0.1 equivalents), then inactivating with saturated aqueous sodium bicarbonate followed by conventional aqueous treatment and chromatography (hexanes) produced 1- (1,1-difluoroethyl) -4-iodobenzene The subsequent exchange of lithium-halogen with n-butyllithium (1.2 equivalents) in THF at -78 ° C in an argon atmosphere and inactivating the resulting organolithium species by bubbling carbon dioxide through the reaction mixture produced 4- (1,1-difluoroethyl) benzoic acid which was converted to 4- (1,1-difluoroethyl) benzoyl chloride by treatment with thionyl chloride (2.2 equivalents) in dichloromethane at room temperature for 2 hours followed by removal of the volatiles in vacuo). The rest of the procedures were followed as indicated in general procedure H to produce? / - (4-chloropheni) -? / -. { (2S, 4R) -1- [4- (1,1-difluoroethyl) benzoyl] -2-methyl-1, 2,3,4-tetrahydroquinolyl-4-yl} acetamide. 1 H NMR (CDCl 3) d: 1, 16 (d, 3 H), 1, 22-1, 26 (m, 1 H), 1.82 (t, 3 H), 2.03 (s, 3 H), 2, 24-2.35 (m, 1H), 4.72-4.83 (m, 1H), 5.63 (sa, 1H), 6.47 (d, 1H), 6.90 (t, 1H) ), 7.16-7.46 (m, 10H). MS m / z: 483 (M + 1). iV - [(2S, 4R) -1- (3. {[[ferc-butyl (dimethyl) silyl] oxy] -4- fluorobenzoyl) -2-methyl-1,2,3, 4-tetrahydroquinolin-4-yl] -? / - (4-chlorophenyl) acetamide (H-89)? / - [(2S, 4R) -1- (3. {[[Ert-butyl (dimethyl)] was prepared Silyl] oxy.} -4-fluorobenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] - / V- (4-chlorophenyl) acetamide following the general procedure H, substituting 6-trifluoromethyl-nicotinyl by 3- chloride. { [tert-butyl (dimethyI) silyl] oxy} -4-fluorobenzoyl. (3- [{[[[(Butyl) (dimethyl) silylkoxy] -4-fluorobenzoyl chloride was prepared in one step from 3- {[[ferc-butyl (dimethyl) silyl] oxy}. 4-Fluorobenzoic acid, 3- [{[[ert-Butyl (dimethyl) silyl] oxy} -4-fluorobenzoic acid was treated with oxalyl chloride and a catalytic amount of DMF to produce sodium chloride., 5-difluoro-4-methoxybenzoyl with a decent yield). The rest of the procedures were followed as indicated in general procedure H to produce / V - [(2S, 4R) -1- (3. {[[Ert-butyl (dimethyl) siIiI] oxy]. 4-fluorobenzoyl) -2-methyl-1,2,3,4-tetrahydroquinolin-4-yl] - / V- (4-chlorophenyl) acetamide. 1 H NMR (CDCl 3) d: 0.1 (s, 9 H), 0.9 (s, 6 H), 1, 15 (d, 3 H), 2.07 (s, 4 H), 2.30 (a, 1 H), 4.75 (m, 1 H), 6.55 (d, 1 H), 6.68 (d, 1 H), 6.62-6.70 (m, 3 H), 7.15-7 , 25 (m, 4H), 7.35-7.42 (m, 2H). MS m / z: 568 (M + 1) (2S, 4R) -1- (4- {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3 -amide, 4-dihydro-2H-quinoline-1-carbonyl.} - phenyl) -piperidine-3-carboxylic acid (H-90) Amide of (2S, 4R) -1- (4-. acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}. phenyl) -piperidine-3-carboxylic acid from (2S) , 4R) -1 - (4- { 4- [acetyl- (4-chloro-phenyl) -amino] -2-methyI-3,4-dihydro-2H-quinol-1- carbonyl.}. phenyl) -piperidine-3-carboxylic acid. The acid (0.2 g, 0.366 mmol) was dissolved in DMF (3 ml) at room temperature and HOBt (0.74 g, 0.55 mmol), HATU (0.209 g, 0.55 mol) were added thereto. diisopropylethylamine (0.25 ml) followed by ammonium chloride (0.040 g, 0.74 mmol) and stirred at room temperature for 16 h. The reaction was diluted with ethyl acetate and washed with 1 N NaOH, 1 N HCl and brine. The organic extracts were dried over MgSO 4, filtered and concentrated. The crude residue was purified by purification by HPLC. 1 H NMR (CDCl 3) d: 1, 10 (d, 3 H), 1, 20 (m, 1 H), 1.73 (m, 2 H), 1.84 (m, 2 H), 2.01 (s, 3H), 2.24 (m, 2H), 2.65 (m, 2H), 3.66 (m, 2H), 4.70 (m, 1 H), 5.62 (a, 2H), 6 , 93 (a, 1 H), 6.56 (d, 1 H), 6.60 (d, 2H), 6.92 (t, 1 H), 7.05-7.27 (m, 6H) 7.37 (d, 2H). MS m / z: 545.3 (M + 1). (2S, 4R) -N-. { 1 - [4- (1-Acetyl-piperidin-4-ylmethoxy) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -W- (4-chloro-phenyl) -acetamide (H-91) (2S, 4R) - / V- (4-chloro-phenyl) -? / - was dissolved. { 2-methyl-1 - [4- (piperidin-4-ylmethoxy) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -acetamide (0.075 g, 0.14 mmol) in dichloromethane at room temperature. DIEA (0.1 ml, 0.56 mmol) and acetyl chloride (0.2 ml, 2.8 mmol) were added. The reaction was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The crude residue was purified by chromatography on silica gel (10% methanol / 90% dichloromethane) to yield the product (0.049 g, 49%). 1 H NMR (CDCl 3) d: 1, 13 (d, 3 H), 1, 15 (t, 1 H), 1, 24 (m, 2 H), 1.81 (m, 2 H), 1.93 (m, 1 H ), 2.04 (s, 3H), 2.09 (s, 3H), 2.27 (m, 1H), 2.55 (t, 1 H), 3.09 (t, 1H), 3, 73 (m, 2H), 3.85 (m, 1 H), 4.63 (m, 1 H), 4.72 (sextuplet, 1 H), 5.58 (sa, 1 H), 6.52 (d, 1 H), 6.67 (d, 2H), 6.86 (t, 1H), 7.08-7.35 (m, 6H), 7.38 (d, 2H). MS m / z: 574 (M + 1) Acid (2S, 4R) - / V-5- (4- { 4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3 , 4-dihydro-2H-quinoline-1-carbonyl.} - phenoxy) -2,2-dimethyl-pentanoic acid (H-92) (2S / 4R) -? / - (4-chloro-phenyl) - ? / - [1- (4-hydroxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide (0.12 g, 0.28 mmol) in 5 ml of DMF at room temperature and K2CÜ3 (0.155 g, 1.12 mmol) was added thereto. 5-Bromo-2,2-dimethyl-pentanoic acid ethyl ester (0.123 g, 0.56 mmol, prepared according to the procedure of Tetrahedron 1994, 50 (32), 9825-30) was added and the reaction was left Heat at 80 ° C overnight. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO 4, filtered and concentrated. The crude residue was purified by chromatography on silica gel (50% EtOAc / 50% Hexane) to yield (2S, 4R) -? - 5- (4-. {4- [acetyl-) methyl ester ( 4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl.] - phenoxy) -2,2-dimethyl-pentanoic acid (0.076 g , 48%). The ester was hydrolyzed in the acid by dissolving in 8 ml of tetrahydrofuran / methanol (1/1) and potassium hydroxide (0.03 g in 2 ml of water) was added thereto. The mixture was heated at 40 ° C for 3 hours. The mixture was cooled to rt and acidified to form a white precipitate. The solid was filtered to give the product (0.057 g, 79%). 1 H NMR (CDCl 3) d: 1, 13 (d, 3 H), 1, 15 (t, 1 H), 1, 27 (s, 6 H), 1, 70 (m, 4 H), 1, 1, 98 ( s, 3H), 2.28 (m, 1 H), 3.89 (t, 2H), 4.72 (sextuplet, 1 H), 5.58 (sa, 1H), 6.52 (d, 1 H), 6.67 (d, 2H), 6.86 (t, 1H), 7.08-7.35 (m, 6H), 7.38 (d, 2H) . MS m / z: 535 (M + 1) (2S, 4R) -4 - [(4. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-2-methyl ester 3,4-dihydro-2H-quinoline-1-carbonyl}. Phenyl) -methyl-amino] -butyric acid (H-93). (2S, 4R) -4 - [(4- {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl] -phenyl) -methyl-amino] -butyric acid from (2S, 4R) - (4-. {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-ethyl ester -carbonyl.}.-phenyl) -methylcarbamic acid. Ethyl (2S, 4R) - (4-. {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-ethyl ester was dissolved. carbonyl, phenyl) -methylcarbamic acid in acetonitrile (2 ml). Yodotrimethylsilane was added and the reaction was allowed to stir at room temperature overnight. The excess reagent was quenched by the addition of methanol (1 ml) and the mixture was concentrated under reduced pressure. The crude residue was partitioned between ethyl acetate and aqueous saturated sodium bicarbonate. The extracts were washed with 1 M sodium hydroxide, saturated aqueous sodium thiosulfate and brine, dried over sodium sulfate, filtered, concentrated and purified by chromatography on silica gel to produce A / - (4-chloro-phenyl) - ? / - [2-Methyl-1- (4-methylamino-benzoyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide. It was dissolved (2S, 4R) - (N- (4-chloro-phenyl) -? / - [2-methyl-1- (4-methylamino-benzoyl) -1,2,3,4-tetrahydro-quinolin-4 -yl] -acetamide (0.015 g, 0.033 mmol) in CH 2 Cl 2 (0.5 mL) at room temperature Sodium borohydride (0.007 g, 1.5 equiv.) was added followed by 4-oxo-butyric acid methyl ester ( 0.020 g, 4 equiv.) And the reaction was allowed to stir overnight The reaction mixture was concentrated in vacuo, the residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried MgSO, filtered and concentrated The crude residue was purified by chromatography on silica gel (gradient of 33% Hexane / EA) to produce the product.1H NMR (CDCl3) d: 1, 09-1, 24 ( m, 4H), 1.84 (m, 2H), 2.00 (s, 3H), 2.27 (m, 3H), 2.86 (s, 3H), 3.29 (t, 2H), 3.62 (s, 3H), 4.70 (m, 1 H), 5.58 (sa, 1 H), 6.39 (d, 2H), 6.59 (d, 1 H), 6, 96 (t, 1 H), 7.05-7.21 (m, 5H), 7.25 (d, 1 H), 7.36 (d, 2H) MS m / z: 548 (M + 1 Acid (2S, 4R) - / V-4- ( 4-. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl} -phenoxy) -2,2-difluoro-butyric acid (H-94) 2,2-difluoro-4-hydroxy-butyric acid methyl ester (0.27 g, 3.21 mmol, prepared according to the procedure of U.S. Patent 4421690) in toluene at room temperature with PPh3 (0.421 g, 3.21 mmol), then (2S, 4R) -? / - ( 4-chloro-phenyl) - / V- [1- (4-hydroxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinoyl-4-yl] -acetamide (0, 20 g, 0.46 mmol) and stirred for 5 min. DEAD (0.028 g, 3.21 mmol) was added and the reaction was stirred for 18 h at room temperature. The reaction was concentrated and purified by chromatography on silica gel (45% CH2CI2 / 55% EtOAc) to yield methyl ester of (2S, 4R) - / V-4- (4-. {4- [ acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl] -phenoxy) -2,2-difluoro-butyric acid ( , 23 g, 87%). The ester was hydrolysed in the acid by dissolving in 8 ml of tetrahydrofuran / methanol (1/1) and potassium hydroxide (0.1 g in 4 ml of water) was added thereto. The mixture was heated at 40 ° C overnight. The mixture was cooled to rt and acidified to form a white precipitate. The solid was filtered to give the product (0.038 g, 97%). 1 H NMR (CDCl 3) d: 1, 13 (d, 3 H), 1, 15 (t, 1 H), 2.04 (s, 3 H), 2.18-2.44 (sa, 4 H), 3, 95 (t, 2H), 4.72 (sextuplet, 1 H), 5.58 (sa, 1 H), 6.52 (d, 1 H), 6.67 (d, 2H), 6.86 ( t, 1H), 7.08-7.35 (m, 6H), 7.38 (d, 2H). MS m / z: 557 (M + 1). Acid { [3- (4-. {[[(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methy-3,4-dihydroquinolin-1 (2H) -yl] carbonyl} phenoxy ) propyl] amino} acetic acid (H-95) Acid was prepared. { [3- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinoline-1 (2H) -yl] carbonyl} phenoxy ) propyl] amino} acetic acid from (2S, 4R) - / V-. { 1- [4- (3-amino-propoxy) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} - / V- (4-chloro-phenyl) -acetamide. It was dissolved (2S, 4R) -? / -. { 1- [4- (3-amino-propoxy) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -? / - (4-chloro-phenyl) -acetamide (0.036 g, 0.07 mmol) in dimethylformamide and ethyl bromoacetate (0.008 ml, 0.07 mmol) and potassium carbonate (0.021 g, 14 mmol). The reaction was heated at 50 ° C for 17 h. The reaction was concentrated and purified using 50% ethyl acetate / 50% hexane to 100% ethyl acetate. 1 H NMR (CDCl 3) d: 0.91 (t, 1 H), 1, 12 (d, 3 H), 1, 24 (t, 3 H), 2.02 (s, 3 H), 2.04 (m, 2H), 2.28 (m, 1 H), 3.47-3.53 (m, 2H), 3.94-4.02 (m, 3H), 4.06 (m, 1 H), 4 , 10-4.22 (c, 2H), 4.54 (d, 2H), 4.72 (sextuplet, 1 H), 5.61 (sa, 1 H), 6.51 (d, 1 H) , 6.64 (d, 2H), 6.92 (t, 1 H), 7.12 (d, 2H), 7.16-7.21 (m, 3H), 7.27 (d, 1 H) ), 7.36 (d, 2H). MS m / z = 577 (M + 1).
Acid ethyl ester was hydrolysed. { [3- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolyl-1 (2H) -yl] carbonyl .}. phenoxy) propyl] amino} acetic acid was dissolved in tetrahydrofuran and ethanol and sodium hydroxide (1N) was added. The mixture was stirred at room temperature overnight. The mixture was cooled to rt and acidified to form a white precipitate. The solid was filtered to give acid. { [3- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinoline-1 (2H) -yl] carbonyl. phenoxy) propyl] amino} acetic acid (0.003 g, 60% yield). MS m / z: 564 (M + 1). (2S, 4R) -? / - 4- (4- { 4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1 -carbonyl .}. -phenoxy) -? / - ethyl-butyramide (H-96) (2S, 4R) -? / - 4- (4-. {4- [acetyl- (4-chloro-phenyl)] -amino] -2-methyl-3,4-dihydro-2H-quinoline-1 -carbonyl.} -1-ethylidene-penta-2,4-dienyloxy) -butyric acid (0.064 g, 0.123 mmoi) in the amide dissolving in THF (2 ml) at room temperature. HOBt (0.025 g), EDCI (0.028 g) and ethylamine (0.36 mmol) were added together with 2 drops of DMF and stirred at room temperature for 11 h. The reaction was diluted with ethyl acetate, washed with 1 N NaOH, 1 N HCl and brine. The organic extracts were dried over MgSO, filtered and concentrated. The crude residue was purified by chromatography on silica gel (50% ethyl acetate / 50% hexane to 100% ethyl acetate) to yield the product (0.050 g, 74%). 1 H NMR (CDCl 3) d: 1, 06 (t, 3 H), 1, 13 (d, 3 H), 1, 15 (t, 1 H), 1.81 (s, 1 H), 2, 04 (s, 3H), 2.06 (m, 2H), 2.27 (m, 1 H), 2.32 (t, 2H), 3.28 (c, 2H), 3.91 (t , 2H), 4.72 (sextuplet, 1 H), 5.66 (sa, 1 H), 6.52 (d, 1 H), 6.67 (d, 2H), 6.88 (t, 1 H), 7.08-7.35 (m, 6H), 7.38 (d, 2H). MS m / z: 548 (M + 1) (2S, 4R) -W- (4-Chloro-phenyl) -N-. { 2-methyl-1- [4- (3-pyrazol-1-yl-propoxy) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -acetamide (H-97) was dissolved (2S, 4R) -? / - (4-chloro-phenyl) -? / - [1- (4-hydroxy-benzoyl) -2-methyl-1, 2, 3,4-tetrahydro-quinolin-4-yl] -acetamide (75 mg, 0.17 mmol) in DMF (1 ml) at room temperature. K2CO3 (47 mg, 0.34 mmol) was added followed by 1- (3-bromopropyl) -pyrazol (64 mg, 0.34 mmol) (prepared from the reaction of 1,3-dibromopropane and pyrazole with sodium hydride in tetrahydrofuran). The reaction was allowed to stir at 70 ° C for 3 h. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water and then extracted three times with ethyl acetate. The organic layers were washed with brine, dried over MgSO 4, filtered and concentrated. The crude residue was purified by chromatography on silica gel (gradient of 1/99 methanol / dichloromethane-3/97 methanol / dichloromethane) to produce the product. 1 H NMR (CDCl 3) d: 1.1 (d, 3 H), 1.2 (m, 1 H), 2.0 (s, 3 H), 2.3 (m, 1 H), 2.3 (m, 2H), 3.8 (t, 2H), 4.3 (t, 2H), 4.7 (m, 1 H), 5.6 (m, 1 H), 6.2 (t, 1H), 6.5 (d, 1H), 6.65 (d, 2H), 6.9 (t, 1 H), 7.1-7.4 (m, 9H), 7.5 (s, 1 H) . MS m / z: 443/445 (M + 1). W- (4-chlorophenyl) -W-. { (2S, 4R) -1 - [(2-ethylpyrimidin-5-yl) carbonyl] -2-methyl-1,2,3,4-tetrahydroquinolin-4-yl} acetamide (H-98)? / - (4-chlorophenyl) -? / - was prepared. { (2S, 4R) -1 - [(2-Ethyl-pyrimidin-5-yl) carbonyl] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} acetamide following general procedure H, substituting 6-trifluoromethylnicotinyl chloride for 2-ethylpyrimidine-5-carbonyl chloride. (2-ethylpyrimidine-5-carbonyl chloride was prepared in four stages) To a solution of 3,3-dimethoxypropionate in ethylene glycol dimethyl ether was added sodium hydride at 0 ° C and then methyl formate. The reaction mixture was heated to 50 ° C for 30 min and then stirred at room temperature for 20 h Anhydrous diethyl ether was added and the precipitate was filtered to give 2- (dimethoxymethyl) -3-methoxy-3-oxoprop-1 Sodium-1-olate Into a solution of propionamide hydrochloride in dimethylformamide was added preformed sodium 2- (dimethoxymethyl) -3-methoxy-3-oxoprop-1-ene-1-olate in the reaction mixture. at 100 ° C for 1 h to give methyl 2-ethylpyrimidine-5-carboxylate The hydrolysis of the ester with sodium hydroxide gave 2-ethylpyrimidine-5-carboxylic acid The subsequent treatment of this carboxylic acid with oxalyl chloride and Catalytic DMF produced 2-ethylpyrimidine-5-carbonyl chloride with a decent yield). The rest of the procedures were followed as indicated in general procedure H to produce? / - (4-chlorophenyl) -? / -. { (2S, 4R) -2-methyl-1 - [(2-ethylpyrimidin-5-yl) carbonyl] -1, 2,3,4-tetrahydroquinolin-4-yl} acetamide. 1 H NMR (CDCl 3) d: 1, 15 (d, 3 H), 1, 25 (t, 3 H), 2.05 (s, 3 H), 2.30 (m, 1 H), 2.90 (c, 2H), 4.75 (m, 1 H), 5.55 (m, 1 H), 6.50 (d, 1 H), 7.00 (t, 1 H), 7.20-7.45 (m, 6H), 8.40 (s, 2H). MS m / z: 449 (M + 1). Acid (2S, 4R) -3- [3- (4- { 4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1- carbonyl.}. -phenoxy) -propyl] -5-methyl-3H-imidazole-4-carboxylic acid (H-99). It was dissolved (2S, 4R) -? / - (4-chloro-phenyl) -? / - [ 1- (4-hydroxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide in DMF at room temperature and K2C03 was added thereto. 3- (3-Bromo-propyl) -5-methyl-3H-imidazole-4-carboxylic acid ethyl ester (prepared from the corresponding dibromide and imidazole with NaH in THF) was added and the reaction allowed to warm to 80 ° C for one night. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO 4, filtered and concentrated. The crude residue was purified by chromatography on silica gel (2% MeOH / 98% CH 2 Cl 2 to 10% MeOH / 90% CH 2 Cl 2) to produce ethyl ester of the acid (2S), 4R) -3- [3- (4- { 4- [acetyl- (4-chloro-phenyl) -amino] -2-metii-3,4-dihydro-2H-quinoline-1-carbonyl .}. -phenoxy) -propyl] -5-methyl-3H-imidazole-4-carboxylic acid. The ester (0.080 g, 0.12 mmol) was hydrolysed in the acid by dissolving in tetrahydrofuran and ethanol and sodium hydroxide (1 N) was added thereto. The mixture was stirred at room temperature 16 hours. The mixture was cooled to room temperature and acidified to form a white precipitate. The solid was filtered to give (2S, 4R) -3- [3- (4. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4- acid. dihydro-2H-quinoline-1-carbonyl.] - phenoxy) -propyl] -5-methyl-3H-imidazole-4-carboxylic acid with a 61% yield. 1 H NMR (CDCl 3) d: 1, 13 (d, 3 H), 1, 29 (m, 1 H), 2.05 (s, 3 H), 2.34 (m, 2 H), 2.45 (m, 1H), 2.61 (s, 3H), 4.08 (m, 2H), 4.43 (m, 2H), 4.73 (sextuplet, 1H), 5.53 (sa, 1H), 6, 55 (d, 1 H), 6.73 (d, 2H), 6.96 (t, 1 H), 7.18 (m, 3H), 7.41 (m, 5H), 9.08 (s) , 1 HOUR).
MS m / z: 601 (M + 1). Acid 5-. { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl} thiophene-2-carboxylic acid (H-100) 5- was dissolved. { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2 - /) - yl] carbonyl} Thiophene-2-carboxylic acid methyl ester (80 mg, 0.17 mmol, 1 equiv.) in methanol (6 ml). A solution of potassium carbonate (200 mg, 1.4 mmol, 8 equiv.) In water (2 ml) was added and the reaction mixture was stirred at room temperature for 20 h. The mixture was concentrated and the residue was acidified with a 1 N aqueous solution of HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give 5- acid. { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2 - /) - yl] carbonyl} thiophene-2-carboxylic acid (76 mg, 99%). 1 H NMR (CDCl 3) d: 1, 10 (d, 3 H), 2.05 (s, 3 H), 2.25 (m, 1 H), 4.70 (m, 1 H), 5.55 (m , 1 H), 6.55 (d, 1 H), 6.85 (d, 1 H), 7.05 (t, 1 H), 7.15-7.45 (m, 7H). MS m / z: 469 (M + 1). Amide of (2S, 4R) -W-1- [2- (4-. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H- acid] quinoline-1-carbonyl.] - phenoxy) -ethyl] -cyclobutanecarboxylic acid (H-101) (2S, 4R) -? / - 1- [2- (4-. {4- [acetyl) amide was prepared - (4-Chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl.] - phenoxy) -eti] -cyclobutanecarboxylic acid (2S, 4R) ) -? / - 1- [2- (4- { 4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline- 1-carbonyl] -phenoxy) -ethyl] -cyclobutanecarboxylic by coupling NH CI, HATU, DIEA and HOBt in DMF at room temperature to produce (2S, 4R) -? M - [2- (2- (4-. {4- [Acetyl- (4-cioro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinol-1-carbonyl}. ) -ethyl-cyclobutanecarboxylic acid. The reaction mixture was concentrated and partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over magnesium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel (10% methanol / 90% dichloromethane) to produce the pure product (63%). 1 H NMR (CDCl 3) d: 1, 16 (d, 3 H), 1, 15 (t, 1 H), 1, 77-1, 96 (m, 4 H), 2.04 (s, 3 H), 2, 16-488 (m, 5H), 3.96 (t, 2H), 4.72 (sextuplet, 1 H), 5.58 (sa, 1 H), 6.52 (d, 1 H), 6.67 (d, 2H), 6.86 (t, 1 H), 7.08-7.35 (m, 6H), 7.38 (d, 2H). MS m / z: 560 (M + 1) (2S, 4R) -W- (4-Chloro-phenyl) -W-. { 2-methyl-1- [4- (2-oxo-oxazolidin-3-yl) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl > -acetamide (H-102) was dissolved? / - [1- (4-amino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -? / - (4- cyoro-phenyl) -acetamide (61 mg, 0.142 mmol) in methylene chloride (2 ml) and triethylamine (0.100 ml, 0.700 mmol) was added thereto. 2-Bromoethylchloroformate (0.023 ml, 0.213 mmol) was added and the reaction was allowed to warm to room temperature. After 1 hour at room temperature, DMF (2 ml) and CS2CO3 (100 mg, 0.307 mmol) were added and the mixture was stirred overnight. The mixture was partitioned between methylene chloride and water; The methylene chloride layer was dried over MgSO 4, filtered and concentrated. The crude residue was purified by chromatography on silica gel (gradient of 1/1 hexanes / ethyl acetate to 100% ethyl acetate) to yield the product. 1 H NMR (CDCl 3) d: 1, 2 (d, 3 H), 1, 2 (m, 1 H), 2.0 (s, 3 H), 2.3 (m, 1 H), 3.8 (t , 2H), 4.4 (t, 2H), 4.8 (m, 1H), 5.6 (m, 1H), 6.5 (d, 1 H), 6.9 (t, 1 H), 7.2 (m, 8H), 7.4 (d, 2H).
MS m / z: 504 (M + 1). 4- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl} phenoxy ) -2- (diethylamino) butanoic (H-103) 2-Fer- butoxycarbonylamino-4-hydroxy-butyric acid (0.79 g, 3.6 mmol) was dissolved in 15 ml of methanol at room temperature and added (trimethylsilyl) diazomethane (2 M solution in hexane) until the solution turned yellow. The mixture was concentrated to yield crude 2-tert-butoxycarbonylamino-4-hydroxy-butyric acid methyl ester. The ester was dissolved in 20 ml of toluene at room temperature with PPh3 (0.94 g., 3.6 mmol), then? / - (4-chlorophenyl) -? / - [(2S, 4R) -1- (4-hydroxybenzoyl) -2-methyl-1, 2,3, was added. 4-tetrahydroquinolin-4-yl] acetamide (0.31 g, 0.71 mmol) and stirred for 5 min. DEAD (0.626 g, 3.6 mmol) was added and the reaction was stirred for 18 h at room temperature. The reaction was concentrated and purified by chromatography on silica gel (45% CH2CI2 / 55% EtOAc) to yield 4- (4- { [(2S, 4R) -4- [acetyl (4- methyl chlorofenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl, phenoxy) -2 - [(ert-butoxycarbonyl) amino] butanoate (0.47 g) ). 4- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl was dissolved. phenoxy) -2 - [(urea-butoxycarbonyl) amine] butanoate in 20 ml of dichloromethane and 4 ml of HCl in dioxane (4 M) were added thereto. The mixture was stirred for 2 hours and concentrated. The residue was washed with ether and then partitioned between 1 M NaOH and dichloromethane. The dichloromethane layer was removed and dried with MgSO 4. Sodium triacetoxyborohydride (0.61 g, 2.9 mmol) and acetaldehyde (0.33 mL, 5.8 mmol) were added. The mixture was stirred for 2 days and washed with 1 M NaOH. The mixture was then concentrated and purified by chromatography on silica gel (40% CH2Cl2 / 60% EtOAc) to yield 4- (4-. { . ((2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methylene-3,4-d-hydroquinol-1 (2H) -l] carbonyl. phenoxy) -2- (diethylamino) butanoate methyl (0.075 g, 17%). It was hydrolyzed 4- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yljcarbonyl.} Phenoxy ) -2- (Diethylammonium) butanoate in the acid was dissolved in 6 ml of tetrahydrofuran / methanol (1/1) and potassium hydroxide (0.04 g in 2 ml of water) was added thereto. The mixture was heated at 50 ° C for 18 hours. The mixture was cooled to room temperature and concentrated. Then, it was neutralized with 1 M HCl and extracted with dichloromethane. The dichloromethane solution was dried and concentrated. The residue was purified by chromatography on silica gel (87% CH2CI2 / 13% methanol) to yield 4- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino]] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl, phenoxy) -2- (diethylamino) butanoic (0.04 g, 55%). 1 H NMR (CDCl 3) d: 1, 14 (m, 1 H), 1, 19 (d, 3 H), 1.38 (m, 7 H), 2.01 (m, 1 H), 2.03 (s, 3H), 2.31 (m, 2H), 2.92 (m, 2H), 3.26 (m, 2H), 3.75 (m, 1 H), 4.23 (m, 2H), 4 , 70 (m, 1 H), 5.58 (a, 2H), 6.48 (d, 1 H), 6.61 (d, 2H), 6.88 (t, 1 H), 7.19 (m, 6H), 7.37 (d, 2H). MS m / z: 593 (M + 1) 3- (4 { (2S, 4R) -4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl} - ferric-butyl ester -3,4-dihydro-2H-quinoline-1-carbonyl.} - benzylamino) -propionic (H-104)? / - was dissolved. { (2S, 4R) -1- [4- (aminomethyl) benzoyl] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} -? / - (4-chlorophenyl) acetamide (145 mg, 0.32 mmol) in methylene chloride (2.5 ml) and ferric-butyl acrolate (0.052 ml, 0.36 mmol) and stirred at room temperature during one night. The mixture was concentrated and then subjected to flash chromatography (5% hexanes / 50% ethyl acetate) to yield the title compound (159 mg, 85%) as a white solid. 1 H NMR (CDCl 3) d: 1, 13 (s, 3 H), 1, 15-1, 20 (m, 1 H), 1.41 (s, 9 H), 1.73-2.05 (m, 1 H), 2.02 (s, 3H), 2.20-2.37 (m, 1 H), 2.40 (t, 2H), 2.77 (t, 2H), 3.72 (s, 2H), 4.69-4.82 (m, 1 H), 5.42-5.76 (m, 1 H), 6.48 (d, 1 H), 6.87 (t, 1 H) , 7.08-7.31 (m, 8H), 7.37 (d, 2H). MS m / z: 576 (M + 1) W-. { (2S, 4R) -1- [3,5-Bis (trifluoromethyl) benzoyl] -6-chloro-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl} -W- (4-chlorophenyl) acetamide (H-105)? / - was prepared. { (2S, 4R) -1- [3,5-bis (trifluoromethyl) benzoyl] -6-chloro-2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} - / V- (4-chlorophenyl) acetamide following general procedure H to intermediate 4, substituting [(2S, 4R) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] carbamate benzyl by benzyl [(2S, 4R) -6-chloro-2-methyl-1, 2,3,4-tetrahydroxy-4-yl] carbamic acid. 1 H NMR (CDCl 3) d: 1, 16 (3 H, t), 1, 20 (1 H, m), 2.02 (s, 3 H), 2.25-2.37 (m, 1 H), 4 , 70-4.80 (m, 1 H), 5.42-5.56 (m, 1 H), 6.40 (d, 1 H), 6.90 (dd, 1H), 7.20-7.40 (m, 5H), 7.60 (s, 2H), 7.80 (s, 1 H). MS m / z: 589 (M + 1). N- (4-Chloro-phenyl) - / V - [(2S, 4R) -2-methyl-1- (4-pyrrolidin-2-yl-benzoyl) -1, 2,3,4-tetrahydro-quinoline- 4-yl] -acetamide (H-106) 2- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinoline- was dissolved. 1 (2 -) -ylcarbonylamino} phenol) pyrrolidine-1-benzylcarboxylate (237 mg, 0.381 mmol) in HBr / acetic acid (5 ml) and stirred for 2 h. The reddish suspension was partitioned between Et 2 O and 1 N HCl. The HCI / water layer was washed with 3 x Et 2 O to remove the benzyl bromide. The water layer was neutralized with 1 N NaOH and washed with 3 x methylene chloride. The organic layer was dried over MgSO) filtered and concentrated to yield the title compound (170 mg, 91%) as a white solid. 1 H NMR (CDCl 3) d: 1, 05-1, 20 (m, 1 H), 1, 13 (s, 3 H), 1, 50-1, 62 (m, 1 H), 1, 76-1, 90 (m, 2H), 2.02 (s, 3H), 2.05-2.20 (m, 2H), 2.20-2.38 (m, 1 H), 2.93-3.03 (m, 1H), 3.09-3.18 (m, 1H), 4.05 (t, 1H), 4.72-4.82 (m, 1H), 5.45-5.75 (m , 1H), 6.49 (d, 1 H), 6.88 (t, 1 H), 7.11-7.29 (m, 8H), 7.37 (d, 2H). MS m / z: 488 (M + 1) (2S, 4R) -W- (4-. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3-methyl ester , 4-dihydro-2H-quinoline-1-carbonyl.} - phenyl) -? / - methyl-succinamic (H-107) (2S, 4R) -? / - (4- { 4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl.} - phenyl) -? / - methyl-succ starting from (2S, 4R) -? / - [1- (4-Amino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] - / V- (4 -chloro-phenyl) -acetamide. To a solution of (2S, 4R) -? / - [1- (4-Amino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -? / - (4-Chloro-phenyl) -acetamide (115 mg, 0.265 mmol) in dichloromethane (5.0 mL) was added diisopropylethylamine (50 μL, 0.265 mmol) followed by the addition of Methylsuccinyl chloride (44 mg, 0.291 mmol) and stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and extracted with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was purified on silica gel by flash chromatography using hexane / ethyl acetate (1: 1), ethyl acetate (100%) and ethyl acetate / methanol (10%) to yield (2S, 4R) methyl ester ) - / V- (4-. {4- [Acetyl- (4-cioro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1 -carbonyl.} - phenyl) -succinámico (55 mg, 35%). 1 H NMR (CDCl 3) d: 1, 11 (3H, s; overlap 1H, t), 2.00 (3H, s), 2.30 (1H, m), 2.60-2.80 (2 x 2H, m), 3.70 (3H, s), 4, 70 (1 H, m), 5.55 (1 H, m), 6.55 (1 H, d), 6.90 (1 H, dd), 7.10-7.40 (9H, complex) 7.80 (1H, sa). ESI-MS m / z: 548 (M + 1). To a solution of (2S, 4R) - / V- (4-. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H) methyl ester -quinol-1-carbonyl) -phenyl) -succinnamic acid (55 mg, 0.100 mmol) in DMF was added sodium hydride (60% dispersion in oil). After 30 minutes, iodomethane (16 μl, 0.11 mmol) was added to the reaction mixture and stirred at room temperature overnight. The reaction was quenched with water and extracted with ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was purified on silica gel by flash chromatography using 100% ethyl acetate and 90% ethyl acetate / 10% methanol to yield (2S, 4R) - / - (4-. 4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl] -phenyl] -? / - methyl- succinamic (16 mg, 26%). 1 H NMR (CDCl 3) d: 1, 11 (3 H, s; overlap 1 H, t), 2.00 (3 H, s), 2.30 (1 H, m, 2 H, m), 2.60 (2 H , m), 3.18 (3H, s), 3.65 (3H, s), 4.80 (1H, m), 5.60 (1H,), 6.55 (1H, d), 6, 90 (1 H, dd), 7.00-7.40 (10H, complex). ESI-MS m / z: 562 (M + 1) (2S, 4R) -? / - (4-Chloro-phenyl) -W-. { 2-methyl-1 - [4- (3-pyrrol-1-yl-propoxy) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -acetamide (H-108) (2S, 4R) -? / - (4-chloro-phenyl) -? / - [1- (4-hydroxyl-benzoyl) -2-methyl-1, 2 was dissolved , 3,4-tetrahydro-quinolin-4-yl] -acetamide (75 mg, 0.17 mmol) in DMF (1 mL) at room temperature. K2C03 (47 mg, 0.34 mmol) was added followed by 1- (3-bromopropyl) -pyrrole and the reaction was allowed to stir at 70 ° C for 3 h. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water and then extracted three times with ethyl acetate. The organic layers were washed with brine, dried over MgSO, filtered and concentrated. The crude residue was purified by chromatography on silica gel (1/1 ethyl acetate / hexanes) to yield the product. 1 H NMR (CDCl 3) d: 1.1 (d, 3 H), 1.2 (m, 1 H), 2.0 (s, 3 H), 2.1 (m, 2 H), 2.3 (m, 1H), 3.8 (t, 2H), 4.1 (t, 2H), 4.8 (m, 1 H), 5.6 (m, 1H), 6.1 (d, 2H), 6 , 5 (d, 1 H), 6.6 (d, 2H), 6.65 (d, 2H), 6.9 (t, 1 H), 7.1-7.3 (m, 6H), 7.4 (d, 2H). MS m / z: 442/444 (M + 1). (2S, 4R) -2- (4-. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}. -phenoxy) -? Msopropyl acetamide (H-109) Obtained (2S, 4R) -2- (4- { 4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3 , 4-dihydro-2H-quinoline-1-carbonyl.}. -phenoxy) - / V-isopropyl-acetamide from ethyl ester of 4- ({4- [acetyl- (4-chloro-phenyl)] -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl-] -phenoxy) -acetic acid (0.050 g, 0.096 mmol) by the addition of isopropylamine (0.680 ml, 8 mmol) with rest of sodium cyanide in ethanol (1 ml) to give a 43% yield of (2S, 4R) -2- (4-. {4- [acetyl- (4-chloro-phenyl) -amino] -2 -methyl-3,4-dihydro-2H-quinoline-1-carbonyl.} - phenoxy) -N-isopropyl-acetamide after purification by HPLC. 1 H NMR (CDCl 3) d: 1, 12-1, 19 (m, 10 H), 2.02 (s, 3 H), 2.28 (m, 1 H), 4.11 (m, 1 H), 4 , 37 (s, 2H), 4.73 (m, 1 H), 5.59 (sa, 1 H), 6.24 (a, 1 H), 6.48 (d, 1 H), 6, 70 (d, 2H), 6.90 (t, 1H), 7.12-7.30 (m, 6H), 7.37 (d, 2H). MS m / z: 534 (M + 1). Ferric-butyl ester of (2S, 4R) -4- (4-. {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline- 1 -carbonyl.}. -phenyl) -piperazine-1-carboxylic acid (H-110). (2S, 4R) -4- (4-. {4- [acetyl-) ferric-butyl ester ( 4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl] -phenyl) -piperazine-1-carboxylic acid following the procedure for ethyl ester of the acid ( 2S, 4R) -1 - (4-. {4- [acetyl- (4-chloro-phenyl) -amino] -2-methylene-3,4-dihydro-2H-quinoxy -1-carbonyl.}. Phenyl) -piperidine-4-carboxylic acid, substituting piperidine-4-carboxylic acid ethyl ester for piperazine-1-carboxylic acid fer-butyl ester to produce the product. 1 H NMR (CDCl 3) d: 1, 10 (d, 3H), 1, 24 (m, 1H), 1.45 (s, 9H), 2.00 (s, 3H), 2.27 (m, 1 H), 3.12 (t , 4H), 3.52 (t, 4H), 4.71 (m, 1 H), 5.56 (sa, 1 H), 6.54 (d, 1 H), 6.62 (d, 2H) ), 6.92 (t, 1 H), 7.09-7.28 (m, 6H), 7.36 (d, 2H). MS m / z: 603.4 (M + 1). (2S, 4R) -? / - (4-Chloro-phenyl) -V- (1- {4- [2- (1-methanesulfonyl-piperidin-4-yl) -ethoxy] -benzoyl} - 2-methyl-1,2, 3,4-tetrahydro-quinolin-4-yl) -acetamide (H-111) 4- (2-Hydroxy-ethyl) -piperidine-1-ferric acid ester was dissolved carboxylic acid (0.119 g, 0.52 mmol) in toluene at room temperature with PPh3 (0.136 g, 0.52 mmol), then (2S, 4R) -? / - (4-chloro-phenyl) -? / - [1- (4-hydroxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide (0.150 g, 0.35 mmol) and was stirred for 5 min. DEAD (0.090 g, 0.52 mmol) was added and the reaction was stirred for 18 h at room temperature. The reaction was concentrated and purified by chromatography on silica gel (45% CH2CI2 / 55% EtOAc) to yield (2S, 4R) -4- [2- (4-. {4 - [acetyl- (4-cioro-phenyl) -amino] -2-methylene-3,4-dihydro-2H-quinoline-1-carbonyl] -phenoxy) -ethyl] -pyridine- 1-carboxylic acid (0.2 g, 90%) The ester was converted to (2S, 4R) -? / - (4-chloro-phenyl) - / V-. { 2-methyI-1- [4- (2-piperidin-4-yl-ethoxy) -benzoyl] -1, 2,3,4-tetrahydro-quinolin-4-yl} -acetamide being reacted with HCl (4 M in dioxane) in dichloromethane at room temperature for 3 hours. The piperidine was dissolved in dichloromethane at room temperature and DIEA was added. Methanesulfonyl chloride was added and the reaction was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo. The crude residue was purified by chromatography on silica gel (10% methanol / 90% dichloromethane) to yield the product in 76% yield. 1 H NMR (CDCl 3) d: 1, 13 (d, 3 H), 1, 15 (t, 1 H), 1, 22-1, 38 (m, 2 H), 1, 68-1, 87 (m, 5 H) , 2.04 (s, 3H), 2.27 (m, 1 H), 2.67 (t, 2H), 2.76 (s, 3H), 3.77 (m, 2H), 3.94 (t, 2H), 4.72 (sextuplet, 1H), 5.58 (sa, 1 H), 6.52 (d, 1H), 6.69 (d, 2H), 6.83 (t, 2H) ), 7.08-7.35 (m, 6H), 7.38 (d, 2H). MS m / z: 624 (M + 1) 4- (4- { [(2S, 4R) -4 - [(4-chlorophenyl) (propionyl) amino] -2-methyl-3,4-dihydroquinoline -1 (2H) -yl] carbonyl.}. Phenoxy) -2,2-dimethylbutane (H-112) 4- (4- { [(2S, 4R) -4 - [(4- chlorophenyl) (propionyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl] phenoxy) -2,2-dimethylbutanoate methyl in methanol / tetrahydrofuran / water (2 / 1/1), then sodium hydroxide (3 equivalents) was added and the reaction mixture was stirred at 40 ° C overnight. The mixture was concentrated, the residue was acidified with a 1 N aqueous solution of HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give 4- (4 { [(2S, 4R) -4- [(4-chlorophenyl) (propionyl) amino] ] -2-methyl-3,4-dihydroquinolin-1 (2 - /) - il] carbonyl, phenoxy) -2,2-dimethylbutanoic acid. 1 H NMR (CDCl 3) d: 1, 12-1, 16 (m, 6H), 1, 22-1, 32 (m, 1 H), 1.25 (s, 6H), 2.02 (t, 2H ), 2.13-2.31 (m, 3H), 3.95 (t, 2H), 4.70-4.77 (m, 1H), 5.60 (sa, 1 H), 6.52 (d , 1H), 6.62 (d, 2H), 6.91 (t, 1H), 7.11-7.24 (m, 6H), 7.37 (d, 2H). MS m / z: 563 (M + 1). (2S, 4R) -3- (4-. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl} acid .-phenoxymethyl) -benzoic acid (H-113) (2S, 4R) -3- (4-. {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl) methyl ester was dissolved. -3,4-dihydro-2H-quinoline-1-carbonyl.} - phenoxymethyl) -benzoic acid (93 mg, 0.16 mmol) in MeOH / THF (2: 1, 3 ml). To this solution was added LiOH (2 M in H2O, 2 ml). The reaction was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo to remove MeOH and THF. Then, a 6 N aqueous solution of HCl was added to acidify the reaction mixture to pH 2-3. The reaction mixture was extracted with DCM (5 ml x 3). The extract was washed with water (15 ml) and brine (15 ml) and dried over MgSO 4, filtered and concentrated under reduced pressure. The crude residue was purified by preparative HPLC to produce the product (90 mg, 100%). 1 H NMR (CDCl 3, 300 MHz) d: 1, 08-1, 09 (d, 3 H), 1, 21-1, 26 (s, 1 H), 2.03 (s, 3 H), 2.24- 2.32 (m, 1 H), 4.70-4.78 (m, 1 H), 5.02-5.05 (s, 2H), 5.58-5.61 (a, 1 H) , 6.51-6.53 (m, 3H), 6.89-7.29 (m, 8H), 7.36-7.46 (m, 2H), 7.56-7.58 (m, 1 H), 7.97-8.04 (m, 2H). MS m / z: 570 (M + 1). 3 - [(4- {[[2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl}. benzyl) amino] propanoic (H-114) 3- (4. {(2S, 4R) -4- [Acetyl- (4-cioro-phenyl) -amino] -2-- ferric acid ester was stirred. methyl-3,4-dihydro-2H-quinoline-1-carbonyl.} - benzylamino) -propionic acid (10 mg, 0.017 mmol, 1 equiv.) in a 1/1 mixture of methylene chloride / trifluoroacetic acid ( 0.8 ml) at room temperature for 2 h. The reaction mixture was concentrated to give 3 - [(4- {[[2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinoline-1 acid. (2 -) -yl] carbonyl.} Benzyl) amino] propanoic acid in the form of the trifluoroacetic acid salt (12 mg, quant). 1 H NMR (MeOD) d: 1, 05 (d, 3 H), 2,00 (s, 3 H), 2.35 (m, 1 H), 2.65 (t, 2 H), 3.15 (t, 2H), 4.10 (s, 2H), 4.70 (m, 1H), 5.50 (m, 1 H), 6.45 (d, 1 H), 6.80 (t, 1 H) , 7.10 (t, 1 H), 7.20-7.45 (m, 9H). MS m / z: 575 (M + 1). (2S, 4R) -W- (4-Chloro-phenyl) -? / -. { 1- [4- (3-methanesulfonylamino-propoxy) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -acetamide (H-115) It was dissolved (2S, 4R) -? / -. { 1- [4- (3-Amino-propoxy) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} - / V- (4-chloro-phenyl) -acetamide (29 mg, 0.059 mmol) in methylene chloride (0.5 ml) and triethylamine (10 drops by pipette) and cooled to -40 ° C. Methanesulfonyl chloride (5 drops by pipette) was added and the mixture was heated at 0 ° C for 30 minutes. The mixture was partitioned between methylene chloride and water; The methylene chloride layer was dried over MgSO 4, filtered and concentrated. The crude residue was purified by chromatography on silica gel (50% hexanes / 50% ethyl acetate - 100% ethyl acetate gradient) to give the product. 1 H-NMR (CDCl 3) d: 1.1 (d, 3 H), 1.2 (m, 1 H), 1.9 (m, 2 H), 2.0 (s, 3 H), 2.3 (m , 1 H), 2.9 (s, 3H), 3.3 (c, 2H), 3.9 (t, 2H), 4.6 (t, 1 H), 4.7 (m, 1 H ), 5.6 (br s, 1H), 6.5 (d, 1 H), 6.7 (d, 2H), 6.9 (t, 1 H), 7.2 (m, 6H), 7 , 4 (d, 2H). MS m / z: 570 (M + 1). Acid 4- [5-. { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl} -2-oxopyridin-1 (2H) -yl] -2,2-dimethylbutanoic acid (H-116) 4- [5-. { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2 -) -yl] carbonyl} -2-oxopyridin-1 (2H) -yl] -2,2-dimethylbutanoic from 4- [5-. { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methylene-3,4-dihydroquinolin-1 (2H) -yl] carbonyl} Methyl -2-oxopyridin-1 (2H) -yl] -2,2-dimethylbutanoate. 4- [5-. { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolyl-1 (2H) -yl] carbonyl} Methyl -2-oxopyrdin-1 (2 - /) - yl] -2,2-dimethylbutanoate (0.010 g, 0.017 mmol) was hydrolyzed to the acid by dissolving it in tetrahydrofuran and methanol and sodium hydroxide (1 N) was added. The mixture was stirred at room temperature overnight. The mixture was cooled to, acidified to pH = 5 with 1 N HCl to form a white precipitate (0.006 g, 63%). The solid was filtered to give 4- [5-. { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-metii-3,4-dihydroquinolin-1 (2ry) -yl] carbonyl} -2-oxopyridin-1 (2H) -yl] -2,2-dimethylbutanoic acid. MS m / z: 550 (M + 1). Acid (2S, 4R) -W-1- [2- (4-. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H- quinoline-1 -carbonyl.} - phenoxy) -ethyl] -cyclobutanecarboxylic acid (H-117) (2SJ4R) -? / - (4-Chloro-phenyl) -? / - [1- (4-hydroxy-benzoyl ) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide (0.17 g, 0.39 mmol) in 5 ml of DMF at room temperature and K2CO3 was added (0.333 g, 2.34 mmol). 1- (2-Bromo-ethyl) -cyclobutanecarboxylic acid ethyl ester (0.184 g, 0.78 mmol) prepared according to the procedure of Tetrahedron 1994, 50 (32), 9825-30 and the reaction was allowed to be added. heat at 80 ° C overnight. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO 4, filtered and concentrated. The crude residue was purified by chromatography on silica gel (50% EtOAc / 50% Hexane) to give the ethyl ester of 1- [2- (4-. {4- [acetyl- (4-cyoro- phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl] -phenoxy) -ethyl] -cyclobutanecarboxylic acid (0.155 g, 67%). The ester was hydrolyzed to the acid by dissolving it in 8 ml of tetrahydrofuran / methanol (1/1) and potassium hydroxide (0.08 g in 3 ml of water) was added. The mixture was heated at 40 ° C for 3 hours. The mixture was cooled to rt, acidified to form a white precipitate. The solid was filtered to give the product (0.145 g, 98%). 1 H-NMR (CDCl 3) d: 1, 13 (d, 3 H), 1, 15 (t, 1 H), 1, 96 (m, 4 H), 2.04 (s, 3 H), 2.27 (m , 1 H), 2.29 (t, 2H), 2.49 (m, 2H), 3.96 (t, 2H), 4.72 (sextet, 1H), 5.58 (sa, 1H), 6.52 (d, 1 H), 6.67 (d, 2H), 6.86 (t, 1 H), 7.08-7.35 (m, 6H), 7.38 (d, 2H) . MS m / z: 561 (M + 1) (2S, 4R) -? / - (4-Chloro-phenyl) -W- (2-methyl-1- { 4- [3- (2-oxo- imidazolidin-1-yl) -propoxy] -benzoyl.] -1, 2,3,4-tetrahydro-quinolin-4-yl) -acetamide (H-118) (2S, 4R) -? / - was dissolved. { 1- [4- (3-amino-propoxy) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -? - (4-chloro-phenyl) -acetamide (120 mg, 0.24 mmol) in DCM (3 ml) at room temperature. TEA (48 mg, 0.48 mmol) was added followed by 2-chloroethyl isocyanate (51 mg, 0.48 mmol) and the reaction was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure and dissolved in ethyl acetate (15 ml). The reaction mixture was washed with aq. NaHCO3. sat (15 ml), water (15 ml) and brine (15 ml). The organic phase was dried over MgSO 4, filtered and concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel (gradient from 5/95 ethyl acetate / hexane - 50/50 ethyl acetate / hexane) to give a light yellow solid product (163 mg, 100%). It was dissolved (2S, 4R) -N - [\ - (4-. {3- [3- (2-Chloro-ethyl) -ureido] -propoxy.} - benzoyl) -2-methyl-1, 2 , 3,4-tetrahydroquinoline-4-yl] - / V- (4-keto-phenyl) -acetamide (151 mg, 0.25 mmol) in DMF (3 mL) at room temperature. Cs2CO3 (98 mg, 0.30 mmol) was added. The reaction was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure and dissolved in ethyl acetate (15 ml). The reaction mixture was washed with aq. NaHCO3. sat (15 ml), water (15 ml) and brine (15 ml). The organic phase was dried over MgSO, filtered and concentrated under reduced pressure. The crude residue was purified by preparative HPLC to give the product (0.009 g, 6.4%). 1 H-NMR (CDCl 3, 300 MHz) d: 1, 11-1, 14 (d, 3 H), 1, 88-1, 93 (m, 1 H), 1.98-2.01 (m, 5H) , 2.26-2.27 (m, 1H), 3.27-3.29 (m, 1 H), 3.43-3.47 (1, 2H), 3.77-3.83 (m , 1 H) 3.93-3.96 (m, 1 H), 4.17-4.20 (m, 1H), 4.51-4.57 (m, 1H), 4.72-4, 74 (m, 1 H), 4.97-4.10 (broad, 1 H), 5.52-5.65 (a, 1H), 6.50-6.93 (m, 4H), 7, 12-7.39 (m, 8H). MS m / z: 562 (M + 1). (2S, 4R) -JV- (4-Chloro-phenyl) -W-. { 2-methyl-1- [4- (2-morpholin-4-yl-2-oxo-ethoxy) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -acetamide (H-119) was prepared (2S, 4R) -? / - (4-chloro-phenyl) -? / -. { 2-methyl-1 - [4- (2-morpholin-4-yl-2-oxo-ethoxy) -benzoyl] -1, 2,3,4-tetrahydro-quinolin-4-yl} -acetamide from (4- {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl) ethyl ester .).-.phenoxy) -acetic acid (0.050 g, 0.096 mmol) by the addition of morpholine (0.400 ml, 4.0 mmol) with traces of sodium cyanide in ethanol (1 ml) to give a 63% yield of (2S, 4R) - / V- (4-chloro-phenyl) -? / -. { 2-methyl-1- [4- (2-morpholin-4-yl-2-oxo-ethoxy) -benzoyl] -1,2,3,4-tetrahydro-quinoIin-4-yl} -acetamide after purification by HPLC. 1 H-NMR (CDCl 3) d: 1.13 (m, 4 H), 2.01 (s, 3 H), 2.27 (m, 1 H), 3.52-3.63 (m, 8 H), 4 , 67 (s, 2H), 4.76 (m, 1 H), 5.57 (sa, 1 H), 6.49 (d, 1 H), 6.70 (d, 2H), 6.90 (t, 1 H), 7.13-7.28 (m, 6H), 7.36 (d, 2H). MS m / z: 562 (M + 1). W- (4-Chlorophenyl) -W - [(2S, 4R) -1- (4-fluoro-3-vinylbenzoyl) -2-methyl-1,2,3,4-tetrahydroquinolin-4-yl] acetamide (H -120) was prepared? / - (4-chlorophenyl) -? / - [(2SJ4R) -1- (4-fIuoro-3-vinylbenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinoline- 4-yl] acetamide following the general procedure H, substituting 4-fluoro-3-vinylbenzoyl chloride for 6-trifluoromethyl-nicotinyl chloride. (4-Fluoro-3-vinylbenzoyl chloride was prepared in 4 steps from 3-bromo-4-fluorobenzoic acid.) 3-Bromo-4-fluorobenzoic acid was converted to methyl 3-bromo-4-fluorobenzoate by Treatment with trimethylsilyl diazomethane (1.5 equivalents) in benzene / methanol (4/1) at room temperature The subsequent reaction with tributyl (vinyl) tin (1.2 equivalents) in DMF in the presence of dichlorobis ( triphenylphosphine) of palladium (11) catalytic (0.1 equivalent) at 80 ° C under an argon atmosphere, followed by aqueous treatment and standard chromatography (10% ethyl acetate / hexanes), gave 4-fluoro-3 Methyl vinylbenzoate This material was dissolved in methanol / tetrahydrofuran / water (2/1/1) then lithium hydroxide (5.0 equivalents) was added and the reaction mixture was stirred at room temperature overnight. The mixture was concentrated, the residue was acidified with an aqueous solution of 1 N HCl and extracted with ethyl acetate. The mixture was washed with brine, dried over magnesium sulfate, filtered and concentrated to give 4-fluoro-3-vinylbenzoic acid. This material was converted directly to 4-fluoro-3-vinylbenzoyl chloride by treatment with thionyl chloride (2.5 equivalents) in dichloromethane at room temperature for 2 hours followed by removal of the volatiles in vacuo). The other procedures were followed as indicated in general procedure H to give N- (4-chlorophenyl) -? / - [(2S, 4R) -1- (4-fluoro-3-vinylbenzoyl) -2-methyl-1 , 2,3,4-tetrahydroquinolin-4-yl-acetamide. 1 H-NMR (CDCl 3) d: 1, 16 (d, 3 H), 1, 22-1, 26 (m, 1 H), 2.03 (s, 3 H), 2.24-2.31 (m, 1 H), 4.72-4.82 (m, 1 H), 5.31 (d, 1 H), 5.61 (sa, 1 H), 5.65 (d, 1 H), 6, 51 (d, 1 H), 6.71 (dd, 1H), 6.80 (dd, 1H), 6.91-7.01 (m, 2H), 7.15-7.31 (m, 4H) ), 7.37-7.45 (m, 3H). MS m / z: 463 (M + 1). W- (4-chlorophenyl) -iV - [(2S, 4R) -1- (4-ethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydroquinolin-4-yl] acetamide (H-121) ) Prepared / V- (4-chlorophenyl) -? / - [(2S, 4R) -1- (4-ethoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinoline-4-yl] acetamide following general procedure I, substituting bromoethane for ethyl 4-bromoacetate. 1 H-NMR (CDCl 3) d: 1, 14 (d, 3 H), 1, 17 (m, 1 H), 1.33 (t, 3 H), 2.02 (s, 3 H), 2.25 (m , 1 H), 3.93 (c, 2H), 4.69 (m, 1 H), 5.58 (a, 1 H), 6.52 (d, 1 H), 6.64 (d, 2H), 6.93 (t, 1 H), 7.18 (m, 6H), 7.36 (d, 2H). MS m / z: 463 (M + 1) Acid (2S, 4R) -1- (4-. {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4- dihydro-2H-quinoline-1-carbonyl.}. phenyl) -piperidine-4-carboxylic acid (H-122). (2S, 4R) -1- (4-. {4- [acetyl- (4 -chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl.] - phenyl) -piperidine-4-carboxylic acid from ethyl ester of (2S, 4R) -1- (4-. {4- [Acetyl- (4-cioro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl} -phenyl) -piperidine-4-carboxylic acid. The acid was hydrolysed by dissolving it in tetrahydrofuran and ethanol and lithium hydroxide (1 N) was added and heated at 50 ° C for 2 h. The mixture was cooled to room temperature, acidified to form a white precipitate. The solid was filtered to give to give the product after purification by HPLC. 1 H-NMR (CDCl 3) d: 1, 10 (d, 3 H), 1, 23 (m, 1 H), 1.64 (m, 2 H), 2.00 (m, 5 H), 2.34 (m , 1 H), 2.59 (m, 1 H), 2.84 (m, 1 H), 3.08 (m, 1 H), 3.40 (m, 1 H), 3.67 (m , 1 H), 4.71 (m, 1 H), 5.58 (sa, 1 H), 6.57 (d, 1 H), 6.66 (d, 2 H), 6.93 (t, 1 H), 7.07-7.28 (m, 6H), 7.37 (d, 2H), 9.30 (a, 1 H). MS m / z: 546.3 (M + 1). (2S, 4R) -W- (4-Chloro-phenyl) - 'V-. { 2-methyl-1- [4- (3-sulfamoyl-propoxy) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -acetamide (H-123) (2S, 4R) -3- (4- {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-) acid was dissolved. 2H-quinoline-1-carbonyl.]. Phenoxy) -propane-1-sulfonic acid (175 mg, 0.315 mmol) in methylene chloride (3 ml) and cooled to 0 ° C. PCI5 (78 mg, 0.378 mmol) was added and the reaction was stirred at room temperature overnight. The mixture was partitioned between methylene chloride and water; the organic layer was dried over Na2SO, filtered and concentrated. The crude sulfonyl chloride was dissolved in acetone (5 ml); concentrated ammonium hydroxide (3.5 ml) was added. After 15 minutes, the mixture was partitioned between methylene chloride and water; the organic layer was dried over Na2SO4, filtered and concentrated. The crude residue was purified by preparative HPLC to give the product. 1 H-NMR (CDCl 3) d: 1.1 (d, 3 H), 1.1 (m, 1 H), 2.0 (s, 3 H), 2.2 (m, 3 H), 3.2 (t, 2H), 3.9 (t, 2H), 4.8 (d, 1 H), 5.6 (sa, 1 H), 6.5 (d, 1 H), 6.6 (d, 2H) , 6.9 (t, 1H), 7.2 (m, 8H), 7.4 (d, 2H). MS m / z: 556 (M + 1). Acid 3-. { [(2SJ4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl} benzoic acid (H-124) 3- acid was prepared. { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methylene-3,4-dihydroquinolin-1 (2 - /) - yl] carbonyl} benzoic acid following general procedure H, substituting methyl 3- (chlorocarbonyl) benzoate for 6-trifluoromethyl nicotinyl chloride. (Methyl 3- (chlorocarbonyl) benzoate was prepared in one step from 3- (methoxycarbonyl) benzoic acid.) Treatment of this carboxylic acid with oxalyl chloride and catalytic DMF gave methyl 3- (chlorocarbonyl) benzoate with a good performance). The hydrolysis of 3-. { [(2SJ4R) -4- [Acetyl (4-cyanophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2 - /) - yl] carbonyl} Methyl benzoate with lithium hydroxide, water, methanol and tetrahydrofuran produced 3- acid. { [(2S, 4R) -4- [acetyl (4-cyranophene) amino] -2-methyl-3,4-dihydroquinolin-1 (2 - /) - il] carbonyl} benzoic. 1 H-NMR (CDCl 3) d: 1, 18 (d, 3 H), 1, 18 - 1, 26 (m, 1 H), 2.05 (s, 3 H), 2.27 - 2.39 ( m, 1 H), 4.74 - 4.86 (m, 1 H), 5.53 - 5.70 (m, 1 H), 6.48 (d, 1 H), 6.88 (t, 1 H), 7.13 -7.24 (m, 5 H), 7.32 (d, 1 H), 7.40 (d, 2 H), 7.97 - 8.02 (m, 1 H) ), 8.12 (sa, 1 H). MS m / z: 463 (M + 1). (2S, 4R) -W- (4-Chloro-phenyl) - / V-. { 1- [4- (3-cyano-propoxy) -benzoyl] -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl} -acetamide (H-125) was dissolved (2S, 4R) - / V- (4-Chloro-phenyl) -? / - [1- (4-hydroxy-benzoyl) -2-methyl-1, 2,3, 4-tetrahydro-quinolin-4-yl] -acetamide in DMF at room temperature and K2CO3 was added. 4-Bromobutylnitrile was added and the reaction was allowed to warm to 80 ° C overnight. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO, filtered and concentrated. The crude residue was purified by chromatography on silica gel (50% EtOAc / 50% Hexane) to give the product. 1 H-NMR (CDCl 3) d: 1, 13 (d, 3 H), 1, 15 (m, 1 H), 1, 90 (m, 1 H), 2.02 (s, 3 H), 2.09 ( m, 1 H), 2.30 (m, 1 H), 2.54 (t, 2H), 3.99 (t, 2H), 4.72 (sextet, 1 H), 5.6 (sa, 1 H), 6.52 (d, 1 H), 6.65 (d, 2H), 6.93 (t, 1 H), 7.15 (m, 5H), 7.27 (t, 1 H) ), 7.37 (d, 2H). MS m / z: 502 (M + 1). (2S, 4R) -W- (4-Chloro-phenyl) -? / - (2-methyl-1- { 4- [3- (3-methyl- [1,2,4] oxadiazole-5- il) -propoxy] -benzoyl.} -1,2,3,4-tetrahydro-quinolin-4-yl) -acetamide (H-126) was prepared (2S, 4R) -? / - (4-chloro- phenyl) -? / - (2-methyI-1 - { 4- [3- (3-methyl- [1, 2,4] oxadiazol-5-yl) -propoxy-3-benzoyl.} -1, 2 , 3,4-tetrahydro-quinolin-4-yl) -acetamide from (2S, 4R) -4- (4-. {4- [acetyl- (4-chloro-phenyl) -amino] methyl ester ] -2-methylene-3,4-dihydro-2H-quinoline-1-carbonyl.] - phenoxy) -butyric acid. Acetamide oxime was suspended (0, 0.43 g, 0.58 mmol) in THF under N2 atmosphere and NaH (60% dispersion in oil) (0.025 g, 1.0 mmol) was added followed by 4 Á molecular sieves and heated to 60 ° C. for 1 h. (2S, 4R) -4- (4- {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro- methyl ester was added. 2H-quinoline-1-carbonyl.]. Phenoxy) -butyric acid and was heated to reflux for 4.5 h. The reaction was filtered and concentrated and partitioned between CH2Cl2 and water. The aqueous layer was extracted 3x with CH2Cl2 and dried over MgSO4, filtered, concentrated and purified by chromatography on silica gel (100% EtOAc) to give (2S, 4R) -? / - (4-Chloro-phen I) - / V- (2-methyl-1 - { 4- [3- (3-methyl- [1, 2,4] oxadiazoI-5-yl) -propoxy] -benzoyl. , 2,3,4-tetrahydro-quinolin-4-yl) -acetamide with a 44% yield. 1 H-NMR (CDCl 3) d: 1, 12 (d, 3 H), 1, 13 (m, 1 H), 2.00 (s, 3 H), 2.23 (m, 2 H), 2.38 (s) , 3H), 3.00 (m, 2H), 3.96 (m, 2H), 4.72 (sextet, 1 H), 5.58 (sa, 1 H), 6.49 (d, 1 H) ), 6.62 (d, 2H), 6.91 (t, 1 H), 7.31-7.25 (m, 7 H), 7.34 (d, 1 H). MS m / z: 559 (M + 1). ? / - (4-chlorophenyl) -? / -. { (2S, 4R) -1- [4- (difluoromethoxy) benzoyl] -2-methyl-1,2,3,4-tetrahydroquinolin-4-yl} acetamide (H-127)? / - (4-chlorophenyl) - / V- was prepared. { (2S, 4R) -1 - [4- (difluoromethoxy) benzoyl] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} acetamide following general procedure I, substituting methyl chlorodifluoroacetate for ethyl 4-bromoacetate. 1 H-NMR (CDCl 3) d: 1, 16 (d, 3 H), 1, 17 (m, 1 H), 2.02 (s, 3 H), 2.29 (m, 1 H), 4.75 (m, 1 H), 5.58 (a, 1 H), 6.52 (d, 1 H), 6.93 (m, 3 H), 7.19 (m, 6 H), 7.38 (m, 3 H) . MS m / z: 485 (M + 1) (2S, 4R) -? / - 1- [2- (4-. {4- [Acetyl- (4-chloro-phenyl) -amino] - amide] - 2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl.} - phenoxy) -ethyl] -1H-imidazole-2-carboxylic acid (H-128) The amide of the acid (2S) was prepared , 4R) -? / - 1- [2- (4-. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline- 1-carbonyl] -phenoxy) -ethyl] -1H-imidazole-2-carboxylic acid from (2S, 4R) -? / - 1- [2- (4-. {4- [Acetyl] - (4-Chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl.] - phenoxy) -ethyl] -1 / - / - imidazole-2- carboxylic acid by coupling NH4CI, HATU, DIEA, HOBt in DMF at room temperature to yield the (2S, 4R) -? / - 1- [2- (4-. {4- [acetyl- (4- chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoIina-1 -carbonyl.} - phenoxy) -ethyl] -1H-imidazole-2-carboxylic acid. The reaction mixture was concentrated and partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over magnesium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel (10% methanol / 90% dichloromethane) to give the pure product in 67% yield. 1 H-NMR (CDCl 3): 1, 15 (d, 3 H), 1, 17 (t, 1 H), 2.03 (s, 3 H), 2.27 (m, 1 H), 4.26 (s) , 2H), 4.72 (sextet, 1 H), 4.78 (sa, 2H), 5.58 (sa, 1 H), 6.48 (d, 1 H), 6.64 (d, 2H) ), 6.91 (t, 1H), 6.98 (s, 1H), 7.03 (s, 1H), 7.08-7.40 (m, 10H). MS m / z: 572 (M + 1). (2S, 4R) - / V- (1 - { 4- [3- (4-Acetyl-piperazin-1-yl) -propoxy] -benzoyl.} -2-methyl-1, 2,3, 4-tetrahydro-quinolin-4-yl) -? / - (4-chloro-phenyl) -acetamide (H-129) It was dissolved (2S, 4R) -? / - (4-cioro-phenyl) -? / - . { 2-methyl-1 - [4- (3-piperazin-1-yl-propoxy) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -acetamide (168 mg) in CH2Cl2 (2 ml). Acetic chloride (47 mg) and DIEA (52 μl) were added. The reaction mixture was stirred at room temperature overnight. The organic phase was washed with sat. NaHCO 3. (2 x 5 ml), dried over Na2SO4 and concentrated. The residue was purified by chromatography on silica gel (EtOAc) to give (2S, 4R) -N- (1- {4- [3- (4-acetyl-piperazin-1-yl) -propoxy] - Pure benzoyl.} -2-methyl-1, 2,3,4-tetrahydro-quinolyl-4-yl) -? / - (4-cyclo-phenyl) -acetamide (100 mg, 57% ). 1 H-NMR (CDCl 3) d: 1, 13 (d, H), 1, 88-1, 94 (m, 2H), 2.02 (s, 3H), 2.06 (s, 3H), 2, 20-2.48 (m, 7H), 3.43 (sa, 2H), 3.59 (sa, 2H), 3.94 (t, 2H), 4.74 (sextet, 1H), 5, 60 (br s, 1 H), 6.53 (d, 1H), 6.66 (d, 2H), 6.91 (t, 1 H) 7.11-7.38 (m, 8H). MS m / z: 603 (M + 1). Ethyl ester of (2S, 4R) -1- (4- {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1 - carbonyl.}. phenyl) -piperidine-3-carboxylic acid (H-130) The ethyl ester of the acid (2S, 4R) -1- (4- {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1 -carbonyl} -phenyl ) -piperidine-3-carboxylic acid was prepared following the same procedure as for the ethyl ester of (2S, 4R) -1- (4- {4- [Acetyl- (4-chloro-phenyl)) ethyl ester. -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl.} - phenyl) -piperidine-4-carboxylic acid, substituting the ethyl ester of piperidine-3-carboxylic acid for ethyl ester of acid piperidine-4-carboxylic acid to produce the product. 1 H-NMR (CDCl 3) d: 1, 10 (d, 3 H), 1, 23 (t, 3 H), 1, 23 (m, 1 H), 1.77 (m, 2 H), 1.94 (m , 2H), 2.01 (s, 3H), 2.28 (m, 1H), 2.40 (m, 1H), 2.77 (t, 2H), 3.62 (m, 2H), 4 , 11 (c, 2H), 4.70 (m, 1H), 5.58 (sa, 1 H), 6.56 (d, 1 H), 6.64 (d, 2H), 6.92 ( t, 1 H), 7.07-7.28 (, 6H), 7.35 (d, 2H). MS m / z: 574.4 (M + 1). 5- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -l] carbonyl acid} -2-fluorophenyl) -2,2-dimethylpentanoic acid (H-131) 5- (4 { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl was dissolved Methyl -3,4-dihydroquinolin-1 (2 - /) - il] carbonyl} -2-fluorophenyl) -2,2-dimethylpentanoate (70 mg, 0.12 mmol, 1 eq.) In methanol / tetrahydrofuran (2/1) (3 ml). A solution of sodium hydroxide (8 mg, 0.20 mmol, 1.7 eq.) In water (1 ml) was added and the reaction mixture was heated at 40 ° C for 8 h. The mixture was concentrated and the residue was acidified with an aqueous solution of 1N HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give the crude acid. Purification by chromatography on silica gel (methylene chloride / methanol gradient: 99/1 to 98/2) gave the acid 5- (4- { [(2SJ4R) -4- [acetiI (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2 - /) - yl] carbonyl] -2- fluorophenyl) -2,2-dimethylpentanoic acid (56 mg, 84%). 1 H-NMR (CDCl 3) d: 1.15 (d, 3H), 1.50 (m, 4H), 2.05 (s, 3H), 2.30 (m, 1 H), 2.55 (m , 2H), 4.80 (m, 1 H), 5.60 (m, 1 H), 6.55 (d, 1 H), 6.75 (d, 1 H), 6.90 (m, 3H), 7.20-7.40 (m, 6H). MS m / z: 565 (M + 1). (2S, 4R) -W- (4-Chloro-phenyl) -lV- (2-methyl-1 -. {4- [3- (2-oxo-pyrrolidin-1-yl) -propoxy] -benzoyl} -1, 2,3,4-tetrahydro-quinolin-4-yl) -acetamide (H-132) A / - (3-hydroxypropyl) -2-pyrrolidone was dissolved in benzene at room temperature by adding PPh3 (0.044 g) , 0.16 mmol), (2S, 4R) -? / - (4-chloro-phenyl) -? / - [1- (4-hydroxy-benzoyl) -2-methyl-1, 2,3,4- tetrahydro-quinolin-4-yl] -acetamide (0.100 g, 0.22 mmol) and stirred for 5 min. DEAD (0.029 g, 0.16 mmol) was added and the reaction was stirred for 18 h at room temperature. The reaction was concentrated and purified by chromatography on silica gel (4% MeOH / 96% CH 2 Cl 2 a MeOHal 5% / CH2CI2 a! 95% to 6% MeOH / 94% CH2Cl2) to give the product in 45% yield. 1 H-NMR (CDCl 3) d: 1, 13 (d, 3 H), 1, 14 (m, 1 H), 1.96 (m, 4 H), 2.02 (s, 3 H), 2.34 (t , 3H), 3.39 (c, 4H), 3.90 (m, 2H), 4.72 (sextet, 1H), 5.59 (sa, 1H), 6.52 (d, 1H), 6, 63 (d, 2H), 7.18 (m, 6H), 7.37 (d, 2H). MS m / z: 560 (M + 1). (2S, 4R) -? F- (4-Chloro-phenyl) -N-. { 1- [4- (3-ethyl-2-oxo-oxazolidin-5-ylmethoxy) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -acetamide (H-133) Prepared (2S, 4R) - / V- (4-chloro-phenyl) - / V-. { 1 - [4- (3-Ethyl-2-oxo-oxazolidin-5-ylmethoxy) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -acetamide from (2S, 4R) - / V- (4-chloro-phenyl) -? / -. { 2-methI-1- [4- (2-oxo-oxazolidin-5-ylmethoxy) -benzoyl] -1,2,4,4-tetrahydro-quinolin-4-yl} -acetamide following the reference (Tetrahedron Lett 2002, 43 (46), 8327) 1 H-NMR (CDCl 3) d: 1, 15 (m, 7H), 2.03 (s, 3H), 2.27 (m, 1 H), 3.28 (c, 2H), 3.47 (m, 1 H), 3.63 (t, 1 H), 4.05 (d, 2H), 4.73 (m, 2H), 5.58 (sa, 1 H), 6.47 (d, 1 H) ), 6.67 (d, 2H), 6.86 (t, 1H), 7.08-7.35 (m, 6H), 7.38 (d, 2H). MS m / z: 563 (M + 1) 4- (4. {[[(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -6-cyoro-2-methyl-3,4 acid. -dihydroquinolin-1 (2 / - /) - il] carbonyl.}. phenoxy) -2,2-dimethylbutanoic acid (H-134) was elaborated? / - [(2S34R) -6-cyoro-1- (4-methoxybenzoyl) ) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] -? / - (4-chlorophenyl) acetamide to 4- (4- { [(2S, 4R) -4- [ acetyl (4-chlorophenyl) amino] -6-chloro-2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl, phenoxy) -2,2-dimethylbutanoic following the procedures described for acid 4 - (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methylene-3,4-dihydroquinolin-1 (2H) -yl] carbonyl. phenoxy) -2,2-dimethylbutanoic acid. 1 H-NMR (CDCl 3) d: 1, 10 (d, 3 H), 1, 13 (t, 1 H), 1, 24 (s, 6 H), 2.01 (s, 3 H), 2.03 (t, 2H), 2.27 (m, 1 H), 3.96 (t, 2H), 4.71 (sextet, 1 H), 5.54 (sa, 1 H), 6.43 (d, 1 H) ), 6.65 (d, 2H), 6.89 (d, 1 H), 7.10-7.20 (m, 5H), 7.38 (d, 2H).
MS m / z: 583 (M + 1). Methyl ester of (2S, 4R) -4- [4- (4-. {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline] -1-carbonyl.}. Phenyl) -piperazin-1-yl] -2,2-dimethyl-l-butyric acid (H-135). (2S, 4R) -4- [4- ( 4- { 4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl.} - phenyl) -piperazin-1-yl. ] -2,2-dimethyl-butyric acid from (2S, 4R) -4- (4. {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl- ethyl ester) 3,4-dihydro-2H-quinoline-1-carbonyl] -phenyl) -piperazine-1-carboxylic acid by removing the carbamate. (2S, 4R) -4- (4-. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-ethyl ester -carbonyl.}. phenyl) -piperazine-1-carboxylic acid was dissolved in acetonitrile (2 ml). Iodotrimethylsilane was added and the reaction was allowed to stir at room temperature overnight. The excess reagent was quenched by the addition of methanol (1 ml) and the mixture was concentrated under reduced pressure. The crude residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The extracts were washed with 1 M sodium hydroxide, saturated aqueous sodium thiosulfate and brine, dried over sodium sulfate, filtered, concentrated and purified by chromatography on silica gel to produce? / - (4-chloro-phenyl) - ? / - [2-methyl-1- (4-piperazin-1-yl-benzoyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide. It was dissolved (2S, 4R) -? / - (4-chloro-phenyl) -? / - [2-methyl-1- (4-piperazin-1-yl-benzoyl) -1, 2,3,4-tetrahydro -quinolin-4-yl] -acetamide in DMF at room temperature. K2CO3 was added followed by 4-bromo-2,2-dimethyl-butyric acid methyl ester and the reaction was allowed to stir at 90 ° C overnight. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO 4, filtered and concentrated. The crude residue was purified by HPLC to give the product. 1 H-NMR (CDCl 3) d: 1, 12 (d, 3 H), 1, 18 (s + m, 7 H), 1.75 (m, 2 H), 2.01 (s, 3 H), 2.32 ( m, 3H), 2.52 (m, 4H), 3.16 (m, 4H), 3.64 (s, 3H), 4.71 (m, 1H), 5.60 (sa, 1H), 6.56 (d, 1 H), 6.62 (d, 2H), 6.93 (t, 1H), 7.08-7.29 (m, 6H), 7.36 (d, 2H). MS m / z: 631 (M + 1).
Methyl ester of (2S, 4R) -4- (4-. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1 - carbonyl.}. -phenoxy) -2-methyl-butyric (H-136) It was dissolved (2S, 4R) -? / - (4-chloro-phenyl) - / V- [1- (4-hydroxy-benzo I) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl-acetamide (230 mg, 0.531 mmol) in DMF (5 ml) at room temperature. Cs2CO3 (433 mg, 1.33 mmol) was added followed by 4-cyclo-2-methyl-butyric acid methyl ester (120 mg, 0.796 mmol) and the reaction was allowed to stir overnight. The mixture was partitioned between methylene chloride and water; the organic layer was dried over Na2SO4, filtered and concentrated. The crude residue was purified by chromatography on silica gel (gradient of 1/1 hexanes / ethyl acetate-ethyl acetate) to give the product. 1 H-NMR (CDCl 3) d: 1.1 (d, 3 H), 1, 2 (d, 3 H), 1, 2 (m, 1 H), 1.8 (m, 1 H), 2.0 ( s, 3H), 2.1 (m, 1 H), 2.2 (m, 1 H), 2.7 (m, 1 H), 3.7 (s, 3H), 3.9 (t, 2H), 4.7 (m, 1H), 5.6 (s, 1 H), 6.5 (d, 1 H), 6.6 (d, 2H), 6.9 (t, 1 H) , 7.2 (m, 6H), 7.4 (d, 2H). MS m / z: 549 (M + 1). Acid (2S, 4R) -? M - [2- (4-. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline -1-carbonyl.}. -phenoxy) -ethyl] -1 // -imidazole-2-carboxylic acid (H-137) was dissolved (2S, 4R) -W- (4-chloro-phenyl) -A / - [ 1- (4-hydroxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolyl-4-yl] -acetamide (0.165 g, 0.38 mmol) in DMF at room temperature and K 2 C 3 (0.315 g, 2.28 mmol) was added. 1- (2-Bromo-ethyl) -1H-imidazole-2-carboxylic acid methyl ester (0.304 g, 1.14 mmol) was added and the reaction was allowed to warm to 80 ° C overnight. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO 4, filtered and concentrated. The crude residue was purified by chromatography on silica gel (50% EtOAc / 50% Hexane) to give (2S, 4R) -? / - 1- [2- (4-. {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl.] - phenoxy) -ethyl] -1 - -midazole-2-carboxylic acid (0.176 g, 83%). The ester was hydrolyzed to the acid by dissolving it in tetrahydrofuran and ethanol and sodium hydroxide (1 N) was added. The mixture was stirred at room temperature 4 hours. The mixture was cooled to room temperature, acidified to form a white precipitate. The solid was filtered to give the product in 74% yield. 1 H-NMR (CDCl 3) d: 1, 13 (d, 3 H), 1, 15 (t, 1 H), 1, 98 (s, 3 H), 2.27 (m, 1 H), 4.29 (sa, 2H), 4.72 (sextet, 1 H), 5.09 (sa, 2H), 5.58 (sa, 1 H), 6.48 (d, 1 H), 6.64 (d, 2H) , 6.91 (t, 1 H), 6.98 (s, 1 H), 7.03 (s, 1 H), 7.08-7.40 (m, 10H), 8.65 (s, 1 HOUR). MS m / z: 573 (M + 1) 4- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 acid (2H) -yl] carbonyl.} Phenyl) -2,2-d-methylbutanoic (H-138) 4- (4 { [(2S, 4R) -4- [acetyl (4-chlorophenyl) was dissolved ) amino] -2-methyl-3,4-dihydroquinolyl-1 (2H) -yl] carbonyl} phenyl) -2,2-dimethylbutanoate methyl in methanol / tetrahydrofuran / water (2/1/1) , then sodium hydroxide (3 equivalents) was added and the reaction mixture was stirred at 40 ° C overnight. The mixture was concentrated, the residue was acidified with an aqueous solution of 1 N HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give 4- (4 { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] - 2-methyl-3,4-dihydroquinolin-1 (2H) -l] carbonyl, phenyl] -2,2-dimethylbutanoic acid. 1 H-NMR (CDCl 3) d: 1, 14 (d, 3 H), 1, 22 (s, 6 H), 1, 22-1, 26 (m, 1 H), 1.75 (ddd, 2 H), 2 , 03 (s, 3H), 2.24-2.32 (m, 1 H), 2.49 (ddd, 2H), 4.72-4.80 (m, 1 H), 5.60 (s) , 1H), 6.49 (d, 1 H), 6.89 (t, 1 H), 6.97 (d, 2H), 7.08-7.29 (m, 6H), 7.37 ( d, 2H). MS m / z: 533 (M + 1). 5- (4- { [(2S, 4R) -4 - [(4-chlorophenyl) (glycolyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl acid} phenyl) -2,2-dimethylpentanoic (H-139) 5- (4. {[[(2S, 4R) -4 - [[(acetyloxy) acetyl] (4-chlorophenol) am was dissolved Methyl-2-methyl-3,4-dihydroquinolin-1 (2 / - /) - l] carbonyl, phenyl) -2,2-dimethylpentanoate (100 mg, 0.16 mmol, 1 eq.) In methanol / tetrahydrofuran (2/1) (2 ml). A solution of sodium hydroxide (32 mg, 0.81 mmol, 5 eq.) In water (1 ml) was added and the reaction mixture was heated at 45 ° C for 8 h and at room temperature for 20 h. The mixture was concentrated and the residue was acidified with an aqueous solution of 1N HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give the crude acid. Purification by chromatography on silica gel gave 5- (4 { [(2S, 4R) -4 - [(4-chlorophenyl) (glycolyl) amino] -2-methyl-3,4-dihydroquinolin-1 acid. (2H) -yl] carbonyl, phenyl) -2,2-dimethylpentanoic acid (63 mg, 70%). 1 H-NMR (MeOD) d: 1, 10 (d, 3H), 1, 15 (s, 6H), 1.45 (m, 4H), 2.45 (m, 1H), 2.50 (t, 2H), 3.90-4.10 (dd, 2H), 4.75 (m, 1H), 5.55 (m, 1H), 6.55 (d, 1H), 6.95 (t, 1H) ), 7.00-7.20 (m, 5H), 7.30-7.55 (m, 5H). MS m / z: 563 (M + 1). Acid (2S, 4R) - [4- (4-. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl} phenyl) -piperazin-1-yl] -acetic acid (H-140). (2S, 4R) - [4- (4-. {4- [Acetyl- (4-chloro-phenyl) - amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl.} - phenyl) -piperazin-1-yl] -acetic following the same procedure as for the ethyl ester of (2S, 4R) ) -1- (4-. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl} -phenyl ) -peridine-4-carboxylic acid, substituting piperazin-1-yl-acetic acid ethyl ester for piperidine-4-carboxylic acid ethyl ester to produce the (2S, 4R) - [4- ethyl ester] (4- {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl} -phenyl) -piperazin-1- il] -acetic. The ester was hydrolyzed to the acid by dissolving it in tetrahydrofuran and ethanol and lithium hydroxide (1 N) was added and heated at 50 ° C for 2 h. The mixture was cooled to room temperature, acidified to form a white precipitate. The solid was filtered to give to give the product after purification by HPLC. 1 H-NMR (CDCl 3) d: 1, 10 (d, 3 H), 1, 20 (m, 1 H), 2.00 (s, 3 H), 2.24 (m, 1 H), 3.04 (t , 4H), 3.50 (m, 6H), 4.70 (m, 1 H), 5.56 (sa, 1 H), 6.51 (d, 1 H), 6.63 (d, 2H) ), 6.89 (t, 1 H), 7.07-7.25 (m, 6H), 7.35 (d, 2H). MS m / z: 561 (M + 1). (2S, 4R) -? / - 4- (4-. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline benzyl ester -1-carbonyl.}. -phenoxymethyl) -piperidine-1-carboxylic acid (H-141) was dissolved (2S, 4R) -? / - (4-chloro-phenyl) -? / - [1- (4-h Drox-benzoyl) -2-methylene-1, 2,3,4-tetrahydro-quinoIin-4-yl] -acetamide (0.31 g, 0.71 mmol) in DMF at room temperature and added K2CO3 (0.392 g, 2.84 mmol). 4-Bromomethyl-piperidine-1-carboxylic acid benzyl ester (0.668 g, 2.14 mmol) was added and the reaction was allowed to warm to 80 ° C overnight. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO 4, filtered and concentrated. The crude residue was purified by chromatography on silica gel (60% EtOAc / 40% Hexane) to give the product (0.25 g, 53%). 1 H-NMR (CDCl 3) d: 1, 13 (d, 3 H), 1, 15 (t, 1 H), 1.24 (m, 2 H), 1.76 (m, 2 H), 1.88 (m , 1 H), 2.04 (s, 3H), 2.27 (m, 1 H), 2.75 (m, 2H), 3.68 (d, 2H), 4.17 (sa, 2H) , 4.72 (sextet, 1 H), 5.12 (s, 2H), 5.58 (sa, 1 H), 6.52 (d, 1 H), 6.67 (d, 2H), 6 , 86 (t, 1H), 7.08-7.38 (m, 13H). MS m / z: 666 (M + 1) (2S, 4R) -2- (4-. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro] -2H-quinoline-1 -carbonyl.}. -phenoxy) -? / - (2-hydroxy-ethyl) -acetamide (H-142) was prepared (2S, 4R) -2- (4-. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}. -phenoxy) -? / - (2-hydroxy-ethyl) -acetamide from (4- {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl) ethyl ester .).-.phenoxy) -acetic acid (0.050 g, 0.096 mmol) by the addition of 2-amino-ethanol (0.145 ml, 2.4 mmol) with traces of sodium cyanide in ethanol (1 ml) at room temperature to give a yield 50% of (2S, 4R) -2- (4- { 4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3, 4-dihydro-2H-quinoline-1-carbonyl} -phenoxy) - / V- (2-hydroxyethyl) -acetamide after purification by HPLC. 1 H-NMR (CDCl 3) d: 1.13 (m, 4 H), 2.02 (s, 3 H), 2.26 (m, 1 H), 2.70 (a, 1 H), 3.46 ( t, 2H), 3.68 (t, 2H), 4.41 (t, 2H), 4.72 (m, 1H), 5.58 (sa, 1 H), 6.50 (d, 1 H) ), 6.67 (d, 2H), 6.90 (t, 1 H), 7.02 (a, 1H), 7.13-7.28 (m, 6H), 7.36 (d, 2H) ). MS m / z: 536.2 (M + 1). 2- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolyl-1 (2W) -yl] carbonyl acid} phenoxy) -2-methylpropanoic acid (H-144) 2- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4 was prepared -dihydroquinolin-1 (2H) -yl] carbonyl, phenoxy) -2-methylpropanoic acid according to general procedure I, substituting ethyl 2-bromo-2-methylpropanoate for ethyl 4-bromoacetate to give 2- (4 - { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl}. Phenoxy) -2-methylpropanoate of ethyl. This material was dissolved in methanol / tetrahydrofuran / water (2/1/1) then sodium hydroxide (3 equivalents) was added and the reaction mixture was heated at 40 ° C for 2 h. The mixture was concentrated, the residue was acidified with an aqueous solution of 1 N HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give the acid 2- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinoline-1 (2H) -l] carbonyl, phenoxy) -2-methylpropanoic acid. 1 H-NMR (CDCl 3) d: 1, 10-1, 14 (m, 1H), 1.13 (d, 3H), 1.53 (d, 6H), 2.24 (s, 3H), 2, 27-2.31 (m, 1 H), 4.72-4.79 (m, 1 H), 5.60 (sa, 1 H), 6.49 (d, 1H), 6.68 (d) , 2H), 6.87 (t, 1 H), 7.11 (t, 2H), 7.08-7.18 (m, 4H), 7.37 (d, 2H). MS m / z: 521 (M + 1). Acid (2S, 4R) -4- (4-. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1 -carbonyl.} .-phenoxy) -2-methyl-butyric (H-145) The (2S, 4R) -4- (4- {4- [acetyl- (4-chloro-phenyl) -amino) methyl ester was dissolved. ] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl.} - phenoxy) -2-methyl-butyric acid (100 mg) in methanol / THF, and lithium hydroxide was added ( 1.0 N, 2 ml). After 1 hour, the reaction was acidified and extracted with methylene chloride. The organic layer was dried, filtered and concentrated. The crude residue was purified by chromatography on silica gel (gradient from ethyl acetate-5% MeOH / ethyl acetate) to give the product. 1 H-NMR (CDCl 3) d: 1.1 (d, 3 H), 1, 2 (d, 3 H), 1, 2 (m, 1 H), 1.8 (m, 1 H), 2.0 (s, 3H), 2.1 (m, 1 H), 2.2 (m, 1H), 2.7 (m, 1H), 3.9 (t, 2H), 4.7 (m, 1 H), 5.6 (br s, 1 H), 6.5 (d, 1 H), 6.6 (d, 2H), 6.9 (t, 1H), 7.2 (m, 6H), 7.4 (d, 2H), 10.6 (br s, 1 H). MS m / z: 535 (M + 1). 3- [1- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2Al) -yl] carbonyl acid. phenyl) -1W-pyrrol-3-yl] propanoic (H-146) A / - [(2S, 4R) -1- (4-amino-benzoyl) -2-methyl-1, 2,3 was prepared , 4-tetrahydro-quinoIin-4-yl] -? / - (4-chloro-phenyl) -acetamide following the general procedure H, substituting 6-trif luoromethyl nicotinyl chloride for 4-nitrocarbonyl chloride, followed by reduction to, using an excess of NH 4 CO 2 H, catalytic Pt (sulfur), in ethanol at reflux for 30 min, filtration and concentration. Was dissolved? / - [(2S, 4R) -1- (4-amino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -? / - (4-chloro phenyl) -acetamide (181 mg, 0.433 mmol) in glacial acetic acid (6 ml) and heated to 90 ° C. 2,5-Dimethoxy-tetrahydrofuran-3-carbaldehyde was dissolved in glacial acetic acid (2 ml) and added dropwise to the aniline mixture. After 15 min at 90 ° C, the reaction was quenched with water, and 2X was extracted with methylene chloride. The organics were combined and concentrated, and the yellowish residue was subjected to flash chromatography (EtOAc) to give the corresponding aldehyde (150 mg, 70%). In a round bottom flask at 0 ° C, the aldehyde (87 mg, 0.175 mmol), triethylphosphonoacetate (40 ml, 0.201 mmol), methylene chloride (1.5 ml), NaOH / H2O (50% v / v) were added. , 1.5 ml), and catalytic ammonium iodide. After 1 hour, the suspension was partitioned between methylene chloride and water. The organic layer was collected and concentrated, and the residue was subjected to flash chromatography (EtOAc) to yield ethyl ester of (E) -3- [1- (4- ({2S, 4R) -4- [ acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl.} - phenyl) -1H-pyrrol-3-yl] -acrylic ( 97 mg, 96%) in the form of a white solid. This product (80 mg, 0.16 mmol) was dissolved in EtOAc (3 mL) and acetic acid (1 drop). The mixture was subjected to ZnBr2 (7 mg, 0.032 mmol) and 1 atm of H2 gas for 4 h. The reaction mixture was filtered, concentrated and used without further purification. The crude residue was dissolved in MeOH (2 ml) and 1 N NaOH (2 ml) and stirred overnight. The mixture was monitored by TLC, neutralized (1N HCl), and partitioned between EtOAc and water. The organic layer was concentrated and the crude residue was purified by preparative HPLC to give the title compound as a white solid. MS m / z: 556 (M + 1) (2S, 4R) -W- (4-Chloro-phenyl) -W-. { 1- [4- (3-Dibenzylsulfamoyl-propoxy) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -acetamide (H-147) (2S, 4R) -? / - (4-Chloro-phenyl) -? / - [1- (4-hydroxy-benzoyl) -2-methyl-1, 2,3, was dissolved 4-tetrahydro-quinolin-4-yl] -acetamide (300 mg, 0.693 mmol) in DMF (10 ml) at room temperature. Cs2CO3 (1.12 g, 3.46 mmol) was added followed by 3-chloro-propane-1-sulfonic acid dibenzylamide (350 mg, 1.03 mmol) and the reaction was allowed to stir overnight. The mixture was partitioned between methylene chloride and water; the organic layer was dried over Na2SO4, filtered and concentrated. The crude residue was purified by chromatography on silica gel (2/1 hexanes / ethyl acetate) to give the product. 1 H-NMR (CDCl 3) d: 1.1 (d, 3 H), 1.1 (m, 1 H), 2.0 (s, 3 H), 2.2 (m, 3 H), 3.0 (t , 2H), 3.9 (t, 2H), 4.3 (s, 4H), 4.7 (d, 1 H), 5.6 (sa, 1 H), 6.5 (d, 1 H) ), 6.6 (d, 2H), 6.9 (t, 1 H), 7.2 (m, 18H). MS m / z: 736 (M + 1). 4- (4- { [(2S, 4R) -4 - [(4-chlorophenyl) (isobutyryl) amino] -2-methyl-3,4-dihydroquinolin-1 (2W) -yl] carbonyl. phenoxy) -2,2-dimethylbutanoate methyl (H-148) 4- (4. {[[(2S, 4R) -4 - [(4-chlorophenyl) (isobutyryl) amino] -2- was synthesized methyl-3,4-dihydroquinolin-1 (2 / - /) - il] carbonyl, phenoxy) -2,2-dimethylbutanoate methyl according to general procedure C substituting / V- (4-chlorophenyl) -? / - [(2S, 4R) -1- (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] acetamide with? / - (4-chlorophenyl) -? / - [ (2S, 4R) -1- (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] -2-methylpropanamide and substituting 4-bromo-2,2-dimethylbutanoate for 4- ethyl bromoacetate. The remainder of general procedure C was followed as indicated to give 4- (4- { [(2S, 4R) -4 - [(4-chlorophenyl) (isobutyryl) amino] -2-methyl-3, 4-dihydroquinolin-1 (2 / -) -yl] carbonyl, phenoxy) -2,2-dimethylbutanoate methyl. 1 H-NMR (CDCl 3) d: 1, 12-1, 26 (m, 16H), 2.00 (t, 2H), 2.20-2.27 (m, 1H), 2.61 (sp, 1H) ), 3.64 (s, 3H), 3.91 (t, 2H), 4.68-4.78 (m, 1H), 5.60 (sa, 1H), 6.51 (d, 1H) , 6.61 (d, 2H), 6.92 (t, 1 H), 7.07-7.31 (m, 6H), 7.39 (d, 2H). MS m / z: 592 (M + 1). (2S, 4R) -W- (4-Chloro-phenyl) - / V-. { 2-methyl-1 - [4- (3-pyrrolidin-1-yl-propoxy) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -acetamide (H-149) (2S, 4R) -? / - (4-Chloro-phenyl) -? / - [1- (4-hydroxy-benzoyl) -2-methyl-1, 2,3, was dissolved 4-tetrahydro-quinolin-4-yl] -acetamide (0.1 g, 0.23 mmol) in DMF (5 ml) at room temperature. K2CO (0.317 g, 2.3 mmol) was added. 1- (3-Bromo-propyl) -pyrrolidine (0.177 g, 0.92 mmol) was added and the reaction was allowed to warm to 80 ° C overnight. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO 4, filtered and concentrated. The crude residue was purified by chromatography on silica gel (10% methanol / 90% dichloromethane) to give the product (0.01 g, 8%). 1 H-NMR (CDCl 3) d: 1, 13 (d, 3 H), 1, 15 (t, 1 H), 1, 58-1, 76 (m, 2 H), 2.04 (s, 3 H), 2 , 05-2.18 (m, 2H), 2.27 (m, 1 H), 2.38 (m, 2H), 3.28 (t, 2H), 3.33 (m, 4H), 3 , 96 (t, 2H), 4.72 (sextet, 1 H), 5.54 (sa, 1 H), 6.52 (d, 1 H), 6.67 (d, 2H), 6.88 (t, 1 H), 7.08-7.35 (m, 6H), 7.38 (d, 2H). MS m / z: 546 (M + 1) (2S, 4R) - V- (4-Chloro-phenyl) -yV-. { 2-methyl-1 - [4- (2-pyrrol-1-yl-ethoxy) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -acetamide (H-150) It was dissolved (2S, 4R) - / V- (4-Chloro-phenyl) - / V- [1- (4-hydroxy-benzoyl) -2-methyl-1, 2,3, 4-tetrahydro-quinolin-4-yl] -acetamide (0.11 g, 0.25 mmol) in DMF at room temperature and K 2 C 3 (0.207 g, 1.5 mmol) was added. 1- (2-Bromo-ethyl) -1H-pyrrole (0.088 g, 0.5 mmol) was added and the reaction was allowed to warm to 80 ° C overnight. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO, filtered and concentrated. The crude residue was purified by chromatography on silica gel (70% EtOAc / 30% Hexane) to give the product (0.114 g, 85%). 1 H-NMR (CDCl 3) d: 1, 13 (d, 3 H), 1, 15 (t, 1 H), 1.98 (s, 3 H), 2.27 (m, 1 H), 4.11 ( t, 2H), 4.17 (t, 2H), 4.72 (sextet, 1 H), 5.58 (sa, 1 H), 6.12 (t, 2H), 6.48 (d, 1 H), 6.57 (d, 2H), 6.68 (t, 2H), 6.86 (t, 1 H), 7.08-7.35 (m, 6H), 7.38 (d, 2H). MS m / z: 528 (M + 1) 4- (4- { [(2S, 4R) -4 - [(4-chlorophenyl) (propionyl) amino] -2-methyl-3,4-dihydroquinoline- 1 (2H) -yl] carbonyl.}. Phenoxy) -2,2-dimethylbutanoate methyl (H-151) 4- (4 { [(2S, 4R) -4 - [(4-chlorophenyl) was synthesized ) (propionyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl, phenoxy) -2,2-dimethylbutanoate according to general procedure C substituting ? / - (4-chlorophenyl) - / V - [(2S, 4R) -1- (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] acetamide with N- ( 4-chlorophenyl) -? / - [(2S, 4R) -1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-ylpropanamide and substituting 4-bromine -2,2-dimethylbutanoate by ethyl 4-bromoacetate. (? / - (4-chlorophenyl) -? / - [(2S, 4R) -1- (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] propanamide was prepared following general procedure A substituting 4-fluorobenzoyl chloride with 4-methoxybenzoyl chloride and substituting acetyl chloride with propanoyl chloride, following the rest of the procedure as indicated to give? / - (4-chlorophenyl) -? / - [ (2S, 4R) -1- (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] propanamide). The remainder of general procedure C was followed as indicated to give 4- (4- { [(2S, 4R) -4 - [(4-chlorophenyl) (propionyl) amino] -2-methyl-3, 4-dihydroquinolin-1 (2H) -yl] carbonyl, phenoxy) -2,2-dimethylbutanoate methyl. 1 H-NMR (CDCl 3) d: 1, 12-1, 16 (m, 7H), 1, 22 (s, 6H), 2.00 (t, 2H), 2.13-2.31 (m, 3H ), 3.63 (s, 3H), 3.91 (t, 2H), 4.69-4.77 (m, 1H), 5.60 (ss, 1 H), 6.51 (d, 1) H), 6.61 (d, 2H), 6.92 (t, 1H), 7.11-7.24 (m, 6H), 7.37 (d, 2H). MS m / z: 577 (M + 1). 3-. { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3, 4-dihydroquinolin-1 (2W) -yl] carbonyl} benzamide (H-152) To a solution of 3- acid. { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methylene-3,4-dihydroquinolin-1 (2H) -yl] carbonyl} Benzoic acid (90.2 mg, 0.195 mmol) in dimethylformamide (5 ml) at room temperature was added diisopropylethylamine (136 μl, 0.780 mmol) followed by addition of O- (7-azabenzotriazol-1-yl) -N hexafluorophosphate, N, N ', N'-tetramethyluronium (HATU) (110.9 mg, 0.292 mmol) and 1-Hydroxybenzotriazole hydrate (HOBT) (39.4 mg, 0.292 mmol). The reaction was allowed to stir overnight at room temperature. The mixture was partitioned between sodium bicarbonate (saturated) (20 ml) and ethyl acetate (20 ml). The aqueous layer was extracted an additional 2 times with ethyl acetate (20 ml). The organics were collected together and washed with a brine solution (15 ml). The organics were dried over sodium sulfate, filtered and concentrated to give a clear white solid (40 mg, quant.) Of 3- acid. { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinoline-1 (2H) -yl] carbonyl} benzoic. 1 H-NMR (CDCl 3) d: 1.17 (d, 3 H), 1.22 (m 1 H), 1.89 (sa, 2 H), 2.03 (s, 3 H), 2.25 -2 , 36 (m, 1 H), 4.78 - 4.93 (m, 1 H), 5.56 - 5.67 (m, 1 H), 6.52 (d, 1 H), 6.62 - 6.68 (m, 1 H), 6.93 (m, 1 H), 7.15 - 7.27 (m, 4 H), 7.36 - 7.41 (m, 3 H), 7 , 63 (d, 1 H), 7.97 (d, 1 H). MS m / z: 462 (M + 1). 5- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl}. Phenyl acid ) -2,2-dimethylpent-3-enoic (H-153) The purification of the raw material in the last stage of the synthesis of acid 5- (4- { (2S, 4R) -4- [acetyl - (4-Chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl} - phenyl) -2,2-dimethyl-pentanoic also allowed to isolate acid - (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl}. Phenyl ) -2,2-dimethylpent-3-enoic as a by-product in the synthesis (5 mg). ? -NMR (MeOD) d: 1, 10 (d, 3H), 1, 20 (s, 6H), 2.05 (s, 3H), 2.45 (m, 1 H), 3.20 (d , 2H), 4.75 (m, 1H), 5.55 (m, 1 H), 5.55-5.60 (m, 2H), 6.55 (d, 1 H), 6.95 ( t, 1 H), 6.90-7.05 (dd, 2H), 7.05-7.20 (m, 4H), 7.25-7.45 (m, 4H). MS m / z: 545 (M + 1). 2-. { [3- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -H] carbonyl} phenyl propanoyl] amino} Methyl methylpropanoate (H-154) was prepared 3- (4 { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinoline- Methyl 1 (2H) -yl] carbonyl, phenyl) propanoate following general procedure B, substituting methyl 3- [4- (chlorocarbonyl) phenyl] propanoate for 6-trifluoromethyl nicotinyl chloride. (Methyl 3- [4- (chlorocarbonyl) phenyl] propanoate was prepared in three steps from 4-iodobenzoic acid To a solution of 4-iodobenzoic acid in dimethylformamide were added methyl acrylate, palladium acetate and triethylamine. The reaction mixture was heated at 100 ° C for 5 h to give 4- (3-methoxy-3-oxoprop-1-en-1-yl) benzoic acid The hydrogenation of this intermediate gave 4- (3 -methoxy-3-oxopropyl) benzoic acid The subsequent treatment of this carboxylic acid with oxalyl chloride and catalytic DMF gave methyl 3- [4- (chlorocarbonyl) phenyl] propanoate with a good yield). It was dissolved 3- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2 -) -yl] carbonyl .) phenyl) methyl propanoate (200 mg, 0.4 mmol, 1 eq.) in methanol / tetrahydrofuran (2/1) (1.5 ml). A solution of sodium hydroxide (32 mg, 0.8 mmol, 2 eq.) In water (0.5 ml) was added and the reaction mixture was stirred at room temperature for 20 h. The mixture was concentrated and the residue was acidified with an aqueous solution of 1N HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give 3- (4 { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] - 2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl, phenyl) propanoic acid (190 mg, 97%). To a suspension of 3- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl .}. phenol) propanoic acid (50 mg, 0.10 mmol, 1 eq.) in methylene chloride (0.5 ml) was added a 2 M solution of oxalyl chloride in methylene chloride (82 μl, 0.16 mmol, 1.6 eq.). The reaction mixture was stirred at room temperature for 30 m, and then concentrated to give 3- (4- {([(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2 chloride. -methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl, phenyl) propanoyl. To a solution of the preformed acid chloride in methylene chloride (0.5 ml) was added methyl-alpha-amino-isobutyrate hydrochloride (31 mg, 0.20 mmol, 2 eq.) And diisopropylethylamine (52 μl, 0.degree. , 30 mmol, 3 eq.). The reaction mixture was stirred at room temperature for 20 h. and concentrated. The residue was dissolved in ethyl acetate and washed with water, brine, and then dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by chromatography on silica gel (gradient ethyl acetate / hexane: 4/1 to 10/0) to give 2-. { [3- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolyl-1 (2H) -yl] carbonyl .}. phenyl) propanoyl] amino} Methyl -2-methylpropanoate (105 mg, 46%). 1 H-NMR (CDCl 3) d: 1.15 (d, 3H), 1.45 (d, 6H), 2.05 (s, 3H), 2.30 (m, 1H), 2.40 (t, 2H), 2.90 (t, 2H), 3.70 (s, 3H), 4.80 (m, 1 H), 5.60 (m, 1 H), 5.90 (s, 1 H) , 6.55 (d, 1 H), 6.90 (t, 1 H), 6.90-7.15 (m, 8H), 7.40 (d, 2H). MS m / z: 590 (M + 1). (2S, 4R) - [3- (4-. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-methyl ester -carbonyl.}. -phenoxy) -propyl] -ethyl-carbamic acid (H-155) The methyl ester of (2S, 4R) - [3- (4-. {4- [Acetyl- (4-cyoro- phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl.] - phenoxy) -propyl] -carbamic acid (41 mg, 0.074 mmol) was dissolved in THF / DMF (10: 1.3 ml). To this solution was added sodium hydride (2 mg, 0.089 mmol), followed by ethyl iodide (14 mg, 0.089 mmol). The reaction was stirred at room temperature for 7 hours and was stopped by adding 1 ml of water. The mixture was concentrated under reduced pressure and dissolved in DCM (15 ml). The reaction mixture was washed with aq. NaHCO. sat (15 ml), water (15 ml) and brine (15 ml). The organic phase was dried over MgSO, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (gradient from 5/95 ethyl acetate / hexane - 50/50 ethyl acetate / hexane) to give a light yellow solid product (15 mg, 35%). 1 H-NMR (CDCl 3, 300 MHz) d: 0.68-0.83 (m, 2H), 1, 00-1, 14 (m, 2H), 1, 18-1, 26 (m, 3H), 1, 23 (t, 3H), 1, 59-1, 67 (width, 1 H), 1, 61-1, 64 (width, 1 H), 1, 96-2.02 (m, 5H) 2 , 26-2.31 (m, 1H), 3.25-3.37 (m, 4H), 3.62-3.64 (m, 3H), 3.89-3.91 (m, 2H) , 4.73-4.77 (m, 1 H) 5.5-5.65 (broad, 1 H), 6.50-6.93 (m, 4H), 7.12-7.39 (m , 8H).
MS m / z: 579 (M + 1). (2S, 4R) - V- (4-Chloro-phenyl) -W-. { 1- [4- (3-diethylamino-2-hydroxy-propoxy) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -acetamide (H-156) (2S, 4R) -? / - (4-Chloro-phenyl) - / V- [2-methyl-1 - (4-oxiranylmethoxy-benzoyl) -1, 2,3 , 4-tetrahydro-quinolin-4-yl] -acetamide was further worked up to (2S, 4R) - / V-. { 1 - [4- (3-amino-2-hydroxy-propoxy) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} - / V- (4-chloro-phenyl) -acetamide following the reference (Tetrahedron Lett 2002, 43 (46), 8327). The amine was reacted with acetaldehyde, Na (OAc) 3BH in dichloromethane at room temperature overnight. It was then washed with 1 N NaOH, dried over MgSO, filtered and concentrated. The crude residue was purified by HPLC to give the product in 38% yield. 1 H-NMR (CDCl 3) d: 1, 05-1, 23 (m, 10H), 2.03 (s, 3H), 2.27 (m, 1 H), 2.69-2.95 (m, 6H), 3.85 (m, 1 H), 3.98 (m, 1 H), 4.18 (m, 1 H), 4.72 (sextet, 1 H), 5.58 (sa, 1H) ), 6.58 (d, 1 H), 6.67 (d, 2H), 6.86 (t, 1H), 7.08-7.35 (m, 6H), 7.38 (d, 2H) ). MS m / z: 564 (M + 1) Acid (2S, 4R) -1- [3- (4-. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3 , 4-dihydro-2H-quinoline-1-carbonyl.]. Phenoxy) -propyl] -1 / - / - imidazole-2-carboxylic acid (H-157). (2S, 4R) -1- [3 - (4-. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl) -phenoxy) -propyl ] -1H-imidazole-2-carboxylic acid from (2S, 4R) -1- [3- (4. {4- [Acetyl- (4-chloro-phenyl) -amino] -2] ethyl ester -methyl-3,4-dihydro-2H-quinoline-1-carbonyl.] - phenoxy) -propyl] -1 / - / - midazole-2-carboxylic acid. The ester (0.100 g, 0.16 mmol) was hydrolyzed to the acid by dissolving it in tetrahydrofuran and ethanol and sodium hydroxide (1 N) was added. The mixture was stirred at room temperature 4 hours. The mixture was cooled to room temperature, acidified to form a white precipitate. The solid was filtered to give (2S, 4R) -1- [3- (4. {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro- 2H-quinoline-1-carbonyl.] - phenoxy) -propyl] -1H-imidazole-2-carboxylic acid with a 65% yield. MS m / z: 587 (M + 1). Acid [4- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl} phenyl) p -pepdin-1-yl-acetic acid (H-158) [4- (4 { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl- 3,4-dihydroquinolin-1 (2H) -yl] carbonyl, phenyl) piperidin-1-yl] acetic acid was prepared following the general procedure H, substituting 4- (4- (chlorocarbonyl) phenyl) piperidine-1 fer-butylcarboxylate by 6-trifluoromethyl nicotinyl chloride (4- (4- (ctorocarbonyl) phenyl) piperidine-1-fer-butylcarboxylate was prepared by treatment of 4- (1- (fer-butoxy) carbonyl) piperdin-4-yl) benzoic acid with oxalyl chloride and catalytic DMF followed by removal of the volatiles). The other procedures were followed as indicated in general procedure B to give the corresponding BOC-protected amine. Ferric-butyl carboxylate was removed by stirring the compound in HCl 4 N / dioxane for 3 h, followed by concentration. The resulting hydrochloride salt (40 mg, 0.079 mmol) was heated in acetonitrile (3 mL), ethyl bromoacetate (88 μL, 0.79 mmol), and potassium carbonate (110 mg, 0.79 mmol) at 65 ° C. 2 h. The crude suspension was subjected to flash chromatography (5% MeOH, EtOAc) to yield the corresponding ethyl ester. The ester was saponified with NaOH in MeOH / THF, then subjected to preparative HPLC to give the title product as a white solid. 1 H-NMR (CDCl 3) d: 1, 02-1, 22 (m, 1 H), 1.13 (s, 3 H), 1, 92 (d, 2 H), 2.02 (s, 3 H), 2 , 10-2.38 (m, 3H), 2.57-2.70 (m, 1 H), 2.79 (t, 2H), 3.49 (s, 2H), 3.65-3, 80 (m, 2H), 4.55 (sa, 1 H), 4.70-4.82 (m, 1 H), 5.40-5.75 (m, 1 H), 6.48 (d) , 1 H), 6.88 (t, 1 H), 7.00-7.30 (m, 8H), 7.37 (d, 2H) MS m / z: 560 (M + 1) (2S, 4R) - / V-4- (4-. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}. -phenoxy) -butyramide (H-159) was prepared (2S, 4R) -? / - 4- (4-. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3 , 4-dihydro-2H-quinoline-1-carbonyl.}. -phenoxy) -butyramide from (2S, 4R) -4- (4-. {4- [acetyl- (4-chloro-phenyl)] -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl} -1-ethylidene-penta-2,4-dienyloxy) -butyric by coupling NH4CI, HATU, DIEA, HOBt in DMF at room temperature to produce (2S, 4R) - / V-4- (4-. {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H -quinoline-1-carbonyl.}. -phenoxy) -butyramide.
The reaction mixture was concentrated and partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over magnesium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel (10% methanol / 90% dichloromethane) to give (2S, 4R) -? / - 4- (4-. {4- [acetyl- (4-chloro- pure phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl;} -phenoxy) -butyramide in 46% yield. 1 H-NMR (CDCl 3) d: 1, 13 (d, 3 H), 1, 15 (t, 1 H), 1.68 (sa, 2 H), 2.04 (s, 3 H), 2.08 (m, 2H), 2.27 (m, 1 H), 2.38 (t, 2H), 3.97 (t, 2H), 4.72 (sextet, 1 H), 5.48 (sa, 1 H) , 6.52 (d, 1H), 6.67 (d, 2H), 6.86 (t, 1H), 7.08-7.35 (m, 6H), 7.38 (d, 2H). MS m / z: 520 (M + 1) 4- (4- { [(2S, 4R) -4- [acetyl (4-chloro-2-methylphenol) amino] -2-methyl- 3,4-dihydroquinolin-1 (2H) -yl] carbonyl, phenoxy) -2,2-dimethylbutanoate methyl (H-160) 4- (4- { [(2S, 4R) -4 was prepared - [Methyl acetyl (4-chloro-2-methylphenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2 - /) - iI] carbonyl, phenoxy) -2,2-dimethylbutanoate from of? / - (4-chloro-2-methylphenyl) -? / - [(2S, 4R) -1- (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinoline-4- il] acetamide following general procedure C, substituting 4-bromo-2,2-dimethylbutanoate for ethyl 4-bromoacetate to produce 4- (4- { [(2S34R) -4- [acetyl (4-chloro-2 methyl) -2,5-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl, phenoxy) -2,2-dimethylbutanoate. 1 H-NMR (CDCl 3) d: 1, 10 (d, 3 H), 1, 25 (s, 6 H), 1, 95 (s, 3 H), 2.05 (t, 2 H), 2.20 (m, 1 H), 2.30 (s, 3 H), 3.70 (s, 3 H), 3.95 (t, 2 H), 4.75 (m, 1 H), 5.60 (m, 1 H), 6.50 (d, 1H), 6.60 (d, 2H), 6.95 (t, 1 H), 7.15-7.30 (m, 6H), 7.40 (s, 1 H) . MS m / z: 577 (M + 1). 4- (4- { [(2S, 4R) -4- [Acetyl (4-chloro-2-methylphenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl acid .}. phenoxy) -2,2-dimethylbutanoic (H-161) 4- (4 { [(2S, 4R) -4- [acetyl (4-chloro-2-methylphenyl) amino] -2 was dissolved methyl-3,4-dihydroquinolyl-1 (2H) -yl] carbonyl, phenoxy) -2,2-dimethylbutanoate (60 mg, 0.10 mmol, 1 eq.) was dissolved in methanol. tetrahydrofuran (2/1) (0.8 ml). A solution of sodium hydroxide (12 mg, 0.30 mmol, 3 eq.) In water (0.3 ml) was added and the reaction mixture was heated at 40 ° C for 2 h. The mixture was concentrated and the residue was acidified with an aqueous solution of 1N HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give 4- (4 { [(2S, 4R) -4- [acetyl (4-chloro-2-methylphenyl) acid. amino) -2-methyl-3,4-dihydroquinolyl-1 (2H) -yl] carbonyl, phenoxy) -2,2-dimethylbutanoic acid (50 mg, 89%). 1 H-NMR (CDCl 3) d: 1, 10 (d, 3 H), 1, 25 (s, 6 H), 1, 90 (s, 3 H), 2.05 (m, 3 H), 2.30 (s, 3H), 3.95 (t, 2H), 4.75 (m, 1 H), 5.60 (m, 1 H), 6.50 (d, 1 H), 6.60 (d, 2H) 6.90 (t, 1 H), 7.10-7.35 (m, 6H), 7.40 (s, 1 H). MS m / z: 563 (M + 1). 2- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl} phenyl) pyrrolidine-1-benzylcarboxylate (H-162) 2- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4- dihydroquinolin-1 (2 -) - I] carbonyl, phenyl) pyrrolidine-1-benzylcarboxylate was prepared following the general procedure H, substituting 2- (4- (chlorocarbonyl) phenyl) pyrrolidin-1 -Benzyl carboxylate by 6-trifluoromethyl nicotinyl chloride. (Benzyl 2- (4- (chlorocarbonyl) phenyl) pyrrolidine-1-carboxylate was prepared by treatment of 4- (1- (benzyloxycarbonyl) pyrrolidin-2-yl) benzoic acid with oxalyl chloride and catalytic DMF followed of removal of volatiles). The other procedures were followed as indicated in general procedure B to give 2- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4- dihydroquinolin-1 (2 -) -yl] carbonyl, phenyl) pyrrolidine-1-benzylcarboxylate. 1 H-NMR (CDCl 3) d: 1, 00-1, 20 (m, 1 H), 1.12 (s, 3 H), 1, 68-1, 90 (m, 3 H), 2.02 (s, 3H), 2.15-2.40 (m, 2H), 3.48-3.70 (m, 2H), 4.70-5.20 (m, 4H), 5.42-5.75 ( m, 1 H), 6.40-6.75 (m, 2H), 6.90-7.42 (m, 15H). MS m / z: 622 (M + 1) W- (4-chlorophenyl) -? - [(2S, 4R) -1- (4-ethyl-3-fluorobenzoyl) -2-methyl-1,2,3,4-tetrahydroquinolin-4-yl] acetamide (H-163) The? / - (4 -chlorofeniI) -? / - [(2S, 4R) -1- (4-ethyl-3-fluorobenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolyl-4-yl] acetamide was prepared following the general procedure B, substituting 4-ethyl-3-fluorobenzoyl by 6-trifluoromethyl nicotinyl chloride. (4-Ethyl-3-fluorobenzoyl chloride was prepared in five steps from commercially available 4-bromo-3-fluorobenzoic acid.) 4-Bromo-3-fluorobenzoic acid (0.828 g, 3.8 mmol) was dissolved in 20 ml of benzene / methanol (5: 1) mixture.To the previous mixture, trimethylsilyldiazomethane was added until the reaction showed a light yellow color, it was left to stir for 30 minutes and concentrated to produce 4-bromo- Methyl 3-fluorobenzoate Methyl 4-bromo-3-fluorobenzoate was dissolved in 2 ml of DMF and vinyl tributyl tin (0.431 ml, 1.5 mmol) and degassed for 5 min with nitrogen gas. Pd (PPh3) 2Cl2 (0.086 g, 0.12 mmol) was added and the mixture was heated at 80 ° C with a condenser for 16 h, cooled to room temperature and diluted with ethyl acetate and washed with an aqueous solution. 10% KF in water The mixture was allowed to stir for -30 min at room temperature, then filtered and the aqueous layer was extracted with acetate of ethyl (3x), dried over MgSO 4, filtered and concentrated. The residue was concentrated and purified with 100% hexane to 10% ethyl acetate / 90% hexane to yield 0.140 g, 63% methyl 3-fluoro-4-vinylbenzoate. The methyl 3-fluoro-4-vinylbenzoate (0.750 g, 4.1 mmol) was reduced in the presence of Pd on carbon (10%) in ethanol to provide methyl 4-ethyl-3-fluorobenzoate (0.450 g, 59% ). Methyl 4-ethyl-3-fluorobenzoate was hydrolysed to the acid by dissolving it in tetrahydrofuran and methanol and sodium hydroxide (1 N) was added. The mixture was stirred at room temperature overnight. The mixture was cooled to rt, acidified to pH = 5 with 1 N HCl to form a white precipitate (0.270 g, 65%). The solid was filtered to give 4-ethyl-3-fluorobenzoic acid. The acid was converted to the acid chloride as described in general procedure B). 1 H-NMR (CDCl 3) «5: 1, 12 (m, 1 H), 1, 13 (d, 3 H), 1, 18 (t, 3 H), 2.02 (s, 3 H), 2.27 ( m, 1H), 3.58 (c, 2H), 4.75 (sextet, 1H), 5.59 (sa, 1H), 6.52 (d, 1H), 6.72 (d, 1H), 6.89 -7.00 (m, 3H), 7.14 -7.21 (m, 3H), 7.28 (d, 1 H), 7.36 (d, 2H). MS m / z: 465 (M + 1). / V- (4-chlorophenyl) - / V - [(2S, 4R) -1- (4-ethyl-3,5-difluorobenzoyl) -2-methyl-1,2,3,4-tetrahydroquinolin-4-yl ] acetamide (H-164)? / - (4-chlorophenyl) -? / - [(2S, 4R) -1 - (4-ethyl-3,5-difluorobenzoyl) -2-methyl-1, 2,3 , 4-tetrahydroquinolin-4-yl] acetamide was prepared following general procedure B, substituting 4-ethyl-3,5-difluorobenzoyl chloride for 6-trifluoromethyl nicotinyl chloride. (4-Ethyl-3,5-difluorobenzoyl chloride was prepared in two steps from 3,5-difluorobenzoic acid.) To a solution of 3,5-difluorobenzoic acid in tetrahydrofuran was added lithium diisopropylamide at -78 °. C. After stirring the reaction mixture at -78 ° C for 1 h, ethyl iodide was added and the reaction mixture was stirred at room temperature for 2 h to give 4-ethyl-3,5-difluorobenzoic acid. Subsequent treatment of this carboxylic acid with oxalyl chloride and catalytic DMF gave 4-ethyl-3,5-difluorobenzoyl chloride in good yield). The other procedures were followed as indicated in general procedure B to give / V- (4-chlorophenyl) -? / - [(2S, 4R) -1- (4-ethyl-3,5-difluorobenzoyl) -2- methyl-1, 2,3,4-tetrahydroquinolin-4-yl] acetamide. 1 H-NMR (CDCl 3) d: 1, 05 (t, 3 H), 1, 15 (d, 3 H), 2.05 (s, 3 H), 2.30 (m, 1 H), 2.60 (c , 2H), 4.75 (m, 1 H), 5.55 (m, 1 H), 6.50 (d, 1H), 6.85 (d, 2H), 7.00 (t, 1H) , 7.2 (m, 3H), 7.25-7.45 (m, 3H). MS m / z: 483 (M + 1). 4 - [(5- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl}. pyridin-2-yl) oxy] -2,2-dimethylbutanoic acid (H-165) 4 - [(5- {[[2S, 4R) -4- [acetyl (4-chlorophenyl) amino] - acid was prepared 2-methyl-3,4-dihydroquinoline-1 (2 -) -yl] carbonyl, pyridin-2-yl) oxy] -2,2-dimethylbutane, from 4 - [ (5- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2 / - /) - il] carbonyl} methyl pyridin-2-yl) oxy] -2,2-d, methylbutanoate. 4 - [(5- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinoline-1 (2H) - The methyl carbonyl, pyridin-2-yl) oxy] -2,2-dimethylbutanoate (0.005 g, 0.0086 mmol) was hydrolyzed to the acid by dissolving it in tetrahydrofuran and methanol and sodium hydroxide (1 N) was added. ). The mixture was stirred at room temperature overnight. The mixture was cooled to rt, acidified to pH = 5 with 1 N HCl to form a white precipitate (0.002 g, 42%). The solid was filtered to give 4 - [(5. {[[(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinoline-1 (2 - / ) -yl] carbonyl] pyridin-2-yl) oxy] -2,2-dimethylbutanoic acid. 1 H-NMR (CDCl 3) d: 0.86 (m, 1 H), 1, 14 (d, 3 H), 1.25 (s, 6 H), 2.01 (s, 3 H), 2.04 (t , 2H), 2.29 (s, 1 H), 4.32 (t, 2H), 4.74 (sextet, 1 H), 5.53 (sa, 1 H), 6.40 (d, 1 H), 6.56 (d, 1H), 6.98 (t, 1H), 7.16-7.31 (m, 5H), 7.37 (d, 2H), 8.12 (s, 1H) ). MS m / z: 552 (M + 1). 5- (4 { (2S, 4R) -4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-methyl ester carbonyl.}. phenyl) -2,2-dimethyl-pentanoic acid (H-166) 5- (4S. (2S, 4R) -4- [acetyl- (4-chloro-phenyl) methyl ester ) -amino] -2-methyl-3,4-dihydro-2 - / - quinoline-1-carbonyl}. phenyl) -2,2-dimethyl-pentanoic acid was prepared following the general procedure B, substituting methyl 5- [4- (chlorocarbonyl) phenyl] -2,2-dimethylpentanoate for 6-trifluoromethyl nicotinyl chloride. (Methyl 5- [4- (chlorocarbonyl) phenyl] -2,2-dimethylpentanoate was prepared in four stages from 2,2-dimethyl-4-pentane-1,2-acid. pentanoic acid (2 g, 15.6 mmol, 1.0 eq.) was dissolved in anhydrous methanol (40 ml) The solution was cooled to 0 ° C, a 2 M solution of trimethylsilyl diazomethane in hexanes was added slowly ( 11 ml, 21.8 mmol, 1.4 eq.) Until the reaction mixture became light yellow indicating that the reaction was complete.The reaction mixture was concentrated to give methyl 2,2-dimethyl-4-pentanoate. in the form of a colorless oil (2 g, 91%). Methyl 2,2-dimethyl-4-pentanoate (1.0 g, 7.0 mmol, 1 eq.) was dissolved in anhydrous dimethylformamide. with nitrogen, and 4-iodobenzoic acid (1.7 g, 7.0 mmol, 1 eq.), triethylamine (1.1 mL, 7.7 mmol, 1.1 eq.) and palladium acetate were added sequentially ( 79 mg, 0.35 mmol, 0.05 eq.) The reaction was then heated to 80 ° C under nitrogen atmosphere. or for 18 h. The reaction mixture was concentrated in vacuo to give a black oil which was partitioned between water and ethyl acetate and extracted. The aqueous layer was separated and the organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give a dark brown solid. The crude product was purified by chromatography on silica gel (methylene chloride / methanol gradient: 98/2 to 96/4) to give 4- (4-methoxycarbonyl-4-methyl-pent-1-enyl) -benzoic acid. in the form of a light brown solid (915 mg, 50%). 4- (4-Methoxycarbonyl-4-methyl-pent-1-enyl) -benzoic acid (900 mg, 3.4 mmol, 1 eq.) Was dissolved in ethanol (13 mL) and then triethylamine (568 μL, 4.1 mmol, 1.2 eq.) And palladium on carbon (90 mg, 10% Pd / C). The mixture was stirred under a hydrogen atmosphere for 20 h. The reaction mixture was filtered over celite and washed with ethanol. The filtrate was evaporated to produce a yellow oil. This oil was dissolved in ethyl acetate and washed with a 1N aqueous solution of hydrochloric acid. The aqueous layer was removed and the organic layer was washed with water, and brine, then dried over magnesium sulfate, filtered and concentrated to give 4- (4-methoxycarbonyl-4-methyl-pentyl) -benzoic acid (763 mg, 85%). 4- (4-Methoxycarbonyl-4-methyl-pentyl) -benzoic acid (763 mg, 2.9 mmol, 1 eq.) Was dissolved in methylene chloride (9 ml) and the solution was cooled to 0 ° C. one was added • 2M solution of oxalyl chloride in methylene chloride (2.9 ml, 5.8 mmol, 2.0 eq.) Followed by a catalytic amount of dimethylformamide. The reaction mixture was stirred at rt for 1 h, then concentrated to give methyl 5- [4- (chlorocarbonyl) phenyl] -2,2-dimethylpentanoate as an oil). To the prepared methyl 5- [4- (chlorocarbonyl) phenyl] -2,2-dimethylpentanoate (2.9 mmol, 1.0 eq.) Was added a solution of? / - (4-chlorophenyl) -? / - ((2S, 4R) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl) acetamide (754 mg, 2.4 mmol, 0.83 eq.) In methylene chloride (8 ml) followed of diisopropylethylamine (505 μl, 2.9 mmol, 1.0 eq.) and the reaction mixture was stirred at room temperature for 20 h. The mixture was concentrated and the residue was dissolved in ethyl acetate and washed with water, brine, and then dried over magnesium sulfate., filtered and concentrated. The crude residue was purified by chromatography on silica gel (ethyl acetate / hexane gradient: 1/3 to 1/2) to give 5- (4- (2S, 4R) -4- methyl ester. [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}. phenyl) -2,2-dimethyl-pentanoic acid (675 mg, 50 %). 1 H-NMR (CDCl 3) d: 1, 10 (s, 6H), 1, 15 (d, 3H), 1.45 (m, 4H), 2.05 (s, 3H), 2.45 (m, 1 Hj, 2.55 (t, 2H), 3.58 (s, 3H), 4.75 (m, 1 H), 5.55 (m, 1H), 6.45 (d, 1H), 6 85 (t, 1H), 6.95 (d, 2H), 7.05-7.35 (m, 8H) MS m / z: 561 (M + 1). (2S, 4R) - / V- (4-Chloro-phenyl) - / V-. { 1- [4- (3-imidazol-1-yl-propoxy) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -acetamide (H-167) was dissolved (2S, 4R) -? / - (4-chloro-phenyl) -? / - [1- (4-hydroxy-benzoyl) -2-methyl-1, 2,3, 4- tetrahydro-quino-4-yl] -acetamide (0.1 g, 0.23 mmol) in DMF (5 ml) at room temperature. K 2 C 3 (0.317 g, 2.3 mmol) was added. 1- (3-Bromo-propyl) -1H-imidazole (0.174 g, 0.92 mmol) was added and the reaction was allowed to warm to 80 ° C overnight. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO, filtered and concentrated. The crude residue was purified by chromatography on silica gel (60% EtOAc / 40% Hexane) to give the product (0.020 g, 16%). ? -NMR (CDCl3) d: 1, 16 (d, 3H), 1, 15 (t, 1 H), 2.02 (s, 3H), 2.18 (m, 2H), 2.28 (m , 1 H), 3.85 (t, 2H), 4.17 (t, 2H), 4.72 (sextet, 1H), 5.58 (sa, 1H), 6.52 (d, 1 H) , 6.67 (d, 2H), 6.84 (s, 1 H), 6.88 (t, 1 H), 7.03 (s, 1 H), 7.08-7.35 (m, 6H), 7.38 (d, 2H), 7.43 (s, 1H). MS m / z: 543 (M + 1) Table 9: Exemplary Compounds: Table 10: Chemical Names of Compounds Represented in Table 9 H-1 3 - [(4- { [(2S, 4) -4- [Acetyl (4-chlorophenyl) amino] -2-m? Til -3,4- dihydroquinolyl-1 (2H) -l] carbonyl}. Phenyl) amino] propanamide H-2 4- (4- { [(2S, 4R) -4- [acetyl ( 4-chiorophenyl) amlno] -2-methyl-3,4- d- hydroquininoin-1 (2 - /) - il] carbonyl} -2-fluorophenoxy) -2,2-dimethylbutanoic acid H-3 (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinoline-1 (2H) -yl] carbonyl, phenoxy) ( fluoro) ethyl acetate H-4 N - ((2S, 4R) -1 -. {4- [4- (2-Amino-2-oxoethyl) piperazin-1-yl] benzoyl} -2-met L-1, 2,3,4-tetrahydroquinolyl-4-yl) -? / - (4-chlorophenyl) acetamide H-5 4- (4- { [(2S, 4R) -4- [(4-chlorophenyl) (isobutyryl) amino] -2-methyl-3,4-dihydroquinolin-1 (2 -) -yl] carbonyl} phenoxy) -2,2-d-methylbutanoic H-6 Acid 2-. { [3- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4- dihydroquinolyl-1 (2H) -yl] carbonyl .}. phenoxy) propyl] amino} -2- methylpropanolco H-7? / - [(2S, 4R) -1 - (4-ferc-Butylbenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinoline-4-yl] -? / - (4-chlorophenyl) acetamide H-8 N- (4-Chlorophene) -? / -. { (2S, 4R) -1- [4- (3-Hydroxy-3-methylbutoxy) benzoyl] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} acetamide H-9? / - (4-Chlorophenyl) -? / - [(2S, 4R) -1 - (4-iodobenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinoline-4 -! l] acetamide H-10? / - ((2S, 4R) -1 -. {4- [3- (Acetylamino) propoxy] benzoyl} -2-met.l-1, 2.3, 4- tetrahydroquinolin-4-yl) -? / - (4-chlorophenyl) acetanpide H-11? / - (4-chlorophen I) -? / - ((2S, 4R) -2-methyl -1- { 4- [4,4,4-trifluoro-3-hydroxy-3- (trifluoromethyl) butoxy] benzoyl} -1, 2,3,4-tetrahydroquinolin-4-yl) acetamide H-12 4- (4- { [(2SJ4R) -4- [Acetyl (4-cyanophenyl) amino] -2-methyl-3,4-dihydroquinoline-1 (2 - /) - il] carbonyl Phenoxy) cyclohexanecarboxamide H-13? / - (4-Chlorophenyl) - N - ((2S, 4R) -2-methyl-1 -. {4- [3- (1H-tetrazole-5 - l) propoxy] benzoyl] -1, 2,3,4-tetrahydroquinolin-4-yl) acetamide H-14 4- (4- { [(2S, 4R) -4- [(4-Chlorophenyl) (cyclopropylcarbonyl) amino] -2-methyl-3,4-d.hydroquinolin-1 (2H) -l] carbonyl, phenoxy) -2,2-dimethylbutanoate methyl H-15 - (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -l] carbonyl. -2-fluorophenyl) -2,2-dmethylp Methyl entanoate H-16 Acid 3- (4-. { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2 - /) - yl] carbonyl} phenoxy) -2,2-dimethylpropanoic acid H-17 3- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinoline-1 (2 -) -yl] carbonyl.}. Phenoxy) propane-1-sulfonic H-18 4- (5- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2 methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl} -2-fluorophenoxy) -2,2-dimethylbutanoate methyl H-19? / - (4-Chlorophenyl) -? / - [( 2S, 4R) -1 - (4-fluoro-3-hydroxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] acetamide H-20 4- (4- { [ (2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2 - /) - yl] carbonyl, phenoxy) -? /, A / - diethylbutanamide H-21? / -. { (2S, 4R) -6-Chloro-2-methyl-1 - [(3-methylisoxazol-5-yl) carbonyl] -1, 23,4- tetrahydroquinolin-4-yl} - / V- (4-chlorophenyl) acetamida H-22 4- (4 { [(2S, 4R) -4- [Acetyl (4-chloropheni) amino] -2-methyl-3,4 acid - dihydroquinolin-1 (2H) -yl] carbonyl, phenoxy) cyclohexanecarboxylic acid H-23 5- (4- { [(2SJ4R) -4 - [[(Acetyloxy) acetyl] (4-chlorophenyl) amino] - Methyl 2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carboniI.}. Phenyl) -2,2-dimethylpentanoate H-24 4- (4- { [(2S, 4R) - 4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2 - /) - yl] carbonyl} phenoxy) -1-methylpyrrolidine-2-carboxylic acid H-25 4- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-d-hydroquinolin-1 (2 -) -yl] carbonyl} phenoxy) -2,2-d-methylbutanamide H-26? / - (4-chlorophen I) -? / -. { (2S, 4R) -2-methyl-1 - [4- (3-pyridin-3-ylpropoxybenzoyl-I ^ .S ^ -tetrahydroquinolin ^ -yl-Jacetamide H-27 5 - [(4- { [ (2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl, phenoxy) methyl] -2-furamide H-28 A / - (4-Chlorophenyl) -? / - { (2S, 4R) -2-methyl-1 - [4- (3-piperazin-1-ylpropoxy) benzoyl] -1, 2,3,4- tetrahydroquinolin-4-yl.} acetamide H-29 4- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4- dihydroquinol N-1 (2V) -yl] carbonyl] -2,6-difluorophenoxy) -2,2-methyl dimethylbutanoate H-30 1 - (4- { [(2S, 4R) - 4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3) 4-dithyquinolin-1 (2H) -yl] carbonyl} phenyl) piperidine-4-carboxamide H-31? / - . { (2S, 4R) -1 - [3,5-Bys (trifluoromethyl) benzoyl] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} -? / - (4-chlorophenyl) acetamide H-32 2- Acid. { [3- (4- { [(2S, 4R) -4- [acetyl (4-cyanophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2 - /) - yl] carbonyl. phenyl) propanoyl] amino} -2- methylpropanoic H-33 4- [5-. { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl} -2-oxopyridin-1 (2H) -yl] -2,2-methyl dimethylbutanoate H-34? / -. { (2S, 4R) -1 - [4- (Aminomethyl) benzoyl] -2-meth i-1, 2,3,4-tetra idroquinolin-4-yl} -? / - (4-chlorophenyl) acetamide H-35? / - [3- (4- { [(2S / 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3, 4- dihydroquinoline-1 (2H) -yl] carbonyl, phenoxy) propyl] -2,2-dimethylpropanamide H-36 4- (4- { [(2S, 4R) -4 - [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4- dithyquinol-1 (2 - /) - yl] carbonyl] -2-fluorophenoxy) -2 , Methyl 2-dimethylbutanoate H-37 / V- (4-Chlorophenyl) - / V-. { (2S, 4R) -2-methyl-1 - [4- (2-oxoimidazolidin-1-yl) benzoyl] -1, 2,3,4-tetrahydroquinolin-4-yl} acetamide H-38 4 - [(4. {[[(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinoline-1 (2 - /) - il] carbonyl.] phen.l) (methyl) amino] butanoic H-39? / - (4-chlorophenyl) -? / - ((2S, 4R) -1- { 4 - [(4-hydroxy 4-methylpentyl) oxy] benzoyl] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl) acetamide H-40 1- [3- (4- { [(2S , 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2 -) -yl] carbonyl}. Phenoxy) propyl] -1H-imidazoI-2 - carboxamide H-41? / - (4-chlorophenyl) -W - ((2S, 4R) -2-methyl-1 -. {4 - [(2-oxo-1,3-oxazolidin-5-yl) methoxy] benzoyl.} -1, 2,3,4-tetrahydroquinolin-4-yl) acetamide H-42 Acid 5- (4- { [(2SJ4R) -4- [Acetyl (4-chlorophenyl) ami no] -2-methyl-3,4-dihydroquinolin-1 (2 / - /) - il] carbonyl.}. phenyl) -2,2-dimethylpentane -co H-43 4- (4- { [( 2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methylene-3,4-dihydroquinolin-1 (2fV) -yl] carbonyl}. PhenyI) -2) 2-dimethylbutanoate methyl H-44 Acid 3- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -6-chloro-2-methyl-3,4-dihydroquinoline-1 (2 - / ) -il] carbon il.}. phenoxy) -2,2-dimethylpropane H-45 A / - (4-Aminophenyl) - / V - [(2S, 4R) -1 - (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] acetamide H-46 4- (4-. { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2 -) -yl] carbonyl} phenoxy) -2,2-dimethylN- (methylsull) butanamide H-47 1 - (4- {[[(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl} -3,4-dihydroquinolin-1 (2H) -yl] carbonyl, phenyl) piperidine-3-carboxylic acid H-48 / V-. { (2S, 4R) -6-Chloro-1 - [(6-ethylpyridin-3-yl) carbonyl] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} - / V- (4-chlorophenol) acetamide H-49 4- (4- { [(2S, 4R) -4 - [(4-chlorophenyl) (cyclopropycarbonyl) amino] -2-methyl-3 , 4-dihydroquinolin-1 (2H) -iI] carbonyl, phenoxy) -2,2- dimethylbutanoic H-50? / - (4-Chlorophenyl) -? / - [(2S, 4R) -1 - ( 3-ethyl-4-fluorobenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] acetamide H-51? / - (4-Chlorophenyl) -? / - ((2S, 4R) -1 -. { 4- [3- (1 H-imidazol-1 -yl) -3-methylbutoxy] benzoyl} -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl) acetamide H-52? / - (4-Chlorophenyl) -? / - ((2S, 4R) -1 - { 4- [ (1-ethylpiperidin-4-yl) methoxy] benzoyl.} - 2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl) acetamide H-53 4 - [(4- { [ (2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2 - /) - yl] carbonyl, phenyl) (methyl) amino] Butanamide H-54 (3S) -4- (4-. {[[(2S, 4R) -4-Acetyl (4-Ciorophenyl) amino] -2-methyl-3,4-dihydroquinoline-1 (2H) - il] carbonyl.}. phenoxy) -3-hydroxybutanoic H-55 3- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4- dihydroquinolin-1 (2H) -yl] carbonyl] phenoxy) -2,2-dimethylpropanamide H-56? / - ((2S, 4R) -1 -. {4- [2- ( 1-Acetyl-1-piperidin-4-yl) -ethoxy] -benzoyl.} -2-methyl-1 ^. S ^ -tetrahydroquinoline ^ -i -? / ^ - chloropheni acetamide H-57 4- (5-. [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2 / -) -yl] carbonyl] -2-fluorophenoxy) - 2,2-Dimethylbutanoic H-58? / - (4-Chlorophenyl) -? - ((2S, 4R) -2-methyl-1 -. {4- [(methylsulfonyl aminolbenzoyl-1-S ^ -tet rahydroquinolin ^ -yl) acetamide H-59 (2S) -? / - [3- (4-. { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinone-1 (2 - /) - il] carbonyl} phenoxy) propyl] -1-methylpyridine-2-carboxamide H-60 4- (4- { [(2R, 4S) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3 4-dihydroquinolin-1 (2 - /) - yl] carbonyl}. Phenoxy) -2,2-dimethylbutanoic acid H-61 / V- [3- (4- ({. [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -I] carbonyl, phenoxy) propyl] -? / - ethylacetamide H-62? / - (4-Chlorophenyl) -? / -. { (2S, 4R) -1- [4- (4-hydroxy-4-methylpentyl) benzoyl] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} acetamide H-63? / - (4-Chlorophen-I) -? / - [(2S, 4R) -1- (3,5-difluoro-4-hydroxybenzoyl) -2-methylene-1, 2 , 3,4-tetrahydroquinolin-4-yl] acetamide H-64 [3- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3 Methyl 4-dihydroquinolin-1 (2 - /) - 1] carbonyl, phenoxy) propyl] carbamate H-65 5-. { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2 -) -yl] carbonyl} methyl thiophene-2-carboxylate H-66 5 - [(4. {[[(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4- dih Droquinolin-1 (2H) -I] carbonyl, phenoxy) methyl] -2-furoic H-67 5- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolyl-1 (2 -) -yl] carbonyl, phenoxy) pentanamide H-68 AÍ- (4-chlorophenyl) -? / -. { (2S34R) -2-methyl-1 - [(2-methylpyrimidin-5-yl) carbonyl] -1,2,3,4-tetrahydroquinolyl-4-yl} acetamide H-69? / - (4-Chlorophenyl) -? / -. { (2S, 4R) -1 - [4- (1,1-dioxidoisothiazolidin-2-yl) benzoyl] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} acetamide H-70? / - (4-Chlorophenyl) -N - [(2S, 4R) -1- (3,5-d.chloro-4-etl-benzoyl) -2-methyl- 1, 2, 3,4-tetrahydroquinolyl-4-yl] acetamide H-71 4- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4 - ethyl dihydroquinolin-1 (2H) -yl] carbonyl, phenoxy) butanoate H-72 3 - [(4- {[[2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] Methyl] -2-methyl-3,4-dihydroquinolin-1 (2 - /) - 1] carbonyl, phenoxy) methyl] benzoate H-73 1 - (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl}. Phenyl] piperidine-4-carboxylate ethyl H-74 / V- (4-Chlorophenyl) - / V-. { (2S, 4R) -1 - [(6-ethylpyridin-3-yl) carbonyl] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} acetamide H-75 V- (4-Chlorophen I) -? / -. { (2S, 4R) -2-methyl-1 - [4- (3. {[[(Trifluoromethyl) sulfonyl] amino} propoxy) benzoyl] -1,2,3,4-tetrahydroquinolin-4-yl} acetamide H-76? / - (4-Chlorophenyl) -? / - ((2S, 4R) -2-methyl-1 - { 4- [3- (2-oxo-1,3-oxazolidin- 3- l) propoxy] benzoyl.] -1, 2,3,4-tetrahydroquinolin-4-yl) acetamide H-77 3 - [(4- {[(2S, 4R) -4 - [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl, phenyl) amino] propane H-78? / - (4-Chlorophenyl) -? / - [(2S, 4R) -1- (3,5-difluoro-4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] acetamide H-79 Acid 4- (4- { [(2S, 4R) -4- [acetyl (phenyl) amino] -2-methyl-3,4- dihydroquinoIin-1 (2 - /) - yl] carbonyl, phenoxy) -2,2-dimethylbutanoic H-80 Acid (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methylene-3,4- dih Droquinolyl-1 (2 - /) - il] carbonyl, phenoxy) (fluoro) acetic H-81 4- (4-. {[[(2S, 4R) -4- [Acetyl] chlorophenol) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl, phenoxy) ethyl cyclohexanecarboxylate H-82 Acid (1R) 2R) -2 - [(4) - { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl} phenoxy) methyl] cyclopentanecarboxylic H-83? / - (4-Chlorophenyl) - V - ((2S, 4R) -2-methyl-1- {[[6- (trifluoromethyl) pyridin-3-yl] carbon] L.} -1, 2,3,4-tetrahydroquinolin-4-yl) acetamide H-84? / - [(2S, 4R) -1- (4-. {3 - [(Aminocarbonyl) am No] propoxy.}. Benzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] - / V- (4-chlorophenyl) acetamide H-85? / - (4-chlorophenyl) - ? / - ((2S, 4R) -1 - { 4- [2- (1 H-imidazol-1-yl) ethoxy] benzoyl.} -2- methyl-1, 2,3,4-tetrahydroquinolin -4-yl) acetamide H-86 1- [3- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl.}. Phenoxy) propyl] -1H-imidazole-2-ethyl carboxylate H-87 4- (4- { [(2S, 4R) -4- [acetyl (4- chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2 / - /) - il] carbonyl, phenoxy) -2,2-dimethylbutanoic H-88? / - (4-chlorophenyl) -? / -. { (2S, 4R) -1- [4- (1,1-difluoroethyl) benzoyl] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} acetamide H-89 / V - [(2S, 4R) -1- (3- {[[ferc-Butyl (dimethyl) silyl] oxy} -4-fluorobenzoyl) -2-methyl- 1, 2,3 , 4-tetrahydroquinol-4-yl] - / V- (4-chlorophenyl) acetamida H-90 1 - (4- { [(2S, 4R) -4- [Acetyl (4- chlorophenyl) amino] -2-methyl-3,4-dihydroquinoline-1 (2H) -I] carbonyl, phenyl) piperidine-3-carboxamide H-91? / - ((2S, 4R) -1 - { 4 - [(1-Acetylpiperidin-4-yl) methoxy] benzoyl} -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl) -? / - (4- chlorophenyl) acetamide H-92 Acid 5- (4- { [(2S34R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinoline-1 (2H) -yl] carbon.l.}. phenoxy) -2,2-dimethylpentanoic H-93 4 - [(4- {[[2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2 methyl-3,4-d-hydroquinolin-1 (2 - /) - yl] carbonyl, phenyl] (methyl) amino] butanoate methyl H-94 4- (4- {[[2S, 4R) -4- [acetyl (4-chlorophenol) amino] -2-methyl-3,4-d-hydroquinolin-1 (2 / - /) - 1] carbonyl, phenoxy) -2.2 -difluorobutanoic acid H-95. { [3- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4- d¡h¡droquinolin-1 (2 - /) - il carbonyl.} phenoxy) propyl] amino} acetic acid H-96 4- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl} phenoxy) -? / - ethylbutanamide H-97? / - (4-Chlorophenyl) -? / - ((2SJ4R) -2-methyl-1 -. {4- [3- (1 H-pyrazoI-1 - il) propoxy] benzoyl.] -1, 2,3,4-tetrahydroquinolin-4-yl) acetamide H-98 N- (4-chlorophenyl) -? / -. { (2S, 4R) -1 - [(2-etl-pyrimidin-5-yl) carbonyl] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} Acetamidate H-99 Acid 1 - [3- (4 { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinoline-1 (2 / - /) - il] carbonyl, phenoxy) propyl] -4-methyl-1H-imidazole-5-carboxylic acid H-100 5- Acid. { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl} thiophene-2-carboxylic acid H-101 1 - [2- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolyl- 1 (2 - /) - il] carbonyl, phenoxy) ethyl] cyclobutanecarboxamide H-102 N- (4-chlorophenyl) -? / -. { (2S, 4R) -2-methyl-1 - [4- (2-oxo-1,3-oxazolidin-3-yl) benzoyl] -1,2,3,4-tetrahydroquinolin-4-yl} acetamide H-103 4- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinoline-1 (2H) -yl] carbonyl.}. phenoxy) -2- (diethylamino) butanoic H-104 3 - [(4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl -3,4-dihydroquinolin-1 (2 - /) - il] carbonyl} benzyl) amino] propane-butyl ester H-105? / -. { (2S, 4R) -1 - [3,5-bis (Trifluoromethyl) benzoyl] -6-chloro-2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} - / V- (4-chlorophenyl) acetamide H-106? / - (4-Chlorophenyl) -? / - [(2S, 4R) -2-methyl-1 - (4-pyrrolidin-2-ylbenzo L) -1, 2,3,4-tetrahydroquinolin-4-yl] acetamide H-107 4 - [(4- {[[2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] ] -2-methyl-3,4-dihydroquinoline-1 (2H) -yl] carbonyl] phenol) (methvl) amino] -4-oxobutanoate methyl H-108? / - (4-Chlorophenyl) - / V - ((2S, 4R) -2-methyl-1- { 4- [3- (1H-pyrrol-1-yl) propoxy-benzoyl] -1, 2,3,4-tetrahydroquinolin-4-yl) acetamide H-109? / - (4-Chlorophenyl) -? / - ((2S, 4R) -1 - { 4- [2- (isopropylamino) -2 - oxoethoxy] benzoyl.] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl) acetamide H-110 4- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl} phenyl) piperazine-1-fer-butylcarboxylate H-111 N- (4- Chlorophenyl) -? / - [(2S, 4R) -2-methyl-1 - (4-. {2- 2- [1 - (methylsulfonyl) p.peridin-4-yl] ethoxy.} Benzoyl) - 1) 2,3,4-tetrahydroquinolin-4-yl] acetamide H-112 4- (4- { [(2SJ4R) -4 - [(4-chlorophenyl) (propionyl) amino] -2-methyl- 3, 4-dihydroquinolin-1 (2 -) -yl] carbonyl} phenoxy) -2,2-dimethylbutanoic acid H-113 3 - [(4- {[[(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4- d} hydroquinolin-1 (2H) -yl] carbonyl, phenoxy) methyl] benzoic acid H-114 3 - [(4- {[[(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] ] -2-methyl-3,4-dihydroquinolin-1 (2 - /) - 1] carbonyl.} Benzyl) amino] propanoic H-115? / - (4-Chlorophenyl) -? / - [(2S, 4R) -2-methyl-1 - (4-. {3- [(methylsulfonyl) amino] propoxy] benzoyl) -1,2,3,4-tetrahydroquinolin-4-yl] acetamide H-116 Acid 4 -[5-. { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4- d, 1-dinoquinolin-1 (2H) -yl] carbonyl} -2-oxopyridin-1 (2H) -yl] -2,2- dimethylbutanoic acid H-117 1 - [2- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenol ) amino] -2-methi-3,4-dihydroquinolin-1 (2H) -yl] carbonyl, phenoxy) ethyl] cyclobutanecarboxylic acid H-118? / - (4-Chlorophenyl) -? / - ((2S , 4R) -2-methyl-1 - { 4- [3- (2-oxoimidazolidin-1-yl) propoxy] benzoyl} -1, 2,3,4-tetrahydroquinolyl-4-yl) acetamide H-119? / - (4-Chlorophenyl) -A / -. { (2S, 4R) -2-methyl-1 - [4- (2-morpholin-4-yl-2-oxoethoxy) benzoyl] -1, 2,3,4-tetrahydroquinolin-4-yl} acetamide H-120? / - (4-Chlorophenyl) -? / - [(2SJ4R) -1- (4-fluoro-3-vinylbenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl ] acetamide H-121 / V- (4-Chlorophenyl) -? / - [(2S, 4R) -1- (4-ethoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] acetamide H-122 Acid 1 - (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4- dithyquinoline-1 (2H) -yl] carbonyl.} phenyl) piperidine-4-carboxylic acid H-123? / - ((2S, 4R) -1-. {4- [3- (Aminosulfonyl) propoxy] benzoyl}. -2-methyl-1, 2,3,4-tetrahydroquinolyl-4-yl) -? / - (4-chlorophenyl) acetamide H-124 3- Acid. { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2 - /) - 1] carbonyl} Benzoic H-125 N- (4-Chlorophenyl) -? / -. { (2S, 4R) -1- [4- (3-Cyanopropoxy!) Benzoyl] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} Acetamide H-126 / V- (4-Chlorophenyl) -? / - ((2S, 4R) -2-methyl-1 -. {4- [3- (3-methyl-1, 2,4-oxadiazole- 5-yl) propoxy] benzoyl.] -1, 2,3,4-tetrahydroquinolin-4-yl) acetamide H-127? / - (4-Chlorophenyl) - / V-. { (2S, 4R) -1- [4- (difluoromethoxy) benzoyl] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} acetamide H-128 1- [2- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinoline-1 (2H) -yl] carbonyl.}. phenoxy) ethyl] -1H-imidazoI-2-carboxamide H-129? / - ((2S, 4R) -1 - { 4- [3- (4-Acetylpiperazine-1 - il) propoxy] benzoyl.} -2-methyl-1, 2,3,4-tetrahydroquinolyl-4-yl) - / V- (4-chlorophenol) acetamide H-130 1 - (4-. [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl} phenyl) piperidine-3-carboxylate ethyl H-131 Acid 5- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinoline-1 (2H) -il carbonyl.} -2-fluorophenyl) -2,2-dimethylpentanoic H-132? / - (4-Chlorophenyl) -? / - ((2S / 4R) -2-methyl-1 -. {4- [ 3- (2-oxo-pyrrolidin-1-yl) -propoxy] -benzoyl-} -1, 2,3,4-tetrahydroquinol-4-yl) acetamide H-133? / - (4-Chlorophenyl) - / V - ((2S, 4R) -1 - { 4 - [(3-etl-2-oxo-1,3-oxazolidin-5-yl) methoxy] benzoyl} -2-methyl-1 , 2,3,4-tetrahydroquinolin-4-yl) acetamide H-134 4- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -6-chloro acid -2-metl-3,4- di hydroquinolin-1 (2H) -yl] carbonyl} phenoxy) -2,2-dimethylbutanoic H-135 4- [4- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methylene -3) 4- dihydroquinolin-1 (2H) -yl] carbonyl} methyl phenyl) piperazin-1-yl] -2,2-dimethylbutanoate H-136 4- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl- 3,4-dihydroquinolin-1 (2H) -yl] carbonyl}. Phenoxy) -2-methylbutanoate methyl H-137 1 - [2- (4- { [(2S, 4R) -4- [ acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl}. phenoxy) ethyl] -1H-methyldazole-2-carboxylic acid H- 138 4- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolyl-1 (2H) acid il] carbonyl.}. phenyl) -2,2-d.methylbutanoic acid H-139 5- (4- { [(2S, 4R) -4 - [(4-chlorophenyl) (glycolyl) amino] -2 methyl-3,4-dihydroquinolin-1 (2 / - /) - il] carbonyl, phenyl) -2,2-dimethylpentanoic acid H-140 [4- (4-. {[[(2S, 4R)] -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl}. Phenyl) piperazin-1-yl] acetic acid H-141 4 - [( 4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methi-3,4-dihydroquinolyl-1 (2 / - /) - il] carbonyl.}. phenoxy) methyl] piperidine-1-carboxylic acid benzyl H-142 / V- (4-Chlorophenyl) -? / - [(2S, 4R) -1- (4- {2 - [(2-hydroxyethyl) amino] -2-oxoethoxy.} Benzoyl) -2-methylene-1, 2,3,4-tetrahydroquinolyl- 4-yl] acetamide H-143 4 - [(5- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinoline-1 ( 2 -) -yl] carbonyl.}. Pyridin-2-yl) oxy] -2,2-dimethylbutanoate methyl H-144 2- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2 / - /) - il] carbonyl, phenoxy) -2-methy1propanoic acid H-145 4- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4- d -hydroquinoln-1 (2H) -yl] carbonyl. phenoxy) -2-methylbutanoic acid H-146 3- [1 - (4 { [(2S, 4R) -4-acetyl (4-chlorophenyl) amino] -2-methyl-3,4 acid - dihydroquinoline-1 (2H) -yl] carbonyl, phenyl] -1-pyrrol-3-yl] propanoic H-147 A / - (4-Chlorophenyl) -? / - [(2S, 4R) -1 - (4- { 3- [(dibenzylamino) sulfonyl] propoxy.} Benzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] acetamide H-148 4- (4- { [(2S, 4R) -4 - [(4-Chlorophenyl) (isobutyryl) amino] -2-methyl-3,4-dihydroquinolin-1 (2 -) -yl] carbonyl. phenoxy) -2,2-dimetyl methyl butanoate H-149? / - (4-Chlorophenyl) -? / -. { (2S, 4R) -2-methy1- [4- (3-pyrrolidin-1-ylpropoxy) benzoyl] -1,2,3,4-tetrahydroquinolin-4-yl} acetamide H-150 N- (4-Chlorophenyl) -? / - ((2S, 4R) -2-methyl-1 -. {4- [2- (1 H -pyrrol-1-yl) ethoxy] benzoyl} -1, 2,3,4-tetrahydroquinolin-4-yl) acetamide H-151 4- (4- { [(2S, 4R) -4 - [(4-Chlorophenyl) (propionyl) amino] - 2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl, phenoxy) -2,2-dimethylbutanoate methyl H-152 3-. { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2 - /) - 1] carbonyl} Benzamide H-153 Acid (3 £) -5- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-d-hydroquinoline-1 (2 - /) - il] carbonyl.] Phen.l) -2,2-dimethyl-3-enoic H-154 2-. { [3- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl} phenyl propanoyl] amino} -2- Methyl methylpropanoate H-155 [3- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinoline-1 (2H ) -yl] carbonyl.}. phenoxy) propyl] methylcarbamate H-156? / - (4-Chlorophenyl) -? - ((2S, 4R) -1- { 4- [3- (diethylamino ) -2- hydroxypropoxy] benzoyl.} -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl) -eetamide H-157 1 - [3- (4- { [(2S, 4R ) -4- [acetyl (4-chlorophenii) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl, phenoxy) propyl] -1H-imidazole-2-carboxylic acid H-158 Acid [4- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2 - /) - il] carbonyl.) phenyl) piperdin-1-yl] acetic H-159 4- (4- { [(2S, 4R) -4- [Acetyl (4-cyranophenol) amino] -2-methyl -3,4- dihydroquinolin-1 (2 - /) - il] carbonyl, phenoxy) butanamide H-160 4- (4- { [(2S, 4R) -4- [acetyl ( 4-Chloro-2-methylphenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl, phenoxy) -2,2-methyl methylbutanoate H-161 Acid 4 - (4- { [(2S, 4R) -4- [acetyl (4-chloro-2-methylphenyl) amino] -2-methyl-3,4- dih idroquinolin-1 (2 -) -yl] carbonyl} phenoxy) -2,2-d.methylbutanoic H-162 2- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinoline- 1 (2H) -yl] carbonyl, phenyl) pyrrolidine-1-benzylcarboxylate H-163 / V- (4-chlorophenyl) - / V - [(2S, 4R) -1 - (4-ethyl-3 -fluorobenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] acetamida H-164 A / - (4-Chlorophenyl) -? / - [(2S, 4R) -1 - ( 4-ethyl-3,5-difluorobenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] acetamide H-165 4 - [(5- { [(2S, 4R) - 4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl} pyridin-2-yl) oxy] -2,2-dimethylbutanoic H -166 5- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -I] carbonyl .) phenyl) -2,2-dimethyipentanoate methyl H-167 N- (4-chlorophenyl) -? / - ((2S, 4R) -1 -. {4- [3- (1 H-imidazole- 1-yl) propoxy] benzoyl.} -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl) acetamide General Procedure J: W-cyclopentyl- / V - [(2S, 4R) -1 - (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] acetamide Obtained (2S, 4R) -1- (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolyl-4-amine following procedure G, substituting 4-fluorobenzoyl chloride for 4-methoxybenzoyl chloride. The rest of the procedures were followed as indicated in general procedure G to produce (2S, 4R) -1 - (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinoline 4-amino with an acceptable yield. A (2S, 4R) -1- (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-amine (200 mg, 0.67 mmol) in MeOH was added cyclopentanone (0.073 ml. , 0.74 mmol) followed by Na (OAc) 3BH (284 mg, 1.34 mmol) and a catalytic amount of HOAc. The reaction mixture was stirred at room temperature overnight. The reaction was stopped by the addition of water. And the mixture was extracted 3 times with EtOAc. The organic layers were combined, then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel (hexanes-ethyl acetate system) to yield (2S, 4R) -? / - cyclopentyl-1- (4-methoxybenzoyl) -2-methyl-1, 2,3 , 4-tetrahydroquinolin-4-amine with an acceptable yield. To a solution of (2S, 4R) -? / - cyclopentyl-1- (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-amine (100 mg, 02.7 mmol) in Methylene chloride (5 ml) was added diisopropylethylamine (120 μl, 0.70 mmol) followed by acetyl chloride (90 μl, 1.27 mmol). The mixture was stirred at t.a. for 4 h. The reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with sat. Aqueous sodium bicarbonate. and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (hexanes-ethyl acetate system) to produce? / -cyclopentyl-α / - [(2S, 4R) -1- (4-methoxybenzoyl) -2-methyl-1, Pure 2,3,4-tetrahydroquinolin-4-yl-acetamide (100 mg, 91%). 1 H NMR (CDCl 3, 300 MHz) d: 1, 24-1, 34 (m, 3H), 1, 48-1, 56 (m, 2H), 1, 90-2.07 (m, 2H), 2 , 26-2.30 (s, 3H), 2.30-2.42 (m, 1H), 2.70-2.77 (m, 2H), 3.35-3.45 (m, 1 H) ), 3.75 (s, 3H), 4.05-4.09 (m, 1 H), 4.32-4.37 (m, 1 H), 4.82-4.88 (m, 1H) ), 6.50-6.58 (m, 1 H), 6.65-6.68 (m, 2H), 6.86-6.89 (m, 1 H), 6.95-7.15 (m, 5H), 7.24-7.28 (m, 2H). MS m / z: 407 (M + 1). / V-cyclopropyl-Wp-metiM - (pyridin-3-ylcarbonyl) -1, 2,3,4-tetrahydroquinolin-4-yl] acetamide To a solution of 2-methyl-4-oxo-3,4-dihydroquinol Na-1 (2 - /) - benzyl carboxylate (1 g, 3.39 mmol) at -5 ° C in DCM was added TEA (3.76 mL, 27.09 mmol) followed by cyclopropylamine (0.24). ml, 3.39 mmol). Then, T¡Cl4 (2.4 mL, 3.39 mmol) was added. The reaction mixture was allowed to warm to room temperature and was stirred overnight. The reaction mixture was concentrated under reduced pressure. The by-product precipitated. After filtration, the filtrate was concentrated. Without purification, it was used directly in the next stage. The crude product (895.1 mg, 3.48 mmol) from the previous step was dissolved in acetic acid (10 ml). NaBH (OAc) 3 (2.27 g, 10.7 mmol) was added. The reaction was stirred at t.a. during one night. The reaction mixture was washed with brine. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel (hexanes-ethyl acetate system) to yield 4- (cyclopropylamino) -2-methyl-3,4-dihydroquinoline-1 (2H) -carboxylic acid benzyl ester. To a solution of benzyl 4- (cyclopropylamino) -2-methyl-3,4-dihydroquinoline-1 (2H) -carboxylic acid ester (492.1 mg, 1.32 mmol) at 0 ° C in methylene chloride (5 ml) acetyl chloride (0.11 ml, 1.57 mmol) was added. Triethylamine (0.27 ml, 1.57 mmol) was added dropwise over 30 min. A precipitate formed during this time. More DCM was added to completely dissolve all the precipitate. The reaction was stirred at t.a. during one night. The mixture was concentrated under reduced pressure and partitioned between ethyl acetate and 1 N sodium hydroxide while cooling to 0 ° C. The aqueous layer was extracted 3 times with ethyl acetate, washed with sat. sodium bicarbonate. and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was used directly in the next step. 4- [Acetyl (cyclopropyl) amino] -2-methyl-3,4-dihydroquinoline-1 (2H) -benzylcarboxylate was dissolved in MeOH and a catalytic amount of Palladium on Carbon (10%) was added. The round bottom flask in which the resulting solution was found was evacuated and charged again with hydrogen. The reaction was stirred in the hydrogen atmosphere overnight. The mixture was carefully filtered through a pad of Celite® and concentrated to yield the crude product. The crude residue was purified by chromatography on silica gel (hexanes / ethyl acetate system) to produce? / -cyclopropyI-? / - (2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl) acetamide . To the solution of N-cyclopropyl-N- (2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl) -acetamide (82 mg, 0.34 mmol) in DCM (5 ml) nicotinoyl chloride hydrochloride (71 mg, 0.40 mmol) was added followed by DIPEA (104 mg, 0.80 mmol). The reaction mixture was stirred at t.a. during one night. The mixture was concentrated under reduced pressure and dissolved in ethyl acetate (15 ml). The reaction mixture was washed with sat. Sodium bicarbonate. and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel (hexanes-ethyl acetate system) to yield a slightly yellow solid product (81 mg, 68%). 1 H NMR (CDCl 3, 300 MHz) d: 0.70-0.81 (m, 4H), 1, 24-1, 26 (m, 3H), 1, 31-1.37 (m, 1 H), 1.75-2.05 (m, 1 H), 2.34 (s, 3H), 2.67-2.89 (m, 1 H), 4.84-4.86 (m, 1 H) , 5.50 (a, 1H), 6.42-6.46 (d, 1H), 6.82 (a, 1 H), 6.84-6.87 (t, 1H), 7.00- 7.06 (t, 1H), 7.24-7.27 (m, 1 H), 8.47-8.49 (m, 1 H), 8.65 (a, 1 H). MS m / z: 350 (M + 1). ? / - cyclopropyl-W- [1- (4-methoxybenzoyl) -2-methyl-1,2,3,4-tetrahydroquinolin-4-yl] acetamide To a solution of 2-methyl-4-oxo-3,4 Benzyl-dihydroquinoline-1 (2H) -carboxylate (1 g, 3.39 mmol) at -5 ° C in DCM was added TEA (3.76 mL, 27.09 mmol) followed by cyclopropylamine (0.24 mL). 3.39 mmol). Then, TiCl 4 (2.4 ml, 3.39 mmol) was added. The reaction mixture was allowed to warm to t.a. and stirred overnight. The reaction mixture was concentrated under reduced pressure. The byproduct precipitated. After filtration, the filtrate was concentrated. Without purification, it was used directly in the next stage. The crude product (895.1 mg, 3.48 mmol) from the previous step was dissolved in acetic acid (10 ml). NaBH (OAc) 3 (2.27 g, 10.7 mmol) was added. The reaction was stirred at room temperature overnight. The reaction mixture was washed with brine. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel (hexanes-ethyl acetate system) to yield 4- (cyclopropylamino) -2-methyl-3,4-dihydroquinoline-1 (2 - /) -carboxylic acid benzyl ester. To a solution of benzyl 4- (cyclopropylamino) -2-methyl-3,4-dihydroquinoline-1 (2H) -carboxylic acid ester (492.1 mg, 1.32 mmol) at 0 ° C in methylene chloride (5 ml) acetyl chloride (0.11 ml, 1.57 mmol) was added. Triethylamine (0.27 ml, 1.57 mmol) was added dropwise during -30 min. A precipitate formed during this time. More methylene chloride was added to completely dissolve all the precipitate. The reaction was stirred at t.a. during one night. The mixture was concentrated under reduced pressure and partitioned between ethyl acetate and 1 N sodium hydroxide while cooling to 0 ° C. The aqueous layer was extracted 3 times with ethyl acetate, washed with sat. Aqueous sodium bicarbonate. and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was used directly in the next step. 4- [Acetyl (cyclopropyl) amino] -2-methyl-3,4-dihydroquinoline-1 (2H) -carboxylic acid benzyl ester was dissolved in MeOH and a catalytic amount of Palladium on Carbon (10%) was added. The round bottom flask in which the resulting solution was located was evacuated and charged again with hydrogen. The reaction was stirred in the hydrogen atmosphere overnight. The mixture was carefully filtered through a pad of Celite® and concentrated to yield the crude product. The crude residue was purified by chromatography on silica gel (hexanes-ethyl acetate system) to yield / V-cyclopropyl-α / - (2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl) acetamide. To the solution of N-cyclopropyl-N- (2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl) -acetamide (82 mg, 0.34 mmol) in DCM (5 ml) was added. added 4-methoxybenzoyl chloride (68 mg, 0.40 mmol) followed by DIPEA (104 mg, 0.80 mmol). The reaction mixture was stirred at t.a. during one night. The mixture was concentrated under reduced pressure and dissolved in ethyl acetate. The reaction mixture was washed with sat. Sodium bicarbonate. and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel (hexanes-ethyl acetate) to produce only the cis isomer as a slightly yellow solid product (81 mg, 68%). The mixture of the two enantiomers was purified by chiral HPLC using the OD column and the two enantiomers were obtained: W-cyclopropyl-W - [(2S, 4R) -1 - (4-methoxybenzoyl) -2-methyl-1, 2 , 3,4-tetrahydroquinolin-4-yl] acetamide 1 H NMR (CDCl 3, 300 MHz) d: 0.75-0.86 (m, 2H), 1.24-1.36 (m, 2H), 1, 56 (s, 3H), 2.03-2.07 (m, 1 H), 2.39 (s, 1 H), 2.68-2.69 (m, 1H), 3.72 (s, 3H), 4.78-4.86 (m, 1 H), 5.50 (a, 1 H), 6.47-6.50 (d, 1 H), 6.63-6.73 (d , 2H), 6.82-6.89 (m, 1 H), 6.96-7.01 (m, 1 H), 7.09-7.12 (m, 2H), 7.24-7.27 (m, 1 H). MS m / z: 379 (M + 1). W-cyclopropyl- / V - [(2R, 4S) -1 - (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] acetamide 1 H NMR (CDCl 3, 300 MHz) d : 0.75-0.86 (m, 2H), 1, 24-1, 36 (m, 2H), 1.56 (s, 3H), 2.03-2.07 (m, 1H), 2 , 39 (s, 1H), 2.68-2.69 (m, 1H), 3.72 (s, 3H), 4.78-4.86 (m, 1H), 5.50 (a, 1 H), 6.47-6.50 (d, 1 H), 6.63-6.73 (d, 2H), 6.82-6.89 (m, 1 H), 6.96-7, 01 (m, 1 H), 7.09-7.12 (m, 2H), 7.24-7.27 (m, 1 H). MS m / z: 379 (M + 1). 4- (4- { [(2S, 4R) -4- [Acetyl (cyclopropyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl} phenoxy) - 2,2-dimethylbutanoic acid 4- (4- { [(2S, 4R) -4- [acetyl (cyclopropyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2 - /) - was synthesized Carbonyl) -2,2-dimethylbutanoic acid according to general procedure I replacing? / - (4-chlorophenyl) -? / - [(2S, 4R) -1- (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] acetamide by? / - cyclopropyl -? / - [1- (4-methoxybenzoyl) -2-methyl-1, 2,3,4- tetrahydroquinolin-4-yl] acetamide and substituting ethyl 4-bromoacetate for 4-bromo-2,2-dimethylbutanoate. The remainder of general procedure I was followed as indicated to produce 4- (4- { [(2S, 4R) -4- [acetyl (cyclopropyl) amino] -2-methyl-3,4-d-hydroquinoline -1 (2H) -I] carbonyl, phenoxy) -2,2-dimethyl-1-butanoate. This material was dissolved in methanol / tetrahydrofuran / water (2/1/1), then sodium hydroxide (3 equivalents) was added and reaction mixture was stirred at 40 ° C overnight. The mixture was concentrated and the residue was acidified with a 1 N aqueous solution of HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give 4- (4. {[[(2S, 4R) -4- [acetyl (cyclopropyl) amino] -2- acid. methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl, phenoxy) -2,2-dimethylbutane. 1 H NMR (DMSO) d: 0.44-0.96 (m, 4H), 1, 01 (s, 6H), 1, 14-1, 22 (m, 1H), 1, 26 (d, 3H) , 1, 76 (t, 2H), 2.02-2.05 (m, 1 H), 2.29 (sa, 3H), 2.69-2.84 (m, 1 H), 3.93 (t, 2H), 4.58-4.70 (m, 1 H), 5.25-5.37 (m, 1 H), 6.46 (d, 1 H), 6.72 (d, 2H), 6.77-6.92 (m, 3H), 6.98 (d, 2H). MS m / z: 479 (M + 1). Table 11: Additional Exemplary Compounds Prepared in Accordance with the General Detailed Methods Previously: The Described Compounds Inhibit the Binding of PGD2 to CRTH2 This membrane radioligand binding assay evaluates the ability of the compounds to inhibit the binding of [3 H] Prostaglandin D2 (PGD2) to the receptor Cloned human CRTH2 stably expressed in HEK-293 cells (expressing the human CRTh2 receptor and the a subunit or the heterotrimeric G protein 16 was prepared by Biosignal Company) using Assay Proximity blinking. A binding buffer containing 50 mM Tris-HCl (pH 7.5) was prepared, 5 mM MgCl 2 and 1 mM EDTA immediately before performing the assay. A bed / membrane solution was prepared at double the final concentration of the assay comprising membranes (membranes purchased in Biosignal) from the cloned HEK-293 cells to express the bound CRTH2 receptor and [3H] PGD2 at double the final concentration of the assay and stored on ice before adding them to the wells. Cold PGD2 was prepared at twenty times the final assay concentration and stored on ice before adding it to the wells. Corning plates No. 3653 for non-specific binding determination were used for this assay (NSB). Concentrations of 10 mM stock solutions of compounds were prepared in 100% DMSO and stored at room temperature. A 10-point concentration response curve was then constructed for each compound, beginning at 10 μM (final assay concentration). The compounds were prepared at 40 times the final assay concentration with nine subsequent 3-fold dilutions. 0.1 μl of each concentration of the compound was added to the appropriate well of plate 384 and 2 μl of cold PGD2 was added to the wells to determine NSB. Then 20 μl of [3 H] PGD2 was added and then 20 μl of 2 × bed / membrane solution to each well. Plates were allowed to incubate at room temperature for approximately 2 hours and then counted in Packard Topcount using the tritium SPA protocol for 1 minute / well. The percentage of inhibition of the binding of PGD2 (PGD2 used at KD value or lower) to the membranes of HEK-293 cells was determined, the test was always performed as a duplicate for n = 1 for a total of n = 2. Compounds G-1 to G-34, H-1-H-22, H-24-H-35, H-37-H63, H-65-H-89, H-91-H-106, H- 105-H167 have K¡ <1 μM.
Although this invention has been shown and described particularly with reference to preferred embodiments thereof, those skilled in the art will understand that various changes may be made in the form and details thereof without departing from the scope of the invention included in the claims. Attached

Claims (70)

1. A compound of formula l-A: l-A or a pharmaceutically acceptable salt thereof, wherein: Ring A is an optionally substituted monocyclic aromatic; R is -XrR1; Rx is -X2-R4; each of X-i and X2 are independently -S (O) 2-, -C (O) -, or -C (O) NH-; R1 is: A) an aromatic group or heteroaromatic group having 5-6 ring atoms, fused to a non-aromatic monocyclic heterocyclic ring or monocyclic aromatic or heteroaromatic ring where the non-aromatic heterocyclic ring, the aromatic ring, or the heteroaromatic ring they are optionally substituted; or B) an aromatic group or heteroaromatic group having 5-6 ring atoms, substituted with: i) T1-V-T-R ?; ii) T1-V-T-M-R ?; or iii) V-R9, wherein R9 is an optionally substituted non-aromatic carbocyclic or heterocyclic group; and wherein the aromatic or heteroaromatic group having 5-6 ring atoms is optionally also substituted with 1-2 groups selected independently represented by Rz; each Rz is independently selected from halogen, haloalkyl, R °, -OR °, -O (haloalkyl), -SR °, -NO2, -CN, -N (R ') 2, -NR'CO2R °, -NR' C (O) R °, -NR'NR'C (O) R °, -N (R ') C (O) N (R') 2, -NR'NR'C (O) N (R ') 2, -NR'NR'CO2R °, -C (O) C (O) R °, -C (O) CH2C (O) R °, -CO2R °, -C (O) R °, -C (O ) N (R °) 2, -OC (O) R °, -OC (O) N (R °) 2, -S (O) 2R °, -SO2N (R '), -S (O) R ° , -NR'SO2N (R ') 2, -NR'SO2R °, -C (= S) N (R') 2 and -C (= NH) -N (R ') 2; each R is independently hydrogen, alkyl, -C (O) OR °, S (O) 2R ° or -C (O) R °; each R ° is independently hydrogen or an alkyl group, non-aromatic heterocyclic group or aromatic group and the alkyl, the non-aromatic heterocyclic group and the aromatic group represented by R ° are optionally substituted with one or more selected groups independently represented by R #; R # is R +, -OR +, -O (haloalkyl), -SR +, -NO2, -CN, -N (R +) 2. -NHCO2R +, -NHC (O) R +, -NHNHC (O) R +, -NHC (O) N (R +) 2, -NHNHC (O) N (R +) 2. -NHNHCO2R +, -C (O) C (O) R +, -C (O) CH2C (O) R +, -CO2R +, -C (O) R +, -C (O) N (R +) 2 > -OC (O) R +, -OC (O) N (R +) 2 > -S (O) 2R +, -SO2N (R +) 2, -S (O) R +, -NHSO2N (R +) 2 > -NHSO2R +, -C (= S) N (R +) 2 or - C (= NH) -N (R +) 2; R + is -H, a C-1-C3 alkyl group, a monocyclic heteroaryl group, a non-aromatic heterocyclic group or a phenyl group optionally substituted with alkyl, haloalkyl, alkoxy, haloalkoxy, halo, -CN, -NO2, amine, alkylamine or dialkylamine; or -N (R +) 2 is a non-aromatic heterocyclic group, with the proviso that the non-aromatic heterocyclic groups represented by R + and -N (R +) 2 comprising a secondary ring amine are optionally attached or alkylated; V is a covalent bond, -O-, -C (O) -, -N (R>, -S-, -S (O) -, -C (O) NR5-, -NR5C (O) -, -S (O) 2NR5-, -NR5S (O) 2- or -S (O) 2-; T is straight chain C-MO alkylene, T1 is a covalent bond or a straight chain C-O alkylene, where T and T1 together contain no more than 10 carbon atoms and where T and T1 are optionally and independently substituted on any one or more of the carbon atoms substitutable with halide, alkyl, gem dialkyl, gem dihalo, haloalkyl, alkoxy, haloalkoxy , spiro cycloalkyl, optionally / V-substituted nitrogen containing a spiro non-aromatic heterocyclic group, a non-aromatic spiro heterocyclic group containing O, amine, alkylamine, dialkylamine, alkoxy or hydroxy; M is an optionally substituted group selected from monocyclic aromatic group , heteroaromatic, monocyclic non-aromatic or heterocyclic carbocyclic, R? is -C (O) OR5, -C (O) R5, -OC (O) R5, -C (O) N (R5) 2, -NR5C (O) R5, -NR5C (O) OR5, -S (O) 2R5, -S (O) 2COR5, -S (O ) 2N (R5) 2, -NR5S (O) 2R5, -NR5S (O) 2R5, S (O) 2OR5, -S (O) OR5, -S (O) R5, -SR5, -C (O) NR5S (O) 2R5, -CN, -NR5C (O) N (R5) 2, -OC (O) N (R5) 2, -N (R5) 2, -OR5, an optionally substituted non-aromatic heterocyclic group or a group optionally substituted heteroaryl; with the proviso that T is C2-10 when V is a covalent bond and T is C2.10 when V is -O-, -S- or -N (R> and R? is -CN, -OH, - SH, -N (R5) 2 each R5 is independently -H, alkyl, haioalkyl, hydroxyalkyl, carboxyalkyl, -C (O) OCH2C6H5, S (O) 2CH3, -C (O) OH, -C (O) OMe, -C (O) OEt, C (O) NH2, benzyl, pyrrolidinyl, morpholinyl or -N (R5) 2 is a non-aromatic heterocyclic group containing nitrogen; R 2 is C 1 - 3 alkyl; R3 is an optionally substituted monocyclic or bicyclic group selected from an aromatic, heteroaromatic, non-aromatic carbocyclic and non-aromatic heterocyclic group; and R4 is optionally substituted Ct-βalkyl, hydroxyCityalkyl, or optionally substituted C3-6cycloalkyl, with the proviso that the compound of formula IA is different from: (±) -C / sN- [1- (1H -indol-2-carbonyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide; (±) -C / s-N- [1 - (benzofuran-2-carbonyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide; ethyl ester of the acid (±) -C / s-. { 4- [2-methyl-4- (phenyl-propionyl-amino) -3,4-dihydro-2H-quinoline-1 -carbonyl] -phenoxy} -acetic; acid (±) -Cis--. { 4- [2-Methyl-4- (phenyl-propionyl-amino) -3,4-dihydro-2H-quinoline-1-carbonyl] -phenoxy} - acetic; (±) -C / s-N-. { 2-methyl-1 - [4- (2-morfoin-4-yl-ethoxy) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -N-phenyl-proponamide; (±) -C / s-N- [1- (4-carbamoylmethoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinoIin-4-yl] -N-phenyl-propionamide; (±) -C / s-N-. { 1 - [4- (2-hydroxy-2-methyl-propoxy) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -N-phenyl-propionamide; (±) -C / s-N- [1- (4-dimethylcarbamoylmethoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide; (±) -C / s-N- [1- (benzo [b] thiophene-3-carbonyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide; (±) -C / sN- [1- (benzo [b] thiophene-2-carbonyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide; acid (±) -C / s-. { 4- [4- (Acetyl-phenyl-amino) -2-methyl-3,4-dihydro-2H-quinoline-1 -carbonyl] -phenylamino} -acetic; (±) -C / sN- [1 - (1-isopropyl-1 H-benzotriazole-5-carbonyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N- phenol-propionamide; ethyl ester of the acid (±) -C / s-4-. { 4- [2-methyl-4- (phenyl-propionyl-amino) -3,4-dihydro-2H-quinoline-1-carbonyl] -phenyl} -piperidine-1-carboxylic acid; (±) -C / sN- [2-methyl-1 - (4-pperidin-4-yl-benzoyl) -1, 2,3,4-tetrahydro-quinolyl-4-yl] -N -phenol-propionamide; (±) -C / s-N-. { 1- [4- (1-Acetyl-p-peridin-4-yl) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinol-4-yl} -N-phenyl-propionamide; (±) -C / s-N-. { 1- [4- (1-ethyl-p.peridin-4-yl) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolyl-4-yl} -N-phenyl-propionamide; (±) -C / s-N-. { 2-methyl-1- [4- (4-methyl-piperazin-1-yl) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -N-phenyl-proponamide; (±) -C / sN- [2-methyl-1 - (4-methyl-3,4-dihydro-2H-benzo [1,4] oxazine-7-carbonyl) -1, 2,3,4-tetrahydro -quinolin-4-yl] -N-phenyl-propionamide; (±) -C / sN- [2-Methyl-1 - (4-morpholin-4-yl-benzoyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenol- propionamide; (±) -C / s-N- [2-methyl-1- (4-pyrrolidin-1-yl-benzoyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide; acid methyl ester (±) -C / s-2-. { 4- [4- (acetyl-phenyl-amino) -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl] -phenylamino} -proponic; (±) -C / s-2-. { 4- [4- (acetyl-phenyl-amino) -2-methyl-3,4-d, 2-d-2H-quinoline-1-carbonyl-phenylamino} -propionamide; (±) -C / sN- [1- (2,3-dihydro-benzo [1,4] dioxine-6-carbonyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl ] -N-phenyl-propionamide; (±) -C / sN- [1 - (benzo [c] isoxazole-3-carbonyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl- proponamide; ethyl ester of (±) -C / s-4- (4- { 4 - [(4-chloro-phenyl) -propionyl-amino] -2-methyl-3,4-dihydro-2H-quinoline- 1-carbonyl.}. -phenoxy) -butyric; acid (±) -C / s-4- (4- { 4 - [(4-chloro-phenyl) -propionyl-amino] -2-methyl-3,4-dihydro-2H-quinoline-1 -carbonyl .}. -phenoxy) -butyric; (±) -C / s-N- (4-chloro-phenyl) -N-. { 2-methyl-1 - [4- (1 H-tetrazol-5-ylmethoxy) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -propionamide; (±) -C / s-N- (4-chloro-phenyl) -N-. { 1- [4- (3-hydroxy-2,2-dimethyl-propoxy) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -acetamide; (±) -C / s -3- (4-. {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinolyl) methyl ester na-1-carbonyl.}. -phenoxy) -2,2-dimethyl-propionic; (+) - C / sN- (4-chloro-phenyl) -N- [1- (4-cyclopentyloxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinoIin-4-yl] - acetamide; (±) -C / s-N-. { 1- [4- (4-Acetyl-piperazin-1-yl) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -N- (4-chloro-phenyl) -acetamide; (2S, 4R) - N- (4-Chloro-phenyl) -N- [2-methyl-1- (4-morpholin-4-yl-benzoyl) -1, 2,3,4-tetrahydro-quinolone -4-il] -acetamida; (2S, 4R) -4- (4- {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl} .-phenoxy) -butyric; (2S, 4R) - N- (4-Chloro-phenyl) -N- [2-methyl-1- (6-morpholin-4-yl-pyridine-3-carbonyl) -1, 2 , 3,4-tetrahydro-quino-4-yl] -acetamide; (2S, 4R) -4- (4-. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-ethyl ester carbonyl.}. -phenoxy) -piperidine-1-carboxylic acid; (2S, 4R) -N- (4-Chloro-phenyl) -N-. { 2-methyl-1- [4- (2-morpholin-4-yl-ethoxy) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -acetamide; (2S, 4R) - (4- {4- [Acetyl- (4-chloro-phenyl) -aminol-2-methyl-3,4-dihydro-2H-quino-1-carbonyl} -phenoxy )-acetic; (2S, 4R) - N- (4-Chloro-phenyl) -N-. { 2-methyl-1 - [4- (1 H -tetrazol-5-ylmethoxy) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -acetamide; (2S, 4R) -N-. { 1 - [4- (1-Acetyl-p-peridin-4-yloxy) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -N- (4-chloro-phenyl) -acetamide; (2S, 4R) - N- (4-Chloro-phenyl) -N-. { 2-methyl-1- [4- (pyridin-4-ylmethoxy) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -acetamide; (2S, 4R) -4- (3- {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbon} I.}. -phenoxy) -butyric; (2S, 4R) -4- (4-. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydric acid ethyl ester 2H-quinoline-1-carbonyl.} - phenyl) -piperidine-1-carboxylic acid; (2S, 4R) -N- (4-Chloro-phenyl) -N- [2-methyl-1- (4-pyrrolidin-1-yl-benzoyl) -1, 2,3,4-tetrahydro-quinolin-4 -l] -acetamide; (2S, 4R) -N- (4-Chloro-phenyl) -N- [1 - (1-isopropyl-1 H-benzotriazole-5-carbonyl) -2-methyl-1, 2,3,4-tetrahydro- quinolin-4-yl] -acetamide; (2S.4R) -3- (4-. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-d-hydroxy-2H-quinoline-1-carbonyl) .}.-phenyl) -propionic; (2S, 4R) -3- (4-. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl} acid. .phenyl) -acrylic; N-. { (2S, 4R) -1- [4- (1-Acetyl-pyridin-4-yl) -benzoyl] -2-methy1-, 2,3,4-tetrahydro-quinolin-4-yl} -N-phenylpropanamide; N-. { (2R, 4S) -1 - [4- (1-Acetyl-piperidin-4-yl) benzoyl] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} -N-phenylpropanamide; N - [(2S, 4R) -2-methiI-1- (4-morfoin-4-ylbenzoyl) -1, 2,3,4-tetrahydroquinolin-4-yl] -N-phenylimpropanamide; N - [(2R, 4S) -2-methyl-1- (4-morpholin-4-ylbenzoyl) -1, 2,3,4-tetrahydroquinolin-4-ii] -N-phenylpropanamide; N-. { (2S, 4R) -1- [4- (1-Acetylpiperidin-4-yl) benzoyl] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} -N-phenylpropanamide; N-. { (2R, 4S) -1 - [4- (1-Acetylpperidin-4-yl) benzoyl] -2-methyl-1, 2,3,4-tetrahydroquinolyl-4-yl} -N-phenylpropanamide; N-. { (2S, 4R) -1 - [4- (1-Acetylpiperidin-4-yl) benzoyl] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} -N- (4-chlorophenyl) acetamide; (4- {[[2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl} phenoxy) butanoic acid; N-. { (2S, 4R) -1- [4- (2-amino-2-oxoethoxy) benzoyl] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} -N- (4-chlorophenyl) acetamide; carboxylate of 4- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolyl-1 (2H) -yl] carbonyl} phenyl) -3,6-dihydropyridine-1 (2H) ethyl; N - [(2S, 4R) -1- (1,3-benzodioxol-5-ylcarbonyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] -N-phenylacetamide; N-. { (2S, 4R) -2-methyl-1 - [(3-methyl-1-benzofuran-2-yl) carbonyl] -1,2,3,4-tetrahydroquinoline-4-yl} -N-phenylacetamide; 4- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl, phenoxy) -N-ethylbutanamida; N- (4-Chlorophenyl) -N- [(2S, 4R) -1- (3-ethyl-4-fluorobenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolyl-4-yl ] acetamide; 4- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -iI] carbonii.}. Phenoxy) -2,2-dimethylbutanamide; N- (4-chlorophenyl) -N-. { (2S, 4R) -2-methyl-1- [4- (4-oxo-4-pyrrolidin-1-ylbutoxy) benzoyl] -1, 2,3,4-tetrahydroquinolin-4-yl} acetamide; 4- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl} phenoxy) butanamide; 4- (4- { [(2S, 4R) -4- [acetyl (4-cyanophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl} phenoxy) -N- (methylsulfonyl) butanamide; butanoate of 4- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl}. phenoxy) ethyl; 4- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl. phenoxy) -Nh! droxybutanamide; N- (4-chlorophenyl) -N-. { (2S, 4R) -1- [4- (3-Cyanopropoxy) benzoyl] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} acetamide; N- (4-chlorophenyl) -N - ((2S, 4R) -2-methyl-1-. {4- [3- (1, 2,4-oxadiazol-5-yl) propoxy] benzoyl}. -1, 2,3,4-tetrahydroquinolin-4-yl) acetamide; 3- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl} phenoxy) propanamide; N-. { (2S, 4R) -1- [4- (3-aminopropoxy) benzoyl] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} -N- (4-chlorophenyl) acetamide; N-. { (2S, 4R) -1 - [4- (2-amino-2-oxoethoxy) benzoyl] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} -N- (4-chlorophenyl) acetamide; N- (4-chlorophenyl) -N - ((2S, 4R) -2-methyl-1- {4- [2- (methylamino) -2-oxoethoxy] benzoyl} -1, 2,3, 4-tetrahydroquinolin-4-yl) acetamide; 2- (4- { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl, phenoxy) -N, N-dimethylacetamide; N- (4-chlorophenyl) -N-. { (2S, 4R) -2-methyl-1- [4- (2-morpholin-4-yl-2-oxoethoxy) benzoyl] -1, 2,3,4-tetrahydroquinolin-4-yl} acetamide; N- (4-chlorophenyl) -N- ((2S, 4R) -2-methyl-1 -. {4- [2- (2-oxopyrrolidin-1-yl) ethoxy] benzoyl.] -1, 2 , 3,4-tetrahydroquinolin-4-yl) acetamide; N- (4-chlorophenyl) -N - ((2S, 4R) -1-. {4- [2- (1 H -imidazol-1-yl) ethoxy] benzoyl} -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl) acetamide; N- (4-chlorophenyl) -N-. { (2S, 4R) -2-methyl-1- [4- (2-pyrrolidin-1-ylethoxy) benzoyl] -1,2,3,4-tetrahydroquinolin-4-yl-acetamide; N- (4-chlorophenyl) -N - [(2S, 4R) -1- (2,3-dihydro-1-benzofuran-5-ylcarbonyl) -2-methyl-1, 2,3,4-tetrahydroquinoline-4 -yl] acetamide; N- (4-Chlorophenyl) -N-. { (2S, 4R) -2-methyl-1 - [4- (3-pyrrolidin-1-ylpropoxy) benzoyl] -1, 2,3,4-tetrahydroquinolin-4-yl} acetamide; N- (4-chlorophenyl) -N-. { (2S, 4R) -2-methyl-1- [4- (3-morpholin-4-ylpropoxy) benzoyl] -1,2,3,4-tetrahydroquinolin-4-yl} acetamide; N- (4-chlorophenyl) -N - ((2S, 4R) -2-methyl-1-. {4 - [(4-oxopentyl) oxy] benzoyl] -1, 2,3,4-tetrahydroquinoline -4-yl) acetamide; N- (4-Chlorophen I) -N-. { (2S, 4R) -1- [4- (3-Hydroxy-3-methyl-butoxy) -benzoyl] -2-methyl-1, 2,3,4-tetrahydroquinol-4-yl-acetamide; N- (4-Chlorophenyl) -N - ((2S, 4R) -1-. {4 - [(4-hydroxy-4-methylpentyl) oxy] benzoyl} -2-methyl-1, 2,3 , 4-tetrahydroquinolin-4-yl) acetamide; N- (4-chlorophenyl) -N - ((2S, 4R) -1 -. {4 - [(1-et.lp.peridin-4-yl) methoxy] benzoyl} -2-methyl-1 , 2,3,4-tetrahydroquinolin-4-yl) acetamide; N- (4-chlorophenyl) -N - ((2S, 4R) -1-. {4- [3- (1 H -imidazol-1-yl) propoxy] benzoyl} -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl) acetamide; (2S, 4R) -N- (4-Chloro-phenyl) -N- [2-methyl-1- (4-methyl-3,4-dihydro-2H-benzo [1,4] oxazine-7-carbonyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide; N- (4-chlorophenyl) -N-. { (2S, 4R) -2-methyl-1 - [(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl) carbonyl] -1,3,4,4-tetrahydroquinoline-4 -il} acetamide; N- (4-chlorophenyl) -N-. { (2S, 4R) -1 - [4- (4-ethylpiperazin-1 -yl) benzoyl! 3-2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} acetamide; N-. { (2S, 4R) -1- [4- (4-acetylpiperazin-1-yl) benzoyl] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} -N- (4-chlorophenyl) acetamide; N- (4-chlorophenyl) -N-. { (2S, 4R) -1- [4- (4-glycololoipyridazin-1-yl) benzoyl] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl-acetamide; N- (4-chlorophenyl) -N-. { (2S, 4R) -2-methyl-1- [4- (3-morpholin-4-ylprop-1-yn-1-yl) benzoyl] -1,2,3,4-tetrahydroquinolin-4-yl} acetamide; 4- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino3-2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl} phenyl) but-3-inoic; N - [(2S, 4R) -1 - (1 H -benzimidazol-2-ylcarbonyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] -N- (4-chlorophenyl) acetamide; N - [(2S, 4R) -1 - (1,3-benzothiazol-2-ylcarbonyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] -N- (4-chlorophenyl) acetamide; N- (4-chlorophenyl) -N-. { (2S, 4R) -2-methyl-1 - [(1-methyl-1 H-1, 2,3-benzotriazol-5-yl) carbonyl] -1, 2,3,4-tetrahydroquinolin-4-yl-acetic acid; N- (4-chlorophenyl) -N-. { (2S, 4R) -1 - [(1-isopropyl-1 H -benzimidazol-5-yl) carbonyl] -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl} acetamide; [4- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl}. phenyl) piperazin-1-yl] acetic acid; N - ((2S, 4R) -1- { 4- [4- (2-amino-2-oxoethyl) piperazin-1-yl] benzoyl.} -2-methyl-1, 2,3,4 -tetrahydroquinolin-4-yl) -N- (4-chlorophenyl) acetamide; 3- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl} phenoxy propanoic; 4- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolyl-1 (2H) -yl] carbonyl} phenoxy) -2,2-dimethylbutanoic; acid { 1 - [(4- {[[2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl} phenoxy ) methyl] cyclopropyl} acetic; (2E) -4- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-d-hydroquinoline-1 (2H) -yl] carbonyl, phenoxy) but-2-enoic; 3- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl} phenoxy -2,2-dimethylpropanoic acid; (2E) -4- (4- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl .}. phenoxy) -2-methylbut-2-enoic; N- (4-chlorophenyl) -N-. { (2S, 4R) -2-methyl-1 - [4- (3. {[[(Trifluoromethyl) sulfonii] amino} propoxy) benzoyl] -1,2,3,4-tetrahydroquinolin-4-yl} acetamide; N- (4-chlorophenyl) -N - ((2S, 4R) -1- { [1- (2-hydroxyethyl) -2-methyl-1H-benzimidazol-5-yl] carbonyl] - 2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl) acetamide; 5- acid. { [(2S, 4R) -4- [acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl} -2-methyl-1 H-benzimidazol-1-yl) acetic acid; 3- (5- { [(2S, 4R) -4- [Acetyl (4-chlorophenyl) amino] -2-methyl-3,4-dihydroquinolin-1 (2H) -yl] carbonyl .} -1 H-1, 2,3-benzotriazol-1-yl) propanoic acid; (2S, 4R) -N- (4-Chloro-phenyl) -N- [1- (1-isopropyl-1 H -indazol-5-carbonyl) -2-methyl-1, 2,3,4-tetrahydro- quinolin-4-yl] -acetamide; or (2S, 4R) -N- (4-Chloro-phenyl) -N- (2-methyl-1 - { 4- [3- (1 H-tetrazol-5-yl) -propoxy] -benzoyl} -1, 2,3,4-tetrahydro-quinolin-4-yl) -acetamide.
2. The compound of claim 1, wherein: Ring A is an optionally substituted monocyclic aromatic; R is -XrR1; Rxes-X2-R4; Xi and X2 are each independently -S (O) 2-, -C (O) -, or -C (O) NH-; R1 is: A) an aromatic group or heteroaromatic group having 5-6 ring atoms, substituted by: i) T1-V-T-R ?; ii) T1-V-T-M-R ?; or iii) V-R9 wherein R9 is an optionally substituted non-aromatic carbocyclic or heterocyclic group; and wherein the aromatic or heteroaromatic group represented by R1 is optionally further substituted by 1-2 selected groups independently represented by Rz; or B) an aromatic group or heteroaromatic group having 5-6 ring atoms, fused to a monocyclic non-aromatic heterocyclic ring or monocyclic aromatic ring wherein the non-aromatic heterocyclic ring or the aromatic ring are optionally substituted; each Rz is independently selected from halogen, haloalkyl, R °, -OR °, -O (haloalkyl), -SR °, -NO2, -CN, -N (R ') 2, -NR'CO2R °, -NR' C (O) R °, -NR'NR'C (O) R °, -N (R ') C (O) N (R') 2, -NR'NR'C (O) N (R ') 2, -NR'NR'CO2R °, -C (O) C (O) R °, -C (O) CH2C (O) R °, -CO2R °, -C (O) R °, -C (O ) N (R °) 2, -OC (O) R °, -OC (O) N (R °) 2, -S (O) 2R °, -SO2N (R ') 2, -S (O) R °, -NR'SO2N (R ') 2, -NR'SO2R °, -C (= S) N (R') 2, and -C (= NH) -N (R ') 2; each R is independently hydrogen, alkyl, -C (O) OR °, S (O) 2R °, or -C (O) R °; each R ° is independently hydrogen or an alkyl group, non-aromatic heterocyclic group or aromatic group and the alkyl, non-aromatic heterocyclic group and aromatic group represented by R ° is optionally substituted with one or more selected groups independently represented by R #; R # is R \ -OR +, -O (haloalkyl), -SR +, -NO2, -CN, -N (R +) 2, -NHCO2R +, -NHC (O) R +, -NHNHC (O) R \ -NHC ( O) N (R +) 2, -NHNHC (O) N (R +) 2, -NHNHCO2R +, -C (O) C (O) R +, -C (O) CH2C (O) R \ -CO2R +, -C ( O) R +, -C (O) N (R +) 2, -OC (O) R +, -OC (O) N (R +) 2, -S (O) 2R +, -SO 2 N (R +) 2, -S ( O) R +, -NHSO2N (R +) 2, -NHSO2R +, -C (= S) N (R +) 2, or -C (= NH) -N (R +) 2; R + is -H, a C1-C3 alkyl group, a monocyclic heteroaryl group, a non-aromatic heterocyclic group or a phenyl group optionally substituted with alkyl, haloalkyl, alkoxy, haloalkoxy, halo, -CN, -NO2, amine, alkylamine or dialkylamine; or -N (R +) 2 is a non-aromatic heterocyclic group, with the proviso that the non-aromatic heterocyclic groups represented by R + and -N (R +) 2 comprising a secondary amine amine ring are optionally adylated or alkylated; R? is -C (O) OR 5, -C (O) R 5, -OC (O) R 5, -C (O) NR 52, -NR 5 C (O) R 5, - NR 5 C (O) OR 5, -S (O) 2 R 5, -S (O) 2COR5, -S (O) 2NR52, -NR5S (O) 2R5, -NR5S (O) 2R5, S (O) 2OR 5, -S (O) OR 5, -S (O) R 5, -SR 5, -C (O) NR 5 S (O) 2 R 5, -CN, -NR 5 C (O) NR 52, - OC (O) NR 52 , -NR52, -OR5, an optionally substituted non-aromatic heterocyclic group or an optionally substituted heteroaryl group; V is a covalent bond, -O-, -C (O) -, -N (R) -, -S-, -S (O) -, -C (O) NR5-, -NR5C (O) -, -S (O) 2NR5-, -NR5S (O) 2-, or -S (O) 2-; T is a straight chain C-O alkylene; with the proviso that T is C2-? 0 when V is a covalent bond, and T is C2-? 0 when V is -O-, -S-, or -N (R ') - and R? is -CN, -OH, -SH, -N (R5) 2; T1 is a covalent bond, or a straight chain C-MO alkylene, where T and T1 together do not contain more than 10 carbon atoms, and where T and T1 are optionally and independently substituted on any one or more substitutable carbon atoms with halide, alkyl, gem dialkyl, gem dihalo, haloalkyl, alkoxy, haloalkoxy, spiro cycloalkyl, optionally / V-substituted nitrogen containing a non-aromatic heterocyclic group spiro, amine, alkylamine, dialkylamine, or hydroxyl; each R5 is independently -H, alkyl, haloalkyl, hydroxyalkyl, carboxyalkyl, -C (O) OCH2C6H5, S (O) 2CH3, -C (O) OH, -C (O) OMe, -C (O) OEt, C (O) NH2, benzyl, pyrrolidinyl, morpholinyl, or -N (R5) 2 is a nitrogen-containing a non-aromatic heterocyclic group; M is an optionally substituted monocyclic, heteroaromatic aromatic or an optionally substituted monocyclic or heterocyclic non-aromatic carbocyclic group; R2 is C1-3 alkyl; R3 is an optionally substituted aromatic group having 5-6 ring atoms; and R 4 is C 1-3 alkyl or C 1 - 3 hydroxyalkyl.
3. The compound of claim 1, wherein: Ring A is an optionally substituted phenyl group; R2 is methyl or ethyl; R3 is an optionally substituted phenyl group; R 4 is methyl, ethyl, hydroxymethyl, hydroxyethyl, cyclopropyl, cyclobutyl, or isopropyl; and X1 and X2 are -C (O) -.
4. The compound of claim 2, wherein: Ring A is an optionally substituted phenyl group; R2 is methyl or ethyl; R3 is an optionally substituted phenyl group; R 4 is methyl, ethyl, hydroxymethyl, or hydroxyethyl; Y
5. The compound of claim 3, wherein: R is a phenyl ring substituted with V-T-R ?, and optionally is also substituted with 1-2 selected groups independently represented by Rz; V is a covalent bond, -O- or -N (R ') -; and T is straight chain C6_6alkylene optionally substituted on any one or more of the carbon atoms substitutable with halide, alkyl, gem dialkyl, gem dihalo, haloalkyl, spiro cycloalkyl, optionally nitrogen / substituted containing a non-aromatic heterocyclic spiro group, O containing a non-aromatic heterocyclic spiro group, amine, alkylamine, dialkylamine, alkoxy, or hydroxyl.
6. The compound of claim 4, wherein: R1 is a phenyl ring substituted with V-T-R ?, and optionally is also substituted with 1-2 groups independently selected represented by Rz; V is a covalent bond, -O- or -N (R ') -; and T is straight chain C? -6 alkylene optionally substituted on any one or more of the carbon atoms substitutable with halide, alkyl, gem dialkyl, gem dihalo, haloalkyl, spiro cycloalkyl, optionally / V-substituted nitrogen containing a non-aromatic heterocyclic spiro group, amine, alkylamine, dialkylamine, or hydroxyl.
7. The compound of claim 5 or 6, wherein: R? is -C (O) OR 5, -C (O) N (R 5) 2, -NR 5 C (O) R 5, -NR 5C (O) OR 5, -S (O) 2 R 5, -NR 5 S (O) 2 R 5, -OR 5, -CN, -NR5C (O) N (R5) 2, -N (R5) 2, an optionally substituted non-aromatic heterocyclic group represented by R7, or an optionally substituted heteroaryl group represented by R8; R7 is an optionally substituted group selected from piperidinonyl, oxazolidinyl, oxazolidinonyl, thiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, tetrahydrothiophene, morpholinyl, thiomorpholinyl, imidazolidinyl, imidazolidinonyl, dioxanyl, dioxolanyl, dithiolanyl, pyrrolidinyl, pyrrolidinonyl, piperazinyl or piperidinyl; and R8 is an optionally substituted group selected from furanyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrimidyl, thiazolyl, thienyl or imidazolyl.
8. The compound of claim 7, wherein: R3 is a phenyl group optionally substituted by one or more groups independently selected represented by R11; and each R 11 is independently selected from halogen, haloalkyl, R °, -OR °, -O (haloalkyl), -SR °, 3,4-methylene-dioxy, 3,4-ethylene-dioxy, -NO 2, -CN, -N (R ') 2, -NR'CO2R °, -NR'C (O) R °, -NR'NR'C (O) R °, -N (R') C (O) N (R ') ) 2, -NR'NR'C (O) N (R ') 2, -NR'NR'CO2R °, -C (O) C (O) R °, -C (O) CH2C (O) R ° , -CO2R °, -C (O) R °, -C (O) N (R °) 2, -OC (O) R °, -OC (O) N (R °) 2, -S (O) 2R °, -SO2N (R ') 2, -S (O) R °, -NR'SO2N (R') 2, -NR'SO2R °, -C (= S) N (R ') 2 - (CH2 ) 1-4CO2R °, -O (CH2) 1-4CO2R °, - (CH2)? - 4CON (R0) 2, -O (CH2) 1-4CON (R °) 2, - (CH2) or -3 ( C (CH3) 2) CO2R0, -O (CH2) or -3 (C (CH3) 2) CO2R0, (CH2) 0-3 (C (CH3) 2) CON (R0) 2, -O (CH2) or -3 (C (CH3) 2) CON (R0) 2, or -C (= NH) -N (R ') 2.
9. The compound of claim 7, wherein: R3 is a phenyl group optionally substituted by one or more groups independently selected represented by R11; and each R 11 is independently selected from halogen, haloalkyl, R °, -OR °, -O (haloalkyl), -SR °, 3,4-methylene-dioxy, 3,4-ethylene-dioxy, -NO 2, -CN, -N (R ') 2, -NR'CO2R °, -NR'C (O) R °, -NR'NR'C (O) R °, -N (R') C (O) N (R ') ) 2) -NR'NR'C (O) N (R ') 2, -NR'NR'CO2R °, -C (O) C (O) R °, -C (O) CH2C (O) R ° , -CO2R °, -C (O) R °, -C (O) N (R °) 2, - OC (O) R °, -OC (O) N (R °) 2, -S (O) 2R °, -SO2N (R ') 2, -S (O) R °, -NR'SO2N (R') 2, -NR'SO2R °, -C (= S) N (R ') 2, or - C (= NH) -N (R ') 2.
10. The compound of claim 9, wherein: R? is -C (O) OR 5, -C (O) R 5, -C (O) N (R 5) 2, -NR 5 C (O) R 5, -NR 5 C (O) OR 5, -S (O) 2 R 5, -NR 5 S ( O) 2R5, -NR5S (O) 2R5, -NR5C (O) N (R5) 2, -OH, an optionally substituted non-aromatic heterocyclic group represented by R7 or an optionally substituted heteroaryl group represented by R8; each R5 is independently -H, alkyl, or -N (R5) 2 is a non-aromatic heterocyclic group containing nitrogen; R7 is an optionally substituted group selected from piperidinonyl, morpholinyl, imidazolidinonyl, pyrrolidinyl, pyrrolidinonyl, piperazinyl or piperidinyl; R8 is an optionally substituted group selected from tetrazolyl, oxazolyl, oxadiazolyl, pyrrolyl, pyrazolyl, pyridinyl or imidazolyl; V is a covalent bond, or -O-; and T is an optionally substituted straight chain C1- alkylene at the carbon atom adjacent to R? with halide, alkyl, gem dialkyl, gem dihalo, haloalkyl, spiro cycloalkyl, optionally N-substituted spiro nonaromatic heterocyclic group containing nitrogen, amine, dialkylamine, alkoxy, or hydroxyl.
11. The compound of claim 9, wherein V is -O-
12. The compound of claim 9, wherein V is a covalent bond and T is a substituted straight chain C al ?. al alkylene at the carbon atom adjacent to R? with alkyl, gem dialkyl, haloalkyl, spiro cycloalkyl, or an optionally / V-substituted nitrogen containing a non-aromatic spiro heterocyclic group.
13. The compound of claim 10, wherein: Ring A is a phenyl group optionally substituted at positions six and seven with R 14; each R14 is independently halogen, haloalkyl, R °, -OR °, -O (haloalkyl), -SR °, -N02, -CN, -N (R ') 2, -NR'CO2R °, -NR'C ( O) R °, -NR'NRO (O) R °, -N (R ') C (O) N (R') 2, -NR'NR, C (O) N (R,) 2, -NR 'NR'CO2R0, -C (O) C (O) R °, -C (O) CH2C (O) R °, -CO2R °, -C (O) R °, -C (O) N (R °) ) 2, -OC (O) R °, -OC (O) N (R °) 2, -S (O) 2R °, -SO2N (R ') 2, -S (O) R °, -NR' SO2N (R ') 2, -NR'SO2R °, -C (= S) N (R') 2 and -C (= NH) -N (R ') 2, (CH2) nCO2R °, -O (CH2 ) nCO2R °, - (CH2) nOH, - (CH2) nOH, - (CH2) nC (O) N (R °) 2, or -O (CH2) nC (O) N (R °) 2; n is an integer of 1-4; R1 is a phenyl ring substituted at the para or meta positions with V-T-R ?, and optionally is also substituted with 1-2 groups independently selected represented by Rz; each Rz is independently selected from halogen, haloalkyl, R °, -OR °, -O (haloalkyl), -CO2R °, -NR'SO2R °, -C (O) R °, -C (O) N (R °) ) 2, -OC (O) R °, and -OC (O) N (R °) 2; each R11 is independently a substituent selected from halogen, haloalkyl, R °, -OR °, -O (haloalkyl), 3,4-methylene dioxy, 3,4-ethylene-dioxy, -CO2R0 ,, -C (O) R °, -N (R ') 2, -NR'SO 2 R °, -C (O) N (R °) 2, -OC (O) R °, and -OC (O) N (R °) 2; each R 'is independently H or alkyl; and each R ° is independently hydrogen, haloalkyl or an alkyl group.
14. The compound of claim 13, wherein: R? is -C (O) OR 5, -C (O) N (R 5) 2, -OH, A / -morpholinyl, 2-morpholinyl, 3-morpholinyl, 2-morpholinyl / V-substituted, 3-morpholinyl / V -substituted, / V-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 5-imidazoIidinium, 2-imidazolidinyl? / -substituted, N-imidazolidinyl / V-substituted, 4-imidazolidinyl / V-substituted, 5-imidazolidinyl N- substituted, / V-imidazolidinonyl, 4-imidazolidinonyl, 5-imidazolidinonyl, 4-imidazolidinonyl / V-substituted, 5-imidazolidinonyl / V-substituted, / V-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolidinyl / V -substituted, 3-pyrrolidinyl / V-substituted, N-pyrrolidin-2-onyl, 3-pyrrolidin-2-onyl, 4-pyrrolidin-2-onyl, 5-pyrrolidin-2-onyl, 3-pyrrolidin-2-onyl / V-substituted, 4-pyrrolidin-2-onyl / V-substituted, N-substituted 5-pyrrolidin-2-onyl, / V-pyrrolidin-3-onyl, 2-pyrrolidin-3-onyl, 4-pyrrolidin-3 -onyl, 5-pyrrolidin-3-onyl, 2-pyrroidin-3-onyl / V-substituted, 4-pyrrolidin-3-onyl / V-substituted, 5-pyrrolidin-3-onyl / V-substituted, / V- piperidini it, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-piperidinyl / V-substituted, 3-piperidinyl / V-substituted, 4-piperidinyl / V-substituted, N-piperidin-2-onyl, 3-piperidin-2-onyl, 4-piperidin-2-onyl, 5-piperidin-2-onyl, 6-piperidin-2-onyl, 3-piperidin-2-onyl / V -substituted, 4-piperidin-2-onyl / V-substituted, 5-piperidin-2-onyl / V-substituted, 6-piperidin-2-onyl / V-substituted, / V-piperidin-3-onyl, 2- piperidin-3-onyl, 4-piperidin-3-onyl, 5-piperidin-3-onyl, 6-piperidin-3-onyl, 2-piperidin-3-onyl? / - substituted, 4-piperidin-3-onyl? / -substituted, N-substituted 5-piperidin-3-onyl, 6-piperidin-3-onyl / V-substituted, / V-piperidin-4-onyl, 2-piperidin-4-onyl, 3-piperidin-4- onyl, 5-piperidin-4-onyl, 6-piperidin-4-one, 2-piperidin-4-onyl N-substituted, 3-piperidin-4-onyl / V-substituted, 5-piperidin-4-onyl / V-substituted, 6-piperidin-4-onyl / V-substituted, / V-piperazinyl, 2-piperazinyl, / N-substituted V-piperazinyl, 2-piperazinyl / V-substituted, furanyl, / V-tetrazolyl, -tetrazolyl, 5-tetrazolyl / V-substituted, 4- (1, 2,3) oxadiazolyl, 5- (1, 2,3) oxadiazolyl, 3- (1, 2,4) oxadiazolyl, 5- (1, 2 , 4) oxadiazoyl, 3- ( 1, 2,5) oxadiazolyl, 4- (1, 2,5) oxadiazolyl, 2- (1, 3,4) oxadiazolyl, 5- (1, 3,4) oxadiazolyl,? / - pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyrrolyl / V-substituted, 3-pyrrolidyl / substituted, / V-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 3-pyrazolyl / V-substituted, 4-pyrazolyl N- substituted, 5-pyrazoyl / V-substituted, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl; 2-imidazolyl / V-substituted, 4-imidazolyl / V-substituted, or 5-imidazolyl / V-substituted; V is -O-; and T is a substituted chain C1-3 alkylene at the carbon atom adjacent to R? with fluorine, methyl, gem dimethyl, gem difluorofluoromethyl, spiro cyclopropyl, spiro cyclobutyl, spiro azetidinyl optionally / V-substituted, spiro aziridinyl optionally / V-substituted, spiro pyrrolidinyl optionally N-substituted, spiro piperidinyl optionally / V-substituted, amine, methylamine, dimethylamine, or hydroxyl.
15. The compound of claim 14, wherein: each Rz is independently selected from halogen, haloalkyl, R °, -OR °, -O (haloalkyl); R3 is a phenyl group optionally substituted in the meta or para position by one or more groups selected independently represented by R11; and each R 11 is independently a substituent selected from halogen, haloalkyl, R °, -OR °, -N (R ') 2, -NR'SO 2 R ° and -O (haloalkyl).
16. The compound of claim 15, wherein: R? is -C (O) OR 5, -C (O) NR 52, -OH, / V-tetrazolyl, 5-tetrazolyl, N-substituted 5-tetrazolyl, / V-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl; 2-imidazolyl AZsubstituted, 4-imidazolyl? / - substituted, or 5-imidazolyl / V-substituted; and R5 is -H, methyl, or ethyl.
17. The compound of claim 16, wherein: Ring A is a phenyl group optionally substituted at positions six and seven with R 14; each R14 is independently halogen, R °, -OR °, -CO2R °, -C (O) R °, -C (O) N (R °) 2, -OC (O) R °, (CH2) nCO2R ° , O (CH2) nCO2R °, NHSO2R °, -NHCOR0, -CN, NHC (O) N (R °) 2, (CH2) nOH, O (CH2) nOH, (CH2) nC (O) N (R0) 2, or O (CH2) nC (O) N (R0) 2; R1 is a phenyl ring substituted in the para position by V-T-R? and optionally it is also substituted in the meta position by Rz; Rz is chloride, fluoride, bromide, -OR °, -N (R ') 2, -NR'SO2R ° or -R °; R 'is independently hydrogen or a C? -3 alkyl group; and R ° is independently hydrogen, haloalkyl, or a C -? - 3 alkyl group.
18. The compound of claim 3, wherein: R1 is a phenyl ring substituted by V-R9 where R9 is an optionally substituted non-aromatic carbocyclic or heterocyclic group and is optionally also substituted by 1-2 independently selected groups represented by R '
19. The compound of claim 18, wherein R3 is a phenyl group optionally substituted by one or more groups independently selected represented by R11; and each R 11 is independently selected from halogen, haloalkyl, R °, -OR °, -O (haloalkyl), -SR °, 3,4-methylene-dioxy, 3,4-ethylene-dioxy, -NO 2, -CN, -N (R ') 2, -NR'CO2R °, -NR'C (O) R °, -NR'NR'C (O) R °, -N ^ CÍO ^ R' ^, -NR, NR ' C (0) N (R,) 2, -NR'NR'CO2R0, -C (O) C (O) R °, -C (O) CH2C (O) R °, -CO2R °, -C (O ) R °, -C (0) N (R °) 2, -OC (O) R °, -OC (O) N (R °) 2, -S (O) 2R °, -SO2N (R ') 2, -S (O) R °, -NR'SO2N (R ') 2, -NR'SO2R °, -C (= S) N (R') 2 - (CH2)? - 4CO2R °, -O ( CH2) 1-4CO2R °, - (CH2) 1-4CON (R °) 2, -O (CH2) 1-4CON (R °) 2, - (CH2) 0-3 (C (CH3) 2) CO2Ro, -O (CH2) o -3 (C (CH3) 2) CO2R0, (CH2) 0. 3 (C (CH3) 2) CON (R0) 2, -O (CH2) or -3 (C (CH3) 2) CON (R0) 2, or -C (= NH) -N (R ') 2.
20. The compound of claim 18, wherein R3 is a phenyl group optionally substituted by one or more groups independently selected represented by R11; and each R 11 is independently selected from halogen, haloalkyl, R °, -OR °, -O (haloalkyl), -SR °, 3,4-methylene-dioxy, 3,4-ethylene-dioxy, -NO 2, -CN, -N (R ') 2, -NR'CO2R °, -NR'C (O) R °, -NR'NRO (O) R °, -N (R') C (O) N (R ') 2 , -NR'NR'CÍO R'k, -NR'NR'COzR0, -C (O) C (O) R °, -C (O) CH2C (O) R °, -CO2R °, -C (O ) R °, -C (O) N (R °) 2, -OC (O) R °, -OC (O) N (R °) 2, -S (O) 2R °, -SO2N (R ') 2, -S (O) R °, -NR'SO2N (R ') 2, -NR'SO2R °, -C (= S) N (R') 2 or -C (= NH) -N (R ') )2.
21. The compound of claim 19 wherein R ,, R99 eess uunn cciicclloohheexxaanniilloo ooxxaazzoolliiddiinniilloo ,, ooxxaazzoolliiddiinnoonniillio, thiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, tetrahydrothienyl, morpholinyl, thiomorpholinyl, imidazolidinyl, imidazolidinonyl, dioxanyl, dioxolanyl, dithiolanyl, pyrrolidinyl, pyrrolidinonyl, piperazinyl, S, S-isothiazolidinyl dioxide, S, S-1, 2,5-thiadiazolidine dioxide, or optionally substituted piperidinyl.
22. The compound of claim 20, wherein: R9 is a cyclohexanyl, oxazolidinyl, oxazolidinonyl, thiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, tetrahydrothienyl, morpholinyl, thiomorpholinyl, imidazolidinyl, imidazolidinonyl, dioxanyl, dioxolanyl, dithiolanyl, pyrrolidinyl, pyrrolidinonyl, piperazinyl, S, S-thiazolidinyl S-dioxide, or optionally substituted piperidinyl.
23. The compound of claim 18, wherein: Ring A is a phenyl group optionally substituted at positions six and seven with R 14; each R14 is independently halogen, haloalkyl, R °, -OR °, -O (haloalkyl), -SR °, -NO2, -CN, -N (R ') 2, -NR'CO2R °, -NR'C ( O) R °, -NR'NR'C (O) R °, -N (R ') C (O) N (R') 2, -NR'NR'C (O) N (R,) 2, -NR'NR'CO2R °, -C (O) C (O) R °, C (O) CH2C (O) R °, -CO2R °, -C (O) R °, -C (O) N ( R °) 2, -OC (O) R °, -OC (O) N (R °) 2, -S (O) 2R °, -SO2N (R ') 2, -S (O) R °, - NR'SO2N (R ') 2, -NR'SOzR0, -C (= S) N (R') 2 and -C (= NH) -N (R ') 2, (CH2) nCO2R °, -O ( CH2) nCO2R °, - (CH2) nOH, - (CH2) nOH, - (CH2) nC (O) N (R °) 2, or -O (CH2) nC (O) N (R °) 2; n is an integer of 1-4; R1 is a phenyl ring substituted in the para position or by a non-aromatic carbocyclic or heterocyclic group represented by V-R9, and is optionally also substituted with 1-2 selected groups independently represented by Rz; each Rz is independently selected from halogen, haloalkyl, R °, -OR °, -O (haloalkyl), -CO2R °, -NR'SO2R °, -C (O) R °, -C (O) N (R °) ) 2, -OC (O) R °, and -OC (O) N (R °) 2; V is a covalent bond or -O-; R3 is a phenyl group optionally substituted by one or more groups independently selected represented by R11; and each R 11 is independently selected from halogen, haloalkyl, -R °, -OR °, -O (haloalkyl), 3,4-methylene-dioxy, 3,4-ethylene-dioxy, -CO 2 R °, -N (R ' ) 2, -C (O) R °, -C (O) N (R °) 2, -NR'SO 2 R °, -OC (O) R °, and -OC (O) N (R °) 2; each R 'is independently H or alkyl; and each R ° is independently hydrogen, haloalkyl or an alkyl group.
24. The compound of claim 23, wherein: R9 is oxazolidinyl, thiazolidinyl, tetrahydrofuranyl, morpholinyl, imidazolidinyl, imidazolidinonyl, pyrrolidinyl, pyrrolidinonyl, piperazinyl or piperidinyl, each optionally substituted by alkyl, halide, haloalkyl, hydroxyalkyl, -C (O) OR12 , -C (O) R12, -OC (O) R12, -R12C (O) OR12, -C (O) NR122, -NR12C (O) R12, -NR2C (O) OR12, -S (O) 2R12 , -S (O) 2COR 12, -S (O) 2N (R 12) 2, -S (O) 2OR 12, -S (O) OR 12, -OR 12, -SR 12, -CN, -NR 12 C (O) N (R 12 ) 2, -OC (O) N (R12) 2, - (CH2) nCO2H, - (CH2) nC (O) NR °, (CH2) nC (CH3) 2CO2H, - (CH2) nC (CH3) 2C ( O) NR0 or -N (R12) 2; n is an integer from 1 to 4; and each R12 is independently -H, alkyl, haloalkyl or hydroxyalkyl.
25. The compound of claim 24, wherein: each Rz is independently selected from halogen, haloalkyl, -R °, -OR °, and -O (haloalkyl); R3 is a phenyl group optionally substituted in the para or meta position by one or more selected groups independently represented by R11; and each R 11 is independently a substituent selected from halogen, haloalkyl, -R °, -OR °, -N (R ') 2, -NR'SO 2 R ° and -O (haloalkyl).
26. The compound of claim 25, wherein: R9 is? / -morpholinyl, 2-morpholinyl, 3-morpholinyl, 2-morpholinyl / V-substituted, 3-morpholinyl / V-substituted, / V-pyrrolidinyl, 2-pyrrolidinyl, -pyrrolidinyl, N-substituted 2-pyrrolidinyl, 3-pyrrolidinyl / V-substituted, / V-piperazinyl, 2-piperazinyl, / V-piperazinyl / V-substituted, 2-piperazinyl / V-substituted, / V-piperidinyl, -piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-piperidinyl / V-substituted, 3-piperidinediol / substituted, 4-piperidinyl N-substituted, each optionally substituted on any carbon atom substitutable with alkyl, halide , haloalkyl, hydroxyalkyl, -C (O) OR 12, -C (O) R 12, -OC (O) R 12 or -C (O) N (R 12) 2, and where the N substituents are alkyl, haloalkyl, hydroxyalkyl, - C (O) OR12, -C (O) R12, - (CH2) nCO2H, - (CH2) nC (O) NR °, - (CH2) nC (CH3) 2CO2H, - (CH2) nC (CH3) 2C ( O) NR0 or -C (O) N (R12) 2; and n is an integer of 1-4.
27. The compound of claim 26, wherein: Ring A is a phenyl group optionally substituted at positions six and seven with R 14; each R14 is independently halogen, R °, -OR °, -CO2R °, -C (O) R °, -C (O) N (R °) 2, -OC (O) R °, (CH2) nCO2R ° , O (CH2) nCO2R °, NHSO2R °, -NHCOR0, -CN, NHC (O) N (R °) 2, - (CH 2) n OH, -O (CH 2) n OH, - (CH 2) n C (O) N (R °) 2, or - O (CH 2) n C (O) N (R °) 2; n is an integer of 1-4; R1 is a phenyl ring substituted in the para position by a carbocyclic or non-aromatic heterocyclic group represented by V-R9, and is optionally also substituted in the meta position by Rz; Rz is chloride, fluoride, bromide, -OR °, or -R °; R3 is a phenyl group optionally substituted in the para position by R11; R11 is chloride, fluoride, bromide, -OR °, -N (R ') 2, -NR'SO2R ° or R °; R 'is independently hydrogen or a C1-3 alkyl group; and R ° is independently hydrogen, haloalkyl, or a C -? - 3 alkyl group.
28. The compound of claim 27, wherein: R9 is / V-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-piperidinyl N-substituted, 3-piperidinyl / V-substituted, 4-piperidinyl / V-substituted, / V-piperazinyl, 2-piperazinyl , A / -piperazinyl / V-substituted, or 2-piperazinyl? / - substituted, and is optionally substituted at any carbon atom substitutable with chloride, fluoride, bromide, methyl, ethyl, -C (O) OR12, - OC (O) R12, -C (O) R12 or C (O) NH2, and where the N substituents are methyl, ethyl, -C (O) OR12, -C (O) R12, - (CH2) nCO2H, - (CH2) nC (O) NR °, - (CH2) nC (CH3) 2CO2H, - (CH2) nC (CH3) 2C (O) NR0, or -C (O) NH2; N is an integer of 1-4; and each R12 is independently -H, methyl or ethyl.
29. The compound of claim 3, wherein: R1 is a phenyl group fused to an optionally substituted monocyclic non-aromatic heterocyclic ring represented by R10, or a monocyclic aromatic ring represented by R13.
30. The compound of claim 29, wherein: Ring A is a phenyl group optionally substituted at positions six and seven with R 14; each R14 is independently halogen, haloalkyl, R °, -OR °, -O (haloalkyl), -SR °, -NO2, -CN, -N (R ') 2, -NR'CO2R °, -NR'C ( O) R °, -NR'NR'C (O) R °, -N (R ') C (O) N (R') 2, -NR'NR'C (O) N (R ') 2, -NR'NR'CO2R °, -C (O) C (O) R °, -C (O) CH2C (O) R °, -CO2R °, -C (O) R °, -C (O) N (R °) 2, -OC (O) R °, -OC (O) N (R °) 2, -S (O) 2R °, -SO2N (R ') 2, -S (O) R °, -NR'SO2N (R ') 2, -NR'SO2R °, -C (= S) N (R') 2 and -C (= NH) -N (R ') 2, (CH2) nCO2R °, - O (CH2) nCO2R °, - (CH2) nOH, - (CH2) nOH, - (CH2) nC (O) N (R °) 2, -O (CH2) nC (O) N (R °) 2; n is an integer of 1-4; R3 is a phenyl group optionally substituted by one or more groups independently selected represented by R11; and R 11 is independently selected from halogen, haloalkyl, -R °, -OR °, -O (haloalkyl), -SR °, 3,4-methylene-dioxy, 3,4-ethylene-dioxy, -NO 2 > -CN, -N (R ') 2, - NR'CO2R °, -NR'C (O) R °, -NR'NR'C (O) R °, -N (R') C (O) N (R ') 2, -NR'NR'C (O) N (R') 2, -NR'NR'CO2R °, -C (O) C (O) R °, -C (O) CH2C (O ) R °, -CO2R °, -C (O) R °, -C (O) N (R °) 2, -OC (O) R °, -OC (O) N (R °) 2, -S (O) 2R °; -SO2N (R ') 2, -S (O) R °, -NR'SO2N (R') 2, -NR'SO2R °, -C (= S) N (R ') 2 - (CH2)? - 4CO2R0, -O (CH2) 1-4CO2R °, - (CH2) MCON (R °) 2, -O (CH2) 1-4CON (R °) 2, - (CH2) 0-3 (C (CH3) 2 ) CO2Ro, -O (CH2) or -3 (C (CH3) 2) CO2R0, (CH2) 0. 3 (C (CH3) 2) CON (R °) 2, -O (CH2) or -3 (C (CH3) 2) CON (R0) 2, or -C (= NH) -N (R ') 2 .
31. The compound of claim 29, wherein: Ring A is a phenyl group optionally substituted at positions six and seven with R 14; each R14 is independently halogen, haloalkyl, R °, -OR °, -O (haloalkyl), -SR °, -NO2, -CN, -N (R ') 2, -NR'CO2R °, -NR'C ( O) R °, -NR'NR'C (O) R °, -N (R ') C (O) N (R') 2, -NR'NR'C (O) N (R ') 2, -NR'NR'CO2R0, -C (O) C (O) R °, C (O) CH2C (O) R °, -CO2R °, -C (O) R °, -C (O) N (R °) 2, -OC (O) R °, -OC (O) N (R °) 2, -S (O) 2R °, -SO2N (R ') 2, -S (O) R °, -NR 'SO2N (R') 2, -NR'SO2R °, -C (= S) N (R ') 2 and -C (= NH) -N (R!) 2, (CH2) nCO2R °, -O ( CH2) nCO2R °, - (CH2) nOH, - (CH2) nOH, - (CH2) nC (O) N (R °) 2, -O (CH2) nC (O) N (R °) 2; n is an integer of 1-4; R3 is a phenyl group optionally substituted by one or more groups independently selected represented by R11; and R 1 is independently selected from halogen, haloalkyl, -R °, -OR °, -O (haloalkyl), -SR °, 3,4-methylene-dioxy, 3,4-ethylene-dioxy, -NO 2, -CN , -N (R ') 2, -NROO2R °, -NR'C (O) R °, -NR'NR'C (O) R °, -N (R') C (O) N (R ') 2, -NR'NR'C (O) N (R ') 2, -NR'NROO2R0, -C (O) C (O) R °, -C (O) CH2C (O) R °, -CO2R ° , -C (O) R °, -C (O) N (R °) 2, -OC (O) R °, -OC (O) N (R °) 2, -S (O) 2R °, - SO2N (R ') 2, -S (O) R °, -NR'SO2N (R') 2, -NR'SO2R °, -C (= S) N (R ') 2 and -C (= NH) -N (R ') 2.
32. The compound of claim 31, wherein: R 10 is oxazolidinyl, oxazolidinonyl, dioxolanyl, thiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothienyl, morpholinyl, thiomorpholinyl, imidazolidinyl, imidazolidinonyl, dioxanyl, dithiolanyl, pyrrolidinyl, piperazinyl, piperidinyl, piperidinyl, S, S tetrahydrothienyl dioxide, S, S-thiomorpholinyl dioxide, or S, S-tetrahydrothiopyranyl dioxide, each of which is optionally substituted; and R13 is pyrazolyl, triazolyl, imidazolyl, furanyl, pyrrolyl, thienyl, cyclopentadienyl and S, S-thienyl dioxide, each of which is optionally substituted.
33. The compound of claim 32, wherein: R3 is a phenyl group optionally substituted by one or more groups independently selected represented by R11; each R 1 is a substituent independently selected from halogen, haloalkyl, -R °, -OR °, -O (haloalkyl), 3,4-methylene-dioxy, 3,4-ethylene-dioxy, -CO 2 R °, -C ( O) R °, -N (R ') 2, -C (O) N (R °) 2, -OC (O) R °, -NR'SO2R °, and -OC (O) N (R °) 2; each R 'is independently H or alkyl; and each R ° is independently hydrogen, haloalkyl or an alkyl group.
34. the compound of claim 33, wherein: R 10 is tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, imidazolidinyl, imidazolidinonyl, pyrrolidinyl, piperazinyl or piperidinyl each of which is optionally substituted at any carbon atom of the ring substitutable with alkyl, halide, haloalkyl, hydroxyalkyl , -C (O) OR12, -C (O) R12, -OC (O) R12, -R12C (O) OR12-, -C (O) N (R12) 2, -NR12C (O) R12, -NR12C (O) OR12, -S (O) 2R12, -S (O) 2COR12, -S (O) 2N (R12) 2, -S (O) 2OR12, -S (O) OR12, -OR12, -SR12, -CN, -NR12C (O) N (R12) 2, -OC (O) N (R12) 2, -N (R12) 2, - (CH2) 1-4CO2R12, -OÍCHz ^ COsR12, (CH2) 1- 4CON (R12) 2, -O (CH2)? - 4CON (R12) 2, - (CH2) 0-3 (C (CH3) 2) CO2R12, -O (CH2) or -3 (C (CH3) 2) CO2R12, - (CH2) or -3 (C (CH3) 2) CON (R12) 2, or -O (CH2) or -3 (C (CH3) 2) CON (R12) 2, and each of which is optionally substituted at any nitrogen atom of the ring substitutable with alkyl, haloalkyl, hydroxyalkyl, -C (O) OR12, -C (O) R12, -R12C (O) OR12-, -C (O) N (R12) 2; R 13 is triazolyl, imidazolyl, furanyl, pyrrolyl, thienyl, each of which is optionally substituted on any carbon atom of the ring substitutable with alkyl, halide, haloalkyl, hydroxyalkyl, -C (O) OR 12, -C (O) R 12 , -OC (O) R12, -C (O) OR12-, -C (O) N (R2) 2, -NR2C (O) R12, -NR12C (O) OR12, -S (O) 2R12, -S (O) 2COR 12, -S (O) 2 N (R 12) 2, -S (O) 2OR 12, -S (O) OR 12, -OR 12, -SR 12, -CN, -NR 12 C (O) N (R 12) 2, -OC (O) N (R12) 2, -N (R12) 2, - (CH2)? - 4CO2R12, -O (CH2) 1-4CO2R12, (CH2)? - 4CON (R12) 2, - - (CH2) 0-3 (C (CH3) 2) CO2R12, -O (CH2) 0-3 (C (CH3) 2) CO2R12, - (CH2) 0-3 (C (CH3) 2) CON (R12) 2, or -O (CH2) or -3 (C (CH3) 2) CON (R12) 2, and each of which is optionally substituted at any nitrogen atom of the ring substitutable with alkyl, haloalkyl, hydroxyalkyl, -C (O) OR12, -C (O) R12, -R12C (O) OR12, -S (O) 2R12, S (O) 2N (R12) 2, -C (O) N (R12) 2, and each R12 is independently H, alkyl, haloalkyl or hydroxyalkyl.
35. The compound of claim 34, wherein: R3 is a phenyl group optionally substituted in the para or meta position by one or more selected groups independently represented by R11; and each R 11 is independently a substituent selected from halogen, haloalkyl, -R °, -OR °, -N (R ') 2, -NR'SO 2 R ° and -O (haloalkyl).
36. The compound of claim 35, wherein: R 10 is piperidinyl, piperazinyl, dioxolanyl, tetrahydrofuranyl, or morpholinyl, each optionally substituted at any carbon atom substitutable with alkyl, halide, haloalkyl, hydroxyalkyl, -C (O) OR 12, -C (O) R12, -OC (O) R12 or -C (O) N (R12) 2, each optionally substituted at any nitrogen atom substitutable with alkyl, haloalkyl, hydroxyalkyl, -C (O) OR12, -C ( O) R 12 or -C (O) N (R 12) 2; R 13 is triazolyl, imidazolyl or pyrrolyl each optionally substituted on any carbon atom substitutable with alkyl, halide, haloalkyl, hydroxyalkyl, -C (O) OR 12, -C (O) R 12, -OC (O) R 12 or -C ( O) N (R12) 2 and each optionally substituted at any nitrogen atom substitutable with alkyl, haloalkyl, hydroxyalkyl, C (O) OR12, -C (O) R12, -R12C (O) OR12, -S (O) 2R12, S (O) 2N (R12) 2, -C (O) N (R12) 2.
37. The compound of claim 36, wherein: Ring A is a phenyl group optionally substituted at positions six and seven with R 14; each R14 is independently halogen, R °, -OR °, -CO2R °, -C (O) R °, -CN, -C (O) N (R °) 2, -OC (O) R °, (CH2) ) nCO2R °, O (CH2) nCO2R °, NHSO2R °, -NHCOR0, NHC (O) NR2, (CH2) nOH, O (CH2) nOH, (CH2) nC (O) N (R °) 2, or O (CH2) nC (O) N (R °) 2; n is an integer of 1-4; R3 is a phenyl group optionally substituted in the para position by R11; R11 is chloride, fluoride, bromide, -OR °, -N (R ') 2, -NR'SO2R ° or -R °; R 'is independently hydrogen or a C -? - 3 alkyl group; and R ° is independently hydrogen, haloalkyl, or a C? -3 alkyl group.
38. The compound of claim 37, wherein: R10 is piperidinyl, piperazinyl, or morpholinyl and is optionally / V-substituted with methyl, ethyl, isopropyl, C (O) OR12, C (O) NH2 or -C (O) R12; R13 is triazolyl and is optionally / V-substituted with methyl, ethyl, -C (O) OR12, C (O) NH2 or -C (O) R12; and each R12 is independently -H, methyl or ethyl.
39. The compound of claim 29, wherein: R 10 is tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, imidazolidinyl, imidazolidinonyl, pyrrolidinyl, piperazinyl or piperidinyl, each of which is optionally substituted on any one or more ring carbon atoms with alkyl, halide , haloalkyl, hydroxyalkyl, -C (O) OR12, -C (O) R12, -OC (O) R12, -R12C (O) OR12-, -C (O) N (R12) 2, -NR12C (O) R12, -NR12C (O) OR12, -S (O) 2R12, -S (O) 2COR12, -S (O) 2N (R12) 2, -S (O) 2OR12, -S (O) OR12, -OR12 , -SR12, -CN, -NR12C (O) N (R12) 2, -OC (O) N (R12) 2, -N (R12) 2, - (CH2) 1-4CO2R12, -OÍCHZJ- COZR12, ( CH2)? - 4CON (R12) 2, -O (CH2) 1-4CON (R12) 2, - (CH2) 0-3 (C (CH3) 2) CO2R12, -O (CH2) 0-3 (C ( CH3) 2) CO2R12, - (CH2) or -3 (C (CH3) 2) CON (R12) 2, or -O (CH2) or -3 (C (CH3) 2) CON (R12) 2, and each one of which is optionally substituted at any nitrogen atom of the ring substitutable with alkyl, haloalkyl, hydroxyalkyl, -C (O) OR 12, -C (O) R 12, -R 12 C (O) OR 12, -C (O) N ( R12) 2; each R12 is independently H, alkyl, haloalkyl, or hydroxyalkyl; R 13 is pyrazolyl, triazolyl, imidazolyl or pyrrolyl, each of which N-substituted with T 2 -RY 1 and optionally also substituted on any one or more carbon atom of the ring with alkyl, halide, haloalkyl, hydroxyalkyl, -C (O ) OR12, -C (O) R12, -OC (O) R12, -C (O) OR12-, -C (O) N (R12) 2, -NR12C (O) R12, -NR 2C (O) OR12 , -S (O) 2R 12, -S (O) 2COR 12, -S (O) 2 N (R 12) 2, -S (O) 2OR 12, -S (O) OR 12, -OR 12, -SR 12, -CN, - NR12C (O) N (R12) 2, -OC (O) N (R12) 2 (-N (R12) 2, - (CH2) 1-4CO2R12, -O (CH2)? - 4CO2R12, (CH2)? - 4CON (R12) 2, -O (CH2)? - 4CON (R 2) 2, - (CH 2) o- 3 (C (CH 3) 2) CO 2 R 12, -O (CH 2) o-3 (C (CH 3) 2 ) CO2R12, - (CH2) or -3 (C (CH3) 2) CON (R12) 2, or -O (CH2) or -3 (C (CH3) 2) CON (R12) 2; T2 is an alkylene C ? _6 of straight chain optionally substituted on any one or more carbon atoms substitutable with halide, alkyl, gem dialkyl, gem dihalo, haloalkyl, spiro cycloalkyl, optionally spiro non-aromatic heterocyclic group / V-substituted nitrogen containing, heterocyclic group not aromatic spiro that with It has O, amine, aikilamine, dialkylamine or hydroxyl; RY1 is -C (O) OR5, -C (O) N (R5) 2, -NR5C (O) R5, -NR5C (O) OR5, -S (O) 2N (R5) 2, -NR5S (O) 2R5, -OR5, -CN, -NR5C (O) N (R5) 2, -N (R5) 2, an optionally substituted non-aromatic heterocyclic group represented by R7 or an optionally substituted heteroaryl group represented by R8; R7 is a piperidinonyl, oxazolidinyl, oxazolidinonyl, thiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, tetrahydrothiophene, morpholinyl, thiomorpholinyl, imidazolidinyl, imidazolidinonyl, dioxanyl, dioxolanyl, dithiolanyl, pyrrolidinyl, pyrrolidinonyl, piperazinyl or optionally substituted piperidinyl; and R8 is an optionally substituted furanyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrimidyl, thiazolyl, thienyl or imidazolyl.
40. The compound of claim 39, wherein: Ring A is a phenyl group optionally substituted at positions six and seven with R 14; each R14 is independently halogen, haloalkyl, R °, -OR °, -O (haloalkyl), -SR °, -NO2, -CN, -N (R ') 2, -NR'CO2R °, -NR'C ( O) R °, -NR'NR'C (O) R °, -N (R ') C (O) N (R') 2, -NR'NR'C (O) N (R ') 2, -NR'NR'CO2R °, -C (O) C (O) R °, -C (O) CH2C (O) R °, -CO2R °, -C (O) R °, -C (O) N (R °) 2, -OC (O) R °, -OC (O) N (R °) 2, -S (O) 2R °, -SO2N (R ') 2, -S (O) R °, -NR'SO2N (R ') 2, -NR'SO2R °, -C (= S) N (R') 2 and -C (= NH) -N (R ') 2, (CH2) nCO2R °, - O (CH2) nCO2R °, - (CH2) nOH, - (CH2) nOH, - (CH2) pC (O) N (R °) 2, or O (CH2) nC (O) N (R °) 2; n is an integer of 1-4; R3 is a phenyl group optionally substituted by one or more groups independently selected represented by R11; and each R 1 is independently selected from halogen, haloalkyl, -R °, -OR °, -O (haloalkyl), -SR °, 3,4-methylene-dioxy, 3,4-ethylene-dioxy, -NO 2, -CN, -N (R ') 2 , -NR'CO2R0, -NR'C (O) R °, -NR'NR'C (O) R °, -N (R ') C (O) N (R') 2, -NR'NR ' C (O) N (R ') 2, -NR'NR'CO2R0, -C (O) C (O) R °, -C (O) CH2C (O) R °, -CO2R °, -C (O) ) R °, -C (O) N (R °) 2, -OC (O) R °, -OC (O) N (R °) 2, -S (O) 2R °, -SO2N (R ') 2, -S (O) R °, -NR'S? 2N (R ') 2, -NR'SO2R °, -C (= S) N (R') 2, - (CH2) 1-4CO2R °, -O (CH2) 1_4CO2R °, - (CH2) 1-4CON (R °) 2, -O (CH2)? - 4CON (R °) 2, - (CH2) or -3 (C (CH3) 2) C? 2R0 , -O (CH2) or -3 (C (CH3) 2) CO2R0, (CH2) 0. 3 (C (CH3) 2) CON (R0) 2, -O (CH2) or -3 (C (CH3) 2) CON (R °) 2, or -C (= NH) -N (R ') 2 .
41. The compound of claim 40, wherein: R3 is a phenyl group optionally substituted by one or more groups independently selected represented by R11; each R11 is independently a substituent selected from halogen, haloalkyl, R °, -OR °, -O (haloalkyl), 3,4-methylene-dioxy, 3,4-ethylene-dioxy, -CO2R0 ,, -C (O) R °, -N (R ') 2, -NR'SO 2 R °, -C (O) N (R °) 2, -OC (O) R °, and -OC (O) N (R °) 2; each R 'is independently H or alkyl; and each R ° is independently hydrogen, haloalkyl or an alkyl group.
42. The compound of claim 41, wherein: RY1 is -C (O) OR5, -C (O) N (R5) 2, -NR5C (O) R5, -NR5C (O) OR5, -S (O) 2N ( R5) 2, -NR5S (O) 2R5, -NR5C (O) N (R5) 2, -OH, an optionally substituted non-aromatic heterocyclic group represented by R7 or an optionally substituted heteroaryl group represented by R8; each R5 is independently H or alkyl, or N (R5) 2 is a non-aromatic heterocyclic group containing nitrogen; R7 is piperidinonyl, morpholinyl, midazolidinonyl, pyrrolidinyl, pyrrolidinonyl, piperazinyl or piperidinyl; R8 is tetrazolyl, oxazolyl, oxadiazolyl, pyrrolyl, pyrazolyl, pyridinyl or imidazolyl; T2 is a straight chain C? -5 alkylene optionally substituted on the carbon atom adjacent to R? with halide, alkyl, gem dialkyl, gem dihalo, haloalkyl, spiro cycloalkyl, optionally N-substituted non-aromatic spiro heterocyclic group containing nitrogen, amine, dialkyamymine or hydroxyl; the group represented by R10 is morpholinyl, thiomorpholino, imidazolidinyl, imidazolidinonyl, pyrrolidinyl, piperazinyl or piperidinyl each of which is / V-substituted with T2-RY1 and optionally further substituted at any substitutable carbon atom by alkyl, halide, haloalkyl, hydroxyalkyl, -C (O) OR12, -C (O) R12, -OC (O) R12, -C (O) OR12, -, C (O) N (R12) 2, -NR12C (O) R12, - NR12C (O) OR12, -S (O) 2R12, -S (O) 2COR12, -S (O) 2N (R12) 2, -S (O) 2OR12, -S (O) OR12, -OR12, -SR12 , -CN, -NR12C (O) N (R12) 2, -OC (O) N (R12) 2, -N (R12) 2 - (CH2) 1-4CO2R12, -O (CH2)? - 4CO2R12, ( CH2y ,, 4CON (R12) 2, -O (CH2) 1-4CON (R12) 2, - (CH2) or -3 (C (CH3) 2) CO2R12, -O (CH2) 0-3 (C (CH3 ) 2) CO2R12, - (CH2) or -3 (C (CH3) 2) CON (R 2) 2, or -O (CH2) 0-3 (C (CH3) 2) CON (R12) 2; group represented by R 3 is triazolyl, imidazolyl or pyrrolyl each of which is / V-substituted with T2-RY1 and optionally also substituted at any carbon atom substitutable with alkyl, halide, haloalkyl, hydroxyalkyl, -C (O) OR12 , -C (O) R12, -OC ( O) R12, -C (O) OR12-, -C (O) N (R12) 2, - NR12C (O) R12, -NR12C (O) OR12, -S (O) 2R12, -S (O) 2COR12 , -S (O) 2N (R 12) 2) -S (O) 2OR 12, -S (O) OR 12, -OR 12, -SR 12, -CN, -NR 12 C (O) N (R 12) 2, -OC (O ) N (R12) 2, -N (R12) 2, - (CH2)? - CO2R12, -O (CH2) 1-4CO2R12, (CH2) 1-4CON (R12) 2, -0 (CH2)? - 4CON (R12) 2, - (CH2) 0-3 (C (CH3) 2) CO2R12, -O (CH2) or -3 (C (CH3) 2) C? 2R12, - (CH2) 0-3 (C ( CH3) 2) CON (R12) 2, or -O (CH2) or -3 (C (CH3) 2) CON (R12) 2.
43. The compound of claim 42, wherein: R3 is a phenyl group optionally substituted at the meta or para position by one or more selected groups independently represented by R11; and each R 11 is independently a substituent selected from halogen, haloalkyl, -R °, -OR °, -N (R ') 2, -NR'SO 2 R ° and -O (haloalkyl).
44. the compound of claim 43, wherein: RY1 is -C (O) OR 5, -C (O) N (R 5) 2, -OH, / V-morpholinyl, 2-morpholinyl, 3-morpholinyl, 2-morpholinyl / V -substituted, 3-morpholinyl / V-substituted -imidazolidinilo, 2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl, 2-imidazolidiniIo / -? substituted N-imidazolidinyl / '- substituted, 4-imidazolidinyl / V- substituted 5-imidazolidinyl N-substituted, / V-imidazolidinonyl, 4-imidazolidinonyl, 5-imidazoIidinonilo, 4-imidazolidinonyl / V-substituted 5-imidazolidinonyl / V-substituted, / V-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl , 2-pyrrolidinyl / V-substituted, 3-pyrrolidinyl / V-substituted, N-pyrrolidin-2-onyl, 3-pyrrolidin-2-onyl, 4-pyrrolidin-2-onyl, 5-pyrrolidin-2-onyl, -pyrrolidin-2-onyl / V-substituted, 4-pyrrolidin-2-onyl? / - substituted, 5-pyrrolidin-2-onyl N-substituted, / V-pyrrolidin-3-onyl, 2-pyrrolidin-3-onyl, 4-pyrrolidin-3-onyl, 5-pyrrolidin-3-onyl, 2-pyrrolidin-3-onyl / V-substituted, 4-pyrrolidin- 3-onyl / V-substituted, 5-pyrrolidin-3-onyl / V-substituted, A / -piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-piperidinyl / V-substituted, 3-piperidinyl / V -substituted, 4-piperidinyl? / - substituted, N-piperidin-2-ynyl, 3-piperidin-2-ynyl, 4-piperidin-2-ynyl, 5-piperidin-2-ynyl, 6-piperidin-2-ynyl , 3-piperidin-2-onyl / V-substituted, 4-piperidin-2-onyl / V-substituted, 5-piperidin-2-onyl / V-substituted, 6-piperidin-2-onyl / V-substituted ,? / - piperidin-3-onyl, 2-piperidn-3-onyl, 4-piperidin-3-one, 5-piperidn-3-one, 6-piperidin-3- onyl, 2- piperidin-3-onyl / V-substituted, 4-piperidin-3-onyl / V-substituted, 5-piperidin-3-onyl N-substituted, 6-piperdin-3-onyl / V-substituted ,? / - piperidin-4-onyl, 2-piperidin-4-onyl, 3-piperidin-4-onyl, 5-piperidin-4-onyl, 6-piperidin-4-onyl, 2-piperidin-4-oni what N-substituted, 3-piper idin-4-onyl / V-substituted, 5-piperidin-4-onyl / V-substituted, 6-piperidin-4-ynyl / - substituted, / V-piperazinyl, 2-piperazinyl, / N-substituted-piperazinyl , 2-piperazinyl / V-substituted, furanyl, / V-tetrazolyl, 5-tetrazolyl, 5-tetrazolyl / V-substituted, 4- (1, 2,3) oxadiazolyl, 5- (1, 2,3) oxadiazoli, 3- (1, 2,4) oxadiazolyl, 5- (1, 2,4) oxadiazolyl, 3- (1, 2,5) oxadiazolyl, 4- (1, 2,5) oxadiazolyl, 2- (1, 3 , 4) oxadiazolyl, 5- (1, 3,4) oxadiazolyl, α / - pyrrolyl, 2-pyrrolyl, 3-pyrroyl, 2-pyrroyl / V-substituted, 3-pyrrolyl / V-substituted, / V- pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 3-pyrazoyl-substituted, 4-pyrazolyl N-substituted, 5-pyrazolyl / V-substituted, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, N -imidazolyl, 2-imidazolyl, 4-imidazoyl, 5-imidazoyl; 2-imidazolyl / V-substituted, 4-imidazolyl / V-substituted or 5-imidazolyl / V-substituted; T2 is a straight chain C? -3 alkylene substituted with fluorine, methyl, gem dimethyl, gem difluoro fluoromethyl, spiro cyclopropyl, spiro cyclobutyl, spiro azetidinyl optionally / V-substituted, spiro aziridinyl optionally / V-substituted, spiro pyrrolidinyl optionally / V-substituted, optionally N-substituted spiro piperidinyl, amine, methylamine, dimethylamine or hydroxyl; the group represented by R10 is morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl each of which is / V-substituted with T2-RY1 and optionally also substituted at any carbon atom substitutable with alkyl, halo, haloalkyl, hydroxyalkyl, -C (O ) OR 12, -C (O) R 12, -OC (O) R 12; and the group representing R13 is imidazolyl or pyrrolyl each of which is / V-substituted with T2-RY1 and optionally also substituted at any carbon atom substitutable with alkyl, halide, haloalkyl, hydroxyalkyl, -C (O) OR12, -C (O) R12, -OC (O) R12 or -C (O) N (R12) 2 and each is optionally substituted at any nitrogen atom substitutable with alkyl, haloalkyl, hydroxyalkyl, C (O) OR12, - C (O) R12, -R12C (O) OR12, -S (O) 2R12, S (O) 2N (R12) 2, -C (O) N (R12) 2.
45. The compound of claim 44, wherein: Ring A is a phenyl group optionally substituted at positions six and seven with R 14; each R14 is independently halogen, R °, -OR0, -CO2R °, -C (O) R °, -CN, -C (O) N (R °) 2, -OC (O) R °, (CH2) nCO2R0, O (CH2) nCO2R0, NHSO2R °, -NHCOR0, NHC (O) N (R °) 2, (CH2) nOH, O (CH2) nOH, (CH2) nC (O) N (R °) 2, or O (CH2) nC (O) N (R °) 2; n is an integer of 1-4; R3 is a phenyl group optionally substituted in the para position by R11; R11 is chloride, fluoride, bromide, -OR °, -N (R ') 2, -NR'SO2R ° or R °; R 'is independently hydrogen or a C? -3 alkyl group; and R ° is independently hydrogen, haloalkyl, or a C1-3 alkyl group.
46. The compound of claim 45, wherein: RY1 is -C (O) OR5, -C (O) N (R5) 2, -OH,? / - tetrazolyl, 5-tetrazolyl, 5-tetrazolyl N-substituted, / V imidazolyl, 2-imidazoyl, 4-imidazolyl, 5-imidazolyl; N-substituted, 4-imidazolyl / V-substituted or 5-imidazolyl / V-substituted 2-imidazolyl; the group represented by R10 is piperidinyl, piperazinyl, or morpholino, / V-substituted with T2-R? 1 and optionally also substituted on the alpha carbon at the nitrogen atom with methyl or gem dimethyl; and the group represented by R13 is thiazolyl / V-substituted with T2-RY1 and optionally also substituted on the alpha carbon at the nitrogen atom with methyl.
47. A compound represented by the following structural formula: or a pharmaceutically acceptable salt thereof, wherein: V is a covalent bond or -O-. T is an unsubstituted straight chain C-MO alkylene; R? is -C (O) OR 5, -C (O) R 5, -OC (O) R 5, -C (O) N (R 5) 2, -NR 5 C (O) R 5, -NR 5 C (O) OR 5, -S ( O) 2R5, -S (O) 2COR5, -S (O) 2N (R5) 2, -NR5S (O) 2, -NR5S (O) 2R5, S (O) 2OR5, -S (O) OR5, - SR5, -C (O) NR5S (O) 2R5, -CN, -NR5C (O) N (R5) 2, -OC (O) N (R5) 2, -N (R5) 2, -OR5, a group optionally substituted non-aromatic heterocyclic or an optionally substituted heteroaryl group; each R5 is independently -H, alkyl, haloalkyl, hydroxyalkyl, carboxyalkyl, -C (O) OCH2C6H5, S (O) 2CH3, -C (O) OH, -C (O) OMe, -C (O) OEt, C (O) NH2, benzyl, pyrrolidinyl, morpholino, or -N (R5) 2 is a non-aromatic heterocyclic group containing nitrogen;
48. A compound represented by the following structural formula: or a pharmaceutically acceptable salt thereof, wherein: V is a covalent bond or -O-; T is a straight chain C-MO alkylene substituted with alkyl, gem dialkyl, spiro cycloalkyl, or a spiro / V-substituted non-aromatic heterocyclic group containing nitrogen; R? is -C (O) OR 5, -C (O) R 5, -OC (O) R 5, -C (O) N (R 5) 2, -NR 5 C (O) R 5, -NR 5 C (O) OR 5, -S ( O) 2R5, -S (O) 2COR5, -S (O) 2N (R5) 2, -NR5S (O) 2, -NR5S (O) 2R5, S (O) 2OR5, -S (O) OR5, - SR5, -C (O) NR5S (O) 2R5, -CN, -NR5C (O) N (R5) 2, -OC (O) N (R5) 2, -N (R5) 2, -OR5, a group optionally substituted non-aromatic heterocyclic or an optionally substituted heteroaryl group; and each R5 is independently -H, alkyl, haloalkyl, hydroxyalkyl, carboxyalkyl, -C (O) OCH2C6H5, S (O) 2CH3, -C (O) OH, -C (O) OMe, -C (O) OEt, C (O) NH2, benzyl, pyrrolidinyl, morpholinyl or -N (R5) 2 is an optionally substituted non-aromatic heterocyclic group containing nitrogen.
49. A compound represented by the following structural formula: or a pharmaceutically acceptable salt thereof, wherein: V is -O-; T is an alkylene C-MO straight chain optionally substituted at any one or more substitutable carbon atoms with halide, alkyl, dialkyl gem, gem dihalo, haloalkyl, alkoxy, haloalkoxy, spiro cycloalkyl, heterocyclic nonaromatic spiro optionally / V -substituted containing nitrogen, amine, alkylamine, dialkyamymine or hydroxyl; R? is -C (O) OR 5, -C (O) R 5, -OC (O) R 5, -C (O) N (R 5) 2, -NR 5 C (O) R 5, -NR 5 C (O) OR 5, -S ( O) 2R5, -S (O) 2COR5, -S (O) 2N (R5) 2, -NR5S (O) 2, -NR5S (O) 2R5, S (O) 2OR5, -S (O) OR5, - SR5, -C (O) NR5S (O) 2R5, -CN, -NR5C (O) N (R5) 2, -OC (O) N (R5) 2, -N (R5) 2, -OR5, a group optionally substituted non-aromatic heterocyclic or an optionally substituted heteroaryl group; and each R5 is independently -H, alkyl, haloalkyl, hydroxyalkyl, carboxyalkyl, -C (O) OCH2C6H5, S (O) 2CH3, -C (O) OH, -C (O) OMe, -C (O) OEt, C (O) NH2, benzyl, pyrrolidinyl, morpholinyl or -N (R5) 2 is an optionally substituted non-aromatic heterocyclic group containing nitrogen.
50. A pharmaceutical composition comprising an acceptable carrier or diluent and a compound of claim 1, 2, 47, 48, or 49.
51. A method for treating an inflammatory disease, disorder or symptom in a subject in need of treatment, comprising the step of administering to the subject an effective amount of a compound represented by the compound of claim 1, 2, 47, 48, or 49 .
52. The method of claim 51 wherein the inflammatory disease, disorder or symptom is allergic rhinitis, rheumatoid arthritis, chronic obstructive pulmonary disease, atopic dermatitis, or allergic asthma.
53. The method of claim 51 wherein the inflammatory disease, disorder or symptom is allergic rhinitis or allergic asthma.
54. A method for preparing a compound represented by the following structural formula: NH _, COOH R ~ ~ comprising the step of reacting Ar-NH2 with R cf ° where Ar is an optionally substituted monocyclic aromatic group and R2 is C1-C3 alkyl.
55. The method of claim 54 wherein Ar is an optionally substituted phenyl group and R 2 is methyl or ethyl.
56. The method of claim 55 wherein Ar is a phenyl group optionally for or meta substituted with R 14; each R14 is independently halo, cyano, R °, -OR30, -CO2R31, -C (O) R °, -C (O) N (Rx) 2, -OC (O) R °, (CH2) nCO2R31, O (CH2) nCO2R31, NHSO2R °, NHC (O) NRx2, (CH2) nOR30, O (CH2) nOR30, (CH2) nC (O) NR2, O (CH2) nC (O) NRx2; n is an integer of 1-4; R ° is independently hydrogen, C1-C3 haloalkyl or a C1-C3 alkyl group; one Rx is -H or C? -C3 alkyl and the other is an amine protecting group; R30 is an alcohol protecting group; and R31 is a carboxylic acid protecting group.
57. The method of claim 56 wherein Ar is a phenyl group.
58. A method for preparing a product compound represented by the following structural formula: from a starting compound represented by the following structural formula: said method comprising the step of reducing the amide carbonyl of the starting compound to form an intermediate and then cyclizing the intermediate to form the product compound, wherein -C (O) ORz is an amide protecting group.
59. The method of claim 58 wherein Rz is a substituted or unsubstituted alkyl group, an allyl group or an aromatic group.
60. The method of claim 59 wherein the amide carbonyl of the starting compound is reduced by reacting the starting compound with sodium borohydride and a Lewis acid and the intermediate is cyclized in the presence of acid.
61. The method of claim 60 wherein Ar is an optionally substituted phenyl group and R 2 is methyl or ethyl.
62. The method of claim 60 wherein Rz is benzyl, methyl, ethyl, allyl, 2,2,2-trichloromethyl, 2,2,2-trichloro-fer-butyl, fer-butyl or fluoromethyl.
63. The method of claim 58 wherein the starting compound is prepared by amidating an amino acid with H2NC (O) ORz, wherein said amino acid is represented by the following structural formula:
64. The method of claim 63 wherein said amidation is performed by reacting the amino acid with a carboxylic acid activation reagent to form an activated intermediate and then reacting the activated intermediate with H2NC (O) ORz.
65. The method of claim 64 wherein the carboxylic acid activating agent is a carbonyldiimidazole.
66. The method of claim 63 wherein said amidation is performed by reacting the amino acid with a carboxylic acid activation reagent to form an activated intermediate and then reacting the activated intermediate with NH3 or a functional equivalent thereof to form a carboxamide intermediate represented by the following structural formula: by reacting the carboxamide intermediate with X-C (O) ORz, where X is a leaving group.
67. The method of claim 63 wherein the amino acid is prepared by reacting Ar-NH2 with
68. The method of claim 67 wherein Ar is an optionally substituted phenyl group and R 2 is methyl or ethyl.
69. The method of claim 68 wherein Ar is a phenyl group optionally substituted at positions six and seven with R 14; each R14 is independently halo, cyano, R °, -OR30, -CO2R31, -C (O) R °, - C (O) N (Rx) 2, -OC (O) R °, (CH2) nCO2R31, O (CH2) nCO2R31, NHSO2R °, NHC (O) NRx2, (CH2) nOR30, O (CH2) nOR30, (CH2) nC (O) N (Rx) 2, O (CH2) nC (O) N (Rx) 2; n is an integer of 1-4; R ° is independently hydrogen, a C1-3 haloalkyl group or an alkyl group C -? - 3; one RX is -H or C1-C3 alkyl and the other is an amine protecting group; R30 is an alcohol protecting group; and R31 is a carboxylic acid protecting group.
70. The method of claim 69 wherein Ar is a phenyl group.
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