MXPA06006572A - Tricyclic indole hydroxyethylamine derivatives and their use in the treatment of alzheimer's disease - Google Patents

Abstract

The present invention relates to novel hydroxyethylamine compounds having Asp2 (&bgr;-secretase, BACE1 or Memapsin) inhibitory activity of formula (I), processes for their preparation, to compositions containing them and to their use in the treatment of diseasescharacterised by elevated&bgr;-amyloid levels or&bgr;-amyloid deposits, particularly Alzheimer's disease. Formula (I) wherein, inter alia, A-B represents -NR5-SO2- or -NR5-CO-;R5 represents hydrogen, C1-6alkyl, C3-6 alkenyl, C3-6 alkynyl, C3-10 cycloalkyl, -C0-6 alkylaryl, -C0-6 alkyl-heteroaryl, -C0-6 alkyl-heterocyclyl, -C3-10 cycloalkyl-aryl or -C3-10 cycloalkyl-heteroaryl;-W- represents -CH2-, -(CH2)2-, -(CH2)3-, -C(H)=C(H)- or -CH2-C(H)=C(H)-;X-Y-Z represents -C=CR8-NR9-

Description

DERIVATIVES TR1C1CL1COS OF INDOL HYDROXYET1LAMINE AND ITS USE IN THE TREATMENT OF ALZHEIMER'S DISEASE DESCRIPTIVE MEMORY The present invention relates to novel hydroxyethylamine compounds having Asp2 (β-secretase, BACE1 or Memapsin) inhibitory activity; procedures for its preparation; compositions that contain them; and its use in the treatment of diseases characterized by high ß-amyloid concentration or ß-amyloid deposits, particularly Alzheimer's disease. Alzheimer's disease is a degenerative brain disorder in which the extracellular deposition of Aß in the form of senile plaques represents a distinctive pathological hallmark of the disease (Selkoe, D. J. (2001), Physiological Reviews, 81: 741-766). The presence of senile plaques is accompanied by a prominent inflammatory response and neuronal loss. Β-amyloid (Aβ) exists in soluble and insoluble fibrillar forms, and a specific fibrillar form has been identified as the predominant neurotoxic species (Vassar, R. and Citron, M. (2000), Neuron 27: 419-422). In addition, it has been reported that dementia correlates more closely with soluble amyloid concentration than with plaque burden (Naslund, J. et al. (2000), J. Am. Med. Assoc. 12: 1571-1577; Younkin, S. (2001) Nat. Med. 1: 8-19). It is known that Aß is produced by the breakdown of the beta-amyloid precursor protein (also known as APP) made by an aspartyl protease enzyme known as Asp2 (also known as β-secretase, BACE1 or Memapsin) (De Strooper, B and Konig, G. (1999), Nature 402: 471-472). Therefore, it has been proposed that the inhibition of the Asp2 enzyme would reduce the processing of APP and consequently reduce the concentration of the Aβ peptides found in the brain. Therefore, it is also considered that the inhibition of the Asp2 enzyme would be an effective therapeutic target in the treatment of Alzheimer's disease. APP is degraded by a variety of proteolytic enzymes (De Strooper, B. and Konig, G. (1999), Nature 402: 471-472). The key enzymes of the amyloidogenic pathway are Asp2 (β-secretase) and β-secretase; both are aspartic proteinases and the breakdown of APP by these enzymes generates Aβ. It has been shown that the a-secretase pathway, not amyloidogenic, which prevents the formation of Aβ, is catalyzed by several proteinases, the best candidate being ADAM10, a disintegrin and metalloproteinase. It has been stated that Asp1 shows both -secretase and β-secretase activity in vitro. The expression pattern of Asp1 and Asp2 is very different, with Asp2 being highly expressed in the pancreas and brain, whereas Asp1 expression occurs in many other peripheral tissues. The mouse Asp2 knockout indicates that the lack of Asp2 suppresses the production of Aβ and also shows that in this animal model endogenous Asp1 can not substitute the Asp2 deficiency (Luo Y. and others (2001), Nat Neurosci 4: 231- 232; Cai, H. et al. (2001), Nat Neurosci, 4: 233-234; Roberds, SL et al. (2001), Hum. Mol. Genet., 10: 1317-1324). For an agent to be therapeutically useful in the treatment of Alzheimer's disease, it is preferable that said agent be a potent inhibitor of the Asp2 enzyme, but ideally it must also be selective for Asp2 on other enzymes of the aspartyl proteinase family, for example Cathepsin D (Connor, GE (1998) "Cathepsin D" in "Handbook of Proteolytic Enzymes", Barrett, AJ, Rawlings, ND, &Woesner, JF (Eds) Academic Press, London, pp. 828-836). WO 01/70672, WO 02/02512, WO 02/02505, WO 02/02506 and WO 03/040096 (Elan Pharmaceuticals Inc.), disclose a series of hydroxy-tyllamine compounds having β-secretase activity, which means that they are useful in the treatment of Alzheimer's disease. The present authors have found a novel series of compounds that are potent inhibitors of the Asp2 enzyme, thus indicating the potential of these compounds as effective in the treatment of the disease characterized by high concentration of β-amyloid or deposits of β-amyloid , as in Alzheimer's disease. Thus, according to a first aspect of the present invention, a compound of formula (I) is provided: (I) wherein: R 1 represents C?-3 alkyl or halogen; R2 represents C? -3 alkyl, C2.4 alkenyl, C2-4 alkynyl, halogen, C? .3 alkoxy > amino, cyano or n hydroxy; m represents an integer from 0 to 4; n represents an integer from 0 to 2; A-B represents -NR5-SO2- or -NR5-CO-; R5 represents hydrogen, Ci-β alkyl, C3.6 alkenyl, C3.6 alkynyl, C3_6 cycloalkyl, (C06) alkyl, alkyl (Co-6) -heteroaryl, alkyl. (Co-6) -heterocyclyl, -3-C-cycloalkyl-aryl or (C3-1o) -heteroaryl -cycloalkyl; -W- represents -CH2-, - (CH2) 2-, - (CH2) 3-, -C (H) = C (H) - or -CH2-C (H) = C (H) -; X-Y-Z represents -C = CR8-NR9-; R8 represents hydrogen, C? -6 alkyl or C3-10 cycloalkyl; R9 represents hydrogen, C1-6 alkyl. C6-6 alkoxy, C3-10 cycloalkyl, -alkyl (C0-6) -aryl, -alkyl (Co-6) -heteroaryl, -alkyl (Co-6) -heterocyclyl, -cycloalkyl l (C3-? o) -aryl, (C3-10) cycloalkyl-heteroaryl, -COOR12a, -OR 2a, -CONR12aR13a, -SO2NR12aR3a, -CO-C1-6alkyl -CO-cycloalkyl of C3-10. -CO-aryl, -CO-heteroaryl, -CO-alkyl (C? 6) -aryl, -CO-alkyl (C 1-6) -heteroaryl, -CO-cycloalkyl (C 3-10) -aryl, - CO-cycloalkyl (C3-? O) -heteroaryl, -SO1-C1-6alkyl, -SO2-cycloalkyl of C3-10, -S02-aryl, -S02-heteroaryl, -SOalkyl (C1-6) -aryl, -S02-alkyl (C1-6) -heteroaryl, -SO2-cycloalkyl (C3-? 0) -aryl or -SO2-cycloalkyl (C3-10) -heteroar (Wherein R12a and R13a independently represent hydrogen, C6 alkyl or C3o cycloalkyl); R3 represents C6-6alkyl, C2-6alkenyl, C2-6alkynyl, -alkyl (C -6) -cycloalkyl of C3-10, -alkyl (C0-6) -aryl, -alkyl (C0-6) 6) -heteroaryl or -alkyl (Cn6) -heterocyclyl; R4 represents hydrogen, C ^ or alkyl, C2-10 alkenyl, C3- [alpha] 0 alkynyl, C3-10 cycloalkyl, C3.0 cycloalkenyl, (C06) alkylaryl, -alkyl Co-6) -heteroaryl, -alkyl (C0-6) -heterocyclyl, -alkyl (C1-6) -cycloalkyl of C3-1o, -cycloalkyl (C3-1o) -aryl, -cycloalkyl (C3-? O) - heteroaryl, -3C-cycloalkyl -heterocyclyl, -cycloalkyl (C3-? o) -alkyl (C6-6) -aryl, -heterocyclyl-aryl, -C1-6alkyl-aryl-heteroaryl, -C (RaRb) -CONH-C1-6 alkyl, -C (RaRb) -CO-NH-cycloalkyl of C3-10, -alkyl (C2.6) -S-C1-6alkyl, -alkyl (C2 .6) -NRcRd, -C (RaRb) -C1-6 alkyl, -C (RaRb) -alkyl (Co-6) -aryl-C (RaRb) -alkyl (Co-6) -heteroaryl, -C ( RaRb) -alkyl (C0-6) -heterocyclyl, -alkyl (C2.6) -O-alkyl (Co-6) -aryl, -alkyl (C2-6) -0-alkyl (Co-6) ) -heteroaryl, or -alkyl (C2.6) -O-alkyl (Co-6) -heterocyclyl; Ra and Rb independently represent hydrogen, alkyl of C1-6, or Ra and Rb, together with the carbon atom to which they are attached, can form a cycloalkyl or heterocyclyl group of C3-10; Rc and Rd independently represent hydrogen, C-? 6 alkyl, C3-0 cycloalkyl, or R ° and Rd, together with the nitrogen atom to which they are attached, can form a heterocyclyl group containing nitrogen; wherein said alkyl, alkenyl, alkynyl and cycloalkyl groups may be optionally substituted with one or more groups (for example 1 to 6) of halogen, C-? 6 alkyl, C2.6 alkynyl, C2-6 alkenyl , haloalkyl of C -? - 6, C 1-6 alkoxy, haloalkoxy of C? -6, amino, cyano, hydroxy, -COOR22, -S-alkyl of o -alkyl (d-6) ) -NR6R7 (wherein R6 and R7 independently represent hydrogen, C? _6 alkyl or cycloalkyl of wherein said aryl, heteroaryl or heterocyclyl groups may be optionally substituted with one or more groups (for example from 1 to 6) of C-? 6alkyl, halogen, haloalkyl of C- .. 6, haloalkoxy of C -? - 6, oxo, hydroxy, Ct-6 alkoxy, C2.6 alkynyl, C2.6 alkenyl, amino, cyano, nitro, -COOR22, -NR22COR23, -CONR22R23, -S02NR22R23, -NR22R23, - (C1-6) alkyl-NR22R23, -alkyl (C6-6) -O-C1-6alkyl or -6-alkanoyl (wherein R22 and R23 independently represent hydrogen, C1-6alkyl or cycloalkyl of C3-? O); or a pharmaceutically acceptable salt or solvate thereof. The specific compounds that may be mentioned are those in which: R5 represents hydrogen, d-6 alkyl, C3-6 alkenyl of C3-6 alkynyl. C3-? 0 cycloalkyl, aryl, heteroaryl, -6- (C1-6) alkyl, aryl, -alkyl (C-? - 6) -heteroaryl, -cycloalkyl (C3.10) -aryl or -cycloalkyl (C3. o) -heteroaryl; and R9 represents hydrogen, d-6 alkyl, C3-10 cycloalkyl, aryl, heteroaryl, -alkyl (C6-6) -aryl, -alkyl (C6-6) -heteroaryl, -cycloalkyl (C3-? ) -aryl, -cycloalkyl (C3-10) -heteroaryl, -COOR12a, -OR12a, -CONR12aR13a, -S02NR12aR13a, -CO-C1-6alkyl, -CO-cycloalkyl of C3-10, -CO-aryl, - CO-heteroaryl, -CO-alkyl (C -6) -aryl, -CO-alkyl (C? -6) -heteroaryl, -CO-cycloalkyl (C3-? O) -aryl, -CO-cycloalkyl (C3 -? o) -heteroaryl, -S02-alkyl of G -? _ 6, -SO2-cycloalkyl of C3-10. -SO2-aryl, -SO2-heteroaryl, -SO2-alkyl (C? -6) -aryl, -SO2-alkyl (C? -6) -heteroaryl, -SO2-cycloalkyl (C3-lO) - aryl or -SO2-cycloalkyl (C3.1 o) -heteroaryl (wherein R1 and R13a independently represent hydrogen, C1-6 alkyl or C3-10 cycloalkyl); and R3 represents optionally substituted C1-6alkyl, C2.6alkenyl, C2.6alkynyl, -alkyl (C -6) -cycloalkyl of C3-? 0, -alkyl (C? -6) -aryl , -alkyl (C? -6) -heteroaryl or -alkyl (C1-6) -heterocyclyl; and R 4 represents hydrogen, optionally substituted C 1 -10 alkyl, C 3 -α-cycloalkyl, aryl, heteroaryl, heterocyclyl, C 1 -C 6 alkylcycloalkyl, or C 3 -cycloalkyl. o) -aryl, -cycloalkyl (C3 .-? o) -alkyl (d-6) -aryl, -heterocyclyl-aryl, -alkyl (C? -6) -aryl-heteroaryl, -C (RaRb) -CONH-C1-6alkyl, -C (RaRb) -CONH-cycloalkyl of C3-? 0, -alkyl (d-6) -S-C1-6alkyl, -alkyl l (d-6) -NRcRd, -C (RaRb) -C1-6 alkyl, -C (RaRb) -alkyl (C0-6) -aryl, -C (RaRb) -alkyl (C0-6) ~ heteroaryl. -C (RaRb) -alkyl (C0-6) -heterocyclyl, -alkyl (C 1-6) -0-alkyl (Co-6) -aryl, -alkyl (C 1-6) -O-alkyl (Co-) 6) -heteroaryl, or -alkyl (C 1-6) -0-alkyl (C0-6) -heterocyclyl; and Rc and Rd independently represent hydrogen, C-? 6 alkyl, C3-10 cycloalkyl, or Rc and Rd, together with the nitrogen atom to which they are attached, can form a heterocyclyl group; and the optional substituents for the alkyl groups of R1, R2, R3, R4. R5, R6, R9, R12a, R13a, Ra, Rb, Rc and Rd, include one or more groups (for example 1, 2 or 3) of halogen, d-β, alkoxy, amino, cyano, hydroxy or -alkyl (C? .6) -NR6R7 (wherein R6 and R7 independently represent hydrogen, d-6 alkyl or C3-1o cycloalkyl); and wherein said aryl, heteroaryl or heterocyclyl groups of R3, R4, R5 and R6 may be optionally substituted with one or more groups (for example 1, 2 or 3) of C? -6 alkyl, halogen, -CF3, - OCF3, oxo, C -? - 6 alkoxy, C2.6 alkynyl, C2.6 alkenyl, amino, cyano, nitro, -NR22COR23, -CONR22R23, -alkyl of d.6-NR22R23 (wherein R22 and R23 independently represent hydrogen, C 1-6 alkyl or C3-? 0 cycloalkyl), -C? -6-O-alkyl of d-6, -alkanoyl of C? -6 or hydroxy; or pharmaceutically acceptable salts or solvates thereof. The term "C-y alkyl", used herein as a group or a part of the group, refers to a straight or branched saturated hydrocarbon group containing x a and carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, -pentyl, neopentyl, hexyl, and the like. The term "Cx.y alkenyl", as used herein, refers to a straight or branched hydrocarbon group containing one or more carbon-carbon double bonds and having x to y carbon atoms. Examples of these groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl and the like. The term "C- alkynyl", as used herein, refers to a linear or branched hydrocarbon group containing one or more triple carbon-carbon bonds and having x a and carbon atoms. Examples of these groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. The term "Cx-y alkoxy", as used herein, refers to an -O-alkyl group of Cx-y, wherein the Cx-y alkyl is as defined herein. Examples of these groups include methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, and the like. The term "Cx-y cycloalkyl", as used herein, refers to a monocyclic hydrocarbon ring saturated with x a and carbon atoms. Examples of these groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. The term "Cx-ycycloalkenyl", as used herein, refers to a non-aromatic monocyclic unsaturated hydrocarbon ring of x a and carbon atoms, which contains one or more carbon-carbon double bonds. Examples of these groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like. The term "halogen", as used herein, refers to a fluorine, chlorine, bromine or iodine atom. The term "Cx-y haloalkyl", as used herein, refers to an alkyl group of Cx-y as defined herein, wherein at least one hydrogen atom is replaced with halogen. Examples of these groups include fluoroethyl, trifluoromethyl, trifluoroethyl, and the like. The term "Cx-y haloalkoxy", as used herein, refers to a Cx-y alkoxy group as defined herein, wherein at least one hydrogen atom is replaced with halogen. Examples of these groups include difluoro methoxy, trifluoromethoxy, and the like. The term "aryl", as used herein, refers to a monocyclic or bicyclic hydrocarbon ring of C6.12. wherein at least one ring is aromatic. Examples of these groups include phenyl, naphthyl, tetrahydronaphthalenyl, and the like. The term "heteroaryl", as used herein, refers to a 5-6 membered monocyclic aromatic ring, or an 8-10 membered fused bicyclic aromatic ring, containing from 1-4 heteroatoms selected from oxygen, nitrogen and sulfur . Examples of such monocyclic aromatic rings include thienyl, furyl, furazanyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazolyl, pyrimidyl, pyridazinyl, pyrazinyl, pyridyl, triazinyl, tetrazinyl, and similar. Examples of such fused aromatic rings include quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, pteridinyl, cinolinyl, phthalazinyl, naphthyridinyl, indolyl, isoindolyl, azaindolyl, indolizinyl, pentanil, purinyl, pyrrolopyridinyl, furopyridinyl, benzofuranyl, isobenzofuranyl, benzothienyl, benzoimidazolyl, benzoxazolyl. , benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzoxadiazolyl, benzothiadiazolyl and the like. The term "heterocyclyl" refers to a 4-7 membered monocyclic ring, or a fused bicyclic ring of 8-12 members, which may be saturated or partially unsaturated, and that contains from 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur. Examples of such monocyclic rings include pyrrolidinyl, azetidinyl, pyrazolidinyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, dioxolanyl, dioxanyl, oxathiolanyl, oxathianyl, dithianyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl , tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, diazepanyl, azepanyl and the like. Examples of such bicyclic rings include indolinyl, isoindolinyl, benzopyranyl, quinuclidinyl, 2,3,4,5-tetrahydro-1 / - / - 3-benzazepine, tetrahydroisoquinolinyl, and the like. The term "nitrogen-containing heterocyclyl" represents any heterocyclyl group as defined above, which contains a nitrogen atom. Preferably, A-B represents -NR5-S02-. Preferably, R 5 represents hydrogen, C 1-6 alkyl (for example methyl, ethyl or isopropyl), or C 1-6 alkylaryl (for example phenyl or benzyl), preferably d-6 alkyl (for example methyl, ethyl or isopropyl), most preferably methyl or ethyl, especially methyl. Preferably, m represents 0 or 1, preferably 0.

Preferably, n represents O or 1, preferably 0. Preferably, R6 represents hydrogen. Preferably, R9 represents hydrogen or alkyl of d6 (for example ethyl, propyl, isopropyl or butyl), preferably ethyl. Preferably, W represents ~ (CH2) 2- or -C (H) = C (H) -, preferably - (CH2) 2-. Preferably, R3 represents (C06) alkylaryl (for example benzyl), optionally substituted with one or two halogen atoms (for example fluorine or chlorine). Preferably R3 represents unsubstituted benzyl. Preferably, R4 represents: -alkyl of C-MO (for example, ethyl, propyl, 1-methylpropyl, butyl, 3-methylbutyl, 2-ethylbutyl, 1-propylbutyl, 3,3- dimethylbutyl, 1,5-dimethylhexyl or 1, 1,5-trimethylhexyl), optionally substituted with one or more halogen groups (eg, 2-fluoroethio, 3-fluoropropyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl) , 3,3,3-trifluoropropyl or 2,2,3,3,3-pentafluoropropyl), C 1-6 alkoxy (eg, methoxy or propoxy), d-6 haloalkoxy (eg, 2,2,2 -trifluoroethoxy), or S-C 1-6 alkyl (for example, -S-methyl, -S-ethyl or -St-Bu); C2-10 alkenyl (for example, propenyl or butenyl), optionally substituted with one or more alkyl groups of d-6 (for example, 2-methyl-2-propen-1-yl or 3-methyl-2-buten) -1-ilo); -C3 alkynyl. 0 (e.g., propynyl, butynyl or pe-tinyl), optionally substituted with one or more C? _6 alkyl groups (e.g., 1,1-dimethyl-2-propin-1-ylo); -C3cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, cyclooctyl, tricyclodecyl or bicycloheptyl), optionally substituted with one or more halogen groups (eg, fluorine), d-6 alkyl (eg, methyl, ethyl or propyl), or C -6 alkynyl (for example, ethynyl); -C3-10 cycloalkenyl (for example, cyclopentenyl); -alkyl (d-6) -cycloalkyl of C3-10 (for example -CH2-cyclopropyl or - (CH2) 2-cyclohexyl); -alkyl (Co-6) -aryl (for example, benzyl or phenyl) optionally substituted with one or more halogen (for example, chloro), cyano, haloalkoxy groups of d6 (for example, -OCF3), haloalkyl of C-? -6 (e.g., -FC3), d6 alkyl (e.g. methyl), C1-6 alkoxy (e.g., methoxy), or -NR22R23 (e.g., -N (Me) 2); -alkyl (Co-6) -heteroaryl (for example -CH2-pyrazolyl, -CH2-pyridinyl, -CH2-thienyl or -CH2-isoxazolyl) optionally substituted with one or more halogen, cyano, C1-6 haloalkoxy groups (by example, rOCF3), haloalkyl of d-6 (for example, -CF3 or trifluoroethyl), C1-6alkyl (for example, methyl or ethyl), or C1-6alkoxy (for example, methoxy); -C (RaRb) -CONH-C3-10 cycloalkyl (for example -C (RaRb) -CONH-cyclohexyl); -cycloalkyl (C3-? o) -aryl; or -alkyl (Co-6) -heterocyclyl (for example, tetrahydropyranyl) optionally substituted with one or more alkyl groups of d-β (for example, methyl). Preferably, Ra and Rb independently represent hydrogen, methyl, or together with the carbon atom to which they are attached, form a cyclopropyl or cyclohexyl group; preferably, both Ra and R represent hydrogen. Preferred compounds according to the invention include the compounds of Examples E1-E90 shown below, or their pharmaceutically acceptable salts. The compounds of formula (I) can form acid addition salts thereof. It will be appreciated that for use in medicine, the salts of the compounds of formula (I) should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art and include those described in J. Pharm. Sci., 1977, 66, 1-19, such as the acid addition salts formed with inorganic or organic acids, for example hydrochlorides, hydrobromides, sulphates, phosphates, acetates, benzoates, citrates, nitrates, succinates, lactates, tartrates, fumarates, maleates, -hydroxy-2-naphthoates, palmoates, methanesulfonates, p-toluenesulfonates, naphthalenesulfonates, formates or trifluoroacetates. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms. The compounds of formula (I) can be prepared in crystalline or non-crystalline form and, if they are crystalline, they can optionally be solvated, for example as the hydrate. This invention includes within its scope stoichiometric solvates (eg, hydrates), as well as compounds containing variable amounts of solvent (eg, water). Some compounds of formula (I) may exist in stereoisomeric forms (e.g., diastereomers and enantiomers), and the invention extends to each of these stereoisomeric forms and mixtures thereof, including racemates. The different stereoisomeric forms can be separated from each other by the usual methods, or any given isomer can be obtained by stereospecific or asymmetric synthesis. The invention also extends to any tautomeric form and mixtures thereof. Preferably, the compounds of formula (I) are in the form of a single enantiomer of formula (la): (la) The compounds of formula (I) and their salts and solvates can be prepared by the methods described herein, which constitute a further aspect of this invention. A process according to the invention for preparing a compound of formula (I), comprises: (a) reacting a compound of formula (II), or an activated or optionally protected derivative thereof, wherein R1, R2, m, n, p, A, B, W, X, Y, and Z are as defined above, with a compound of formula (III), (III) wherein R3 and R4 are as defined above; or (b) preparing a compound of formula (I), comprising the reductive alkylation of a compound of formula (IV), (IV) wherein R1, R2, R3, m, n, A, B, W, X, Y, and Z are as defined above, with an appropriate aldehyde or ketone; or (c) deprotecting a compound of formula (I) that is protected; and then, optionally: (d) converting the compounds of formula (I) into other compounds of formula (I). When in process (a) an activated derivative of the compound of formula (11) is used (for example by activation of a carboxylic acid to an acid chloride, mixed anhydride, active ester, O-acyl-isourea or another species), the process (a) normally comprises the treatment of said activated derivative with an amine (Ogliaruso, MA, Wolfe, JF, in "The Chemistry of Functional Groups "(Ed. Patai, S.) Suppl. B:" The Chemistry of Acid Derivatives ", P 1 (John Wiley and Sons, 1979), pp. 442-8; Beckwith, A. L.

J. in "The Chemistry of Functional Groups" (Ed. Patai, S.) Suppl. B: "The Chemistry of Amides "(Ed. Zabricky, J.) (John Wiley and Sons, 1970), pp. 73 et seq .. Preferably, the acid of formula (II) and the amine are reacted in the presence of activating agents such as hydrochloride of 1- (dimethylaminopropyl) -3-ethylcarbodiimide (EDC) and 1-hydroxybenzotriazole (HOBT), or O- (7-azabenzotriazol-1-yl) -? /,? /,? and ',? / - tetramethyluronium hexafluorophosphate (HEY YOU). When the compound of formula (II) is a carboxylic acid, process (a) typically comprises the use of water-soluble carbodiimide, HOBT and a suitable base, such as tertiary alkylamine or pyridine, in a suitable solvent such as DMF and at a temperature suitable, for example between 0 ° C and room temperature. Process (b) typically comprises the use of sodium triacetate borohydride in the presence of a suitable solvent, such as ethanol, dichloromethane and 1,2-dichloroethane, and at a suitable temperature, for example between 0 ° C and room temperature. For process (c) examples of protecting groups and means for their removal can be found in T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis" (J. Wiley and Sons, 3rd ed., 1999). Suitable amine protecting groups include arylsulfonyl (for example tosyl), acyl (for example acetyl), carbamoyl (for example benzyloxycarbonyl or t-butoxycarbonyl) and arylalkyl (for example benzyl), which can be removed by hydrolysis or hydrogenolysis as appropriate . Other suitable amine protecting groups include trifluoroacetyl (-COCF3), which can be removed by base catalyzed hydrolysis. Suitable hydroxy protecting groups would be silyl-based groups, such as t-butyldimethylsilyl, which can be removed using the normal methods, for example using an acid such as trifluoroacetic or hydrochloric acid, or a fluoride source such as n-butylammonium fluoride . Process (d) can be carried out using conventional interconversion methods, such as epimerization, oxidation, reduction, alkylation, aromatic substitution, ester hydrolysis, formation or elimination of amide bond and sulfonylation. For example, compounds of formula (I) wherein W represents -C (H) = C (H) - or -CH2-C (H) = C (H) -, can be converted to the compounds of formula (I) ) wherein W represents - (CH2) 2- or - (CH2) 3-, by catalytic hydrogenation compounds as described herein. The compounds of formula (II) or the activated and optionally protected derivatives thereof wherein W represents -C (H) = C (H) - or -CH2-C (H) = C (H) -, can be prepared according to the following process: step (IV) ('I1 where R1, R2, m, n, A, B, X, Y, and Z are as defined above, P1 represents a suitable group such as C1-6 alkyl, P2 represents a suitable group, such as -CO-d-6-alkyl-C02-alkyl of d-6 or -SO2-aryl, L1 and L2 independently represent a suitable leaving group, such as a halogen atom (e.g., chlorine), and Hal represents a halogen atom, such as bromine or iodine Step (!) normally comprises the reaction of a compound of formula (V) with a compound of formula (Vl) a or (Vl) b in the presence of a suitable base, such as pyridine, in the presence of a suitable reagent, for example DMAP, and a suitable solvent such as dichloromethane, at a suitable temperature, for example at room temperature Step (ii) normally comprises the use of a halogen, such as bromine, the presence of a suitable solvent such as dimethylformamide, at a suitable temperature, for example at room temperature, Step (iii) normally comprises the introduction of a group N-protector using standard protocols. For example, an acetate group may be introduced by treatment with acetic anhydride in the presence of a suitable solvent, such as pyridine, at a suitable temperature, for example at room temperature. Step (iv) typically comprises a standard procedure for the addition of a vinyl halide to an alkene, such as the use of a mixture of tetrabutylammonium chloride, palladium acetate and triortotolylphosphine, in an appropriate solvent such as tetrahydrofuran, at an appropriate temperature, for example 65 ° C. Step (v) normally comprises the use of standard deprotection conditions (for example, treatment with a suitable amine, such as triethylamine, in a suitable solvent such as ethanol, at an appropriate temperature, for example at 80 ° C), and modification of Z using standard methods (for example, treatment with a base such as sodium hydride and an alkylating agent such as ethyl iodide, in a suitable solvent, such as dimethylformamide, at an appropriate temperature, for example at room temperature). Step (vi) normally comprises a standard procedure for the conversion of a carboxylic ester to an acid, for example using an appropriate hydroxide salt, such as the lithium or sodium salt, in an appropriate solvent such as methanol, at an appropriate temperature , for example at 50 ° C. In the case of a tert-butyl ester, this conversion can be done using an appropriate acid, such as trifluoroacetic acid, in an appropriate solvent such as dichloromethane, at an appropriate temperature, such as 0 ° C. The activated derivatives of the compounds of formula (II) can then be prepared as described in process (a) above. The compounds of formula (II) wherein W represents - (CH 2) 2 - or - (CH 2) 3 - can be prepared in an identical manner to the process described above, except that an additional step is required in which the compounds of formula (XI) are hydrogenated before step (vi) .. This step usually includes the use of standard reducing conditions, such as treatment with 10% palladium on carbon and ammonium formate in a suitable solvent such as methanol, at a temperature suitable, for example, to reflux. The compounds of formula (II) wherein W represents -C (H) = C (H) -, A-B represents -NR5-SO2- and m represents 0, can also be prepared according to the following procedure: wherein R 2, n, R 5, X, Y, and Z are as defined above, and P 3 represents a suitable group, such as alkyl of Step (i) normally comprises the reaction of a compound of formula (V) with methyl (chlorosulfonyl) acetate in the presence of a suitable base, such as pyridine, in the presence of a suitable reagent, for example DMAP, and a suitable solvent such as dichloromethane, at a suitable temperature, for example at room temperature. Step (ii) normally comprises the reaction with an alkyl halide, as iodomethane, in the presence of a suitable base such as potassium carbonate, and a suitable solvent such as dimethylformamide, at a suitable temperature, for example at room temperature. Step (iii) typically comprises the reaction with a reagent prepared by mixing phosphorus oxychloride and dimethylformamide in the presence of a suitable solvent, such as dimethylformamide, at a suitable temperature, for example at 60 ° C. Step (iv) typically comprises the reaction with an alkyl halide such as iodoethane, in the presence of a suitable base such as sodium hydride and a suitable solvent such as dimethylformamide, at a suitable temperature, for example at room temperature. Step (v) normally comprises a standard method of converting a carboxylic ester into an acid, for example using an appropriate hydroxide salt such as the lithium or sodium salt, in a suitable solvent such as methanol, at a suitable temperature, for example at 65 ° C. Step (vi) normally comprises a standard decarboxylation process, for example treatment with an acid such as hydrogen chloride, in a suitable solvent such as dioxane, at a suitable temperature, for example at 100 ° C. The activated derivatives of the compounds of formula (II) can then be prepared as described in process (a) above. The compounds of formula (III) can be prepared according to the following procedure: (XVII) (xvpi) (Hl) wherein R3 and R4 are as defined above and P4 represents a suitable amine protecting group, such as t-butoxycarbonyl. Step (i) normally comprises the reaction of a compound of formula (XVll) with a compound of formula NH 2 R 4, in the presence of a suitable solvent, for example ethanol, at a suitable temperature, for example, at reflux. Step (ii) normally comprises the use of suitable deprotection reactions as described above for process (c); for example, when P4 represents t-butoxycarbonyl, the deprotection typically comprises the use of trifluoroacetic acid in the presence of a suitable solvent, such as dichloromethane, at a suitable temperature, for example, between 0 ° C and room temperature.

The compounds of formula (IV) can be prepared according to the following process: (XVll) (XIX) Í X) Step (ii) Step W wherein R1, R2, R3, m, n, A, B, W, X, Y, Z and P4 are as defined above, and P5 represents a suitable amine protecting group other than P4, such as -COOCH2-phenyl . Step (i) typically comprises the reaction of a compound of formula (XVll) in aqueous ammonia in the presence of a suitable solvent, for example ethanol, at a suitable temperature, for example, at reflux. When P5 represents -COOCH2-phenyl, step (ii) typically comprises the use of CICOOCH2-phenyl, in the presence of a suitable base, for example triethylamine, and a suitable solvent, for example dimethylformamide, at a suitable temperature, for example between 0 ° C and room temperature. Step (iii) typically comprises the use of suitable deprotection reactions as described above for process (c); for example, when P4 represents t-butoxycarbonyl, the deprotection typically comprises the use of trifluoroacetic acid in the presence of a suitable solvent, such as dichloromethane, at a suitable temperature, for example between 0 ° C and room temperature. Step (iv) typically comprises the reaction of a compound of formula (XXI) with a compound of formula (II), in the presence of water-soluble carbodiimide and HOBT. Step (v) typically comprises the use of suitable deprotection reactions as described above for process (c); for example, when P5 represents -COOCH2-phenyl, the deprotection typically comprises the use of a suitable catalyst, for example palladium, in the presence of a suitable solvent, for example water and ethanol, and in the presence of a suitable hydrogen source, for example. example, ammonium formate, at a suitable temperature, for example at 60 ° C. The compounds of formulas (V), (Vl) a, (Vl) b and (XVll) are commercially available or can be prepared from commercially available compounds using standard procedures.

As a further aspect of the invention, there is thus provided a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use as a pharmaceutical agent, particularly in the treatment of patients with diseases characterized by high ß concentration. -amyloid or ß-amyloid deposits. According to another aspect of the invention, there is provided the use of a compound of formula (1) or a physiologically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of patients with diseases characterized by high concentration of ß -amyloid or ß-amyloid deposits. In a further or alternative aspect, there is provided a method of treating a human or animal subject with diseases characterized by high concentration of β-amyloid or β-amyloid deposits, said method comprising administering to said human or animal subject an effective amount of a compound of formula (I) or a physiologically acceptable salt or solvate thereof. As a further aspect of the invention, a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is provided herein, for use in the treatment of diseases characterized by high ß-amyloid concentration or ß-amyloid deposits. It will be appreciated by the person skilled in the art that when referring here to the treatment, this extends to the prophylaxis and also to the treatment of diseases characterized by high concentration of β-amyloid or deposits of β-amyloid. The compounds according to the invention can be formulated for administration by any convenient route and, therefore, the invention also includes within their scope pharmaceutical compositions for use in the therapy of diseases characterized by high concentration of β-amyloid or deposits of β-amyloid, comprising a compound of formula (I) or a physiologically acceptable salt or solvate thereof, if appropriate together with one or more physiologically acceptable diluents or carriers. It will be appreciated that diseases characterized by elevated β-amyloid or β-amyloid deposits include Alzheimer's disease, mild cognitive impairment, Down syndrome, hereditary cerebral hemorrhage with β-amyloidosis of the Dutch type, β-amyloid cerebral angiopathy and several types of degenerative dementias, such as those associated with Parkinson's disease, progressive supranuclear palsy, cortical basal degeneration, and Lewis diffuse body type Alzheimer's disease. Most preferably, the disease characterized by high concentration of β-amyloid or deposits of β-amyloid is Alzheimer's disease. A method is also provided for preparing said pharmaceutical formulation, which comprises mixing the ingredients.

The compounds of formula (I) can be used in combination with other therapeutic agents. Suitable examples of these other therapeutic agents may be acetylcholine esterase inhibitors (such as tetrahydroaminoacridine, donepezil hydrochloride and rivastigmine), gamma secretase inhibitors, nti inflammatory agents (such as cyclooxygenase II inhibitors), antioxidants (such as vitamin E and ginkolidesor), statins or p-glycoprotein (P-gp) inhibitors (such as cyclosporin A, verapamil, tamoxifen, quinidine, vitamin E-TGPS, ritonavir, megestrol acetate, progesterone, rapamycin, 10,11-methanodibenzosuberane, phenothiazines , acridine derivatives such as GF120918, FK506, VX-710, LY335979, PSC-833, GF-102 and 918). The compounds according to the invention can be formulated for example for oral, inhalation, intranasal, buccal, enteral, parenteral, topical, sublingual, intrathecal or rectal administration, preferably for oral administration. Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, starch mucilage, cellulose or polyvinylpyrrolidone; fillers, for example lactose, microcrystalline cellulose, sugar, corn starch, calcium phosphate or sorbitol; lubricants, for example magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrants, for example, potato starch, croscarmellose sodium or sodium starch glycolate; or wetting agents such as sodium lauryl sulfate. The tablets may be coated according to methods known in the art. Liquid oral preparations may be in the form, for example, of aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or they may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Said liquid preparations may contain conventional additives, such as suspending agents, for example, sorbitol syrup, methylcellulose, glucose / sugar syrup, gelatin, hydroxymethylcellulose. carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; or preservatives, for example, methyl or propyl p-hydroxybenzoates, or sorbic acid. The preparations may also contain buffer salts, flavors, coloring agents or sweeteners (for example mannitol), as appropriate. For buccal administration, the compositions may take the form of tablets or lozenges formulated in the conventional manner. The compounds can also be formulated as suppositories, for example containing conventional suppository bases such as cocoa butter or other glycerides. The compounds according to the invention can also be formulated for parenteral administration by bolus injection or continuous infusion, and can be presented in unit dose form, for example as ampoules, flasks, small volume infusions or prepared syringes, or in containers of multiple doses with a conservative. The compositions may take such forms as solutions, suspensions or emulsions, in aqueous or non-aqueous vehicles, and may contain formulatory agents such as antioxidants, buffers, antimicrobial agents or tonicity adjusting agents. Alternatively, the active ingredient may be in powder form for reconstitution before use with a suitable vehicle, for example sterile, pyrogen-free water. Dry solid presentation can be prepared by aseptically loading a sterile powder into individual sterile containers, or aseptically loading a sterile solution into each container and freeze drying. When the compounds of the invention are administered topically, they can be presented as a cream, ointment or patch. The composition may contain from 0.1% to 99% by weight, preferably from 10% to 60% by weight of the active material, depending on the method of administration. The dose of the compound used in the treatment of the aforementioned disorders varies as usual depending on the seriousness of the disorders, the weight of the patient and other similar factors. However, as a general guide, suitable unit doses can be from 0.05 to 3,000 mg, and such unit doses can be administered more than once a day, for example, once, twice, three times or four times a day. (preferably once or twice); and such therapy can be prolonged several weeks, months or years. All publications cited in this specification, including without limitation, patents and patent applications, are incorporated herein by reference as if it were specifically and individually indicated that each individual publication is incorporated herein by reference.

EXAMPLES Preparation of intermediaries Description 1 Methyl 4-methyl-3,5-dinitrobenzoate (D1) To a suspension of 4-methyl-3,5-dinitrobenzoic acid (commercially available from Aldrich; 100 g, 440 mmol) in methanol (300 ml) was added drop thionyl chloride (72 g, 615 mmol) with stirring. The resulting solution was allowed to stand at room temperature overnight and the formed precipitate was then collected by filtration. The filtrate was washed with cold methanol to give the title compound (D1), as a white solid (104 g, 430 mmol), which was used in the next step without further purification.

Description 2 4 - [(E) -2- (Dimethylamino) -ethenin-3,5-dinitrobenzoate methyl (D2) A solution of methyl 4-methyl-3,5-dinitrobenzoate (D1) (40 g, -170 mmol) in dimethylformamide (50 ml), treated with N, N-dimethylformamide dimethylacetal (50 ml, 380 mmol), and the resulting mixture was heated at 50 ° C. for 1 h, then the solvent was evaporated and the residue was triturated with ether diethyl / i-hexane (1: 1), to give the crude title compound (D2) (40 g, 136 mmol) as a dark red solid, this was used in subsequent reactions without further purification.

Description 3 Methyl 4-Amino-1 / - / - indole-6-carboxylate (D3) Methyl 4 - [(E) -2- (dimethylamino) ethenyl] -3,5-dinitrobenzoate (D2) (10.0 g, 34 mmol) in methanol (150 ml) with ammonium formate (21.4 g, 340 mmol) and 10% palladium on humid carbon (3 g, 50% water), under a nitrogen atmosphere. Then, the mixture was heated at 50 ° C for 1 h. The mixture was filtered and the solvent was removed by evaporation. The residue was dissolved in ethyl acetate (200 ml) and washed with a saturated aqueous sodium hydrogen carbonate solution (100 ml). The organic phase was then dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was triturated with diethyl ether / i-hexane (1: 1), to give the title compound (D3) (5.0 g, 26 mmol), as a pale pink solid, which was used in subsequent reactions without further ado. purification. [M + H] + = 191.1, TR = 2.17 min.

Description 4 4 - [(Ethenylsulfonyl) aminol-1 / - / - indole-6-carboxylic acid methyl ester (D4) To a solution of methyl 4-amino-1 / - / - indole-6-carboxylate (D3) (2.0 g, 10.5 mmol) in dichloromethane (100 ml), triethylamine (2.13 g, 21 mmol) was added, and the mixture was gently heated to dissolve any remaining solids. Then 2-chloro-1-ethanesulfonyl chloride (1.63 g, 10 mmol) was added dropwise and stirring was continued for 30 min. At this point an additional amount of 2-chloro-1-ethanesulfonyl chloride (0.39 g, 2.4 mmol) was added and stirring was continued 30 min more. The mixture was washed sequentially with 2M aqueous hydrogen chloride (50 ml) and a saturated aqueous sodium hydrogen carbonate solution (50 ml); then, the organic phase was dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was triturated with diethyl ether / i-hexane (1: 1) to give the crude title (D4) (1.6 g, 5.7 mmol), as a brown solid which was used in subsequent reactions without further purification. [M + H] + = 281.1, RT = 2.23 min.

Description 5 4-r (Ethenylsulfonyl) (methyl) amino1-1 / - / - indole-6-carboxylic acid methyl ester D5) A solution of methyl 4 - [(ethenylsulfonyl) amino] -1 - / - indole-6-carboxylate (D4) ) (5.0 g, 17.9 mmol) in dimethylformamide (50 ml), treated with potassium carbonate (2.48 g, 18 mmol) and iodomethane (1.12 ml, 18 mmol) at room temperature for 90 min. Diethyl ether (200 ml) was added to the mixture and then the mixture was washed sequentially with 2M aqueous hydrogen chloride (100 ml), saturated aqueous sodium hydrogen carbonate solution (100 ml) and water (3 x 100 ml). Then the aqueous phase was dried over magnesium sulfate and then filtered and evaporated in vacuo to give the title compound (D5) (4.5 g, 15.3 mmol) as a brown foam. This was used without further purification in subsequent reactions. [M + H] + = 295.1, TR = 2.48 min.

Description 6 4-r (Ethenesulfonyl) (ethyl) amino-1 H-indole-6-carboxylic acid methyl ester (D6) The methyl 4 - [(ethenylsulfonyl) (ethyl) amino] -1H-indole-6-carboxylate (D6) was obtained analogously to the synthesis of (D5), but using iodoethane in place of iodomethane. [M + H] + = 309.1, RT = 2.65 min.

Description 7 3-Bromo-4-f (ethenylsulfonyl) (methyl) amino-1 H-indole-6-carboxylic acid methyl ester (D7) A solution of 4 - [(ethenylsulfonyl) (methyl) amino] -1H-indole-6- Methyl carboxylate (D5) (0.700 g, 2.4 mmol) in dimethylformamide (20 ml) was treated dropwise with a solution of bromine (0.12 ml, 2.3 mmol) in dimethylformamide (5 ml) for 15 min. The solvent was then evaporated in vacuo and the residue taken up in ethyl acetate (50 ml) and washed with water (2 x 50 ml). The organic phase was then dried over magnesium sulfate, filtered and evaporated, to give the title compound (D7) (0.800 g, 2.2 mmol) as a pale brown foam. [M + H] + = 373.0, RT = 2.74 min.

Description 8 3-Bromo-4- (ethenylsulfonyl) (ethyl) amino1-1 / - -indole-6-carboxylic acid methyl ester (D8) 3-bromo-4 - [(ethenylsulfonyl) (ethyl) amino] -1H-indole Methyl 6-carboxylate (D8) was obtained analogously to the synthesis of (D7), but using methyl 4 - [(ethenylsulfonyl) (ethyl) amino] -1 / - / - idol-6-carboxylate (D6) ) instead of methyl 4- ((ethynylsulfonyl) (methylal) amino] -1H-indole-6-carboxylate (D5). [M + f = 389. 1, RT = 2.89 min.

Description 9 1 - . 1-Acetyl-3-bromo-4 - [(ethenylsulfonyl) (methyl) amino] -1 / - / - methyl-6-carboxylate (D9) A solution of 3-bromo-4 - [(ethenesulfonyl ) (methyl) amino] -1H-indol-6-carboxylic acid methyl ester (D7) (0.800 g, 2.2 mmol) in pyridine (5 ml), treated with acetic anhydride (1 ml, 10.6 mmol) and the resulting mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate (50 ml) and washed sequentially with 2M aqueous hydrogen chloride (50 ml) and saturated aqueous sodium hydrogen carbonate solution (50 ml). The organic phase was dried over magnesium sulfate and then filtered and evaporated in vacuo. The crude product was recrystallized from ethyl acetate // -hexane, to obtain the title compound (D9) (0.510 g, 1.23 mmol) as a pink solid. [M + H] + = 417.0, RT = 2.85 min.

Description 10 1-Acetyl-3-bromo-4 - [(ethenylsulfonyl) (ethyl) amino-1H-indol-6-carboxylic acid methyl ester (D10) 1-Acetyl-3-bromo-4 - [(ethenylsulfonyl) (ethyl) amino] ] -1 / - / - Methyl indole-6-carboxylate (D10) was obtained analogously to the synthesis of (D9), but using 3-bromo-4 - [(ethenylsulfonyl) (ethyl) amino] - 1 methyl H-indole-6-carboxylate (D8) in place of 3-bromo-4 - [(ethenylsulfonyl) (methyl) amino] -1 H -indole-6-carboxylic acid methyl ester (D7). TR = 3.01 min Description 11 2,2-1-Ethyl-1,6-dihydroM, 21-thiazepine | 5,4,3-ca-indol-8-carboxylic acid methyl ester (D11) A solution of 1-acetyl-3-bromo-4 - [(ethenylsulfonyl ) (ethyl) amino] -1H-indol-6-carboxylic acid methyl ester (D10) (0.400 g, 0.94 mmol) in tetrahydrofuran (30 ml), treated with tetrabutylammonium chloride (0.560 g, 2.0 mmol), palladium diacetate (0.220 g, 1.0 mmol) and triortotolylphosphine (0.304 g, 2.0 mmol), under a nitrogen atmosphere. The mixture was refluxed for 30 min. The solvent was evaporated and the residue was dissolved in ethyl acetate (100 ml) and washed sequentially with 2M aqueous hydrogen chloride (50 ml) and saturated aqueous sodium hydrogen carbonate solution (50 ml). The organic phase was dried over magnesium sulfate and then filtered and evaporated in vacuo. The residue was now dissolved in ethanol (50 ml) and treated with triethylamine (0.5 ml, 3.5 mmol). Then, the mixture was refluxed for 15 min before cooling and a treatment as described above gave the crude product, which was crystallized from ethyl acetate // -hexane to give the title compound (D11) (0.280). g, 0.92 mmdl), as a brown solid that was used in subsequent reactions without further purification. [M + H] + = 307.1, RT = 2.54 min.

Description 12 2,2-1-methyl-1,6-dihydroH, 21-thiazepine dioxide ["5,4,3-ca1indol-8-carboxylic acid methyl ester (D12) 2,2-dioxide of 1-methyl-1, 6- dihydro [1,2] thiazepino [5,4,3-cd] indol-8-carboxylic acid methyl ester (D12) was obtained analogously to the synthesis of (D 1), but using 1-acetyl-3-bromo- 4 - [(Ethynylsulfonyl) (methyl) amino] -1H-indol-6-carboxylic acid methyl ester (D9) in place of 1-acetyl-3-bromo-4 - [(ethenylsulfonyl) (ethyl) amino] -1 H- Methyl indole-6-carboxylate (D10). [M + Hf = 293.1, RT = 2.37 min.

Description 13 2,2-1-Methyl-1, 3,4,6-tetrahydropy, 2-tiazepinor-5,4,3-cc / jindol-d-carboxylic acid methyl ester (D13) A solution of 2,2-dioxide of 1-methyl-1 , 6-dihydro [1,2] thiazepin [5,4,3-ca-indol-8-carboxylic acid methyl ester (D12) (0.400 g, 1.37 mmol) in methanol (50 ml) was treated with ammonium formate ( 0.800 g, 12.7 mmol) and 10% palladium on carbon (0.4 g), and the mixture was heated to reflux for 3.5 h. Then, the mixture was filtered and evaporated in vacuo. The residue was dissolved in ethyl acetate (100 ml) and washed with a saturated aqueous sodium hydrogen carbonate solution (50 ml); it was then dried over magnesium sulfate. Filtration and evaporation in vacuo gave the title compound (D13) (0.220 g, 0.75 mmol) as a brown solid. This was used in subsequent reactions without further purification. [M + H] + = 295.1, RT = 2.32 min.

Description 14 4- ( { [2- (Methyloxy) -2-oxoetylsulfonyl) aminoV1 / - / - indole-6-carboxylic acid methyl ester (D14) A solution of 4-amino-1 / - / - indole-6- Methyl carboxylate (D3) (9 g, 47 mmol) in dichloromethane (180 ml) was treated with pyridine (5.8 ml) and DMAP (0.577 g), and then methyl (chlorosulfonyl) acetate was added dropwise [56146- 83-9] (8.63 g, 50 mmol). The resulting black mixture was stirred at room temperature overnight. An additional amount of methyl (chlorosulfonyl) acetate (1.2 g) was added and the mixture was stirred an additional 48 hours at room temperature. The mixture was diluted with ethyl acetate and washed sequentially with saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting solid was triturated with ether to give the crude title compound (D14) as a brown solid (9.37 g). [M-H] "= 325.2, TR = 2.14 min.

Description 15 4- (Methyl- { R2- (methyloxy) -2-oxoethyl] sulfonyl> amino) -1H-indol-6-carboxylic acid methyl ester (D15) A solution of 4- ( { [2- (methyloxy) -2-oxoethyl] sulfonyl.} amino) -1 - / - indole-6-carboxylic acid methyl ester (D14) (13.4 g, 41.1 mmol) in dimethylformamide (145 ml) was treated with potassium carbonate ( 19.8 g) and iodomethane (2.6 ml), and stirred overnight at room temperature. The mixture was evaporated and the residue was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution; then the ethyl acetate layer was dried over magnesium sulfate and concentrated in vacuo. The crude material was purified by biotage (eluting with ethyl acetate: hexane), and the resulting solid was triturated with ether to give the title compound (D15), as an orange solid (4.93 g). [M-H] "= 339.2, TR = 2.38 min.

Description 16 2,2-dimethyl-1-methyl-, 6-dihydro [1,1-thiazepino [5,4,3-ccf] indol-3,8-dicarboxylate dioxide (D16) Phosphorus oxychloride (1.4 ml) was added dropwise to dimethylformamide (4.5 ml) at 0 ° C, and the mixture was stirred an additional 15 minutes. The mixture was then treated with a solution of methyl 4- (methyl. {[2- (methyloxy) -2-oxoethyl] sulfonyl}. Amino) -1 / - / - indole-6-carboxylate (D15) (4.93 g, 14.5 mmol) in dimethylformamide (18 ml) and heated at 50 ° C for 1 h. An additional amount of phosphorus oxychloride (0.7 ml) was added to the mixture and heating was continued overnight at 60 ° C. The mixture was cooled and any excess phosphorus oxychloride and dimethylformamide was removed by evaporation. The residue was carefully diluted with dichloromethane (500 ml) and water (200 ml) and 2N aqueous sodium hydroxide was added to obtain a pH of 7 in the aqueous mixture. All the precipitated solid was collected by filtration and removed. The dichloromethane layer was separated and then washed with water and dried over anhydrous sodium sulfate. Filtration and evaporation of the dichloromethane layer gave a yellow solid which was combined with the previously separated solid. The solid was washed with dichloromethane and ether to give the title compound (D16) as a yellow solid (2.85g). [M + Hf = 351.1, TR = 2.27 min.

Description 17 2,2-6-Ethyl-1-methyl-1,6-dihydroH, 21-tiazole [5 A3-CQ1-indol-3,8-dicarboxylic acid dimethyl ester (D17) A solution of 2,2- 1-methyl-1, 6-dihydro [1,2] thiazepine dioxide [5,4,3-cc.indol-3,8-dimethyl dicarboxylate (D16) (2.67 g, 7. 63 mmol) in dimethylformamide (11 ml) was treated with sodium hydride (0.305 g, 60% suspension in oil) and stirred at room temperature for 10 minutes. Then, the mixture was treated with ethyl iodide (1.22 ml) and stirred overnight at room temperature. The mixture was diluted with ethyl acetate and washed with a saturated aqueous solution of sodium acid carbonate and then with brine. The solid precipitated in this step was collected by filtration and washed with ether and water, and then removed. The remaining organic fraction was dried over magnesium sulfate and concentrated in vacuo. The crude material was purified by trituration with ether and the resulting solid was combined with the solid collected above to give the title compound (D17), as a yellow solid (2.57 g). [M + H] + = 379.1, RT = 2.61 min.

Description 18 2,2-1-Methyl-6- (1-methylethyl) -1,6-dihydroH, 21 -thiazepine- [5,4,3-cc l-indol-3,8-dicarboxylate dimethyl (D18) dioxide) analogous to the preparation of the compound (D17), but using 2-iodopropane instead of iodoethane, the 2,2-dioxide of dimethyl-1-methyl-1 ^ -dihydrotl-thiazepino.dAS-cdJindol-Sd-dicarboxylate was reacted (D16), to give the title compound (D18) as a yellow solid.

[M + H] + = 391.2, RT = 2.86 min.

Description 19 2,2-Di- oxide 1-methyl-6-propyl-1,6-dihydrof1,2] thiazepine [5,4,3-CG ndol-Sd-dicarboxylic acid dimethyl ester (D19) Analogously to the preparation of the compound ( D17), but using 1-bromopropane instead of iodoethane, the 2,2-dioxide of 1-methyl-1,6-dihydro [1,2] thiazole [5,4,3-cc] was reacted. dimethyl-3,8-dicarboxylate (D16), to give the title compound (D19) as a yellow solid. [M + H = 393.2, TR = 2.87 min.

Description 20 2,2-6-Butyl-1-methyl-1,6-dihydrof1,2] thiazepine [5,4,3-ccpindol-3, dimethyl dicarboxylate (D20) dioxide analogously to the preparation of the compound (D17), but, using 1-iodobutane instead of iodoethane, the 2,2-dioxide of 1-methyl-1,6-dihydro [1,2] thiazepine [5,4,3-cc /] was reacted indol-3, dimethylcarboxylate (D16), to give the title compound (D20) as a yellow solid. [M + Na] + = 429.18, RT = 3.04 min.

Description 21 2,2-β-ethyl-1-methyl-1,6-dihydro [1,11-thiazepine] [5.4, 3-co1-indole-3, d-dicarboxylic acid dioxide (D21) 2,2-dioxide was dissolved of 6-ethyl-1-methyl-1,6-dihydro [1,2] thiazepine [dA3-cc /] dimethyl dimethyl-3,3-dicarboxylate (D17) (2.57 g, 6.79 mmol) in methanol (50 ml ), and treated with 2N aqueous sodium hydroxide (50 ml); then it was heated to reflux for 2 hours. The mixture was cooled and evaporated in vacuo and the residue was then taken up in ethyl acetate and acidified with 2M aqueous hydrogen chloride. The precipitate was collected by filtration and washed very well with water and then with ether. Vacuum drying gave the title compound (D21) as a yellow solid (2.02 g). [M-H] "= 349.2, TR = 1.62 min.

Description 22 2,2-1-Methyl-6- (1-methylethyl) -1,6-dihydro-1,2-thiazepinophyd-cc-ndoi-SS-dicarboxylic acid dioxide (D22) Analogously to the preparation of the compound (D21) , 2,2-dioxide of 1-methyl-6- (1-methylethyl) -1,6-dihydro [1,2] thiazepine [5,4,3-cd] -indol-3, d-dicarboxylate was reacted of dimethyl (D18), to give the title compound (D22) as a gum. [M-H] "= 363.2, TR = 2.20 min.

Description 23 2,2-1-Methyl-6-propyl-1,6-dihydroxy, 2] thiazepino-rd, 4,3-co-indoi-3,8-dicarboxylic acid dioxide (D23) Analogous to the preparation of the compound (D21), 2,2-dioxide of 1-methyl-6-propyl-1,6-dihydro [1,2] thiazepine [5.4.3-cs indole-3,8-dicarboxylate of dimethyl (D19), to give the title compound (D23) as a yellow solid. [M-H] "= 363.2, TR = 2.23 min.

Description 24 2,2-6-Butyl-1-methyl-1,6-dihydro [1, 2] thiazepine-r5A3-ca1indol-3,8-dicarboxylic acid dioxide (D24) Analogously to the preparation of the compound (D21) , dimethyl 6-butyl-1-methyl-1,6-dihydro [1,2] thiazepine [5, 4,3-cd] indol-3,8-dicarboxylate 2,2-dioxide (D20) was reacted give the title compound (D24) as a fawn-colored solid. [M-H] "= 377.2, TR = 2.39 min PREPARATION OF ESTERS Ester 1 2,2-1,6-Diethyl-, 6-dihydrof1, 21-thiazepine [5,4,3-cd1indol-8 ^ methyl carboxylate (C1) dioxide A solution of 1-ethyl-1-2,2-dioxide, 6-dihydro- [1,2] thiazepino [5,4,3-c] indol-8-carboxylic acid methyl ester (D11) (0.250 g, 0.82 mmol) in dimethylformamide (15 ml) was treated with a 60% suspension. % sodium hydride in oil (0.034 g, 0.85 mmol) under a nitrogen atmosphere. The mixture was stirred 10 min and then iodoethane (0.156 g, 1.0 mmol) was added and stirring was continued for 30 min more. An additional amount was added, first of sodium hydride (0.034 g, 0.85 mmol) and then of iodoethane (0.156 g, 1.0 mmol), and the mixture was allowed to stand overnight. The solvent was evaporated in vacuo and the crude title compound thus obtained (C1) was used in the next step without further purification. [M + H] + = 335.2, RT = 2.83 min.

Ester 2 2,2-D-ethyl-1-methyl-1, 3,4,6-tetrahydro [1, 2] thiazepinor5 A3-cc lindol-d-carboxylic acid methyl ester (C2) A solution of 2,2-dioxide of 1-methyl-1, 3,4,6-tetrahydro [1,2] thiazepine [dA3-cd] indole-8-carboxylic acid methyl ester (D13) (0.200 g, 0.6d mmol) in dimethylformamide (15 ml ) was treated with a 60% suspension of sodium hydride in oil (0.034 g, 0.65 mmol) under a nitrogen atmosphere, and stirred at room temperature for 10 min. The mixture was treated with iodoethane (0.156 g, 1.0 mmol) and stirring was continued for 30 min. The solvent was evaporated in vacuo and the residue was dissolved in ethyl acetate and washed sequentially with 2M aqueous hydrogen chloride (50 ml) and a saturated aqueous sodium hydrogen carbonate solution (50 ml). The organic phase was then dried over magnesium sulfate, filtered and evaporated in vacuo to give the crude title compound (C2) (0.250 g, 0.78 mmol). This was used without further purification in subsequent reactions. [M + H] + = 323.1, RT = 2.70 min.

PREPARATION OF ACIDS Acid 1 2,2-6-Ethyl-1-methyl-1, 3,4,6-tetrahydrop, 21-thiazepinofd, 4,3-colindol-d-carboxylic acid dioxide (A1) To a solution of 2,2-dioxide of methyl 6-ethyl-1-methyl-1, 3,4,6-tetrahydro [1,2] thiazepine [d, 4,3-cc] indol-d-carboxylate (C2) (0.260 g, 0.7d mmol ) in methanol (20 ml), was added a 2N aqueous sodium hydroxide solution (10 ml, 20 mmol). The resulting mixture was heated to dO ° C until the solution was clarified and then the solvent was evaporated in vacuo. The residue was extracted with diethyl ether and then the aqueous layer was acidified using 2M aqueous hydrogen chloride and extracted twice with ethyl acetate. The ethyl acetate extract was dried over MgSO, concentrated in vacuo, and then triturated with diethyl ether to give the title compound (A1) (0.1 dOg, 0.49 mmol) as a white solid, which was used in the next step without further purification. [M + H] + = 309.1, RT = 2.33 min.

Acid 1 (Alternative procedure) 2,2-6-Ethyl-1-methyl-1,3,6-tetrahydro [1,11-thiazepino- [d, 4,3-c] indole-d-carboxylic acid dioxide (A1) d The title compound (A1) it can be prepared analogously to the synthesis of 7 (A7) acid, from 6-ethyl-1-methyl-1,6-dihydro [1,2] thiazepine-2,2-dioxide [5.4, 3-cc_indol-d-carboxylic acid (A3).

Acid 2 0 2,2-1,6-Diethyl-1,6-dihydrof1.21-thiazepinoid, 4,3-c / 1-indole-8-carboxylic acid (2) acid dioxide 1, 6-diethyl acid Diethyl-1,6-dihydro [1,2] thiazepino [d, 4,3- cd] indole-8-carboxylic acid (A2) was obtained analogously to the synthesis of (A1), 5 but using 2, 2-dioxide, 1,6-diethyl-1,6-dihydro [1,2] thiazepine [5,4,3-cd] ndol-8-methyl carboxylate (C1), instead of 2,2- 6-ethyl-1-methyl-1, 3,4,6-tetrahydrothylthiazepinofd ^^ -coximide d-carboxylic acid (C2) dioxide. [M + H] + = 321.2, RT = 2.45 min.

Acid 3 2,2-6-Ethyl-1-methyl-1,6-dihydrop, 2] thiazepinord, 4,3-ccf.indol-8-carboxylic acid dioxide (A3) Acid 2,2-dioxide was dissolved ethyl-1-methyl-1,6-dihydro [1,2] -thiazepino [d, 4,3-cd] indole-3,8-dicarboxylic acid (D21) (2.16 g, 6.17 mmol) in 2N hydrogen chloride in dioxane (120 ml), and refluxed for 1 hour. Then, the mixture was cooled and evaporated in vacuo to give a solid. The solid was washed sequentially with water, ether, ethyl acetate, and then again with ether, to give the title compound (A3) as a pale yellow solid (1.76 g). [M + H] + = 307.1, TR = 2.18 min.

Acid 4 2,2-1-Methyl-6- (1-methylethyl) -1,6-dihydro [1,2-thiazepino [5A3-CG ndol-8-carboxylic acid (A4)] dioxide In a manner analogous to the synthesis of (A3), 1-methyl-6- (1-methylethyl) -1,6-dihydro [1,2] thiazepine [5,4,3-cc /] indole was reacted with 2,2-dioxide -3,8-dicarboxylic (D22), to give the title compound (A4) as a pale yellow solid. [M + H] + = 321.2, TR = 2.49 min. Acid d 2,2-1-Methyl-6-propyl-1,6-dihydrof1,11-thiazepino- [dA3-cc ndol-8-carboxylic acid (Ad) acid dioxide In a manner analogous to the synthesis of 3 (A3) acid , 1-methyl-6-propyl-1,6-dihydro [1,2] thiazepine [5,4,3-cd] indole-3,8-dicarboxylic acid 2,2-dioxide (D23) was reacted, to give the title compound (Ad) as a cream colored solid. [M + H] + = 321.2, TR = 2.dd min Acid 6 2,2-6-Butyl-1-methyl-1,6-dihydro [1,2] thiazepine-fdA3-cd1indol-d-carboxylic acid dioxide (A6) In a manner analogous to the synthesis of 3 (A3) acid , 2,6-butyl-1-methyl-1,6-dihydro [1,2] thiazepino [d, 4,3-cc-ddol-3, d-dicarboxylic acid (D24), 2, 2-dioxide was reacted, to give the title compound (A6) as a fawn-colored solid. [M + H] + = 355.09, RT = 2.65 min.

Acid 7 2,2-1-Methyl-6- (1-methylethyl) -1, 3,4,6-tetrahydrop, 21-thiazepino [d, 4,3-ccindole d-carboxylic acid (A7) acid dioxide A solution of 1-methyl-6- (1-methylethyl) -1,6-dihydro [1, 2] thiazepine [5,4,3-cc] -dol-8-carboxylic acid 2,2-dioxide (A4) ( 0.22 g, 0.69 mmol) in ethanokawa (9: 1, 20 ml), treated with ammonium formate (0.44 g) and 10% palladium on carbon (0.1 g), and heated at 90 ° C for 3 hours. When the mixture cooled, it was filtered and evaporated in vacuo to dryness. The residue was dissolved in ethyl acetate and washed sequentially with saturated sodium hydrogen carbonate solution and water. The organic layer was dried over magnesium sulfate, then filtered and evaporated in vacuo. The residue was triturated with ether and the resulting solid was washed with water and then more ether, before drying to give the title compound (A7), as a white solid (0.12 g). [M + H] + = 323.2, RT = 2.57 min.

Acid 8 2,2-1-Methyl-6-propyl-1, 3,4,6-tetrahydro [1, 21-thiazepinophos-cc-n-d-carboxylic acid (A8) acid dioxide In a manner analogous to the synthesis of the acid 7 (A7), 2,2-dioxide of 1-methyl-6-propyl-1,6-dihydro [1,2] thiazepine [5,4,3-cc ndol-d-carboxylic acid (A5) was reacted ), to give the title compound (A8) as a white solid. [M + H] + = 323.2, RT = 2.56 min.

Acid 9 2,2-6-Butyl-1-methyl-1,3A6-tetrahydroM, 21-thiazepine [5A3-cd] indole-8-carboxylic acid dioxide (A9) In a manner analogous to the synthesis of acid 7 (A7) , 6-butyl-1-methyl-1,6-dihydro [1,2] thiazepine [5, 4,3-cd] indole-d-carboxylic acid (6) dioxide was reacted to give the title compound (A9) as a pale yellow solid (0.24 g). [M + Hf = 337.1, TR = 2.75 min.

Acid 10 2,2-Dioxyde 1,6,6-diethyl, 3,4,6-tetrahydrof 1,2-thiazepine-fd, 4,3-cc / lindol-d-carboxylic acid (A10) In a manner analogous to the synthesis of the acid 7 (A7), 1,6-diethyl-1,6-dihydro [1,2] thiazepine [d, 4,3-ccfndol-d-carboxylic acid (2) dioxide was reacted give the title compound (A10) as a white solid. [M + H] + = 323.2, RT = 2.60 min.

PREPARATION OF AMINES Amina 1 (B1) (2R, 3S) -3-amino-1- (3-methoxy-benzylamino) -4-phenyl-butan-2-ol ditosylate Step A: ((S) - (S) fer-butyl ester was dissolved ) -1-oxiranyl-2-phenyl-ethyl) -carbamic acid (10 g, 38 mmol) [Chirex 1819W94 Lot # 9924382] in ethanol (100 ml), and 3-methoxy-benzylamine (14.6 ml, 114 mmol) was added thereto. ). The resulting mixture was heated under a nitrogen atmosphere for 12 h at reflux temperature. The mixture was cooled and the solvent was removed by evaporation in vacuo. The residue was dissolved in ethyl acetate and washed three times with water, dried over magnesium sulfate and concentrated in vacuo. Purification by flash chromatography on silica gel (dichloromethane / methanol: 98/2 to 95/5)gave the [(1S, 2R) -1-benzyl-2-hydroxy-3- (3-methoxy-benzylamino) -propyl] -carbamic acid fer-butyl ester (10.0 g, 66%) as a white solid. Step B: To a solution of the [(1S, 2R) -1-benzyl-2-hydroxy-3- (3-methoxy-benzylamino) -propyl] -carbamic acid fer-butyl ester (product of B1, step A) (10 g, 25 mmol) in acetonitrile (100 ml), p-toluenesulfonic acid monohydrate (14 g, 75 mmol) was added, and the resulting mixture was stirred for 16 h. The white precipitate formed was filtered and washed with diethyl ether; it was then dried under vacuum to give the title compound (B1) (15.6 g) as a white solid which was used in the next step without further purification.

Amina 2 (2 / ?, 3S) -3-amino-4-phenyl-1 - (tetrahydro-2H-pyran-4-ylamino) -2-butanol (B2) ditosylate Step A: Fer-butyl acid ester was dissolved ( (S) - (S) -1-oxiranyl-2-phenyl-ethyl) -carbamic acid (1.1 g, 4.1 mmol) [Chirex 1819W94 Lot # 9924382] in ethanol (100 mL), and tetrahydro-2H-pyran was added -4-iAmino (0.83 g, 8.22 mmol). The resulting mixture was heated under a nitrogen atmosphere for 4 h at reflux temperature. The mixture was cooled and the solvent was removed by evaporation in vacuo. The residue was dissolved in ethyl acetate and washed three times with water, dried over magnesium sulfate and concentrated in vacuo. There was thus obtained [1,1-dimethylethyl] -2-hydroxy-1- (phenylmethyl) -3- (tetrahydro-2H-pyran-4-ylamino) propyl] carbamate, as a white solid ( 0.96 g, 2.6 mmol). [M + H] + = 366.4, RT = 2.16 min. Step B: (2 3S) -3-amino-4-phenyl-1- (tetrahydro-2 - / - pyran-4-ylammon) -2-butanol (B2) ditosylate was obtained analogously to the synthesis of (B1), but using [(1 S, 2R) -2-hydroxy-1- (phenylmethyl) -3- (tetrahydro-2H-pyran-4-ylamino) propyl] -carbamic acid 1,1-dimethylethyl ester (product of B2, step A), in place of the [(1S, 2R) -1-benzyl-2-hydroxy-3- (3-methoxy-benzylamino) -propyl] -carbamic acid fer-butyl ester (product of B1, step A).

Amines B3-82 Amines B3-82 were obtained in a manner analogous to amines 1 and 2, using ((S) - (S) -1-oxiranyl-2-phenyl-ethyl) -carbamic acid fer-butyl ester. (1.1 g, 4.1 mmol) [Chirex 1819W94 Lot # 9924332], and the appropriate amine or a salt thereof (obtained from commercial sources or prepared as described in WO 2004/094430). When the salt of the initial amine was used instead of the free base, a molar equivalent of an appropriate base (such as triethylamine) was also added to the reaction mixture. In some cases the dihydrochloride salt of the amine was prepared in place of the ditosylate salt. These can be prepared in a manner analogous to the amines (B1) and (B2), but using a solution of 4M HCl in dioxane instead of p-toluenesulfonic acid monohydrate (as described in WO 2004/094430): EXAMPLES EXAMPLE 1 2,2-1,6-Diethyl- / v-. 1 S, 2?) -2-hydrox? -1- (phenylmethyl) -3- (tetrahydro-2-t-pyran-4-ylamino) propyl] -1,6-dihydroxy-1,2-azothin-5A3-cd-indole-8-carboxamide ( E1) To a solution of 1,6-diethyl-1,6-dihydro [1,2] thiazepine [d, 4,3-cd] indole-d-carboxylic acid 2,2-dioxide (A2) (0.036 g) , 0.12 mmol) in dimethylformamide (3 ml), (2R, 3S) -3-amino-4-phenyl-1- (tetrahydro-2yr-pyran-4-ylamino) -2-butanol (B2) ditosylate was added. (0.730 g, 0.12 mmol), 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride (0.030 g, 0.16 mmol), hydrated 1-hydroxybenzotriazole (0.02dg, 0.1 d mmol), and triethylamine (0.100 g) ml, 0.72 mmol). The mixture was stirred overnight at room temperature and then the solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate (60 ml) and washed with saturated aqueous sodium hydrogen carbonate solution (60 ml). The organic phase was dried over magnesium sulfate, filtered and evaporated to give the crude product. Purification by biotage (eluting with 2-6% methanol in dichloromethane) and drying in freezing, gave the title compound (E1) (0.030 g, O.Od mmol) as a white solid. [M + H] + = 667.6, TR = 2.3 min.

EXAMPLES 2-89 (E2-E89) The compounds of examples 2-89 were obtained in a procedure analogous to example 1 (in the examples where the formate salt is indicated, the compounds were purified by means of mass-directed automatic preparative HPLC, using acetonitrile / water / formic acid as eluent, instead of biotage as indicated above), using the appropriate acid and the appropriate amine indicated in the following table: EXAMPLE 90 2.2-Dioxide of 1.6-dietü -? / - r (1 S, 2ff) -2-hydroxy-1 - (phenylmethyl-3- (tetrahydro-2f-pyran-4-ylamino) propin-1.3.4 < 6-tetrahydrof1,2Uiazepinor5A3-cd1indol-8-carboxamide (E90) A solution of 2, 1, 6-diethyl -? / - [(1 S, 2R) -2-hydroxy-1- (phenylmethyl) -3- (tetrahydro-2H-pyran-4-ylamino) propyl ] -1,6-Dihydro [1,2] thiazepino- [5,4,3-cd] indole-8-carboxamide (E1) (0.010 g, 0.02 mmol) in methanol (d ml) was treated with Ammonium formate (0.020 g, 0.32 mmol) and 10% palladium on carbon (0.016 g), and heated to reflux 1 h. The mixture was filtered and evaporated in vacuo. The residue was dissolved in ethyl acetate (50 ml) and washed with saturated aqueous sodium hydrogen carbonate solution (30 ml). The organic phase was dried over magnesium sulfate, filtered and evaporated in vacuo. Freeze drying gave the title compound (E90) (0.006 g, 0.01 mmol) as a white solid. [M + H] + = 669.6, TR = 2.3 min. The in vitro biological activity of the compounds of the invention can be tested according to the following tests.

(I) Asp-2 inhibition test For each compound to be tested, a 36-well plate is added: (a) 1 μl of a solution of the test compound in DMSO (in the CI5 curve, ten dilutions are used in 1 in 2 series from 600 μM). (b) 10 μl of substrate solution (FAM- [SEVNLDAEFK] -TAMRA) in buffer. This is prepared by diluting 2 ml of a substrate solution in 2 mM DMSO, in 400 ml of buffer (100 mM sodium acetate, pH = 4.6, Milli-Q 1 I water, 0.06% Triton X-100 (Od ml / l), pH adjusted to 4.6 using glacial acetic acid). Aminomethyl fluororescein (FAM) and tetramethylrhodamine (TAMRA) are fluorescent molecules that cooperate to fluoresce at 535 nm after separation of the SEVNLDAEFK peptide. (c) 10 μl of enzyme solution. This is prepared by diluting 16 ml of a 500 nM solution of enzyme in 384 ml of buffer (prepared as above). White cavities are included in each plate (the enzyme solution is replaced with buffer) as controls. The cavities are incubated 1 h at room temperature and the fluorescence is read using a Tecan Ultra fluorometer / spectrophotometer (486 nm excitation, 636 nm emission).

(II) Cathepsin D inhibition test For each compound to be tested, it is added in a plate of 384 cavities: (a) 1 μl of a solution of the test compound in DMSO (in the IC50 curve, ten serial dilutions are used) 1 in 2 from 500 μM). (b) 10 μl of substrate solution (FAM- [SEVNLDAEFK] - TAMRA) in buffer. This is prepared by diluting 2 ml of a substrate solution in 2 mM DMSO, in 400 ml of buffer (100 mM sodium acetate, pH = 4.5, Milli-Q 1 I water, 0.06% Triton X-100 (0.5 ml / l), pH adjusted to 4.5 using glacial acetic acid). (c) 10 μl of enzyme solution. This is prepared by diluting 1.6 ml of an enzyme solution of 200 units / ml (in 10 mM HCl), in 396.4 ml of buffer (prepared as above). White cavities are included in each plate (the enzyme solution is replaced with buffer) as controls. The cavities are incubated 1 h at room temperature and the fluorescence is read using a Tecan Ultra fluorometer / spectrophotometer (excitation 435 nm, emission 535 nm).

PHARMACOLOGICAL DATA Compounds E1-E90 were analyzed in tests (I) and (II) and exhibited an inhibition within the following scale: 2 nM -10 μM (Asp2) and 30 nM - > 100 μM (Cat D).

Abbreviations DMF dimethylformamide DMSO dimethyl sulfoxide DMAP dimethylaminophenol DABCO 1,4-diazabicyclo [2.2.2] octane DME dimethyl ether THF tetrahydrofuran HOBT N-hydroxybenzotriazole FAM carboxyfluorescein TAMRA carboxitetramethylrhodamine [] amino acid code of a peptide sequence

Claims (3)

1. NOVELTY OF THE INVENTION CLAIMS 1. - A compound of formula (I): 0 (I) wherein: R1 represents d-3 alkyl or halogen; R2 represents d-3 alkyl, C2-4 alkenyl, C2 alkynyl. , halogen, C1-3 alkoxy, amino, cyano or n hydroxy; m represents an integer from 0 to 4; n represents an integer from 0 to 2; A-B represents -NR5-SO2- or -NR5-CO-; R5 represents hydrogen, dd6 alkyl, C3-6 alkenyl, C3-6 alkynyl, C3-10 cycloalkyl, -C0-6 alkyl- aryl, (C0-6) alkylheteroaryl, (C0-) alkyl 6) -heterocyclyl, -cycloalkyl (C3-o) -aryl or -cycloalkyl (C3-yl) -heteroaryl; -W- represents -CH2-, - (CH2) 2-, - (CH2) 3-, - C (H) = C (H) - or -CH2-C (H) = C (H) -; X-Y-Z represents -C = CR8-NR9-; R8 represents hydrogen, C, -6 alkyl or C3-10 cycloalkyl; R9 represents 0 hydrogen, C1-6 alkyl. C? -6 alkoxy, cycloalkyl of 03-10, -alkyl (Co-6) -aryl, -alkyl (C0-6) -heteroaryl, -alkyl (Co-6) -heterocyclyl, -cycloalkyl ( C3-? O) -are, cycloalkyl (C3-? O) -heteroaryl, -COOR12a, -OR12a, -CONR12aR3a, -SO2NR12aR13a, -CO-C6-6 alkyl, -CO-cycloalkyl C3.10, -CO-aryl, -CO-heteroaryl, -CO- (C-6) alkyl-aryl, -CO-alkyl (C? -6) -heteroaryl, -CO-cycloalkyl (C3-? O) -aryl , -00-cycloalkyl (C3-? O) -heteroaryl, -S02-C1-6 alkyl, -SO2-C3-10 cycloalkyl, -S02-aryl, -S02-heteroaryl, -SO2-alkyl (C? -6) -aryl, -SO2-alkyl (C? -6) -heteroaryl, -SO2-cycloalkyl (C3-? O) -aryl or -S02-cycloalkyl (C3-? O) -heteroar lo (wherein R 12a and R 13a independently represent hydrogen, C 1-6 alkyl or C 3-10 cycloalkyl); R3 represents C-? 6 alkyl, C2-6 alkenyl, C2-6 alkynyl. -alkyl (C? -6) -cycloalkyl of C3-? 0, -alkyl (C0-6) -aryl, -alkyl (Co-β) -heteroaryl or -alkyl (Co-6) -heterocyclyl; R4 represents hydrogen, C1- TO alkyl, C2-10 alkenyl. alkynyl of C3.10, -cycloalkyl of 03.10, -cycloalkenyl of C3-10, alkyl (Co-6) -aryl, -alkyl (C0-6) -heteroaryl, -alkyl (Co-6) -heterocyclyl, -alquii ( C? -6) -cycloalkyl of C3-10, -cycloalkyl (C3-? O) -aryl, -cycloalkyl (C3-? 0) -heteroaryl, -cycloalkyl (C3-? 0) -heterocyclyl, -cycloalkyl ( C3-10) -alkyl (C? -6) -aryl, -heterocyclyl-aryl, -alkyl (C-6) -aryl-heteroaryl, -C (RaRb) -CONH-C? -6 alkyl, -C ( RaRb) -CO-NH-cycloalkyl of C3-10, -alkyl (C2-6) -S-alkyl of C? _6, -alkyl (C2.6) -NRcRd, -C (RaRb) -alkyl of d-6 , -C (RaRb) -alkyl (Co-6) -aryl, -C (RaRb) -alkyl (Co-6) -heteroaryl, -C (RaRb) -alkyl (C0-6) -heterocyclyl, -alkyl (C2 .6) -0-alkyl (Co-6) -aryl, -alkyl (C2-6) -0-alkyl (Co-6) -heteroaryl, or -alkyl (C2-6) -0-alkyl (C0-6) ) -heterocyclyl; R a and R b independently represent hydrogen, C 1-6 alkyl, or Ra and R b, together with the carbon atom to which they are attached, can form a cycloalkyl or heterocyclyl group of C 3- 0; R c and R d independently represent hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, or R c and R d, together with the nitrogen atom to which they are attached, can form a heterocyclyl group containing nitrogen; wherein said alkyl, alkenyl, alkynyl and cycloalkyl groups may be optionally substituted with one or more groups (for example 1 to 6) of halogen, d-6 alkyl, C 2-6 alkynyl, C 2-6 alkenyl, halo -alkyl of C? -6, C 1-6 alkoxy, C? _6 haloalkoxy, amino, cyano, hydroxy, -COOR22, -S-alkyl of d.6 do-alkyl (C? -6) -NR6R7 (wherein R6 and R7 independently represent hydrogen, C1-6 alkyl or C3-10 cycloalkyl); and wherein said aryl, heteroaryl or heterocyclyl groups may be optionally substituted with one or more groups (for example from 1 to 6) of C? -6 alkyl, halogen, C? -6 haloalkyl, haloalkoxy C? -6, oxo, hydroxy, C1-6 alkoxy, C2.6 alkynyl, 0 C2.6 alkenyl, amino, cyano, nitro, -COOR22, -NR22COR23, -CONR22R23, -SO2NR22R23, -NR22R23, - alkyl (d-6) -NR22R23, -alkyl (d-6) -0-C- or C-6 alkanoyl-alkyl (wherein R22 and R23 independently represent hydrogen, C1-6alkyl or cycloalkyl) of C3-? o); or a pharmaceutically acceptable salt or solvate thereof.
2. 2. The compound according to claim 1, further characterized in that A-B represents -NR5-SO2-. 3. The compound according to claim 1 or claim 2, further characterized in that R5 represents alkyl of d-6. 4. The compound according to any of the preceding claims, further characterized in that m represents 0. d.- The compound according to any of the preceding claims, further characterized in that n represents 0. 6. The compound in accordance with any of the preceding claims, further characterized in that R8 represents hydrogen. 7. The compound according to any of the preceding claims, further characterized in that R9 represents hydrogen or C1-6 alkyl.
3. 3. The compound according to any of the preceding claims, further characterized in that W represents - (CH2) 2-. 9. The compound according to any of the preceding claims, further characterized in that R3 represents -alkyl (Co-6) -aryl optionally substituted with one or two halogen atoms. 10. The compound according to any of the preceding claims, further characterized in that R4 represents: - C1-10 alkyl optionally substituted with one or more halogen groups, 6-d-6 alkoxy, d-6 haloalkoxy, or S -alkyl of C -.- 6. -C2 alkenyl- or optionally substituted with one or more alkyl groups of d-6; -C3-alkynyl or optionally substituted with one or more alkyl groups of d-6; - C3-? 0 cycloalkyl optionally substituted with one or more halogen, d-6 alkyl, or C2-6 alkynyl groups; -C3-10 cycloalkenyl. -alkyl (C? -6) -cycloalkyl of C3.10; -alkyl (Co-6) -aryl optionally substituted with one or more halogen, cyano, d-6 haloalkoxy, C? -6 haloalkyl, C- .6 alkyl, C1-6 alkoxy, or -NR22R23 groups; -alkyl (C0-6) -heteroaryl optionally substituted with one or more halogen groups, cyano, haloalkoxy of C? -6, haloalkyl of C? -6, alkyl of d-6,? alkoxy of d-β; -C (RaRb) -CONH-C3-10 cycloalkyl. "-cycloalkyl (C3-? O) -aryl; or -alkyl (Co-6) -heterocyclyl optionally substituted with one or more alkyl groups of d-6. The compound according to any of the preceding claims, further characterized in that both Ra and Rb represent hydrogen 12. The compound according to claim 1, further characterized in that it is: 2,2-dioxide of 1, 6 diethyl-? - [(1 S, 2R) -2-hydroxy-1 - (phenylmethyl) -3- (tetrahydro-2H-pyran-4-ylamino) propyl] -1,6-dihydro [1, 2] - thiazepine [5,4,3-cd] indole-8-carboxamide; 1, 6-diethyl-β / - [(1 S, 2R) -2-hydroxy-3- ( { [ 3- (methyloxy) phenyl] methyl.} Amino) -1 - (phenylmethyl) propyl] -1,6-dihydro [1,2] -thiazepine [5,4,3-cc /] indole-8-carboxam da; 6-ethyl-γ / - [(1 S, 2R) -2-hydroxy-3- ( { [3- (methyloxy) phenyl] methyl} amino} -1-dioxide (phenylmethyl) propyl] -1-methyl-1, 3,4,6-tetrahydro [1,2] thiazepine [d, 4,3-cct] indole-d-carboxamide; 2,2-dioxide 6-ethyl- ? / - [(1 S, 2R) -2-hydroxy-1 - (phenyl) ethyl) -3- (tetrahydro-2H-pyran-4-ylamino) propyl] -1-methyl-1, 3,4,6-tetrahydro [1,2] thiazepine [5,4,3-cc_indol-d-carboxamide]; 2,2-dioxide -? / - [(1 S, 2R) -2-hydroxy-1- (phenylmethyl) -3- ( { [1- (2,2,2-trifluoroethyl) ) -1 H-pyrazol-4-yl] methyl.}. Amino) propyl] -1-methyl-1, 3,4,6-tetrahydro [1,2] thiazepine [5,4,3-cc. indole-d-carboxamide; 6-Ethyl 2,2-dioxide. { (1 S, 2R) -2-hydroxy-1- (phenylmethyl) -3 - [(phenylmethyl) amino] propyl} -1-methyl-1, 3, 4,6-tetrahydro [1,2] thiazepino [5,4,3-cd] indole-d-carboxamide; 6-Ethyl 2,2-dioxide. { (1S, 2R) -2-hydroxy-1- (phenylmethyl) -3 - [(4-pyridinylmethyl) amino] propyl} -1-methyl-1, 3,4,6-tetrahydro [1,2] thiazepino [5,4,3-ct] indole-d-carboxamide; 6-Ethyl 2,2-dioxide. { (1S, 2R) -2-hydroxy-1- (phenylmethyl) -3 - [(3-pyridinylmethyl) amino] propyl} -1-methyl-1, 3,4,6-tetrahydro [1,2] -thiazepino [5,4,3-co-indole-8-carooxamide; 2,2-dioxide, / - [(1 S.2R) -3 - [(2,2-dimethyltetrahydro-2H-pyran-4-yl) amino] -2-hydroxy-1 - (phenylmethyl) propyl] - 6-ethyl-1-methyl-1, 3,4,6-tetrahydro [1,2] thiazepine [d, 4,3-cd] indole-d-carboxamide; 6-ethyl- / V - [(1 S, 2R) -3- 2,2-dioxide. { [(3-ethyl-5-isoxazolyl) methyl] amino} -2-hydroxy-1- (phenylmethyl) -propyl] -1-methyl-1, 3,4,6-tetrahydro [1,2] thiazepino [d, 4,3-c] indole-d-carboxamide; 2,2-dioxide, / - [(1 S, 2R) -3- (cyclobutylamino) -2-hydroxy-1- (phenylmethyl) propyl] -6-ethyl-1-methyl-1, 3,4,6 -tetrahydro [1,2] thiazepine [d, 4,3-cc7] ndol-8-carboxamide; 2,2-dioxide A / - [(1 S, 2R) -3 - [(4,4-difluorocyclohexyl) amino] -2-hydroxy-1- (phenylmethyl) -propyl] -6-ethyl-1-methyl -1, 3,4,6-tetrahydro [1,2] thiazepino [5,4,3-cc] indole-8-carboxamide; 2,2-dioxide 6-ethyl-? / - [(1 S, 2R) -3 - [(2-fluoroethyl) amino] -2-hydroxy-1 - (phenylmethyl) propyl] -1-methyl-1, 3 , 4,6-tetrahydro [1,2] thiazepine [5,4,3-cc7] indole-d-carboxamide; 6-Ethyl -? / - [(1 S, 2R) -2-hydroxy-3 - [(2,2,3,3,3-pentafluoropropyl) amino] -1 - (phenylmethyl) propyl 2,2-dioxide ] -1-methyl-1, 3, 4,6-tetrahydro [1,2] -thiazepino [5,4,3-cd] indole-d-carboxamide; 6-ethyl-2 - [/ 1 - [(1 S, 2R) -3- dioxide. { [d-ethyl-3-thienyl) methyl] amino} -2-hydroxy-1- (phenylmethyl) propyl] -1-methyl-1, 3,4,6-tetrahydro [1,2] thiazepino [5,4,3-c] indole-d-carboxamide; 2,2-ethyl-V - [(1 S, 2R) -2-hydroxy-3-dioxide. { [2- (methyloxy) ethyl] amino} -1 - (phenylmethyl) propyl] -1-methyl-1, 3,4,6-tetrahydro [1,2] thiazepine [d, 4,3-ct7] indole-d-carboxamide; 2,2-dioxide of 6-etii-A-. { (1 SI2R) -2-hydroxy-1- (phenylmethyl) -3 - [(2,2) 2-trifluoroethy) amino] propyl} -1-methyl-1, 3,4,6-tetrahydro [1,2] thiazepino [d, 4,3-cc] indole-d-carboxamide; 2,2-Di-ethyl -? / - [(1 S, 2R) -3- (ethylamino) -2-hydroxy-1- (phenylmethyl) propyl] -1-methyl-1, 3,4,6 dioxide -tetrahydro [1,2] thiazepine [d, 4,3-cct] ndol-d-carboxamide; N- - [(1 S, 2R) -3 - [(cyclopropylmethyl) amino] -2-hydroxy-1 - (phenylmethyl) propyl] -6-ethyl-1-methyl-1, 2,2-dioxide , 4,6-tetrahydro [1,2] thiazepine [5,4,3-ct7] ndol-d-carboxamide; 2,2-dioxide, [- 1 S, 2R) -3- (cyclohexylamino) -2-hydroxy-1- (phenylmethyl) propyl] -6-ethyl-1-methyl- 1, 3, 4,6 -tetrahydro [1,2] thiazepino [d, 4,3-cd] indole-8-carboxamide; 2,2-dioxide of d / V - [(1 S, 2R) -3- (3-cyclopenten-1-ylamino) -2-hydroxy-1- (phenylmethyl) propyl] -6-ethyl-1-methyl- 1, 3,4,6-tetrahydro [1,2] thiazepine [d, 4,3-ca.indol-d-carboxamide; 6-ethyl-2 - [/ 1 - [(1 S, 2R) -3- dioxide. { [2- (ethylthio) ethyl] amino} -2-hydroxy-1- (phenylmethyl) propyl] -1-methyl-1,3,6,6-tetrahydro [1,2] thiazepine [d, 4,3-cc] indole-d-carboxamide; 2,2-ethyl-6-dioxide? - [(1 S, 2R) -2-hydroxy-3 - [(4-methylcyclohexyl) amino] -1 - (phenylmethyl) propyl] -1 -0 methyl-1,3,6-tetrahydro [1, 2] thiazepine [d, 4,3-cc] indole-8-carboxamide; 6-ethyl- / v - [(1 S, 2R) -2-hydroxy-1 - (phenylmethyl) -3- ( { [3- (trifluoromethyl) phenyl] methyl 2,2-dioxide. amino) propyl] -1-methyl-1,3,6,6-tetrahydro [1,2] thiazepino [5,4,3-cc] indole-8-carboxamide; 6-Ethyl 2,2-dioxide. { (1S, 2R) -2-hydroxy-1- (phenylmethyl) -3 - [(1-propylbuty) amino] propyl} -1-methyl-1, 3,4,6-tetrahydro [1,2] thiazepine [5, 4, 4-catdol d-d-carboxamide; 2,2-dioxide [/ 1 S, 2R) -3 - [(4,4-dimethylcyclohexyl) amino] -2-hydroxy-1- (phenylmethyl) propyl] -6-ethyl-1-methyl- 1, 3,4,6-tetrahydro [1,2] thiazepine [5, 4,3-cylindol-d-carboxamide; 2,2-ethyl- / V - [(1S, 2R) -2-hydroxy-1- (phenylmethyl) -3- (2-propin-1-ylamino) propyl] -1-methyl-1-2,2-dioxide, 3,4,6-tetrahydro [1,2] thiazepino- [dA3-cct] indole-d-carboxamide; 2,2-ethyl-6-dioxide? - [(1 S, 2R) -2-hydroxy-1-0 (phenylmethyl) -3- (2-propen-1-ylamino) propyl] -1-methyl-1, 3,4,6-tetrahydro [1, 2] -thiazepino [d, 4,3-cc] indole-8-carboxamide; 2,2-dioxide / - [(1 S, 2R) -3 - [(3,3-dimethylbutyl) amino] -2-hydroxy-1- (phenylmethyl) propyl] -6-ethyl-1-methyl-1 , 3,4,6-tetrahydro [1,2] thiazepino [d, 4,3-cc /] indole-8-carboxamide; 6-Ethyl 2,2-dioxide. { (1S, 2R) -2-hydroxy-1- (phenylmethyl) -3 - [(3,3, d, d-tetramethylcyclohexyl) amino] propyl} -1-methyl-1, 3,4,6-tetrahydro [1,2] thiazepino [d, 4,3-cc / | indole-d-carboxamide; 2,2-dioxide - [(1 S, 2R) -3 - [(1, d-dimethylhexyl) amino-2-hydroxy-1- (phenylmethyl) propyl] -6-ethyl-1-methyl-1 , 3,4,6-tetrahydro [1,2] thiazepino [d, 4,3-cc_indol-d-carboxamide; 2,2-dioxide d of 6-ethyl- / V - [(1 S, 2R) -2-hydroxy-1- (phenylmethyl) -3- (propylamino) propyl] -1-methyl- 1, 3,4, 6-tetrahydro [1,2] thiazepino [d, 4,3-cd] indole-8-carboxamide; 6-ethyl-6-dioxide -? / -. { (1 S, 2R) -2-hydroxy-1- (phenyl [methyl] -3 - [(3,3,3-trifluoropropyl) amino] propyl} -1- methyl-1, 3,4,6-tetrahydro [1,2] thiazepino [d, 4,3-ccfndol-d-carboxamide; 2,2-dioxide - [(1 S, 2R) -3 - [(2,2-difluoroethyl) amino] -2-hydroxy-1 - (phenylmethyl) propyl] -6-ethyl-1-methyl -1, 3,4,6-tetrahydro [1,2] thiazepino [d, 4,3-cct] indole-d-carboxamide; 2,2-Di-ethyl-? / - [(1 S, 2R) -3 - [(2-ethylbutyl) amino] -2-hydroxy-1 - (phenylmethyl) propyl] -1-methyl-1 2,2-dioxide, 3,4,6-tetrahydro [1,2] thiazepine [d, 4,3-cc /] indole-8-carboxamide; 2,2-dioxide-6-ethyl- / V - [(1 S, 2R) -2-hydroxy-3 - [(3-methylbutyl) amino] -1- (phenylmethyl) propyl] -1-methyl-1, 3,4,6-tetrahydro [1,2] thiazepino [d, 4,3-cc] indole-d-carboxamide; 6-d-ethyl-? / - 2,2-dioxide. { (1S, 2R) -2-hydroxy-1- (phenylmethyl) -3 - [(2,2,6,6-tetramethylcyclohexyl) amino] -propyl} -1-methyl-1, 3, 4,6-tetrahydro [1,2] thiazepino [d, 4,3-ccy] ndol-8-carboxamide; 2,2-dioxide / V - [(1S, 2R) -3 - [(2,2-dimethylcyclohexyl) amind] -2-hydroxy-1- (phenylmethyl) propyl] -6-ethyl-1-methyl -1, 3,4,6-tetrahydro [1,2] thiazepino [d, 4,3-c /] indole-8-carboxamide; 2,2-Di-ethyl -? / - [(1 S, 2R) -2-hydroxy-3-dioxide. { [2-0 (methylthio) ethyl] amino} -1 - (phenylmethyl) propyl] -1-methyl-1, 3,4,6-tetrahydro [1,2] -thiazepino [d, 4,3-cct] indole-d-carboxamide; N - [(1 S, 2R) -3 - [(2-cyclohexylethyl) amino] -2-hydroxy-1 - (phenylethyl) propyl] -6-ethyl-1-methyl-1,3-dioxide , 4,6-tetrahydro [1,2] thiazepino [d, 4,3-cc7] indole-d-carboxamide; 6-Ethyl -? / - [(1 S, 2R) -2-hydroxy-3 - [(2-methyl-2-propen-1-yl) amino] -2- ( phenylmethyl) propyl] -1-methyl-1, 3,4,6-tetrahydro [1,2] thiazepino [5,4,3-cd] indole-3-carboxamide; 2,2-Dioxide - [(1 S, 2R) -3- (3-buten-1-ylamino) -2-hydroxy-1- (phenylmethyl) propyl] -6-ethyl-1-methyl-1 3,4,6-tetrahydro [1,2] thiazepine [5,4,3-cc] indole-d-carboxamide; 2,2-dioxide / V - [(1 S, 2R) -3- (cycloheptylamino) -2-hydroxy-1- (phenylmethyl) propyl] -6-ethyl-1-methyl- 1, 3,4,6 tetrahydro [1,2] thiazepi [5,4,3-cc] indol-d-carboxamide; 2,2-dioxide -? / - [(1 S, 2R) -2-hydroxy-1- (phenylmethyl) -3- (tricyclo [3.3.1.13'7] dec-2-ylamino) propyl] -1-methyl-1, 3,4,6-tetrahydro [1,2] thiazepine [d, 4,3-cc /] indole-d-carboxamide; - 2,2-dioxide in? / - [(1S, 2R) -3 - [(1S, 4R) -bicyclo [2.2.1] hept-2-ylamino] -2-hydroxy-1- (phenylmethyl) propyl] -6-ethyl-1 -methyl-, 3,6,6-tetrahydro [1,2] thiazepino [5,4,3-cd] indole-8-carboxamide; 6-Ethyl-? / - ((1 S, 2R) -2-hydroxy-1- (phenylmethyl) -3- { [2- (propyloxy) ethyl] amino} propyl) 2,2-dioxide -1-methyl-1, 3,4,6-tetrahydro [1,2] thiazepino [5, 4,3-c] indole-d-carboxamide; 2,2-ethyl-A / - [(1 S, 2R) -3 - [(1-ethynylcyclohexyl) -amino] -2-hydroxy-1 - (phenylmethyl) propyl] -1-methyl-1-2,2-dioxide 3,4,6-tetrahydro [1,2] thiazepino- [d, 4,3-co-indole-8-carboxamide; 2,2-Di-ethyl -? / - [(1 S, 2R) -2-hydroxy-3 - [(4-methylphenyl) amino] -1- (phenylmethyl) propyl] -1-methyl- 1, 3,4,6-tetrahydro [1,2] thiazepino- [d, 4,3-cd] indole-d-carboxamide; 2,2-Di-ethyl -? / - [(1 S, 2R) -2-h¡drox¡-3 - [(1-methylcyclohexyl) amino] -1 - (phenylmethyl) propyl] -1 -met L-1, 3,4,6-tetrahydro [1, 2] -thiazepino [d, 4,3-cd] ndol-8-carboxamide; 2,2-Di-ethyl-? / - [(1 S, 2R) -3 - [(1-ethylcyclohexyl) amino] -2-hydroxy-1- (phenylmethyl) propyl] -1-methyl-1-2,2-dioxide, 3,4,6-tetrahydro- [1,2] thiazepin [d, 4,3-cct] indole-d-carboxamide; 6-Ethyl 2,2-dioxide. { (1 S, 2R) -2-hydroxy-1 - (phenylmethyl) -3 - [(1-propylcyclohexyl) amino] propyl} -1-methyl-1, 3,4,6-tetrahydro [1,2] thiazepino [5,4,3-c] indol-d-carboxamide; N- [(1 S, 2R) -3- (. {2 - [(1, 1-dimethylethyl) thio] etl.] Amino) -2-hydroxy-1-2,2-dioxide - (phenylmethyl) propyl] -6-ethyl-1-methyl-1, 3,4,6-tetrahydro [1,2] thiazepi [5,4,3-cc7] indole-8-carboxamide; 6-Ethyl -? / - [(1 S, 2R) -2-hydroxy-1- (phenylmethyl) -3- (. {2 - [(2,2,2-trifluoroethyl) - 2,2-dioxide oxy] ethyl.} amino) propyl] -1-methyl-1, 3,4,6-tetrahydro [1,2] thiazepino [d, 4,3-c] indole-8-carboxamide; 2,2-dioxide -? / - [(1 S, 2R) -2-hydroxy-3- (phenylamino) -1- (phenylmethyl) propyl] -1-methyl-1, 3,4,6 -tetrahydro [1,2] thiazepino [5,4,3-c] indol-d-carboxamide; 2,2-Di-ethyl-γ / - [(1 S, 2R) -2-hydroxy-3 - [(3-methylphenyl) amino] -1 - (phenylmethyl) propyl] -1-methyl-1 2,2-dioxide, 3,4,6-tetrahydro [1,2] thiazepino [5, 4,3-cc7] indole-8-carboxamide; 2,2-Di-ethyl-? / - [(1 S, 2R) -2-hydroxy-3 - [(2-methylphenyl) amino] -1 - (phenylmethyl) propyl] -1-methyl-1 2,2-dioxide, 3,4,6-tetrahydro [1,2] thiazepino [5,4,3-cd] indole-8-carboxamide; 6-ethyl-2 - [/ 1 - [(1 S, 2R) -3- dioxide. { [(1-ethyl-1 / - / - pyrazol-4-yl) methyl] amino} -2-hydroxy-1- (phenylmethyl) propyl] -1-methyl-1, 3,4,6-tetrahydro [1,2] -thiazepino [5,4,3-cc7] indole-8-carboxamide; 2,2-Di-ethyl -? / - [(1 S, 2R) -2-hydroxy-3 - [(3-metii-2-buten-1-yl) amino] -1 - (phenylmethyl) propyl 2,2-dioxide ] -1-methyl-1, 3,4,6-tetrahydro [1,2] thiazepino [5,4,3-cc] indo! -8-carboxamide; 6-Butyl-γ / - [(1S, 2R) -3- (cyclohexylamino) -2-hydroxy-1- (phenylmethyl) propyl] -1-methyl-1, 3,4-dioxide, 6-tetrahydro [1,2] thiazepino [5,4,3-cc] indole-d-carboxamide; N- [(1 S, 2R) -3 - [(2-chlorophenyl) amino] -2-hydroxy-1- (phenylmethyl) propyl] -6-ethyl-1-methyl-1, 2,2-dioxide , 4,6-tetrahydro [1,2] thiazepino [d, 4,3-cc7] indole-d-carboxamide; 2,2-ethyl- / V - [(1 S, 2R) -2-hydroxy-3-dioxide. { [2- (methyloxy) phenyl] amino} -1 - (phenylmethyl) propyl] -1-methyl-1, 3,4,6-tetrahydro [1,2] thiazepino [d, 4,3-c] indole-d-carboxamide; 2,2-Di-ethyl -? / - [(1 S, 2R) -2-hydroxy-3-dioxide. { [4- (methyloxy) phenyl] amino} -1- (phenylmethyl) propyl] -1-methyl-1,3,6,6-tetrahydro [1,2] thiazepino [d, 4,3-cc-indol-d-carboxamide; 2,2-dioxide A / - [(1 S, 2R) -3 - [(3-chlorophenyl) amino] -2-hydroxy-1 - (phenylmethyl) propyl] -6-ethyl-1-methyl-1, 3,4,6-tetrahydro [1,2] thiazepino [5,4,3-c] indol-d-carboxamide; 2,2-Di-ethyl -? / - [(1 S, 2R) -2-hydroxy-3-dioxide. { [3- (methyloxy) phenyl] amino} -1- (phenylmethyl) propyl] -1-methyl-1, 3,4,6-tetrahydro [1,2] thiazepino [5, 4,3-cc7] indole-3-carboxamide; 2,2-dioxide [/ 1 S, 2R) -3 - [(4-chlorophenyl) amino] -2-hydroxy-1- (phenylmethyl) propyl] -6-ethyl-1-methyl-1, 3,4,6-tetrahydro [1,2] thiazepino [d, 4,3-cc /] indole-d-carboxamide; 2,2-dioxide / V - [(1 S, 2R) -3- (cyclohexylamino) -2-hydroxy-1- (phenylmethyl) propyl] -1-methyl-6-propyl-1, 3,4 , 6-tetrahydro [1,2] thiazepine [d, 4,3-c] indole-d-carboxamide; 2,2-dioxide [/ 1 S, 2R) -3- (cyclohexylamino) -2-hydroxy-1- (phenylmethyl) propyl] -1-methyl-6- (1- "methylethyl) -1, 3,4,6-tetrahydro [1,2] thiazepino [d, 4,3-cct] indol-d-carboxamide; 2,2-dioxide of? / - [(1 S, 2R) -3- ( cyclopropylammonyl) -2-hydroxy-1- (phenylmethyl) propyl] -6-ethyl-1-methyl-1, 3,4,6-tetrahydro [1,2] thiazepine [d, 4,3-cc] indole-d-carboxamide; 2,2-dioxide of? / - [(1 S, 2R) -2-hydroxy-3- ( { [3- (methyloxy) phenyl] methyl.}. amino) -1 - (phenylmethyl) propyl] -1-methyl-6-propyl-1, 3,4,6-tetrahydro [1,2] thiazepine [5,4,3-cc /] indole-d-carboxamide; 2,2-dioxide of? / - [(1 S, 2R) -3- (cyclohexylamino) -2-hydroxy-1- (phenylmethyl) propyl] -1,6-diethyl-1, 3 , 4,6-tetrahydro [1,2] thiazepine [5,4,3-cc7] indole-d-carboxamide; 2,2-dioxide of / V - [(1 S, 2R) -3 - [(2, 4-dimethylphenyl) amino] -2-hydroxy-1- (phenylmethyl) propyl] -6-ethyl-1-methyl-1, 3,4,6-tetrahydro [1,2] thiazepine [5.4, 3-cc /] indole-8-carboxamide; 2,2-dioxide of? / - [(1 S, 2R) -3- { [4- (dimethylamino) phenyl] amino.} -2- hydroxy-1- (phenylmethyl) propyl] -6-ethyl-1-methyl-1, 3,4,6- tetrahydro [1,2] thiazepine [5,4,3-cc /] indole-d-carboxamide; 2,2-dioxide A / - [(1 S, 2R) -3- (2-butin-1-ylamino) -2-hydroxy-1 - (phenylmethyl) propyl] -6-ethyl-1-methyl-1 3,4,6-tetrahydro [1,2] thiazepine [5,4,3-ccdindol-d-carboxamide; 6-ethyl-A / - 2,2-dioxide. { (1S, 2R) -2-hydroxy-1- (fe n i I met i I) -3 - [(1, 1, 5-trimethylhexyl) amino] propyl} -1-methyl-1,3,4,6-tetrahydro- [1,2] thiazepine [5,4,3-co-indole-8-carboxamide; 2,2-Dioxide - [(1 S, 2R) -3- (Butylamino) -2-hydroxy-1 - (phenylmethyl) propyl] -6-ethyl-1-methyl-1,3,6,6 -tetrahydro- [1,2] thiazepino [5,4,3-cd] indol-d-carboxamide; 2,2-dioxide of? / - [(1 S, 2R) -3-. { [2,3-bis (methyloxy) phenyl] amino} -2-hydroxy-1- (phenylmethyl) propyl] -6-ethyl-1-methyl-1, 3,4,6-tetrahydro [1,2] thiazepine [5,4,3-ct] indole-d-carboxamide; 6-Ethyl 2,2-dioxide. { (1 S, 2R) -2-hydroxy-1- (phenylmethyl) -3 - [(. {3 - [(trifluoromethyl) oxy] phenyl] - .methyl) amino] propyl} -1-methyl-1, 3,4,6-tetrahydro [1,2] thiazepino [5, 4, 4-cc /] ndol-3-carboxamide; 2,2-Di-ethyl -? / - [(1 S, 2R) -2-hydroxy-3-dioxide. { [(6-methyl-2-pyridinyl) methyl] amino} -1 - (phenylmethyl) propyl] -1-methyl-1, 3,4,6-tetrahydro [1,2] -thiazepino [5,4,3-cc] indole-d-carboxamide; 2,2-dioxide - [(1 S, 2R) -3-. { [(1S) -2- (cyclohexylamino) -1-methyl-2-oxoethyl] amino} -2-hydroxy-1- (phenylmethyl) propyl] -6-ethyl-1-methyl-1, 3,4,6-tetrahydro [1,2] thiazepine [5,4,3-c /] indole-d -carboxamide; 2,2-ethyl- / V - [(1 S, 2R) -2-hydroxy-3-dioxide. { [(1 R) -1-methylpropyl] amino} -1- (phenylmethyl) propyl] -1-methyl-1,3,6,6-tetrahydro [1,2] thiazepi [5,4,3-cc (] indole-d-carboxamide; 2,2- 6-Ethyl -? / - [(1 S, 2R) -2-hydroxy-3. {[[(1 S) -1-methylpropyl] amino]} -1- (phenylmethyl) -propyl] dioxide -1-methyl-1,3,4,6-tetrahydro [1,2] thiazepine [5,4,3-cc] indole-d-carboxamide; 2,2-dioxide in 6-ethyl- / V-. { (1S, 2R) -2-hydroxy-1- (phenylmethyl) -3 - [(2-pyridinylmethyl) -amino] propyl} -1- methyl-1, 3,4,6-tetrahydro [1, 2] thiazepine [5,4,3-cc] indole-d-carboxamide; 2,2-dioxide 6-ethyl-? / - [(1 S, 2R) -2-hydroxy-3 { [2 -methyl-4- (methyloxy) phenylal] amino.} -1- (phenylmethyl) propyl] -1-methyl-1, 3,4,6-tetrahydro [1, 2] -thiazepine [5,4, 3-ccl] indole-d-carboxamide; 2,2-dioxide-6-ethyl-? / - [(1 S, 2R) -3 - [(1-ethylcyclopropyl) amino] -2-hydroxy-1 - (phenylmethyl) propyl] -1-methyl-1,3,6,6-tetrahydro- [1,2] thiazepine [5,4,3-cct] indole-d-carboxamide; 2,2-dioxide-6-ethyl-? / - [(1 S, 2R) -2-hydroxy-3- (2-pentin-1 -lamino) -1- (phenylmethyl) propyl] -1-methyl-1, 3,4, 6-tetrahydro- [ 1, 2] thiazepine [5,4,3-c] indole-d-carboxamide; 2.2 6-ethyl-? / - [(1 S, 2R) -3 - [(3-fluoropropyl) amino] -2-hydroxy-1- (phenylmethyl) propyl] -1-methyl-1 dioxide, 3, 4,6-tetrahydro- [1,2] thiazepino [5 A3-ctt] indole-3-carboxamide; 2,2-Di-ethyl-? / - [(1 S, 2R) -2-hydroxy-3 - [(1-methylcyclopropyl) amino] -1- (phenylmethyl) propyl] -1-methyl-1-2,2-dioxide, 3,4,6-tetrahydro [1,2] thiazepino [5,4,3-c] indol-d-carboxamide; N - [(1 S, 2R) -3 - [(1,1-dimethyl-2-propin-1-yl) amino] -2-hydroxy-1- (phenylmethyl) propyl] -2-dioxide] -6 -ethyl-1-methyl-1, 3,4,6-tetrahydro [1,2] thiazepine [5 A3-cct] indole-3-carboxamide; 2,2-dioxide [/ 1 S, 2R) -3- (cyclooctylamino) -2-hydroxy-1- (phenylmethyl) propyl] -6-ethyl-1-methyl-1, 3 , 4,6-tetrahydro [1,2] thiazepino [5, 4,3-cd] indole-3-carboxamide; and 1, 6-diethyl-β / - [(1 S, 2R) -2-hydroxy-1- (phenylmethyl) -3- (tetrahydro-2H-pyran-4-ylamino) propyl] 2,2-dioxide 1, 3,4,6-tetrahydro [1,2] thiazepine [5,4,3-cc] indole-8-carboxamide; or a pharmaceutically acceptable salt or solvate thereof. 13. A pharmaceutical composition comprising a compound of formula (I) as claimed in any of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, in admixture with one or more pharmaceutically acceptable diluents or vehicles. 14. The compound of formula (I) according to any of claims 1 to 12, or a pharmaceutically acceptable salt or solvate thereof, further characterized in that it is used as a pharmaceutical agent. 15. The use of a compound of formula (I) as claimed in any of claims 1 to 12, or a pharmaceutically acceptable salt or solvate thereof, for preparing a medicament for the treatment of diseases characterized by high concentration of β -amyloid or ß-amyloid deposits.