MXPA99011901A

MXPA99011901A - New amidino derivatives and their use as thrombin inhibitors

Info

Publication number: MXPA99011901A
Application number: MXPA/A/1999/011901A
Authority: MX
Inventors: Nystrom Janerik; Karlsson Olle; Linschoten Marcel
Original assignee: Astra Aktiebolag; Karlsson Olle; Linschoten Marcel; Nystroem Janerik
Priority date: 1997-06-19
Filing date: 1999-12-16
Publication date: 2000-05-01

Abstract

There is provided compounds of formula (I), wherein R1, Rx, Y, Ry, n and B have meanings given in the description which are useful as competitive inhibitors of trypsin-like proteases, such as thrombin, and in particular in the treatment of conditions where inhibition of thrombin is required (e.g. thrombosis) or as anticoagulants.

Description

NEW AMIDINO DERIVATIVES AND THEIR USE AS THROMBIN INHIBITORS FIELD OF THE INVENTION This invention relates to novel pharmaceutically useful compounds, in particular competitive inhibitors of trypsin-like serine proteases, especially thrombin, their use as medicaments, pharmaceutical compositions containing them and synthetic routes for their production.

BACKGROUND OF THE INVENTION Blood coagulation is the key process involved in both hemostasis (ie preventing blood loss from a damaged vessel) and thrombosis (i.e. the formation of a blood clot in a blood vessel, sometimes leading to vessel obstruction). blood). Coagulation is the result of the complex series of enzymatic reactions. One of the last stages in this series of reactions is the conversion of proenzyme prothrombin to the active enzyme thrombin.

REF .: 32239 Thrombin is known to play a central role in coagulation. This active platelets, leading to the aggregation of platelets, converts fibrinogen into fibrin monomers, which polymerize spontaneously in fibrin polymers, and activates factor XIII, which in turn reticulates the polymers to form insoluble fibrin. Additionally, thrombin activates factor V and factor VIII leading to a generation "positive feedback" of thrombin from prothrombin. By inhibiting platelet aggregation and the formation of fibrin crosslinking, inhibitors of thrombin effects can be expected to exhibit antithobiotic activity. In addition, antithrombotic activity can be expected to be increased by effective inhibition of the positive feedback mechanism.

PREVIOUS TECHNIQUE The prior development of low molecular weight thrombin inhibitors has been described by Claesson in Blood Coagul. Fibrinol. (1994) 5, 411. Blomback et al (in J. Clin. Lab. Invest. 24, suppl. 107, 59, (1969)) reports thrombin inhibitors based on the amino acid sequence located around the cleavage site or decomposition for the fibrinogen chain Aa. Of the amino acid sequences discussed, these authors suggest the tripeptide sequence Phe-Val-Arg (P9-P2-P1, referred to hereinafter as the sequence P3-P2-P1) which can be expected to be the most effective inhibitor. Thrombin inhibitors based on dipeptidyl derivatives with an a, -aminoalkyl guanidine in the Pl position are known from U.S. Patent No. 4,346,078 and International Patent Application WO 93/11152. Similarly, structurally related dipeptidyl derivatives have also been reported. For example, International Patent Application WO 94/29336 describes compounds with, for example, aminomethylbenzamidines, cyclic aminoalkylamides and cyclic aminoalkylguanidines in the Pl position; European Patent Application 0 648 780 describes compounds with, for example, cyclic aminoalkylguanidines in the Pl position. Thrombin inhibitors based on peptidyl derivatives, which also have cyclic aminoalkylguanidines (for example, 3 or 4-aminomethyl-1-amidinopiperidine) in the Pl position are known from European Patent Applications 0 468 231, 0 559 046 and 0 641 779. Thrombin inhibitors based on tripeptidyl derivatives with arginine aldehyde are first described in the Pl position in European Patent Application 0 185 390. More recently, peptidyl derivatives based on of arginine aldehyde, modified at position P3, have been reported. For example, International Patent Application WO 93/18060 describes hydroxy acids, European Patent Application 0 526 877 des-amino acids, and European Patent Application 0 542 525 O-methylmandelic acids at the P3 position. Serine protease inhibitors (for example thrombin) are also known based on the electrophilic ketones in the Pl position. For example, European Patent Application 0 195 212 describes peptidyl α-keto esters and amides, European Patent Application 0 362 002 fluoroalkylamide ketones, European Patent Application 0 364 344 a, β, d-triceto compounds, and European Patent Application 0 530 167 derivatives of arginine a-alcoxyketone in the Pl position.

Other structurally different inhibitors of trypsin-like serine proteases based on the C-terminal boronic acid derivatives of arginine and isothiouronium analogs thereof are known from European Patent Application 0 293 881. More recently, they have been described thrombin inhibitors based on the peptidyl derivatives described in European Patent Application 0 669 317 and International Patent Applications WO 95/35309, WO 95/23609 and WO 96/25426. However, a need remains for effective trypsin-like serine protease inhibitors, such as thrombin. There is a particular need for compounds that are both orally and selectively bioavailable to inhibit thrombin over other serine proteases. Compounds that exhibit competitive inhibitory activity towards thrombin can be expected to be especially useful as anticoagulants and therefore in the therapeutic treatment of thrombosis and related disorders.

DESCRIPTION OF THE INVENTION According to the invention there is provided a compound of the formula I, wherein R 1 represents H, Cx_4 alkyl (optionally substituted by one or more substituents selected from cyano, halo, OH, C (0) ORla or C (O) N (Rlb) Rlc) or ORld; Rld represents H, CIOJR11, SiR12R13R14 or C? -6 alkyl, wherein the latter group is optionally substituted or terminated by one or more substituents selected from OR15 or (CH2) qR16; R12, R13 and R14 independently represent H, phenyl or C? _6 alkyl; Rld represents C? _4 alkyl phenyl, OH, C (0) OR17 or C (0) N (H) R18; R18 represents H, C? - alkyl or CH2C (0) OR19; R15 and R17 independently represent H, C? _6 alkyl or C? -3 alkylphenyl; Rla, Rlb, Rlc, R11 and R19 independently represent H or C? _4 alkyl; and q represents 0, 1 or 2; Rx represents a structural fragment of the formula bundle, Ilb or líe, where dotted lines independently represent optional links; A and B independently represent O or S, CH or CH2 (as appropriate), or N or N (R21) (as appropriate); D represents -CH2-, O, S, N (R22), - (CH2) 2-. -CH = CH-, -CH2N (R22) -, -N (R22) CH2-, -CH = N-, -N = CH-, -CH20-, -OCH2-, -CH2S- or -SCH2-; Xx represents C2-4 alkylene; C2-3 alkylene interrupted by Z; -CÍO-Z-A1; -Z-C (0) -A1-; -CH2-C (0) -Aa; -Z-C (O) -Z-A2-; -CH2-Z-C (O) -A2-; -Z-CH2-C (O) -A2-; -Z-CH2-S (0) m-A2-; -CH2-Z-S (0) m-A2-; -C (0) -A3; -Z-A3-; or -A -Z- X2 represents C2-3 alkylene, -C (O) -A4- or -A4-C (O) -; X3 represents CH or N; X4 represents a simple link, O, S, C (0), N (R23), -CH (R23) -, -CH (R23) -CH (R24) - or -C (R23) = C (R2) -; A1 represents a single bond or alkylene of C? _2; A2 represents a; single link or -CH2-; A3 represents alkylene of C? _3; A4 represents C (O) or alkylene of C? -2; Z represents, in each occurrence, O, S (O) or m represents, in each occurrence, 0, 1 or 2; R2 and R4 independently represent one or more optional substituents selected from C? _4 alkyl (wherein the latter group is optionally substituted by one or more halo substituents), C? - / methylenedioxy alkoxy, halo, hydroxy, cyano, nitro, S02NH2, C (0) OR 26 R represents an optional substituent selected from OH or C? -4 alkoxy; R .21, R, 2"2, R 2-3-, RR 2" 4, RR2"5, RR2'6", R 2"7 and R 28 independently represent H or C? _4 alkyl; represents CH 2, (CH 2) 2, CH = CH, (CH 2) 3, CH 2 CH = CH or CH = CHCH 2, wherein the last three groups are optionally substituted by C 4 alkyl, methylene, oxo or hydroxy; Ry represents H or C? -4 alkyl; n represents 0, 1, 2, 3 or 4; and B represents a structural fragment of the formula Illa, Illb or lile llia lllb lile where X5, X6, X7 and X8 independently represent CH, N or N-O; X9 and X10 independently represent a single bond or CH2; and R 31 represents an optional substituent selected from halo, C? _4 alkyl; or a pharmaceutically acceptable salt thereof; with the proviso that: (a) A and B do not represent both O or S; (b) B and D do not represent both O or S; (c) when R represents OR and Xi represents -C (0) -Z-Aa, -Z-CH2-S (0) m-A2, -CH2-ZS (0) m-A2- or -ZC (O) -Z-A2, then A1 or A2 (as appropriate) do not represent a single link; and (d) when X4 represents -CH (R23) -, R1 does not represent OH. The compounds of formula I may exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention. It will further be appreciated by those skilled in the art that, in the structural fragment of the formula lia, the optional double bonds may, together with certain identities of the substituent D, provide a ring bearing aromatic A, B and D in character. The compounds of formula I may also contain one or more asymmetric carbon atoms and may therefore exhibit optical isomer and / or diastereoisomerism. All diastereomers can be separated using conventional techniques, for example, chromatography or fractional crystallization. The various stereoisomers can be isolated by separation of a racemic mixture or other of the compounds using conventional techniques, for example, fractional crystallization, or HPLC.

Alternatively, the desired optical isomers may be made by reaction of the appropriate optically active starting materials, under conditions that will not cause racemization or epimerization or by derivatization, for example, with a homochiral acid followed by separation of the diastereoisomeric derivatives, by conventional (for example, HPLC, chromatography on silica). All stereoisomers are included within the scope of the invention. The alkyl groups in which R1, Rla, Rlb, p i e p l d p 2 r > 4 p l l p l 2 p l 3 R 1 4 R 15 p 1 6 R 1 7 R 18 p 1 9 R21, R22, R23, R24, R25, R26, R27, R28, R31 and Ry can represent and with which Y can be substituted; the alkyl part of the 'alkylphenyl groups in which R15 and R17 may represent; and alkoxy groups, which R2, R3 and R4 may represent, may, when there is a sufficient number of carbon atoms, be linear or branched, saturated or unsaturated, cyclic or acyclic. The alkylene groups in which Xx, X2, A1, A3 and A4 can represent, can when there are a sufficient number of carbon atoms, be linear or branched, saturated or unsaturated. The halo groups, which R31 can represent, and with which R1, R2 and R4 can be substituted, include fluorine, chlorine, bromine and iodine.

In the structural fragments of the formulas lia, Ilb, and líe, the points indicate the carbon atom which binds to the group -C (0) - and R1 in a compound of the formula I (to avoid doubt, there is no a hydrogen atom bonded to the carbon atom therefore indicated). * The wave lines in the links in the fragments of the formulas Illa, Illb and IIIc, signify the binding position of the fragment. According to a further aspect of the invention there is provided a compound of the formula I as mentioned below, defined with the additional conditions that: R? represent H; R28 represents H; X4 does not represent -CH (R3) -. According to a further aspect of the invention there is provided a compound of the formula I as defined above with the additional conditions that: R y represents C? _ Alkyl; R28 represents alkyl of C? -4; X4 represents -CH (R23) -. The abbreviations are listed at the end of this specification.

When n represents 2 and B represents a structural fragment of formula Illb, preferred compounds of formula I include those wherein X9 and X10 do not represent both CH2. Preferred compounds of the formula I include those wherein: R 1 represents OH or C 4 -4 alkyl (wherein the latter group is optionally substituted by cyano or OH); Rx represents a structural fragment of the formula lía; when Rx represents a structural fragment of the bundle formula, dotted lines represent bonds, A and B represent CH and D represents -CH = CH-; when Rx represents a structural fragment of the compound formula, Xx represents alkylene of C2 or C3, -OCH2- or -0 (CH2) 2-; Y represents CH2, (CH2) 2 or (CH2) 3; B represents a structural fragment of the formula Illa, wherein X5, X6, X7 and X8 all represent CH. More preferred compounds of the invention include those wherein, when Rx represents a structural fragment of the formula ly, Xi represents C3 alkylene or -0 (CH2) 2-.

When Rx represents a structural fragment of the formula lia and R 2 represents at least one substituent, a preferred substitution point is at the carbon atom, which is at the B position. When R x represents a structural fragment of the formula lia, the; dotted lines represent bonds, A and B represent CH and D represents -CH = CH- (ie, the ring carrying R2 is a benzo group), and R2 represents at least one substituent, the ring is preferably substituted either in the carbon atom in the group -CH = CH- (position D) which is adjacent to the ring junction, or more preferably at the carbon atom which is at position B, or at both of these sites. For example, when the fragment lia represents a tetralin-1-yl group (ie, dotted lines represent bonds, A and B represent both CH, D represents -CH = CH and Xx represents saturated C3 alkylene), preferred substitution are in 5- or especially in the 7- position or in both of these positions. Accordingly, when the fragment la represents a chroman-4-yl group (ie dotted lines represent bonds, A and B represent CH, D represents -CH = CH and Xx represents -0 (CH2) 2-), the positions preferred substitution are in position 8 or especially in position 6, or in both of these positions. Preference is given to compounds of the formula I in which the fragment is in the S configuration. The wavy lines in the links in the previous fragment mean in the link position of the fragment. Preferred compounds of formula I include the compounds of the Examples described later herein.

Preparation According to the invention there is also provided a process for the preparation of compound of formula I comprising: (i) coupling a compound of formula IV, wherein R1 and Rx are as defined above with a compound of the formula V, wherein R ?, Y, n and B are as defined above, or (ii) coupling a compound of formula VI, wherein R1, Rx and Y are as defined above with a compound of formula VII, H (RY) N- (CH2) n-B VII wherein Ry, n and B are as defined above, for example in the presence of a coupling agent (e.g., oxalyl chloride in DMF, EDC, DCC, HBTU, HATU or TBTU), an appropriate base (e.g., pyridine) , 2, 4, 6-trimethylpyridine, DMAP, TEA or DIPEA) and a suitable organic solvent (for example, dichloromethane, acetonitrile or DMF). The compounds of formula IV are commercially available, are well known in the literature, or are available using known and / or standard techniques. For example, compounds of formula IV in which R 1 represents OH can be prepared by reaction of a compound of formula VIII, wherein Rx is as defined above, with: (a) KCN, for example at 20 ° C in the presence of sodium bisulfite in water, followed by hydrolysis in the presence of an aqueous acid (eg, HCl), for example 20 ° C in the presence of a suitable solvent (for example, alcohol and / or water); (b) CHC13 in the presence of an aqueous base (for example NaOH); (c) TMSCN, for example, at 20 ° C in the presence of a suitable organic solvent (for example, CH2C12), followed by hydrolysis in the presence of acid (for example, HCl, or H2S04) for example at 20 ° C (per example, in accordance, or analogously to the method described by Bigge et al in J. Med. Chem. (1993) 36, 1977), followed by alkaline hydrolysis to give the free acid. The compounds of the formula IV in which R 1 represents H can be prepared from the corresponding compounds of the formula IV in which R 1 represents OH (or a lower alkyl ester of the acid), for example, by elimination of water, followed by hydrogenation of the resulting alkene using techniques that are well known to those skilled in the art, followed by, if necessary, hydrolysis to give the free acid. Compounds of the formula IV in which R 1 represents C 1 -4 alkyl can be prepared from the corresponding compounds of the formula IV in which R 1 represents H (or a lower alkyl ester of the acid), for example, by reaction with an appropriate alkylhalide using techniques well known to those skilled in the art, followed by, if necessary, hydrolysis to give the free acid. The compounds of the formula IV in which R represents 0Rld and R? A represent C (0) Rí, SiR 112¿RT_.113JrR.14 C6-6 alkyl can be prepared by acylation, silylation or alkylation (as appropriate) of a corresponding compound of formula IV in which R1 represents OH (or lower alkyl ester of the acid) under conditions that are well known to those skilled in the art. the technique, followed by, if necessary, hydrolysis to give the free acid. - Compounds of the formula V can be prepared by reaction of a compound of the formula IX wherein Y is as defined above with a compound of the formula VII as defined above, for example, under conditions such as those described above for the synthesis of the compounds of the formula I. The compounds of the formulas V can be prepared and VII in which Ry represents C1-4 alkyl by reaction of a corresponding compound of formula V or formula VII, as appropriate, in which Ry represents H with a compound of formula IXa, RyHal IXa wherein Hal represents halo (eg, Cl, Br or I) and Ry is as defined above, for example, under conditions that are well known to those skilled in the art. The compounds of formula VI are readily available using known techniques. For example, compounds of formula VI can be prepared by reacting a compound of formula IV as defined above with a compound of formula IX as defined above, for example, under conditions such as those described above for the synthesis of compounds of the formula I.

The compounds of the formula VIII are commercially available, are well known in the literature, or can be prepared according to known techniques. For example, compounds of the formula VIII can be prepared as follows: r • (a) The compounds of the formula VIII in which Rx represents a structural fragment of the formula lia, in which the dotted lines represent bonds, can be prepared. , A and B both represent CH and D represents -CH = CH-; X_. represents alkylene of C2_4, -Z-A3- or -C (0) -A3-, in which A3 is as defined above; and R3 is absent by cyclization of a compound of formula X, wherein Xia represents C2-4 alkylene, -Z-A3- or -C (0) -A3-, and Z, A and R2 are as defined above, using an appropriate acylating agent, for example 100 ° C in the presence of polyphosphoric acid or using PC15 leading to reflux followed by A1C13. Compounds of formula X can be prepared in which Xla represents C3 alkylene or -C (0) -A3-, in which A3 represents C2 alkylene, according to known techniques, for example, by reaction of succinic anhydride with the corresponding phenyl lithium and, by compounds of the formula X in which X_a represents C3 alkylene. selective reduction of the resulting ketone under conditions that are well known to those skilled in the art. Compounds of formula X can be prepared, in which Xla represents -Z-A3- and A3 represents C2-3 alkylene as described hereinafter. (b) Compounds of the formula VII can alternatively be prepared in which Rx represents a structural fragment of the formula lia, in which the dotted lines represent bonds, A and B represent CH and D represents -CH = CH; X_ represents alkylene of C2- or -C (0) -A3-, in which A3 is as defined above; and R3 is absent, by cyclization of a compound of formula XI, XI wherein R represents C? _6 alkyl and Xia and R are as defined above, for example, at 20 ° C in the presence of a suitable base (for example, an alkali metal alkoxide) and an appropriate organic solvent (per example, lower alkyl alcohol), followed by hydrolysis and decarboxylation. The compounds of the formula XI can be prepared according to known techniques. For example, compounds of formula XI in which XXa represents C3 alkylene or -C (0) -A3 in which A3 represents C2 alkylene can be prepared by reaction of a succinic anhydride with a compound of formula XII, wherein R 'represents C6_6 alkyl and R and R2 are as defined above for compounds of the formula XI in which Xia represents C3 alkylene, selective reduction of the resulting ketone, followed by functional group transformations of the amide , and the acid to ester groups, under conditions well known to those skilled in the art. (c) Compounds of the formula VIII in which Rx represents a structural fragment of the formula lia, in which the dotted lines represent bonds, A and B represent CH and D represents -CH = CH-; Xi represents -Z-A3- in which A represents alkylene ide C2 and Z represents 0 or S; and R is absent, by cyclization of a compound of formula XIII, wherein Hal and R2 are as defined above, for example, at 20 ° C in the presence of aqueous ethanolic NaOH. For corresponding compounds of the formula VIII in which Xi represents -Z-A3- and Z represents S (0) m in which m is 1 or 2, this cyclization mentioned above must be followed when performing an oxidation reaction in the product cyclized comprising an S atom, for example, using nieloroperbenzoic acid. (d) Compounds of the Formula VIII in which Rx represents a structural fragment of the formula lia, in which the dotted lines represent bonds, A and B represent CH and D represents -CH = CH; Xi represents -Z-A3- in which A3 represents alkylene of C2 or -Z-C (0) - in which A represents alkylene of Ci / and R3 is absent, by reaction of the compound of formula XIV, wherein R2 and Z are as defined above, with either: (1) for compounds of the formula VIII in which Xi represents -Z-A3- in which A3 represents C2 alkylene a compound of the formula XV, H2C = CH-C02R XV wherein R is as defined above, for example at 20 ° C in the presence of a suitable base (e.g., triethylamine or sodium ethoxide) and an appropriate organic solvent (e.g., ethanol or DMF); or (2) a compound of formula XVI, I ^ -G-CHa C02R XVI wherein L1 represents a suitable leaving group (such as Cl, Br, I, mesylate or tosylate), G represents CH2 or C (0) and R is as defined above, for example at 20 ° C in the presence of a suitable base (e.g., triethylamine) and an appropriate organic solvent (e.g., THF); followed by cyclization 'under appropriate conditions (for example those described above). (e) Compounds of the formula VIII in which Rx represents a structural fragment of the formula Ilia, in which the ring bearing A, B and D is a carbocyclic, aromatic or heterocyclic aromatic ring, as defined above, may be prepared. with respect to the compounds of the formula I; Xx represents -CH2-Z-, alkylene of C? _2, in which Z is as defined above, and R3 is absent, by reaction of a compound of formula XVII, wherein the ring carrying Aa, Ba and Da is a carbocyclic aromatic, or aromatic heterocyclic ring as defined above with respect to the compound of the formula I, and Z and R2 is as defined above, with a compound of the formula XVIII , L1-Alk-C02H XVIII wherein Alk represents alkylene of C? _2 and L1 is as defined above, for example, at 20 ° C in the presence of a suitable base (for example, sodium methoxide) and an appropriate organic solvent (for example, THF) . (f) Compounds of the formula VIII in which Rx represents a structural fragment of the formulas Ilb, lie, or lia, in which the last case in which the ring carrying A, B and D is a carbocyclic aromatic or heterocyclic aromatic ring, as defined above with respect to the compounds of the formula I; and, in the cases when Rx represents a structural fragment of the formula lia or Ilb, R3 is absent by cyclization of a compound of the formula XX, where Rxa represents a structural fragment of the formulas XXa, XXb, or XXc XXa XXb XXc wherein, in XXa, the ring bearing Aa, Ba and Da is a carbocyclic aromatic, heterocyclic aromatic ring, is defined above with respect to the compounds of the formula I, and R2, R4, Xl r X2, X3 and X4 are as defined above, in the presence of a polyphosphoric acid, for example at 100 ° C. The points adjacent to the carbon atoms in the fragments of the formulas XXa, XXb, and XXc signify the point of attachment of the fragments to the group - C02H in the compound of the formula XX. The compounds of the formula XX can be prepared by hydrolysis of a corresponding compound of the formula XXI, wherein Rxa and R are as defined above (and in which C02H in the fragments of formulas XXa, XXb and XXc in Rxa can also be replaced by C02R) for example, under reaction conditions that are well known to those skilled in the art. in the technique. (g) Compounds of formula VIII may be prepared in which Rx represents a structural fragment of the formula I in which the ring carrying A, B and D is a carbocyclic or aromatic heterocyclic aromatic ring as defined above with respect to to the compounds of the formula I; Xx represents -0-CH2-; and R3 is absent, by reaction of a compound of formula XXII, wherein the ring carrying Aa, Ba and Da is an aromatic, carbocyclic or heterocyclic aromatic ring as defined above with respect to the compounds of the formula I, and R2, Hal and R are as defined above with diazomethane, for example , at 20 ° C in the presence of an appropriate organic solvent (for example, diethyl ether). (h) Compounds of the formula VIII in which Rx represents a structural fragment of the formula lia, in which the dashed lines represent bonds, A and B both represent CH and D represents -CH = CH-; X_ represents -C (O) -0-CH2-; and R3 is absent by cyclization of the compound of formula XXIII, XXIII wherein R2 and R are as defined above, for example, -20 ° C in the presence of sulfuric acid and an appropriate organic solvent (for example, methanol).

The compounds of formula XXIII can be prepared by reacting a corresponding acid halide with diazomethane, for example at 20 ° C in the presence of a suitable organic solvent (for example, diethyl ether). (i) Compounds of formula VIII can be prepared in which Rx represents a structural fragment of the formulas lia or lie in which Xi includes (R 25 • X, represents N (R), (as appropriate) and R23 and R25 (as appropriate) represent Cx- alkyl by reaction of a corresponding compound of formula VIII in which Xx includes, or X represents (as appropriate) NH with a compound of formula XXV Ra-Hal XXV wherein Ra represents Cx-4 alkyl and Hal is as defined above, for example, under conditions that are well known to those skilled in the art. (j) Compounds of the formula VIII in which Rx represents a structural fragment of the formula lia, in which the dashed lines represent bonds, A and B both represent CH and D represents -CH = CH; Xx represents -C (O) -N (H) -CH2-; and R3 is absent by catalytic hydrogenation of a hydroxamic acid of the formula XXVI, wherein R2 is as defined above, using an appropriate catalyst system (e.g., Pd / C) in the presence of a suitable organic solvent (e.g., methanol). The compounds of formula XXVI can be prepared by cyclization of a corresponding compound of formula XXVII, XXVII wherein R is as defined above, for example, at 20 ° C in the presence of fuming HCl and tin dichloride. (k) Selective oxidation of a compound of formula XXX, H-Rx-H XXX wherein Rx is as defined above, for example in the presence of a suitable oxidizing agent (for example Cr03 or KMn04) and a suitable solvent (for example water). (1) Selective oxidation of a compound of the formula XXXI, H-Rx-0H XXXI wherein Rx is as defined above, for example, in the presence of a suitable oxidizing agent (e.g., Mn02) in an appropriate organic solvent (e.g., CH2C12). (m) Hydrolysis of an oxime of formula XXXII, Rx = N-0H XXXII wherein Rx is as defined above, for example when heating in the presence of acid (eg, HCl) and an appropriate organic solvent. Compounds of formula XXXII can be prepared by reaction of a corresponding compound of formula XXX, as defined above, with propyl nitrite, for example, in the presence of HCl in ethanol. (n) Compounds of the formula VIII in which Rx represents a structural fragment of the formula lia and X represents -CH2-CH = CH- can be prepared by elimination of a compound of the formula XXXIII, XXXIII wherein L represents a suitable leaving group (e.g., Br or SePh) and dotted lines, A, B, D, R2 and R3 are as defined above, under appropriate reaction conditions, for example in the presence of aqueous ethanolic NaOH or hydrogen peroxide and an appropriate organic solvent (eg, THF). (o) The compounds of the formula VIII are prepared in which Rx represents a structural fragment of the formula Ilb, X2 represents -C (0) -A4 and A4 is as defined above, by cyclization of a compound of the formula XXXIV , XXXIV wherein Rb represents H, Cx-6 alkyl or Hal and R 2, R 3, A4, X 3 and Hal are as defined above, for example in the presence of a polyphosphoric acid, as described above, or in the case where Rb represents Hal, in the presence of A1C13 in nitromethane at, for example, 20 ° C. (p) Compounds of the formula VIII in which Rx represents a structural fragment of the formula Ilb and X2 represents -A4-C (0) - and A4 represents alkylene of C? _2 can be prepared by cyclization of a compound of the formula XXXV , wherein A represents alkylene of C _. 2 and Hal, R, R and X3 are as defined above. The compounds of formula VII, IX, IX, XII, XIII, XIV, XV, XVI, XVII, XVIII, XXI, XXII, XXV, XXVII, XXX, XXXI, XXXIII, XXIV and XXV are either commercially available, are well known in the literature, or are available using known techniques, including techniques that are the same as, or analogous to, those described herein. Substituents on the aromatic and / or nonaromatic, carbocyclic and / or heterocyclic rings in compounds of the formulas I, IV, V, VI, VII, VIII, X, XI, XII, XIII, XIV, XVII, XX, XXI, XXII, XXIII, XXVI, XXVII, XXX, XXXI, XXXII, XXXIII, XXXIV and XXV can be interconverted using techniques well known to those skilled in the art. For example, the nitro can be reduced to amino, hydroxy can be alkylated to give alkoxy, alkoxy can be hydrolyzed to hydroxy, the alkenes can be hydrogenated to give; alkanes, halo can be hydrogenated to H, etc. The compounds of the formula I of their reaction mixtures can be isolated using conventional techniques. It will be appreciated by those skilled in the art that in the process described above, functional groups of the intermediate compounds may need to be protected by protecting groups. Functional groups that are desirable to protect include hydroxy, amino and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl or diarylalkysilyl groups (for example, t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl) and tetrahydropyranyl. Suitable protecting groups for carboxylic acid include C? _6 alkyl or benzyl esters. Suitable protecting groups for amino, amidino and guanidino include t-butyloxycarbonyl, benzyloxycarbonyl or 2-trimethylisilylethoxycarbonyl (Teoc). The amidino and guanidino nitrogens can also be protected by hydroxy or alkoxy groups and can be either mono or di-protected. The protection and deprotection of the functional groups can take place before or after the coupling or before or after any other reaction in the schemes mentioned above. In particular, the compounds of the formula I can be prepared by processes comprising the coupling of an N-acylated amino acid or an N-protected amino acid. When an N-protected amino acid is attached, the acyl group can be introduced after coupling. The deprotection of the nitrogen atom can then be carried out using standard methods. The protecting groups can be removed according to techniques that are well known to those skilled in the art and as described hereinafter. Certain protected derivatives are novel (which can also be referred to as "intermediates") of compounds of the formula I, which can be made before a final deprotection step to form the compounds of the formula I.

According to a further aspect of the invention there is provided a compound of the formula la, where B1 represents a structural fragment of the formulas lid, lile or Illf Ifld Ule lllf wherein D1 and D2 independently represent H, OH, 0Ra, OC (0) Rb, OC (0) ORc, C (0) ORd, C (0) Re; wherein Ra represents phenyl, benzyl, C? _7 alkyl (the latter group is optionally interrupted by oxygen or is optionally substituted by halo) or -C (Rf) (R?) -OC (0) Rh; Rb represents C alquilo-β7 alkyl (wherein the latter group is optionally substituted by C?-C alco alkoxy, C? _6 acyloxy, amino or halo); C6_6 alkoxy, C3_7 cycloalkyl, phenyl, naphthyl or C3_3 alkylphenyl (wherein the last five groups are optionally substituted by C6_6 alkyl or halo); or - l C (Ri) (R3)] m0C (0) Rk; Rc represents Ci-p alkyl, phenyl, 2-naphthyl (wherein the last three groups are optionally substituted by -C 6 alkyl, Si (Raa) (Ra) (Rac) or halo), - [C (Rm) ) (Rn)] n0C (O) Rp, or -CH2-ARX; Rd represents 2-naphthyl, phenyl, C alqu-3 alkylphenyl (wherein the last three groups are optionally substituted by C?-6 alkyl, C?-6 alkoxy, nitro, Si (Rba) (Rbb) (Rbc ) or halo), d-12 alkyl (wherein the latter group is optionally substituted by C? -6 alkoxy, C? _6 acyloxy or halo), - [C (Rq) (Rr)] P0C (O) Rs or -CH2-Ar2; Re represents phenyl, benzyl, C_6 alkyl (the latter group is optionally interrupted by oxygen) or - [C (Rfe) (Ru)] rOC (O) Rv; Raa, Rab, Rac, Rba, Rbb and Rbe independently represent C? -6 alkyl or phenyl; Rf, Rg, R1, Rj, Rm, Rn, Rq, Rr, R and Ru independently represent H or C? _6 alkyl; R \ R ?, Rp. R £ Rv independently represent C1-17 alkyl (wherein the latter group is optionally substituted by C6-6 alkoxy, C1-6 acyloxy or halo); C6-6 alkoxy, C3-7 cycloalkyl / phenyl, naphthyl or C1-3 alkylphenyl (wherein the last five groups are optionally substituted by C6-6 alkyl or halo); Ar1 and Ar2 independently represent the structural fragment; m and r independently represent 3 or 4; n and p independently represent 1, 2 or 3; and R1, Rx, Y, Ry, n, X5, X6, X7, X8, X9, X10 and R31 are as defined above; or a pharmaceutically acceptable salt thereof; with the proviso that D1 and D2 do not represent both H.

Alkyl groups which Ra, Raa, Rab, Rac, Rb, R a, Rbb, Rbc, Rc, Rd, Re, Rf, Rg, Rh, R1, Rj, Rk, Rm, Rn, Rp, Rq, Rr, Rs, Rt, Ru, and Rv can represent and with which Rb, Rc, Rd, Rh, Rk, Rp, Rs and Rv can be substituted; cycloalkyl groups which Rb, Rh, Rk, Rp, Rs and Rv can represent; alkyl of C? _3 of alkylphenyl groups which Rb, Rd, Rh, Rk, Rp, R = and Rv can represent; alkoxy groups which Rb, Rh, Rk, Rp, Rs and Rv may represent; and an alkoxy and acyloxy groups with which Rb, Rd, R, Rk, Rp, Rs and Rv can be substituted, can, when there is a sufficient number of carbon atoms, be linear or branched, and can be saturated or unsaturated. The halo groups with which Ra, Rb, Rc, Rd, Rh, Rk, Rp, Rs and Rv can be substituted include fluoro, chloro, bromo and iodo. The wavy lines on the links in the fragments of the formulas Illd, lile or Illf signify the binding position of the fragment. Preferred compounds of the formula include those wherein D1 represents H and D2 represents OH, OCH3, OC (0) Rb or C (0) ORd, wherein Rb and Rd are as defined above. The compounds of the formula can also be prepared directly from the compounds of the formula I according to techniques well known to those skilled in the art. For example, compounds of the formula la can be prepared in which D1 or D2 represent C (0) ORd by reaction of a corresponding compound of the formula I with a compound of the formula XXXVa, L -C (0) 0RC XXXVa wherein L3 represents a leaving group, such as Hal or p-nitrophenoxy, and Hal and Rd are as defined above for example at 0 ° C in the presence of a suitable base (e.g., NaOH) and an appropriate organic solvent (per THF example). The compounds of the formula la can also be prepared directly from other compounds of the formula I according to techniques well known to those skilled in the art. Compounds of the formula I can be prepared in which D1 or D2 represents OH by reaction of a corresponding compound of the formula wherein D1 or D2 (as appropriate) represents COORd and Rd is as defined above with hydroxylamine ( or a hydrohalide salt thereof), for example, at 40 ° C in the presence of a suitable base (for example, TEA) and an appropriate organic solvent (for example THF). Compounds of the formula I can be prepared in which D1 or D2 represent OC (0) ORc and Rc is as defined above, by reaction of a corresponding compound of the formula the in which D1 or D2 (as appropriate) represents OH with a compound of formula XXXVI, L3C (0) ORc XXXVI wherein L3 and Rc are as defined above, for example at room temperature in the presence of a suitable base (e.g., TEA, pyridine or DMAP) and an appropriate organic solvent. Compounds of the formula wherein D1 or D2 represents OC (0) Rb and Rb is as defined above, can be prepared by reaction of a corresponding compound of the formula la in which D1 or D2 (as appropriate) represents OH with a compound of formula XXXVIa.

RbC (0) L XXXVIa wherein L4 represents a suitable leaving group such as OH, Hal or RbC (0) 0, and Hal and Rb are as defined above, for example at or below room temperature in the presence of a adequate base (e.g., TEA, pyridine or DMAP) and an appropriate organic solvent (e.g., CH2C12). The compounds of the formula la in which B1 represents a structural fragment of the formula Illd (in which X5, X6, X7 and X8 all represent CH) or Illf, in which, in both cases, D1 represents H and D2 represents OH or 0Ra where Ra is as defined above may alternatively be prepared by reaction of a compound of formula XXXVII, XXXVII wherein Ba represents phenyl-1,4-ene or cyclohexyl-1, 4-ene R 1, R-r Y. n are as defined above with a compound of the formula XXXVIII H2N0Ral XXVIll wherein R represents H or Ra and Ra is as defined above, for example, between 40 and 60 ° C, in the presence of a suitable base (for example, TEA) and an appropriate organic solvent (for example, THF, CH3CN, DMF or DMSO). Alternatively compounds of the formula EMI may be prepared in which D1 or D2 represent OH or 0Ra in an analogous manner by reaction of a corresponding compound of the formula la, wherein D1 or D2 (as appropriate) represents C (0) 0Rd and Rd is as defined above, with a compound of formula XXXVIII, as defined above. Compounds of the formula XXXVII may be prepared according to peptide coupling techniques, for example in a manner analogous to the methods described above for compounds of the formula I. The compounds of the formulas XXXVa, XXXVI, XXXVIa and XXXVIII are commercially available available, are well known in the literature, or are available using techniques.

According to a further aspect of the invention there is provided a compound of the formula la as defined above, except that: Rb and Rc independently represent C? -7 alkyl, phenyl or 2-naphthyl (all of which are optionally substituted by C? -6 alkyl or halo); R represents 2-naphthyl, phenyl, C1-3 alkylphenyl (wherein the last three groups are optionally substituted by C? -6 alkyl, C? -6 alkoxy, nitro or halogen), CH (Rf) (CH ( Rg)) pOC (O) Rh (in which Rf and Rg independently represent H or C? -6 alkyl), Rh represents 2-naphthyl, phenyl, C? -6 alkoxy or C? _8 alkyl (wherein the latter group is optionally substituted by halo, C? -6 alkoxy, or C? _6 acyloxy). and P represents 0 or 1) or C? -i2 alkyl (wherein the latter group is optionally substituted by C? _6 alkoxy, C? -6 acyloxy or halogen), Ra and Re independently represent phenyl, benzyl, ( CH2) 20C (0) CH3 or C? _6 alkyl, wherein the latter group is optionally interrupted by oxygen; or a pharmaceutically acceptable salt thereof. Those skilled in the art will appreciate that, in order to obtain compounds of formula I, or formula it in an alternative form, and, on some occasions, more conveniently, the individual process steps mentioned above can be performed in an order different, and / or individual reactions may be performed at a different stage in the total route (ie, the substituents a and / or chemical transformations performed in, different intermediates for those mentioned above may be added together with a particular reaction). This may negate, or necessarily lead to the need for protective groups. Therefore, the order and type of chemistry involved will dictate the need, and type of protective groups, as well as the sequence to perform the synthesis. The use of protecting groups is fully described in "Protective Groups in Organic Chemistry", edited by JW F McOmie, Plenum Press (1973), and "Protective Groups in Organic Synthesis", 2nd edition, T W Greeene & P G M Wutz, Wiley-Interscience (1991). The protected derivatives of the compounds of the formula I (for example, compounds of the formula la) can be chemically converted to compounds of the formula I using standard deprotection techniques (for example, hydrogenation), for example, as described later in the present. It will also be appreciated by those skilled in the art that, although such protected derivatives of compounds of the formula I (e.g., compounds of the formula la) may not possess pharmacological activity as such, they may be administered parenterally or orally and subsequently metabolized in the body to form compounds of formula I that are pharmacologically active. Such derivatives can therefore be described as "prodrugs". All prodrugs of the compounds of formula I are included within the scope of the invention. The protected derivatives of the compounds of the formula I that are particularly useful as prodrugs include compounds of the formula la. The compounds of the formula I, pharmaceutically acceptable salts, tautomers and stereoisomers thereof, as well as prodrugs thereof (including compounds of the formula which are prodrugs of compounds of the formula I), are hereinafter referred to as "the compounds of the invention".

Medical and Pharmaceutical Use The compounds of the invention are useful since they possess pharmacological activity. Therefore they are indicated as pharmacists. According to a further aspect of the invention, the compounds of the invention are provided in this way for use as pharmaceuticals. In particular, the compounds of the invention are potent inhibitors of thrombin either as such or, in the case of prodrugs, after administration, for example as demonstrated in the tests described below. The compounds of the invention are thus expected to be useful in those conditions where inhibition of thrombin is required. In this way, the compounds of the invention are indicated in the treatment and / or prophylaxis of thrombosis and hypercoagulability in blood and tissues of animals including man. It is known that hypercoagulability can reach thrombo-embolic diseases. Conditions associated with hypercoagulable and thromboembolic diseases, which may be mentioned, include resistance to inherited or acquired activated protein C, such as the mutation of factor V (factor V Leiden), and acquired or inherited deficiencies in antithrombin III. , protein C, protein S, heparin cofactor II. Other conditions known to be associated with hypercoagulability and thromboembolic disease include antibodies; circulating antiphospholipids (anticoagulants of Lupus), homocysteinemia, thrombocytopenia induced by heparin and defects in fibrinolysis. The compounds of the invention are thus indicated both in the therapeutic and / or prophylactic treatment of these conditions. The compounds of the invention are further indicated in the treatment of conditions where there is an undesirable excess of thrombin without signs of hypercoagulability, for example, in neurodegenerative diseases such as Alzheimer's disease. Particular disease states that may be mentioned include the therapeutic and / or prophylactic treatment of venous thrombosis and pulmonary embolism, arterial thrombosis (eg, myocardial infarction, unstable angina, thrombosis-based infarction and peripheral arterial thrombosis) and systemic embolism usually from the atrium during arterial or left ventricular fibrillation after infarction to the transmural myocardium. On the other hand, it is expected that the compounds of the invention have utility in the prophylaxis of reocclusion (ie thrombosis) after thrombolysis, cutaneous transluminant angioplasty (PTA) and coronary bypass operations; the prevention of re-thrombosis after microsurgery and vascular surgery in general. Additional indications include the therapeutic and / or prophylactic treatment of disseminated intravascular coagulation caused by bacteria, multiple trauma, intoxication or any other mechanism; anticoagulant treatment when the blood is in contact with foreign surfaces in the body such as vascular grafts, vascular stents, vascular catheters, prosthetic mechanical and biological valves or any other mechanical device; and anticoagulant treatment when the blood is in contact with medical devices outside the body such as during cardiovascular surgery using a heart-lung machine or in hemodialysis. In addition to its effects on the coagulation process, it is known that thrombin activates a large number of cells (such as neutrophils, fibroblasts, endothelial cells and smooth muscle cells). Therefore, the compounds of the invention can also be useful for the therapeutic and / or prophylactic treatment of syndromes of adult and idiopathic respiratory failure, pulmonary fibrosis following treatment with radiation or chemotherapy, septic shock, septicemia, inflammatory responses, which include, but are not limited to, edema, acute or chronic atherosclerosis such as coronary artery disease, cerebral arterial disease, peripheral arterial disease, reperfusion injury and restenosis after percutaneous transluminal angioplasty (PTA). The compounds of the invention that inhibit trypsin and / or thrombin may also be useful in the treatment of pancreatitis. According to a further aspect of the present invention, there is provided a method for treating a condition wherein inhibition of thrombin is required, the method comprises administering a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt of it, to a person who suffers from, or is susceptible to, such a condition.

The compounds of the invention will normally be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally and bronchially, by any other parenteral routes or via inhalation, in the form of pharmaceutical preparations comprising the active compound either as a free base or a non-toxic pharmaceutically acceptable organic or inorganic acid addition salt in a pharmaceutically acceptable dosage form. Depending on the disorder and patient to be treated and the route of administration, the compositions may be administered in various doses. The compounds of the invention can also be combined and / or co-administered with any antithrombotic agent with a different mechanism of action, such as antiplatelet agents, acetylsalicylic acid, ticlopidine, clopidogrel, thromboxane receptor and / or synthetase inhibitors, antagonists of fibrinogen receptor, prostacyclin mimetic inhibitors and phosphodiesterase and ADP receptor antagonists (P2T). The compounds of the invention can also be combined and / or co-administered with thrombolytic agents such as the tissue plasminogen activator (natural, recombinant or modified), streptokinase, urokinase, prourokinase, anisolated streptokinase plasminogen activator complex (APSAC). , plasminogen activators of animal salivary gland, and the like, in the treatment of thrombotic diseases, in particular of myocardial infarction. According to a further aspect of the invention there is thus provided a pharmaceutical formulation which includes a compound of the invention, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. Suitable daily doses of the compounds of the invention in the therapeutic treatment of humans are about 0.001-100 mg / kg of body weight in peroral administration and 0.001-50 mg / kg of body weight in parenteral administration. The compounds of the invention have the advantage that they are more effective, less toxic, longer acting life, have a broader range of activity, are more potent, produce fewer side effects, are more easily absorbed than, or may have other properties pharmacological useful on, compounds known in the prior art.

Biological tests Test A Determination of Thrombin Coagulation Time (TT) The inhibitor solution (25 μl) is incubated with plasma (25 μl) 'ppr three minutes. Human thrombin (T 6769; Sigma Chem Co) is then added in buffer solution, pH 7.4 (25 μl) and the coagulation time is measured in an automatic device (KC 10; Amelung). The coagulation time in seconds is plotted against the inhibitor concentration, and the IC50TT is determined by interpolation. The IC50TT is the concentration of the inhibitor in the test that doubles the coagulation time of thrombin for human plasma.

Test B Determination of thrombin inhibition with a chromogenic assay Rev. robófico The potency of the thrombin inhibitor is measured with a chromogenic substrate method in a robotic Plato 3300 microplate processor (Rosys AG, CH-8634 Hombrechti kon, Switzerland) using 96-well half-volume microtiter plates (Costar, Cambridge , MA, USA; Cat No. 3690). DMSO test substance stock solutions are diluted (72 μl), 1 mmol / l, serial 1: 3 (24 + 48 μl) with DMSO to obtain ten different concentrations, which are analyzed as samples in the assay. 2 μl of the test sample is diluted with 124 μl of the assay buffer, 12 μl of chromogenic substrate solution (S-2366, Chromogenix, Molndal, S eden) in assay buffer and finally 12 μl of a-thrombin solution , (Human -thrombin, Sigma Chemical Co.) both in assay buffer, samples are added, and mixed. The final test concentrations are: test substance 0.00068 - 13.3 μmol / 1, S-2366 0.30 mmol / l, a-thrombin 0.-020 NIHU / ml. The linear absorbance increase during incubation of 40 minutes at 37 ° C is used to calculate the percent inhibition for the test samples, compared to blank without inhibitor. The robotic value of IC50. which corresponds to the concentration of inhibitor that causes 50% inhibition of thrombin activity, is calculated from the logarithm curve dose against% inhibition.

Test C Determination of the constant K, of inhibition for human thrombin The determinations of Kj are made. using a chromogenic substrate method performed at 37 ° C on a Bio Cobas centrifuge analyzer (Roche, Basel, Switzerland). Residual enzyme activity is determined after incubation of human a-thrombin with various concentrations of the test compound at three different substrate concentrations and is measured as the change in optical absorbance at 405 n. The solutions of test compounds (100 μl, normally in saline or buffer containing 10 g / 1 BSA) are mixed with 200 μl of human a-thrombin (Sigma Chemical Co) in assay buffer (0.05 mol / 1 Tris). -HCl, pH 7.4, 0.15 ionic strength adjusted with NaCl) containing BSA (10 g / 1), and analyzed as samples in Cobas Bio. A 60 μl sample, together with 20 μl of water, is added to 320 μl of the substrate S-2238 (Chro ogenix AB, Mólndal, S eden) in assay buffer, and the absorbance change is monitored (ΔA / minutes) . The final concentrations of S-2238 are 16, 24 and 50 μmol / 1 and of thrombin 0.125 NIH U / ml.

The steady-state reaction ratio is used to construct the Dixon plots, ie, inhibitor concentration diagrams against 1 / (? A / minutes). For reversible, competitive inhibitors, data points for different substrate concentrations usually form straight lines which intersect at x = -Ki.

Test D Determination of Inactive Partial Activated Tromboplast Time (APTT) The APP is determined in normal human coded plasma grouped with the automated PTT reagent 5 manufactured by Stago. Inhibitors are added to the plasma (10 μl of inhibitor solution to 90 μl of plasma) and incubated with the APTT reagent for 3 minutes followed by the addition of 100 μl of calcium chloride solution (0.025 M) and determined APTT in the mixture by use of the KC10 coagulation analyzer (Amelung) according to the instructions of the reagent producer. The coagulation time in seconds is plotted against the concentration of inhibitor in plasma and the IC50APTT is determined by interpolation.

IC50APTT is defined as the concentration of inhibitor in human plasma that doubles the Activated Partial Thromboplastin time.

Test E Determination of thromboma ex vi Vo The inhibition of thrombin is examined after oral or parenteral administration of the compounds of the formula I and the one, dissolved in ethanol: Solutol ™: water (5: 5: 90), in rats aware of which one or a few days before the experiment are equipped with a catheter for a blood sample of the carotid artery. On the experimental day, blood samples are taken at five different times after administration of the compound in plastic tubes containing 1 part sodium citrate solution (0.13 mole per 1) and 9 parts blood. The tubes are centrifuged to obtain platelet-deficient plasma. The plasma is used for determination of thrombin time as described below. The coded rat plasma, 100 μl, is diluted with a saline solution, 0.9%, 100 μl, and plasma coagulation is initiated by the addition of human thrombin (T 6769, Sigma Chem Co, USA) in a buffer solution. , pH 7.4, 100 μl. The coagulation time is measured in an automatic device (KC 10, Amelumg, Germany). When a compound of the formula is administered, the concentrations of the appropriate additive thrombin inhibitor of formula I in rat plasma are estimated by the use of standard curves relating the thrombin time in the coded rat plasma grouped to known concentrations of the corresponding "active" thrombin inhibitor, dissolved in saline. Based on the estimated plasma concentrations of the active thrombin inhibitor of the formula I (which assumes that the prolongation of the thrombin time is caused by the compound mentioned above) in the rat, the area under the curve after oral administration and / or parenteral of the corresponding prodrug of the formula is calculated (AUCpd) using the trapezoidal rule and extrapolation of data to infinity. The bioavailability of the active thrombin inhibitor of formula I is calculated after oral or parenteral activation of the prodrug of formula I.a as follows: [(AUCpd / dose) / (AUCactive, parenteral / dose] x 100 wherein AUCactive, parenterally represents the AUC obtained after parenteral administration of the corresponding active thrombin inhibitor of formula I to conscious rats as described in the foregoing.

Test F Determination of thrombin time in ex vivo urine The amount of the active thrombin inhibitor of formula I which is excreted in the urine after oral or parenteral administration of the compounds of the invention, dissolved in ethanol is estimated: Solutol ™ : water (5: 5: 90) by determining the type of thrombin in ex vivo urine (assuming that the prolongation of thrombin time is caused by the compound mentioned above). The conscious rats are placed in metabolism cages, allowing separate collection of urine and feces for 24 hours after oral administration of compounds of the invention. The thrombin time in the collected urine is determined as described below. The pooled normal cipher human plasma (100 μl) is incubated with the concentrated rat urine, or saline dilutions thereof, for one minute. The coagulation of the plasma is then initiated by the administration of human thrombin (T 6769, Sigma Chem Company) in buffer solution (pH 7.4, 100 μl). The coagulation time is measured in an automatic device (KC 10; Ame? Uñg) • The concentrations of the active thrombin inhibitors of formula I in the rat urine are estimated by the use of standard curves that relate the thrombin time. in normal encrypted human plasma grouped at known concentrations of the aforementioned active thrombin inhibitor dissolved in concentrated rat urine (or saline dilutions thereof). By multiplying the production of total rat urine during the 24-hour period by the estimated average concentration of active inhibitor mentioned above in the urine, the amount of the active inhibitor excreted in the urine (AMOUNTpd) can be calculated. The bioavailability of the active thrombin inhibitor of the formula I is calculated as follows after oral or parenteral administration of the prodrug: [(AMOUNTpd / dose) / (AMOUNTactive, parenteral / dose] X 100 where AMOUNTactive, parenteral represents the amount excreted in the urine after parenteral administration of the corresponding active thrombin inhibitor of formula I to conscious rats as described in The invention is illustrated by the form of the following examples: The amino acids Pro and Aze are defined as the S-isomers unless otherwise specified The examples are obtained as diastereoisomers unless otherwise specified.

And emplos General Experimental Procedures Mass spectra are recorded on a Finnigan MAT TSQ 700 triple quadrupole mass spectrometer equipped with an electro-dew interface (FAB-MS) and the mass spectrometer of VG Platform II equipped with an electro-dew interface (LC-MS). H NMR and H NMR measurements are performed on BRUKER ACP 300 and Varian UNITY plus 400, 500 and 600 spectrometers operating at -i frequencies of 300.13, 399.96, 499.82, and 599.94 MHz respectively, and at frequencies of 13C 75.46, 100.58, 125.69 and 150.88 MHz respectively. Flash chromatography on silica gel (230-400 mesh) is performed. Preparative RPLC is performed on reverse phase columns (250 mm, 20 or 50 mm, 5 to 7 μM of Chromasil C8 phase) with flow rates of 10 to 50 ml / minute using a UV detector (270 to 280 nm). Example 1 (S) - or (R) -l-Hydroxy-7-methoxytetralin-1-yl-C (O) -Pro-Pab (i) Methyl ester of l-hydroxy-7-methoxytetralin-1-yl-carboxylic acid The sub-title compound is prepared according to the method described by C.F. Bigge et al. (J.

Med. Chem (1993) 36, 1977) using 7-methoxytetralone (1.0 g, 5.67 mmoles) and methanol instead of ethanol. Yield: 1.22 g (90%). NMR-aH (300 MHz; CDC13) d 7.05 (d, 1H), 6.80 (d, 1H), 6.65 (s, 1H), 3.80 (s, 3H), 3.75 (s, 3H), 2. 85-2.65 (, 2H), 2.25-2.90 (m, 4H) (ii) L-hydroxy-7-methoxy tetralin-1-yl-carboxylic acid Methyl ester of l-hydroxy-7-methoxytetralin-1-yl-carboxylic acid (1.16 g, 4.9 mmol, from step (i) above) is dissolved in THF (10 ml) and lithium hydroxide (0.41 g, 9.8 mmoles). ) to the resulting solution, followed by water (4 ml). The reaction mixture is stirred at room temperature for 3 hours, the TH is evaporated and the aqueous phase is washed with methylene chloride. The reaction mixture is acidified with HCl (2M) and then saturated with NaCl (s). After extraction with CH2C12, the organic phase is dried and concentrated. Yield: 765 mg (70%). LC-MS (m / z) 221 (M-1) ~ NMR-1- (400 MHz, CDC13) 6 7.07 (d, 1H), 6.82 (dd, 1H), 6.77 (d, 1H), 3.76 (s) , 3H), 2.83-2.71 (m, 2H), 2.32-2.21 (m, 1H), 2.12-1.88 (m, 3H) (iii) (R) - and (S) -l-Hydroxy-7-methoxytetralin-1-yl-C (0) -Pro-Pab (Z) A solution of l-hydroxy-7-methoxytetralin-1 acid is prepared -carboxylic acid (222 mg, 1.0 mmol, from step (ii) above), H-Pro-Pab (Z) (499 mg, 1.1 mmol, according to the method described in International Patent Application WO 97 / 02284) and TBTU (353 mg, 1.1 mmol) in DMF (10 ml) is cooled to 0 ° C, and DIPEA (517 mg, 4.0 microwells) is added. The reaction mixture is stirred at room temperature for 4 days and then the same amounts of H-Pro-Pab (Z), TBTU and DIPEA are added at 0 ° C. After 3 days the reaction mixture is concentrated and dissolved in water: EtOAc (1: 1). The aqueous phase is extracted with EtOAc and the combined organic phase is dried (Na2SO) and concentrated. The product is purified using flash chromatography (EtOAc: EtOH, 100: 0 to 95: 5). Further purification using preparative RPLC (CH3CN: 0.1M ammonium cetate, 40:60) separates the r 'diastereoisomers: Compound IA (moves faster than the diastereomer, 10 mg, 1.7%) and Compound IB (moves more slower than the diastereoisomer, 10 mg, 1.7%). Yield: 20 mg (3.4%).

Composite ÍA: RMN-1 !! (400 MHz, CDC13): d 7.82 (d, 2H), 7.44 (d, 2H), 7.38-7.29 (m, 4H), 7.05 (d, 2H), 6.80 (dd, 1H), 6.54 (d, 1H), 5.21 (s, 2H), 4.68-4.63 (dd, 1H), 4. 45 (, 2H), 3.71 (s, 3H), 3.12 (m, 1H), 2.83 (m, 1H), 2.68-2.53 (m, 2H), 2.22-2.13 (m, 2H), 2.05-1.84 (, 7H), 1.59-1.50 (m, 1H) Compound IB: RMN-1 !! (400 MHz, CDC13): d 7.82 (d, 2H), 7.43 (d, 2H), 7.37-7.28 (m, 4H), 7.02 (d, 2H), 6.77 (dd, 1H), 6.57 (d, 1H), 5.20 (s, 2H), 4.58-4.51 (m, 2H), 4.42 (m, 1H), 3.62 (s, 3H), 3.12-3.04 (m, 1H), 2.83 (broad d, 1H), 2.68-2.58 (m, 1H), 2.55-2.47 (m, 1H), 2.13-1.79 (, 7H), 1.76-1-65) (m, 1H) (iv) (S) - or (R) -l-Hydroxy-7-methoxytetralin-1-yl-C (O) -Pro-Pab Pd / C (5%, 10 mg) is added to a solution of (R) - or (S) -l-hydroxy-7-methoxytetralin-1-yl-C (O) -Pro-Pab (Z9 (10 mg, 0.017 mmol; Composite IA of the stage (iii) above) in EtOH. (5 ml) and HOAc (1 μl, 0.017 mmol) and is hydrogenated for 3 hours at room temperature and atmospheric pressure. The resulting mixture is filtered through Celite, the solution is concentrated, water is added and the solution is lyophilized, yielding 10 mg (98%, 92.2% purity) of the title compound as a white powder. LC-MS (m / z) 451 (M + 1) + RMN-1 !! (400 MHz, CD3OD): d 7.75 (d, 2H), 7.57 (d, 2H), 7.08 (d, 1H), 6.83 (dd, 1H), 6.60 (d, 1H), 4.63-4.40 (m, 3H), 3.69 (s, 3H), 3.43-3.35 (m, 1H) ), 2.88-2.67 (m, 3H), 2.23-2.11 (m, 2H), 2.20-1.77 (m, 8H), 1.63-151 (m, 1H) Example 2 (R) - o. { S) -lh.hydroxy-7-ethoxytetralin-1-yl-C (0) -Pro-Pab The title compound is prepared according to the method described in Example 1 (iv) above of (R) - or (S) ) -l-hydroxy-7-methoxytetralin-1-yl-C (O) -Pro-Pab (Z) (10 mg, 0.017 mmol, Compound IB of Example I (iii) above). Yield: 10 mg (98%, purity 80.4%). LC-MS (m / z) 451 (M + 1) + NMR-aH (400 MHz, CD3OD): d 7.78 (d, 2H), 7.63. (d, 2H), 7.04 (d, lH), d.78 (dd, 1H), 6.75 (d, 1H), 4.67-4.48 (m, 3H), 3.68 (s, 3H), 3.30-3.23 (m , 1H), 2.86-2.61 (m, 3H), 2.23-1.17 (m, 11H) Example 3 (S) -o JR) -l-Hydroxy-7-methoxytetralin-l7l-C (O) -Aze-Pab xHOAc (i) (S) - (R) - l-Hydroxy-7-methoxytetral? - l-il-C (O) - Az e - Pab (Z) TBTU (0.584 g, 1.7 mmol) is added, followed by DIPEA (0.200 g, 1.55 mmol) to an ice-cooled solution of l-hydroxy acid 7-methoxytetralin-1-yl-carboxylic acid (0.345 g, 1.55 mmol, see Example 1 (ii) above) in DMF (10 ml). After stirring at 0 ° C for 15 minutes, H-Aze-Pab (Z) x 2HC1 (0.750 g, 1.7 mmol, prepared according to the method described in International Patent Application WO 97/02284) and DIPEA ( 0.603 g, 4.65 mmol) and the mixture is stirred at room temperature for 4 days. The DMF is evaporated, and the resulting material is partitioned in water and EtOAc. The organic layer is separated, the water phase is extracted 3 times with EtOAc, and the combined organic layer is dried (Na2SO) and concentrated. The product, a white powder, is further purified using preparative RPLC (CH3CN: 0.1M ammonium acetate; 46:54) yielding 122 mg (28%) of a faster moving fraction (Compound 3A) and 63 mg (14%). %) of a fraction that moves slower (Compound 3B).

Compound 3A: LCMS (m / z) 571 (M + 1) + H NMR (400 MHz, CDC13): - (complex due to rotamers) d 8.22 (t, 0.5H, rotary); 7.94 (t, 0. 5H; rotamer); 7.83 (t, 1H); 7.45-7.3 (m, 9H); 7.4 (t, 1H); 6.80 (m, 1H); 4.93 (m, 1H); 4.55 (M, 5H); 3. 76 (s, 3H); 3.0 (, 2H); 2.8 (m, 2H); 2.6 (M, 2H); 2.5 (m, 1H); 2.38 (m, 1H); 2.25 (, 1H); 2.0-1.8 (m, 9H) (ii) (S) - (R) -l-Hydroxy-7-methoxytetrain-l-yl-C (O) Aze-Pab x HOAc Prepared according to the method described in Example 1 (iv) of (S) - or (R) -l-hydroxy-7-methoxy-in-1-yl-C (09-Aze-Pa (Z ) (0.058 g, 0.1 mmol, Compound 3A from stage (i) above), HOAc (5.8 μl, 0.1 mmol), and Pd / C (5%, 50 mg) in EtOH (5 ml) Yield 15 mg ( 59%). LC-MS (m / z) 437 (M + 1) + NMR-aH (400 MHz;; D20): 7.65 (d, 2H); 7.47 (d, 2H); 7.16 (d, 1H); ), 6.90 (d, 1H '), 6.71 (d, 1H), 4.91 (dd, 1H), 4.40 (m, 1H), 4.15 (m, 1H), 3.94 (m, 1H), 3.60 (s, 3H) ), 2.75 (m, 3H), 2.53 (m, 1H), 2.1 (m, 2H), 2.0-1.75 (m, 7H) 13 C-NMR (100 MHz, CDC13) d 182.5, 178.3, 174.0 Example 4 (R) - or (S) -1-Hydroxy-7-methoxytetralin-1-yl-C (O) -Aze-Pab (i) 4- (Amino, methoiminomethyl) benzylamine (H-Pab (Ome)) Platinum oxide (200 mg) is added to a solution of 4- (amino, methoxy-inomethyl) -benzylazide (10 g, 0.049 mmol, prepared from according to the method described in WO 94/29336) in 200 ml of ethanol. The mixture is hydrogenated at atmospheric pressure for 8 hours, filtered through Hyflo and concentrated. The product is used without purification directly in the next step.

RMN-1 !! (400 MHz, CD3OD): d 7.60 (d, 2H); 7.37 (d, 2H); 3.81 (s, 3H); 3.80 (s, 3H). (ii) Boc-Aze-Pab (OMe) DIPEA (17.5 ml, 105 mmol) is added to a hydrochloride solution of Boc-Aze-OH (9.7 g, 48 mmol) and H-Pab (OME) ( 9.4 g, 52 mmole, from step (i) above) and TBTU (18.5 g, 58 mmole) in DMF (100 ml), and the mixture is stirred overnight at room temperature. The resulting mixture is poured into water (50 ml), the pH adjusted to 9, and the mixture extracted three times with EtOAc. The combined organic layer is washed with NaHCO3 / aq, water and brine, dried (Na2S04), and concentrate. Purify the product without purification using flash chromatography (Si-gel, EtOAc). Yield: 11.9 g (69%). NMR ^ H (400 MHz, CDC13): d 7.60 (d, 2H); 7.31 (d, 2H); 4.78 (b, 2H); 4.69 (, 1H); 4.50 (b, 2H); 3.92 (s + m, 4H); 3.79 (m, 1H); 2.46 (b, 2H); 1.42 (s, 9H) (iii) H-Aze-Pab (OMe) x 2HC1 A solution of Boc-Aze-Pab (OMe) (9.4 g, 26 mols, from step (ii) above) is saturated in EtOAc (250 ml) with HCl (g) EtOH (absolute; 125 ml) to the resulting emulsion and the mixture is sonified for 10 minutes. EtOAc is added until the solution becomes cloudy, after which the subtitled product is crystallized soon. Yield: 6.7 g (77%). LC-MS (m / z) 263; (M + 1) + RMN-1 !! (400 MHz, CD30D)? d 7.74 (d, 2H); 7.58 (d, 2H); 5.13 (t, 1H); 4.57 (m, 2H); 4.15 (m, 2H); 3.97 (s + m, 4H); 2.87 (m, 1H); 2.57 (m, 1H) 13 C-NMR (75 MHz, CDC13): (carbonyl and / or amidine carbons) d 168.9; 168.8; 161.9 (iv) 1-Hydroxy-7-methoxytetralin-1-yl-C (O) -Aze-Pab (OMe) H-Aze-Pab (OMe) (0.587 g, 1.85 mmol, from step (iii) above) are added. ), TBTU (0.594 g, 1.85 mmoles) and DIPEA (0.87 g, 6.73 mmoles), in such order to an ice-cooled solution of 1-hydroxy-7-methoxytetralin-1-yl-carboxylic acid (0.374 g; mmoles, see Example l (ii) above) in CH3CN. The resulting mixture is stirred at room temperature for 6 days. The solution is concentrated and the unpurified material is purified using preparative HPLC (CH3CN: 0.1M ammonium acetate: 25:75), which produces separated diastereoisomers, yielding 122 mg (31.2%) of a diastereomer that moves faster ( Compound 4A) and 120 mg (30.7%) of a diastereomer that moves slower (Compound 4B).

Compound 4B: LCMS (m / z) 466 (M + 1) + 1H-NMR (500 MHz ,: CDC13): d 8.08 (t, 1H); 7.63 (d, 2H); 7.35 (d, 2H); 7.02 (d ', 1H); 6.80 (dd, 1H); 6.57 (d, 1H); 4.90 (dd, 1H); 4.79 (b, 2H); 4.53 (m, 2H); 3.91 (s, 3H); 3.65 (s + m, 4H); 2.97 (q, 1H); 2.81 (broad d, 1H); 2.59 (m, 1H); 2.49 (m, 1H); 2.38 (m, 1H); 2.03-1.85 (m, 4H) (v; (R) or (S) -l-Hydroxy-7-methoxytetralin-1-yl-C (0) -Aze-Pab The title compound is prepared according to the method described in Example 1 (iv) above from l-hirdoxy-7-methoxytetralin-1-yl-C (O) -Aze-Pab (OMe) (20 mg, 0.043 mmol, Compound 4B from step (iv) above), AcOH (3 mg, 0.05) mmoles) and Pd / C (10%, 20 mg) in EtOH (5 ml) Yield 19 mg (89%) LC-MS (m / z) 436 (M + 1) + NMR-aH (400 MHz; D20): d 7.79 (d, 2H), 7.55 (M, 2H), 7.20 (d, 1H), 6.95 (m, 1H), 6.79 (d, 1H), 4.92 (dd, 1H), 4.58 (m, 2H); 4.18 (m, 2H); 3.77 (s, 3H); 3. 63 (m, 2H); 2.8 (m, 3H); 2.6 (m, 2H); 2.1 (m, 4H); 1.9 (, 2H) 13 C-NMR (75 MHz, CDC13): (carbonyl and / or amidine carbons) d 177.9; 173.8; 167.6 Example 5 '; l-Hydroxy-5-methoxytetralin-l-yl-C (0) -Aze-Pab x HOAc (i) L-Hydroxy-5-methoxytetralin-1-ylcarboxylic acid methylester The subtitle compound is prepared according to a method described by Bigge et al (J. Med.

Chem. (1993) 36, 1977) from 5-methoxytetralone (1.0 g, 5.67 mmoles), Me3SiCN (0.619 g, 6.24 mmoles) and Znl; (8 mg; cat.). Yield 1.11 g (83%). RMN-1 !! (500 MHz; CDC13): d 7.16 (m, 1H); 6.91 (d, 1H); 6.76 (t, 1H, 6.45 (broad, 1H), 5.97 (broad, 1H), 3.815 (s, 2H), 3.81 (s, 3H), 2.88 (m, 1H), 2.56 (, 2H), 2.14 (m , 2H); 1.95 (, 2H) (ii) l-Hydroxy-5-methoxytetralin-1-ylcarboxylic acid It is prepared according to the method described in Example 1 (ii) above from the methyl ester of 1-hydroxy-5-methoxy tetralin-1-yl- carboxylic (1.11 g, 4.7 mmoles, from stage (i) above) and LiOH.H20 (0.395 g, 9.4 mmoles). Yield 460 mg (36%). X-NMR (400 MHz, CDC13): d 7.18 (m, 1H); 6.86 (d, 1H); 6.79 (d, 1H); 3.82 (s, 3H); 2.86 (dt, 1H); 2.58 (m, 1H); 2.20 (M, 1H); 2.10-1.85 (m, 4H) (iii) l-Hydroxy-5-methoxytetralin-l-yl-C (O) -Aze-Pab (Z) TBTU (0.528 g, 1.64 mmol) is added to an ice-cooled solution of l-hydroxy-5- methoxytetralin-1-yl-carboxylic acid (0.332 g, 1.49 mmol, from step (ii) above) in CH3CN (15 ml).

The mixture is stirred at 0 ° C for 2 hours, and added H-Aze-Pab (Z) x 2HC1 (0.656 g, 1.49 mmole) and DIPEA (0.599 g, 3.1 mmoles). The resulting mixture is stirred at room temperature overnight, and the solution is concentrated. Purify the product without purification using preparative RPLC (CH3CN: ammonium acetate 0. 1M; 40:60). Yield 140 mg (16%). LC-MS (m / z) 571 (M + 1) + RMN-1 !! (400 MHz; CDC13): d 7.82 (dd, 2H); 7.43 (d, 2H); 7.33 (t, 2H); 7.27 (m, 3H); 6.73 (m, 2H); . 20 (s, 2H); 4.89 (m, 1H); 4.60-4.40 (m, 2H); 3.80 (s, 3H); 3.62 (m, 1H); 2.94 (M, 2H); 2.34 (m, 2H); 1. 95-1.8 (m, 4H) 13 C-NMR (100 MHz, CDC13): (carbonyl and / or amidine carbons) d 184.2; 179.0; 178.6; 172.3; 171.6; 168.9 (iv) l-Hydroxy-5-methoxytetralin-l-yl-C (O) -Aze-Pab x HOAc 'is prepared according to the method described in Example 1 (iv) from l-hydroxy-5-methoxytetralin-1-yl-C (O) -Aze-Pab (Z) (47 mg, 0.082 mmol, from step (iii) above), AcOH (5 mg, 0.082 mmol) and Pd / C (5%, 20 mg) in EtOH (5 ml). Yield 37 mg (100%) LC-MS (m / z) 437 (M + 1) + NMR-1! (400 MHz, D20): d 7.76 (dd, 2H); 7.54 (dd, 2H); 7.27 (, 1H); 7.01 (t, 1H); 6.90 (dd, 1H); 4. 91 (dd, 1H); 4.5 (m, 1H); 4.20 (m, 1H); 3.87 (s, 3H); 3.63 (m, 1H); 2.90 (m, 1H); 2.7-2.4 (m, 2H); 2.24 (m, 1H) 13 C-NMR (100 MHz, CDC13): (carbonyl and / or amidine carbons) d 181.5; 177.5; 177.2; 173.1; 173.0; 166.7 Example 6 l-Hydroxy-5,7-dimethyltetralin-1-yl-C (O) -Aze-Pab x HOAc (i) Methyl ester of l-hydroxy-5,7,7-dimethyltetralin-1-yl-carboxylic acid, prepare the subtitle compound according to the method described by Bigge et al. (J. Med. Chem. (1993, 36, 1977) from 5,7-dimethyltetralone (1.0 g, 5.74 mmoles) / ü.e3SiCN (0.626 g, 6.31 mg), and Znl2 (8 mg, cat.). Yield 1. _-4 g (92%). RM ^ H (400 MHz, CDC13): d 6.94 (s, 1H), 6.81 (s, 1H), 3.77 (s, 3H), 2.82 (t, 1H); 2.73 (m, 1H); 2.60 (m, 3H); 2.25 (s, 3H), 2.21 (s, 3H); 2.00 (m, 3H); (ii) l-Hydroxy-5,7-dimethyl-tetralin-1-yl-carboxylic acid is prepared according to the method described in Example 1 (ii) from the methyl ester of 1-hydroxy-5,7-dimethyltetralin-1-yl-carboxylic acid (1.24 g; . 27 mmoles; from stage (i) above) and LiOH.H20 (0.443 mg, 10.6 mmol). Yield 0.629 g (50%). LC-MS (m / z) 437 (M + 1) + H-NMR (400 MHz, CDC13): d 6.97 (s, 1H); 6.92 (s, 1H); 2.72 (m, 1H); 2.60 (m, 1H); 2.27 (s, 3H); 2.22 (s, 3H); 2.06 (m, 2H); 1.95 (m, 2H) (iii) l-Hydroxy-5,7-dimethyltetralin-1-yl-C (O) -Aze-Pab (OMe) Prepared according to the method described in Example 4 (iv) above from 1-hydroxy acid 5, 7-dimethyltetralin-1-yl-carboxylic acid (0.20 g, 0.91 mmol, from step (ii) above); H-Aze-Pab (OMe) x 1.5 HCl (0.317 g, 1.0 mmol, see Example 4 (iii) above) / TBTU (0.321 g, 1.0 mmol) and DIPEA (0.469 g, 3.63 mmol). The solution is concentrated and the residue is purified using preparative RPLC (CH3CN: 0.1M ammonium acetate, 30:70). The fractions of interest are concentrated and then extracted (x3) with EtOAc. Dry the combined organic layer (Na2SO4) and concentrate. The dried product is dissolved in a small amount of water / CH 3 CN and lyophilized. Yield 40 mg (9.5%). LC-MS (m / z) 463 (M + 1) + NMR-1! (400 MHz, CDC13): (complex due to diastereoisomers / rotamers) d 8.19 (broad t, 0.5H, rotamer); 7.91 (broad t, 0.5H, rotamer); 7.61 (dd, 2H); 7.35 (d, 1H), 7.28 (d, 1H); 6.93 (s, 0.5H; rotamer); 6.91 (s, 0.5H, rotamer); 6.80 (s, 0.5H, rotamer), 6.70 (s, 0.5H, rotamer); 4.91 (m, 2H); 4.79 (b, 2H); 4.50 (m, 3H); 3.91 (d, 3H); 3.74 (m, 0.5H, rotamer); 3.61 (m, 0.5H, rotamer); 2.78 (broad d, 1H); 2.57 (m, 1H); 2.38 (, 2H); 2.26 (m, 2H); 2.19 (d, 6H); 1.95 (m, 3H) 13 C-NMR (100 MHz; CDC13) (carbonyl and / or amidine carbons) d 179.2; 178.9; 171.6; 171.4 (iv) 1-Hydroxy-5,7-dimethyltetralin-1-yl-C (O) -Aze-Pab x HOAc It is prepared from the method described in Example 1 (iv) from l-hydroxy-5, 7-dimethyltetralin-1-yl-C (O) -Aze-Pab (OMe) (20 mg, 0.043 mmol, from step (iii) above) , HOAc (2.6 mg, 0.043 mmol) and Pd / C (10%, 10 mg). Yield 20 mg (94%). LC-MS (m / z) 435 (M + 1) + 2 H-NMR (400 MHz; D 20): d 7.79 (dd, 1H); 7.70 (d, 1H); 7.53 (m, 2H); 7.07 (d, -1H); 6.92 (s, 1H); 4.91 (m, 1H); 4.17 (m, 1H); 3.76 (m, 0.5H, rotamer); 3. 60 (m, 0.5H, rotamer); 2.80 (d, 1H); 2.55 (m, 2H); 2. 23 (s, 3H); 2.07 (m, 2H); 1.95 (s, 6H) 13 C-NMR (100 MHz; D20): (carbonyl and / or amidine carbons) d 177.9; 173.3 Example 7 l-Hydroxy-7-aminotetralin-l-yl-C (O) -Aze-Pab x HOAc (i) 1-Hydroxy-7-nitrotetralin-1-yl-carboxylic acid methyl ester The subtitle compound is prepared according to the method described by Bigge et al (J. Med. Chem. (1993, 36, 1977) from of 7-nitrotetralone (2.0 g, 10.5 mmol), Me3SiCN (1.14 g, 11.5 mg) and Znl2 (8 mg, cat.) Yield 2.87 g (100%) (in 3 stages). RMN-1 !! (400 MIÍz; / CDC13): d 8.16 (dd, 1H), 8.04 (m, 1H), 7.36 (dd, 1H), 3.73 (s, 3H), 2.92 (m, 2H), 2.30 (m, 1H), 2.00 (m, 3H) (ii) l-Hydroxy-7-nitrotetralin-1-yl-carboxylic acid The subtitle compound is prepared according to the method described in Example 1 (ii) above from the methyl ester of 1-hydroxy-7-nitrotetralinic acid. 1-yl-carboxylic acid (2.0 g, 8.3 mmole, from step (i) above) and LiOH.H20 (0.7 g, 16.6 mmole). Yield 1.72 g (88%). LCMS (m / z) 236 (M + 1) + NMR-: H (400 MHz, CDC13): d 8.10 (dd, 1H); 8.05 (m, 1H); 7.30 (d, 1H); 2.92 (m, 2H); 2.30 (, 1H); 2.15-1.85 (m, 3H) (iii) 1-Hydroxy-7-nitrotetralin-1-yl-C (O) -Aze-Pab (Z) HATU (0.352 g, 0.93 mmol) and DIPEA are added (0.200 g, 1.55 mmol) to an ice-cooled solution of l-hydroxy-7-nitrotetralin-1-yl-carboxylic acid (0.200 g, 0.84 mmol, from step (ii) above) in DMF (5 ml. ). After stirring at 0 ° C for 15 minutes, add a solution of H-Aze-Pab (Z) x 2HC1 (0.408 g, 0.93 mmol) and 2,4,6-trimethylpyridine (0.409 g, 3.37 mmol) in 5 ml. of DMF at 0 ° C, and the mixture is stirred at room temperature overnight. The DMF is evaporated, and the product is purified without purification using preparative RPLC (CH3CN: 0.1 M ammonium acetate: 40:60). The product is further purified using HPLC (CH3CN: 0.1M ammonium acetate: 46:54), yield 214 mg (44%) of the subtitle compound. LCMS (m / z) 586 (M + 1) t NMR-'H (400 MHz, CDC13): d 8; 1 (m, 2H); 7.77 (d, 1H); 7.71 (d, 1H); 7.40 (d, 2H); 7.32 (t, 2H); 7.27 (m, 2H); 7.18 (d, 1H); 4.88 (m, 1H); 4.54 (m, 0.5H, rotamer); 4.45 (dd, 0.5H, rotamer); 4.34 (m, 1H); 3.94 (m, 0.5H, rotamer); 3.82 (m, 0.5H; rotamer); 3.17 (m, 1H); 2.90 (t, 1H); 2.73 (m, 1H); 2.45-2.20 (m, 2H); 2.05-1.85 (m, 5H) (iv) l-Hydroxy-7-aminotetralin-l-il-C (O) -Aze-Pab x HOAc The title compound is prepared according to the method described in Example 1 (iv) above from l-hydroxy-7-nitrotetralin-1-yl-C (O) -Aze-Pab (Z) (0.064 g; 0.11 mmole, from step (iii) above), HOAc (6.3 μl, 0.11 mmole), and Pd / C (32 mg). The product is dissolved without purifying solid in water, and the solution in water is lyophilized to yield 40 mg (76%).; LCMS (m / z) 422 (M + 1) + NMR-aH (400 MHz; D20): d 7.75 (m, 2H); 7.53 (dd, 2H); 7.07 (d, 1H); 6.82 (broad t, 1H); 6.67 (b, 1H); 4.93 (m, 1H); 4.6-4.4 (m, 2H); 4.29 (, 0.5H, rotamer); 4.18 (m, 1H); 3.7 (m, 1H); 2.8-2.5 (, 3H) 13 C-NMR (100 MHz, CDC13) (carbonyl and / or amidine carbons) d 178.4; 178.1; 173.9; 173.8; 167.5 Example 8 1-Hydroxytetralin-1-yl-C (O) -Aze-Pab x HOAc (i) 1-Hydroxytetralin-1-yl-carboxylic acid methyl ester The subtitle compound is prepared according to a method described by Bigge et al (J. Med.

Chem. (1993) 36; 1977) from tetralone (2.0 g; 13. 7 mmol), Me3SiCN (1.49 g, 15 mmol) and Znl2 (8 mg; cat.). Yield 2.5 g (88%). (ii) 1-Hydroxytetralin-1-yl-carboxylic acid The subtitle compound is prepared according to the method described in Example 1 (ii) above from 1-hydroxytetralin-1-yl-carboxylic acid, methyl ester (2.5 g) 12.1 mmole, from step (i) above) and LiOH.H20 (1.02 g, 24.2 mmoles). Yield 400 mg (17%). NMR-1- (400 MHz, CDC13): d 7.18 (m, 4H); 2.92 (t, 0.5H, rotamer); 2.78 (m, 2H): 2.61 (t, 0.5H, rotamer); 2.22 (m, 1H); 2.1-1.8 (m, 4H) (iii) 1-Hydroxytetralin-1-yl-C (O) -Aze-Pab (Z) The subtitle compound is prepared according to the method described in Example 5 (iii) above from the 1-hydroxytetralinic acid 1-yl-carboxylic acid (0.284 g, 1.50 mmol, from step (ii) above), TBTU (0.531 g, 1.65 mmol), H-Aze-Pab (Z) x 2HC1 (0.660 g, 1.50 mmol) and DIPEA (0.602 g, 3.1 mmoles). Purify the product without purification by re-using preparative RPLC (CH 3 C: 0.1 M ammonium acetate, 40:60). Yield 70 mg (8.6%). LCMS (m / z) 542 (M + 1) + 1H-NMR (400 MHz; D20): (complex due to diastereoisomers / rotamers) d 8.15 (t, 0.5H, rotamer); 7.97 (t, 0.5H, rotamer); 7.81 (dd, 2H); 7. 43 (dd, 2H); 7.30 (m, 4H); 7.19 (m, 2H); 7.12 (, 2H); 4.88 (m, 1H), 4.47 (m, 2H); 3.79 (, 0.5H, rotamer); 2.89 (m, 2H); 2.66 (, 1H), 2.50 (, 0.5H, rotamers), 2.35 (m, 1H); 2.19 (m, 0.5H, rotamer); 1.95 (, 5H) 13 C-NMR (100 'MHz, CDC13): (carbonyl and / or amidine carbons, complex due to diastereoisomers- / rotamers) d 177.7; 177.4; 171.1; 170.5; 170.3; 167.7; 164.4 (iv) 1-Hydroxytetralin-1-yl-C (O) -Aze-Pab x HOAc The title compound is prepared according to the method described in Example 1 (iv) above from 1-hydroxytetralin-1-yl. -C (O) -Aze-Pab (Z) (70 mg, 0.13 mmol, from step (iii) above), AcOH (5 mg, 0.13 mmol) and Pd / C (5%, 35 mg) in EtOH (5 ml). Yield 61 mg (100%). LCMS (m / z) 407 (M + 1) + XH-NMR (400 MHz, CD3OD): d 7.74 (dd, 2H); 7.55 (dd, 2H); 7.29 (d, 1H); 7.15, 3H); 4.59 (m, 1H); 4. 46 (m, ÍH] 4.25 .m, IH: 4.08 (m, 1H), 3.69 (m, 1 HOUR); 2.80 (m, 2H); 2.46 (m, 1H); 2.3-2.15 (m, 2H) 13 C-NMR (100 MHz, CD3OD): (carbonyl and / or amidine carbons) d 180.1; 178.0; 177.8; 173.2; 168.2 Ex 9 9-Methoxy-thienin-1-yl-C (O) -Aze-Pab x HOAc (i) 7-Methoxy-3-dihydronaphthalen-1-yl-carboxylic acid methylester A solution of l-hydroxy-7-methoxytetralin-1-ylcarboxylic acid methyl ester (0.5 g, 2.1 mmol, see Example 1) is added. (i) previous) in toluene (5 ml) was added to a refluxing solution of p-TsOH (0.6 g, 3.2 mmol) in toluene (10 ml), and the resulting mixture was refluxed for 45 minutes. After cooling, a reaction mixture is diluted with ether, washed with water and NaHCO3 / aqueous, dried with Na2SO4 and concentrated. Yield 392 mg (85%). NMR ^ H (500 MHz, CDC13): d 7.46 (d, 1H); 7.19 (t, 1H); 7.06 (d, 1H); 6.75 (dd, 1H); 3.84 (s, 3H); 3.83 (s, 3H); 2.69 (t, 2H); 2.38 (m, 2H) ü) 7-Methoxy-3,4-dihydronaphthalene-l-yl-carboxylic acid The subtitle compound is prepared according to the method described in Example 1 (ii) above from the 7-methoxy-3-methoxy methyl ester. -dihydronaphthalen-1-yl-carboxylic acid (0.39 g, 1.79 mmole, from step (i) above) and LiOH.H20 (0.15 g, 3.57 mmole). Yield 148 mg (40%). LC-MS (m / z) 203 (M + 1) + • RMN-1 !! (500 MHz; CDC13): d 7.56 (d, 1H); 7.44 (t, 1H); 7.09 (d, 1H); 6.77 (dd, 1H); 3.82 (s, 3H); 2.72 (t, 2H); 2.44 (m 2¿) (iii) 7-Methoxy-3,4-dihydronaphthalen-1-yl-C (0) -Aze-Pab (Z) The subtitle compound is prepared according to the method described in Example 3 (i) above from the acid 7-methoxy-3,4-dihydronaphthalen-1-yl-carboxylic acid (0.145 g, 0.71 mmol, from step (ii) above), H-Aze-Pab (Z-) x 2 HCl (0.343 g, 0.78 mmol) ), TBTU (0.251 g, 0.78 mmol) and DIPEA (0.364 g, 2.84 moles). Purify the product without purification using preparative RPLC (CH3CN: 0.1M ammonium acetate: 54:46). The resulting solution is concentrated and the aqueous layer is extracted with EtOAc three times. Dry the combined organic layer (Na2SO4) and concentrate, yielding 121 mg (31%). LC-MS (m / z) 553 (M + 1) + RMN-1! (500 MHz; CDC13): d 8.25 (t, 1H); 7.82 (d, 2H); 7.43 (d, 2H); 7.37-7.27 (m, 5H); 7.06 (d, 1H); 6.81 (d, 1H); 6.72 (dd, 1H) -; 6.35 (t, 1H); 5.20 (s, 2H); 5.03 (dd, 1H); 4.52 (m, 2H); 3.93 (m, 2H); 2.71 (t, 2H); 2.35 (m, 2H) (iv) 7-Methoxytetralin-1-yl-C (O) -Aze-Pab x HOAc The title compound is prepared according to the method described in Example l (iv) above from 7-methoxy-3, 4-dihydronaphthalen-1-yl-C (O) -Aze-Pab (Z) (88 mg, 0.16 mmol), AcOH (9 mg, 0.16 mmol) and Pd / C (10%, 44 mg). Yield 56 mg (73%), diastereoisomeric mixture 60:40. LC-MS (m / z) 421 (M + 1) + RMN-1 !! (500 MHz; D20): d 7.78 (t, 1H); 7.65 (d, 1H); 7.55 (dd, 1H); 7.49 (d, 1H); 7.42 (d, 2H); 7.36 (d, 2H); 7.16 (m, 1H); 7.05 (d, -1H), "6.84 (dd, 1H), 6.73 (dd, 1H), 6.06 (d, 1H), 5.18 (dd, 1H), 4.96 (, 1H), 4.12 (m, 2H); 3.92 (m, 2H), 3.82 (d, 1H), 3.62 (m, 3H), 2.7 (m, 6H), 2.4 (m, 2H), 2.05 (m, 2H), 1.9 (m, 1H), 1.2 (m, 2H); 1.5 (, 1H) 13 C-NMR (100 MHz; D20): (carbonyl and / or amidine carbons) d 182.3; 179.3; 179.1; 178.8; 173.7; 173.4; 173.0; 166.3 Example 10 (R) - y (Sj.-7-Methoxy-l-methyltetralin-1-yl-C (O) -Aze-Pab (i) 7-Methoxytetralin-1-yl-carboxylic acid methyl ester The compound is prepared of the subtitle according to the method described in Example 1 (iv) above from 7-methoxy-3,4-dihydronaphthalen-1-ylcarboxylic acid methyl ester (3.3 g; 15 mmoles; see Example 9 (i) above) and Pd / C (10%; 0.5 g). The resulting mixture is filtered through Hyflo and concentrated. Purify the product without purification using flash chromatography (Si-gel, heptane: EtOAc, 4: 1). Yield 2.4 g (72%). RMN-1 !! (400 MHz, CDC13): d 7.04 (d, 1H); 6.77 (dd, 1H); 6.72 (d, 1H); 3.82 (t, 1H); 3.78 (s, 3H); 3.73 (s, 3H); 2.75 (, 3H), 2.14 (M, 1H); 1.99 (m, 2H); 1.77 (m, 1H) (ii) 7-Methoxy-l-methyltetralin-1-yl-carboxylic acid methyl ester 7-methoxytetralin-1-yl-carboxylic acid methyl ester (0.4 g, 1.8 mmol, from step (i) above) Mel (0.13 ml, 2.0 mmol) was added to a suspension of NaH (55% in oil, 87 g, 2.0 mmol) in DMF (5 ml) and the mixture was stirred at room temperature overnight. The resulting mixture is poured into water, and the mixture of water is extracted with EtOAc: toluene 3 times. The combined organic layer is washed with water, dried (Na 2 SO) and concentrated. Instantaneous chromatography (Si-gel, heptane: EtOAc; 4: 1) yield 0.18 g (42%) of the subtitle compound. NMR-aH (500 MHz; CDC13): d 7.04 (d, 1H); 6.76 (m, 2H); 3.79 (s, 3H); 3.69 (s, 3H); 2.76 (, 2H); 2.32 (m, 1H); 1.91 (m, 1H); 1.83 (m, 2H); 1.75 (M, 1H); 1.58 (s, 3H) (iii) 7-Methoxy-l-methyltetralin-1-yl-carboxylic acid A mixture of 7-methoxy-1-methyltetralin-1-yl-carboxylic acid methyl ester (0.67 g, 2.9 mmol; of the stage (ii) above) and KOH (4 ml) in EtOH: H20 (1: 1, 50 ml). The resulting mixture is diluted with water and extracted with ether. The aqueous layer is acidified (HCl) and extracted 3 times with ether. The combined organic layer is washed with water, dried (Na 2 SO 4) and concentrated. Yield 0.58 g (81%). RM ^ H (300 MHz; CDC13): d 7. Q2 (d, 1H); 6.85 (d, 1H); 6.75 (dd, 1H); 3.77 (s, 3H); 2.75 (m, 2H); 2.32 (, 1H); 1.91 (m, 1H); 1.82 (m, 1H); 1.75 (m, 2H); 1.55 (s, 3H) (iv) 7-Methoxy-l-methyltetralin-1-yl-C (0) -Aze-Pab (Z) The subtitle compound is prepared according to the method described in Example 3 (i) above from 7-methoxy-l-methyltetralin-1-yl-carboxylic acid (0.14 g, 0.64 mmole, from step (iii) above) TJBTU (0.31 g, 0.97 mmole), H-Aze-Pab ( Z) (0.42 g, 0.97 mmoles) "and DIPEA (0.50 g, 0.67 mmoles) .The product is purified without purification using flash chromatography (Si-gel, EtOAc) Yield 0.26 mg (72%). NMR-1! (400 MHz, CDC13): d 8.40 (b, 0.5H, rotamer), 8.27 (b, 0.5H, rotamer), 7.90 (d, 2H), 4.84 (d, 2H), 7.45 (, 2H), 7.4- 7.25 (m, 5H), 7.00 (t, 1H), 6.75 (dd, 0.5H, rotamer), 6.71 (dd, 0.5H, rotamer), 6.62 (d, 0.5H, rotamer), 6.50 (d, 0.5H , rotamer), 5.22 (s, 2H), 4.87 (dd, 1H), 4.65-4.40 (m, 2H), 3.78 (s, 3H), 3.69 (s, 3H), 3.60 (m, 1H), 2.78 ( , 2H), 2.65 (m, 1H), 2.45 (m, 1H), 2.20 (m, 1H), 1.90 (m, 3H), 1.75 (m, 3H), 1.50 (s, 3H) (v) (R) - and (S) -7-Methoxy-l-methyltetralin-1-yl-C (O) -Aze-Pab The title compounds are prepared according to the method described in Example 1 (iv) above from 7-methoxy-1-methytetralin-1-yl-C (0) -Aze-Pab (Z) (0.10 g, 0.18 mmol, from step (iv) above) and Pd / C ( 10%) in EtOH (10 ml). Purify the product without purification using the preparative RPLC (CH3CN: 0.1M ammonium acetate: 30:70 to 32.5: 67.5) yielding two diastereoisomers. Individual solutions containing diastereoisomers are concentrated. The lyophilisate of the solutions produces the compound obtained from the faster fraction (Compound 10A, 30 mg, 69%) and the lowest fraction (Compound 10B, 28 mg, 64%). Compound 10A (hereinafter referred to as (R) or (S)): LC-MS (m / z) 435 (M + 1) + RMN-1! (400 MHz, D20): d 7.-74 (d, 2H); 7.49 (d, 2H); 7.10 (d, 1H); 6.85 (dd, 1H); 6.66 (d, 1H); .4.53 (q, 1H); 3.85 (m, 1H); 3.77 (s, 3H); 2.98 (m, 1H); 2. 70 (m, 2H); 2.28 (m, 1H); 2.03 (m, 2H); 1.95 (s, 3H); 1.88 (m, 1H); 1.72 (m, 1H); 1.44 (s, 3H) 13 C-NMR (100 MHz, CDC13): (carbonyl and / or amidine carbons) d 180.8; 174.1; 167.6; 158.5 Compound 10B (hereinafter referred to as (S) or (R)); LCMS (m / z) 435 (M + 1) + 1H-NMR (400 MHz; D20): d 7.75 (d, 2H); 7.50 (d, 2H); 7.06"(d, 1H); 6.80 (broad d, 1H); 6.68 (b, 1H); 4. 52 (q, 2H); 3.75 (m, 4H); 2.88 (m, 1H); 2.68 (m, 2H); 2.37 (m, 1H); 1.90 (s, 3H); 2.0-1.6 (, 4H); 1.41 (s, 3H) 13 C-NMR (100 MHz, CDC13): (carbonyl and / or amidine carbons) d 180.9; 174.0; 167.5; 158.4 Example 11 4-Hydroxy-6-methoxy-chroman-4-yl-C (O) -Aze-Pab x OAc (i) 4-Hydroxy-6-methoxy-roman-4-yl-carboxylic acid methyl ester The subtitle compound is prepared according to the method described by Bigge et al (J. Med.

Chem. (1993) 36, 1977) from 6-methoxy-roman-4-one (1.29 g, 7.23 mmol), Me3SiCN (0.79 g, 8.0 mmol) and Znl2 (20 mg, cat.). Yield 1.11 g (64%). NMR-aH (500 MHz, CD3OD): d 6.80 (dd, 1H); 6.73 (d, 1H); 6.72 (s, 1H); 4.28 (m, 1H); 4.14 (dt, 2H); 3. 74 (s, 3H); 3.70 (s, 3H); 2.47 (m, 1H); 2.02 (m, 1H) (ii) 4-Hydroxy-6-methoxy-chroman-4-yl-carboxylic acid The subtitle compound is prepared according to a method described in Example 1 (ii) above from 4-hydroxy-6-methyl ester methoxy-chroman-4-yl-carboxylic acid (1.09 g, 4.58 mmol; from step (i) above) and LiOH.H20 (0.39 g; 9.2 mmoles). Yield 0.1 g (69%). LC-MS (m / z) 223 (M + 1) + RMN-1! (300 MHz, CD3OD): d 6.81 (, 1H), 6.77 (m, 1H); 6.74 (m, 1H); 4.31 (m, 1H); 4.14 (m, 1H); 3.71 (s, 3H); 2.50 (m, 'l ^); 2.03 (m, 1H) (iii) 4-Hydroxy-6-methoxy-chroman-4-yl-C (O) -Aze-Pab (Z) The subtitle compound is prepared according to the method described in Example 3 (i) above from the -hydroxy-6-methoxy-roman-4-yl-carboxylic acid (0.104 g, 0.464 mmol, from step (ii) above), TBTU (0.29 g, 0.90 mmol), DMF (8 ml), DIPEA (80 μl + 320 μl, -0.46 mmoles + 1.84 mmoles) and H-Aze-Pab (Z) (0.4 g, 0.91 mmoles) Purify the product without purification, 0.27 g of an oil viscous yellow, using preparative RPLC (CH3CN: ammonium acetate 0.M.40:60), concentrate the fractions of interest and extract with EtOAc. Yield 0.089 g (33%). LC-MS (m / z) 573 (M + 1) + (iv) 4-Hydroxy-6-methoxy-chroman-4-yl-C (O) -Aze-Pab x HOAc The title compound is prepared according to the method described in Example 1 (iv) above from 4-Hydroxy -6-methoxy-chroman-4-yl-C (O) -Aze-Pab (Z) (0.089 g, 0.155 mmol, from top (iii) above), AcOH (0.5 μl, 0.44 mmol) and Pd / C (5%, 0.080 g). Yield 55.5 mg (72%). LCMS (m / z) 439 (M + 1) + RM ^ H (300H2 /; CD3OD): (complex due to diastereomerism / rotamerism) d 7.7-7.5 (m, 2H); 7.5-7.3 (m, 2H); 6.75-6.55 (m, 3H); 4.8 (m, 1H, partially hidden by HDO); 4.5-3.5 (m, 9H, same 3.74 (s) and 3.69 (s)) 2.7-1.7 (m, 7H, same 1.95 s, 3H) 13 C-NMR (75 MHz, CDC13): (carbonyl and / or carbons amidine) d 176.4; 173.1; 168.1 Example 12 (S) - and (R) -l-Hydroxy-4-methoxydandan-1-yl-C (O) -Aze-Pab (i) 4-Methoxy-1-indanone Cs 2 CO 3 (7 g, 21.5 mmol) is added followed by CH 3 I (10 g, 70 mmol) to a solution of 4-hydroxy-1-indanone (5.0 g, 34 mmol) in THF (30 ml) and the mixture is stirred at room temperature for 60 hours. The reaction mixture is filtered and concentrated, the product without purification is purified using flash chromatography (SiO 2, methylene chloride to yield 3.1 g (56%) of the sub-title substance. (ii) Ethyl ester of l-Hydroxy-4-methoxyindan-1-yl-carboxylic acid. Composed of the subtitle according to the method described by Bigge et al (J. Med. Chem. (1993) 36, 1977) from 4-methoxy-1-indanone (2.2 g, 13.5 mmol, from step ( i) above, Me3SiCN (2.0, 20 mmol), and Znl2 (200 mg 0.62 mmol, cat.) Yield 0.9 g (28%) 1 H-NMR (400 MHz, CDC13): d 7.21 (t, 1H); 6.85 (d, 1H), 6.79 (d, 1H), 4.20 (m, 2H), 3.85 (s, 3H), 3.07 (m, 3H), 2.97 (m, 1H), 2.67- (m, 1H); 2.27 (m, 1H); 1.20 (t, 3H) (iii) l-Hydroxy-4-methoxyindan-1-yl-carboxylic acid NaOH (19M, 1.0 ml) is added to a solution of 1-hydroxy-4-methoxyindan-1-yl-carboxylic acid ethyl ester (0.90 g). 3.8 mmole, from step (ii) above) in EtOH (20 ml) and the solution is stirred for 30 minutes. Brine (40 ml) is added and the mixture is washed with EtOAc, the acid is carefully brought to pH 2 (HCl, 2M), and the aqueous solution is extracted with EtOAc. The organic layer is washed with brine, dried (Na2SO4) and concentrated, yielding 0.70 g (88%) of the sub-title substance. NMR-1- (400 MHz, CDC13): d 7.23 (t, 1H); 6.89 (d, 1H); 6.81 (d, 1H); 3.85 (s, 3H); 3.0 (m, 2H), 2.77 (m, 1H); 2.3 (m, 1H) (iv) l-Hydroxy-4-methoxyindan-1-yl-C (O) -Aze-Pab (Z) The title compound described in Example 4 (iv) above is prepared from 1-hydroxy-4 acid. -methoxyindane-1-yl-carboxylic acid (350 mg, 1.68 moles, from step (iii) above), methylene chloride (25 ml), H-Aze-Pab (Z) / 750 mg; 1.7 mmol), TBTU (600 mg, 1.8 mmol and DIPEA (770 mg, 1.8 mmol) The mixture is concentrated and the residue is purified using flash chromatography (Si-gel, acetone: EtOAc), yielding 350 mg (37.5). NMR-1 !! (400 MHz, CDC13) (complex due to diastereoisomers / rotamers) d 8.05 (t, 0.5H, rotamer), 7.95 (t, 0.5H, rotamer), 7.82 (dd, 2H), 7.45 ( d, 2H), 7.35 (m, 5H), 7.20 (m, 1H), 6.82 (m, 2H), 4.92 (m, 1H), 4.48 (m, 2H), 3.84 (s, 3H), 3.66 (m , 2H), 3.30 (m, 1H), 2.95 (m, 1H), 2.55 (m, 1H), 2.46 (m, 1H), 2.30 (m, 1H) (v) (S) and (R) -l Hydroxy-4-methoxyindan-1-yl-C (O) -Aze-Pab Ammonium formate (1.0 g, 16 mmol) and Pd / C (5%, 200 mg) are added to a solution of 1-hydroxy 4-methoxyindan-1-yl-C (O) -Aze-Pab (Z) (340 mg, 0.61 mmol, starting from step (iv) above) in MeOH (30 ml). (200 mg, 4.4 mmol) and the mixture is stirred for 30 minutes.The reaction mixture is filtered through Hyflo and the solution is concentrated. purify the product without purification using RPLC (CH 3 CN: 0.1 M ammonium acetate; 15:85). The fractions of interest are collected and concentrated, and the water solution is lyophilized, yielding a fraction that moves faster (Compound 12A, 50 mg, 34%) and a fraction that moves slower (Compound 12B, 5 mg; 3.4%). Compound 12A (hereinafter referred to as R) or (S)): LC-MS (m / z) 423 (M + 1) + NMR-XH (400 MHz, CD3OD): (complex due to rotamerism) d 7.74 (d, 2H, minor rotamer); 7.70 (d, 2H, major rotamer); 7.60 (d, 2H, minor rotamer); 7.48 (d, 1H, major rotamer); 7.20 (t, 1H); 6.95 (d, 1H, major rotamer); 6.87 (d, 1H, minor rotamer); 6.84 (d, 1H, major rotamer); 6.83 (d, 1H, minor rotamer); 4.82 (m, 1H); 4.5 (m, 1H); 4.6-4.4 (m, 2H); 4.11 (m, 1H, major rotamer); 4.00 (m, 1H, minor rotamer); 3.82 (s, 3H); 3.0 (m, 1H); 2.9 (, 1H); 2.65 (m, 1H); 2.5 (M, 1H); 2.3-2.0 (m, 2H) 13 C-NMR (100 MHz, CD3OD): (carbonyl and / or amidines carbons d 180.3;; 176.4; 173.0; 167.9 Compound 12B (hereinafter referred to as (S) or R)): LC-MS (m / z) 423 (M + 1) + RMN ^ H (400 MHz, CD30D): (due complex of rotamerism) d 7.8-7.7 (m, 2H); 7.54 (d, 2H); 7.23 (m, 1H); 6.97 (, 1H); 6.9-6.8 (m, 1H); 4.80 (m, 1H); 4.6-4.4 (m, 2H), 4.25 (m, 1H); 4.1-3.9 (m, 1H), 3.82 (s, 3H); 3.0-2.85 (m, 2H); 2.8-2.5 (, 2H); 2.3-2.1 (m, 2H), 1.90 '(s, 3H) Example 13 l-Hydroxy-5-methoxytetralin-1-yl-C (O) -Aze-Pab (OH) A solution of hydroxylamine x HCl (39 mg, 0.56 mmol) and TEA (0.26 ml, 1.86 mmol) is sonified in THF (10 ml) at 40 ° C for 1 hour, after which l-hydroxy-5-methoxy tetralin-1-yl-C (O) -Aze-Pab (Z) (53 mg, 0.093 mmol; Example 5 (iii) above) in a small amount of THF, and the mixture is stirred at 40 ° C for 3 days. The mixture is concentrated, and the product is purified using preparative RPLC (CH3CN: 0.1M ammonium acetate, 30:70). The fractions of interest are concentrated and the remainder is lyophilized. Producing 29 mg (70%). LC-MS (m / z) 453 (M + 1) + RM ^ H (400 MHz, CD3OD): (complex due to diastereoisomers / rotamers) d 7.58 (m, 2H); 7.33 (dd, 2H); 7.16 (m, 1H); 7.85 (m, 2H), 4.78 (dd, 2H); 4.44 (, 2H), 4.2-4.0 (m, 2H), 3.80 (s, 3H); 3.58 (m, 0.5H, rotamer); 3.47 (m, 0.5H, rotamer), 2.91 (broad d, 1H); 2.44 (m, 2H), 2.34 (m, 1H), 2.19 (m, 1H); 2.08 (, 2H); 1.98 (b, 2H); 1.89 (b, 2H) 13 C-NMR (100 MHz, CDC13): (carbonyl and / or amidine carbons) d 178.0; 177.8; 172.-9, 158.4; 158.2; 155.3 Example 14 (S) - or (R) -l-Hydroxy-7-methoxytetralin-1-yl-C (O) -Aze-Pab (OH) The title compound is prepared according to the method described in Example 13 above from hydroxylamine x HCl (48 mg, 0.69 mmol), TEA (0.32 ml, 2.31 mmol) and (S) - or (R) -l-hydroxy-7-methoxytetralin-1-yl-C (O) -Aze-Pab (Z) (66 mg, 0.12 mmol, Compound 3A of the Example 3 (i) above). The mixture is concentrated, and the product is purified without purification using preparative RPLC (CH3CN: 0.1M ammonium acetate: 28:72), yielding 17 mg (31%). Purity 94.5%, diastereoisomeric ratio 87:13. LC-MS (m / z) 453 (M + 1) + NMR-aH (400 Mííz / CD3OD): d 5.75 (d, 2H); 7.37 (m, 3H); 7.04 (d, 1H); 6.81 (m, 1H); 4.82 (m, 1H); 4.44 (, 2H); 4.28 (m, 1H); 4.08 (m, 1H); 3.72 (s, 3H); 3.64 (, 1H); 2.72 (m, 3H); 2.40 (m, 1H); 2.22 (, 1H); 2.12 (m, 2H); 1.95 (m, 2H); 1.88 (m, 3H) 13 C-NMR (100 MHz, CDC13): (carbonyl and / or amidine carbons) d 177.6; 172.6; 159.4.

Example 15 4-Hydroxy-6-methoxy-chroman-4-yl-C (O) -Aze-Pab (OH) The title compound is prepared according to the method described in Example 13 above from hydroxylamine x HCl (74 mg 1.06 immoles) ASD (0.50 mL, 3.6 mmol) and 4-Hydroxy-6-methoxy-chroman-4-yl-C (0) -Aze-Pab (Z) (92 mg, 0-16 mmol, see Example 11 (iii) above). The product was purified without purification using preparative RPLC (CH3CN: ammonium acetate: 0.1 M 28:72) yielding 55 mg (75%). Diastereoisomeric proportion 53:47.

NMR-aH (400 MHz, CDC13): (complex due to diastereomerism / rotamerism) d 7.65-7.5 (m, 2H); 7.4- 7.3 (, 2H); 6.85-6.65 (m, 3H); 4.81 (m, 1H; partially hidden by HDO); 4.5-3.9 (m, 5H); 3.9-3.6 (, 4H); 2.8-1.9 (, 4H) 13 C-NMR (100 'pz; CDC13): (carbonyl and / or amidine carbons) d 176.5; 176.2; 172.8; 155.2 Example 16 4-Hydroxy-6-methoxy-chroman-4-yl-C (O) -Aze-Pab (OMe) The title compound is prepared according to the method described in Example 3 (i) above from acid 4- hydroxy-6-methoxy-roman-4-yl-carboxylic acid (95 mg, 0.42 mmol, see Example 11 (ii) above), TBTU (0.26 g, 0.81 mmol), DMF (5 ml), H-Aze-Pab (OMe) x HCl (0.256 g, 0.81 mmol, see Example 4 (iii) above) and DIPEA (75 + 300 μl; o.42 + 1.68 mmoles). Purify the product without purification using preparative RPLC (CH3CN: ammonium acetate 0.MI, 30.70), yielding 67 mg (37%). RMN-1 !! (400 MHz, CDC13): (complex due to diastereomerism / rotamerism) d 7.65-7.5 (m, 2H); 7.4-7.3 (, 2H); 6.85-6.7 (m, 3H); 4.80 (, 1H; ++ by HDO); 4.5-4.0 (m, 5H); 3.81 (s, 3H); 3.75-3.65 (m, 4H); 2.8-1.9 (m, 4H) 13 C-NMR (100 MHz, CDC13): (carbonyl and / or amidine carbons, complex due to diastereomerism- / rotameris or) d 177.8; 176.5; 176.1; 172.8; 172.6; 155.2; 155.0 '/ Example 17 (S) - or (R) -l-Hydroxy-7-methoxytetralin-1-yl-C (O) -Aze-Pab (C (O) 0CH2CC13) NaOH (aqueous, 2M, 0.78 ml) is added and then 2, 2, 2-trichloroethyl chloroformate (21 μl, 0.155 mmol) is added to an ice-cooled solution of (S) - or (R) -l-hydroxy-7-methoxytetralin-1-yl-C (O) -Aze-Pab by xHOAc (70 mg, 0.14 mmol, see Example 3 above) in THF (3 ml), and the mixture is stirred for 3 hours. The reaction mixture is diluted in water and the resulting mixture is extracted 4 times with methylene chloride. The collected organic phase is washed with brine, dried (Na 2 SO 4) and evaporated. Yield 79.8 mg (92.5%). LC-MS (m / z) 613 (M + 1) + RMN-1 !! (400 MHz, CDC13): d 9.42 (b, 1H); 7.98 (t, 1H); 7.83 (d, 2H); 7.30 (b, 1H); 7.29 (d, 2H); 7.06 (d, 1H); 6.84 (dd, 1H); 6.67 (d, 1H); 4.92 (dd, 1H); 4.86 (s, 2H); 4.48 (m, 2H); 4.12 (s, 1H); 3.86 (m, 1H); 3.75 (s, 3H); 3.08 (m, 1H); 2.81 (broad d, 1H); 2.58 (m, 2H); 2.27 (, 1H); 1.95 (m, 3H) 13 C-NMR (100 MHz, CDC13): (carbonyl and / or amidine carbons) d 178.7; 171.5; 170.1; 164.0 Example 18 (S) - or (R) -l-Hydroxy-7-methoxytetralin-1-yl-C (O) -Aze-Pab (C (O) 0CH 2 CH 3) The title compound is prepared according to the method described in Example 17 above from (S) - or (R) -l-hydroxy-7-methoxytetralin-1-yl-C (O) -Aze-Pab x HOAc (52 mg, 0.10 mmol, see Example 3 above) , NaOH (aqueous, 2M, 0.58 ml), and ethyl chloroformate (9.4 μl, 0.089 mmol). Purify the product without purification using preparative RPLC (CH3CN: ammonium acetate 0. IM 30:70). Yield 29 mg (69%). LC-MS (m / z) 509 (M + 1) + NMR-1! (400 MHz, CDC13): d 9.55 (b, 1H); 7.96 (t, 1H); 7.85 (d, 2H); 7.34 (d, 2H); 7.06 (d, 1H); 6.83 (dd, 1H); 6.68 (d, 1H); 4.94 (dd, 1H); 4.52 (m, 3H); 4.24 (q, 2H); 3.84 (m, 1H); 3.77 (s, 3H); 3.04 (m, 1H); 2.82 (m, 1H); 2.62 (, 2H); 2.27 (m, lh); 2.0-1.85 (M, 5h); 1.37 (t, 3H) 13 C-NMR (100 MHz, CDC13): carbonyl and / or amidine carbons) d 178.9; 171.4. 159.6 Example 19 7-Methoxy-1-allyltralin-1-yl-C (O) -Aze-Pab x HOAc (i) 7-Methoxy-1-allyltetralin-1-yl-carboxylic acid The subtitle compound according to the method described in Example 10 (ii) above is prepared from the methyl ester of 1-methoxytetratin-1-yl carboxylic acid (0.80 g, 3.6 mmol, see Example 10 (i) above), NaH (55% in oil; 0. 23 mg; 5.4 mmol) and allyl bromide (0.65 g, 5.4 mmol), after which the product is hydrolyzed without purifying directly according to the method described in Example 10 (iii) above with KOH (3 g) in EtOH: H20 (40 ml; 1 :). Yield 0.39 (44%). NMR ^ H (400 MHz; CDC13) d 7.00 (d, 1H); 6.93 (d, 1H); 6.72 (dd, 1H); 5.64 (m, 1H); 5.05 (m, 2H); 3.75 (s, 3ü); 2.85-2.60 (m, 4H); 2.20 (m, 2H); 1.95-1.70 (m, 3H) (ii) Boc-Aze-Pab x HCOOH The subtitle compound is prepared according to the method described in Example 12 (v) above from ammonium phosphate (3.0 g, 50 mmol), Pd / C (5% 1.0 g), Boc-Aze-Pab (Z) (4.7 g, 10 mmol, see international patent application WO 94/29336) and formic acid (1.0 g, 22 mmol) in 50 ml of MeOH. The crude product is suspended in CH2C12 (50 ml), filtered and washed with more CH2C12. The solid material f 'is dried and used in the next step without further purification. (iii) Boc-Aze-Pab (Teoc) Teoc-p-nitrophenyl carbonate is added (3.5 g, 12.3 mmol) to a solution of Boc-Aze-Pab x HCOOH (3.7 g, 10 mmol, from step (ii) above) in THF (100 ml) thereafter a solution of K2C03 (1.8 g, 13 mmol) in water (20 ml) is added over 2 minutes. The resulting solution is stirred for 3 days, concentrated and the remainder taken up in EtOAc (150 ml) and NaOH (aqueous, 0.5M, 50 ml). The organic layer is washed with brine (2 x 50 ml), dried (Na 2 SO) and concentrated. The product is purified without purification using flash chromatography (Si-gel, methylene chloride: acetone, 4: 1). Yield 4.6 g (96%). X-NMR (500 MHz; CDC13): d 7.86 (d, 2H); 7.39 (d, 2H); 4.72 (broad t, 1H); 4.53 (b, 2H); 3.93 (q, 1H); 3.81 (q, 1H); 2.48 (b, 2H); 1.43 (s, 9H) (iv) H-Aze-pab (Teoc) x HCl A solution of Boc-Aze-Pab (Teoc) (4.6 g, 0.6 mmol, from step (ii) above) is saturated in methylene chloride (150 ml) with dry HCl. The solution is kept at room temperature in a stopped flask for 10 minutes, after which it is concentrated. Yield 4.2 g (97%). NMR-1 !! (400 MHz, CD3OD): d 7.80 (d, 2H); 7.60 (d, 2H); 5.10 (t, 1H); 4.60 (s, 2H), 4.15 (q, 1H); 3.97 (q 1H); 2.86 (m, 1H); 2.57 (m, 1H) (v) 7-Methoxy-1-allyltralin-1-yl-C (O) -Aze-Pab (Teoc) The subtitle compound is prepared according to the method described in Example 3 (i) above from the acid 7 -methoxy-1-allyltetralin-1-yl-carboxylic acid (0.30 g, 1.2 mmol, from step (i) above), TBTU (0.43 g, 1.3 mmol), H-Aze-Pab (Teoc) (0.60 g) 1.3 mmol, from step (iv) above) and DIPEA (0.69 g, 5.4 mmol) The product is purified without purification using flash chromatography (Si-gel, EtOAc) Yield 0.41 mg (56%). 1 !! (500 MHz, CDC13) (complex due to diastereomerism / rotamerism) d 8.35 (b, 0.5H), 8.20 (bt, 0.5H), 7.90 (d, 1H), 7.85 (d, 1H), 7.90 ( d, 1 H); 7. 35 (d, 1H); 7.01 (t, 1H); 6.75 (m, 1H); 6.65 (d, 0.5H); 6.53 (d, 0.5H); 5.80-5.65 (m, 1H); 5.02 (dd, 1H); 4.96 (m, 1H); 4.87 (dd, 1H); 4.61 (m, 1H); 4.43 (dt, 1H); 4.25 (m, 2H); 3.70 (m + s, 3H); 3.54 (m, 0.5H); 2.95-2.40 (m, 6H); 2.23 (m, 1H); 2.13 (m, 1H); 1.98 (m, 2H); 1.80 (m, 2H); 1/13 (m, 2H); 0.13 (d, 9H) (vi) 7-Methoxy-l-allyltralin-l-yl-C (O) -Aze-Pab x HOAc A solution of Bu4NF (ÍM in THF) is added; 0.66 ml) was added to a solution of 7-methoxy-1-allyltetralin-1-yl-C (O) -Aze-Pab (Teoc) (0.36 g, 0.60 mmol, from step (v) above) in THF ( 40 ml), and the solution is stirred at 60 ° C for 24 hours. Purify the product without purification using preparative RPLC (CH3CN: ammonium acetate 0.MI (50:50)) and lyophilize. Yield 0.22 g (71%). RMN-1 !! (500 MHz; CDC13): d 7.77 (dd, 2H); 7.52 (t, 2H); 7.13 (t, 1H); 6.87 (dt, 1H); 6.77 (dd, 1H); 5.71 (m, 1H); 5.02 (m, 2H); 4.53 (b, 1H); 3.85-3.65 (m, 4H); 3.02 (m, 1H); 2.70 (b; 4H); 2.40-2.20 (m, 1H); 2.05-1.70 (b, 8H, 192 s;) 13 C-NMR (100 MHz; D20); (carbonyl and / or carbons amidine) d 179.1; 173.7; 167.3; 158.5 LC-MS (m / z) 459 (M-1) "Example 20 (S) - or (R) -l-Hydroxy-7-chlorotetralin-1-yl-C (0) -Aze-Pa (i) 7-Amino-1-tetralone Ammonium formate (2 g), Pd / C (5%, lg), and formic acid (0.; 5 g, cat.) are added in such order to a solution of 7-Nitro-1-tetralone (1.95 g, 10 mmol) in methanol (50 ml) and the mixture is stirred for 30 minutes. The solution is filtered, and the filtrate is concentrated. The rest is soaked with methylene chloride (50 + 25 ml), and the mixture is filtered and concentrated. Yield 1.4 g (88%). <1> H NMR (500 MHz; CDC13): d 7.32 (d, 1H); 7.03 (d, 1H); 6.83 (dd, 1H); 3.70 (b, • 2H); 2.85 (t, 2H); 2.61 (t, 2H); 2.10 (m, 2H) (ii) 7-Chloro-1-tetralone NaN02 (0.7 g, 10 mmol) dissolved in water (10 ml) is added with stirring to an ice-cooled solution of 7-amino-1-tetralone (1.4 g, 8.8 mmol; from step (i) above) in HCl (aqueous) for a period of 5 minutes. The resulting cold solution is then added slowly to one. ice-cooled solution of CuCl (1.5 g, 15 mmol) in concentrated HCl (aqueous), after which the resulting solution is stirred at room temperature during 2 hours and at 60 ° C for 30 minutes. The suspension is cooled with ice, and the resulting precipitate is filtered by suction, washed with water and dried in air. Yield 1.50 g (94%). RMN-1 !! (500 MHz / CDC13): d 8.00 (d, 1H); 7.41 (dd, 1H); 7.20 (d, 1H); 2.95 (t, 2H); 2.66 (m, 2H); 2.14 (m, 2H) (iii) 7-Chloro-l-hydroxytetralin-1-carboxylic acid methyl ester It is prepared according to the method described by C.F. Bigge e t al. in J. Med. Chem (1993) 36, 1977 using 7-chloro-l-tetralone (1.5 g, 8.3 mmol, from step (ii) above), Me3Si-CN (1.0 g, 10 mmol), and Znl2 (0.3 g). Yield 0.8 g (36%). RMN-1 !! (600 MHz, CDC13): d 7.72 (s, 1H); 7.25 (d, 1H); 7.17 (d, 1H); 7.09 (dd, 1H); 4.35-4.20 (m, 2H); 2.80 (, 2H); 2.35 (m, 1H); 2.12-1.92 (m, 3H), 1.25 (, 3H) (iv) 7-Chloro-l-hydroxytetralin-1-carboxylic acid NaOH (10M, 1 ml) is added to a solution of 7-chloro-1-hydroxytetraline-1-carboxylic acid ethyl ester (0.8 g, 3.1 mmol; from step (iii) above), in DMSO (20 ml). and the mixture is heated at 100 ° C for 3 hours. The resulting mixture is diluted with compressed ice (40 g) and brine (40 ml), and extract the mixture with EtOAc. The aqueous layer is acidified to pH 2 with 2M HCl and extracted with EtOAC (2 x 40 ml). The combined organic layer is dried (Na2S0) and concentrate. Yield 0.22 mg (30%). RMN-1 !! (500 MHz, 00013): 'd 7.25 (d, 1H); 7.20 (d, 1H); 7.09 (d, 1H); 2.80 (m, 2H); 2.27 (m, 1H); 2.17-2.00 (m, 2H); 1.98 (m, 1H) (v) 7-Chloro-l-hydroxytetralin-1-yl-C (0) -Aze-Pab (Z) HATU (400 mg, 1.05 mmol) is added to a solution of 7-chloro-l-hydroxytetratin-1 -carboxylic acid (220 mg, ca 1 mmol, from step (iv) above in DMF (50 ml) and, after stirring for a short time, a solution of H-Aze-Pab (Z) is added in drops. x 2HC1 (450 mg, 1.02 mmol) and 2,4,6-trimethylpyridine (425 mg, 3.5 mmol) in DMF (10 ml) After stirring overnight, the resulting mixture is diluted with an aqueous solution of NaCl (15%, 100 ml) and extracted with EtOAc (2 x 50 ml). The organic layer is washed with brine (20 ml), dried (Na2S04), and concentrate. The residue is purified using flash chromatography (Si-gel, EtOAc). Yield 300 mg (52%).

NMR-XH (400 MHz, CDC13): (complex due to diastereomerism and / or rotamerism) d 7.89 (d, 1H); 7.82 (d, 1H); 7.42 (d, 2H); 7.40-7.30 (m, 6H); 7.18 (m, 1H); 7.06 (d, 1H); 5.20 (s, 2H); 4.93 (m, 1H); 4.60-4.40 (, 3H); 3.83 (m, 0.5H); 3.72 (m, 0.5H); 3.07 (, 1H); 2.7-2.5 (m, 3H); 2.40 (m, 1H); 2.03-1.80 (m, 5H) (vi) 7-Chloro-l-hydroxytetralin-l-yl-C (O) -Aze-Pab x HOAc Anisole (65 mg, 0.6 mmol) and trifluoromethanesulfonic acid (400 mg, 2.6 mmol) are added, in that order, to a solution of 7-chloro-l-hydroxytetralin-1-yl-C (0) -Aze-Pab (Z) (300 mg, 0.52 mmol, from step (v) above) in methylene chloride (20 ml) and the solution is stirred at room temperature for 10 minutes. Water (20 ml) is added and the organic phase is separated and removed, after which the aqueous phase is adjusted to pH 4-5 with saturated NaHCO 3 (aqueous). The solution is partially concentrated and the product is purified without purification using preparative RPLC (CH3CN: water, 10:90 to 90:10). The fractions of interest are partially concentrated, a few drops of HOAc (concentrate) are added and the solution is lyophilized. Yield 40 mg (15%).

NMR-2H (500 MHz, CD3OD): d 7.78 (dd, 2H); 7.59 (m, 2H); 7.30 (d, lh); 7.22 (d, 1H); 7.15 (d, 1H); 4.65-4.35 (m, 3H); 4.20-3.90 (m, 1H); 2.85-2.70 (m, 1H); 2.55 (m, 1H); 2.35-1.95 (m, 9H) 13 C-NMR (100 MHz, CDC13): (carbonyl and / or amidine carbons) d 177.0; 172.8; 167.9 Example 21 ln-Propyl-7-methoxytetralin-l-yl-C (O) -Aze-Pab x HOAc A small amount of Pd / C (10%) is added to a solution of l-allyl-7-methoxytetralin- 1-yl-C (O) -Aze-Pab x HOAc (80 mg, 0.15 mmol, see Example 19 above) in EtOH (5 mL) and the mixture is hydrogenated at room temperature and pressure for two hours. The mixture is filtered through celite and the resulting solution is concentrated. It is lyophilized from water yielding 68 mg (85%) of the title compound. RMN-1 !! (400 MHz, CDC13): d 7.77 (t, 2H); 7.52 (t, 2H); 7.12 (t, 1H); 6.87 (m, 1H); 6.75 (d, 1H); 4. 75 (m, 1H, partially hidden-); 4.54 (s, 2H); 3.77 (m, 4H); 3.66 (M, 1H); 3.10 (m, 1H); 2.70 (b, 2H); 2. 30 (m, 1H); 2.1-1.6 (m, 10H, of the same 1.91, s, 3H); 1. 25 (m, 1H); 1.10 (M, 1H); 0.83 (q, 3H) LC-MS (m / z) 463 (M + 1) + Example 22 6-Chloro-4-hydroxyroman-4-yl-C (0) -Aze-Pab x HOAc (i) 6-Chloro-4-hydroxychroman-4-yl-carboxylic acid methyl ester The < - 'composed of the subtitle according to the method described by Bigge et al (J. Med. Chem (1993) 36, 1977ff) from 6-chlorochromanone (2.45 g, 13.4 mmoles), Me3SiCN (1.51 g, 15.2 mmoles), and Znl2 (40 mg; cat.). Yield 0.58 g (18%). RMN-1 !! (300 MHz, CDC13): d 7.17 (d, 1H); 7.08 (d, 1H); 6.82 (d, 1H); 4.41 (m, 1H); 4.37 (m, 1H); 2.7 (m, 1H); 2.09 (m, 1H) (ii) 6-Chloro-4-hydroxycarbon-4-yl-carboxylic acid LiOH.H20 (0.19 g; 4.6 mmol) and water (4 ml) are added to a solution of 6-chloro-4-hydroxychromic acid methyl ester. 4-yl-carboxylic acid (0.56 g, 2.3 mmol, from step (i) above) in THF (6 ml). The reaction mixture is stirred at room temperature for 3 hours, THF is evaporated and the water solution is washed with methylene chloride. The reaction mixture is acidified with HCl (2M) and extracted with ethyl acetate. The organic layer is dried (Na2SO4) and evaporated, yielding a slightly crystalline oil. Yield: 490 mg (93%). LC-MS (m / z) 228 (M-1) ~ (iii) 6-Chloro-4-hydroxyroman-4-yl-C (0) -Aze-Pab (Teoc). < A solution of 6-chloro-4-hydroxychroman-4-yl-carboxylic acid (222 mg, 1.00 mmol, from step (ii) above) and HATU (370 mg, 0.97 mmol) in DMF (5 ml) is stirred. ) at 0 ° C for 1.5 hours, and a mixture of H-Aze-Pab (Teoc) x HCl (440 mg, 0.98 mmol, see Example 19 (iv) above), and 2,4,6-trimethylpyridine ( 0.48 g, 3.9 mmol) in DMF (5 ml) at 0 ° C. After stirring for 3 hours at 0 ° C, the reaction mixture is concentrated and the product is purified without purification using preparative RPLC (CH3CN: 0.1M ammonium acetate (55:45)). The fractions of interest are partially concentrated and extracted with methylene chloride. The organic layer is dried (Na2SO4) and concentrated to yield 350 mg (67%) of a diastereoisomeric mixture. NMR-aH (400 MHz, CDC13): d 7.31 (, 1H); 7.19 (dt, 1H); 7.09 (d, 0.5H); 7.00 (d, 0.5H); 6.88 (dd, 1H); 4.93 (m, 1H); 4.80 (broad, 0.5H); 4.61 (dd, 1H); 4.53-4.43 (m, 2H); 4.36 (, 1H); 4.15 (t, 1H); 3.89 (m, 0.5H); 3.74 (m, 0.5H); 3.09 n (, 1H); 2.46-2.28 (, 1H); 2.21 (, 1H); 1.96 (m, 1H); 0.06 (s, 9H) NMR-C (100 MHz CDC13, carbonyl and / or amidine carbons) d 176.9; 171.5; 171.3; 169.8; 155.4; 155.2 LC-MS (m / z) 58'8 / (M + 1) + (iv) 6-Chloro-4-hydroxyroman-4-yl-C (O) -Aze-Pab x HOAc Bu4NF (l.OM in THF, 0.35 ml) is added to a solution of 6-chloro-4-hydroxy chroman 4-yl-C (O) -Aze-Pab (Teoc) (190 mg, 0.32 mmol, from step (iii) above) in THF (20 ml) at 0 ° C. The solution is stirred for two days at 40 ° C. The solution is concentrated and the unpurified material is purified using preparative RPLC (CH3CN: 0.1M ammonium acetate (25:75)). Yield 115 mg (71%). X-NMR (400 MHz, CD3OD): d 7.73 (m, 2H); 7.55 (m, 2H); 7.28 (dd, 1H); 7.15 (m, 1H); 6.79 (m, 1H); 4.60 (, 1H); 4.47 (m, 2H); 4.33 (m, 1H); 4.15 (m, 2H:? -2.46, m, 1H) 2.3: 1H) 2.23 (m, 1H); 2. 06 (, 1H); 1.90 (s, 3H) 13 C-NMR (100 MHz, CDC13): (carbonyl and / or amidine carbons) d 175.9; 175.6; 174.4; 173.1; 173.0 LC-MS (m / z) 444 (M + 1) + EXAMPLE 23 4-Hydroxychroman-4-yl-C (O) -Aze-Pab x HOAc Pd / C (5%, 25 mg) is added to a solution of 6-chloro-4-hydroxyroman-4-yl-C (O) -Aze-Pab x HOAc (14.7 mg, 0.029 mmol, see Example 22 above) in EtOH (5 ml) and the mixture is hydrogenated at room temperature environment and pressure for a day. Filter the mixture through Celite, and purify the product without purification using preparative RPLC (CH3CN: 0.1M ammonium acetate (25:75)). The fractions of interest are concentrated. The lyophilized product yields 4 mg (30%) of the title compound. RMN-1 !! (400 MHz, CD3OD): d 7.79 (m, 2H); 7.56 (, 2H); 7.4-7.2 (m, 2H); 7.00 (m, -2H); 4.96 (dd, 1H); 4.5-4.3 (m, 2H); 4.20 (m, 2H); 3.88 (, 1H); 2.8-2.4 (, 2H), 2.27 (m, 1H); 2.17 (m, 1H); 2.07 (s, 3H) 13 C-NMR (100 MHz CDC13): (carbonyl and / or amidine carbons) d 173.7; 167.7 LC-MS (m / z) 409 (M + 1) + Example 24 6, 8-Dichloro-4-hydroxyroman-4-yl-C (O) -Aze-Pab x HOAc (i) 6,8-Dichloro-4-hydroxychroman-4-yl-carboxylic acid methyl ester 11! The subtitle compound is prepared according to the method described by Bigge et al. (J. Med. Chem. (1993) 36, 1977ff) from 6,8-dichlorocromanone (1.36 g, 6.27 mmol), Me 3 SiCN (0.68 g, 6.9 mmol), and Znl 2 (20 mg; cat.). Yield 0.52 g (30%). RMN-1! (300 MHz, CDC13):% d 7.30 (s, 1H); 7.00 (s, 1H); 4.53 (m, 1H); 4.33 (m, 1H); 3.83 (s, 3H); 2.47 (m, 1H); 2.12 (m, 1H) (ii) 6,8-Dichloro-4-hydroxyroman-4-yl-carboxylic acid LiOH.H20 (0.15 g, 3.6 mmol) and water are added. (2 ml) was added to a solution of 6,8-dichloro-4-hydroxychroman-4-yl-carboxylic acid methyl ester (0.50 g, 1.8 mmol, from step (i) above) in THF (5 ml). The resulting mixture is stirred at room temperature for 30 minutes. The THF is evaporated and the water phase is washed with methylene chloride, the reaction mixture is made acidic with HCl (2M) and extracted with methylene chloride.

(Na2SO4) and evaporated, yielding the subtitle compound. Yield: 390 mg (83%). LC-MS (m / z) 262 (M-1) "(iii) 6, 8 -Pieloro-4-hydroxyroman-4-yl-C (O) -Aze-Pab (Teoc) The subtitle compound of according to the method described in Example 22 (iii) above of 6,8-dichloro-4-hydroxy chroman-4-yl-carboxylic acid (100 mg, 0.38 mmol, from step (ii) above); HATU (160 mg, 0.41 mmol), H-Aze-Pab (Teoc) x HCl, (190 mg, 0.42 mmol, see Example 19 (iv) above), and 2,4,6-trimethylpyridine (0.19 g, 1.6 mmol). purify the product without purification using preparative RPLC (CH3CN: ammonium acetate 0.MI (55:45)) .The fractions of interest are partially concentrated and extracted with methylene chloride.The organic layer is dried (Na2SO4) and concentrate by producing 206 mg (87%) of a tereosisomeric mixture CL-MS (m / z) 623 (M + 1) + (i) 6, 8-Dichloro-4-hydroxyroman-4-yl-C (O) -Aze-Pab x HOAc The title compound is prepared according to the method described in Example 19 (vi) above from 6 , 8-dichloro-4-hydroxy chroman-4-yl-C (O) -Aze-Pab (Teoc) (150 mg, 0.24 mmol, from step (iii) above) and Bu4NF (0.10 g, 0.32 mmol) . Purify the material without purification using preparative RPLC (CH3CN: 0.1M ammonium acetate (30:70)). Yield 45 mg (35%). <1> H-NMR (400 MHz, CD3OD): d 7.73 (m, 2H); 7.54 (M, 2H); 7.32 (m, 2H); 7.23 (d, 1H); 4.65-4.40 (m, 4H); 4.30 (m, 2H); Four . l'l -ß. 91 (m, 1H), 2.8-2.5 (m, 1H); 2.40 (m, 1H); 2.35-2.20 (m, 1H); 2.15 (m, 2H); 1.95 (s, 3H) 13 C-NMR (100 MHz, CDC13): (carbonyl and / or amidine carbons) d 175.4; 174.0; 174.3; 173.0; 168.1 LC-MS (m / z) 477 (M + 1) + Example 25 6-Fluoro-4-hydroxyroman-4-yl-C (O) -Aze-Pab x HOAc (i) 6-Fluoro-4-hydroxychroman-4-yl-carboxylic acid methyl ester The subtitle compound is prepared according to the method described by Bigge et al (J. Med. Chem. (1993), 36, 1977ff) a from 6-fluorochromanone (2.53 g, 15.2 mmol), Me3SiCN (1.66 g, 16.7 mmol) and Znl2 (3 mg, cat.). Yield 2.51 g (73%). NMR-aH (400 MHz, CDC13): d 6.93 (, 1H); 6.82 (m, 2H); 4.34 (m, 1H); 4.23 (dt, 1H); 3.81 (s, 3H); 2.47 (m, 1H), 2.10 (m, 1H) (ii) 6-Fluoro-4-hydroxychroman-4-yl-carboxylic acid A solution of LiOH.H20 (0.95 g; 22. 6 mmole) in water (30 ml) to a solution of 6-fluoro-4-hydroxychroman-4-yl-carboxylic acid methyl ester (2.47 g, 10.9 mmol, from step (i) above) in THF (1 »'0 ml). The reaction mixture is stirred at room temperature for 2 days, THF is evaporated and the water phase is acidified with HCl. (2M) and extracted with ethyl acetate. The organic layer is dried (Na2SO) and evaporated, yielding the subtitled compound. Yield: 1.41 g (61%). LC-MS (m / z) 211 (M-1) ~ (iii) 6-Fluoro-4-hydroxy chroman-4-yl-C (0) -Aze-Pab (Z) The subtitle compound is prepared according to the method described in Example 22 (iii) above from the acid 6-fluoro-4-hydroxy-roman-4-yl-carboxylic acid (250 mg, 1.18 mmol, from step (ii) above); HATU (500 mg, 1.32 mmol), H-Aze-Pab (Z) x HCl (570 mg, 1.3 mmol) prepared according to the method described in the Patent Application International WO 97/02284) and 2,4,6-trimethylpyridine (0.70 g, 5.3 mmol). Purify the product without purification using preparative RPLC (CH 3 CN: 0.1 M ammonium acetate: 55.45). The fractions of interest are partially concentrated and extracted with methylene chloride. The organic layer is dried (Na 2 SO 4) and concentrated to yield 290 mg (40%) of a tereoisomeric mixture. FAB-MS (M / z) 561 (M + 1) + (iv) 6-Fluoro-4-hydroxyroman-4-yl-C (O) -Aze-Pab x HOAc HOAc (80 μl) and Pd / C (5%, 93 mg) are added to a 6-fluoro solution -4-hydroxychroman-4-yl-C (O) -Aze-Pab (Z) (140 mg, 0.25 mmol, from stage (iii) above) in EtOH (10 ml), and the mixture is hydrogenated at room temperature and pressure for 4 hours. The mixture is filtered through Celite. The solution is concentrated and the unpurified material is purified using preparative RPLC (CH3CN: 0. IM ammonium acetate (20:80)). Yield 72 mg (59%). RMN-1 !! (400 MHz, D20): d 7.78 (dd, 1H); 7.73 (d, 1H); 7.55 (m, 2H); 7.18-6.96 (m, 3H); 4.96 (dd, 1 HOUR); 4.58 (s, 1H); 4.50-4.35 (m, 2H); 4.19 (m, 2H); 2.63 (m, 1H); 2.45 (m, 1H); 2.35-2.12 (m, 2H); 1.98 (s, 3H) 13 C-NMR (100 MHz; D20): (carbonyl and / or amidine carbons) d 176.1; 175.9; 174.7; 173.7; 167.6 Example 26 4-Hydroxy-6-methyl-chroman-4-yl-C (O) -Aze-Pab x HOAc (i) 4-Hydroxy-6-methyl-chroman-4-yl-carboxylic acid methyl ester The subtitle compound is prepared according to a method described by Bigge et al (J. Med. Chem. (1993) 36, 1977ff) a from 6-methylchromanone (3.11 g, 19.2 mmol), Me3SiCN (2.1 g, 21.2 mmol) and Znl2 (20 mg, cat.). Yield 2.80 g (62%). RMN-1 !! (300 MHz, CDC13): d 7.01 (dd, 1H); 6.89 (d, 1H); 6.77 (d, 1H); 4.37 (dt, 1H); 4.32-4.20 (, 3H); 2.49 (m, 2H); 2.34 (s, 3H); 2.08 (m, 1H); 1.24 (t, 3H) (ii) 4-Hydroxy -methyl chroman-4-yl-carboxylic acid A solution of LiOH.H20 (0.78 g, 18.6 mmol) in water (15 ml) is added to a solution of 4-hydroxymethyl ester. 6-methyl-chroman-4-yl-carboxylic acid (2.2 g, 9.3 mmol, from step (i) above) in THF (10 ml). The reaction mixture is stirred at room temperature for 1 night, THF is evaporated and the water phase is washed with ether. The resulting solution is acidified with HCl (2M) and extracted with ether. The organic layer is dried (Na2SO) and evaporated, yielding the subtitle compound. Yield: 1.21 mg (62%). RMN-1 !! (300 MHz, CD3OD): d 7.06 (d, 1H); 6.98 (d, 1H); 6.69 (d, 1H); 4.32 (m, 1H); 4.17 (m, 1H); 2.50 (m, 1H); 2.21 (s, 3H); 2.03 (m, 1H) LC-MS (m / z) 201 (K-1) ' (iii) 4-Hydroxy-6-methylchroman-4-yl-C (O) -Aze-Pab (Z) The subtitle compound is prepared according to the method described in Example 22 (iii) above of 4-hydroxy acid 6-methyl-chroman-4-yl-carboxylic acid (310 mg, 1.49 mmol, from step (i) above), HATU (620 mg, 1.63 mmol), H-Aze-Pab (Z), (790 mg; 2.2 mmol, prepared according to the method described in International Patent Application WO 97/02284) and 2,4,6-trimethylpyridine (0.37 g, 3.0 mmol). Purify the product without purification using preparative RPLC (CH3CN: 0.1 M ammonium acetate (45.55)). The fractions of interest are partially concentrated and extracted with methylene chloride. The organic layer is dried (Na 2 SO 4) and concentrated to yield 675 mg (81%) of a di-astereoisomeric mixture. LC-MS (m / z) 557 (M + 1) + (iv) 4-Hydroxy-6-methyl-chroman-4-yl-C (O) -Aze-Pab x HOAc Add HOAc (80 μl) and Pd / C (5%, 150 mg) to a solution of 4-hydroxy-6-methyl-chroman-4-yl-C (O) -Aze-Pab (Z) (240 mg; 0.43 mmol; from step (iii) above) is dissolved in EtOH (10 ml), and the mixture is hydrogenated at room temperature and pressure overnight. The mixture is filtered through Celite. The lyophilisate gives the title compound in a yield of 159 mg (76%). RMN-1 !! (500 MHz, CD3OD): d 7.72 (dd, 2H); 7.53 (dd, 2H); 7.08 (d, 1H); 7.00 (d, 1H); 6.71 (d, 1H); 4.84 (m, partially hidden); 4.60 (m, 1H); 4.46 (m, 1H); 4.29 (m, 2H); 4.14 (t, 1H); 2.40 (m, 2H); 2.26-2.10 (m, 3H); 2.00 (m, 1H); 1.90 (s, 3H) 13 C-NMR (100 MHz, CD3OD): (carbonyl and / or amidine carbons) d 176.6; 174.5; 173.1; 168.1 LC-MS (m / z) 423 (M + 1) + Example 27 8 - Chlor o-4-hydr oxy-6-methoxyr ornan- 4 -yl -C (O) -Aze-Pab x HOAc i) Ethyl 3- (2-chloro-4-methoxyphenoxy) propionate Sodium (0.055 g, 2.4 mmol) and ethanol 1.5 ml) is added to a molten mixture of 2-chloro-4-methoxyphenol (5.20 g, 32.8 mmol) . When all sodium is dissolved, ethyl acrylate (4.1 g, 41 mmol) is added and the mixture is heated at 105 ° C for 7 days. The mixture is then cooled to room temperature and fractionated between ether and water. The mixture is made acidic with HCl (2M, aqueous) and extracted with ether three times. The combined organic layer is washed with NaOH (2M, aqueous), dried (CaCl2) and evaporated. Purify the crude product (2.7 g) using preparative RPLC (CH3CN: 0. IM ammonium acetate (60:40)). Yield 1.90 g (22%). (ii) 3- (2-Chloro-4-methoxyphenoxy) propionic acid A solution of -LiOH.H20 (0.67 g, 16 mmol) in water (20 ml) is added to a solution of 3- (2-chloro-4) -methoxyphenoxy) ethyl propionate (1.90 g, 7.3 mmol, from step (i) above) in THF (10 ml). The reaction mixture is stirred at room temperature overnight, THF is evaporated and the water phase is washed with ether. The resulting solution is acidified with HCl (2M) and extracted with ether. Dry the organic layer (Na2SO4) and evaporate to yield 0.90 g (54%) of the subtitle compound. LC-MS (m / z) 229 (M-1) '(iii) 8-Chloro-6-metho-chroman-4 -one Phosphorus pentachloride (1.3 g, 6.2 mmol) is added to a suspension (2-Chloro-4-methoxyphenoxy) propionic acid (0.85 g, 3.7 mmol, from step (ii above) in benzene (10 ml) The resulting clear solution is heated rapidly to boiling and then cooled in a water bath. Ice: Aluminum chloride (1.5 g, 11 mmol) is added in portions and, after complete addition, water is added to ice, extraction with ether, washing of the organic layer with NaHCO3 / aqueous and NaOH (2M; aqueous), dried (Na2SO4) and the concentration afforded 0.73 g (93%) of the subtitle compound.H NMR (300 MHz, CDC13): d 7.27 (d, 1H); 7.19 (d, 2H); 4.59 (t, 2H); 3.80 (s, 3H); 2.81 (t, 2H) (iv) 8-Chloro-4-hydroxy-6-methoxy chroman-4-yl-carboxy lamide The sub-title compound is obtained during an attempt to prepare the corresponding methyl ester according to the method described by Bigge et al (J. Med. Chem. (1993) 36, 1977ff) of 8-chloro-6-methoxy chromanone (0.73 g, 3.4 mmol, from step (iii) above); Me3SiCN (0.94 g, 7.6 mmol) and Znl2 (50 mg; cat.). The unpurified product consists of a minor amount of the corresponding methyl ester and a larger amount of the amide. Amide is purified by preparative RPLC (CH3CN: 0.1M ammonium acetate: 30:70 to 70:30). Yield 0.39 g (44%). LC-MS (m / z 256 (M-1) ~ (v) Acid-Chloro-4-hydroxy-6-methoxy-chroman-4-yl-carboxylic acid KOH (1.2 g, 21 mmol) and water are added. (25 ml) was added to a solution of 4-hydroxy-8-chloro-6-methoxydroman-4-yl-carboxylic acid amide (0.39 g, 1.5 mmol, from step (iv) above) in i-PrOH (25). ml).

The reaction mixture is refluxed overnight, i-PrOH is evaporated and the water solution is washed with ether. The reaction mixture is acidified with HCl (2M) and extracted with ethyl acetate. The organic layer is dried (Na 2 SO 4) and evaporated. Performance: 0. 38 mg (97%). LC-MS (m / z) 257 (M-1) ~ (vi) 8-Chloro-4-hydroxy-6-methoxy chroman-4-yl-C (O) -Aze-Pab (Teoc) The subtitle compound is prepared according to the method described in Example 22 (iii) above to from 4-hydroxy-8-chloro-6-methochroman-4-yl-carboxylic acid (260 mg, 1.00 mmol, from step (v) above), HATU (420 mg, 1.1 mmol), H -Aze-Pabe (Teoc) x HCl (490 mg, 1.1 mmol, see Example 19 (iv) above), and 2,4,6-trimethylpyridine (600 mg, 4.5 mmol). Purify the product without purification using preparative RPLC (CH3CN: ammonium acetate; 0.MI (55:45)). The fractions of interest are partially concentrated and extracted with methylene chloride. The organic layer is dried (Na 2 SO) and concentrated, yielding 340 mg (55%) of a diastereoisomeric mixture. LC-MS (m / z) 617 (M + 1) + (viii) 8-Chloro-4-hydroxy-6-methoxy chroman-4-yl-C (O) -Aze-Pab x HOAc The title compound is prepared according to the method described in Example 19 (vi) above using 4 -hydroxy-8-chloro-6-methoxy-chroman-4-yl-C (O) -Aze-Pab (Teoc) (150 mg, 0.24 mmol, from step (vi) above) and Bu4NF (l.OM. in THF, 0.32 ml). Purify the unpurified material using preparative RPLC (CH3CN: 0. IM ammonium acetate (20:80)). Yield 113 mg (87%). RMN-1 !! (400 MHz, CD3OD): d 7.69 (d, 2H); 7.54 (d, 2H); 6.90 (d, 1H); 6.85 (d, 1H); 4.57 (m, 3H); 4.48-4.30 (m, 4H); 4.17 (m, 2H); 4.00 (m, 1H); 2.8-2.5 (, 2H); 2.40 (m, 2H); 2.26 (m, 1H); 2.15 (m, 2H); 2.06 (d, 1H) LC-MS (m / z) 473 (M-1) ~ Example 28 6-Chloro-4-hydroxy-8-methyl-chroman-4-yl-C (O) -Aze-Pab x HOAc (i) Ethyl 3- (4-chloro-2-methylphenoxy) propionate The sub-title compound is prepared according to the method described in Example 27 (i) above from 4-chloro-2-methylphenol (4.99 g; . 0 mmol), sodium (0.055 g, 2.4 mmol), ethanol (1.5 ml) and ethyl acrylate (4.1 g, 41 mmol). The unpurified product (1.98 g, 23%) is used for the next step without further purification. (ii) 3- (4-Chloro-2-methylphenoxy) propionic acid A solution of LiOH.H20 (0.50 g, 12 mmol) in water (10 ml) is added to a solution of 3- (4-chloro-2-) methylphenoxy) ethyl ropionate (1.98 g, 8.15 mmol, from step (i) above) in THF (20 ml). The reaction mixture is stirred at room temperature overnight, the THF is evaporated and the water phase is washed with ether. The resulting solution is acidified with HCl (2M), after which a solid material is precipitated. The product is filtered and dried in the air yielding 0.62 g (35%) of the subtitle compound. LC-MS (m / z) 213 (M-1) ~ (iii) 6-Chloro-8-methylchroman-4-one Pentaqioride phosphorus (0.95 g, 4.6 mmol) is added to a suspension of 3- (4-chloro-2-methylphenoxy) propionic acid (0.59 g, 2.7 mmol; from step (ii) above) in benzene (10 ml). The resulting clear solution is heated rapidly to boiling and then cooled in an ice bath. Aluminum chloride (1.0 g, 7.5 mmol) is added in portions and, after complete addition, water is added to ice. The mixture is extracted with ether, the organic layer is washed with NaHC03 / aqueous and NaOH (2M, aqueous) is dried (Na2SO4) and the concentration yields 0.27 g (50%) of the subtitle compound. RMN-1 !! (500 MHz, CDC13): d 7.70 (d, 1H); 7.29 (d, 2H); 4.56 (t, 2H); 2.79 (t, 2H); 2.22 (s, 3H) (iv) 6-Chloro-4-hydroxy-8-methyl-chroman-4-yl-carboxyl acid amide The subtitle compound is prepared as described in Example 27 (iv) above using the method described by Bigge et al (J. Med. Chem. (1993) 36, 1977ff) from 6-chloro-8-methylchromanone (0.27 g, 1.37 mmol, from step (iii) above), Me3SiCN (0.29 g, 1.52 mmol), and Znl2 (46 mg; cat.). The unpurified product consists of a minor amount of the corresponding methyl ester and a larger amount of the amide. The amide is purified by preparative RPLC (CH3CN: 0.1M ammonium acetate: 30:70 to 70:30). Yield: 0.17 g (50%). LC-MS (m / z) 240 (M-1) " (v) Acid-Chloro-4-hydroxy-8-methyl-1-chroman-4-yl-carboxylic acid KOH (1.25 g, 22.3 mmol) and water (20 ml) are added to a solution of -4-hydroxy-6-chloro -8-methyl-chroman-4-yl-carboxylic acid amide (0.17 g, 0.69 mmol, from step (iv) above) in i-PrOH (20 ml). The reaction mixture is refluxed overnight, i-PrOH is evaporated and the water solution is washed with ether. The reaction mixture is acidified with HCl (2M) and extracted with ethyl acetate. The organic layer is dried (Na 2 SO) and evaporated. Yield: 0.13 g (78%). (vi) 6-Chloro-4-hydroxy-8-methyl-chroman-4-yl-C (O) -Aze-Pab (Teoc) A solution of 6-chloro-4-hydroxy-8-methyl-chroman-4- acid is stirred il-carboxylic acid (130 mg, 0.54 mmol, from step (v) above) and HATU (220 mg, 0.59 mmol) in DMF (5 ml) at 0 ° C for 1.5 hours, and a mixture of H-Aze-Pab (Teoc) x HCl is added. (270 mg, 0.59 mmol is i see Example 19 (iv) above) and 2,4,6-trimethylpyridine (320 mL, 2.4 mmol) in DMF (3 mL) at 0 ° C. After stirring for 3 hours at 0 ° C the reaction mixture is concentrated, and the product is purified without purification using preparative RPLC (CH3CN: 0.1 M ammonium acetate (55:45)). The fractions of interest are partially concentrated and extracted with methylene chloride. Dry the organic layer (Na2SO4) and concentrate, - yielding 79 mg (24%) of a diastereoisomeric mixture. LC-MS (m / z) 601 (M-1) ~ (vii) 6-Chloro-4-hydroxy-8-methyl-chroman-4-yl-C (O) -Aze-Pab x HOAc Bu4NF (l.OM in THF, 0.20 ml) is added to a solution of 6-chloro- 4-hydroxy-8-methyl-chroman-4-yl-C (O) -Aze-Pab (Teoc) (79 mg, 0.13 mmol, from step (vi) above) in THF (5 ml) at 0 ° C . The solution is stirred at 60 ° C overnight and concentrated subsequently. Purify the unpurified material using preparative RPLC (CH3CN: 0. IM ammonium acetate (20:80)). Yield 37 mg (54%). RMN-1 !! (400 MHz, CD3OD): d 7.72 (m, 2H); 7.54 (, 2H); 7.15-6.98 (m, 2H); 4.60 (m, 1H); 4.5-4.3 (m, 3H); 4.25-4.10 (m, 2H), 4.03 (m, 1H); 2.80-2.45 (m, 1H); 2.37 (m, 1H); 2 .'26 (m, 1H); 2.14 (s, 3H); 2.05 (d, 1H); 1.92 (s, 3H) LC-MS (m / z) 473 (M-1) " Example 29 (S) - or, (R) -l-hydroxy-7-methoxytetralin-1-yl-C (O) -Aze-Pab (0-C (0) -i-Pr) 2-methylpropanoic anhydride is added (7.3 mg, 46 μmol) to an ice-cooled solution of (S) - or (R) -l-hydroxy-7-methoxytetralin-1-yl-C (0) -Aze-Pab (OH) (20 mg, 44 μmol, see Example 14 above) and Et3N (4.9 mg, 49 μmol) in methylene chloride (1 ml), and the mixture is stirred at room temperature overnight. The mixture is diluted with an additional amount of methylene chloride, washed 3 times with water and once with brine, dried (Na 2 SO 4) and concentrated. Purify the product without purification using preparative RPLC (CH3CN: 0.MM ammonium acetate (40:60)), and concentrate the fractions of interest. The lyophilisate produces 13 mg (56%) of the title compound.

X-NMR (300 MHz, CDC13): d 7.90 (m, 1H); 7.65 (d, 2H); 7.29 (d, 2H); 7.05 (d, 1H); 6.83 (dd, 1H); 6.67 (d, 1H); 5.13 (b, 2H); 4.93 (dd, 1H); 4.48 (m, 3H); 3.84 (, 1H); 3.76 (s, 3H); 3.03 (m, 1H); 2.85-2.70 (m, 2H); 2.5-2.7 (m, 2H); 2.25 (M, 1H); 2.00-1.93 (m, 4H); 1.29 (d, 6H) '/ NMR-13, (75 MHz, CDCl3; (carbonyl and / or amidine carbons) d 177.7; 174.3; 170.3 LC-MS (m / z) 523 (M + 1) + E p 30 ... (S) - or ... (R) -l-Hydroxy-7-me toxitetralin-1-yl-C (O) -Aze-Pab (0-C (0) -Et) It is added propanoic anhydride (9.5 mg, 73 μmoles) to an ice-cooled solution of (S) - or (R) - 1-Hydroxy-7-methoxytetralin-1-yl-C (O) -Aze-Pab (OH) (30 mg, 66 μmol, see Example 14 above and Et3N (7.4 mg, 73 μmol) in methylene chloride (1 ml). The mixture is stirred at room temperature overnight. The product is purified without purifying using Preparative RPLC (CH3CN: 0.1M ammonium acetate, 30.70 a 40:60) and the fractions of interest are concentrated. The lyophilisate affords 19 mg (56%) of the title compound. RMN-1 !! (400 MHz; CDC13): d 7.93 (t, H); 7.67 (d, 2H); 7.32 (d, 2H); 7.06 (d, 1H); 6.83 (dd, 1H); 6. 68 (d, 1H), 5.12 (b, 2H); 4.93 (dd, 1H); 4.50 (m, 2H); 3.84 (m, 1H); 3.76 (s, 3H), 3.03 (m, 1H); 2.67-2.50 (m, 2H); 2.5-2.7 (m, 4H); 2.26 (m, 1H); 1.92 (m, 4H); 1.26 (t, 3H) 13 C-NMR (100 MHz, CDC13): (carbonyl and / or amidine carbons) d 17.8; 173.1; 171.4 LC-MS (m / z) 509 (M + 1) + ' Example 31 (S) - or (R) -l-Hydroxy-7-methoxytetralin-1-yl-C (O) -Aze-Pab (OC (O). -CH) Cyclohexanecarboxylic chloride (7.3 mg; 46 μmol) to an ice-cooled solution of (S) - or (R) -l-hydroxy-7-metho? -itetralin-1-yl-C (0) -Aze-Pa (OH) (30 mg; μmol, see Example 14 above) and Et3N (7 mg, 73 μmol) in methylene chloride (1 ml). The mixture is stirred at room temperature overnight. The mixture is diluted with an additional amount of methylene chloride and the mixture is washed three times with water and once with brine, dried (Na 2 SO 4) and concentrated. Purify the product without purification using preparative RPLC (CH3CN: 0.MM ammonium acetate (40:60)) and concentrate in the fractions of interest. The lyophilisate provides 18 mg (50%) of the title compound.r.

RMN-1 !! (400 MHz; CDC13): d 7.91 (t, 1H); 7.67 (d, 2H); 7.30 (d, 2H); 7.06 (d, 1H); 6.83 (m, 1H); 6.67 (d, 1H); 5.09 (b, 2H); 4.93 (dd, 1H); 4.50 (m, 3H); 3.83 (m, 1H); 3.76 (s, 3H); 3.02 (q, 1H); 2.68-2.45 (, 3H); 2.26 (m, 1H); 2.1-1.9 (m, 6H); 1.83 (m, 2H); 1.70 (m, 1H); 1.59 m, 2H); 1.32 (, 3H) 13 C-NMR (100 MHz, CDC13): (carbonyl and / or amidine carbons) d 178.7; 174.2; 171.4 LC-MS (m / z) 563 (M + 1) + Example 32 (S) - or (R) -l-hydroxy-7-methoxytetralin-1-yl-C (O) -Aze-Pab (O-allyl) i) S) - or (R) -1-hydroxy-7-methoxyteralin-1-yl-C (O) -Aze-Pab (Teoc) The subtitle compound is prepared according to the method described in Example 22 ( iii) above from l-hydroxy-7-methoxytetralin-1-carboxylic acid (0.44 g, 2.0 mmol, see Example l (ii) above), HATU (0.80 g, 2.1 mmol), H-Aze-Pa (eoc) ) x HCl (1.17 g, 2.6 mmol, see Example 19 (iv) above) and 2,4,6-trimethylpyridine (1.2 g, 10 mmol). Purify the product without purification (1.73 g) using preparative RPLC (CH3CN: ammonium acetate 0.MI, 55:45 to 45:55). The fractions of interest are partially concentrated and extracted with methylene chloride. The organic layer is dried (Na 2 SO 4) and concentrated to yield 0.32 g (28%) of a diastereomeric mixture. The RP. Preparative LC (CH CN: 0.1M ammonium acetate (46:54)) yields two diastereoisomers: Compound 32A (diastereomer that moves faster, 0.16 g, 28%) and Compound 32B (diastereomer that moves slower: 0.16 g) 28%). Compound 32A: RMN-1 !! (400 MHz; CDC13): d 7.96 (t, 1H); 7.86 (dd, 2H); 7.36 (dd, 2H); 7.07 (d, 1H); 6.87 (dd, 1H); 6.68 (d, 1H); 4.95 (dd, 1H); 4.54 (m, 3H); 4.26 (m, 2H); 3.84 (m, 1H); 3.78 (s, 3H); 3.04 (q, 1H); 2.83 (d, 1H); 2.63 (m, 2H); 2.28 (m, 1H); 2.02-1.85 (m, 4H); 1.15 (dt, 2H); 0.08 (s, 9H) LC-MS (m / z) 581 (M + 1) + (ii) (S) - or (R) -l-Hydroxy-7-methoxytetralin-1-yl-C (O) -Aze-Pab (Teoc) (O-allyl) O-allylhydroxylamine x HCl (57 mg 0.52 mmole) to a solution of (S) - or (R) -l-hydroxy-7-methoxy-tetrain-1-yl-C (O) -Aze-Pab (Teoc) (50 mg, 86 μmol; Compound 32A of step (i) above) in THF (3 ml), and the mixture is stirred at 60 ° C overnight.

The solution is concentrated, and the product is purified without purification using preparative RPLC (CH 3 CN: ammonium acetate 0., 55:45 to 60:40). The fractions of interest are concentrated, and the remaining mixture is extracted with methylene chloride. The organic layer is washed with brine, dried (Na2SQ) and concentrated to yield 28 mg (51%) of the subtitle compound. 1 H-NMR (400 MHz, CDC13): d 7.81 (t, 1H); 7.59 (s, 1H); 7.48 (d, 2H); 7.30 (d, 2H); 7.06 (d, 1H); 6.83 (dd, 1H); 6.69 (d, 1H); 6.04 (m, 1H); 5.35 (m, 1H); 5.27 (d, 1H); 4.92 (dd, 1H); 4.66 (dd, 1H); 4.50 (m, 1H); 4.16 (m, 2H); 3.81 (m, 1H); 3.78 (s, 3H); 2.97 (q, 1H); 2.82 (d, 1H); 2.60 (m, 2H); 2.26 (, 1H); 2.05-1.85 (m, 4H); 0.98 (m, 2H); 0.03 (s, 9H) (iii) (S) or (R) -l-hydroxy-7-methoxytetralin-1-yl-C (O) -Aze-Pab (O-allyl) The title compound is prepared according to the method described in the Example 19 (vi) from (S) - or (R) -l-hydroxy-7-methoxytetralin-1-yl-C (O) -Aze-Pab (Teoc) (O-allyl) (28 mg, 44 μmol from step (ii) above) in CH3CN (2 ml) and Bu4NF (IM in THF, 0.1 ml, 0.1 mmol). The crude product is purified (21.3 mg) using flash chromatography (Si gel, ethyl acetate). yield 10 mg (46%).

RMN-1 !! (400 MHz; CDC13): d 7.88 (t, 1H); 7.62 (d, 2H); 7.30 (d, 2H); 7.06 (d, 1H); 6.83 (dd, 1H); 6. 68 (d, 1H); 6.09 (m, 1H); 5.35 (m, 1H); 5.23 (m, 1 HOUR); 4.93 (dd, 1H); 4.84 (s, 3H); 4.68 (m, 1H); 4.50 (m, 2H); 3.82 (m, 1H); 3.77 (s, 3H); 3.01 (, 1H); 2. 82 (d, 1H); 2.62 (m, 2H) /; 2.26 (m, 1H); 2.0-1.8 (m, 4H) 13 C-NMR (100 MHz; CDC13): (carbonyl and / or amidine carbons) d 178.8; 171.2; 159.6 LC-MS: (m / z) 493 (M + 1) + Example 33 (S) - or (R) -l-Hydroxy-7-methoxytetralin-1-yl-C (O) -Aze-Pab (O-Bz) (i) (S) - or (R) -l-Hydroxy-7-methoxytetralin-1-yl-C (O) -Aze-Pab (Teoc) (O-Bzl) O-Benzylhydroxylamine x HCl (82 mg; 0.52 mmole) to a solution of (S) - or (R) -1-hydroxy-7-methoxytetralin-1-yl-C (O) -Aze-Pab (Teoc) (50 mg, 86 μmol, see Example 32 ( i) above) in THF (3 ml), and the mixture is stirred at 60 ° C overnight. The solution is concentrated, and the product is purified without purification using preparative RPLC (CH3CN: 0.1M ammonium acetate: 60:40 to 70:30). The fractions of interest are concentrated and the remaining mixture is extracted with methylene chloride. The organic layer is washed with brine, dried (Na2SO4) and concentrated to yield 41 mg (70%) of the subtitle compound. NMR-aH (400 MHz, CDC13): d 7.81 (t, 1H); 7.60 (s, 1H); 7.47 (d, 2H); 7.40 (m, 5H); 7.30 (d, 2H); 7.06 (d, 1H); 6.83 (d'd, 1H); 6.69 (d, 1H); 5.18 (s, 2H); 4.92 (dd, 1H); 4.51 (m, 2H); 4.15 (m, 2H); 3.81 (m, 1H); 3.77 (s, 3H); 2.81 (d, 1H); 2.60 (m, 2H); 2.25 (m, 1H); 2.1-1.8 (m, 4H); 0.96 (m, 2H); 0.02 (s, 9H) LC-MS (m / z) 687 (M + 1) + (ii) (S) - or (R) -l-Hydroxy-7-methoxytetralin-1-yl-C (0) -Aze-Pab (O-Bzl) The title compound is prepared according to the method described in Example 19 (vi) above from (S) - or (R) -1-hydroxy-7-methoxytetralin-1-yl-C (O) -Aze-Pab (Teoc) (OBzl) (28 mg 44 μmoles; of the stage (i) above) and Bu4NF (1M in THF, 0.1 ml, 0.1 mmol). The crude product is purified (21 mg) using flash chromatography (Si gel, ethyl acetate). Yield: 10 mg (35%). NMR-aH (400 MHz, CDC13): d 7.88 (t, 1H); 7.61 (d, 2H); 7.45 (d, 2H); 7.40-7.35 (, 5H); 7.06 (d, 1H); 6.83 (dd, 1H); 6.68 (d, 1H); 5.15 (s, 2H); 4.92 (dd, 1H); 4.85 (b, 2H); 4.50 (b + m, 3H); 3.83 (m, 1H); 3.77 (s, 3H); 3.02 (m, 1H); 2.82 (d, 1H); 2.62 (m, 2H); 2.26 (m, 1H); 2..0-1.8 (m, 4H) 13 C-NMR (100 MHz, CDC13): (carbonyl and / or amidine carbons) d 178.8; 171.3; 159.6 LC-MS (m / z) 543 ¿(M + 1) + Example 34 (S) - or (R) -l-Hydroxy-7-methoxytetralin-1-yl-C (O) -Aze-Pab- (CO-O-metalloyl) (i) p-Nitrophenyl-methallylcarbonate Pyridine (1.21 g, 15 mmol) is added to an ice-cooled solution of • metal alcohol (1.0 g, 14 mmol) and p-nitrophenyl chloroformate (3.07 g, 15 mmol). in methylene chloride (40 ml), and the resulting mixture is stirred at room temperature for 1 hour, after which the solution is washed with KHSO 4 (3x) and brine, dried (Na 2 SO) and concentrated to yield 2.9 g ( 88%) of the subtitle compound. RMN-1 !! (400 MHz, CDC13): d 8.29 (d, 2H); 7.40 (d, 2H); 5.12 (s, 1H); 5.06 (s, 1H); 4.70 (s, 2H); 1.85 (s, 3H) (ii) (S) - or (R) -l-Hydroxy-7-methoxytetralin-1-yl-C (O) -Aze-Pab- (CO-0-methallyl) NaOH is added ( aqueous, 2M, 0.35 ml, 0.7 mmol) to a solution of (S) - or (R) -l-hydroxy-7-methoxytetralin-1-yl-C (O) -Aze-Pab x HOAc (32 mg; μmoles, see Example 3 above) in THF (3 ml), after which p-nitrophenyl-methallyl carbonate (17 mg, 71 μmol, from step (i) above) is added and the solution is stirred at room temperature for 1 hour. The product is purified without purifying using Preparative RPLC (CH3CN: ammonium acetate 0. ÍM (40:60)). The fractions of interest are concentrated and the water solution is extracted with methylene chloride. The organic layer is washed with brine, dried (Na 2 SO) and concentrated. The product is dissolved in CH3CN / water and lyophilized to yield 23 mg (67%) of the title compound. RMN-1 !! (400 MHz, CDCl 3): d 7.97 (t, 1H); 7.83 (d, 2H); 7.33 (d, 2H); 7.06 (d, 1H); 6.83 (dd, 1H); 6.67 (d, 1H); 5.06 (s, 2H); 4.93 (m, 2H); 4.60 (s, 2H); 4.51 (m, 2H); 3.84 (m, 1H); 3.76 (s, 3H); 3.05 (m, 1H); 2.82 (d, 1H); 2.60 (m, 2H); 2.27 (, 1H); 2.0-1.85 (m, 4H); 1.83 (s, 3H) 1 C-NMR (100 MHz, CDCl 3): (carbonyl and / or amidine carbons) d 178. 8; 1 71. 4; 159 LCMS (m / z) 535 (M + 1) + Example 35 1-Hydroxy-7-aminotetralin-1-yl-C (0) -Aze-Pab (OH) (i) l-Hydroxy-7-nitrotetralin-l-yl-C (O) -Aze-Pab (Teoc) The subtitle compound is prepared according to the method described in Example 22 (iii) above from acid l -hydroxy-7-nitrotetranyl-1-yl-carboxylic acid (200 mg, 0.84 mmol, see Example 7 (ii) above), HATU (353 mg, 0.93 mmol), H-Aze-Pab (Teoc) (417 mg 0.93 mmoles, see Example 19 (iv) above) and 2,4,6-trimethylpyridine (309 mg, 3.37 mmoles). Purify the product without purification using preparative RPLC (CH3CN: 0. IM ammonium acetate (50:50)). The fractions of interest are concentrated and lyophilized to yield 226 mg (45%) of the subtitle compound. RMN-1 !! (400 MHz, CDC13): d 8.04 (m, 2H); 7.84 (d, 2H); 7.77 (d, 1H); 7.29 (m, 2H); 4.93 (m, 1H); 4.65-4.50 (m, 1H); 4.40 (dd, 1H); 3.96 (m, 1H); 3.82 (m, 5H); 3.15 (m, 1H); 2.95 (, 1H); 2.75 (m, 1H); 2.52 (, 1H); 2.44-2.25 (m, 1H); 2.1-1.9 (m, 5H); 0.05 (s, 9H) LC-MS (m / z) 596 (M + 1) + (ii) l-Hydroxy-7-aminotetralin-1-yl-C (O) -Aze-Pab (Teoc) A hydrogenated mixture of l-hydroxy-7-nitrotetralin-1-yl-C (O) -Aze-Pab (Teoc) (48 mg, 81 μmol, from step (i) above), acetic acid (5 mg, 81 μmoles) and Pd / C (5%, 24 mg) at room temperature and pressure at 3 hours. The resulting mixture is filtered through Celite and concentrated to yield 37 mg (85%) of the title compound. RMN-1 !! (400 MHz; CDC13): d 7.86 (dd, 2H); 7.42 (d, 1H); 7.33 (d, 1H); 6.89 (dd, 1H); 6.58 (dd, 1H); 6.47 (b, 0.5H); 6.23 (b, 0.5H); 4.91 (m, 1H); 4.68-4.52 (, 1H); 4.5-4.4 (m, 1H); 4.23 (, 2H); 3.85 (, 1H); 3.69 (m, 1H), 3.2-3.0 (m, 1H); 2.74 (d, 1H); 2.65-2.45 (m, 2H), 2.4-2.2 (m, 1H-); 2.0-1.8 (m, 5H); 0.05 (s, 9H) LC-MS (m / z) 566 (M + 1) + (iii) l-Hydroxy-7-aminoteralin-1-yl-C (0) -Aze-Pab (OH) A mixture of hydroxylamine x HCl (29 mg, 41 mmol and TEA (140 mg, 1.38 mmol) is sonified). THF (10 mL) at 40 ° C for 1 hour A solution of l-hydroxy-7-aminotetralin-1-yl-C (O) -Aze-Pab (Teoc) (140 mg, 1.38 mmol; from step (ii) above) in THF (5 ml), and the mixture is stirred at 40 ° C for 3 days .. The resulting mixture is concentrated and the product is purified without purification using preparative RPLC (CH3CN: ammonium acetate 0. IM (30:70).) The concentration and lyophilization of the solution yielded 20 mg (65%) of the title product: 1-NMR (400 MHz, CDC13): d 8.26 (b, 0.5H); 8.03 (b, 0.5H), 7.57 (dd, 2H) /, 7.39 (d, 1H), 7.30 (d, 1H), 6.91 (dd, 1H), 6.65-6.55 (m, 1H), 4.98 (m, 3H), 4.65-4.30 (m + b, 4H), 3.88 (m, 0.5H), 3.69 (, 0.5H), 3.14 (m, 1H), 2.77 (d, 1H), 2.65-2.50 (m, 2H 2.45-2.25 (m, 1H (; 2.10 (s, 2H); 2.00-1.85 (m, 4H) 13 C-NMR (100 MHz, CD30D): (carbonyl and / or amidine carbons) d 178.2; 172.9; 155.2 CL-MS (m / z) 438 (M + 1) t Example 36 (S) - or (R) -l-Hydroxy-7-methoxytetralin-1-yl-C (0) -Aze-Pab (O-Val) (i) (S) - or (R) -l-hydroxy-7-methoxytetralin-1-yl-C (0) -Aze-Pab (O-Val (Boc)) EDC x HCl (16 mg; μmoles) to an ice-cooled solution of (S) - or (R) -l-hydroxy-7-methoxytetralin-1-yl-C (O) -Aze-Pab (OH) (30 mg, 66 μmoles; Example 14 above), Boc-Val-OH (18 mg, 83 μmoles) and DMAP (24 mg-, 0.20 mmol) in DMF (3 ml), and the solution is stirred overnight. The resulting mixture is poured into water (200 ml) and the mixture extracted three times with EtOAc. The combined organic phases are washed with dilute nitric acid solution and brine, dried (Na 2 SO) and concentrated. It is purified; Unpurified product (41 mg) using preparative RPLC (CH3CN: 0.1 M ammonium acetate (40:60)). Yield 13 mg (30%). RMN-1 !! (500 MHz; CDC13): d 7.94 (bt, 1H); 7.68 (d, 2H); 7.33 (d, 2H); 7.08 (d, 1H); 6.85 (dd, 1H); 6.69 (d, 1H); 5.30 (b, 2H); 5.18 (bd, 1H); 4.95 (m, 1H); 4.60-4.55 (m, 3H); 4.48 (dd, 1H); 4.32 (, 1H); 3.86 (m, 1H); 3.79 (s, 3H); 3.05 (m, 1H); 2.83 (m, 1H); 2.7-2.55 (m, 2H); 2.28 (, 1H); 2.22 (m, 1H); 2.05-1.85 (m, 5H); 1.48 (s, 9H); 1.08 (d, 3H); 1.04 (d, 3H) LC-MS (m / z) 652 (M + 1) + (ii) (S) - or (R) -l-Hydroxy-7-methoxytetralin-1-yl-C (O) -Aze-Pab (O-Val) An ice-cooled solution of 1-hydroxy-7 is stirred -methoxytetralin-l-yl-C (O) -Aze-Pab (O-Val (Boc)) (12 mg, 18 μmol, from step (i) above) in EtOAc saturated with HCl (5 ml) for 80 minutes, after the solution is concentrated, dissolved in water and lyophilized overnight to yield 11 mg (96%) of the title compound. RMN-1 !! (400 MHz, D20): d 7.66 (d, 1H, minor); 7.59 (d, 2H, greater); 7.45-7.35 (m, 2H); 7.2-7.1 (m, 1H); 6.95-6.85 (m, 1H); 6.75-6.65 (m, 1H); 5.25 (, 1H, minor); 4.89 (m, l?; / Ayor); 4.6-4.3 (m, 3H); 4.21 (m, 1H); 4.14 (m, 1H, greater); 3.87 (m, 1H, greater); 3.81 (s, 3H, minor); 3.63 (s, 3H, greater); 2.8-1.7 (m, 9H); 1.11 (d, 6H) 13 C-NMR (100 MHz; D20): (carbonyl and / or amidine carbons) d 178.3; 173.8; 169.1; 161.4 LC-MS (m / z) 552 (M + 1) * E p plo_ 37 (S) - or (R) -l-Hydroxy-7-methoxytetralin-l-yl-C (O) -Aze-N (Me) -Bzl-4-C (NH2) NH x HOAc (i) Methyl-4-cyanobenzylidene a A solution of p-cyanobenzaldehyde (13.1 g, 0.1 mole), methylamine (3.1 g, 0.1 mole) and p-TsOH (50 mg, cat.) in toluene (150 ml) was stirred. at room temperature overnight, then washed with NaHCO3 / (aqueous (2x) and brine, dried (Na2SO4) and concentrated Yield 14.4 g (100%).

NMR-aH (300 MHz, CDC13): d 8.2 (s, 1H); 7.78 (d, 2H); 7.68 (d, 2H); 3.54 (s, 3H) (i i) Methyl-4-cyanobenzylamine NaBH 4 (4.54 g, 0.42 mole) is added in portions to a solution; Ice-cooled methyl-4-cyanobenzylideneimine (14.4 g, 0.1 mole; (i) above) in EtOH. The solution is stirred at room temperature overnight and the resulting solution is partitioned with HCl (2M, aqueous), washed with ether (2x), made alkaline with NaOH (2M, aqueous) to pH 10, and extracted with EtOAc (3x). The organic solution is washed with water and brine, dried (Na 2 SO 4), and concentrated. Yield 11.4 g (78%) -. NMR ^ H (300 MHz, CDC13): d 7.92 (d, 2H); 7.76 (d, 2H); 4.82 (s + b, 5H); 4.40 (s, 2H) (iii) Boc-Aze-N (Me) Bzl-4-CN EDC x HCl (14.5 g, 76 mmol) is added portionwise to an ice-cooled solution of ethyl 4-cyanobenzylamine (11.4 g, 78 mmol), Boc-Aze (OH) (15.4 g, 78 mmol) and DMAP (10.5 g, 82 mmol) in CH3CN (500 ml), after this the mixture is stirred at room temperature overnight. The resulting mixture is partitioned between EtOAc and water, the aqueous phase is extracted with EtOAc (3 x 100 ml) and the combined organic layer is washed with NaHS04 (2x), water (2x) and brine (lx), dried (Na2S04). ) and concentrates. The yield of the unpurified product is 23.2 g (90%). A small amount (6.17 g, 18.7 mmol) is purified using flash chromatography (Si gel, EtOAc). Performance 4.0 g (65%). NMR-XH (400 MHz, CDC13) (complex due to rotamers): d 7.66 (d, 2H, minor); 7.60 (d, 2H, greater); 7.38 (d, 2H, greater); 7.31 (d, 2H, minor); 5.01 (dd, 1H), 4.9-4.7 (b, 1H); 4.6-4.45 (b, 1H); 4.07 (m, 1H); 3.90 (m, 1H); 3.00 (s, 3H, minor); 2.96 (s, 3H, greater); 2.46 (m, 1H); 1.43 (s, 3H) (iv) Aze-N (Me) -Bzl-4-CN x HCl A solution of Boc-Aze-N (Me) -Bzl-4-CN (4.0 g, 12 mmol, from step (iii) is stirred. ) above) in EtOAc (saturated with HCl: 50 ml) during minutes, after this the solution is concentrated. Yield 3.1 g (quantify). <1> H NMR (400 MHz, D20): d 7.80 (m, 2H); 7.45 (m, 2H); 5.6-5.45 (m, 1H); 4.72 (s, 2H), 4.3-4.1 (m, 1H); 4.08-3.95 (m, 1H); 2.94 (s, 3H); 2.8-2.55 (m, 1H) (v) (S) - or (R) -l-Hydroxy-7-methoxytetralin-1-yl-C (O) -Aze-N (Me) -Bzl-4-CN Se add a solution of Aze-N (Me) -Bzl-4-CN x HCl (0.56 g, 2.1 mmol, from step (iv) above) and 2,4,6-trimethylpyridine (0.51 g, 4.2 mmol) in DMF (3 ml) to an ice-cooled solution of l-hydroxy-7-methoxytetralin-1-yl-carboxylic acid (0.44 g, 2.0 mmol, see Example l (ii) above) and HATU (0.80 g; mmoles) in DMF (3 ml), and the mixture is stirred at room temperature overnight. The resulting mixture is poured into water (0.5 1) and extracted with EtOAc (3x). The organic solution is washed with brine, dried (Na2SO4), and evaporated. The crude product was purified (1.06 g) using preparative RPLC (CH3CN: 0.1M ammonium acetate (32.5: 67.5)), yielding two diastereoisomers, a faster diastereomer (Compound 37A, yield 215 mg (50%)), and slower diastereomer (Compound 37B, yield 205 mg (48%)). Compound 37A RMN-1 !! (400 MHz, CDC13) (complex due to rotamerism): d 7.74 (d, 2H, lower); 7.66 (d, 2H, greater); 7.42 (d, 2H, minor); 7.39 (d, 2H, greater); 7.07 (m, 1H); 6.87-6.81 (m, 1H); 6.80 (d, 2H, greater); 6.75 (d, 2H, minor); 5.22 (dd, 1H, greater); 5.02 (dd, 2H, minor); 4.71 (dd, 2H); 4.60 (m, 1H); 3.98 (, 1H); 3.81 (s, 3H, greater); 3.78 (s, 3H, minor); 3.05-2.05 (m, 4H, 3.05; s, 3H, lower and 3.01, s, 3H, higher); 2.92-2.82 (, 1H), 2.67 (, 1H); 2.40 (, 1H, minor); 2.25-2.07 (m, 3H), 1.98 (m, 2H) (vi) (S) - or (R) -l-Hydroxy-7-methoxytetralin-1-yl-C (O) -Aze-N (Me) -Bzl-4-C (NH 2) NOH A solution of (S) - or (R) -1-hydroxy-7-methoxytetralin-1-yl-C (O) -Aze-N (Me) -Bzl-4-CN (0.18 g; 0. 42 mmol), Compound 37A from step (v) above), hydroxylamine x HCl (88 mg, 1.3 mmol) and TEA (0.18 ml, 1.3 mmol) in ethanol (absolute, 3 ml) was stirred at room temperature for 6 hours, after which the product was purified without purification using flash chromatography (methylene chloride-methanol (90:10)). . The combined fractions of interest are concentrated. Yield: 0.18 g (91%) RMN-1 !! (400 MHz, CDC13) (complex due to rotamerism): d 7.67 (d, 2H, minor); 7.60 (d, 2H, greater); 7.28 (m, 2H, partially obscured by CHCl3); 7.04 (dd, 1H); 6.85-6.72 (m, 2H); 5.65 (b, 2H, greater); 5.33 (b, 2H, minor); 5.20 (dd, 1H, greater); 5.06 (dd, 1H, minor); 4.75-4.45 (m, 3H); 3.95 (m, 1H); 3. 78 (s, 3H, greater); 3.75 (s, 3H, minor); 3.00 (s, 3H, minor); 2.94 (d, 3H, greater); 2.9-2.75 (m, 1H); 2.65 (m, 1H); 2.40 (m, 2H, greater); 2.10 (, 3H); 1.95 (m, 2H) ~ LC-MS (m / z) 467 (M + 1) + (vii) (S) - or (R) -l-hydroxy-7-methoxytetralin-l-yl-C (O) -Aze-N (Me) -Bzl-4-C (NH2) NH x HOAc Subjected to chromatography a mixture of (S) - or (R) -l-hydroxy-7-methoxytetralin-1-yl-C (O) -Aze-N (Me) -Bzl-4-C (NH2) NOH (60 mg; 0.13 mmol, from stage (vi) above), HOAc (15 mg, 0.26 mmol) and Pd / C (10%, 27 mg) in ethanol for two days. After this the mixture is filtered through -celite. The resulting solution is concentrated, and the product is purified without purification using preparative RPLC (CH3CN: 0.1M ammonium acetate: 10:90 to 20:80). The fractions of interest are partially concentrated and lyophilized overnight. Yield 18 mg (27%). RMN-1 !! (400 MHz, D20) (complex due to rotamerism): d 7.83-7.73 (m, 1H); 7.68 (d, 1H); 7.50 (t, 1H); 7.43 (d, 1H); 7.17 (d, 1H); 6.93 (m, 1H); 6.82 (d, 1H); 5.40 (dd, 1H); 4.85 (d, 1H); 4.70 (m, 1H); 4.58 (d, 1H); 4.4-4.0 (, 2H); 3.70 (s, 3H); 3.10 (s, 3H); 2.9-2.6 (m, 3H); 2.25-2.05 (m, 4H); 2.01-1.7 (m, 4H) 13 C-NMR (100 MHz; D20): (carbonyl and / or amidine carbons) (complex due to rotamerism) d 178.6; 177.6; 173.8; 173.3; 173.1; 167.5; 158.5; 158.4; 158.2 Example 38 9-Hydroxyfluoren-9-yl-C (O) -Aze-Pab x HOAc (i) 9-Hydroxyfluoren-9-yl-C (O) -Aze-Pab (Z) The subtitle compound is prepared according to the method described in Example 3 (i) above from 9-hydroxyfluoren-9 acid -carboxylic acid (230 mg, 1.0 mmol), TBTU (350 mg, 1.1 mmol), H-Aze-Pab (Z) x HCl (500 mg, 1.25 mmol) prepared according to the method described in the Patent Application International WO 97/02284) and DIPEA (0.52 g, 4.0 mmol). The crude product is purified using preparative RPLC (CH3CN: ammonium acetate 0.MI, 50:50). The fractions of interest were partially concentrated and extracted with EtOAc (3x). The organic layer is dried (Na2SO4) and concentrated to yield 266 mg (46%) of the subtitle compound.

NMR-aH (400 MHz, CDC13): d 7.92 (d, 3H); 7.66 (dd, 2H); 7.5-7.2 (m, 11H); 5.25 (s, 3H); 4.85 (dd, 1H); M 4.52 (M, 2H), 2.83 (t, 2H); 2.33 (m, 1H); 2.12 (m, 1H) LC-MS (m / z) 575 (M + 1) + (ii) 9-Hydroxyfluoren-9-yl-C (O) -Aze-Pab x HOAc Pd / C (5%, 100 mg) and HOAc (9 μl) are added to a mixture of 9-hydroxyfluoren-9-yl. -C (O) -Aze-Pab (Z) (70 mg, 0.12 mmol, from step (i) above) in EtOH (10 mL). The mixture is hydrogenated at room temperature and pressure for 6 hours. The mixture is filtered through Celite, concentrated and dissolved in water, after which the aqueous solution is lyophilized. Yield 53 mg (88%). NMR_? H (00 MHz, D20): d 7.9-7-.65 (m, 4H); 7. 60-7.35 (m, 8H); 4.51 (s, 1H); 4.05 (m, 2H); 3.25 (t, 1H); 2.49 (m, 0.5H, rotamer); 2.28 (m, 0.5H, rotamer); 1.98-1.84 (m, 7H; within it: -1.95, s, 3H) 13 C-NMR (100 MHz, D20): (carbonyl and / or amidine carbons) d 173.4; 173.0; 172.6; 167.0 FAB-MS (m / z) 441 (M + 1) + Example 39 The compounds of the title of the Examples 1 to 12, 19, 28, 37 and 38 (which are all the compounds of Formula I) in Test A above and found to be all exhibit a value IC50TT less than 0.3 μM.

EXAMPLE 40 The title compounds of Examples 13 to 18 and 29 to 36 (which all with compounds of the formula la) are tested in Test A above and all are found to exhibit an IC50TT value of more than 1 μM.

EXAMPLE 41 The title compounds of Examples 13 to 18 and 29 to 36 (which are all compounds of the formula la) are tested in Test E above and all are found to exhibit oral and / or parenteral bioavailability in the rat as the corresponding active inhibitor of formula I.

Abbreviations Ac = acyl AcOH = acetic acid Aze = azetidin-2-carboxylate AzeOH = azetidine-2-carboxylic acid DCC = dicyclohexylcarbodiimide DIPEA = diisopropylethylamine DMAP = N, N-dimethyl amino pyridine DMF = dimethyl formamide DMSO = dimethyl sulfoxide EDC = 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride Et = ethyl Et20 = diethyl ether EtOAc = ethyl acetate EtOH = ethanol h = hours HATU = O- (azabenzotriazol-1-yl) hexafluorophosphate -N, N, N ', N' -tetramethyluronium HBTU = [N, N, N ', N' -tetramethyl- O- (benzotriazol-1-yl) uronium] HCl (g) hydrochloric acid gas HOAc = acetic acid LC = chromatography liquid Me = methyl MeOH = methanol Pab-H = para-amidinobenzylamino H-Pab-H = para-amidinobenzylamine QF = tetrabutylammonium fluoride (Bu4NF) RPLC = preparative reverse phase high performance liquid chromatography RT = room temperature TBTU = [tetrafluoroborate of N, N, N ', N' -tetramethyl- 0- (benzotriazol-1-yl) uronium] TEA = triethylamine Teoc = 2- (trimethylsilyl) ethoxycarbonyl THF = tetrahydrofuran TLC = thin layer chromatography Val = L-valine Z = benzyloxycarbonyl The prefixes n, s, i and t have their usual meanings: normal, iso, secondary and tertiary.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. A compound of formula I, characterized in that R1 represents H, C? -4 alkyl (optionally substituted by one or more substituents selected from cyano, halo, OH, C (0) 0Rla or C (0) N (Rlb) Rlc) or 0Rld; Rld represents H, C (0) Rl, SiR12R13R14 or C? -6 alkyl, wherein the latter group is optionally substituted or terminated by one or more substituents selected from OR15 or (CH2) qR16; R12, R13 and R14 independently represent H, phenyl or C? _6 alkyl; RJ represents Cx-phenyl alkyl, OH, C (0) OR17 or C (0) N (H) R1S RJ represents H, C? -4 alkyl or CH 2 C (0) 0R R 15 RJ independently represent H, C?-6 alkyl or C alqu alkylphenyl 3; Rla, Rlb, Rlc, '.R11 and R19 independently represent H or C? -4 alkyl; and q represents 0, 1 or 2; Rx represents a structural fragment of the formula bundle, Ilb or lie, where dotted lines independently represent optional links; A and B independently represent O or S, CH or CH2 (as appropriate), or N or N (R21) (as appropriate); D represents -CH2-, O, S, N (R22 - - (CH2) 2- -CH = CH-, -CH2N (R22) -, -N (R22) CH2-, -CH = N-, -N = CH-, -CH20-, -OCH2-, -CH2S- or -SCH2-, Xi represents C2_4alkylene, C2-3alkylene interrupted by Z; -CYOJ-Z-A1; -ZC (O) -A1-; -CH2-C (0) -Ax; -ZC (O) -Z-A2-; -H2-ZC (O) -A2-; -Z-CH2-C (O) -A2-; -Z-CH2-S (0) m-A -CH2-Z-S (0) m-A2-; -C (0) -A3 -Z-A3- -A -Z-; X2 represents C2-3 alkylene, -C (0) -A4-A4-C (0) -; X3 represents CH or N; X4 represents a single bond, O, S, C (O), N (R23), -CH (R23) -, -CH (R23) -CH (R24) - or -C (R23) = C (R24) -; A1 represents a single bond or alkylene A represents a single bond or -CH2-; A3 represents alkylene of C? _3; A4 represents C (O) or Cx-2 alkylene; Z represents, in each occurrence, O, S (O) or N (R25); m represents, in each occurrence, 0, 1 or 2; R2 and R4 independently represent one or more optional substituents selected from C? - alkyl (wherein the latter group is optionally substituted by one or more halo substituents), C? -4 alkoxy, methylenedioxy, halo, hydroxy, cyano, nitro , S02NH2, C (0) 0R26 or N (R27) R28); R3 represents an optional substituent selected from OH or C? - alkoxy; R21, R22, R23, R24, R25, R 2 6 R 2 1 r "independently represent H or Cx-4 alkyl; Y represents CH 2, (CH 2) 2, CH = CH, (CH 2) 3, CH 2 CH = CH or CH = CHCH 2, wherein the last three groups are optionally substituted by C 4 alkyl, methylene, oxo or hydroxy; Ry represents H or C? -4 alkyl; n represents 0, 1, 2, 3 or 4; and B represents a structural fragment of the formula Illa or IIIc illa lile wherein X5, X6, X7 and X8 independently represent CH, N or N-O; and R 31 represents an optional substituent selected from halo and C? - alkyl; or a pharmaceutically acceptable salt thereof; with the proviso that: (a) A and B do not represent both O or S; (b) B and D do not represent both O or S; (c) when R1 represents 0Rld and Xx represents -C (0) -Z-Aa, -Z-CH2-S (0) m-A2, -CH2-ZS (0) m-A2- or -ZC (O) -Z-A2, then A1 or A2 (as appropriate) do not represent a single link; and (d) when X4 represents -CH (R23) -, R1 does not represent OH.

2. A compound of formula I, according to claim 1, characterized in that R1 represents OH or C? -4 alkyl (wherein the latter group is optionally substituted by cyano or OH).

3. A compound of formula I, according to any of the preceding claims, characterized in that Rx represents a structural fragment of the formula lia.

4. A compound of formula I, according to any of the preceding claims, characterized in that, when Rx represents a structural fragment of the formula lia, dotted lines represent bonds, A and B both represent CH and D represents -CH = CH-. .

5. A compound of formula I, according to any of the preceding claims, characterized in that, when Rx represents a structural fragment of the formula lia, Xx represents C2 or C3 alkylene, -0 (CH2) - or -0 (CH2) 2 -.

6. A compound of formula I, according to claim 5, characterized in that Xi represents C3 alkylene or -0 (CH2) 2--

7. A compound of formula I, according to any of the preceding claims, characterized in that Y represents CH2, (CH2) 2 or (CH2) 3.

8. A compound of formula I, according to any of the preceding claims, characterized in that, when B represents a structural fragment of formula Illa, X5, X6, X7 and X8 all represent CH.

9. A compound of formula I, according to any of the preceding claims, characterized in that, when Rx represents a structural fragment 2 of the formula lia, and R represents at least one substituent, a substitution point is at the carbon atom which is in position B.

10. A compound of formula I, according to any of the preceding claims, characterized in that, when Rx represents a structural fragment of the formula lia, the dotted lines represent bonds, A and B both represent CH, D represents -CH = CH- , and R2 represents at least one substituent, the ring is substituted either at the carbon atom in the group -CH = CH- (position D) which is adjacent to the binding ring, or at the carbon atom which is in position B, or both of these sites.

11. A compound of formula I, according to any of the preceding claims, characterized in that the fragment is -in configuration S.

12. A pharmaceutical formulation, characterized in that it includes a compound according to any of claims 1 to 11, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

13. A compound according to any of claims 1 to 11, or a pharmaceutically acceptable salt thereof, characterized in that it is used as a pharmaceutical.

14. A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, characterized in that it is used in the treatment of a condition where inhibition of thrombin is required.

15. A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, characterized in that it is used in the treatment of thrombosis.

16. A compound according to any of claims 1 to 11, or a pharmaceutically acceptable salt thereof, characterized in that it is used as an anticoagulant.

17. The use of a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, as an active ingredient in the manufacture of a medicament for the treatment of a condition wherein inhibition of thrombin is required.

18. The use according to claim 17, characterized in that the condition is thrombosis.

19. The use of a compound according to any of claims 1 to 11, or a pharmaceutically acceptable salt thereof, as an active ingredient in the manufacture of an anticoagulant.

20. A method "for the treatment of a condition where inhibition of thrombin is required, which method is characterized in that it comprises the administration of a therapeutically effective amount of a compound according to any of claims 1 to 11, or a pharmaceutically salt acceptable to a person who suffers from, or is susceptible to, such a condition.

21. A method according to claim 20, characterized in that the condition is thrombosis.

22. A method according to claim 20, characterized in that the condition is hypercoagulability in the blood and tissues.

23. A process for the preparation of compounds of formula I, characterized in that it comprises: (a) a coupling reaction comprising: (i) coupling a compound of formula IV, wherein R1 and Rx are defined in claim 1 with a compound of the formula V, wherein Ry, Y, n and B are defined in claim 1; or (ii) coupling a compound of formula VI, wherein R1, Rx and Y are defined in claim 1 with a compound of formula VII, H (Ry) N- (CH2: -B VII where R ?, n and B are defined in the claim 1; (b) deprotection of a compound of formula la, defined in claim 24.

24. A compound of formula la, characterized in that B1 represents a structural fragment of the formula Illd or Illf Ilid lllf wherein D1 and D2 independently represent H, OH, ORa, OC (0) Rb, OC (0) ORc, C (0) ORd, C (0) Re; wherein Ra represents phenyl, benzyl, C alquilo - alkyl (the latter group is optionally interrupted by oxygen or is optionally substituted by halo) or -C (Rf) (Rg) -OC (O) Rh; Rb represents' C 1-17 alkyl (wherein the latter group is optionally substituted by C? -6 alkoxy, C? -6 acyloxy, amino or halo); C6-6 alkoxy, C3-7 cycloalkyl, phenyl, naphthyl or C1-3 alkylphenyl (wherein the last five groups are optionally substituted by C6-6alkyl or halo); or - [CÍR1) (Rj)] mOC (0) Rk; Rc represents C? - ?? alkyl, phenyl, 2-naphthyl (wherein the last three groups are optionally substituted by C? _6 alkyl, Si (Raa) (Rab) (Rac) or halo), - [C ( Rm) (Rn)] nOC (O) Rp, or -CHs-AR1; Rd represents 2-naphthyl, phenyl, C 1 -3 alkylphenyl (wherein the last three groups are optionally substituted by C?-6 alkyl, de-alkoxy, nitro, Si (Rba) (Rbb) (Rbc) or halo) , C alquilo _? alquiloalkyl (wherein the latter group is optionally substituted by C?-6alkoxy, C? _6 acyloxy or halo), - [C (Rq) (Rr)] p0C (0) RS or -CH2-Ar2; Re represents phenyl, benzyl, C? -6 alkyl (the latter group is optionally interrupted by oxygen) or - [C (Rt) (Ru)] rOC (0) Rv; Raa, Rab, Rac, Rba, Rb and Rbe independently represent C? -6 alkyl or phenyl; Rf, Rg, R1, Rj, Rm, Rn, Rq, Rr, Rfc and Ru independently represent H or C? -6 alkyl; Rh, Rk, Rp, R3 and Rv independently represent Ci-n alkyl (wherein the latter group is optionally substituted by C6-6 alkoxy, C6-6 acyloxy or halo); C6-6 alkoxy, C3-7 cycloalkyl, phenyl, naphthyl or C1-3 alkylphenyl (wherein the last five groups are optionally substituted by C6-6alkyl or halo); Ar1 and Ar2 independently represent the structural fragment; m and r independently represent 3 or 4; n and p independently represent 1, 2 or 3; and R1, Rx, Y, R ?, n, X5, X6, X7, X8 and R31 are as defined above; or a pharmaceutically acceptable salt thereof; with the proviso that D1 and D2 do not represent both H.

25. A compound of the formula la, according to claim 24, characterized in that D1 represents H and D2 represents OH, 0CH3, OC (0) Rb or C (0) ORd, wherein Rb and Rd are defined in claim 24.